Mild and late onset forms of type I 3-methylglutaconic aciduria presenting as isolated cerebellar ataxia without leukodystrophy: case reports and phenotype expansion.

INTRODUCTION: Type I 3-Methylglutaconic Aciduria (MGCA1) is a metabolic disorder inherited in an autosomal recessive manner. It is caused by a deficiency in the 3-methylglutaconyl-CoA hydratase encoded by the AUH gene, leading to abnormal excretion of urinary organic acids. While the pediatric phenotype encompasses a spectrum ranging from isolated developmental delay to severe forms with leukodystrophy, developmental delay, spastic tetraplegia and movement disorders, the adult phenotype corresponds to a leukodystrophy with spastic ataxia, progressive dementia, and optic neuropathy. Due to its rarity, MGCA1 is most likely underdiagnosed, or diagnosed with an important delay, leading to inadequate care or genetic counselling. A better understanding of the disease's phenotype is thus required to facilitate its clinical and genetic diagnosis, in turn favoring clinical care and genetic counselling.

METHODS AND RESULTS: We report two new MGCA1 patients, including an adult male patient with pure, late-onset, and progressive cerebellar ataxia, without optic neuropathy or leukodystrophy. A young female patient case is also reported with moderate developmental delay and leukodystrophy, offering 14-year follow-up data under carnitine supplementation. In both cases, urinary organic acid chromatography was critical to the diagnostic process by demonstrating abnormal and specific urinary organic acids excretion.

DISCUSSION AND CONCLUSION: The description of new, mild and/or late-onset phenotypes expands the clinical and radiological spectrum of MGCA1. Our results show that late-onset MGCA1 patients may present with pure cerebellar ataxia without leukodystrophy, contrasting with current knowledge. These results support the fact that AUH should always be sequenced in patients with pure cerebellar ataxia, but also that urinary organic acid chromatography being a simple, rapid, and cost-effective test, should be performed as a first-tier analysis in all patients with unresolved neurological symptoms. The importance of identifying MGCA1 patients is reinforced by the possibility of implementing a low-risk and possibly effective therapy with low-protein diet and L-carnitine supplementation.