{"paper_id":"066c2a4f-bc5d-4eac-954e-48cbcce4d394","body_text":"Late-onset methylmalonic acidemia with a rare MMACHC c.457C>T mutation: a case report 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 Case Report Late-onset methylmalonic acidemia with a rare MMACHC c.457C>T mutation: a case report and literature review Qingmei Huang, Zhenmei Liao, Honghua Li, Xiu Lu, Lingdong Zeng This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7649582/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 13 You are reading this latest preprint version Abstract Background Methylmalonic acidemia (MMA) is a rare autosomal recessive metabolic disorder with heterogeneous clinical phenotypes. The combined form of MMA associated with MMACHC mutations (cblC type) is the most common subtype in China. Late-onset MMA often presents with atypical manifestations, which frequently lead to misdiagnosis and delayed treatment. Case presentation: We report a 13-year-old female patient who presented with progressive cognitive impairment, psychiatric and behavioral abnormalities, and motor dysfunction. Due to atypical clinical features, she was initially misdiagnosed as having autoimmune encephalitis. Laboratory findings revealed markedly elevated plasma homocysteine, decreased methionine, and increased propionylcarnitine with a high propionylcarnitine/acetylcarnitine ratio. Urinary organic acid analysis showed significantly elevated methylmalonic acid and methylcitric acid. Genetic testing identified compound heterozygous mutations in the MMACHC gene: c.482G > A (p.Arg161Gln, maternal) and c.457C > T (p.Arg153Ter), the latter being rarely reported in China. Following treatment with hydroxocobalamin, folate, L-carnitine, and betaine, the patient’s symptoms improved and metabolic abnormalities normalized, although residual cognitive and motor dysfunction persisted. Conclusion This case expands the genotypic spectrum of MMA in China and underscores the importance of metabolic screening and genetic testing in pediatric patients with unexplained neuropsychiatric symptoms. Early recognition and intervention may prevent irreversible neurological sequelae. methylmalonic acidemia MMACHC late-onset combined type cblC Figures Figure 1 Figure 2 Case presentation A 13-year-old girl was admitted to our hospital with progressive neuropsychiatric symptoms. Since June 2021, she had developed cognitive impairment, incoherent speech, self-talk, inappropriate answers, emotional lability with frequent crying and laughing, irritability, unsteady gait, confusion, staring episodes, sluggish responses, memory decline, and urinary and fecal incontinence. She was previously hospitalized at another institution, where she was diagnosed with “autoimmune encephalitis” and treated with intravenous methylprednisolone pulse therapy and supportive care including vitamins. The symptoms partially improved, and she was switched to oral prednisone for maintenance. However, five months later she experienced relapse with worsening cognitive dysfunction, speech disturbance, motor impairment, impaired consciousness, and autonomic dysfunction, prompting referral to our hospital for further evaluation. Past history and family history: The patient was born at term via spontaneous vaginal delivery without perinatal asphyxia. Feeding during infancy was normal. Developmental milestones were age-appropriate: rolling at 4 months, sitting unsupported at 6 months, and independent walking at around 12 months. Language development was also normal, with single words at 1 year and short sentences by 2 years. Academic performance was average. Menarche occurred at age 11, with regular menstrual cycles and normal volume thereafter. She denied any history of infectious diseases. Her parents were non-consanguineous. No family history of intellectual disability, epilepsy, or metabolic disorders was reported. Physical examination: On admission, her temperature was 36.6°C, heart rate 97 bpm, respiratory rate 22 breaths/min, and blood pressure 112/79 mmHg. She was alert but displayed a flat affect. Higher cortical function was impaired with memory loss, slurred speech, and psychomotor slowing. Neurological examination revealed an abnormal scissoring gait, impaired finger-to-nose and heel-to-shin coordination, poor performance on alternating movement tests, and a positive Romberg sign. Laboratory and imaging findings: Complete blood count showed mild anemia (hemoglobin 104.8 g/L, reference 120–140 g/L). Serum vitamin B12 was reduced (100 pg/mL; reference 187–883 pg/mL). Other laboratory results including blood gas, urinalysis, liver and renal function, coagulation tests, thyroid function, iron studies, ferritin, and autoimmune antibody panels were unremarkable. Cerebrospinal fluid analysis and autoimmune encephalitis antibodies were negative. Electroencephalograms repeatedly demonstrated severe abnormalities. Brain MRI revealed mild demyelination in the periventricular white matter, widened cerebral sulci and fissures, and mild cerebral atrophy (Fig. 1 ). Metabolic screening demonstrated markedly elevated plasma homocysteine (153.63 µmol/L; normal 0–15 µmol/L). Tandem mass spectrometry revealed decreased methionine, elevated propionylcarnitine (C3), and an increased C3/acetylcarnitine (C2) ratio. Gas chromatography–mass spectrometry of urine showed significantly increased methylmalonic acid and methylcitric acid (Tables 1 and 2). Genetic testing: Genomic analysis was performed using PCR amplification and Sanger sequencing of all exons. The patient and her mother underwent testing (the father was unavailable). Results revealed compound heterozygous mutations in the MMACHC gene: c.482G > A (p.Arg161Gln, maternal) and c.457C > T (p.Arg153Ter, paternal origin unknown) (Fig. 2 ). Based on the biochemical profile and genetic findings, a diagnosis of combined methylmalonic acidemia and homocystinuria, cblC type, was established. Treatment and follow-up: The patient received specialized metabolic formula, intramuscular hydroxocobalamin (1 mg/day), oral folic acid (10 mg/day), L-carnitine (55 mg/kg/day), and betaine. After treatment, her clinical symptoms improved. Follow-up laboratory tests showed increased methionine and decreased homocysteine, C3, C3/C2, methylmalonic acid, and methylcitric acid, approaching normal ranges (Tables 1 and 2). Despite