Methylmalonate semialdehyde dehydrogenase deficiency (MMSDD; MIM 614105) is a rare autosomal recessive defect of valine and pyrimidine catabolism. Four prior MMSDD cases are published. We present a fifth case, along with functional and metabolomic analysis. The patient, born to non-consanguineous parents of East African origin, was admitted at two weeks of age for failure to thrive. She was nondysmorphic, had a normal brain MRI, and showed mild hypotonia. Gastroesophageal reflux occurred with feeding. Urine organic acid assessment identified excess 3-hydroxyisobutyrate and 3-hydroxypropionate, while urine amino acid analysis identified elevated concentrations of β-aminoisobutyrate and β-alanine. Plasma amino acids showed an elevated concentration of β-aminoisobutyrate with undetectable β-alanine. ALDH6A1 gene sequencing identified a homozygous variant of uncertain significance, c.1261C > T (p.Pro421Ser). Management with valine restriction led to reduced concentration of abnormal analytes in blood and urine, improved growth, and reduced gastroesophageal reflux. Western blotting of patient fibroblast extracts demonstrated a large reduction of methylmalonate semialdehyde dehydrogenase (MMSD) protein. Patient cells displayed compromised mitochondrial function with increased superoxide production, reduced oxygen consumption, and reduced ATP production. Metabolomic profiles from patient fibroblasts demonstrated over-representation of fatty acids and fatty acylcarnitines, presumably due to methylmalonate semialdehyde shunting to β-alanine and subsequently to malonyl-CoA with ensuing increase of fatty acid synthesis. Previously reported cases of MMSDD have shown variable clinical presentation. Our case continues the trend as clinical phenotypes diverge from prior cases. Recognition of mitochondrial dysfunction and novel metabolites in this patient provide the opportunity to assess future patients for secondary changes that may influence clinical outcome.

丙二酸甲酯半醛脱氢酶缺乏症（MMSDD; MIM 614105）是缬氨酸和嘧啶分解代谢的罕见常染色体隐性缺陷。公开了四个先前的MMSDD案例。我们提出第五种情况，以及功能和代谢组学分析。该患者出生于东非血缘非亲生父母，两周龄因for壮未能入院。她没有畸形，脑部MRI正常，表现为轻度肌张力低下。进食时发生胃食管反流。尿液有机酸评估确定了过量的3-羟基异丁酸酯和3-羟基丙酸酯，而尿液氨基酸分析鉴定了升高的β-氨基异丁酸酯和β-丙氨酸浓度。血浆氨基酸显示β-氨基异丁酸酯浓度升高，而β-丙氨酸无法检测到。ALDH6A1基因测序鉴定出具有不确定意义的纯合变体，c.1261C> T（p.Pro421Ser）。限制使用缬氨酸可减少血液和尿液中异常分析物的浓度，改善生长，并减少胃食管反流。患者成纤维细胞提取物的蛋白质印迹显示丙二酸甲酯半醛脱氢酶（MMSD）蛋白大大降低。患者细胞显示线粒体功能受损，超氧化物生成增加，氧气消耗减少，ATP生成减少。患者成纤维细胞的代谢组学特征表明脂肪酸和脂肪酰基肉碱的含量过高，这可能是由于丙二酸甲酯的半醛分流至β-丙氨酸，随后是丙二酰辅酶A与随之而来的脂肪酸合成增加所致。先前报道的MMSDD病例显示出可变的临床表现。由于临床表型与以前的病例不同，我们的病例继续保持这种趋势。对该患者线粒体功能障碍和新代谢产物的认识为评估未来患者的可能影响临床结果的继发变化提供了机会。