Natural History, Outcome, and Treatment Efficacy in Children and Adults with Glutaryl-CoA Dehydrogenase Deficiency

Abstract

Glutaryl-CoA dehydrogenase (GCDH) deficiency is a rare inborn disorder of L-lysine, L-hydroxylysine, and L-tryptophan metabolism complicated by striatal damage during acute encephalopathic crises. Three decades after its description, the natural history and how to treat this disorder are still incompletely understood. To study which variables influenced the outcome, we conducted an international cross-sectional study in 35 metabolic centers. Our main outcome measures were onset and neurologic sequelae of acute encephalopathic crises. A total of 279 patients (160 male, 119 female) were included who were diagnosed clinically after clinical presentation (n ϭ 218) or presymptomatically by neonatal screening (n ϭ 23), high-risk screening (n ϭ 24), or macrocephaly (n ϭ 14). Most symptomatic patients (n ϭ 185) had encephalopathic crises, characteristically resulting in bilateral striatal damage and dystonia, secondary complications, and reduced life expectancy. First crises usually occurred during infancy (95% by age 2 y); the oldest age at which a repeat crisis was reported was 70 mo. In a few patients, neurologic disease developed without a reported crisis. Differences in the diagnostic criteria and therapeutic protocols for patients with GCDH deficiency resulted in a huge variability in the outcome worldwide. Recursive partitioning demonstrated that timely diagnosis in neurologically asymptomatic patients followed by treatment with L-carnitine and a lysine-restricted diet was the best predictor of good outcome, whereas treatment efficacy was low in patients diagnosed after the onset of neurologic disease. Notably, the biochemical phenotype did not predict the clinical phenotype. Our study proves GCDH deficiency to be a treatable disorder and a good candidate for neonatal screening.

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

“…More than 150 pathogenic mutations (missense, nonsense, and intronic variants) in the GCDH gene have been so far documented (Strauss et al 2003;K€ olker et al 2006a, 2012. The disease exhibits a remarkable clinical variability, but apart from a covert correlation between residual enzymatic activity as determined by the so-called "severe" or "mild" mutations and biochemical phenotype, no other genotypic-phenotypic relationship has been established (Busquets et al 2000b;M€ uhlhausen et al 2003;Funk et al 2005;Gallagher et al 2005;Christensen et al 2004).…”

“…Typically, GA-I presents in infancy after a precipitating illness with acute metabolic encephalopathy that in a matter of days results in striatal necrosis with stroke-like characteristics and a severe irreversible neurological syndrome variably encompassing axial hypotonia, generalized dystonia and other dyskinetic/ hyperkinetic movement disorders, spasticity, developmental regression, seizures, and ultimately dystonic tetraparesis (Strauss et al 2003;K€ olker et al 2006aKyllerman et al 1994;Bjugstad et al 2000). According to a metaanalysis (n ¼ 115), GA-I onset before 24 months of age occurs in 87% of cases, with a critical susceptibility time window between 6 and 9 months, when about 25% of infantile acute encephalopathic cases debut and the probability of a poor outcome is highest (Bjugstad et al 2000).…”

“…Prevalence has been variably estimated between 1:100,000 and 1:30,000 in different studies and populations (Strauss et al 2003;K€ olker et al 2006a. Incidence is highest in certain genetically homogeneous communities such as the Old Order Amish of Lancaster County, Pennsylvania (1 in 300-400 newborns), and the aboriginal Ojibway-Cree Indians of Northern Canada (1 in 300 newborns) where common mutations in homozygous state are often found (Morton et al 1991;Haworth et al 1991).…”

“…The GCDH gene is located on chromosome 19p13.2, is 7 kb large, contains 11 exons and 10 introns, and codes for a polypeptide product of 438 amino acids, from which the functional GCDH is derived after cleavage of the 44-amino acids N-terminal targeting sequence following import into the mitochondrial matrix (Koeller et al 1995;Schwartz et al 1998). More than 150 pathogenic mutations have been identified of which the most frequent mutation in Caucasians is R402W (c.1204C>T) found in up to 10-20% of alleles, while the IVS10-2A>C mutation is found almost exclusively in patients of Chinese/Taiwanese origin (Strauss et al 2003;K€ olker et al 2006aBusquets et al 2000a;Tang et al 2000;Shu et al 2003).…”

Prenatal cerebral ultrasound and MRI findings in glutaric aciduria Type 1: a de novo case

“…PRCs are uncommon, with only 25 published cases in the English literature 1 . We report the first case of PRC with endometrial differentiation presenting as a pelvic abscess.…”