Phenotypic and genotypic characteristics of adult-onset glutaric aciduria type 1: report of two cases and a literature review

Abstract

Abstract Glutaric aciduria type 1 (GA-1) is an autosomal recessive inherited disorder caused by GCDH variations. GA-1 is a rare disease that typically manifests in infancy and early childhood, with adult-onset cases being even rarer. Currently, data on the clinical and genetic characteristics of adult-onset GA-1 remains limited. We hereby reported two new cases of adult-onset GA-1 and systematically summarized reported studies to investigate its genotypic and phenotypic features. Patient 1 presented with seizures as the onset symptom. Patient 2 exhibited recurrent stroke-like episodes. Brain magnetic resonance imaging showed subependymal lesions. Urine organic acid analyses were performed since both patients had hyperhomocysteinemia (HHcy) and found significantly elevated glutaric acid and 3-hydroxyglutaric acid. Genetic analysis further identified four missense variants in the GCDH gene (c.937C > T, c.383G > A, c.533G > A, c.1205G > A). A literature review found seven cases and 12 variants in adult-onset GA-1. Most of them showed nonspecific neurological manifestations. The most common symptoms were cognitive impairment and headache. Subependymal lesions have been reported in 5/7 cases. One of them also had HHcy. All adult-onset GA-1 cases were high excretors. A common feature of the 12 variants was that they spared the binding site of flavin adenine dinucleotide or 4-nitrobutyryl-CoA. This study characterized the phenotype of adult-onset GA-1 emphasizing subependymal lesions and the coexistence of HHcy. The latter might suggest the influence of environmental factors on the age of onset. No clear phenotype-genotype correlation was found. However, the variants in adult-onset GA-1 mainly affect the non-active binding regions.