Phenotypic and Genotypic Characteristics of Adult-Onset Glutaric Aciduria Type 1: Report of Two Cases and a Literature Review

Introduction

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 remain limited.

Methods

We hereby reported two new cases of adult-onset GA-1 and systematically summarized reported studies to investigate its genotypic and phenotypic features.

Results

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 biallelic missense variants in GCDH in both patients (Patient 1: c.383G> A, c.937C> T; Patient 2: 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 five of seven cases. One of them also had HHcy. All adult-onset GA-1 cases were high excretors. All GCDH variants are located in nonactive binding regions.

Conclusion

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 genotype–phenotype correlation was found.