Clinical, neuroimaging, and genetic analysis of isolated sulfite oxidase deficiency in Chinese neonates: A case series and literature review

Clinical, neuroimaging, and genetic analysis of isolated sulfite oxidase deficiency in Chinese neonates: A case series and literature review | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Clinical, neuroimaging, and genetic analysis of isolated sulfite oxidase deficiency in Chinese neonates: A case series and literature review Weifeng Zhang, Hongyuan Yang, Liping Xu, Zhiyong Liu, Junzi Huang, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8105066/v1 This work is licensed under a CC BY 4.0 License Status: Under Revision Version 1 posted 5 You are reading this latest preprint version Abstract Background : Currently, no curative treatment is available for infantile sulfite oxidase deficiency (ISOD), and disease progression is primarily managed by restricting sulfur-containing amino acids in the diet. Furthermore, despite its overall rarity, the prevalence of ISOD has demonstrated an upward trend in the Chinese population in recent years. Accordingly, this study investigated the clinical phenotype, imaging characteristics, mutation spectrum, and prognosis of ISOD in Chinese newborns. Methods : We retrospectively analyzed the clinical data from seven neonates with genetically confirmed ISOD from southeastern China between November 2018 and March 2025. The collected data included maternal and infant factors, clinical manifestations, laboratory results, and neuroimaging and genetic findings. The study cohort was further expanded through a systematic review of 13 additional neonatal ISOD cases reported in the Chinese and international literature, resulting in a combined cohort comprising 20 patients. Results : All infants (100%) presented with intractable seizures within the first few days of life. Other common clinical presentations included increased muscle tone (75%) and feeding difficulty (70%). Lens dislocation was uncommon in this neonatal cohort (5%). Abnormalities in cranial imaging—primarily presenting as symmetric abnormal signals in both cerebral hemispheres and basal ganglia—were observed in all cases, which could be misdiagnosed as hypoxic-ischemic encephalopathy. Laboratory tests revealed elevated urinary sulfite levels or decreased plasma homocysteine levels in some cases. Genetic analysis identified 11 distinct pathogenic variants of the SUOX gene, with c.1200C>G (p.Tyr400Ter) being the most common hotspot mutation in China. The prognosis was extremely poor; only five patients (25%) survived following symptomatic treatment, including sulfur-restricted diets, with a median follow-up of 10 months (range: 6–22 months). All surviving infants exhibited refractory epilepsy and severe developmental delays. Conclusion : The hallmark features of ISOD in Chinese neonates include refractory seizures occurring shortly after birth and characteristic neuroimaging patterns. The c.1200C>G (p.Tyr400Ter) mutation in the SUOX gene is the most common pathogenic variant in this population. Given the extremely poor prognosis and lack of effective treatment, prenatal genetic diagnosis is recommended to enable early intervention in high-risk families. sulfite oxidase deficiency newborn China refractory epilepsy early intervention Figures Figure 1 Figure 2 Figure 3 Background Isolated sulfite oxidase deficiency (ISOD) (OMIM: 272300) is a rare autosomal recessive metabolic disorder caused by mutations in the SUOX gene [ 1 ]. Sulfite oxidase (SO) encoded by this gene is a key enzyme in the sulfur metabolism pathway that converts sulfite into sulfate. Pathogenic mutations in the SUOX gene result in reduced or absent SO activity, leading to sulfite accumulation and subsequent neurological damage [ 2 , 3 ]. Clinical manifestations include refractory epilepsy, abnormal muscle tone, feeding difficulties, and progressive neurodegeneration [ 4 ], with some patients exhibiting lens displacement [ 5 ]. Currently, no curative treatment is available for ISOD, and disease progression is primarily managed by restricting sulfur-containing amino acids in the diet. The prognosis remains extremely poor, with approximately 60% of affected children dying in early infancy. ISOD is an extremely rare condition worldwide, with only approximately 70 cases documented in the literature to date [ 6 ]. However, with the increasing implementation of genetic diagnoses, reports from China have demonstrated a marked upward trend in ISOD incidence in recent years, suggesting that the disease may be more prevalent than previously recognized in certain populations. Accordingly, this retrospective study analyzed the clinical data, ancillary test results, and genetic mutation characteristics of neonates diagnosed with ISOD from southeastern China. Furthermore, through a review of the relevant domestic and international literature, we systematically summarized the mutation spectrum and core phenotypic features of SUOX in a Chinese population with ISOD. Methods Study Population A retrospective analysis was conducted using clinical data from seven newborns with genetically confirmed ISOD from southeastern China between November 2018 and March 2025. Five patients were admitted to Quanzhou Maternal and Child Health Hospital in Fujian Province, one to Zhangzhou Hospital Affiliated to Fujian Medical University, and one to Fuzhou First General Hospital Affiliated to Fujian Medical University. All patients presented with neonatal-onset disease and underwent whole-exome sequencing for genetic analysis. Informed consent was obtained from all parents, permitting the use of clinical and genetic data for research and publication. This study protocol was reviewed and approved by the Medical Ethics Committee of Quanzhou Maternal and Child Health Hospital (approval no. 2022 No. 5). The study was conducted in accordance with the Declaration of Helsinki. Case Data Herein, data regarding maternal-fetal factors, clinical manifestations, laboratory results, and neuroimaging and genetic findings were collected from seven neonates with genetically confirmed ISOD neonates. The cohort was further expanded through a systematic review of 13 additional neonatal ISOD cases reported in the Chinese and international literature, forming a combined study cohort of 20 patients. Observation Indicators Data regarding the following general characteristics were collected: sex, gestational age, birth weight, and age at onset. Assessed clinical features included the incidence of seizures, feeding difficulties, altered muscle tone, lens abnormalities, microcephaly, and respiratory distress. Abnormal laboratory findings included elevated urinary sulfite, decreased serum homocysteine, and an abnormal urinary organic acid profile. Additionally, the following neuroimaging features were assessed: symmetrical abnormal signals in the cerebral hemispheres and basal ganglia, corpus callosum hypoplasia, and ventricular enlargement. Genetic analyses were performed to identify SUOX mutation sites and amino acid alterations. Assessed outcomes included mortality, survival, follow-up duration, and neurodevelopmental outcomes. Related Definitions and Diagnostic Criteria Refractory epilepsy [ 7 ] was defined as epilepsy that remained poorly controlled despite the appropriate use of two or more antiepileptic drugs. Developmental delay [ 8 ] was defined as scores below age-appropriate levels on the Bayley III developmental screening test or clinically significant delays in achieving developmental milestones. The ISOD diagnostic criteria [ 9 ] were as follows: typical neurological manifestations beginning in the neonatal period; positive urinary sulfite levels or reduced plasma homocysteine levels; and the presence of pathogenic or likely pathogenic SUOX variants. Literature Review Literature search was conducted using the keywords “sulfite oxidase deficiency” and “infant, newborn.” Domestic literature was retrieved from the China National Knowledge Infrastructure, Wanfang Database, and National Science and Technology Library, with database coverage up to May 2025, identifying seven Chinese. After excluding non-neonatal cases, four Chinese neonatal ISOD cases from four articles were included herein. Literature search using the terms “isolated sulfite oxidase deficiency,” “isolated sulphite oxidase deficiency,” “ISOD,” “SUOX deficiency,” and “sulfocysteinuria” in the PubMed, Web of Science, and Embase databases (up to May 2025) yielded 231 articles. After screening for Chinese neonatal cases, nine English-language articles were identified, comprising nine Chinese neonatal ISOD cases. Statistical Analysis All data were analyzed using the SPSS software (version 26.0). Normally distributed quantitative data are expressed as mean ± standard deviation (± s); otherwise, median (interquartile range) was used. Qualitative data are presented as frequencies and percentages. Results Clinical Data of Seven Patients with ISOD This study included seven pediatric patients: four males and three females, including one preterm infant. The mean birth weight was 3672.86 ± 358.69 g. None of the patients had a history of intrauterine distress, asphyxia requiring resuscitation, perinatal infection, or genetic familial disorders. Symptom onset occurred within 1 and 5 days of life. All patients presented with seizures and feeding difficulties. Increased muscle tone was observed in five patients. One patient presented with an occipital skull fracture, while another had a clavicle fracture. No lens dislocation was noted in any patient. All patients underwent combination therapy using 2–3 anticonvulsants. Patient 4 developed acute respiratory and cardiac failure during hospitalization, exhibited poor response to vasoactive agents, and died on postnatal day 4. Patients 1 and 5 received palliative care after genetic diagnosis and died from recurrent seizures on postnatal days 15 and 13, respectively. The remaining four patients received anticonvulsant therapy post-discharge, with a non-strict restriction of sulfur-containing amino acid intake. Persistent recurrent seizures prompted the families to pursue palliative care. At the last follow-up (6–26 months), all patients exhibited severe developmental delay and microcephaly; however, lens status was not assessed. Patient 2 died 26 months after respiratory failure due to pneumonia. Table 1. Laboratory and Auxiliary Examination Findings in Seven Patients with ISOD No significant abnormalities were observed in the complete blood counts, liver and kidney function tests, or electrolyte levels in any of the seven patients. Urinary organic acid analysis revealed abnormalities in three cases: elevated pyruvic acid and 3-hydroxybutyric acid in one case and elevated 4-hydroxyphenylpyruvic acid in two cases. Cranial imaging (Figure 1) demonstrated varying degrees of abnormalities: symmetrical abnormal signals in both cerebral hemispheres or basal ganglia in five cases; ventricular enlargement or hematoma in two cases; corpus callosum agenesis with interhemispheric cyst formation in one case; frontal subdural hemorrhage in one case; and cerebral hemisphere swelling with patchy hypodensity in one case. Genetic analysis (Figure 2) revealed SUOX gene mutations in all cases: five carried the c.1200C>G (p.Tyr400Ter) mutation, one carried the c.1406_1421del:p.Thr469SerfsTer20 mutation, and one case exhibited compound heterozygous mutations of both c.1200C>G (p.Tyr400Ter) and