metabolic improvement, long-term follow-up revealed persistent cognitive deficits and motor impairment. Table 1 Changes in plasma homocysteine before and after treatment Time point Reference range Unit Before treatment 1 month after treatment 6 months after treatment 1 year after treatment 2 years after treatment Homocysteine 0–15 µmol/L 153.63 98.12 65.08 33.42 12.26 Table 2. Metabolic profiles before and after treatment Parameter Reference range Unit Before treatment After treatment Methionine (Met) 10–47 μmol/L 6.30 21.29 Propionylcarnitine (C3) 0.4–4.8 μmol/L 4.92 3.82 C3/C2 ratio 0.04–0.22 – 0.32 0.23 Methylmalonic acid 0.00–4.00 mmol/mol Cr 290.82 3.59 Methylcitrate 0.00–0.70 mmol/mol Cr 2.80 0.58 Abbreviations: Met, methionine; C3, propionylcarnitine; C2, acetylcarnitine; Cr, creatinine. Discussion Methylmalonic acidemia (MMA) was first described in 1967 and is classified into two major groups: methylmalonyl-CoA mutase deficiency (mut type) and defects of cobalamin metabolism (cbl type) [16]. Among Chinese patients, the combined type MMA is the most prevalent, accounting for approximately 70% of cases, and the vast majority (about 99%) belong to the cblC subtype [17,18]. The combined form results from MMACHC gene mutations, which impair the intracellular conversion of cobalamin into its active cofactors, methylcobalamin and adenosylcobalamin [19]. Deficiency of methylcobalamin disrupts methionine synthase activity, leading to elevated plasma homocysteine and decreased methionine. Adenosylcobalamin deficiency impairs methylmalonyl-CoA mutase, resulting in the accumulation of methylmalonic acid and homocysteine [20]. These biochemical disturbances contribute to multi-organ involvement, with neurological manifestations being most prominent. The clinical presentation of MMA varies with the age of onset. Early-onset cases usually present in infancy with severe metabolic decompensation and poor prognosis, whereas late-onset MMA tends to have more heterogeneous and nonspecific features, often involving the nervous system, liver, kidney, or hematopoietic system [21]. Neurological symptoms in late-onset cases may include cognitive impairment, psychiatric abnormalities, motor dysfunction, speech disorders, visual impairment, and seizures. Because of its atypical features, late-onset MMA is frequently misdiagnosed. For example, Li et al. [22] reported three patients who initially presented with psychiatric symptoms, one of whom was misdiagnosed with autoimmune encephalitis. Liu et al. [23] described a patient with respiratory dysfunction due to high cervical spinal cord involvement who was later confirmed to have MMA. Our patient also presented with psychiatric and motor symptoms and was initially misdiagnosed as autoimmune encephalitis, highlighting the diagnostic challenge posed by late-onset MMA. The advancement of genetic testing has greatly improved the diagnostic yield of MMA. The most common MMACHC mutations reported in China include c.482G>A and c.609G>A [5,13,25]. In particular, the c.482G>A mutation is often associated with late-onset and relatively mild clinical phenotypes [26]. However, our patient, who carried the compound heterozygous mutations c.482G>A and c.457C>T, exhibited significant neurological sequelae despite treatment, suggesting that the second allele may contribute to disease severity. The c.457C>T mutation is a nonsense mutation in MMACHC , which introduces a premature stop codon at codon 153, resulting in truncated nonfunctional protein [27,28]. Previous studies have suggested that c.457C>T is often found in early-onset patients as part of compound heterozygosity and is associated with increased oxidative stress and apoptosis in patient-derived cells [29]. Vitamin B12 supplementation may partially ameliorate oxidative stress in these cells [29]. In our case, the c.457C>T mutation occurred in compound heterozygosity with c.482G>A and was associated with a late-onset phenotype but persistent neurological sequelae despite metabolic improvement. The severity of MMA phenotypes has been correlated not only with the genotype but also with the residual enzymatic activity [30]. While nonsense mutations usually abolish protein function completely, some missense mutations retain partial activity, leading to delayed onset and milder presentation. This mechanism may explain why our patient manifested late in childhood despite harboring a nonsense mutation. In addition, metabolic parameters such as elevated propionylcarnitine (C3) and C3/C2 ratio have been proposed as predictors of poor neurological outcomes and mortality [31]. Our patient’s markedly elevated C3 and C3/C2 at onset, combined with delayed diagnosis and treatment due to initial misdiagnosis, may have contributed to the unfavorable neurological outcome. Even with appropriate therapy including hydroxocobalamin, betaine, folate, and carnitine, many patients with MMA continue to develop long-term neurological complications [32]. Therefore, early recognition and intervention are critical. Our case expands the spectrum of MMACHC mutations in China by documenting the rare c.457C>T variant and emphasizes the importance of considering inherited metabolic disorders in children and adolescents presenting with unexplained neuropsychiatric symptoms. Conclusion In summary, we report a rare case of late-onset methylmalonic acidemia combined with homocystinuria caused by compound heterozygous MMACHC mutations, including the rarely reported c.457C>T variant in China. The patient presented with atypical neuropsychiatric manifestations and was initially misdiagnosed as autoimmune encephalitis, which delayed appropriate treatment. Although metabolic correction was achieved with hydroxocobalamin, folate, betaine, and carnitine, neurological sequelae persisted. This case expands the genotypic spectrum of MMA in China and underscores the importance of metabolic screening and genetic testing in pediatric patients with unexplained psychiatric or neurological symptoms. Early recognition and intervention remain crucial to improving long-term outcomes. Declarations Data Availability The anonymized whole-exome sequencing report supporting the findings of this study has been deposited in the Figshare repository and is publicly available at https://doi.org/10.6084/m9.figshare.30308008. All other data generated or