Differential Diagnosis
3-Methylglutaconic Aciduria Increased urinary excretion of the branched-chain organic acid 3-methylglutaconate (3-MGC) is a relatively common finding in children investigated for suspected inborn errors of metabolism . 3-MGC is an intermediate of leucine degradation and the mevalonate shunt pathway that links sterol synthesis with mitochondrial acetyl-CoA metabolism. A classification of inborn errors of metabolism with 3-methylglutaconic aciduria (3-MGCA) as the discriminative feature was published by and . Clinical features and biochemical findings of syndromes associated with 3-MGCA vary. Tissues with higher requirements for oxidative metabolism, such as the central nervous system and cardiac and skeletal muscle, are predominantly affected. The only disorder in which the exact source of 3-MGC is known (a block of leucine degradation) is AUH defect, the rarest 3-MGCA, caused by primary deficiency of the mitochondrial enzyme 3-methylglutaconyl-CoA hydratase (3-MGCH). Table 2. Inborn Errors of Metabolism Associated with 3-Methylglutaconic Aciduria
3-MGCA | Gene | MOI | Disorder | Key Clinical Characteristics in Addition to 3-MGCA1 |
|---|
AGK | AR | Sengers syndrome(See Mitochondrial DNA Maintenance Defects Overview.) | Cataracts; cardiomyopathy (DD) | — |
AUH | AR | AUH defect(OMIM 250950) | Nonspecific speech language delay w/o metabolic derangement in some individuals w/hypoglycemia metabolic acidosis in others; Failure to thrive, ID, DD common; Microcephaly progressive neurologic impairment w/spastic quadriplegia, seizures, dystonia reported3 | — |
CLPB | AR | CLPB deficiency | Cataracts; central hypopnea; DD ID; movement disorder; neutropenia (epilepsy) | — |
DNAJC19 | AR | DNAJC19 defect (DCMA syndrome)(OMIM 610198) | Cardiomyopathy; DD ID; growth restriction; cerebellar ataxia; may be assoc w/optic atrophy; Seen in Dariusleut Hutterite population of Canada.4 | — |
HTRA2 | AR | MGCA8(OMIM 617248) | Cataracts; central hypopnea; DD ID; epilepsy; movement disorder; neutropenia OPA3 | AR |
SERAC1 | AR | SERAC1 defect(MEGDEL syndrome) | DD ID; deafness; movement disorder (epilepsy optic atrophy) | — |
TAFAZZIN (TAZ) | XL | TAFAZZIN defect(Barth syndrome) | Cardiomyopathy;5 skeletal myopathy; DD; growth restriction; neutropenia | — |
TIMM50 | AR | MGCA9(OMIM 617698) | DD ID; epilepsy | — |
TMEM70 | AR | TMEM70 defect | Cardiomyopathy; DD ID Occasional feature | POLG |
SUCLA2 | AR | SUCLA2 mtDNA depletion syndrome, encephalomyopathic form w/methylmalonic aciduria | Hypotonia; epilepsy; muscular atrophy; movement disorder; growth retardation | — |
SUCLG1 | AR | SUCLG1 mtDNA depletion syndrome, encephalomyopathic form w/methylm... | — | — |
Source: GeneReviews — "Costeff Syndrome"
