IllnessIsolated methylmalon acidemia, differential diagnosis

NGS +

Methylmalonacidemia represents a group of inherited disorders in which proteins and lipids are not properly broken down. Methylmalonacidemia regularly begins in early infancy and varies from mild to life-threatening. Affected infants may experience vomiting, dehydration, hypotension, developmental delays, lethargy, hepatomegaly and failure to thrive. Long-term complications include mental retardation, movement disorders, chronic kidney disease and pancreatitis, in addition to metabolic acidosis, which is always possible. If left untreated, the disorder can also lead to coma and death. The main causes include variants in the guideline genes MMUT, MMAA, MMAB, MMADHC (and MCEE). Approximately 60% of patients have mutations in the MMUT gene with varying degrees of disease severity. Because variants in the aforementioned genes exclusively cause elevated levels of methylmalonic acid, this disorder is sometimes referred to as „isolated“ in order to distinguish it from methylmalonic acidemia with homocystinuria. The disease is inherited in an autosomal recessive manner. Because the molecular genetic diagnostic yield rarely exceeds 97%, a negative DNA test result may not exclude the clinical diagnosis.

Reference: https://www.ncbi.nlm.nih.gov/books/NBK1231/

• Alias: Isolated methylmalonic aciduria/acidemia
• Alias: Methylmalonazidurie ohne Homocystinurie
• Allelic: Homocystinuria, cblD type, variant 1 (MMADHC)
• Allelic: Proteinuria, chronic benign (CUBN)
• Biotinidase deficiency (BTD)
• Combined malonic + methylmalonic aciduria (ACSF3)
• Combined methylmalonic acidemia + homocystinuria [GeneReviews; AdoCbl + MeCbl deficiency} (THAP11)
• Combined methylmalonic acidemia + homocystinuria [GeneReviews; AdoCbl + MeCbl deficiency} (ZNF143)
• Holocarboxylase synthetase deficiency (HLCS)
• Imerslund-Grasbeck syndrome 1 (CUBN)
• Imerslund-Grasbeck syndrome 2 (AMN)
• Intellectual developmental disorder, AR 69 (ZBTB11)
• Malonyl-CoA decarboxylase deficiency (MLYCD)
• Mental retardation, XL 3 [methylmalonic acidemia + homocysteinemia, cblX type] (HCFC1)
• Methylmalonic aciduria + homocystinuria, cblC type (MMACHC)
• Methylmalonic aciduria + homocystinuria, cblC type, digenic (PRDX1)
• Methylmalonic aciduria + homocystinuria, cblD type (MMADHC)
• Methylmalonic aciduria + homocystinuria, cblF type (LMBRD1)
• Methylmalonic aciduria + homocystinuria, cblJ type (ABCD4)
• Methylmalonic aciduria, cblD type, variant 2 (MMADHC)
• Methylmalonic aciduria, mut(0) type (MMUT)
• Methylmalonic aciduria, transient, due to transcobalamin receptor defect (CD320)
• Methylmalonic aciduria, vitamin B12-responsive, cblA type (MMAA)
• Methylmalonic aciduria, vitamin B12-responsive, cblB type (MMAB)
• Methylmalonyl-CoA epimerase deficiency (MCEE)
• Mitochondrial DNA depletion syndrome 5 [encephalomyopathic with/-out methylmal. aciduria] (SUCLA2)
• Mitochondrial DNA depletion syndrome 9 [encephalomyopathic with methylmalonic aciduria] (SUCLG1)
• Mitochondrial encephalomyopathy with elevated methylmalonic acid (SUCLG2)
• Propionicacidemia (PCCA, PCCB)
• Transcobalamin II deficiency (TCN2)