analyzed during the current study are included in this published article and its supplementary information files. Ethics Approval and Consent to Participate This case report was approved by the Medical Ethics Committee of the Second Affiliated Hospital of Guangxi Medical University (Approval No. 2025-KYL(020)) and conducted in accordance with the Declaration of Helsinki. Written informed consent to participate was obtained from the patient’s legal guardians. Consent for Publication Written informed consent was obtained from the patient’s guardians to publish the case details. Acknowledgements We would like to thank the Guangxi Medical University and the clinical staff of the Second Affiliated Hospital of Guangxi Medical University for their assistance and support in this study. Authors’ Contributions All authors made substantial contributions to the conception and design of the work, data acquisition, analysis, and interpretation. All authors participated in drafting or critically revising the manuscript, approved the final version to be published, agreed on the journal to which the article has been submitted, and take full responsibility for all aspects of the work. Funding No specific funding was received for this work. References Fumiya Y, Satoshi A, Pin Fee C, et al. Methylmalonic acidemia with recurrent hemophagocytic lymphohistiocytosis: a case report and review of the literature. BMC Pediatr. 2025;25(1):259. Matthias RB, Friederike H, Carlo D-V, et al. Proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemia. 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Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 04 Jan, 2026 Reviews received at journal 12 Nov, 2025 Reviews received at journal 11 Nov, 2025 Reviewers agreed at journal 07 Nov, 2025 Reviews received at journal 06 Nov, 2025 Reviewers agreed at journal 01 Nov, 2025 Reviewers agreed at journal 30 Oct, 2025 Reviewers agreed at journal 30 Oct, 2025 Reviewers invited by journal 30 Oct, 2025 Editor assigned by journal 29 Oct, 2025 Editor invited by journal 08 Oct, 2025 Submission checks completed at journal 08 Oct, 2025 First submitted to journal 08 Oct, 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-7649582\",\"acceptedTermsAndConditions\":true,\"allowDirectSubmit\":false,\"archivedVersions\":[],\"articleType\":\"Case Report\",\"associatedPublications\":[],\"authors\":[{\"id\":542217398,\"identity\":\"4cd570ec-c169-474f-8fa5-ea08307970f1\",\"order_by\":0,\"name\":\"Qingmei Huang\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"The Second Affiliated Hospital of Guangxi Medical 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16:38:40\",\"extension\":\"html\",\"order_by\":8,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"acdc-reference\",\"size\":72136,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"earlyproof.html\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7649582/v1/6c270e15fff1537ca5a79e57.html\"},{\"id\":95663445,\"identity\":\"84e1e734-f583-4df5-8d78-b0fad3360ec8\",\"added_by\":\"auto\",\"created_at\":\"2025-11-11 16:38:56\",\"extension\":\"jpg\",\"order_by\":1,\"title\":\"Figure 1\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":93578,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eBrain MRI findings of the patient.\\u003c/p\\u003e\\n\\u003cp\\u003e(a) T1-weighted image showing hypointensity in the periventricular white matter.\\u003c/p\\u003e\\n\\u003cp\\u003e(b) T2-weighted image showing hyperintensity in the same region.\\u003c/p\\u003e\\n\\u003cp\\u003e(c) FLAIR sequence confirming hyperintense lesions.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"1.jpg\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7649582/v1/302efb06e1ce84b4e9e03bd8.jpg\"},{\"id\":95663345,\"identity\":\"80503d5d-42b7-4371-954f-213535330324\",\"added_by\":\"auto\",\"created_at\":\"2025-11-11 16:38:45\",\"extension\":\"jpg\",\"order_by\":2,\"title\":\"Figure 2\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":122274,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eGenetic analysis of the MMACHC gene in the proband and her mother.\\u003c/p\\u003e\\n\\u003cp\\u003eSanger sequencing revealed a compound heterozygous mutation in the proband: (a) c.482G\\u0026gt;A heterozygous variant; (b) c.457C\\u0026gt;T heterozygous variant. (c) The proband’s mother carried the c.482G\\u0026gt;A heterozygous variant; (d) no c.457C\\u0026gt;T variant was detected in the mother.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"2.jpg\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7649582/v1/90c339b8566e662b513d20f5.jpg\"},{\"id\":95797200,\"identity\":\"519ed93e-53ea-41e7-9400-d620fc915991\",\"added_by\":\"auto\",\"created_at\":\"2025-11-13 08:01:48\",\"extension\":\"pdf\",\"order_by\":0,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"manuscript-pdf\",\"size\":697047,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"manuscript.pdf\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7649582/v1/0f46bd27-c2d6-45fb-9bba-21457e9f9799.pdf\"}],\"financialInterests\":\"No competing interests reported.\",\"formattedTitle\":\"Late-onset methylmalonic acidemia with a rare MMACHC c.457C\\u003eT mutation: a case report and literature review\",\"fulltext\":[{\"header\":\"Case presentation\",\"content\":\"\\u003cp\\u003eA 13-year-old girl was admitted to our hospital with progressive neuropsychiatric symptoms. Since June 2021, she had developed cognitive impairment, incoherent speech, self-talk, inappropriate answers, emotional lability with frequent crying and laughing, irritability, unsteady gait, confusion, staring episodes, sluggish responses, memory decline, and urinary and fecal incontinence. She was previously hospitalized at another institution, where she was diagnosed with \\u0026ldquo;autoimmune encephalitis\\u0026rdquo; and treated with intravenous methylprednisolone pulse therapy and supportive care including vitamins. The symptoms partially improved, and she was switched to oral prednisone for maintenance. However, five months later she experienced relapse with worsening cognitive dysfunction, speech disturbance, motor impairment, impaired consciousness, and autonomic dysfunction, prompting referral to our hospital for further evaluation.