c.1406_1421del:p.Thr469SerfsTer20. Table 2. Clinical Data and Manifestations of Cases Identified in the Literature Search A case enrollment flowchart is presented in Figure 3. Among the 13 pediatric patients, four were male and nine were female. Symptom onset occurred within 1 day of birth in eight cases (61.5%). A family history was noted in five cases (38.5%), with four siblings experiencing refractory seizures during the neonatal period, which led to their death during early infancy. Among these siblings, two were diagnosed with ISOD but did not undergo genetic testing. In one case, symptom onset occurred at 1 year of age; the mother of the patient terminated a subsequent pregnancy at 21 weeks of gestation after cranial magnetic resonance imaging and genetic confirmation of ISOD. All 13 patients exhibited seizures, four experienced respiratory distress, 10 (76.9%) presented with increased muscle tone, five (38.5%) had microcephaly, and seven (53.9%) experienced feeding difficulties. Seven (53.9%) patients exhibited developmental delays (Table 3). Cranial Imaging and Auxiliary Test Results of Cases Identified in the Literature Search Cranial imaging was performed in 12 patients, all of whom presented with abnormalities (100%). Abnormal signals in the cerebral cortex and basal ganglia were observed in seven cases (53.9%), cystic changes in the cerebral white matter in two cases (15.4%), ventricular enlargement in two cases (15.4%), and corpus callosum hypoplasia in two cases (15.4%). Ten patients underwent urinary sulfite testing (urinary sulfite test strip assay), with seven (70%) testing positive. Seven patients underwent blood homocysteine testing, with five showing reduced homocysteine levels (Table 4). Genetic Analyses of Cases Identified in the Literature Search All 13 patients exhibited SUOX gene mutations, with six homozygous and seven compound heterozygous variants. Ten distinct mutation sites were identified, with the most frequent being the c.1200C>G variant (7/13) (Table 4). Treatment and Clinical Outcomes of Cases Identified in the Literature Search Patients received symptomatic management, including anticonvulsant therapy and restricted intake of sulfur-containing amino acids. Ultimately, three patients died between postnatal days 6 and 31, and two patients were lost to follow-up. Among the remaining eight patients, the median follow-up age was 12 months (range: 6 months to 2 years 4 months). Two patients died between 6 and 8 months of age, with the longest survivor reaching an age of 2 years and 4 months. All surviving patients exhibited refractory epilepsy and severe developmental delays (Table 3). Discussion ISOD is a rare genetic metabolic disorder that warrants attention owing to its high mortality and disability rates, as well as challenges in accurate clinical diagnosis. To our knowledge, this study provides the first systematic summary of the clinical and molecular genetic characteristics of ISOD in the Chinese population by analyzing seven genetically confirmed pediatric cases from southeastern China and reviewing 13 additional Chinese neonatal cases from the literature. Herein, Chinese newborns with ISOD exhibited highly consistent and severe core clinical phenotypes. Symptoms appeared within the first day of life in 55.0% of patients (n = 11). The most prominent and common clinical manifestations were seizures (100.0%), hypertonia (75.0%), and feeding difficulties (70.0%); lens dislocation (5%) was extremely rare. The underlying cause of these core clinical phenotypes is mutations in the SUOX gene, which lead to neurotoxic sulfite accumulation. This accumulation disrupts cellular energy metabolism, inhibits mitochondrial function, and triggers oxidative stress, causing rapid and severe damage to the developing central nervous system. These mechanisms may account for the acute neurological symptoms observed in affected infants during the early postnatal period [ 1 ]. In contrast, lens dislocation represents long-term cumulative structural injury. Due to the extremely brief disease course in the neonatal period, it typically remains undetected at birth, resulting in a very low incidence. Regarding major neurological manifestations such as seizures and increased muscle tone, our findings were consistent with those of an analysis of 74 ISOD cases by Göde et al. [ 6 ]. However, an international study reported a 26% incidence of lens dislocation at a median age at diagnosis of 15 months. Our data suggest that lens dislocation may not be apparent or universally present during the neonatal period, potentially limiting its value as an early diagnostic indicator. This comparison suggests that early-onset refractory seizures and progressive neurological impairment are core warning signs that warrant greater attention in neonatal patients. Typical biochemical markers of ISOD include elevated levels of urinary sulfite, thiosulfate, and S-sulfocysteine [ 23 ]. Among the 20 patients included in this study, only 10 underwent urine sulfite dipstick testing. The low detection rate may be related to regional variations in disease awareness and testing capabilities. Of the aforementioned 10 patients, seven (70.0%) tested positive. Urine sulfite dipstick testing should be the initial assessment for clinically suspected ISOD, particularly in cases of refractory neonatal epilepsy. However, caution should be exercised regarding false-negative results, which are common in clinical practice due to the extreme instability and susceptibility to degradation of urinary sulfite [ 24 ]. Conversely, sulfite can react with homocysteine to form S-sulfocysteine; thus, plasma homocysteine levels are often significantly reduced when SO activity is low [ 25 ]. In this study, seven pediatric patients underwent this test, with five (71.4%) exhibiting decreased plasma homocysteine levels. This suggests that reduced plasma homocysteine levels may serve as potential early diagnostic markers of neonatal ISOD. However, current criteria for defining decreased homocysteine levels remain inconsistent [ 21 , 24 ], necessitating further investigations to establish diagnostic thresholds and standardized protocols. Herein, all 19 infants who underwent comprehensive cranial imaging demonstrated abnormal findings, primarily characterized by symmetric abnormal signals in both cerebral hemispheres and basal ganglia. Notably, early-stage imaging manifestations may be easily mistaken for hypoxic-ischemic encephalopathy. Additionally, some infants present with concomitant structural brain malformations, such as corpus callosum agenesis and ventricular enlargement. Our findings suggest that imaging manifestations of neonatal ISOD encompass not only symmetric abnormal signals but also complex structural brain malformations, indicating potential impacts of early fetal development on brain architecture. Furthermore, nonspecific features such as ventricular enlargement or subdural hemorrhage in some patients may be misdiagnosed as hypoxic-ischemic encephalopathy. Therefore, for neonates presenting with early-onset refractory seizures, careful interpretation of imaging abnormalities in conjunction with genetic testing is crucial. Previous studies have reported multiple cystic changes in the white matter and brain atrophy as typical imaging manifestations of ISOD [ 26 , 27 ]. However, only two patients in this cohort demonstrated white matter cystic changes on imaging within 72 h after birth. Brain injury may ultimately progress to characteristic cystic changes and atrophy, suggesting that the pathological processes originate in utero. This aligns with the findings of Lee et al. [ 18 ] who reported a case in which fetal cranial magnetic resonance imaging and genetic testing confirmed ISOD at 21 weeks of gestation, prompting the mother to terminate the pregnancy. This indicates that early identification and termination could effectively spare disease onset. ISOD is caused by biallelic pathogenic mutations in the SUOX gene located on chromosome 12q13.2 [ 1 ]. To date, 36 distinct pathogenic SUOX gene mutations distributed across various SUOX domains have been identified [ 6 ]. Herein, all 20 pediatric patients harbored SUOX mutations: 12 with homozygous mutations and eight with compound heterozygous mutations. Eleven distinct mutation sites were identified, with c.1200C > G (13/20) being the most frequent, suggesting that this site represents a hotspot mutation for SUOX in the Chinese population. Additional sites included c.1201A > G, c.475G > T, c.68C > G, c.650G > A, and c.188G > A. Some of these represented novel mutations that have not been previously reported domestically or internationally, thereby expanding the SUOX mutation spectrum. Previous studies [ 6 ] have indicated that c.1200C > G is a global hotspot mutation in the SUOX gene. However, SUOX mutations exhibit regional and racial variations. Some common mutation sites reported in European and American populations were not identified in our cohort, suggesting potential regional and racial specificity in SUOX mutation distribution. Currently, no effective treatments are available for neonatal ISOD. Restricting dietary sulfur content and reducing methionine and cysteine intake constitute the primary symptomatic support strategies [ 1 ]. In this study, 20 pediatric patients received symptomatic nutritional intervention (low-sulfur amino acid formula), anticonvulsant medication to control seizures, vitamin and coenzyme supplementation in some cases, and supportive care (tube feeding and management of infections or respiratory/circulatory abnormalities). Ultimately, nine patients died, six were lost to follow-up, and only five survived, with a median follow-up age of 10 months (range: 6 months to 1 year 10 months). All surviving infants exhibited refractory epilepsy and severe developmental delay, indicating that restricting the intake of sulfur-containing amino acids yields suboptimal outcomes in improving neonatal ISOD. The limitations of this study include its retrospective nature and limited sample size, which may have introduced selection bias. Additionally, biochemical test results and follow-up information were incomplete in some cases, potentially affecting the comprehensive assessment of natural disease history and biochemical characteristics. Conclusion Neonatal ISOD is clinically characterized by intractable seizures, increased muscle tone, and feeding difficulties. Cranial imaging findings typically present as symmetric abnormal signals in both the cerebral hemispheres and basal ganglia regions; however, a definitive diagnosis relies on genetic testing. The c.1200C > G mutation in the SUOX gene is the most common hotspot variant in Chinese pediatric patients. Given the lack of effective treatment and extremely poor overall prognosis, families with index cases are advised to undergo prenatal diagnosis during subsequent pregnancies. Early identification and termination of pregnancy can effectively spare the occurrence of ISOD. Abbreviations ISOD, isolated sulfite oxidase deficiency; SO, sulfite oxidase Declarations Ethics Approval and consent to participate This study was approved by the Ethics Committee of Quanzhou Maternal and Child Health Hospital (Approval No. 2022005). The parents of the patients signed a written informed consent form, whereby they agreed to their children’s participation in this study and the use of their data and information for scientific research. All methods were performed in accordance with the relevant guidelines and regulations. Consent for publication Patients’ parents signed a written informed consent form for the publication of their own and their children’s genetic data, clinical details, and any accompanying images. Data availability The datasets used and analyzed in the current study are available from the corresponding author upon reasonable request. Competing interests The authors declare that they have no competing interests. Funding This research was supported by the Quanzhou Science and Technology Program of China (Grant numbers 2022C002 and 2022N039S) and the "Science and Technology Rejuvenating Mongolia" Shanghai Jiaotong University Action Plan Special Project (No.2023XY JG0001-01-09). Author Contributions WZ, HY, and LX conceived the study and prepared the first draft of the manuscript. DC, YH, CC, and LZ helped critically revise the manuscript for important intellectual content and guided the design and research process followed in the study. ZL and JH performed the variant analysis. LX, ZL, JH, JX, and YH provided care for the patients and collected the clinical data. All authors have approved the final manuscript. Acknowledgements We would like to thank Editage (www.editage.cn) for the English language editing and the patient’s family for participating in this study. References Schwahn BC, van Spronsen F, Misko A, et al. 