Correlation between toxic organic acid fluctuations and neurodevelopment in patients with methylmalonic acidemia

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These metabolites, particularly affecting nerve cells, contribute to suboptimal neurodevelopment in MMA patients. While fluctuations in these toxic metabolites are common in MMA patients, their precise impact on neurodevelopment remains unclear. Results This study enrolled 20 MMA patients, comprising 14 methylmalonyl-CoA mutase (MMUT) type and 6 cobalamin (cbl) type. Diverse parameters were assessed, including methylmalonic acid (MA), methylcitric acid (MCA), propionylcarnitine (C3), acylcarnitine (C2), ammonia, glycine, and lactate. Cognitive function was evaluated using the Bayley-III and Wechsler intelligence scale, and brain imaging was conducted through magnetic resonance spectroscopy (MRS). The frequency and extent of fluctuations in toxic organic acids were computed based on blood test results. MMUT-type patients exhibited elevated levels of MA, MCA, C3, C3/C2 ratio and lactate, with more frequent and significant MA and C3 fluctuations than cbl-type patients. Brain imaging revealed central nervous system (CNS) demyelination in MMUT-type patients, while cbl-type patients displayed normal MRS results. Cbl-type patients exhibited significantly better neurocognitive outcomes, with higher scores in cognitive, motor, language, and social-emotional domains. A negative correlation was identified between the frequency of MA fluctuations and the developmental status of MMA patients. Conclusion Variances between MMUT-type and cbl-type MMA patients extend to neurocognitive outcomes, along with differences in frequency and magnitude of toxic organic acid fluctuations. MMA, particularly in MMUT-type patients, is associated with developmental delays and cognitive deficits, contrasting with more favorable outcomes in cbl-type patients due to treatment efficacy. Furthermore, a negative correlation was identified between the frequency of widely fluctuating MA and developmental conditions in MMA patients. Methylmalonic acidemia methylmalonic acid methylcitric acid mutase cobalamin neurodevelopment Figures Figure 1 Figure 2 Figure 3 Background Methylmalonic academia (MMA) is a rare and clinically diverse autosomal recessive disorder characterized by a deficiency in methylmalonyl-CoA mutase, leading to the accumulation of harmful metabolites [ 1 , 2 ]. The primary genetic defects behind MMA are mutations in the MMUT gene, responsible for encoding methylmalonyl-CoA mutase, or mutations in genes involved in cobalamin metabolism, crucial for adenosylcobalamin generation–a vital cofactor of mutase [ 3 , 4 ]. Biochemical analysis plays a pivotal role in MMA diagnosis, with detectable elevations in methylmalonic acid (MA) and methylcitric acid (MCA) levels serving as key indicators [ 1 , 2 ]. This accumulation disrupts regular cellular processes, contributing to the spectrum of clinical manifestations, varying from severe to fatal [ 2 ]. Elevated propionylcarnitine (C3) levels and the ratio of propionylcarnitine to acylcarnitine (C2) are significant markers in newborn screening programs, facilitating early detection of MMA [ 5 ]. Increased ammonia levels in MMA result from interconnected mechanisms, with MMA-induced oxidative stress impeding urea cycle enzyme functionality, and hindering ammonia clearance [ 6 ]. The endpoint of MA metabolism is the generation of succinyl-CoA, an important intermediate of the tricarboxylic acid (TCA) cycle. However, disrupted MA metabolism can interfere with the TCA cycle, potentially resulting in elevated lactate levels [ 6 – 8 ]. Treatment approaches for MMUT and cobalamin defects (cbl type), the two main MMA subtypes, differ markedly. MMUT-type MMA involves protein restriction, carnitine supplementation for organic acid clearance, and medication for ammonia removal. Severe cases may warrant liver transplantation. In contrast, cbl-type MMA primarily requires vitamin B12 supplementation, often with hydroxocobalamin or derivatives, and a less strict protein-restricted diet [ 9 – 11 ]. Despite having distinct genetic origins and treatments, MMUT-type and cbl-type MMA share commonalities in biochemical markers and symptoms. Key biomarkers such as MA, MCA, and C3 are specific indicators used to monitor and evaluate treatment responses in both types [ 2 , 9 ]. Both variants of MMA impact multiple organ systems, including neurological, gastrointestinal, hematological, cardiovascular, and renal systems [ 2 , 12 , 13 – 17 ]. Neurological manifestations, particularly affecting development and cognition, significantly contribute to the clinical burden of MMA, ranging from mild developmental delays to severe cognitive impairment and neurological deficits, highlighting the crucial role of toxic organic acid accumulation in MMUT and cobalamin defects [ 7 , 13 ]. This study aims to comprehensively review and compare neurodevelopmental outcomes, brain imaging data, and biochemical markers in our cohort of MMA patients in Taiwan. Emphasis is placed on exploring the variability in toxic organic acid levels and quantifying its correlation with neurocognitive outcomes. Specifically, we investigate whether greater fluctuations in organic acid levels correspond to poorer neurodevelopmental outcomes, a facet not explored in existing literature. Methods Study population This study enrolled a total of 20 MMA patients, with 14 individuals exhibiting defects in methylmalonyl-CoA mutase (classified as MMUT type), and the remaining 6 patients having defects in cobalamin metabolism (classified as cbl type). The average follow-up period spanned 85 months. MMUT-type patients are treated with protein restriction, L-carnitine supplementation, and sodium benzoate. In cases where patients encountered highly fluctuating serum ammonia levels and demonstrated failure to thrive due to malnutrition, liver transplantation (LT) was considered as one of the available treatment options. Additionally, cbl-type patients received hydroxycobalamin as part of their treatment regimen. Biochemical markers Patients with MMA were assessed for various biomarkers, including MA, MCA, C3, C3/C2, ammonia, glycine, and lactate during each visit. To gauge the fluctuation of these biomarkers, we initially examined concentration of each biomarker in serum or urine, calculating the standard deviation (SD) for each among the 20 MMA patients. Subsequently, we defined a positive widely fluctuating event as the absolute difference between two blood test results taken six months apart being greater than one SD. The total number of fluctuation events for each biomarker was quantified and then normalized to the total number of blood tests conducted for each patient. Cognitive function tests Various cognitive function assessments were administered based on the patient's chronological age. Bayley-III cognitive tests were utilized for individuals aged 0 to 36 months, the Wechsler Preschool Scale for those aged 36 to 72 months, and the Wechsler Intelligence Quotient (IQ) IV for those exceeding 72 months. Eight patients underwent the Bayley-III screening test, while six patients participated in the Wechsler Intelligence scale test. Developmental delay was defined as a Bayley III composite score below 85. In the Wechsler intelligence scale test, a score between 55 and 70 indicated mild cognitive developmental impairment, 40 to 55 as moderate impairment, 25 to 40 as severe impairment, and a score below 25 as profound impairment. Analysis of brain imaging Magnetic resonance spectroscopy (MRS) was conducted to assess potential metabolic irregularities in the brain. Statistical analysis Quantitative data were presented as means ± SD, and categorical variables were summarized accordingly. The difference between the two subgroups was assessed using an unpaired t-test. Pearson correlation analysis was employed to determine the potential correlation coefficient between developmental delay and fluctuations in toxic organic acids in MMA patients. Results This study included 20 participants, with a distribution of 9 boys and 11 girls, encompassing 14 MMUT-type and 6 cbl-type MMA cases. The average age of the patients was 6.8 ± 5.6 years. Within the 14 MMUT-type individuals, eight had undergone LT at an average age of 1.5 ± 2.1 years. Additionally, among the 6 cbl-type patients, there were 2 siblings with cbl-B type MMA and 4 with cbl-C type MMA (Table 1 ). Table 1 The clinical features of the twenty subjects in this study Case No. Gende 1 Age (years) MMA subtype Age at LT 2 (years) Zygosity 3 Mutation type 1 F 8 cblB - H MMAB : c.523G > A,p.Gly175Ter 2 M 0.33 cblB - H MMAB : c.523G > A,p.Gly175Ter 3 M 10 cblC - CH MMACHC:c.609G > A,p.Trp203Ter/ c.658_660delAAG,p.Lys220del 4 M 7 cblC - CH MMACHC:c.228_231delTGAC, p.Asp77Glnfs*22/c.394C > T,p.Arg132Ter 5 F 3 cblC - CH MMACHC:c.609G > A,p.Trp203Ter/ c.626dupT,p.Thr210Aspfs*35 6 M 1 cblC - CH MMACHC:c.482G > A, p.Arg161Gln/ c.398_399del,p.Gln133Argfs*4 7 F 20 MMUT - CH MMUT:c.919T > C,p.Phe307Leu/ c.1280G > A,p.Gly427Asp 8 F 17 MMUT 6.75 H MMUT:c.1280G > A,p.Gly427Asp 9 M 14 MMUT 0.67 H MMUT:c.982C > T,p.Leu328Phe 10 F 11 MMUT 0.67 CH MMUT:c.454C > T,p.Arg152Ter/ c.1677-1G > A 11 F 9 MMUT 1 CH MMUT:c.1159 A > C,p.Thr387Ile/ c.1630_1631 GG > TA,p.Gly544Ter 12 M 9 MMUT 0.92 CH MMUT:c.729_730insTT,p.Asp244Leufs*39/c.982C > T,p.Leu328Phe 13 F 8 MMUT 1.17 H MMUT:c.1280G > A,p.Gly427Asp 14 M 6 MMUT - CH MMUT:c.1105C > T,p.Arg369Cys/ c.1280G > A,p.Gly427Asp 15 F 4 MMUT - CH MMUT:c.1280G > A,p.Gly427Asp/ c.323G > A, p.Arg108His 16 M 2 MMUT 0.5 CH MMUT:c.1280G > A,p.Gly427Asp/ c.1782_1786delTAAAG,p.Ser594Argfs*11 17 F 2 MMUT 0.5 CH MMUT:c.1280G > A,p.Gly427Asp/ c.1782_1786delTAAAG,p.Ser594Argfs*11 18 F 2 MMUT - CH MMUT: c.1192A > C,p.Thr398Pro/c.454C > T,p.Arg152Ter 19 M 2 MMUT - CH MMUT: c.1655C > T,p.Ala552Val/c.1655C > T,p.Ala552Val 20 F 0.33 MMUT - CH MMUT: c.1106G > A,p.Arg369His/c.1677-1G > A 1 F, female; M, male; 2 LT, liver transplantation; 3 H, homozygous; CH, compound heterozygous The Bayley III screening test was administered to two cbl-type and six MMUT-type patients aged younger than 3 years. Upon comparing the percentile rank (PR) values across cognitive, motor, language, and social-emotional scales, it was observed that cbl-type patients displayed more favorable developmental outcomes than their MMUT-type counterparts. The average PR values for the cognitive, motor, language, and social-emotional scales in MMUT-type patients were below 50. Except for two MMUT-type patients (Case 12, 17) who demonstrated normal motor development, all other MMUT-type patients experienced a global developmental delay. Furthermore, one cblC type patient (Case 5) was classified as having developmental delay in cognitive functions, as evidenced by a Bayley-III composite score (CS) of 80 and a PR value of 9 for cognitive function (Table 2 ). Table 2 Bayley-III screening test results for MMA patients Case No. MMA subtype Cognitive development and scale