Glutaric Acidemia Type 1: Diagnosis, Clinical features, and Outcome in a Portuguese Cohort

Patrícia Lipari Pinto; Beatriz Câmara; Cristina Florindo; Rita Santos Loureiro; Inês Jardim; Carmen Sousa; Laura Vilarinho; Patrícia Janeiro; Isabel Tavares de Almeida; Ana Gaspar

doi:10.2174/1871530323666230914122946

Glutaric Acidemia Type 1: Diagnosis, Clinical features, and Outcome in a Portuguese Cohort

Endocr Metab Immune Disord Drug Targets. 2023 Sep 14. doi: 10.2174/1871530323666230914122946. Online ahead of print.

Affiliations

¹ Hereditary Metabolic Disease Reference Center, Metabolic Unit, Pediatric Department, Santa Maria's Hospital-Lisbon North University Hospital Center, EPE, Pediatric University Clinic, Faculty of Medicine, University of Lisbon, Lisbon, Portugal.
² Laboratory of Metabolism and Genetics, Department of Pharmaceutical Sciences and Medicines, Faculty of Pharmacy, University of Lisbon, Lisbon, Portugal.
³ Hereditary Metabolic Diseases Reference Center, Dietetic and Nutrition Department, Santa Maria's Hospital-Lisbon North University Hospital Center, EPE, Pediatric University Clinic, Faculty of Medicine, University of Lisbon, Lisbon, Portugal.
⁴ Newborn Screening, Metabolism and Genetics Unit, Human Genetics Department, National Institute of Health Dr Ricardo Jorge, Porto, Portugal.

PMID: 37711119
DOI: 10.2174/1871530323666230914122946

Abstract

Introduction: Glutaric acidemia type 1 (GA1) is a rare autosomal recessive disorder characterized by a deficiency of glutaryl-CoA dehydrogenase, resulting in the accumulation of glutaric acid (GA), 3-hydroxyglutaric acid, and glutarylcarnitine, especially in the brain. GA1-affected children are clinically characterized by macrocephaly. Neurological abnormalities usually appear between 6 and 18 months of age, often triggered by a catabolic event. On the other hand, several biochemically affected individuals may remain asymptomatic or experience an insidious onset of mild neurological abnormalities.

Methods: Retrospective study of GA1 patients followed at a Portuguese Hereditary Metabolic Disease Center, to characterize the phenotypic and genotypic variations associated with GA1. Therefore, we analyzed the clinical, neuroradiological, biochemical, and genetic information from 14 patients.

Results: 14 patients (four months-27 years old) were identified in the last 26 years, 9 were male, 1 was from a consanguineous family. 11 were diagnosed by newborn screening (NBS), and 3 identified following clinical symptoms (later diagnosed, LD). There were 3 phenotypic presentations: 6 asymptomatic, 3 with a motor disability after encephalopathic crisis (EC), and 5 with insidious onset. Acute EC occurred in 1/3 of the LD patients and in 2/11 NBS-identified patients. About urinary GA concentrations: 5 were low excretors (LE), 9 were high excretors (HE). All LE showed symptoms, and 2 had EC. Concerning HE, 3 showed symptoms and 1 had EC. GCDH analysis showed: 6 compound heterozygotes and 8 homozygotes. most frequent variant was c.1204C>T (p.R402W). All of them received appropriate therapy from the time of diagnosis, with a mean age of 23.3 months in LD patients and 13.3 days in NBS-identified patients.

Conclusion: The outcomes were different between the two groups: all the LD patients presented motor dysfunction however in the NBS-identified patients only 5 developed this symptom. Patients identified by NBS had better outcomes showing that NBS enables an early diagnosis, and treatment, and consequently improves the clinical outcomes for these patients. No correlation was observed with clinical phenotype between LE and HE, as both groups can suffer the most severe neurological manifestations. These conclusions are in agreement with previous cohorts described in the literature.

Keywords: Glutaric acidemia type 1; encephalopathic crisis; glutaric acid; low/high excretors; newborn screening.