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Clinical Data of Seven Pediatric Patients with ISOD Case 1 Case 2 Case 3 Case 4 Case 5 Case 6 Case 7 Sex Female Female Female Male Male Male Male Age at onset (days) 1 1 5 1 3 3 1 Gestational age (weeks) 39 +5 40 +1 40 36 +3 39 +1 39 +2 40 +6 Birth weight (g) 3650 4350 3560 3350 3600 3300 3900 Intrauterine growth restriction - - - - - - - Choking first aid - - - - - - - Fracture Left occipital bone Right clavicle - - - - - Family History - - - - - - - convulsive seizure + + + + + + + Feeding difficulties + + + + + + + Shortness of breath - - - - - - - Muscle tone ↑ ↑ ↑ ↑ - - ↑ Outcome Death within 15 days 26-month mortality 8-month survival Death at 4 days Death at 13 days 6 months survival 18 months survival Note: Positive +, Negative -, Elevated ↑ ISOD, isolated sulfite oxidase deficiency Table 2. Laboratory and auxiliary examination results for 7 pediatric ISOD cases Case 1 Case 2 Case 3 Case 4 Case 5 Case 6 Case 7 Complete Blood Count - - - - - - - Liver and kidney function - - - - - - - Electrolyte - - - - - - - Blood glucose - - - - - - - Urinary organic acids - Pyruvate, 3-hydroxybutyrate↑ 4-hydroxyphenylbutyric acid - - - 4-hydroxyphenylbutyrate Urea sulfite / / / / / / / Cranial imaging findings Abnormal signal in both cerebral hemispheres Bilateral symmetrical abnormal signal intensity in cerebral parenchyma, bilateral ventricular enlargement Symmetrical abnormal signal intensity in bilateral frontal lobes, corpus callosum, bilateral basal ganglia, and internal capsule Right parieto-temporal-occipital lobe DWI hyperintensity, bilateral ventricular hematoma Corpus callosum agenesis with interhemispheric fissure cyst formation, enlarged lateral ventricles Bilateral cerebral hemisphere edema with patchy slightly hypointense areas Symmetrical abnormal signal intensity in bilateral cerebral hemispheres, basal ganglia, pons, medulla oblongata, and corpus callosum SUOX gene mutations c.1200C>G c.1200C>G c.1406_1421del c.1200C>G c.1200C＞G, c.1406_1421del c.1200C>G c.1200C>G Note: Positive: +; Negative: -; Elevated: ↑; Not performed: /; c.1200C＞G: c.1200C＞G (p.Tyr400Ter); c.1406_1421del: c.1406_1421del:p.Thr469SerfsTer20 ISOD, isolated sulfite oxidase deficiency; DWI, diffusion-weighted image Table 3. Clinical data of 13 pediatric patients with ISOD Case 8 [10] Case 9 [11] Case 10 [12] Case 11 [13] Case 12 [14] Case 13 [15] Case 14 [16] Case 15 [17] Case 16 [18] Case 17 [19] Case 18 [20] Case 19 [21] Case 20 [22] Sex Female Female Male Male Female Female Male Female Female Female Female Female Male Age at onset (days) 27 1 1 18 1 1 16 1 1 1 3 1 21 Gestational age (weeks) Full-term 40 +3 35 39 +3 38 +4 Full-term Full-term 38 +4 40 / 38 Full-term Full-term Birth weight (g) / 2800 2400 3020 3170 / 3020 2330 / / 2850 / / History of resuscitation following asphyxia - - - - - - - - - - - - - Family History - - - - Sister developed cyanosis and convulsions 1 day after birth and died Sister died three days after birth following the onset of illness - Brother developed symptoms 3 days after birth and died after one month The mother terminated a pregnancy with one ISOD fetus when the current patient was 1 year of age - - Both older and younger sisters developed symptoms 1 day after birth and died shortly thereafter - Initial presenting symptom Convulsions Respiratory distress Vomiting Abnormal eye movements Convulsions Convulsions Vomiting Convulsions Feeding difficulties Respiratory distress Feeding difficulties Convulsions Vomiting Convulsions + + + + + + + + + + + + + Time of seizure (days) 27 3 1 27 1 1 33 1 8 1 3 1 24 Feeding difficulties - + + + - - + + + - + + + Shortness of breath - + + - - - + - - + - - - Muscle tone ↑ ↑ ↑ ↑ ↑ - ↑ ↑ ↑ / ↑ ↑ ↑ Microcephaly - - - - - - + + + / / + + Lens dislocation - - - - - - - - - / / - + Developmental delay + - - + - + + + + / / + + Outcome Standing head instability at 1 year of age Died on day 7 due to inability to maintain heart rate and blood oxygen levels, high lactate levels observed Died on day 31 following recurrent convulsions and respiratory failure Died at 8 months of age Died on day 6 due to cardiac failure. Medical cost approx. £40,000–£50,000 Alive at 6 months Died at 9 months of age Alive at 18 months Alive at 2 years 4 months of age. Comprehensive developmental delay Unknown Unknown Alive at 10 months of age Alive at 10 months of age Note: Positive +, Negative -, Elevated ↑ ISOD, isolated sulfite oxidase deficiency Supplementary Files Table4.docx Cite Share Download PDF Status: Under Revision Version 1 posted Editorial decision: Major revision 30 Apr, 2026 Reviewers agreed at journal 27 Jan, 2026 Reviewers invited by journal 26 Nov, 2025 Editor assigned by journal 16 Nov, 2025 First submitted to journal 14 Nov, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8105066","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":551102169,"identity":"bde9463c-32de-4b68-ac96-3eb11ae457b6","order_by":0,"name":"Weifeng Zhang","email":"","orcid":"","institution":"Children's Hospital of Shanghai","correspondingAuthor":false,"prefix":"","firstName":"Weifeng","middleName":"","lastName":"Zhang","suffix":""},{"id":551102170,"identity":"bbfe452d-e570-4e6f-a2f6-f21c77acb698","order_by":1,"name":"Hongyuan Yang","email":"","orcid":"","institution":"Quanzhou Maternal and Child Health 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University","correspondingAuthor":false,"prefix":"","firstName":"Liyan","middleName":"","lastName":"Zhang","suffix":""},{"id":551102177,"identity":"b5e86ec4-02a0-47a2-bca9-44d48a86b5f5","order_by":8,"name":"Dongmei Chen","email":"","orcid":"","institution":"Quanzhou Maternal and Child Health Hospital","correspondingAuthor":false,"prefix":"","firstName":"Dongmei","middleName":"","lastName":"Chen","suffix":""},{"id":551102178,"identity":"101a50ef-453d-47d8-8012-5fa1978b0007","order_by":9,"name":"cheng cai","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA7UlEQVRIiWNgGAWjYFACxgZmEMXPzNhg8MHAxo54LZLtzQcKZxSkJRNlD1iLwZljCZ95PhxibCCknL/9cOPngoo7dg03cgw32xgcYGZgP3x0Az4tEmcSm6VnnHmW3Dgjx9g4x+AOHwNPWtoNfFoMGBLbmHnbDiczS+SYAbU8Y2aQ4DHDr4X/IVDLv8PJbBI55r8tDA4zNhDUIgGypeGwHQ/PsQRjBmK0SNx42CzNc+xwggR78wHDHoO0ZDZCfuHvT3/4mafmsL090HyDH39s7PjZDx/DqwUGEhtgLDZilIOAPbEKR8EoGAWjYAQCAHu+TJDvmDUWAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0002-5486-9639","institution":"Children's Hospital of Shanghai","correspondingAuthor":true,"prefix":"","firstName":"cheng","middleName":"","lastName":"cai","suffix":""}],"badges":[],"createdAt":"2025-11-13 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13:57:27","extension":"xml","order_by":18,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":130926,"visible":true,"origin":"","legend":"","description":"","filename":"ITJPD25013050structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-8105066/v1/e00eed3f6ec808dc3eca4992.xml"},{"id":97260349,"identity":"84e0d96b-8fd9-462f-b8f0-a33ceb1a79f8","added_by":"auto","created_at":"2025-12-02 13:57:27","extension":"html","order_by":19,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":137686,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-8105066/v1/913175f474ac3ccb089f088f.html"},{"id":97260330,"identity":"27fbac61-5e86-4f52-a4f3-12021763fbab","added_by":"auto","created_at":"2025-12-02 13:57:27","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1496638,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCranial Imaging Findings of Seven ISOD Pediatric Cases\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ea (Case 1) Abnormal signal in bilateral cerebral hemispheres; b-c (Case 2) Symmetrical abnormal signal intensity in bilateral cerebral parenchyma with enlarged lateral ventricles; d-f (Case 3) Symmetrical abnormal signal intensity in bilateral frontal lobes, corpus callosum, bilateral basal ganglia, and internal capsule; g-h (Case 4) High signal intensity on diffusion-weighted imaging in right parietal-temporal-occipital lobes; i-j (Case 5) Corpus callosum agenesis with interhemispheric fissure cyst formation, enlarged lateral ventricles; k-i (Case 6) Bilateral cerebral hemisphere swelling with patchy hypodensity; m-o (Case 7) Symmetrical abnormal signal intensity in bilateral cerebral hemispheres, basal ganglia, pons, medulla, and corpus callosum.\u003c/p\u003e\n\u003cp\u003eISOD, isolated sulfite oxidase deficiency\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8105066/v1/f87fd356f3a125b6376dd4cf.jpg"},{"id":97260337,"identity":"420e65d8-4af7-433f-9117-89b18e4645c3","added_by":"auto","created_at":"2025-12-02 13:57:27","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1751941,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eGenetic reports for seven ISOD pediatric patients: \u003c/strong\u003e\u003cem\u003e\u003cstrong\u003eSUOX\u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003egene mutation results from first-generation sequencing.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ea. Case 1 carries a homozygous mutation c.1200C\u0026gt;G (p.Tyr400Ter); b. Case 2 carried a c.1200C\u0026gt;G (p.Tyr400Ter) homozygous mutation; c. Case 3 carried a c.1406_1421del:p.Thr469SerfsTer20 heterozygous mutation; d. Case 4 carried a c.1200C\u0026gt;G (p.Tyr400Ter) homozygous mutation; e-f. Case 5 carried c.1200C\u0026gt;G (p.Tyr400Ter) and c.1406_1421del:p.Thr469SerfsTer20 heterozygous mutations; g. Case 6 carries a c.1200C\u0026gt;G (p.Tyr400Ter) homozygous mutation; h. Case 7 carried a c.1200C\u0026gt;G (p.Tyr400Ter) homozygous mutation.\u003c/p\u003e\n\u003cp\u003eISOD, isolated sulfite oxidase deficiency\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8105066/v1/9daaea47ca52e3b1c0e03519.jpg"},{"id":97366778,"identity":"67dfce40-a5bb-4bd3-b861-61fd89a4fc86","added_by":"auto","created_at":"2025-12-03 16:08:33","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":97056,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCase Enrollment Flowchart.