PR # Motor development and scale PR Language development and scale PR Social emotional development and scale PR 4 cblC Normal (98) Normal (88) Normal (80) Normal (99.6) 5 cblC Delay (9) Delay (32) Delay (34) Normal (75) 11 MMUT Delay (5) Delay (12) Delay (13) Delay (9) 12 MMUT Delay (14) Normal (68) Delay (0.1) Delay (15) 13 MMUT Delay (1) Delay (0.1) Delay (3) Delay (16) 14 MMUT Delay (0.1) Delay (0.1) Delay (0.1) Delay (3) 16 MMUT Delay (5) Delay (10) Delay (1) Delay (7) 17 MMUT Delay (5) Delay (30) Delay (5) Delay (16) #PR, percentile rank; number in parentheses indicates the PR value Two cbl-type and four MMUT-type patients underwent a Wechsler Intelligence scale test. The test results indicated that cbl-type patients achieved higher scores in terms of full-scale IQ (FSIQ), verbal IQ, and performance IQ. Specifically, the average FSIQ score was 85 (PR value 14.5) for cbl-type patients and 63 (PR value 6.8) for MMUT type patients (Table 3 ). Among MMUT-type patients, only one individual (case 9) was diagnosed with profound intellectual disability. At the age of 11, his FSIQ score was 22. After liver transplantation, he had recurring hyperammonemia, liver dysfunction, and jaundice episodes. Subsequent pathological examination of his transplanted liver revealed the presence of Dubin Johnson syndrome. Table 3 Wechsler Intelligence scale test results for MMA patients Case No. MMA subtype Full scale IQ and PR # Verbal IQ and PR Performance IQ and PR Intellectual Disability 1 cblB 84 (14) 89 (23) 80 (9) - 3 cblC 86 (15) 90 (23) 90 (15) - 7 MMUT 78 (10) 80 (13) 76 (9) - 8 MMUT 74 (5) 76 (5) 72 (4) - 9 MMUT 22 (1) 23 (1) 21 (1) Profound 10 MMUT 79 (11) 79 (12) 79 (10) - #: PR, percentile rank; number in parentheses indicates the PR value Fifteen patients, consisting of 11 MMUT type and 4 cbl-type, underwent brain MRS studies at an average age of 4.8 ± 3.3 years. Elevated levels of choline complex with white matter demyelination were observed in 11 MMUT-type patients, eight of whom had undergone liver transplantation. In contrast, all four cbl-type patients exhibited normal brain MRS results. The brain MRS results for case 9, conducted at the age of 7, revealed not only white matter demyelination but also indications of prior injury, including patches of encephalomalacia and tissue loss in bilateral globus pallidi. Notably, case 9 was the sole individual with evident encephalomalacia on the brain image (Fig. 1 ). None of our patients displayed signs of optic nerve atrophy in their brain MRS examinations. The comparison of biochemical markers between patients with cbl-type and MMUT type revealed notable elevations in MA, MCA, C3, C3/C2, and lactate levels in the MMUT group. However, the level of ammonia and glycine showed no significant differences between these two groups (Table 4 ). Notably, Case 5, the sole cbl-type patient with delayed neurocognitive development in the Bayley III screening test, exhibited concentration levels of MA (76 µmol/mmol creatinine), MCA (4.48 µmol/L), and C3/C2 ratio (1.04) higher than those of another cbl-type patient (Case 4) who demonstrated completely normal neurocognitive development. Case 4 had MA levels of 16.6 µmol/mmol creatinine, MCA levels of 0.45 µmol/L, and a C3/C2 ratio of 0.23 (Table S1 ). Furthermore, Case 5 displayed the highest levels of MA, MCA, and C3/C2 among all cbl-type patients. Additionally, Case 9, the only MMUT-type patient diagnosed with profound intellectual disability, showed elevated serum ammonia, averaging 125 µg/dL, in contrast to the average levels observed in other MMUT-type patients (Table S1 ) Table 4 Biochemical markers between cbl-type and MMUT-type patients. Patient cbl-type 1 MMUT 2 P value Serum ammonia(ug/dL) 53.4 ± 20.9 77.9 ± 35.6 0.07 Serum lactate(mg/dL) 40.4 ± 10.5 31.2 ± 14.4 0.13 Urine MA 3 (µmol/mmol CRE) 69.5 ± 23.9 262.5 ± 67.8 0.002 Urine MCA 4 (µmol/L) 2.82 ± 3.5 15.6 ± 11.6 0.07 Glycine (µmol/L) 238.8 ± 151.9 294.0 ± 60.9 0.42 C3 5 (µM) 7.0 ± 3.9 28.1 ± 10.8 9.28×10 − 5 C3/C2 6 0.6 ± 0.42 0.8 ±0.28 0.36 1 Cbl, cobalamin; 2 MMUT, methylmalonyl-CoA mutase; 3 MA, methylmalonic acid; 4 MCA, methylcitric acid; 5 C3, propionylcarnitine; 6 C2, acylcarnitine MMUT-type patients demonstrated significantly higher frequencies of widely fluctuating MA and C3 levels compared to cbl-type patients. Moreover, MMUT-type patients exhibited greater absolute differences in MA, MCA, and C3 between two blood test results compared to cbl-type patients (Table 5 ). In the case of Case 5, the only cbl-type patient displaying a delay in neurocognitive development, there was a higher frequency of widely fluctuating MA (0.5 per blood test result), MCA (0.33 per blood test result), and C3 (0.17 per blood test result) compared to Case 4, who exhibited completely normal neurocognitive development. Case 4 demonstrated lower frequencies of widely fluctuating MA (0.06 per blood test result), MCA (0 per blood test result), and C3 (0 per blood test result). Notably, Case 5 displayed the highest frequency of widely fluctuating MA, MCA, and C3 among the entire group of cbl-type patients (Table S1 ). Table 5 Variability in biomarker levels between cbl type and MMUT type patients. cbl type MMUT p value Frequency of widely fluctuating MA # 0.14 ± 0.2 0.55 ± 0.29 0.01 Average MA fluctuation range (µmol/mmol CRE) 28.6 ± 33.6 139.7 ± 179.3 < 0.0001 Frequency of widely fluctuating MCA 0.07 ± 0.15 0.23 ± 0.23 0.18 Average MCA fluctuation range (µmol/L) 2.8 ± 3.41 5.16 ± 5.26 < 0.0001 Frequency widely fluctuating C3 0.07 ± 0.09 0.32 ± 0.21 0.02 Average C3 fluctuation range (µM) 3.2 ± 5.07 10.12 ± 14.55 < 0.0001 MA: methylmalonic acid; MCA: methylcitric acid; C3: propionylcarnitine # Frequency of wide fluctuation for each biomarker is normalized to the total number of blood tests. To understand the relationship between neurocognitive development and toxic organic acids, we examined the correlation between the frequency of widely fluctuating toxic organic acids and the developmental status of MMA patients. We identified a negative correlation between the frequency of widely fluctuating MA and the cognitive PR value, motor PR value, language PR value, social-emotional PR value, and the average PR value across the four domains (Fig. 2 ). The Pearson correlation coefficients (r) were − 0.87, -0.81, -0.89, -0.84, and − 0.92, respectively. Notably, we also noted a negative correlation between the frequency of widespread fluctuation in MA and the composite scores in the Bayley III screening test (Fig. 3 ). Discussion Collective evidence from various studies consistently indicates that MMA is linked with neurological symptoms and damage. The diverse clinical range of neurological symptoms associated with MMA encompass developmental delays, intellectual disabilities, seizures, movement disorders, psychiatric issues, and potentially life-threatening encephalopathy during metabolic crises [ 2 , 7 , 9 , 13 , 18 – 20 ]. The severity and onset of these neurological symptoms often align with the degree of metabolic derangement, highlighting the critical importance of early diagnosis and intervention [ 9 ]. Numerous prior studies consistently identify developmental delays as one of the most prevalent neurological symptoms in MMA [ 21 – 23 ]. Recent research by Manoli et al.[ 2 ] demonstrated a correlation between higher levels of MA and more pronounced developmental delays and cognitive impairments in pediatric patients with MMA. Similarly, Carrillo-Carrasco et al.[ 24 ] found a positive correlation between elevated MA levels and an increased risk of seizures in affected individuals. Similarly, a study by Baulny et al.[ 25 ] emphasized the potential reversibility of neurological deficits when MA levels are effectively controlled, underlining the imperative nature of timely intervention and metabolic management. These findings underscore the pivotal role of MA as a neurotoxic metabolite and suggest that its accumulation leads to neurological dysfunction [ 2 , 13 ]. Therefore, monitoring and managing MA levels through diet modifications, vitamin B12 supplementation, and other therapeutic interventions become important not only to prevent metabolic crises but also to alleviate the severity of neurological symptoms. MMA manifests as a metabolic disorder with discernible features in brain magnetic resonance imaging (MRI), offering valuable insights into its neurological implications. These distinctive observations include characteristic changes in the basal ganglia, evident as hyperintensities on T2-weighted images [ 2 , 26 – 28 ]. Consistent with prior research, our study aligns with the documented occurrence of demyelination in the CNS among MMA patients, a phenomenon previously explored in studies such as the work by Manoli et al.[ 2 ]. In our investigation, we observed that 11 out of 20 MMA patients exhibited demyelination in the CNS. Our study underscores the presence of developmental delays across multiple domains, encompassing cognitive, motor, language, and social-emotional scales, in individuals with MMA. Specifically, the mean PR values derived from Bayley-III screening tests for all MMA patients reveal significant deficits in cognitive function (PR = 17), motor function (PR = 30), language function (PR = 17), and social-emotional scales (PR = 30). Notably, all these PR values fall below the 50th percentile, emphasizing the severity of developmental delay in individuals with MMA. These study results align with prior research findings, consistent with several studies associating MMA with developmental delays [ 2 , 21 – 23 ]. In addition to developmental delays, MMA has shown variable impacts on IQ among affected individuals [ 10 , 13 , 19 , 29 ]. Similarly, in our study, a patient was diagnosed with profound intellectual disability at the age of 11. The average PR value of FSIQ of our MMA patients was 11. These findings reinforce the intricate connection between MMA and neurocognitive deficits, highlighting the importance of early intervention and comprehensive care for affected individuals. In our study, brain imaging assessments and neurocognitive function in cbl-type patients surpassed those of MMUT patients. None of the cbl-type patients exhibited brain demyelination, in contrast to 11 out of 14 MMUT patients who displayed this condition. When assessing developmental delay using the Bayley-III screening test, cbl-type patients demonstrated higher PR values across cognitive, motor, language, and social-emotional scales compared to MMUT patients, indicative of more favorable developmental outcomes for cbl-type patients. In the Wechsler Intelligence Scale test, only one MMUT patient exhibited profound intellectual disability, with all others scoring within the normal range. However, the average FSIQ for cbl-type patients was 85 (PR value: 14.5), exceeding the average score for MMUT patients, which was 63 (PR value: 6.8). Our study's results align with established research, notably the study conducted by Colin J. O’Shea et al. in 2012. Their research