\\u003c/p\\u003e\\n\\u003ch3\\u003ePast history and family history:\\u003c/h3\\u003e\\n\\u003cp\\u003eThe patient was born at term via spontaneous vaginal delivery without perinatal asphyxia. Feeding during infancy was normal. Developmental milestones were age-appropriate: rolling at 4 months, sitting unsupported at 6 months, and independent walking at around 12 months. Language development was also normal, with single words at 1 year and short sentences by 2 years. Academic performance was average. Menarche occurred at age 11, with regular menstrual cycles and normal volume thereafter. She denied any history of infectious diseases. Her parents were non-consanguineous. No family history of intellectual disability, epilepsy, or metabolic disorders was reported.\\u003c/p\\u003e\\u003cdiv id=\\\"Sec3\\\" class=\\\"Section2\\\"\\u003e\\u003ch2\\u003ePhysical examination:\\u003c/h2\\u003e\\u003cp\\u003eOn admission, her temperature was 36.6\\u0026deg;C, heart rate 97 bpm, respiratory rate 22 breaths/min, and blood pressure 112/79 mmHg. She was alert but displayed a flat affect. Higher cortical function was impaired with memory loss, slurred speech, and psychomotor slowing. Neurological examination revealed an abnormal scissoring gait, impaired finger-to-nose and heel-to-shin coordination, poor performance on alternating movement tests, and a positive Romberg sign.\\u003c/p\\u003e\\u003c/div\\u003e\\n\\u003ch3\\u003eLaboratory and imaging findings:\\u003c/h3\\u003e\\n\\u003cp\\u003eComplete blood count showed mild anemia (hemoglobin 104.8 g/L, reference 120\\u0026ndash;140 g/L). Serum vitamin B12 was reduced (100 pg/mL; reference 187\\u0026ndash;883 pg/mL). Other laboratory results including blood gas, urinalysis, liver and renal function, coagulation tests, thyroid function, iron studies, ferritin, and autoimmune antibody panels were unremarkable. Cerebrospinal fluid analysis and autoimmune encephalitis antibodies were negative. Electroencephalograms repeatedly demonstrated severe abnormalities. Brain MRI revealed mild demyelination in the periventricular white matter, widened cerebral sulci and fissures, and mild cerebral atrophy (Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig2\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e).\\u003c/p\\u003e\\u003cp\\u003eMetabolic screening demonstrated markedly elevated plasma homocysteine (153.63 \\u0026micro;mol/L; normal 0\\u0026ndash;15 \\u0026micro;mol/L). Tandem mass spectrometry revealed decreased methionine, elevated propionylcarnitine (C3), and an increased C3/acetylcarnitine (C2) ratio. Gas chromatography\\u0026ndash;mass spectrometry of urine showed significantly increased methylmalonic acid and methylcitric acid (Tables\\u0026nbsp;\\u003cspan refid=\\\"Tab1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e and 2).\\u003c/p\\u003e\\n\\u003ch3\\u003eGenetic testing:\\u003c/h3\\u003e\\n\\u003cp\\u003eGenomic analysis was performed using PCR amplification and Sanger sequencing of all exons. The patient and her mother underwent testing (the father was unavailable). Results revealed compound heterozygous mutations in the \\u003cem\\u003eMMACHC\\u003c/em\\u003e gene: c.482G\\u0026thinsp;\\u0026gt;\\u0026thinsp;A (p.Arg161Gln, maternal) and c.457C\\u0026thinsp;\\u0026gt;\\u0026thinsp;T (p.Arg153Ter, paternal origin unknown) (Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig1\\\" class=\\\"InternalRef\\\"\\u003e2\\u003c/span\\u003e). Based on the biochemical profile and genetic findings, a diagnosis of combined methylmalonic acidemia and homocystinuria, cblC type, was established.\\u003c/p\\u003e\\u003cp\\u003e\\u003c/p\\u003e\\n\\u003ch3\\u003eTreatment and follow-up:\\u003c/h3\\u003e\\n\\u003cp\\u003eThe patient received specialized metabolic formula, intramuscular hydroxocobalamin (1 mg/day), oral folic acid (10 mg/day), L-carnitine (55 mg/kg/day), and betaine. After treatment, her clinical symptoms improved. Follow-up laboratory tests showed increased methionine and decreased homocysteine, C3, C3/C2, methylmalonic acid, and methylcitric acid, approaching normal ranges (Tables\\u0026nbsp;\\u003cspan refid=\\\"Tab1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e and 2). Despite metabolic improvement, long-term follow-up revealed persistent cognitive deficits and motor impairment.\\u003c/p\\u003e\\u003cp\\u003e\\u003cdiv class=\\\"gridtable\\\"\\u003e\\u003ctable float=\\\"Yes\\\" id=\\\"Tab1\\\" border=\\\"1\\\"\\u003e\\u003ccaption language=\\\"En\\\"\\u003e\\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 1\\u003c/div\\u003e\\u003cdiv class=\\\"CaptionContent\\\"\\u003e\\u003cp\\u003eChanges in plasma homocysteine before and after treatment\\u003c/p\\u003e\\u003c/div\\u003e\\u003c/caption\\u003e\\u003ccolgroup cols=\\\"8\\\"\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c1\\\" colnum=\\\"1\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c2\\\" colnum=\\\"2\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c3\\\" colnum=\\\"3\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c4\\\" colnum=\\\"4\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c5\\\" colnum=\\\"5\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c6\\\" colnum=\\\"6\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c7\\\" colnum=\\\"7\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c8\\\" colnum=\\\"8\\\"\\u003e\\u003c/div\\u003e\\u003cthead\\u003e\\u003ctr\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eTime point\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003eReference range\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003eUnit\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003eBefore treatment\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e1 month after treatment\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003e6 months after treatment\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c7\\\"\\u003e\\u003cp\\u003e1 year after treatment\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c8\\\"\\u003e\\u003cp\\u003e2 years after treatment\\u003c/p\\u003e\\u003c/th\\u003e\\u003c/tr\\u003e\\u003c/thead\\u003e\\u003ctbody\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eHomocysteine\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e0\\u0026ndash;15\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e\\u0026micro;mol/L\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e153.63\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e98.12\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003e65.08\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e\\u003cp\\u003e33.42\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e\\u003cp\\u003e12.26\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003c/tbody\\u003e\\u003c/colgroup\\u003e\\u003c/table\\u003e\\u003c/div\\u003e\\u003c/p\\u003e\\u003cp\\u003eTable 