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Figure3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8105066/v1/b97c1b65885dbf73eed6db21.jpg"},{"id":97664717,"identity":"30644f7b-944f-44c0-9f09-8f4fda196b3c","added_by":"auto","created_at":"2025-12-08 09:13:26","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":4410768,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8105066/v1/8b1e1b50-20cb-482f-984b-12377bd54ea8.pdf"},{"id":97367462,"identity":"da446027-3e4d-4a34-8334-b9fab86d7a43","added_by":"auto","created_at":"2025-12-03 16:18:48","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":17570,"visible":true,"origin":"","legend":"","description":"","filename":"Table4.docx","url":"https://assets-eu.researchsquare.com/files/rs-8105066/v1/2eba5134904259ab122670f9.docx"}],"financialInterests":"","formattedTitle":"Clinical, neuroimaging, and genetic analysis of isolated sulfite oxidase deficiency in Chinese neonates: A case series and literature review","fulltext":[{"header":"Background","content":"\u003cp\u003eIsolated sulfite oxidase deficiency (ISOD) (OMIM: 272300) is a rare autosomal recessive metabolic disorder caused by mutations in the \u003cem\u003eSUOX\u003c/em\u003e gene [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Sulfite oxidase (SO) encoded by this gene is a key enzyme in the sulfur metabolism pathway that converts sulfite into sulfate. Pathogenic mutations in the \u003cem\u003eSUOX\u003c/em\u003e gene result in reduced or absent SO activity, leading to sulfite accumulation and subsequent neurological damage [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Clinical manifestations include refractory epilepsy, abnormal muscle tone, feeding difficulties, and progressive neurodegeneration [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], with some patients exhibiting lens displacement [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Currently, no curative treatment is available for ISOD, and disease progression is primarily managed by restricting sulfur-containing amino acids in the diet. The prognosis remains extremely poor, with approximately 60% of affected children dying in early infancy.\u003c/p\u003e\u003cp\u003eISOD is an extremely rare condition worldwide, with only approximately 70 cases documented in the literature to date [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. However, with the increasing implementation of genetic diagnoses, reports from China have demonstrated a marked upward trend in ISOD incidence in recent years, suggesting that the disease may be more prevalent than previously recognized in certain populations. Accordingly, this retrospective study analyzed the clinical data, ancillary test results, and genetic mutation characteristics of neonates diagnosed with ISOD from southeastern China. Furthermore, through a review of the relevant domestic and international literature, we systematically summarized the mutation spectrum and core phenotypic features of \u003cem\u003eSUOX\u003c/em\u003e in a Chinese population with ISOD.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eStudy Population\u003c/h2\u003e\u003cp\u003eA retrospective analysis was conducted using clinical data from seven newborns with genetically confirmed ISOD from southeastern China between November 2018 and March 2025. Five patients were admitted to Quanzhou Maternal and Child Health Hospital in Fujian Province, one to Zhangzhou Hospital Affiliated to Fujian Medical University, and one to Fuzhou First General Hospital Affiliated to Fujian Medical University. All patients presented with neonatal-onset disease and underwent whole-exome sequencing for genetic analysis. Informed consent was obtained from all parents, permitting the use of clinical and genetic data for research and publication. This study protocol was reviewed and approved by the Medical Ethics Committee of Quanzhou Maternal and Child Health Hospital (approval no. 2022 No. 5). The study was conducted in accordance with the Declaration of Helsinki.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eCase Data\u003c/h3\u003e\n\u003cp\u003eHerein, data regarding maternal-fetal factors, clinical manifestations, laboratory results, and neuroimaging and genetic findings were collected from seven neonates with genetically confirmed ISOD neonates. The cohort was further expanded through a systematic review of 13 additional neonatal ISOD cases reported in the Chinese and international literature, forming a combined study cohort of 20 patients.\u003c/p\u003e\n\u003ch3\u003eObservation Indicators\u003c/h3\u003e\n\u003cp\u003eData regarding the following general characteristics were collected: sex, gestational age, birth weight, and age at onset. Assessed clinical features included the incidence of seizures, feeding difficulties, altered muscle tone, lens abnormalities, microcephaly, and respiratory distress. Abnormal laboratory findings included elevated urinary sulfite, decreased serum homocysteine, and an abnormal urinary organic acid profile. Additionally, the following neuroimaging features were assessed: symmetrical abnormal signals in the cerebral hemispheres and basal ganglia, corpus callosum hypoplasia, and ventricular enlargement. Genetic analyses were performed to identify \u003cem\u003eSUOX\u003c/em\u003e mutation sites and amino acid alterations. Assessed outcomes included mortality, survival, follow-up duration, and neurodevelopmental outcomes.\u003c/p\u003e\n\u003ch3\u003eRelated Definitions and Diagnostic Criteria\u003c/h3\u003e\n\u003cp\u003eRefractory epilepsy [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] was defined as epilepsy that remained poorly controlled despite the appropriate use of two or more antiepileptic drugs. Developmental delay [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] was defined as scores below age-appropriate levels on the Bayley III developmental screening test or clinically significant delays in achieving developmental milestones. The ISOD diagnostic criteria [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] were as follows: typical neurological manifestations beginning in the neonatal period; positive urinary sulfite levels or reduced plasma homocysteine levels; and the presence of pathogenic or likely pathogenic \u003cem\u003eSUOX\u003c/em\u003e variants.\u003c/p\u003e\n\u003ch3\u003eLiterature Review\u003c/h3\u003e\n\u003cp\u003eLiterature search was conducted using the keywords \u0026ldquo;sulfite oxidase deficiency\u0026rdquo; and \u0026ldquo;infant, newborn.\u0026rdquo; Domestic literature was retrieved from the China National Knowledge Infrastructure, Wanfang Database, and National Science and Technology Library, with database coverage up to May 2025, identifying seven Chinese. After excluding non-neonatal cases, four Chinese neonatal ISOD cases from four articles were included herein. Literature search using the terms \u0026ldquo;isolated sulfite oxidase deficiency,\u0026rdquo; \u0026ldquo;isolated sulphite oxidase deficiency,\u0026rdquo; \u0026ldquo;ISOD,\u0026rdquo; \u0026ldquo;SUOX deficiency,\u0026rdquo; and \u0026ldquo;sulfocysteinuria\u0026rdquo; in the PubMed, Web of Science, and Embase databases (up to May 2025) yielded 231 articles. After screening for Chinese neonatal cases, nine English-language articles were identified, comprising nine Chinese neonatal ISOD cases.\u003c/p\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003eStatistical Analysis\u003c/h2\u003e\u003cp\u003eAll data were analyzed using the SPSS software (version 26.0). Normally distributed quantitative data are expressed as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (\u0026plusmn;\u0026thinsp;s); otherwise, median (interquartile range) was used. Qualitative data are presented as frequencies and percentages.\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003eClinical Data of Seven Patients with ISOD\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study included seven pediatric patients: four males and three females, including one preterm infant. The mean birth weight was 3672.86 ± 358.69 g. None of the patients had a history of intrauterine distress, asphyxia requiring resuscitation, perinatal infection, or genetic familial disorders. Symptom onset occurred within 1 and 5 days of life. All patients presented with seizures and feeding difficulties. Increased muscle tone was observed in five patients. One patient presented with an occipital skull fracture, while another had a clavicle fracture. No lens dislocation was noted in any patient.\u003c/p\u003e\n\u003cp\u003eAll patients underwent combination therapy using 2–3 anticonvulsants. Patient 4 developed acute respiratory and cardiac failure during hospitalization, exhibited poor response to vasoactive agents, and died on postnatal day 4. Patients 1 and 5 received palliative care after genetic diagnosis and died from recurrent seizures on postnatal days 15 and 13, respectively.\u003c/p\u003e\n\u003cp\u003eThe remaining four patients received anticonvulsant therapy post-discharge, with a non-strict restriction of sulfur-containing amino acid intake. Persistent recurrent seizures prompted the families to pursue palliative care. At the last follow-up (6–26 months), all patients exhibited severe developmental delay and microcephaly; however, lens status was not assessed. Patient 2 died 26 months after respiratory failure due to pneumonia. Table 1.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eLaboratory and Auxiliary Examination Findings in Seven Patients with ISOD\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo significant abnormalities were observed in the complete blood counts, liver and kidney function tests, or electrolyte levels in any of the seven patients. Urinary organic acid analysis revealed abnormalities in three cases: elevated pyruvic acid and 3-hydroxybutyric acid in one case and elevated 4-hydroxyphenylpyruvic acid in two cases. Cranial imaging (Figure 1) demonstrated varying degrees of abnormalities: symmetrical abnormal signals in both cerebral hemispheres or basal ganglia in five cases; ventricular enlargement or hematoma in two cases; corpus callosum agenesis with interhemispheric cyst formation in one case; frontal subdural hemorrhage in one case; and cerebral hemisphere swelling with patchy hypodensity in one case. Genetic analysis (Figure 2) revealed \u003cem\u003eSUOX\u003c/em\u003e gene mutations in all cases: five carried the c.1200C\u0026gt;G (p.Tyr400Ter) mutation, one carried the c.1406_1421del:p.Thr469SerfsTer20 mutation, and one case exhibited compound heterozygous mutations of both c.1200C\u0026gt;G (p.Tyr400Ter) and c.1406_1421del:p.Thr469SerfsTer20. Table 2.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eClinical Data and Manifestations of Cases Identified in the Literature Search\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA case enrollment flowchart is presented in Figure 3. Among the 13 pediatric patients, four were male and nine were female. Symptom onset occurred within 1 day of birth in eight cases (61.5%). A family history was noted in five cases (38.5%), with four siblings experiencing refractory seizures during the neonatal period, which led to their death during early infancy. Among these siblings, two were diagnosed with ISOD but did not undergo genetic testing. In one case, symptom onset occurred at 1 year of age; the mother of the patient terminated a subsequent pregnancy at 21 weeks of gestation after cranial magnetic resonance imaging and genetic confirmation of ISOD. All 13 patients exhibited seizures, four experienced respiratory distress, 10 (76.9%) presented with increased muscle tone, five (38.5%) had microcephaly, and seven (53.9%) experienced feeding difficulties. Seven (53.9%) patients exhibited developmental delays (Table 3).