3-Methylglutaconic Aciduria Type I via the AUH Gene

3-methylglutaconic aciduria type I (MGA1) is a rare disorder resulting from deficiency of 3-methylglutaconyl-CoA hydratase, a mitochondrial enzyme that catalyzes the fifth step of leucine catabolism. Accumulation of toxic leucine metabolites results in mainly a neurologic condition, although clinical severity varies widely. The first two patients with molecular confirmation of 3-methylglutaconyl-CoA hydratase deficiency were children reported to have motor and speech delays in one case and only speech delay in the other (IJlst et al. 2002). Among five other MGA1 patients from four families (Ly et al. 2003), speech and motor delays were the most common findings. Remarkably, one individual in this cohort had deficiency of 3-methylglutaconyl-CoA hydratase resulting from a homozygous null mutation in the AUH gene, but was completely asymptomatic at the age of 2 years. Another confirmed patient presented with febrile seizures from the age of 1 year, but had no speech or motor delay (Illsinger et al. 2004). An adult-onset patient with progressive forgetfulness, unsteady gait, hyperreflexia in all four limbs, cerebellar ataxia, dysarthria, and urinary incontinence has also been reported (Eriguchi et al. 2006). Gait disturbance and incontinence presented when the patient was in her 50’s. She was also found to have impaired cognitive function. Wortmann et al. reported optic atrophy in one of his patients who was genetically confirmed to have 3-MGS-uria Type 1 (Wortmann et al. 2010). Mercimek-Mahmutoglu reported two siblings with phenotypic heterogeneity (2011). The older sister was diagnosed at 10 years old with a learning disability and attention deficit, while the younger brother had febrile seizures early in childhood and was diagnosed with an expressive language delay and severe delay in speech sound development at 3 years of age.

3-methylglutaconic aciduria type I is an autosomal recessive disorder caused by pathogenic variants in the AUH gene. This gene is located on chr 9q22 and encodes the 3-methylglutaconyl-CoA hydratase protein. Based on the small number of reported cases, null mutations that abolish enzyme activity are the most common form of pathogenic variants (Human Gene Mutation Database). Complete absence of 3-methylglutaconyl-CoA hydratase may be compatible with normal development (Ly et al. 2003; Wortmann et al. 2012).

At this time, the sensitivity of this test is difficult to estimate due to the low number of cases reported in the literature. Analytical sensitivity may be high as the majority of reported causative variants are detectable by sequencing (Human Gene Mutation Database).

To date, only a single large deletion has been reported in the AUH gene (Mercimek-Mahmutoglu et al. 2011).

This test provides full coverage of all coding exons of the AUH gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).