2. Metabolic profiles before and after treatment\\u003c/p\\u003e\\n\\u003ctable border=\\\"1\\\" cellspacing=\\\"0\\\" cellpadding=\\\"0\\\" width=\\\"99%\\\"\\u003e\\n \\u003ctbody\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 31.3131%;\\\"\\u003e\\n \\u003cp\\u003eParameter\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 17.1717%;\\\"\\u003e\\n \\u003cp\\u003eReference range\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 17.1717%;\\\"\\u003e\\n \\u003cp\\u003eUnit\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 17.1717%;\\\"\\u003e\\n \\u003cp\\u003eBefore treatment\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 17.1717%;\\\"\\u003e\\n \\u003cp\\u003eAfter treatment\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 31.3131%;\\\"\\u003e\\n \\u003cp\\u003eMethionine (Met)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 17.1717%;\\\"\\u003e\\n \\u003cp\\u003e10\\u0026ndash;47\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 17.1717%;\\\"\\u003e\\n \\u003cp\\u003e\\u0026mu;mol/L\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 17.1717%;\\\"\\u003e\\n \\u003cp\\u003e6.30\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 17.1717%;\\\"\\u003e\\n \\u003cp\\u003e21.29\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 31.3131%;\\\"\\u003e\\n \\u003cp\\u003ePropionylcarnitine (C3)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 17.1717%;\\\"\\u003e\\n \\u003cp\\u003e0.4\\u0026ndash;4.8\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 17.1717%;\\\"\\u003e\\n \\u003cp\\u003e\\u0026mu;mol/L\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 17.1717%;\\\"\\u003e\\n \\u003cp\\u003e4.92\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 17.1717%;\\\"\\u003e\\n \\u003cp\\u003e3.82\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 31.3131%;\\\"\\u003e\\n \\u003cp\\u003eC3/C2 ratio\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 17.1717%;\\\"\\u003e\\n \\u003cp\\u003e0.04\\u0026ndash;0.22\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 17.1717%;\\\"\\u003e\\n \\u003cp\\u003e\\u0026ndash;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 17.1717%;\\\"\\u003e\\n \\u003cp\\u003e0.32\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 17.1717%;\\\"\\u003e\\n \\u003cp\\u003e0.23\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 31.3131%;\\\"\\u003e\\n \\u003cp\\u003eMethylmalonic acid\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 17.1717%;\\\"\\u003e\\n \\u003cp\\u003e0.00\\u0026ndash;4.00\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 17.1717%;\\\"\\u003e\\n \\u003cp\\u003emmol/mol Cr\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 17.1717%;\\\"\\u003e\\n \\u003cp\\u003e290.82\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 17.1717%;\\\"\\u003e\\n \\u003cp\\u003e3.59\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 31.3131%;\\\"\\u003e\\n \\u003cp\\u003eMethylcitrate\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 17.1717%;\\\"\\u003e\\n \\u003cp\\u003e0.00\\u0026ndash;0.70\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 17.1717%;\\\"\\u003e\\n \\u003cp\\u003emmol/mol Cr\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 17.1717%;\\\"\\u003e\\n \\u003cp\\u003e2.80\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 17.1717%;\\\"\\u003e\\n \\u003cp\\u003e0.58\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003c/tbody\\u003e\\n\\u003c/table\\u003e\\n\\u003cp\\u003eAbbreviations: Met, methionine; C3, propionylcarnitine; C2, acetylcarnitine; Cr, creatinine.\\u003c/p\\u003e\"},{\"header\":\"Discussion\",\"content\":\"\\u003cp\\u003eMethylmalonic acidemia (MMA) was first described in 1967 and is classified into two major groups: methylmalonyl-CoA mutase deficiency (mut type) and defects of cobalamin metabolism (cbl type) [16]. Among Chinese patients, the combined type MMA is the most prevalent, accounting for approximately 70% of cases, and the vast majority (about 99%) belong to the cblC subtype [17,18]. The combined form results from \\u003cem\\u003eMMACHC\\u003c/em\\u003e gene mutations, which impair the intracellular conversion of cobalamin into its active cofactors, methylcobalamin and adenosylcobalamin [19]. Deficiency of methylcobalamin disrupts methionine synthase activity, leading to elevated plasma homocysteine and decreased methionine. Adenosylcobalamin deficiency impairs methylmalonyl-CoA mutase, resulting in the accumulation of methylmalonic acid and homocysteine [20]. These biochemical disturbances contribute to multi-organ involvement, with neurological manifestations being most prominent.\\u003c/p\\u003e\\n\\u003cp\\u003eThe clinical presentation of MMA varies with the age of onset. Early-onset cases usually present in infancy with severe metabolic decompensation and poor prognosis, whereas late-onset MMA tends to have more heterogeneous and nonspecific features, often involving the nervous system, liver, kidney, or hematopoietic system [21]. Neurological symptoms in late-onset cases may include cognitive impairment, psychiatric abnormalities, motor dysfunction, speech disorders, visual impairment, and seizures. Because of its atypical features, late-onset MMA is frequently misdiagnosed. For example, Li et al. [22] reported three patients who initially presented with psychiatric symptoms, one of whom was misdiagnosed with autoimmune encephalitis. Liu et al. [23] described a patient with respiratory dysfunction due to high cervical spinal cord involvement who was later confirmed to have MMA. Our patient also presented with psychiatric and motor symptoms and was initially misdiagnosed as autoimmune encephalitis, highlighting the diagnostic challenge posed by late-onset MMA.