indicated that cognitive deficits were more pronounced among patients with early-onset MMUT, while patients with other subtypes exhibited relatively normal cognitive outcomes. Early-onset MMUT patients demonstrated a mean FSIQ of 71.1 ± 14.75, whereas patients with CblA or CblB variants displayed mean FSIQ of 100.7 ± 10.95 and 96.6 ± 10.92, respectively [ 13 ]. In contrast to MMUT patients, our study unveiled significantly reduced levels of MA, MCA, C3, C3/C2, and lactate in individuals with cbl-type MMA. Prior research has clarified that patients responding to cobalamin typically exhibit lower levels of MA and MCA [ 2 , 23 – 24 ]. Conversely, patients unresponsive to cobalamin often maintain persistently elevated MA and MCA levels despite treatment attempts [ 1 , 25 ]. These findings may be connected to the observed normal brain MRS patterns and superior neurocognitive outcomes in our cbl-type patients compared to MMUT patients. For instance, Case 5, the sole cbl-type patient classified as developmentally delayed in cognitive function, displayed elevated levels of MA, MCA, and C3/C2 ratios compared to Case 4, who demonstrated normal neurocognitive development, as well as the entire cbl-type group. Moreover, our study has concentrated on examining the consequences of fluctuations in toxic organic acids, potentially exerting a significant influence on the neurodevelopmental outcomes of MMA patients—an aspect not previously explored in the current literature. For all MMA patients, we identified a negative correlation between the frequency of widespread fluctuations in MA and the PR value of the developmental status, encompassing cognitive, motor, language, and social-emotional scales. Differences between MMUT and cbl-type MMA patients manifest not only in absolute values but also in the frequency of widely fluctuating toxic organic acids. These findings strongly imply a connection between the disparities in brain imaging results and neurocognitive functioning observed between these two groups. As previously mentioned, the more frequent the widely fluctuating MA experienced by an MMA patient, the higher the likelihood of developmental delays. These distinctions are attributed to diverse treatment approaches. MMUT patients primarily rely on dietary control with protein restriction. However, striking the right balance between effectively managing toxic organic acids and meeting the patient's nutritional needs can pose a challenge [ 2 , 30 – 31 ]. Moreover, adherence to the dietary regimen may be problematic for some patients, potentially contributing to the instability of toxic organic acid levels. In contrast, hydroxycobalamin has been proven effective in treating cbl-type MMA. All cbl-type MMA patients in our study exhibited well-controlled urinary organic acid levels and relatively low-amplitude fluctuations in toxic metabolites. They also demonstrated a normal brain myelination status and better neurocognitive functioning throughout the follow-up period. On the other hand, Case 9, an individual with MMUT, demonstrated the lowest FSIQ among MMUT patients in our study and was diagnosed with profound intellectual disability. Notably, this patient presented elevated serum ammonia levels, surpassing the average levels observed in MMUT patients. This rise in ammonia levels could be linked to the patient's liver transplant, which subsequently unveiled the presence of Dubin-Johnson syndrome. This discovery aligns with findings from various studies [ 10 , 24 ]. These studies have emphasized the detrimental impact of elevated ammonia levels on cognitive function in individuals with MMA. Conclusions In our study on MMA, distinctive outcomes were observed in two MMA subtypes. Patients with cbl-type MMA, undergoing treatment with hydroxycobalamin, displayed lower organic acid levels and less frequent fluctuations, leading to better neurocognitive outcomes and improved brain imaging results. In contrast, patients with MMUT MMA encountered greater challenges, with higher organic acid levels, frequent fluctuations, brain demyelination, and poorer neurocognitive development. A negative correlation was identified between the frequency of widely fluctuating MA and the PR value of the developmental status for MMA patients. Overall, our findings underscore the significance of addressing organic acid fluctuations and tailoring treatments for MMA subtypes to improve neurodevelopmental outcomes. Abbreviations MMA Methylmalonic acidemia MMUT methylmalonyl-CoA mutase cbl cobalamin MA methylmalonic acid MCA methylcitric acid,C3,propionylcarnitine C2 acylcarnitine MRS magnetic resonance spectroscopy TCA tricarboxylic acid LT liver transplantation SD standard deviation IQ Intelligence Quotient PR percentile rank CS composite score FSIQ full-scale intelligence quotient MRI magnetic resonance imaging CNS central nervous system Declarations Ethics approval and consent to participate The study received approval from the Institutional Review Board at Taipei Veterans General Hospital, Taiwan. Written informed consent was waived, and all data were extracted from the medical charts of the participating patients Consent for Publication All participants gave their consent for participation in this study. Data Availability Statement Data sharing is not applicable to this article as no new data were created or analyzed in this study. Competing Interest The authors declare that they have no competing interests. Funding This research did not receive specific grants from funding agencies in the public, commercial, or non-profit sectors. Author Contributions All authors made substantial contributions to the conception of the work and the analysis and interpretation of data. I-Chih Ling drafted the manuscript and created tables and figures, while Yann-Jang Chen revised all content. All authors are accountable for their contributions. Acknowledgments The authors would like to thank all patients and their caregivers, the study centers, and the clinical teams involved in these studies for their participation. References Almási T, Guey LT, Lukacs C, Csetneki K, Vokó Z, Zelei T. 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Curr Opin Pediatr. 2016;28(6):682–93. 10.1097/MOP.0000000000000422 . Morath MA, Okun JG, Müller IB, Sauer SW, Hörster F, Hoffmann GF, Kölker S. Neurodegeneration and chronic renal failure in methylmalonic aciduria–a pathophysiological approach. J Inherit Metab Dis. 2008;31(1):35–43. 10.1007/s10545-007-0571-5 . O'Shea CJ, Sloan JL, Wiggs EA, Pao M, Gropman A, Baker EH, Manoli I, Venditti CP, Snow J. Neurocognitive phenotype of isolated methylmalonic acidemia. Pediatrics. 2012;129(6):e1541–51. 10.1542/peds.2011-1715 . Liu Y, Yang L, Shuai R, Huang S, Zhang B, Han L, Sun K, Wu Y. Different Pattern of Cardiovascular Impairment in Methylmalonic Acidaemia Subtypes. Front Pediatr. 2022;10:810495. 10.3389/fped.2022.810495 . Prada CE, Al Jasmi F, Kirk EP, Hopp M, Jones O, Leslie ND, Burrow TA. Cardiac disease in methylmalonic acidemia. J Pediatr. 2011;159(5):862–4. 10.1016/j.jpeds.2011.06.005 . Stephen G, Kahler WG, Sherwood D, Woolf ST, Lawless A, Zaritsky J, Bonham CJ, Taylor, Joe TR, Clarke P, Durie JV, Leonard. Pancreatitis in patients with organic acidemias. J Pediatr, Volume 124, Issue 2,1994, Pages 239–243, ISSN 0022-3476, https://doi.org/10.1016/S0022-3476(94)70311-6 . Inoue S, Krieger I, Sarnaik A, Ravindranath Y, Fracassa M, Ottenbreit MJ. Inhibition of bone marrow stem cell growth in vitro by methylmalonic acid: a mechanism for pancytopenia in a patient with methylmalonic acidemia. Pediatr Res. 1981;15(2):95–8. 10.1203/00006450-198102000-00001 . Surtees R, Leonard JV. Acute metabolic encephalopathy: A review of causes, mechanisms and treatment. J Inherit Metab Dis. 1989;12(Suppl 1):42–54. https://doi.org/10.1007/BF01799285 . Nicolaides P, Leonard J, Surtees R. Neurological outcome of methylmalonic acidaemia. Arch Dis Child. 1998;78(6):508–12. 10.1136/adc.78.6.508 . Waisbren SE. Review of neuropsychological outcomes in isolated methylmalonic acidemia: recommendations for assessing impact of treatments. Metab Brain Dis. 2022;37(5):1317–35. 10.1007/s11011-022-00954-1 . Hörster F, Baumgartner M, Viardot C, Suormala T, Burgard P, Fowler B, Hoffmann GF, Garbade SF, Kölker S, Baumgartner ER. Long-Term Outcome in Methylmalonic Acidurias Is Influenced by the Underlying Defect (mut0, mut–, cblA, cblB). Pediatr Res. 2007;62:225–30. https://doi.org/10.1203/PDR.0b013e3180a0325f . Hörster F, Garbade SF, Zwickler T, Aydin HI, Bodamer OA, Burlina AB, Das AM, De Klerk JBC, Dionisi-Vici C, Geb S, Gökcay G, Guffon N, Maier EM, Morava E, Walter JH, Schwahn B, Wijburg FA, Lindner M, Grünewald S, Baumgartner MR, Kölker S. Prediction of outcome in isolated methylmalonic acidurias: combined use of clinical and biochemical parameters. J Inherit Metab Dis. 2009;32(5):630. 10.1007/s10545-009-1189-6 . Matsui SM, Mahoney MJ, Rosenberg LE. The natural history of the inherited methylmalonic acidemias. N Engl J Med. 1983;308(15):857–61. 10.1056/NEJM198304143081501 . Carrillo-Carrasco N, Venditti CP. Combined methylmalonic acidemia and homocystinuria, cblC type. II. Complications, pathophysiology, and outcomes. J Inherit Metab Dis. 2012;35(1):103–14. 10.1007/s10545-011-9365-x . de Baulny HO, Benoist JF, Rigal O, Touati G, Rabier D, Saudubray JM. Methylmalonic and propionic acidaemias: management and outcome. J Inherit Metab Dis. 2005;28(3):415–23. 10.1007/s10545-005-7056-1 . Michel SJ, Given CA 2nd, Robertson WC Jr.. Imaging of the brain, including diffusion-weighted imaging in methylmalonic acidemia. Pediatr Radiol. 2004;34(7):580–2. 10.1007/s00247-004-1155-2 . Rossi A, Cerone R, Biancheri R, Gatti R, Schiaffino MC, Fonda C, Zammarchi E, Tortori-Donati P. Early-onset combined methylmalonic aciduria and homocystinuria: neuroradiologic findings. AJNR Am J Neuroradiol. 2001;22(3):554–63. PMID: 11237984; PMCID: PMC7976836. Chen T, Gao Y, Zhang S, Wang Y, Sui C, Yang L. Methylmalonic acidemia: Neurodevelopment and neuroimaging. Front Neurosci. 2023;17:1110942. 10.3389/fnins.2023.1110942 . Chu TH, Chien YH, Lin HY, Liao HC, Ho HJ, Lai CJ, Chiang CC, Lin NC, Yang CF, Hwu WL, Lee NC, Lin SP, Liu CS, Hu RH, Ho MC, Niu DM. Methylmalonic acidemia/propionic acidemia - the biochemical presentation and comparing the outcome between liver transplantation versus non-liver transplantation groups. Orphanet J Rare Dis. 2019;14(1):73. 10.1186/s13023-019-1045-1 . Hauser NS, Manoli I, Graf JC, Sloan J, Venditti CP. Variable dietary management of methylmalonic acidemia: metabolic and energetic correlations. Am J Clin Nutr. 2011;93(1):47–56. 10.3945/ajcn.110.004341 . E. Molema F, Haijes HA, Janssen MC, Bosch AM, van Spronsen FJ, Mulder MF, Verhoeven-Duif NM, Jans JJM, van der Ploeg AT, Wagenmakers MA, Rubio-Gozalbo ME, Brouwers MCGJ, de Vries MC, Fuchs S, Langendonk JG, Rizopoulos D, van Hasselt PM, Williams M. High protein prescription in methylmalonic and propionic acidemia patients and its negative association with long-term outcome. Clin Nutr. 2021;40(5):3622–30. 