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eCranial Imaging and Auxiliary Test Results\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cem\u003eof Cases Identified in the Literature Search\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCranial imaging was performed in 12 patients, all of whom presented with abnormalities (100%). Abnormal signals in the cerebral cortex and basal ganglia were observed in seven cases (53.9%), cystic changes in the cerebral white matter in two cases (15.4%), ventricular enlargement in two cases (15.4%), and corpus callosum hypoplasia in two cases (15.4%). Ten patients underwent urinary sulfite testing (urinary sulfite test strip assay), with seven (70%) testing positive. Seven patients underwent blood homocysteine testing, with five showing reduced homocysteine levels (Table 4).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eGenetic Analyses\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cem\u003eof Cases Identified in the Literature Search\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll 13 patients exhibited \u003cem\u003eSUOX\u003c/em\u003e gene mutations, with six homozygous and seven compound heterozygous variants. Ten distinct mutation sites were identified, with the most frequent being the c.1200C\u0026gt;G variant (7/13) (Table 4).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eTreatment and Clinical Outcomes\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cem\u003eof Cases Identified in the Literature Search\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatients received symptomatic management, including anticonvulsant therapy and restricted intake of sulfur-containing amino acids. Ultimately, three patients died between postnatal days 6 and 31, and two patients were lost to follow-up. Among the remaining eight patients, the median follow-up age was 12 months (range: 6 months to 2 years 4 months). Two patients died between 6 and 8 months of age, with the longest survivor reaching an age of 2 years and 4 months. All surviving patients exhibited refractory epilepsy and severe developmental delays (Table 3).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eISOD is a rare genetic metabolic disorder that warrants attention owing to its high mortality and disability rates, as well as challenges in accurate clinical diagnosis. To our knowledge, this study provides the first systematic summary of the clinical and molecular genetic characteristics of ISOD in the Chinese population by analyzing seven genetically confirmed pediatric cases from southeastern China and reviewing 13 additional Chinese neonatal cases from the literature.\u003c/p\u003e\u003cp\u003eHerein, Chinese newborns with ISOD exhibited highly consistent and severe core clinical phenotypes. Symptoms appeared within the first day of life in 55.0% of patients (n\u0026thinsp;=\u0026thinsp;11). The most prominent and common clinical manifestations were seizures (100.0%), hypertonia (75.0%), and feeding difficulties (70.0%); lens dislocation (5%) was extremely rare. The underlying cause of these core clinical phenotypes is mutations in the \u003cem\u003eSUOX\u003c/em\u003e gene, which lead to neurotoxic sulfite accumulation. This accumulation disrupts cellular energy metabolism, inhibits mitochondrial function, and triggers oxidative stress, causing rapid and severe damage to the developing central nervous system. These mechanisms may account for the acute neurological symptoms observed in affected infants during the early postnatal period [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. In contrast, lens dislocation represents long-term cumulative structural injury. Due to the extremely brief disease course in the neonatal period, it typically remains undetected at birth, resulting in a very low incidence. Regarding major neurological manifestations such as seizures and increased muscle tone, our findings were consistent with those of an analysis of 74 ISOD cases by G\u0026ouml;de et al. [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. However, an international study reported a 26% incidence of lens dislocation at a median age at diagnosis of 15 months. Our data suggest that lens dislocation may not be apparent or universally present during the neonatal period, potentially limiting its value as an early diagnostic indicator. This comparison suggests that early-onset refractory seizures and progressive neurological impairment are core warning signs that warrant greater attention in neonatal patients.\u003c/p\u003e\u003cp\u003eTypical biochemical markers of ISOD include elevated levels of urinary sulfite, thiosulfate, and S-sulfocysteine [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Among the 20 patients included in this study, only 10 underwent urine sulfite dipstick testing. The low detection rate may be related to regional variations in disease awareness and testing capabilities. Of the aforementioned 10 patients, seven (70.0%) tested positive. Urine sulfite dipstick testing should be the initial assessment for clinically suspected ISOD, particularly in cases of refractory neonatal epilepsy. However, caution should be exercised regarding false-negative results, which are common in clinical practice due to the extreme instability and susceptibility to degradation of urinary sulfite [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Conversely, sulfite can react with homocysteine to form S-sulfocysteine; thus, plasma homocysteine levels are often significantly reduced when SO activity is low [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. In this study, seven pediatric patients underwent this test, with five (71.4%) exhibiting decreased plasma homocysteine levels. This suggests that reduced plasma homocysteine levels may serve as potential early diagnostic markers of neonatal ISOD. However, current criteria for defining decreased homocysteine levels remain inconsistent [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e], necessitating further investigations to establish diagnostic thresholds and standardized protocols.\u003c/p\u003e\u003cp\u003eHerein, all 19 infants who underwent comprehensive cranial imaging demonstrated abnormal findings, primarily characterized by symmetric abnormal signals in both cerebral hemispheres and basal ganglia. Notably, early-stage imaging manifestations may be easily mistaken for hypoxic-ischemic encephalopathy. Additionally, some infants present with concomitant structural brain malformations, such as corpus callosum agenesis and ventricular enlargement. Our findings suggest that imaging manifestations of neonatal ISOD encompass not only symmetric abnormal signals but also complex structural brain malformations, indicating potential impacts of early fetal development on brain architecture. Furthermore, nonspecific features such as ventricular enlargement or subdural hemorrhage in some patients may be misdiagnosed as hypoxic-ischemic encephalopathy. Therefore, for neonates presenting with early-onset refractory seizures, careful interpretation of imaging abnormalities in conjunction with genetic testing is crucial.\u003c/p\u003e\u003cp\u003ePrevious studies have reported multiple cystic changes in the white matter and brain atrophy as typical imaging manifestations of ISOD [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. However, only two patients in this cohort demonstrated white matter cystic changes on imaging within 72 h after birth. Brain injury may ultimately progress to characteristic cystic changes and atrophy, suggesting that the pathological processes originate in utero. This aligns with the findings of Lee et al. [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e] who reported a case in which fetal cranial magnetic resonance imaging and genetic testing confirmed ISOD at 21 weeks of gestation, prompting the mother to terminate the pregnancy. This indicates that early identification and termination could effectively spare disease onset.\u003c/p\u003e\u003cp\u003eISOD is caused by biallelic pathogenic mutations in the \u003cem\u003eSUOX\u003c/em\u003e gene located on chromosome 12q13.2 [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. To date, 36 distinct pathogenic \u003cem\u003eSUOX\u003c/em\u003e gene mutations distributed across various \u003cem\u003eSUOX\u003c/em\u003e domains have been identified [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Herein, all 20 pediatric patients harbored \u003cem\u003eSUOX\u003c/em\u003e mutations: 12 with homozygous mutations and eight with compound heterozygous mutations. Eleven distinct mutation sites were identified, with c.1200C\u0026thinsp;\u0026gt;\u0026thinsp;G (13/20) being the most frequent, suggesting that this site represents a hotspot mutation for \u003cem\u003eSUOX\u003c/em\u003e in the Chinese population. Additional sites included c.1201A\u0026thinsp;\u0026gt;\u0026thinsp;G, c.475G\u0026thinsp;\u0026gt;\u0026thinsp;T, c.68C\u0026thinsp;\u0026gt;\u0026thinsp;G, c.650G\u0026thinsp;\u0026gt;\u0026thinsp;A, and c.188G\u0026thinsp;\u0026gt;\u0026thinsp;A. Some of these represented novel mutations that have not been previously reported domestically or internationally, thereby expanding the \u003cem\u003eSUOX\u003c/em\u003e mutation spectrum. Previous studies [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e] have indicated that c.1200C\u0026thinsp;\u0026gt;\u0026thinsp;G is a global hotspot mutation in the \u003cem\u003eSUOX\u003c/em\u003e gene. However, \u003cem\u003eSUOX\u003c/em\u003e mutations exhibit regional and racial variations. Some common mutation sites reported in European and American populations were not identified in our cohort, suggesting potential regional and racial specificity in \u003cem\u003eSUOX\u003c/em\u003e mutation distribution.\u003c/p\u003e\u003cp\u003eCurrently, no effective treatments are available for neonatal ISOD. Restricting dietary sulfur content and reducing methionine and cysteine intake constitute the primary symptomatic support strategies [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. In this study, 20 pediatric patients received symptomatic nutritional intervention (low-sulfur amino acid formula), anticonvulsant medication to control seizures, vitamin and coenzyme supplementation in some cases, and supportive care (tube feeding and management of infections or respiratory/circulatory abnormalities). Ultimately, nine patients died, six were lost to follow-up, and only five survived, with a median follow-up age of 10 months (range: 6 months to 1 year 10 months). All surviving infants exhibited refractory epilepsy and severe developmental delay, indicating that restricting the intake of sulfur-containing amino acids yields suboptimal outcomes in improving neonatal ISOD.\u003c/p\u003e\u003cp\u003eThe limitations of this study include its retrospective nature and limited sample size, which may have introduced selection bias. Additionally, biochemical test results and follow-up information were incomplete in some cases, potentially affecting the comprehensive assessment of natural disease history and biochemical characteristics.