グルタル酸血症1型

Glutaric aciduria type 1 (GA1) is an autosomal recessive neurometabolic disorder caused by pathogenic variants in the GCDH gene, typically presenting in infancy with dystonia following encephalopathic crisis. Late- and adult-onset forms are rare and may manifest with nonspecific neurological features. We describe a 43-year-old woman with levodopa-responsive parkinsonism and presynaptic dopaminergic dysfunction. Genetic analysis revealed compound heterozygous GCDH variants, consistent with GA1. One of the reported variants (c.1178G > A, p. Gly393Glu) is extremely rare and has never been associated with adult-diagnosed GA1 with atypical features. Furthermore, this is the first report of GA1 patient presenting with parkinsonism in whom we demonstrated presynaptic dopaminergic dysfunction, along with a favorable response to levodopa.

Glutaric acidemia type 1 (GA I) is caused by deficient activity of glutaryl-CoA dehydrogenase, leading to predominant accumulation of glutaric acid (GA) in the brain. GA I patients present progressive neurological deterioration whose pathophysiology is only partially elucidated. We investigated whether intracerebral GA administration, alone or combined with quinolinic acid (QA), a pro-inflammatory intermediate of the kynurenine pathway, could alter the expression of genes associated with inflammatory signaling, endoplasmic reticulum (ER) stress, and neurotrophic support in cerebral cortex of wild-type (WT) and Gcdh-/- mice. We also tested the effects of L-carnitine (Carn) on these parameters. GA alone increased mRNA levels of the genes encoding NF-κB (NFKB1), COX-2 (PTGS2), iNOS (NOS2), and TLR2 (TLR2) in both genotypes, while reducing those of IL-10 (IL10) and VEGF-A (VEGFA) only in Gcdh-/- mice. Combined QA + GA treatment produced a larger response, including increased TNF-α (TNF), IL-1β (IL1B), IL-6 (IL6), NLRP3 (NLRP3), CHOP (DDIT3) and PERK (EIF2AK3) mRNA levels in the Gcdh-/- mice, besides reducing IκBα (NFKBIA), IL-10 (IL10) and BDNF (BDNF) expression in both genotypes, and VEGF-A (VEGFA) in the Gcdh-/- mice. We also found that lysine (Lys) and QA treatment elevated TNF-α, IL-1β, and IL-6 protein levels in Gcdh-/- mice. Carn prevented or attenuated most transcriptional alterations induced by QA + GA and reduced cytokine protein elevations elicited by Lys + QA administration. These findings indicate that Carn modulates acute molecular responses related to inflammation, ER stress, and neurotrophic factors in the cerebral cortex of the GAI mouse model.

Introduction - Glutaric aciduria (or glutaric acidemia) type 1 (GA1) is a rare autosomal recessive neurometabolic disorder caused by mutations in the GCDH gene that results in a deficiency of the glutaryl-CoA dehydrogenase enzyme. It plays a vital role in the degradation of L-lysine, L-hydroxylysine, and L-tryptophan. Accumulating toxic metabolites (namely glutaric acid/GA and 3-hydroxyglutaric acid/3-OH-GA) leads to progressive neurological deterioration. GA1 is one of the limited neurometabolic disorders, where we can stop the progression of the disease with a diet and aggressive emergency treatment during excessive catabolism. If undiagnosed through newborn screening, symptoms start to present in childhood between 3-36 months, with neurological symptoms related to sepsis or fever. However, 10-20% of cases start insidiously.Case report - We report the case of a 53-year-old male with GA1, who presented progressive spastic tetraparesis, dysarthria, and focal seizures. His initial symptoms, misattributed to cerebral palsy and previous ischemic strokes, had gradually worsened in recent years, leaving him bedridden. Specific metabolic laboratory testing and radiological evaluations revealed the characteristic features of the disease. Genetic testing identified a known pathogenic homozygous mutation in the GCDH gene, which confirms the diagnosis of GA1. Low-lysine diet and supplementation with carnitine and riboflavin were started. After the initiation of treatment, no further progression was observable.Conclusion - This case underscores the importance of considering hereditary neurometabolic disorders like GA1 - taking into account the available metabolic screening - not only in pediatric patients but also in adult patients with progressive neurological decline. This case contributes to the limited literature available on GA1 cases in adults and highlights the need for early detection strategies to avoid irreversible neurological damage.

A 15-year-old boy with a severe phenotype of Glutaric Acidemia Type 1 (GA-1) presented for planned major thoracolumbar scoliosis correction under general anesthesia. Propofol is relatively contraindicated in patients with GA-1 according to latest guidance because of the risk of propofol infusion syndrome. Because of previous use of propofol in the patient when admitted to intensive care and the potential benefits as a sleep agent we decided to use propofol for his surgery and postoperative sedation. We report the successful use of propofol for general anesthesia and postoperative sedation on intensive care.

AIM: Improved newborn screening and critical care allow more individuals with inherited metabolic disorders (IMDs) to survive to adulthood and reach reproductive age. However, given the rarity of these conditions, evidence on pregnancy management is limited and clinical practice is largely informed by case reports and expert opinions. This study aims to evaluate pregnancy outcomes and metabolic management strategies in women with IMDs, addressing a critical gap in evidence-based care for this unique and growing patient population. METHODS: This retrospective, single-center study included female patients aged 15-49 years with genetically confirmed IMDs who initiated treatment before conception and gave birth. RESULTS: Seven pregnancies in six women were included. The median maternal age at conception was 29.0 years and the median gestational age of infants was 38.4 weeks. In two patients with glutaric aciduria type I, individualized peripartum management protocols were successfully implemented. Enzyme replacement therapy was continued without complications throughout pregnancy in the woman with Gaucher disease. A previously unreported congenital heart defect was detected in the infant of a mother with tyrosinemia type II. Notably, one patient with 3-Hydroxy-3-Methylglutaryl-CoA Lyase Deficiency, whose first pregnancy ended in a healthy birth despite peripartum metabolic instability, experienced fatal metabolic decompensation following a miscarriage in her second pregnancy. CONCLUSIONS: These findings indicate that while successful pregnancies are possible, severe maternal complications and fetal anomalies can still occur. These observations highlight the urgent need for structured adult care pathways and disease-specific pregnancy management strategies as this population continues to grow.