10.1016/j.clnu.2020.12.027 . Supplementary Files TableS1BiochemicalMarkers2.docx Cite Share Download PDF Status: Published Journal Publication published 15 Apr, 2025 Read the published version in Orphanet Journal of Rare Diseases → Version 1 posted Editorial decision: Major revision 02 Jun, 2024 Reviewers agreed at journal 18 Mar, 2024 Reviewers invited by journal 17 Mar, 2024 Editor assigned by journal 22 Jan, 2024 First submitted to journal 19 Jan, 2024 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-3875822","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":280518334,"identity":"93ed8516-4471-42bf-bd93-babe4aab12f5","order_by":0,"name":"I CHIH LING","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA7ElEQVRIiWNgGAWjYNCCCgk5fvnHB4AsCRkitZyxMZZsSEsAaeEhTgdjS1rihgM5BiA2YS3y0YcffvjYcDix4cCZz69u1FjwMLAfProBnxbDc2nGkjN3HDZubOzdZp1zDOgwnrS0G3i19DCYMfOeOSzbzMy7zTiHDahFgseMgBb2b8x/2w4ztrHxPDPO+UeEFnkeHjNmxrY0xR4eHubHuW1EaDHg4SmW7AEGsoQEmxlzbp8EDxshv8j3sG/88AMYlfY3mB9/zvlWJ8fPfvgYflsOINhsEmASn3KwLQ0INvMHQqpHwSgYBaNgZAIAHCxHU/4wZWcAAAAASUVORK5CYII=","orcid":"https://orcid.org/0009-0004-5548-3633","institution":"Taipei Veterans General Hospital","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"I","middleName":"CHIH","lastName":"LING","suffix":""},{"id":280518335,"identity":"1ac9bed1-f5de-4fd6-a79c-81b4090292df","order_by":1,"name":"Dau-Ming Niu","email":"","orcid":"","institution":"Taipei Veterans General Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Dau-Ming","middleName":"","lastName":"Niu","suffix":""},{"id":280518336,"identity":"404d2640-fa4b-4c9a-8afa-6ab33265d712","order_by":2,"name":"Chia-Feng Yang","email":"","orcid":"","institution":"Taipei Veterans General Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Chia-Feng","middleName":"","lastName":"Yang","suffix":""},{"id":280518337,"identity":"ab39e196-685a-4c5f-8e7c-c25fc582b32b","order_by":3,"name":"Cheng-Yu Lee","email":"","orcid":"","institution":"Taipei Veterans General Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Cheng-Yu","middleName":"","lastName":"Lee","suffix":""},{"id":280518338,"identity":"98247dc9-6497-47a7-ad1a-4af092aabca6","order_by":4,"name":"Sheng-Bin Liang","email":"","orcid":"","institution":"Cardinal Tien Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Sheng-Bin","middleName":"","lastName":"Liang","suffix":""},{"id":280518339,"identity":"b8cf563b-7d4e-428e-96d6-73c36e6eb4ef","order_by":5,"name":"Yann-Jang Chen","email":"","orcid":"https://orcid.org/0000-0002-5175-4772","institution":"National Yang Ming Chiao Tung University - Yangming Campus","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yann-Jang","middleName":"","lastName":"Chen","suffix":""}],"badges":[],"createdAt":"2024-01-18 12:58:11","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3875822/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3875822/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s13023-025-03687-3","type":"published","date":"2025-04-15T15:56:50+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":53183015,"identity":"deaba274-ef74-4d6e-ab31-093798e8b0ca","added_by":"auto","created_at":"2024-03-21 16:01:06","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1004912,"visible":true,"origin":"","legend":"\u003cp\u003eBrian MRI image of Case 9 at 7 years old (DWI, axial view.). The arrows highlight the regions of encephalomalacia, which are prominently located in the bilateral lentiform nucleus, particularly affecting the pallid globus.\u003c/p\u003e","description":"","filename":"Figure11.png","url":"https://assets-eu.researchsquare.com/files/rs-3875822/v1/106e21be367630e5fa40e27c.png"},{"id":53183018,"identity":"c7cb5dc7-f6b8-4106-8c26-9b27cd1aa850","added_by":"auto","created_at":"2024-03-21 16:01:07","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":244074,"visible":true,"origin":"","legend":"\u003cp\u003eScatter plot of PR values from Bayley III screening test at different frequencies of MA fluctuation (\u0026gt; 1SD). Each dot represents an individual's mean frequency of widely fluctuating MA per blood test and their corresponding developmental PR value. A) Cognitive development result, B) motor development result, C) language development result, D) Social-emotional development result, E) average development result across all four domains.\u003c/p\u003e","description":"","filename":"Figure21.png","url":"https://assets-eu.researchsquare.com/files/rs-3875822/v1/c3872e4659c9e8c27c0909f3.png"},{"id":53183017,"identity":"1302d211-b78b-489c-93d7-792c5a306513","added_by":"auto","created_at":"2024-03-21 16:01:06","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":226603,"visible":true,"origin":"","legend":"\u003cp\u003eScatter plot of the composite scores from Bayley III screening test at different frequencies of widely fluctuating MA (\u0026gt;1 SD). Each dot represents an individual's mean frequency of widely fluctuating MA per blood test and their corresponding composite score. A) Cognitive development result, B) Motor development result, C) Language development result, D) Social-emotional development result, E) average development result across all four domains.\u003c/p\u003e","description":"","filename":"Figure31.png","url":"https://assets-eu.researchsquare.com/files/rs-3875822/v1/435c649ead7598dbbcafdf06.png"},{"id":81050599,"identity":"842e049b-2066-4373-a805-3e2726124c75","added_by":"auto","created_at":"2025-04-21 15:59:24","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3326338,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3875822/v1/17d8b648-19bc-445c-9253-5fe8519b3d36.pdf"},{"id":53183016,"identity":"13853f95-d217-48ac-8242-5932126fa10c","added_by":"auto","created_at":"2024-03-21 16:01:06","extension":"docx","order_by":8,"title":"","display":"","copyAsset":false,"role":"supplement","size":35714,"visible":true,"origin":"","legend":"","description":"","filename":"TableS1BiochemicalMarkers2.docx","url":"https://assets-eu.researchsquare.com/files/rs-3875822/v1/40a3ec7db1f388b7c5b3b5ad.docx"}],"financialInterests":"","formattedTitle":"Correlation between toxic organic acid fluctuations and neurodevelopment in patients with methylmalonic acidemia","fulltext":[{"header":"Background","content":"\u003cp\u003eMethylmalonic academia (MMA) is a rare and clinically diverse autosomal recessive disorder characterized by a deficiency in methylmalonyl-CoA mutase, leading to the accumulation of harmful metabolites [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. The primary genetic defects behind MMA are mutations in the MMUT gene, responsible for encoding methylmalonyl-CoA mutase, or mutations in genes involved in cobalamin metabolism, crucial for adenosylcobalamin generation\u0026ndash;a vital cofactor of mutase [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eBiochemical analysis plays a pivotal role in MMA diagnosis, with detectable elevations in methylmalonic acid (MA) and methylcitric acid (MCA) levels serving as key indicators [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. This accumulation disrupts regular cellular processes, contributing to the spectrum of clinical manifestations, varying from severe to fatal [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Elevated propionylcarnitine (C3) levels and the ratio of propionylcarnitine to acylcarnitine (C2) are significant markers in newborn screening programs, facilitating early detection of MMA [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Increased ammonia levels in MMA result from interconnected mechanisms, with MMA-induced oxidative stress impeding urea cycle enzyme functionality, and hindering ammonia clearance [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. The endpoint of MA metabolism is the generation of succinyl-CoA, an important intermediate of the tricarboxylic acid (TCA) cycle. However, disrupted MA metabolism can interfere with the TCA cycle, potentially resulting in elevated lactate levels [\u003cspan additionalcitationids=\"CR7\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTreatment approaches for MMUT and cobalamin defects (cbl type), the two main MMA subtypes, differ markedly. MMUT-type MMA involves protein restriction, carnitine supplementation for organic acid clearance, and medication for ammonia removal. Severe cases may warrant liver transplantation. In contrast, cbl-type MMA primarily requires vitamin B12 supplementation, often with hydroxocobalamin or derivatives, and a less strict protein-restricted diet [\u003cspan additionalcitationids=\"CR10\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Despite having distinct genetic origins and treatments, MMUT-type and cbl-type MMA share commonalities in biochemical markers and symptoms. Key biomarkers such as MA, MCA, and C3 are specific indicators used to monitor and evaluate treatment responses in both types [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Both variants of MMA impact multiple organ systems, including neurological, gastrointestinal, hematological, cardiovascular, and renal systems [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan additionalcitationids=\"CR14 CR15 CR16\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Neurological manifestations, particularly affecting development and cognition, significantly contribute to the clinical burden of MMA, ranging from mild developmental delays to severe cognitive impairment and neurological deficits, highlighting the crucial role of toxic organic acid accumulation in MMUT and cobalamin defects [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e This study aims to comprehensively review and compare neurodevelopmental outcomes, brain imaging data, and biochemical markers in our cohort of MMA patients in Taiwan. Emphasis is placed on exploring the variability in toxic organic acid levels and quantifying its correlation with neurocognitive outcomes. Specifically, we investigate whether greater fluctuations in organic acid levels correspond to poorer neurodevelopmental outcomes, a facet not explored in existing literature.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy population\u003c/h2\u003e \u003cp\u003eThis study enrolled a total of 20 MMA patients, with 14 individuals exhibiting defects in methylmalonyl-CoA mutase (classified as MMUT type), and the remaining 6 patients having defects in cobalamin metabolism (classified as cbl type). The average follow-up period spanned 85 months. MMUT-type patients are treated with protein restriction, L-carnitine supplementation, and sodium benzoate. In cases where patients encountered highly fluctuating serum ammonia levels and demonstrated failure to thrive due to malnutrition, liver transplantation (LT) was considered as one of the available treatment options. Additionally, cbl-type patients received hydroxycobalamin as part of their treatment regimen.