グルタル酸血症1型

OBJECTIVES: Organic acidemias (OADs) are inherited disorders of branched chain amino acid catabolism, typically presenting in neonatal or infantile period, with encephalopathy, metabolic acidosis, and seizures. While an early clinical and biochemical recognition is pivotal for immediate survival, molecular characterization is essential for accurate diagnosis, genetic counseling, and future preventive strategies in families. METHODS: A study was performed on 394 patients/families suspected of OADs between year 2010 to 2025. Molecular studies were performed in biochemically diagnosed cases, using targeted Sanger sequencing, or next-generation sequencing. Cases were classified according to age and type of clinical presentations: acute, sub-acute/chronic, or presymptomatic/ newborn screening. RESULTS: A molecular confirmation was achieved in 293 patients from 283 families (95.4% diagnostic yield). Glutaric acidemia type 1 (100 cases) and methylmalonic acidemia (98 cases) were most common disorders identified. One-fourth of variants were novel (61/221, 27.6%) across 16 genes. Homozygosity was observed in 71.5% families. Apart from previously described recurrent variants in GCDH c.1204C>T, MMACHC c.394C>T and BTD c.38_44delGCGCTGinsTCC identified in index study, BCKDHB c.1065delT variant was noted to be geographically clustered in north-western India. High number of variants, including unique novel variants underscores the distinct genetic landscape of the Indian population. The prevalence of homozygous variants, many in the absence of consanguinity, suggests the impact of endogamy. CONCLUSIONS: Molecular characterization of OADs in India provides a critical framework for future studies in addition to clinical care advancements. This study adds 61 new variants to the global scientific record, facilitating improved prenatal diagnosis and early intervention strategies.

Glutaric Acidemia type I is an inborn error of metabolism that impairs the metabolism of lysine, hydroxylysine, and tryptophan, leading to neurologic and, as more recently described, acute and chronic kidney damage. This mini review explores the available literature regarding renal impairment in GA-1 and highlights the possible mechanisms involved. Most case reports regarding patients presenting acute kidney dysfunction indicate the tubules as the main site of impairment, which was also found in the animal model for this disease, especially under metabolic decompensation. In addition to that, a mild progressive decline in glomerular filtration rates has been found in GA-1 patients, independently of treatment quality and neurologic outcomes. Taken together, such findings reveal the importance of further investigation on the association between GA-1 and kidney function, encompassing the need for adequate therapeutic approaches and biomarkers that target these alterations.

Glutaric aciduria type 1 (GA1) is a rare neurometabolic disorder caused by glutaryl-CoA dehydrogenase (GCDH) deficiency, leading to the accumulation of neurotoxic metabolites that can cause both acute encephalopathic crises and progressive, insidious brain injury. Current management primarily relies on a protein-restricted diet, which remains therapeutically insufficient and burdensome for patients, highlighting the need for disease-modifying therapies. In this study, we established a novel GA1 mouse model using CRISPR/Cas9 technology and evaluated the preclinical efficacy of systemic recombinant adeno-associated virus (rAAV)-mediated gene therapy. Under standard dietary conditions without high-lysine challenge, our GA1 model exhibited sustained cerebral and hepatic glutaric acid (GA) accumulation and distinct chronic vacuolation in the hippocampus and cerebellum, mirroring the insidious-onset GA1 phenotype. Five-week-old mice received a single intravenous injection of rAAV-hGCDH using either rAAV2/8 or rAAV2/9 serotypes. Systemic rAAV-mediated gene therapy significantly reduced GA accumulation and attenuated chronic neuropathological changes in this GA1 mouse model for both serotypes. Our findings support the hypothesis that peripheral metabolic correction may play an important role in preventing the chronic neuropathological changes associated with GCDH deficiency. However, further investigation using tissue-specific expression systems is required to definitively delineate the relative contributions of hepatic versus central GCDH restoration to the observed neuroprotection.

BACKGROUND: Chorea is a hyperkinetic movement disorder with a broad differential diagnosis, ranging from acute symptomatic causes to slowly progressive neurogenetic diseases. While Huntington's disease (HD) remains the most prevalent hereditary form, numerous other genetic disorders may mimic its clinical presentation. A major diagnostic challenge arises in patients with a seemingly negative family history, which can obscure the suspicion of a genetic etiology. In patients with sporadic chorea, the potential contribution of genetic testing to the diagnostic process has not yet been systematically analyzed. METHODS: We conducted a retrospective analysis of 81 patients presenting with chorea as a prominent symptom at the movement disorders outpatient clinic between 2013 and 2024. Clinical data, family history, laboratory results, imaging, and genetic analyses were evaluated. Genetic testing included a chorea-related gene panel and, if unremarkable, whole-exome or whole-genome sequencing. RESULTS: Out of 81 patients, 44 presented with slowly progressive chorea and unremarkable family history of HD or chorea-related syndromes. After exclusion of secondary etiologies (n = 8), 36 patients remained, of whom 30 (83, 33%) received a confirmed genetic diagnosis. HD was the most frequent diagnosis (n = 20), followed by rare genetic disorders such as Spinocerebellar Ataxia Type 17 (n = 2), Wilson's Disease (n = 2), Ataxia with Oculomotor Apraxia Type 2 (n = 1), C9orf72-related Neurodegeneration (n = 1), Choreoacanthocytosis (n = 1), KMT2B-related Dystonia (n = 1), ERCC4-related Neurodegeneration (n = 1), and Glutaric Acidemia Type 1 (n = 1). DISCUSSION: These findings support the systematic use of genetic testing-even in apparently sporadic cases-and suggest that the prevalence of hereditary choreatic disorders, may be significantly underestimated.