\\u003c/p\\u003e\\n\\u003cp\\u003eThe advancement of genetic testing has greatly improved the diagnostic yield of MMA. The most common \\u003cem\\u003eMMACHC\\u003c/em\\u003e mutations reported in China include c.482G\\u0026gt;A and c.609G\\u0026gt;A [5,13,25]. In particular, the c.482G\\u0026gt;A mutation is often associated with late-onset and relatively mild clinical phenotypes [26]. However, our patient, who carried the compound heterozygous mutations c.482G\\u0026gt;A and c.457C\\u0026gt;T, exhibited significant neurological sequelae despite treatment, suggesting that the second allele may contribute to disease severity. The c.457C\\u0026gt;T mutation is a nonsense mutation in \\u003cem\\u003eMMACHC\\u003c/em\\u003e, which introduces a premature stop codon at codon 153, resulting in truncated nonfunctional protein [27,28]. Previous studies have suggested that c.457C\\u0026gt;T is often found in early-onset patients as part of compound heterozygosity and is associated with increased oxidative stress and apoptosis in patient-derived cells [29]. Vitamin B12 supplementation may partially ameliorate oxidative stress in these cells [29]. In our case, the c.457C\\u0026gt;T mutation occurred in compound heterozygosity with c.482G\\u0026gt;A and was associated with a late-onset phenotype but persistent neurological sequelae despite metabolic improvement.\\u003c/p\\u003e\\n\\u003cp\\u003eThe severity of MMA phenotypes has been correlated not only with the genotype but also with the residual enzymatic activity [30]. While nonsense mutations usually abolish protein function completely, some missense mutations retain partial activity, leading to delayed onset and milder presentation. This mechanism may explain why our patient manifested late in childhood despite harboring a nonsense mutation. In addition, metabolic parameters such as elevated propionylcarnitine (C3) and C3/C2 ratio have been proposed as predictors of poor neurological outcomes and mortality [31]. Our patient\\u0026rsquo;s markedly elevated C3 and C3/C2 at onset, combined with delayed diagnosis and treatment due to initial misdiagnosis, may have contributed to the unfavorable neurological outcome.\\u003c/p\\u003e\\n\\u003cp\\u003eEven with appropriate therapy including hydroxocobalamin, betaine, folate, and carnitine, many patients with MMA continue to develop long-term neurological complications [32]. Therefore, early recognition and intervention are critical. Our case expands the spectrum of \\u003cem\\u003eMMACHC\\u003c/em\\u003e mutations in China by documenting the rare c.457C\\u0026gt;T variant and emphasizes the importance of considering inherited metabolic disorders in children and adolescents presenting with unexplained neuropsychiatric symptoms.\\u003c/p\\u003e\"},{\"header\":\"Conclusion\",\"content\":\"\\u003cp\\u003eIn summary, we report a rare case of late-onset methylmalonic acidemia combined with homocystinuria caused by compound heterozygous \\u003cem\\u003eMMACHC\\u003c/em\\u003e mutations, including the rarely reported c.457C\\u0026gt;T variant in China. The patient presented with atypical neuropsychiatric manifestations and was initially misdiagnosed as autoimmune encephalitis, which delayed appropriate treatment. Although metabolic correction was achieved with hydroxocobalamin, folate, betaine, and carnitine, neurological sequelae persisted. This case expands the genotypic spectrum of MMA in China and underscores the importance of metabolic screening and genetic testing in pediatric patients with unexplained psychiatric or neurological symptoms. Early recognition and intervention remain crucial to improving long-term outcomes.\\u003c/p\\u003e\"},{\"header\":\"Declarations\",\"content\":\"\\u003cp\\u003e\\u003cstrong\\u003eData Availability\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe anonymized whole-exome sequencing report supporting the findings of this study has been deposited in the Figshare repository and is publicly available at https://doi.org/10.6084/m9.figshare.30308008.\\u003c/p\\u003e\\n\\u003cp\\u003eAll other data generated or analyzed during the current study are included in this published article and its supplementary information files.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eEthics Approval and Consent to Participate\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThis case report was approved by the Medical Ethics Committee of the Second Affiliated Hospital of Guangxi Medical University (Approval No. 2025-KYL(020)) and conducted in accordance with the Declaration of Helsinki. Written informed consent to participate was obtained from the patient\\u0026rsquo;s legal guardians.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eConsent for Publication\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eWritten informed consent was obtained from the patient\\u0026rsquo;s guardians to publish the case details.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eAcknowledgements\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eWe would like to thank the Guangxi Medical University and the clinical staff of the Second Affiliated Hospital of Guangxi Medical University for their assistance and support in this study.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eAuthors\\u0026rsquo; Contributions\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eAll authors made substantial contributions to the conception and design of the work, data acquisition, analysis, and interpretation. All authors participated in drafting or critically revising the manuscript, approved the final version to be published, agreed on the journal to which the article has been submitted, and take full responsibility for all aspects of the work.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eFunding\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eNo specific funding was received for this work.\\u003c/p\\u003e\"},{\"header\":\"References\",\"content\":\"\\u003col\\u003e\\n\\u003cli\\u003eFumiya Y, Satoshi A, Pin Fee C, et al. Methylmalonic acidemia with recurrent hemophagocytic lymphohistiocytosis: a case report and review of the literature. BMC Pediatr. 2025;25(1):259.\\u003c/li\\u003e\\n\\u003cli\\u003eMatthias RB, Friederike H, Carlo D-V, et al. Proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemia. Orphanet J Rare Dis. 2014;9:130.\\u003c/li\\u003e\\n\\u003cli\\u003eHaining Y, Mian L, Liang Z, et al. A regionally adapted HRM-based technique to screen MMACHC carriers for methylmalonic acidemia with homocystinuria in Shandong Province, China. Intractable Rare Dis Res. 2023;12(1):29-34.