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eBiochemical markers\u003c/h2\u003e \u003cp\u003ePatients with MMA were assessed for various biomarkers, including MA, MCA, C3, C3/C2, ammonia, glycine, and lactate during each visit. To gauge the fluctuation of these biomarkers, we initially examined concentration of each biomarker in serum or urine, calculating the standard deviation (SD) for each among the 20 MMA patients. Subsequently, we defined a positive widely fluctuating event as the absolute difference between two blood test results taken six months apart being greater than one SD. The total number of fluctuation events for each biomarker was quantified and then normalized to the total number of blood tests conducted for each patient.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eCognitive function tests\u003c/h2\u003e \u003cp\u003eVarious cognitive function assessments were administered based on the patient's chronological age. Bayley-III cognitive tests were utilized for individuals aged 0 to 36 months, the Wechsler Preschool Scale for those aged 36 to 72 months, and the Wechsler Intelligence Quotient (IQ) IV for those exceeding 72 months. Eight patients underwent the Bayley-III screening test, while six patients participated in the Wechsler Intelligence scale test. Developmental delay was defined as a Bayley III composite score below 85. In the Wechsler intelligence scale test, a score between 55 and 70 indicated mild cognitive developmental impairment, 40 to 55 as moderate impairment, 25 to 40 as severe impairment, and a score below 25 as profound impairment.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eAnalysis of brain imaging\u003c/h2\u003e \u003cp\u003eMagnetic resonance spectroscopy (MRS) was conducted to assess potential metabolic irregularities in the brain.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eQuantitative data were presented as means\u0026thinsp;\u0026plusmn;\u0026thinsp;SD, and categorical variables were summarized accordingly. The difference between the two subgroups was assessed using an unpaired t-test. Pearson correlation analysis was employed to determine the potential correlation coefficient between developmental delay and fluctuations in toxic organic acids in MMA patients.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eThis study included 20 participants, with a distribution of 9 boys and 11 girls, encompassing 14 MMUT-type and 6 cbl-type MMA cases. The average age of the patients was 6.8\u0026thinsp;\u0026plusmn;\u0026thinsp;5.6 years. Within the 14 MMUT-type individuals, eight had undergone LT at an average age of 1.5\u0026thinsp;\u0026plusmn;\u0026thinsp;2.1 years. Additionally, among the 6 cbl-type patients, there were 2 siblings with cbl-B type MMA and 4 with cbl-C type MMA (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\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\u003eThe clinical features of the twenty subjects in this study\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\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 \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCase No.\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGende\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003cp\u003e(years)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMMA\u003c/p\u003e \u003cp\u003esubtype\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAge at LT\u003csup\u003e2\u003c/sup\u003e (years)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eZygosity\u003csup\u003e3\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMutation type\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ecblB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMMAB : c.523G\u0026thinsp;\u0026gt;\u0026thinsp;A,p.Gly175Ter\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ecblB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMMAB : c.523G\u0026thinsp;\u0026gt;\u0026thinsp;A,p.Gly175Ter\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ecblC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMMACHC:c.609G\u0026thinsp;\u0026gt;\u0026thinsp;A,p.Trp203Ter/\u003c/p\u003e \u003cp\u003ec.658_660delAAG,p.Lys220del\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ecblC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMMACHC:c.228_231delTGAC,\u003c/p\u003e \u003cp\u003ep.Asp77Glnfs*22/c.394C\u0026thinsp;\u0026gt;\u0026thinsp;T,p.Arg132Ter\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ecblC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMMACHC:c.609G\u0026thinsp;\u0026gt;\u0026thinsp;A,p.Trp203Ter/\u003c/p\u003e \u003cp\u003ec.626dupT,p.Thr210Aspfs*35\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ecblC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMMACHC:c.482G\u0026thinsp;\u0026gt;\u0026thinsp;A, p.Arg161Gln/\u003c/p\u003e \u003cp\u003ec.398_399del,p.Gln133Argfs*4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMMUT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMMUT:c.919T\u0026thinsp;\u0026gt;\u0026thinsp;C,p.Phe307Leu/\u003c/p\u003e \u003cp\u003ec.1280G\u0026thinsp;\u0026gt;\u0026thinsp;A,p.Gly427Asp\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMMUT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMMUT:c.1280G\u0026thinsp;\u0026gt;\u0026thinsp;A,p.Gly427Asp\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMMUT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMMUT:c.982C\u0026thinsp;\u0026gt;\u0026thinsp;T,p.Leu328Phe\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMMUT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMMUT:c.454C\u0026thinsp;\u0026gt;\u0026thinsp;T,p.Arg152Ter/\u003c/p\u003e \u003cp\u003ec.1677-1G\u0026thinsp;\u0026gt;\u0026thinsp;A\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMMUT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMMUT:c.1159 A\u0026thinsp;\u0026gt;\u0026thinsp;C,p.Thr387Ile/\u003c/p\u003e \u003cp\u003ec.1630_1631 GG\u0026thinsp;\u0026gt;\u0026thinsp;TA,p.Gly544Ter\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMMUT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.92\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMMUT:c.729_730insTT,p.Asp244Leufs*39/c.982C\u0026thinsp;\u0026gt;\u0026thinsp;T,p.Leu328Phe\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMMUT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMMUT:c.1280G\u0026thinsp;\u0026gt;\u0026thinsp;A,p.Gly427Asp\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMMUT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMMUT:c.1105C\u0026thinsp;\u0026gt;\u0026thinsp;T,p.Arg369Cys/\u003c/p\u003e \u003cp\u003ec.1280G\u0026thinsp;\u0026gt;\u0026thinsp;A,p.Gly427Asp\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMMUT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMMUT:c.1280G\u0026thinsp;\u0026gt;\u0026thinsp;A,p.Gly427Asp/\u003c/p\u003e \u003cp\u003ec.323G\u0026thinsp;\u0026gt;\u0026thinsp;A, p.Arg108His\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMMUT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMMUT:c.1280G\u0026thinsp;\u0026gt;\u0026thinsp;A,p.Gly427Asp/\u003c/p\u003e \u003cp\u003ec.1782_1786delTAAAG,p.Ser594Argfs*11\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMMUT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMMUT:c.1280G\u0026thinsp;\u0026gt;\u0026thinsp;A,p.Gly427Asp/\u003c/p\u003e \u003cp\u003ec.1782_1786delTAAAG,p.Ser594Argfs*11\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMMUT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMMUT: c.1192A\u0026thinsp;\u0026gt;\u0026thinsp;C,p.Thr398Pro/c.454C\u0026thinsp;\u0026gt;\u0026thinsp;T,p.Arg152Ter\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMMUT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMMUT: c.1655C\u0026thinsp;\u0026gt;\u0026thinsp;T,p.Ala552Val/c.1655C\u0026thinsp;\u0026gt;\u0026thinsp;T,p.Ala552Val\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMMUT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMMUT: c.1106G\u0026thinsp;\u0026gt;\u0026thinsp;A,p.Arg369His/c.1677-1G\u0026thinsp;\u0026gt;\u0026thinsp;A\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003e\u003csup\u003e1\u003c/sup\u003e F, female; M, male; \u003csup\u003e2\u003c/sup\u003e LT, liver transplantation; \u003csup\u003e3\u003c/sup\u003e H, homozygous; CH, compound heterozygous\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe Bayley III screening test was administered to two cbl-type and six MMUT-type patients aged younger than 3 years. Upon comparing the percentile rank (PR) values across cognitive, motor, language, and social-emotional scales, it was observed that cbl-type patients displayed more favorable developmental outcomes than their MMUT-type counterparts. The average PR values for the cognitive, motor, language, and social-emotional scales in MMUT-type patients were below 50. Except for two MMUT-type patients (Case 12, 17) who demonstrated normal motor development, all other MMUT-type patients experienced a global developmental delay. Furthermore, one cblC type patient (Case 5) was classified as having developmental delay in cognitive functions, as evidenced by a Bayley-III composite score (CS) of 80 and a PR value of 9 for cognitive function (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBayley-III screening test results for MMA patients\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\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 \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCase No.\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMMA subtype\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCognitive development and scale PR\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMotor development and scale PR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLanguage development and scale PR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSocial emotional development and scale PR\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ecblC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNormal (98)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNormal (88)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNormal (80)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNormal (99.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ecblC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDelay (9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDelay (32)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eDelay (34)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNormal (75)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMMUT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDelay (5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDelay (12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eDelay (13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eDelay (9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMMUT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDelay (14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNormal (68)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eDelay (0.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eDelay (15)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMMUT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDelay (1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDelay (0.