RESUMEN
3-Methylglutaconyl-CoA hydratase deficiency (MGA1) is a defect in leucine catabolism, which causes the accumulation of urinary 3-methylglutaconate, with or without 3-hydroxyisovalerate and 3-methylglutarate. It is an ultra-rare condition, with <30 cases published in the literature. It is unclear whether the clinical features seen in reported patients are caused by the biochemical abnormalities, or whether they simply represent an ascertainment bias in patients that come to clinical attention. We reviewed the collective Australian experience of patients with confirmed MGA1, four of whom were diagnosed when asymptomatic through newborn screening (NBS). When our cohort is considered alongside the broader literature, there is no clear evidence of a specific childhood-onset clinical phenotype associated with this disorder. Some patients have non-specific clinical features (such as autism spectrum disorder [ASD]); however, there are also other family members with ASD in the absence of MGA1, suggesting a multifactorial aetiology. Importantly, all four patients diagnosed through NBS (including three with over 18 years of clinical follow-up) remain asymptomatic in the absence of treatment. Based on the available literature, we suggest that MGA1 represents a biochemical phenotype, with an absence of a childhood clinical phenotype. The burdens of sustained treatment (particularly with intensive dietary leucine restriction) in asymptomatic individuals may be of little benefit, and likely to result in poor compliance. Longer-term follow-up of patients detected via NBS (or biochemical screening of large cohorts of asymptomatic adult individuals) will be required to conclusively prove or disprove the association with adult-onset leukoencephalopathy.
RESUMEN
3-methylglutaconic aciduria type 1 (3-MGA-I) (MIM ID #250950) is an ultra-rare, autosomal recessive organic aciduria, resulting from mutated AUH gene, leading to the deficient 3-methylglutaconyl-CoA hydratase (3-MGH). Only around 40 cases are previously reported, caused by a spectrum of 10 mutations. The clinical spectrum of 3-MGA-I in children is heterogeneous, varying from asymptomatic individuals to mild neurological impairment, speech delay, quadriplegia, dystonia, choreoathetoid movements, severe encephalopathy, psychomotor retardation, basal ganglia involvement. Early dietary treatment with leucine restriction and carnitine supplementation may be effective in improving neurological state in pediatric patients with 3-MGA-I. We presented a girl with 3-MGA-I due to novel AUH gene mutation (homozygous variant c.330 + 5G > A) and confirmed by almost undetectable 3-MGH-enzyme activity, who initially presented with central precocious puberty at an early age of 4.5 years. Precocious puberty might be associated with the 3-MGA-I, as is reported previously in some other metabolic disorders that result in pathologic accumulation of metabolites or toxic brain damage. Therapy with GnRH agonist triptorelin effectively arrested pubertal development.
RESUMEN
3-Methylglutaconic aciduria type I (3-MGA I) is a rare inherited disorder of the leucine metabolism pathway due to mutations in the AUH gene for 3-methylglutaconyl-CoA hydratase enzyme and enzyme deficiency. It has a variable phenotypic presentation from infancy to adulthood. Here, we report a three-year-old female patient with normal development presented with acute encephalopathy and status dystonicus. Neuroimaging was normal. Urine organic acid analysis showed high levels of 3-methylglutaconic acid, 3-hydroxyisovaleric acid. Next-generation sequencing revealed a novel homozygous mutation of variant c.505+1G>C (5' splice site) in intron 4 of the AUH gene that was compatible with the diagnosis of 3-MGA I. The child was asymptomatic on follow-up with a low leucine diet. Clinicians should suspect rare inherited metabolic disorders in acute onset unexplainable neurological symptoms and evaluate with urine organic acid analysis.
RESUMEN
3-Methylglutaconic aciduria is a member of inborn errors of leucine metabolism pathway. 3-Methylglutaconic aciduria type I (MGA1) causes neurological problems which are present during infancy or childhood but the diagnosis may be delayed until adulthood. Here we report a 3years old patient with developmental delay from a relative parent's that his medical evaluations include analyses of urinary organic acid and blood acylcarnitine showed high level of 3-methylglutacoic acid, 3-hydroxyisovaleric acid and increased level of 3-hydroxyisovalerylcarnitine respectively. Further evaluation and genetic tests revealed a novel homozygous mutation of variant c.179del G (p.Gly60Valfs*12) in exon 1 of the AUH gene that was compatible with the diagnosis of MGA1. In segregation analysis of his family, both parents were heterozygous for the respective mutation, confirming obligate parental carrier status and segregation of the mutation.