\\u003c/li\\u003e\\n\\u003cli\\u003eTu W, Chen H, He J. Methylmalonic aciduria: newborn screening in mainland China? J Pediatr Endocrinol Metab. 2013;26:399-400.\\u003c/li\\u003e\\n\\u003cli\\u003eLiu Y, Liu YP, Zhang Y, et al. Clinical phenotypes, genotypes, and prevention and treatment of 1003 cases of methylmalonic acidemia in China. Zhonghua Er Ke Za Zhi. 2018;56(6):7. [in Chinese]\\u003c/li\\u003e\\n\\u003cli\\u003eTao C, Yian G, Shengdong Z, et al. Methylmalonic acidemia: Neurodevelopment and neuroimaging. Front Neurosci. 2023;17:1110942.\\u003c/li\\u003e\\n\\u003cli\\u003eJoseph B, Antonysunil A, Jinous S, et al. Low vitamin B12 and lipid metabolism: evidence from pre-clinical and clinical studies. Nutrients. 2020;12(7):1925.\\u003c/li\\u003e\\n\\u003cli\\u003eArhip L, Brox-Torrecilla N, Romero I, et al. Late-onset methylmalonic acidemia and homocysteinemia (cblC disease): systematic review. Orphanet J Rare Dis. 2024;19(1):20.\\u003c/li\\u003e\\n\\u003cli\\u003eNuria C-C, Randy JC, Charles PV. Combined methylmalonic acidemia and homocystinuria, cblC type. I. Clinical presentations, diagnosis and management. J Inherit Metab Dis. 2011;35(1):91-102.\\u003c/li\\u003e\\n\\u003cli\\u003eWang S, Wang X, Xi J, et al. A case of adult methylmalonic acidemia with bilateral cerebellar lesions caused by a new mutation in MMACHC gene: case report. Front Neurol. 2022;13:935604.\\u003c/li\\u003e\\n\\u003cli\\u003eCocuzzo B, Kalirao S. Uncommonly missed diagnosis of methylmalonic acidemia (MMA) in adults and usefulness of testing for MMA in cases of seizures/neuropathy/weakness/ataxia. Cureus. 2023;15(10):e47577.\\u003c/li\\u003e\\n\\u003cli\\u003eXu B, Zhang L, Chen Q, et al. A case of late-onset combined methylmalonic acidemia and hyperhomocysteinemia induced by a vegetarian diet: case report. Front Pediatr. 2022;10:896177.\\u003c/li\\u003e\\n\\u003cli\\u003eMulticenter study of clinical and molecular genetic characteristics of late-onset cobalamin C defect patients in northern China. 2024. [in Chinese]\\u003c/li\\u003e\\n\\u003cli\\u003eWu SN, Han LS, Ye J, et al. Analysis of blood tandem mass spectrometry and urine gas chromatography\\u0026ndash;mass spectrometry in patients with methylmalonic acidemia. Zhonghua Yi Xue Za Zhi. 2013;93(8):5. [in Chinese]\\u003c/li\\u003e\\n\\u003cli\\u003eAnna JE, Srijan M, Ilia ADK, et al. Versatile enzymology and heterogeneous phenotypes in cobalamin complementation type C disease. iScience. 2022;25(9):104981.\\u003c/li\\u003e\\n\\u003cli\\u003eOberholzer VG, Levin B, Burgess EA, et al. Methylmalonic aciduria: an inborn error of metabolism leading to chronic metabolic acidosis. Arch Dis Child. 1967;42(225):492-504.\\u003c/li\\u003e\\n\\u003cli\\u003eCoelho JC, Huang MA, Xu X, et al. Purification and interaction analyses of two human lysosomal vitamin B12 transporters: LMBD1 and ABCD4. Mol Membr Biol. 2014;31:250-61.\\u003c/li\\u003e\\n\\u003cli\\u003eLiu Y, Li X, Wang Q, et al. Five novel SUCLG1 mutations in three Chinese patients with succinate-CoA ligase deficiency noticed by mild methylmalonic aciduria. Brain Dev. 2016;38(1):61-7.\\u003c/li\\u003e\\n\\u003cli\\u003eTheodoros G, Olga G, Anna M, et al. A case series of Cypriot patients with cblC defect: clinical, biochemical and molecular characteristics. Mol Genet Metab Rep. 2024;41:101158.\\u003c/li\\u003e\\n\\u003cli\\u003eGon\\u0026ccedil;alo P, Sandra J, Augusto R, et al. Clinical, biochemical and molecular features of a cohort of 8 patients with inherited disorders of vitamin B12 metabolism in a metabolic reference center. Endocr Metab Immune Disord Drug Targets. 2023.\\u003c/li\\u003e\\n\\u003cli\\u003eCao TT, Zhang JP, Ren BY, et al. Advances in research on neurological impairment in late-onset methylmalonic acidemia. Zhongfeng Yu Shenjing Jibing Zazhi. 2018;35(10):958-60. [in Chinese]\\u003c/li\\u003e\\n\\u003cli\\u003eLi SS, Yao YF, Liu F, et al. Clinical and genetic analysis of three late-onset MMA children with psychiatric symptoms as the initial manifestation. Shandong Yiyao. 2023;63(9):65-7. [in Chinese]\\u003c/li\\u003e\\n\\u003cli\\u003eLiu LJ, Wang YC, Liu ZH, et al. A case of methylmalonic acidemia with respiratory failure caused by involvement of the high cervical spinal cord. Zhongguo Zonghe Linchuang. 2021;37(5):4. [in Chinese]\\u003c/li\\u003e\\n\\u003cli\\u003eMu WJ, Hao LT, Dong Q, et al. Clinical phenotypes, gene mutations, and therapeutic outcomes of 14 children with methylmalonic acidemia. Zhongguo Shengyu Jiankang Zazhi. 2022;33(6):564-9. [in Chinese]\\u003c/li\\u003e\\n\\u003cli\\u003eShen PT. Clinical features and genotypes of children with methylmalonic acidemia. 2023. [in Chinese]\\u003c/li\\u003e\\n\\u003cli\\u003eWu SN, En HS, Yue Y, et al. Variable phenotypes and outcomes associated with the MMACHC c.482G\\u0026gt;A mutation: follow-up in a large cblC disease cohort. World J Pediatr. 2023;20(8):848-58.\\u003c/li\\u003e\\n\\u003cli\\u003eLerner-Ellis JP, Tirone JC, Pawelek PD, et al. Identification of the gene responsible for methylmalonic aciduria and homocystinuria, cblC type. Nat Genet. 2006;38(1):93-100.\\u003c/li\\u003e\\n\\u003cli\\u003eNogueira C, Aiello C, Cerone R, et al. Spectrum of MMACHC mutations in Italian and Portuguese patients with combined methylmalonic aciduria and homocystinuria, cblC type. Mol Genet Metab. 2008;93(4):475-80.\\u003c/li\\u003e\\n\\u003cli\\u003eRichard E, Jorge-Finnigan A, Garcia-Villoria J, et al. Genetic and cellular studies of oxidative stress in methylmalonic aciduria (MMA) cobalamin deficiency type C (cblC) with homocystinuria (MMACHC). Hum Mutat. 2009;30(11):1558-66.\\u003c/li\\u003e\\n\\u003cli\\u003eForny P, Bonilla X, Lamparter D, et al. Integrated multi-omics reveals anaplerotic rewiring in methylmalonyl-CoA mutase deficiency. Nat Metab. 2023;5(1):80-95.\\u003c/li\\u003e\\n\\u003cli\\u003eHao L, Ling S, Ding S, et al. Long-term follow-up of Chinese patients with methylmalonic acidemia of the cblC and mut subtypes. Pediatr Res. 2024;97(6):2010-19.\\u003c/li\\u003e\\n\\u003cli\\u003eRosa P, Maria Rosalia M, Maria Grazia O, et al. Investigation on a MMACHC mutant from cblC disease: the c.394C\\u0026gt;T variant. Biochim Biophys Acta Proteins Proteom. 2022;1870(6):140793.