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eNeonatal ISOD is clinically characterized by intractable seizures, increased muscle tone, and feeding difficulties. Cranial imaging findings typically present as symmetric abnormal signals in both the cerebral hemispheres and basal ganglia regions; however, a definitive diagnosis relies on genetic testing. The c.1200C\u0026thinsp;\u0026gt;\u0026thinsp;G mutation in the \u003cem\u003eSUOX\u003c/em\u003e gene is the most common hotspot variant in Chinese pediatric patients. Given the lack of effective treatment and extremely poor overall prognosis, families with index cases are advised to undergo prenatal diagnosis during subsequent pregnancies. Early identification and termination of pregnancy can effectively spare the occurrence of ISOD.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eISOD, isolated sulfite oxidase deficiency; SO, sulfite oxidase\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003eEthics Approval and consent to participate\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the Ethics Committee of Quanzhou Maternal and Child Health Hospital (Approval No. 2022005). The parents of the patients signed a written informed consent form, whereby they agreed to their children’s participation in this study and the use of their data and information for scientific research. All methods were performed in accordance with the relevant guidelines and regulations.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eConsent for publication\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatients’ parents signed a written informed consent form for the publication of their own and their children’s genetic data, clinical details, and any accompanying images.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eData availability\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and analyzed in the current study are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eCompeting interests\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eFunding\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research was supported by the Quanzhou Science and Technology Program of China (Grant numbers 2022C002 and 2022N039S) and the \"Science and Technology Rejuvenating Mongolia\" Shanghai Jiaotong University Action Plan Special Project (No.2023XY JG0001-01-09).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAuthor Contributions\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWZ, HY, and LX conceived the study and prepared the first draft of the manuscript. DC, YH, CC, and LZ helped critically revise the manuscript for important intellectual content and guided the design and research process followed in the study. ZL and JH performed the variant analysis. LX, ZL, JH, JX, and YH provided care for the patients and collected the clinical data. All authors have approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAcknowledgements\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to thank Editage (www.editage.cn) for the English language editing and the patient’s family for participating in this study.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSchwahn BC, van Spronsen F, Misko A, et al. Consensus guidelines for the diagnosis and management of isolated sulfite oxidase deficiency and molybdenum cofactor deficiencies. J Inherit Metab Dis. 2024;47:598\u0026ndash;623. https://doi.org/10.1002/jimd.12730\u003c/li\u003e\n\u003cli\u003eWyse ATS, Grings M, Wajner M, et al. The role of oxidative stress and bioenergetic dysfunction in sulfite oxidase deficiency: Insights from animal models. Neurotox Res. 2019;35:484\u0026ndash;94. https://doi.org/10.1007/s12640-018-9986-z\u003c/li\u003e\n\u003cli\u003eMudd SH, Irreverre F, Laster L. Sulfite oxidase deficiency in man: Demonstration of the enzymatic defect. Science. 1967;156:1599\u0026ndash;602. https://doi.org/10.1126/science.156.3782.1599\u003c/li\u003e\n\u003cli\u003eClaerhout H, Witters P, R\u0026eacute;gal L, et al. Isolated sulfite oxidase deficiency. J Inherit Metab Dis. 2018;41:101\u0026ndash;8. https://doi.org/10.1007/s10545-017-0089-4\u003c/li\u003e\n\u003cli\u003eBosley TM, Alorainy IA, Oystreck DT, et al. Neurologic injury in isolated sulfite oxidase deficiency. Can J Neurol Sci. 2014;41:42\u0026ndash;8. https://doi.org/10.1017/s0317167100016243\u003c/li\u003e\n\u003cli\u003eG\u0026ouml;de L, Zielonka M, Garbade SF, et al. Ultra-orphan diseases: A cross-sectional quantitative analysis of the natural history of isolated sulfite oxidase deficiency. PLOS One. 2025;20:e0323043. https://doi.org/10.1371/journal.pone.0323043\u003c/li\u003e\n\u003cli\u003ePressler RM, Abend NS, Auvin S, et al. Treatment of seizures in the neonate: Guidelines and consensus-based recommendations-Special report from the ILAE Task Force on Neonatal Seizures. Epilepsia. 2023;64:2550\u0026ndash;70. https://doi.org/10.1111/epi.17745\u003c/li\u003e\n\u003cli\u003eDel Rosario C, Slevin M, Molloy EJ, et al. How to use the Bayley Scales of infant and toddler development. Arch Dis Child Educ Pract Ed. 2021;106:108\u0026ndash;12. https://doi.org/10.1136/archdischild-2020-319063\u003c/li\u003e\n\u003cli\u003eHolder JL, Agadi S, Reese W, et al. Infantile spasms and hyperekplexia associated with isolated sulfite oxidase deficiency. JAMA Neurol. 2014;71:782\u0026ndash;4. https://doi.org/10.1001/jamaneurol.2013.5083\u003c/li\u003e\n\u003cli\u003eZhiHong T, Qian P, GaoYang D. Clinical and genetic analysis of SUOX gene variant in a Chinese patient with isolated sulfite oxidase deficiency. Chin J Birth Health Hered. 2022;30:95\u0026ndash;8\u003c/li\u003e\n\u003cli\u003eYujuan W, Xinqiang L. Analysis of SUOX gene variants and clinical features in a child with Isolated sulfite oxidase deficiency. Chin J Med Genet. 2023;40:177\u0026ndash;80\u003c/li\u003e\n\u003cli\u003eJuan H, Li T, Wei Z, et al. A case report of neonatal sulfite oxidase deficiency. Chin J Neonatol. 2022;37:171\u0026ndash;2\u003c/li\u003e\n\u003cli\u003eWei J, Zhao Y, Zhao J. Neonatal isolated sulfite oxidase deficiency: A case report and literature review. Chin J Neonatol. 2022;37:49\u0026ndash;54\u003c/li\u003e\n\u003cli\u003eZhang R, Hao Y, Xu Y, et al. Whole exome sequencing identified a homozygous novel mutation in SUOX gene causes extremely rare autosomal recessive isolated sulfite oxidase deficiency. Clin Chim Acta. 2022;532:115\u0026ndash;22. https://doi.org/10.1016/j.cca.2022.06.005\u003c/li\u003e\n\u003cli\u003eRen Z, Wang J, Liang R, et al. Very early neuroimages of sulfite oxidase deficiency mimicing severe hypoxic ischemic encephalopathy in a neonate. Pediatr Neonatol. 2021;62:443\u0026ndash;4. https://doi.org/10.1016/j.pedneo.2021.03.005\u003c/li\u003e\n\u003cli\u003eZhao J, An Y, Jiang H, et al. Novel compound heterozygous pathogenic variants in SUOX cause isolated sulfite oxidase deficiency in a Chinese Han Family. Front Genet. 2021;12:607085. https://doi.org/10.3389/fgene.2021.607085\u003c/li\u003e\n\u003cli\u003eDu P, Hassan RN, Luo H, et al. Identification of a novel SUOX pathogenic variants as the cause of isolated sulfite oxidase deficiency in a Chinese pedigree. 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Clin Chim Acta. 2013;426:13\u0026ndash;7. https://doi.org/10.1016/j.cca.2013.08.013\u003c/li\u003e\n\u003cli\u003eHuang YL, Lin DS, Huang JK, et al. ⁹⁹mTc-ethyl cysteinate dimer cranial single-photon emission computed tomography and serial cranial magnetic resonance imaging in a girl with isolated sulfite oxidase deficiency. Pediatr Neurol. 2012;47:44\u0026ndash;6. https://doi.org/10.1016/j.pediatrneurol.2012.03.012\u003c/li\u003e\n\u003cli\u003eLee HF, Mak BS, Chi CS, et al. A novel mutation in neonatal isolated sulphite oxidase deficiency. Neuropediatrics. 2002;33:174\u0026ndash;9. https://doi.org/10.1055/s-2002-34491\u003c/li\u003e\n\u003cli\u003eHobson EE, Thomas S, Crofton PM, et al. Isolated sulphite oxidase deficiency mimics the features of hypoxic ischaemic encephalopathy. Eur J Pediatr. 2005;164:655\u0026ndash;9. https://doi.org/10.1007/s00431-005-1729-5\u003c/li\u003e\n\u003cli\u003eTan W-H, Eichler FS, Hoda S, et al. Isolated sulfite oxidase deficiency: A case report with a novel mutation and review of the literature. Pediatrics. 2005;116:757\u0026ndash;66. https://doi.org/10.1542/peds.2004-1897\u003c/li\u003e\n\u003cli\u003eKožich V, Schwahn BC, Sokolov\u0026aacute; J, et al. Human ultrarare genetic disorders of sulfur metabolism demonstrate redundancies in H(2)S homeostasis. Redox Biol. 2022;58:102517. https://doi.org/10.1016/j.redox.2022.102517\u003c/li\u003e\n\u003cli\u003eClaerhout H, Witters P, R\u0026eacute;gal L, et al. Isolated sulfite oxidase deficiency. J Inherit Metab Dis. 2018;41:101\u0026ndash;8. https://doi.org/10.1007/s10545-017-0089-4\u003c/li\u003e\n\u003cli\u003eHoffmann C, Ben-Zeev B, Anikster Y, et al. Magnetic resonance imaging and magnetic resonance spectroscopy in isolated sulfite oxidase deficiency. J Child Neurol. 2007;22:1214\u0026ndash;21. https://doi.org/10.1177/0883073807306260\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 4 is available in the Supplementary Files section\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1. Clinical Data of Seven Pediatric Patients with ISOD\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"1019\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 250px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 124px;\"\u003e\n \u003cp\u003e\u0026nbsp;Case 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003e\u0026nbsp;Case 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e\u0026nbsp;Case 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026nbsp;Case 4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e\u0026nbsp;Case 5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026nbsp;Case 6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e\u0026nbsp;Case 7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 250px;\"\u003e\n \u003cp\u003e\u0026nbsp;Sex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 124px;\"\u003e\n \u003cp\u003e\u0026nbsp;Female\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003e\u0026nbsp;Female\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e\u0026nbsp;Female\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026nbsp;Male\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e\u0026nbsp;Male\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026nbsp;Male\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e\u0026nbsp;Male\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 250px;\"\u003e\n \u003cp\u003e\u0026nbsp;Age at onset (days)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 124px;\"\u003e\n \u003cp\u003e\u0026nbsp;1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003e\u0026nbsp;1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e\u0026nbsp;5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026nbsp;1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e\u0026nbsp;3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026nbsp;3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e\u0026nbsp;1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 250px;\"\u003e\n \u003cp\u003e\u0026nbsp;Gestational age (weeks)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 124px;\"\u003e\n \u003cp\u003e\u0026nbsp;39\u003csup\u003e+5\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003e\u0026nbsp;40\u003csup\u003e+1\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e\u0026nbsp;40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026nbsp;36\u003csup\u003e+3\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e\u0026nbsp;39\u003csup\u003e+1\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026nbsp;39\u003csup\u003e+2\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e\u0026nbsp;40\u003csup\u003e+6\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 