Type I glutaric aciduria, part 1: Natural history of 77 patients

Abstract

Type I glutaric aciduria (GA1) results from mitochondrial matrix flavoprotein glutaryl-CoA dehydrogenase deficiency and is a cause of acute striatal necrosis in infancy. We present detailed clinical, neuroradiologic, molecular, biochemical, and functional data on 77 patients with GA1 representative of a 14-year clinical experience. Microencephalic macrocephaly at birth is the earliest sign of GA1 and is associated with stretched bridging veins that can be a cause of subdural hematoma and acute retinal hemorrhage. Acute striatal necrosis during infancy is the principal cause of morbidity and mortality and leads to chronic oromotor, gastroesophageal, skeletal, and respiratory complications of dystonia. Injury to the putamen is heralded by abrupt-onset behavioral arrest. Tissue degeneration is stroke-like in pace, radiologic appearance, and irreversibility. It is uniformly symmetric, regionally selective, confined to children under 18 months of age, and occurs almost always during an infectious illness. Our knowledge of disease mechanisms, though incomplete, is sufficient to allow a rational approach to management of encephalopathic crises. Screening of asymptomatic newborns with GA1 followed by thoughtful prospective care reduces the incidence of radiologically and clinically evident basal ganglia injury from approximately 90% to 35%. Uninjured children have good developmental outcomes and thrive within Amish and non-Amish communities.

Rare Late-Onset Presentation of Glutaric Aciduria Type I in a 16-Year-Old Woman with a Novel GCDH Mutation

“…Glutaric aciduria type I (GA-I, OMIM 231670) is a rare but treatable autosomal recessive inborn error of lysine, hydroxylysine, and tryptophan metabolism caused by mutations in the glutaryl-CoA dehydrogenase gene (GCDH) resulting in GCDH deficiency (Goodman et al 1975;Koeller et al 1995Koeller et al , 2004Strauss et al 2003). GCDH is a homotetramer mitochondrial matrix enzyme that catalyzes the oxidative decarboxylation of glutaryl-CoA to crotonyl-CoA and carbon dioxide (Strauss et al 2003).…”

“…GCDH is a homotetramer mitochondrial matrix enzyme that catalyzes the oxidative decarboxylation of glutaryl-CoA to crotonyl-CoA and carbon dioxide (Strauss et al 2003). Clinical presentation with acute encephalopathic crises in infancy or early childhood (typically between 6 and 18 months) often triggered by febrile illness resulting in striatal degeneration and severe dystonic-dyskinetic movement disorder is common, but insidious-onset, late-onset, or slowly progressive cases have also been described (Strauss et al 2003;K€ olker et al 2011;Kyllerman et al 1994).…”

“…GCDH is a homotetramer mitochondrial matrix enzyme that catalyzes the oxidative decarboxylation of glutaryl-CoA to crotonyl-CoA and carbon dioxide (Strauss et al 2003). Clinical presentation with acute encephalopathic crises in infancy or early childhood (typically between 6 and 18 months) often triggered by febrile illness resulting in striatal degeneration and severe dystonic-dyskinetic movement disorder is common, but insidious-onset, late-onset, or slowly progressive cases have also been described (Strauss et al 2003;K€ olker et al 2011;Kyllerman et al 1994). In presymptomatic patients, macrocephaly at birth or developing in the first months of life, wide Sylvian fissures and expansion of anterior frontotemporal CSF spaces are characteristic findings (Strauss et al 2003;K€ olker et al 2011;Kyllerman et al 1994;Gitiaux et al 2008;Oguz et al 2005).…”

“…Thus increased urinary concentrations of 3OHGA is the most sensitive and specific biochemical marker of GA-I (Al-Dirbashi et al 2011). The diagnosis is confirmed by GCDH enzyme assay in fibroblasts or leucocytes and molecular genetic analysis (Strauss et al 2003;K€ olker et al 2011). Prenatal or newborn screening and presymptomatic evaluation of asymptomatic siblings are essential for early diagnosis and treatment and prevention of striatal necrosis and permanent neurological sequelae (Strauss et al 2003;K€ olker et al 2011).…”

“…The diagnosis is confirmed by GCDH enzyme assay in fibroblasts or leucocytes and molecular genetic analysis (Strauss et al 2003;K€ olker et al 2011). Prenatal or newborn screening and presymptomatic evaluation of asymptomatic siblings are essential for early diagnosis and treatment and prevention of striatal necrosis and permanent neurological sequelae (Strauss et al 2003;K€ olker et al 2011). Currently, treatment consists of lysine-restricted diet and carnitine supplementation and prompt symptomatic and anticatabolic treatment of intercurrent illness (K€ olker et al 2006a, 2012).…”