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eDelay (3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eDelay (16)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMMUT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDelay (0.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDelay (0.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eDelay (0.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eDelay (3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMMUT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDelay (5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDelay (10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eDelay (1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eDelay (7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMMUT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDelay (5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDelay (30)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eDelay (5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eDelay (16)\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\u003e#PR, percentile rank; number in parentheses indicates the PR value\u003c/p\u003e \u003cp\u003eTwo cbl-type and four MMUT-type patients underwent a Wechsler Intelligence scale test. The test results indicated that cbl-type patients achieved higher scores in terms of full-scale IQ (FSIQ), verbal IQ, and performance IQ. Specifically, the average FSIQ score was 85 (PR value 14.5) for cbl-type patients and 63 (PR value 6.8) for MMUT type patients (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Among MMUT-type patients, only one individual (case 9) was diagnosed with profound intellectual disability. At the age of 11, his FSIQ score was 22. After liver transplantation, he had recurring hyperammonemia, liver dysfunction, and jaundice episodes. Subsequent pathological examination of his transplanted liver revealed the presence of Dubin Johnson syndrome.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eWechsler Intelligence scale test results for MMA patients\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\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 \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCase No.\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMMA subtype\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eFull scale IQ and PR\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eVerbal\u003c/p\u003e \u003cp\u003eIQ and PR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePerformance\u003c/p\u003e \u003cp\u003eIQ and PR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eIntellectual Disability\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ecblB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e84 (14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e89 (23)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e80 (9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ecblC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e86 (15)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e90 (23)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e90 (15)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMMUT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e78 (10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e80 (13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e76 (9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMMUT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e74 (5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e76 (5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e72 (4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMMUT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22 (1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e23 (1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e21 (1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eProfound\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMMUT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e79 (11)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e79 (12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e79 (10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\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\u003e#: PR, percentile rank; number in parentheses indicates the PR value\u003c/p\u003e \u003cp\u003eFifteen patients, consisting of 11 MMUT type and 4 cbl-type, underwent brain MRS studies at an average age of 4.8\u0026thinsp;\u0026plusmn;\u0026thinsp;3.3 years. Elevated levels of choline complex with white matter demyelination were observed in 11 MMUT-type patients, eight of whom had undergone liver transplantation. In contrast, all four cbl-type patients exhibited normal brain MRS results. The brain MRS results for case 9, conducted at the age of 7, revealed not only white matter demyelination but also indications of prior injury, including patches of encephalomalacia and tissue loss in bilateral globus pallidi. Notably, case 9 was the sole individual with evident encephalomalacia on the brain image (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). None of our patients displayed signs of optic nerve atrophy in their brain MRS examinations.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe comparison of biochemical markers between patients with cbl-type and MMUT type revealed notable elevations in MA, MCA, C3, C3/C2, and lactate levels in the MMUT group. However, the level of ammonia and glycine showed no significant differences between these two groups (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Notably, Case 5, the sole cbl-type patient with delayed neurocognitive development in the Bayley III screening test, exhibited concentration levels of MA (76 \u0026micro;mol/mmol creatinine), MCA (4.48 \u0026micro;mol/L), and C3/C2 ratio (1.04) higher than those of another cbl-type patient (Case 4) who demonstrated completely normal neurocognitive development. Case 4 had MA levels of 16.6 \u0026micro;mol/mmol creatinine, MCA levels of 0.45 \u0026micro;mol/L, and a C3/C2 ratio of 0.23 (Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e). Furthermore, Case 5 displayed the highest levels of MA, MCA, and C3/C2 among all cbl-type patients. Additionally, Case 9, the only MMUT-type patient diagnosed with profound intellectual disability, showed elevated serum ammonia, averaging 125 \u0026micro;g/dL, in contrast to the average levels observed in other MMUT-type patients (Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e)\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBiochemical markers between cbl-type and MMUT-type patients.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatient\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ecbl-type\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMMUT\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSerum ammonia(ug/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e53.4\u0026thinsp;\u0026plusmn;\u0026thinsp;20.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e77.9 \u0026plusmn; 35.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.07\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSerum lactate(mg/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e40.4 \u0026plusmn; 10.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e31.2 \u0026plusmn; 14.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.13\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUrine MA\u003csup\u003e3\u003c/sup\u003e (\u0026micro;mol/mmol CRE)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e69.5\u0026thinsp;\u0026plusmn;\u0026thinsp;23.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e262.5 \u0026plusmn; 67.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.002\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUrine MCA\u003csup\u003e4\u003c/sup\u003e (\u0026micro;mol/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e2.82 \u0026plusmn; 3.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e15.6 \u0026plusmn; 11.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.07\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGlycine (\u0026micro;mol/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e238.8 \u0026plusmn; 151.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e294.0 \u0026plusmn; 60.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.42\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC3\u003csup\u003e5\u003c/sup\u003e (\u0026micro;M)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e7.0 \u0026plusmn; 3.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e28.1 \u0026plusmn; 10.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e9.28\u0026times;10\u003csup\u003e\u0026minus;\u0026thinsp;5\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC3/C2\u003csup\u003e6\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e0.6 \u0026plusmn; 0.42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e0.8 \u0026plusmn;0.28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.36\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e\u003csup\u003e1\u003c/sup\u003e Cbl, cobalamin; \u003csup\u003e2\u003c/sup\u003e MMUT, methylmalonyl-CoA mutase; \u003csup\u003e3\u003c/sup\u003e MA, methylmalonic acid; \u003csup\u003e4\u003c/sup\u003e MCA, methylcitric acid; \u003csup\u003e5\u003c/sup\u003e C3, propionylcarnitine; \u003csup\u003e6\u003c/sup\u003e C2, acylcarnitine\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eMMUT-type patients demonstrated significantly higher frequencies of widely fluctuating MA and C3 levels compared to cbl-type patients. Moreover, MMUT-type patients exhibited greater absolute differences in MA, MCA, and C3 between two blood test results compared to cbl-type patients (Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn the case of Case 5, the only cbl-type patient displaying a delay in neurocognitive development, there was a higher frequency of widely fluctuating MA (0.5 per blood test result), MCA (0.33 per blood test result), and C3 (0.17 per blood test result) compared to Case 4, who exhibited completely normal neurocognitive development. Case 4 demonstrated lower frequencies of widely fluctuating MA (0.06 per blood test result), MCA (0 per blood test result), and C3 (0 per blood test result). Notably, Case 5 displayed the highest frequency of widely fluctuating MA, MCA, and C3 among the entire group of cbl-type patients (Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eVariability in biomarker levels between cbl type and MMUT type patients.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ecbl type\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMMUT\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFrequency of widely fluctuating MA #\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e0.14\u0026thinsp;\u0026plusmn;\u0026thinsp;0.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e0.55\u0026thinsp;\u0026plusmn;\u0026thinsp;0.29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAverage MA fluctuation range (\u0026micro;mol/mmol CRE)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e28.6\u0026thinsp;\u0026plusmn;\u0026thinsp;33.