250px;\"\u003e\n \u003cp\u003e\u0026nbsp;Birth weight (g)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 124px;\"\u003e\n \u003cp\u003e\u0026nbsp;3650\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003e\u0026nbsp;4350\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e\u0026nbsp;3560\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026nbsp;3350\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e\u0026nbsp;3600\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026nbsp;3300\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e\u0026nbsp;3900\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 250px;\"\u003e\n \u003cp\u003eIntrauterine growth restriction\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 124px;\"\u003e\n \u003cp\u003e\u0026nbsp;-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003e\u0026nbsp;-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e\u0026nbsp;-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026nbsp;-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e\u0026nbsp;-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026nbsp;-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e\u0026nbsp;-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 250px;\"\u003e\n \u003cp\u003e\u0026nbsp;Choking first aid\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 124px;\"\u003e\n \u003cp\u003e\u0026nbsp;-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003e\u0026nbsp;-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e\u0026nbsp;-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026nbsp;-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e\u0026nbsp;-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026nbsp;-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e\u0026nbsp;-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 250px;\"\u003e\n \u003cp\u003e\u0026nbsp;Fracture\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 124px;\"\u003e\n \u003cp\u003e\u0026nbsp;Left occipital bone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003e\u0026nbsp;Right clavicle\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e\u0026nbsp;-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026nbsp;-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e\u0026nbsp;-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026nbsp;-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e\u0026nbsp;-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 250px;\"\u003e\n \u003cp\u003e\u0026nbsp;Family History\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 124px;\"\u003e\n \u003cp\u003e\u0026nbsp;-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003e\u0026nbsp;-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e\u0026nbsp;-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026nbsp;-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e\u0026nbsp;-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026nbsp;-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e\u0026nbsp;-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 250px;\"\u003e\n \u003cp\u003e\u0026nbsp;convulsive seizure\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 124px;\"\u003e\n \u003cp\u003e\u0026nbsp;+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003e\u0026nbsp;+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e\u0026nbsp;+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026nbsp;+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e\u0026nbsp;+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026nbsp;+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e\u0026nbsp;+\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 250px;\"\u003e\n \u003cp\u003e\u0026nbsp;Feeding difficulties\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 124px;\"\u003e\n \u003cp\u003e\u0026nbsp;+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003e\u0026nbsp;+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e\u0026nbsp;+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026nbsp;+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e\u0026nbsp;+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026nbsp;+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e\u0026nbsp;+\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 250px;\"\u003e\n \u003cp\u003e\u0026nbsp;Shortness of breath\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 124px;\"\u003e\n \u003cp\u003e\u0026nbsp;-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003e\u0026nbsp;-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e\u0026nbsp;-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026nbsp;-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e\u0026nbsp;-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026nbsp;-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e\u0026nbsp;-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 250px;\"\u003e\n \u003cp\u003e\u0026nbsp;Muscle tone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 124px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u0026uarr;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u0026uarr;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u0026uarr;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u0026uarr;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e\u0026nbsp;-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026nbsp;-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u0026uarr;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 250px;\"\u003e\n \u003cp\u003eOutcome\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 124px;\"\u003e\n \u003cp\u003e\u0026nbsp;Death within 15 days\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003e\u0026nbsp;26-month mortality\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e\u0026nbsp;8-month survival\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026nbsp;Death at 4 days\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e\u0026nbsp;Death at 13 days\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026nbsp;6 months survival\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e\u0026nbsp;18 months survival\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;Note: Positive +, Negative -, Elevated \u0026uarr;\u003c/p\u003e\n\u003cp\u003eISOD, isolated sulfite oxidase deficiency\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2. Laboratory and auxiliary examination results for 7 pediatric ISOD cases\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"112%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003eCase 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003eCase 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003eCase 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003eCase 4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003eCase 5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003eCase 6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 133px;\"\u003e\n \u003cp\u003eCase 7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003eComplete Blood Count\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 133px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003eLiver and kidney function\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 133px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003eElectrolyte\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 133px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003eBlood glucose\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 133px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003eUrinary organic acids\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003ePyruvate, 3-hydroxybutyrate\u0026uarr;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e4-hydroxyphenylbutyric acid\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 133px;\"\u003e\n \u003cp\u003e4-hydroxyphenylbutyrate\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003eUrea sulfite\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 133px;\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003eCranial imaging findings\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003eAbnormal signal in both cerebral hemispheres\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003eBilateral symmetrical abnormal signal intensity in cerebral parenchyma, bilateral ventricular enlargement\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003eSymmetrical abnormal signal intensity in bilateral frontal lobes, corpus callosum, bilateral basal ganglia, and internal capsule\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003eRight parieto-temporal-occipital lobe DWI hyperintensity, bilateral ventricular hematoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003eCorpus callosum agenesis with interhemispheric fissure cyst formation, enlarged lateral ventricles\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003eBilateral cerebral hemisphere edema with patchy slightly hypointense areas\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 133px;\"\u003e\n \u003cp\u003eSymmetrical abnormal signal intensity in bilateral cerebral hemispheres, basal ganglia, pons, medulla oblongata, and corpus callosum\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e\u003cem\u003eSUOX\u003c/em\u003e gene mutations\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003ec.1200C\u0026gt;G\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003ec.1200C\u0026gt;G\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003ec.1406_1421del\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003ec.1200C\u0026gt;G\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003ec.1200C＞G, c.1406_1421del\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003ec.1200C\u0026gt;G\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 133px;\"\u003e\n \u003cp\u003ec.1200C\u0026gt;G\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;Note: Positive: +; Negative: -; Elevated: \u0026uarr;; Not performed: /; c.1200C＞G: c.1200C＞G (p.Tyr400Ter); c.1406_1421del: c.1406_1421del:p.Thr469SerfsTer20\u003c/p\u003e\n\u003cp\u003eISOD, isolated sulfite oxidase deficiency; DWI, diffusion-weighted image\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3. Clinical data of 13 pediatric patients with ISOD\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"945\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 111px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003eCase 8 \u003csup\u003e[10]\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003eCase 9 \u003csup\u003e[11]\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003eCase 10 \u003csup\u003e[12]\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003eCase 11 \u003csup\u003e[13]\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003eCase 12 \u003csup\u003e[14]\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003eCase 13 \u003csup\u003e[15]\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003eCase 14 \u003csup\u003e[16]\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003eCase 15 \u003csup\u003e[17]\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003eCase 16 \u003csup\u003e[18]\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003eCase 17\u003csup\u003e\u0026nbsp;[19]\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003eCase 18 \u003csup\u003e[20]\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003eCase 19\u003csup\u003e\u0026nbsp;[21]\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003eCase 20 \u003csup\u003e[22]\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 111px;\"\u003e\n \u003cp\u003eSex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 111px;\"\u003e\n \u003cp\u003eAge at onset (days)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e21\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 111px;\"\u003e\n \u003cp\u003eGestational age (weeks)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003eFull-term\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e40\u003csup\u003e+3\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e39\u003csup\u003e+3\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e38\u003csup\u003e+4\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003eFull-term\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003eFull-term\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e38\u003csup\u003e+4\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e38\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003eFull-term\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003eFull-term\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 111px;\"\u003e\n \u003cp\u003eBirth weight (g)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e2800\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e2400\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e3020\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e3170\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e3020\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e2330\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e2850\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 111px;\"\u003e\n \u003cp\u003eHistory of resuscitation following asphyxia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 111px;\"\u003e\n \u003cp\u003eFamily History\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003eSister developed cyanosis and convulsions 1 day after birth and died\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003eSister died three days after birth following the onset of illness\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003eBrother developed symptoms 3 days after birth and died after one month\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003eThe mother terminated a pregnancy with one ISOD fetus when the current patient was 1 year of age\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003eBoth older and younger sisters developed symptoms 1 day after birth and died shortly thereafter\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 111px;\"\u003e\n \u003cp\u003eInitial presenting symptom\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003eConvulsions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003eRespiratory distress\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003eVomiting\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003eAbnormal eye movements\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003eConvulsions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003eConvulsions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003eVomiting\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003eConvulsions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003eFeeding difficulties\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003eRespiratory distress\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003eFeeding difficulties\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003eConvulsions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003eVomiting\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 111px;\"\u003e\n \u003cp\u003eConvulsions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 111px;\"\u003e\n \u003cp\u003eTime of seizure (days)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e24\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 111px;\"\u003e\n \u003cp\u003eFeeding difficulties\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 111px;\"\u003e\n \u003cp\u003eShortness of breath\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 111px;\"\u003e\n \u003cp\u003eMuscle tone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e\u0026uarr;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e\u0026uarr;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e\u0026uarr;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e\u0026uarr;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e\u0026uarr;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e\u0026uarr;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e\u0026uarr;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e\u0026uarr;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e\u0026uarr;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e\u0026uarr;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e\u0026uarr;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 111px;\"\u003e\n \u003cp\u003eMicrocephaly\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 111px;\"\u003e\n \u003cp\u003eLens dislocation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 111px;\"\u003e\n \u003cp\u003eDevelopmental delay\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 111px;\"\u003e\n \u003cp\u003eOutcome\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003eStanding head instability at 1 year of age\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003eDied on day 7 due to inability to maintain heart rate and blood oxygen levels, high lactate levels observed\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003eDied on day 31 following recurrent convulsions and respiratory failure\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003eDied at 8 months of age\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003eDied on day 6 due to cardiac failure. Medical cost approx. \u0026pound;40,000\u0026ndash;\u0026pound;50,000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003eAlive at 6 months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003eDied at 9 months of age\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003eAlive at 18 months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003eAlive at 2 years 4 months of age. Comprehensive developmental delay\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003eUnknown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003eUnknown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003eAlive at 10 months of age\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003eAlive at 10 months of age\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eNote: Positive +, Negative -, Elevated \u0026uarr;\u003c/p\u003e\n\u003cp\u003eISOD, isolated sulfite oxidase deficiency\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"italian-journal-of-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"itjp","sideBox":"Learn more about [Italian Journal of Pediatrics](http://ijponline.biomedcentral.com)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ITJP/default.aspx","title":"Italian Journal of Pediatrics","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"sulfite oxidase deficiency, newborn, China, refractory epilepsy, early intervention","lastPublishedDoi":"10.21203/rs.3.rs-8105066/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8105066/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e: Currently, no curative treatment is available for infantile sulfite oxidase deficiency (ISOD), and disease progression is primarily managed by restricting sulfur-containing amino acids in the diet. Furthermore, despite its overall rarity, the prevalence of ISOD has demonstrated an upward trend in the Chinese population in recent years. Accordingly, this study investigated the clinical phenotype, imaging characteristics, mutation spectrum, and prognosis of ISOD in Chinese newborns.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e: We retrospectively analyzed the clinical data from seven neonates with genetically confirmed ISOD from southeastern China between November 2018 and March 2025. The collected data included maternal and infant factors, clinical manifestations, laboratory results, and neuroimaging and genetic findings. The study cohort was further expanded through a systematic review of 13 additional neonatal ISOD cases reported in the Chinese and international literature, resulting in a combined cohort comprising 20 patients.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e: All infants (100%) presented with intractable seizures within the first few days of life. Other common clinical presentations included increased muscle tone (75%) and feeding difficulty (70%). Lens dislocation was uncommon in this neonatal cohort (5%). Abnormalities in cranial imaging—primarily presenting as symmetric abnormal signals in both cerebral hemispheres and basal ganglia—were observed in all cases, which could be misdiagnosed as hypoxic-ischemic encephalopathy. Laboratory tests revealed elevated urinary sulfite levels or decreased plasma homocysteine levels in some cases. Genetic analysis identified 11 distinct pathogenic variants of the \u003cem\u003eSUOX \u003c/em\u003egene, with c.1200C\u0026gt;G (p.Tyr400Ter) being the most common hotspot mutation in China. The prognosis was extremely poor; only five patients (25%) survived following symptomatic treatment, including sulfur-restricted diets, with a median follow-up of 10 months (range: 6–22 months). All surviving infants exhibited refractory epilepsy and severe developmental delays.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e: The hallmark features of ISOD in Chinese neonates include refractory seizures occurring shortly after birth and characteristic neuroimaging patterns. The c.1200C\u0026gt;G (p.Tyr400Ter) mutation in the\u003cem\u003e SUOX\u003c/em\u003e gene is the most common pathogenic variant in this population. Given the extremely poor prognosis and lack of effective treatment, prenatal genetic diagnosis is recommended to enable early intervention in high-risk families.\u003c/p\u003e","manuscriptTitle":"Clinical, neuroimaging, and genetic analysis of isolated sulfite oxidase deficiency in Chinese neonates: A case series and literature review","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-02 13:57:22","doi":"10.21203/rs.3.rs-8105066/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revision","date":"2026-04-30T05:31:39+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2026-01-27T16:15:55+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-11-26T10:31:36+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-11-17T04:22:57+00:00","index":"","fulltext":""},{"type":"submitted","content":"Italian Journal of Pediatrics","date":"2025-11-15T00:15:07+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"italian-journal-of-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"itjp","sideBox":"Learn more about [Italian Journal of Pediatrics](http://ijponline.biomedcentral.com)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ITJP/default.aspx","title":"Italian Journal of Pediatrics","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"6fb20663-65df-44b6-927d-b01fbcdbbdd5","owner":[],"postedDate":"December 2nd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"in-revision","subjectAreas":[],"tags":[],"updatedAt":"2026-04-30T09:59:16+00:00","versionOfRecord":[],"versionCreatedAt":"2025-12-02 13:57:22","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8105066","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8105066","identity":"rs-8105066","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}