\\u003c/li\\u003e\\n\\u003c/ol\\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\":\"info@researchsquare.com\",\"identity\":\"bmc-pediatrics\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":false,\"externalIdentity\":\"bped\",\"sideBox\":\"Learn more about [BMC Pediatrics](http://bmcpediatr.biomedcentral.com/)\",\"snPcode\":\"\",\"submissionUrl\":\"https://www.editorialmanager.com/bped/default.aspx\",\"title\":\"BMC Pediatrics\",\"twitterHandle\":\"BMC_series\",\"acdcEnabled\":true,\"dfaEnabled\":false,\"editorialSystem\":\"em\",\"reportingPortfolio\":\"BMC Series\",\"inReviewEnabled\":true,\"inReviewRevisionsEnabled\":true},\"keywords\":\"methylmalonic acidemia, MMACHC, late-onset, combined type, cblC\",\"lastPublishedDoi\":\"10.21203/rs.3.rs-7649582/v1\",\"lastPublishedDoiUrl\":\"https://doi.org/10.21203/rs.3.rs-7649582/v1\",\"license\":{\"name\":\"CC BY 4.0\",\"url\":\"https://creativecommons.org/licenses/by/4.0/\"},\"manuscriptAbstract\":\"\\u003ch2\\u003eBackground\\u003c/h2\\u003e\\u003cp\\u003eMethylmalonic acidemia (MMA) is a rare autosomal recessive metabolic disorder with heterogeneous clinical phenotypes. The combined form of MMA associated with \\u003cem\\u003eMMACHC\\u003c/em\\u003e mutations (cblC type) is the most common subtype in China. Late-onset MMA often presents with atypical manifestations, which frequently lead to misdiagnosis and delayed treatment.\\u003c/p\\u003e\\u003ch2\\u003eCase presentation:\\u003c/h2\\u003e\\u003cp\\u003eWe report a 13-year-old female patient who presented with progressive cognitive impairment, psychiatric and behavioral abnormalities, and motor dysfunction. Due to atypical clinical features, she was initially misdiagnosed as having autoimmune encephalitis. Laboratory findings revealed markedly elevated plasma homocysteine, decreased methionine, and increased propionylcarnitine with a high propionylcarnitine/acetylcarnitine ratio. Urinary organic acid analysis showed significantly elevated methylmalonic acid and methylcitric acid. Genetic testing identified compound heterozygous mutations in the \\u003cem\\u003eMMACHC\\u003c/em\\u003e gene: c.482G\\u0026thinsp;\\u0026gt;\\u0026thinsp;A (p.Arg161Gln, maternal) and c.457C\\u0026thinsp;\\u0026gt;\\u0026thinsp;T (p.Arg153Ter), the latter being rarely reported in China. Following treatment with hydroxocobalamin, folate, L-carnitine, and betaine, the patient\\u0026rsquo;s symptoms improved and metabolic abnormalities normalized, although residual cognitive and motor dysfunction persisted.\\u003c/p\\u003e\\u003ch2\\u003eConclusion\\u003c/h2\\u003e\\u003cp\\u003eThis case expands the genotypic spectrum of MMA in China and underscores the importance of metabolic screening and genetic testing in pediatric patients with unexplained neuropsychiatric symptoms. Early recognition and intervention may prevent irreversible neurological sequelae.\\u003c/p\\u003e\",\"manuscriptTitle\":\"Late-onset methylmalonic acidemia with a rare MMACHC c.457C\\u0026gt;T mutation: a case report and literature review\",\"msid\":\"\",\"msnumber\":\"\",\"nonDraftVersions\":[{\"code\":1,\"date\":\"2025-11-11 16:30:16\",\"doi\":\"10.21203/rs.3.rs-7649582/v1\",\"editorialEvents\":[{\"type\":\"communityComments\",\"content\":0},{\"type\":\"decision\",\"content\":\"Revision requested\",\"date\":\"2026-01-04T08:38:04+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"editorInvitedReview\",\"content\":\"\",\"date\":\"2025-11-12T16:42:58+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"editorInvitedReview\",\"content\":\"\",\"date\":\"2025-11-11T17:53:50+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"reviewerAgreed\",\"content\":\"92113340903269265578501912973427554485\",\"date\":\"2025-11-07T19:39:27+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"editorInvitedReview\",\"content\":\"\",\"date\":\"2025-11-07T01:06:54+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"reviewerAgreed\",\"content\":\"205004577716610304938255564362440862704\",\"date\":\"2025-11-01T18:19:57+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"reviewerAgreed\",\"content\":\"282872376533826481706689563412938828544\",\"date\":\"2025-10-30T17:25:30+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"reviewerAgreed\",\"content\":\"69335680313014699195621341439243743008\",\"date\":\"2025-10-30T15:53:34+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"reviewersInvited\",\"content\":\"\",\"date\":\"2025-10-30T15:36:09+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"editorAssigned\",\"content\":\"\",\"date\":\"2025-10-29T18:43:35+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"editorInvited\",\"content\":\"\",\"date\":\"2025-10-08T18:01:22+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"checksComplete\",\"content\":\"\",\"date\":\"2025-10-08T17:41:44+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"submitted\",\"content\":\"BMC Pediatrics\",\"date\":\"2025-10-08T17:39:10+00:00\",\"index\":\"\",\"fulltext\":\"\"}],\"status\":\"published\",\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"bmc-pediatrics\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":false,\"externalIdentity\":\"bped\",\"sideBox\":\"Learn more about [BMC Pediatrics](http://bmcpediatr.biomedcentral.com/)\",\"snPcode\":\"\",\"submissionUrl\":\"https://www.editorialmanager.com/bped/default.aspx\",\"title\":\"BMC Pediatrics\",\"twitterHandle\":\"BMC_series\",\"acdcEnabled\":true,\"dfaEnabled\":false,\"editorialSystem\":\"em\",\"reportingPortfolio\":\"BMC Series\",\"inReviewEnabled\":true,\"inReviewRevisionsEnabled\":true}}],\"origin\":\"\",\"ownerIdentity\":\"a9342a80-9a23-48f4-9548-ccd04a64fd33\",\"owner\":[],\"postedDate\":\"November 11th, 2025\",\"published\":true,\"recentEditorialEvents\":[],\"rejectedJournal\":[],\"revision\":\"\",\"amendment\":\"\",\"status\":\"under-review\",\"subjectAreas\":[],\"tags\":[],\"updatedAt\":\"2026-04-26T09:23:30+00:00\",\"versionOfRecord\":[],\"versionCreatedAt\":\"2025-11-11 16:30:16\",\"video\":\"\",\"vorDoi\":\"\",\"vorDoiUrl\":\"\",\"workflowStages\":[]},\"version\":\"v1\",\"identity\":\"rs-7649582\",\"journalConfig\":\"researchsquare\"},\"__N_SSP\":true},\"page\":\"/article/[identity]/[[...version]]\",\"query\":{\"redirect\":\"/article/rs-7649582\",\"identity\":\"rs-7649582\",\"version\":[\"v1\"]},\"buildId\":\"8U1c8b4HqxoKbykW_rLl7\",\"isFallback\":false,\"isExperimentalCompile\":false,\"dynamicIds\":[84888],\"gssp\":true,\"scriptLoader\":[]}","source_license":"CC-BY-4.0","license_restricted":false}