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e139.7\u0026thinsp;\u0026plusmn;\u0026thinsp;179.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFrequency of widely fluctuating MCA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e0.07\u0026thinsp;\u0026plusmn;\u0026thinsp;0.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e0.23\u0026thinsp;\u0026plusmn;\u0026thinsp;0.23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.18\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAverage MCA fluctuation range (\u0026micro;mol/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e2.8\u0026thinsp;\u0026plusmn;\u0026thinsp;3.41\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e5.16\u0026thinsp;\u0026plusmn;\u0026thinsp;5.26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFrequency widely fluctuating C3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e0.07\u0026thinsp;\u0026plusmn;\u0026thinsp;0.09\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e0.32\u0026thinsp;\u0026plusmn;\u0026thinsp;0.21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.02\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAverage C3 fluctuation range (\u0026micro;M)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e3.2\u0026thinsp;\u0026plusmn;\u0026thinsp;5.07\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e10.12\u0026thinsp;\u0026plusmn;\u0026thinsp;14.55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eMA: methylmalonic acid; MCA: methylcitric acid; C3: propionylcarnitine\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e# Frequency of wide fluctuation for each biomarker is normalized to the total number of blood tests.\u003c/p\u003e \u003cp\u003eTo understand the relationship between neurocognitive development and toxic organic acids, we examined the correlation between the frequency of widely fluctuating toxic organic acids and the developmental status of MMA patients. We identified a negative correlation between the frequency of widely fluctuating MA and the cognitive PR value, motor PR value, language PR value, social-emotional PR value, and the average PR value across the four domains (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The Pearson correlation coefficients (r) were \u0026minus;\u0026thinsp;0.87, -0.81, -0.89, -0.84, and \u0026minus;\u0026thinsp;0.92, respectively. Notably, we also noted a negative correlation between the frequency of widespread fluctuation in MA and the composite scores in the Bayley III screening test (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eCollective evidence from various studies consistently indicates that MMA is linked with neurological symptoms and damage. The diverse clinical range of neurological symptoms associated with MMA encompass developmental delays, intellectual disabilities, seizures, movement disorders, psychiatric issues, and potentially life-threatening encephalopathy during metabolic crises [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan additionalcitationids=\"CR19\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. The severity and onset of these neurological symptoms often align with the degree of metabolic derangement, highlighting the critical importance of early diagnosis and intervention [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Numerous prior studies consistently identify developmental delays as one of the most prevalent neurological symptoms in MMA [\u003cspan additionalcitationids=\"CR22\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Recent research by Manoli et al.[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e] demonstrated a correlation between higher levels of MA and more pronounced developmental delays and cognitive impairments in pediatric patients with MMA. Similarly, Carrillo-Carrasco et al.[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e] found a positive correlation between elevated MA levels and an increased risk of seizures in affected individuals. Similarly, a study by Baulny et al.[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e] emphasized the potential reversibility of neurological deficits when MA levels are effectively controlled, underlining the imperative nature of timely intervention and metabolic management. These findings underscore the pivotal role of MA as a neurotoxic metabolite and suggest that its accumulation leads to neurological dysfunction [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Therefore, monitoring and managing MA levels through diet modifications, vitamin B12 supplementation, and other therapeutic interventions become important not only to prevent metabolic crises but also to alleviate the severity of neurological symptoms.\u003c/p\u003e \u003cp\u003eMMA manifests as a metabolic disorder with discernible features in brain magnetic resonance imaging (MRI), offering valuable insights into its neurological implications. These distinctive observations include characteristic changes in the basal ganglia, evident as hyperintensities on T2-weighted images [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan additionalcitationids=\"CR27\" citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Consistent with prior research, our study aligns with the documented occurrence of demyelination in the CNS among MMA patients, a phenomenon previously explored in studies such as the work by Manoli et al.[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. In our investigation, we observed that 11 out of 20 MMA patients exhibited demyelination in the CNS.\u003c/p\u003e \u003cp\u003eOur study underscores the presence of developmental delays across multiple domains, encompassing cognitive, motor, language, and social-emotional scales, in individuals with MMA. Specifically, the mean PR values derived from Bayley-III screening tests for all MMA patients reveal significant deficits in cognitive function (PR\u0026thinsp;=\u0026thinsp;17), motor function (PR\u0026thinsp;=\u0026thinsp;30), language function (PR\u0026thinsp;=\u0026thinsp;17), and social-emotional scales (PR\u0026thinsp;=\u0026thinsp;30). Notably, all these PR values fall below the 50th percentile, emphasizing the severity of developmental delay in individuals with MMA. These study results align with prior research findings, consistent with several studies associating MMA with developmental delays [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan additionalcitationids=\"CR22\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. In addition to developmental delays, MMA has shown variable impacts on IQ among affected individuals [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Similarly, in our study, a patient was diagnosed with profound intellectual disability at the age of 11. The average PR value of FSIQ of our MMA patients was 11. These findings reinforce the intricate connection between MMA and neurocognitive deficits, highlighting the importance of early intervention and comprehensive care for affected individuals.\u003c/p\u003e \u003cp\u003eIn our study, brain imaging assessments and neurocognitive function in cbl-type patients surpassed those of MMUT patients. None of the cbl-type patients exhibited brain demyelination, in contrast to 11 out of 14 MMUT patients who displayed this condition. When assessing developmental delay using the Bayley-III screening test, cbl-type patients demonstrated higher PR values across cognitive, motor, language, and social-emotional scales compared to MMUT patients, indicative of more favorable developmental outcomes for cbl-type patients. In the Wechsler Intelligence Scale test, only one MMUT patient exhibited profound intellectual disability, with all others scoring within the normal range. However, the average FSIQ for cbl-type patients was 85 (PR value: 14.5), exceeding the average score for MMUT patients, which was 63 (PR value: 6.8). Our study's results align with established research, notably the study conducted by Colin J. O\u0026rsquo;Shea et al. in 2012. Their research indicated that cognitive deficits were more pronounced among patients with early-onset MMUT, while patients with other subtypes exhibited relatively normal cognitive outcomes. Early-onset MMUT patients demonstrated a mean FSIQ of 71.1\u0026thinsp;\u0026plusmn;\u0026thinsp;14.75, whereas patients with CblA or CblB variants displayed mean FSIQ of 100.7\u0026thinsp;\u0026plusmn;\u0026thinsp;10.95 and 96.6\u0026thinsp;\u0026plusmn;\u0026thinsp;10.92, respectively [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn contrast to MMUT patients, our study unveiled significantly reduced levels of MA, MCA, C3, C3/C2, and lactate in individuals with cbl-type MMA. Prior research has clarified that patients responding to cobalamin typically exhibit lower levels of MA and MCA [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Conversely, patients unresponsive to cobalamin often maintain persistently elevated MA and MCA levels despite treatment attempts [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. These findings may be connected to the observed normal brain MRS patterns and superior neurocognitive outcomes in our cbl-type patients compared to MMUT patients. For instance, Case 5, the sole cbl-type patient classified as developmentally delayed in cognitive function, displayed elevated levels of MA, MCA, and C3/C2 ratios compared to Case 4, who demonstrated normal neurocognitive development, as well as the entire cbl-type group.\u003c/p\u003e \u003cp\u003eMoreover, our study has concentrated on examining the consequences of fluctuations in toxic organic acids, potentially exerting a significant influence on the neurodevelopmental outcomes of MMA patients\u0026mdash;an aspect not previously explored in the current literature. For all MMA patients, we identified a negative correlation between the frequency of widespread fluctuations in MA and the PR value of the developmental status, encompassing cognitive, motor, language, and social-emotional scales.\u003c/p\u003e \u003cp\u003eDifferences between MMUT and cbl-type MMA patients manifest not only in absolute values but also in the frequency of widely fluctuating toxic organic acids. These findings strongly imply a connection between the disparities in brain imaging results and neurocognitive functioning observed between these two groups. As previously mentioned, the more frequent the widely fluctuating MA experienced by an MMA patient, the higher the likelihood of developmental delays. These distinctions are attributed to diverse treatment approaches. MMUT patients primarily rely on dietary control with protein restriction. However, striking the right balance between effectively managing toxic organic acids and meeting the patient's nutritional needs can pose a challenge [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. Moreover, adherence to the dietary regimen may be problematic for some patients, potentially contributing to the instability of toxic organic acid levels. In contrast, hydroxycobalamin has been proven effective in treating cbl-type MMA. All cbl-type MMA patients in our study exhibited well-controlled urinary organic acid levels and relatively low-amplitude fluctuations in toxic metabolites. They also demonstrated a normal brain myelination status and better neurocognitive functioning throughout the follow-up period.\u003c/p\u003e \u003cp\u003eOn the other hand, Case 9, an individual with MMUT, demonstrated the lowest FSIQ among MMUT patients in our study and was diagnosed with profound intellectual disability. Notably, this patient presented elevated serum ammonia levels, surpassing the average levels observed in MMUT patients. This rise in ammonia levels could be linked to the patient's liver transplant, which subsequently unveiled the presence of Dubin-Johnson syndrome. This discovery aligns with findings from various studies [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. These studies have emphasized the detrimental impact of elevated ammonia levels on cognitive function in individuals with MMA.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn our study on MMA, distinctive outcomes were observed in two MMA subtypes. Patients with cbl-type MMA, undergoing treatment with hydroxycobalamin, displayed lower organic acid levels and less frequent fluctuations, leading to better neurocognitive outcomes and improved brain imaging results. In contrast, patients with MMUT MMA encountered greater challenges, with higher organic acid levels, frequent fluctuations, brain demyelination, and poorer neurocognitive development. A negative correlation was identified between the frequency of widely fluctuating MA and the PR value of the developmental status for MMA patients. Overall, our findings underscore the significance of addressing organic acid fluctuations and tailoring treatments for MMA subtypes to improve neurodevelopmental outcomes.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMMA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eMethylmalonic acidemia\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMMUT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003emethylmalonyl-CoA mutase\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ecbl\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ecobalamin\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003emethylmalonic acid\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMCA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003emethylcitric acid,C3,propionylcarnitine\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eC2\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eacylcarnitine\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMRS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003emagnetic resonance spectroscopy\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eTCA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003etricarboxylic acid\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eLT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eliver transplantation\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003estandard deviation\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIQ\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eIntelligence Quotient\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003epercentile rank\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ecomposite score\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eFSIQ\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003efull-scale intelligence quotient\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMRI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003emagnetic resonance imaging\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCNS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ecentral nervous system\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eThe study received approval from the Institutional Review Board at Taipei Veterans General Hospital, Taiwan. Written informed consent was waived, and all data were extracted from the medical charts of the participating patients\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for Publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll participants gave their consent for participation in this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData sharing is not applicable to this article as no new data were created or analyzed in this study.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe\u0026nbsp;authors\u0026nbsp;declare that they\u0026nbsp;have\u0026nbsp;no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis\u0026nbsp;research\u0026nbsp;did not receive specific grants from funding agencies in the public, commercial, or non-profit sectors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll\u0026nbsp;authors\u0026nbsp;made\u0026nbsp;substantial contributions to the conception of the work and the analysis and interpretation of data. I-Chih Ling drafted the manuscript and created tables and figures, while Yann-Jang Chen revised all content. All authors are accountable for their contributions.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors would like to thank all patients and their caregivers, the study centers, and the clinical teams involved in these studies for their participation.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eAlm\u0026aacute;si T, Guey LT, Lukacs C, Csetneki K, Vok\u0026oacute; Z, Zelei T. Systematic literature review and meta-analysis on the epidemiology of methylmalonic acidemia (MMA) with a focus on MMA caused by methylmalonyl-CoA mutase (mut) deficiency. 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E.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMolema F, Haijes HA, Janssen MC, Bosch AM, van Spronsen FJ, Mulder MF, Verhoeven-Duif NM, Jans JJM, van der Ploeg AT, Wagenmakers MA, Rubio-Gozalbo ME, Brouwers MCGJ, de Vries MC, Fuchs S, Langendonk JG, Rizopoulos D, van Hasselt PM, Williams M. High protein prescription in methylmalonic and propionic acidemia patients and its negative association with long-term outcome. Clin Nutr. 2021;40(5):3622\u0026ndash;30. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.clnu.2020.12.027\u003c/span\u003e\u003cspan address=\"10.1016/j.clnu.2020.12.027\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"orphanet-journal-of-rare-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ojrd","sideBox":"Learn more about [Orphanet Journal of Rare Diseases](http://ojrd.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ojrd/default.aspx","title":"Orphanet Journal of Rare Diseases","twitterHandle":"@bmc","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Methylmalonic acidemia, methylmalonic acid, methylcitric acid, mutase, cobalamin, neurodevelopment","lastPublishedDoi":"10.21203/rs.3.rs-3875822/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3875822/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 disorder, that causes multisystem damage by accumulating toxic metabolites. These metabolites, particularly affecting nerve cells, contribute to suboptimal neurodevelopment in MMA patients. While fluctuations in these toxic metabolites are common in MMA patients, their precise impact on neurodevelopment remains unclear.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThis study enrolled 20 MMA patients, comprising 14 methylmalonyl-CoA mutase (MMUT) type and 6 cobalamin (cbl) type. Diverse parameters were assessed, including methylmalonic acid (MA), methylcitric acid (MCA), propionylcarnitine (C3), acylcarnitine (C2), ammonia, glycine, and lactate. Cognitive function was evaluated using the Bayley-III and Wechsler intelligence scale, and brain imaging was conducted through magnetic resonance spectroscopy (MRS). The frequency and extent of fluctuations in toxic organic acids were computed based on blood test results. MMUT-type patients exhibited elevated levels of MA, MCA, C3, C3/C2 ratio and lactate, with more frequent and significant MA and C3 fluctuations than cbl-type patients. Brain imaging revealed central nervous system (CNS) demyelination in MMUT-type patients, while cbl-type patients displayed normal MRS results. Cbl-type patients exhibited significantly better neurocognitive outcomes, with higher scores in cognitive, motor, language, and social-emotional domains. A negative correlation was identified between the frequency of MA fluctuations and the developmental status of MMA patients.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eVariances between MMUT-type and cbl-type MMA patients extend to neurocognitive outcomes, along with differences in frequency and magnitude of toxic organic acid fluctuations. MMA, particularly in MMUT-type patients, is associated with developmental delays and cognitive deficits, contrasting with more favorable outcomes in cbl-type patients due to treatment efficacy. Furthermore, a negative correlation was identified between the frequency of widely fluctuating MA and developmental conditions in MMA patients.\u003c/p\u003e","manuscriptTitle":"Correlation between toxic organic acid fluctuations and neurodevelopment in patients with methylmalonic acidemia","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-03-21 16:00:59","doi":"10.21203/rs.3.rs-3875822/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revision","date":"2024-06-03T03:00:34+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2024-03-18T09:10:10+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-03-17T13:07:01+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-01-22T13:44:25+00:00","index":"","fulltext":""},{"type":"submitted","content":"Orphanet Journal of Rare Diseases","date":"2024-01-19T12:03:17+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"orphanet-journal-of-rare-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ojrd","sideBox":"Learn more about [Orphanet Journal of Rare Diseases](http://ojrd.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ojrd/default.aspx","title":"Orphanet Journal of Rare Diseases","twitterHandle":"@bmc","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"025f2f6d-91d1-4066-83b9-6cf44682ff49","owner":[],"postedDate":"March 21st, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-04-21T15:58:11+00:00","versionOfRecord":{"articleIdentity":"rs-3875822","link":"https://doi.org/10.1186/s13023-025-03687-3","journal":{"identity":"orphanet-journal-of-rare-diseases","isVorOnly":false,"title":"Orphanet Journal of Rare Diseases"},"publishedOn":"2025-04-15 15:56:50","publishedOnDateReadable":"April 15th, 2025"},"versionCreatedAt":"2024-03-21 16:00:59","video":"","vorDoi":"10.1186/s13023-025-03687-3","vorDoiUrl":"https://doi.org/10.1186/s13023-025-03687-3","workflowStages":[]},"version":"v1","identity":"rs-3875822","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3875822","identity":"rs-3875822","version":["v1"]},"buildId":"-HB7Z8yhvgn0wM9Nzuekk","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}