Glutaric Acidemia I (GA I) is an autosomal recessive neurometabolic disorder caused by the deficiency of glutaryl-CoA dehydrogenase enzyme. GA I is biochemically characterized by the accumulation of the dicarbonic glutaric acids (GA), 3-hydroxyglutaric (3-OH-GA) and glutaconic acids, and glutarylcarnitine in body fluids and brain tissue of affected patients. It is clinically characterized by progressive macrocephaly and muscle hypotonia in pre encephalopathic children followed by acute encephalopathy during infancy or early childhood. The latter results in acute striatal degeneration and, consequently, in severe dystonic dyskinetic movement disorder. This distinct neuropathology exceptionally presents with classical metabolic symptoms, such as hypoglycemia or acidosis.
The estimated incidence of GA I is 1: 30,000-40,000 in newborn Caucasians. It is much more common in some ethnic communities, such as the Old Order Amish Community in Pennsylvania, U.S.A., and the Saulteaux/Ojibway Indians in Canada (up to 1:300 neonates). GA I is caused by mutations in the GCDH (glutaryl-CoA dehydrogenase) gene localized to chromosome 19p13.2.
[See: Palestine > Anikster et al. 1996].
ElSori et al. (2004) reported the first Kuwaiti male infant, aged 3.5 years, with glutaric aciduria type 1. He is the sixth and youngest child to first-cousin phenotypically normal parents and has 5 healthy sisters. He was admitted to hospital at the age of 10 months because of fever, cough, and repeated vomiting of one week duration. After admission, he developed a series of short left-sided seizures followed a few days later by right-sided seizures. Phenobarbital therapy was started. The seizures continued for 5 days. Shortly after, he developed a left hemiplegia, and he was no longer able to sit or crawl and lost his words. Following treatment measures, the patient became stable but with only minor improvement.
In a retrospective analysis of IEMs diagnosed over a 12-year period (1998-2010) in a hospital in Lebanon, Karam et al. (2013) found two patients diagnosed with glutaric acidemia type I. One of these was through newborn screening. The median age of diagnosis was 3-years.
The Centre for Arab Genomic Studies Work Group (2006) conducted a retrospective study for lipid disorders described at AlWasl Hospital in Dubai between 1997 and 2006. Only one case of GA I was observed in a 3-year-old girl from Oman.
Al-Riyami et al (2012) reported on the types and patterns of IEMs encountered in a sample of 1100 high-risk neonates referred to SQU Hospital in Oman over a 10-year period (1998-2002). MS/MS was used to analyze blood samples from heel pricks. A total of 119 of these neonates were found to test positive for an IEM. Glutaric Acidemia-I was detected in one male neonate.
Among eight families with glutaric acidemia I, six of Muslim origin and two of non-Ashkenazi Jewish background, Anikster et al. (1996) identified seven mutations in the GCDH gene among 15 of 16 mutated alleles. The mutations included six point mutations: p.T416I (4 alleles), p.G390R (1 allele), and p.S305L, p.A293T, p.L283P, and p.G1O1R (2 alleles each). In addition, a 1-bp deletion at position 1173 was identified in two alleles. Anikster et al. (1996) stated that the occurrence of multiple novel alleles in a small geographic area was explained by their recent origin in isolated communities with a high consanguinity rate. Among the families, Anikster et al. (1996) described a Palestinian family in which at least three sibs were homozygous for an ACA>ATA transition in codon 416 of the GCDH gene, resulting in a thr416ile (p.T416I) amino acid substitution. Remarkably, one of three homozygous sibs was asymptomatic and the asymptomatic father was also homozygous for the same mutation. The mother was a heterozygote for the p.T416I mutation.
Coates et al., (1994) described three Saudi patients with glutaric aciduri Type 1 (GAT1). All three patients presented with typical clinical and biochemical characteristics of the disease. Patients had normal development between the age of 3 -14 months, after which sudden and severe encephalopathy occurred. Patients also suffered from severe choreathetosis, dystonia, spastic quadriplegia, mental retardation, as well as frontotemporal lobe hypoplasia and while matter disease.
Moammar et al. (2010) reviewed all patients diagnosed with inborn errors of metabolism (IEM) from 1983 to 2008 at Saudi Aramco medical facilities in the Eastern province of Saudi Arabia. During the study period, 165530 Saudi infants were born, of whom a total of 248 newborns were diagnosed with 55 IEM. Affected patients were evaluated based on clinical manifestations or family history of similar illness and/or unexplained neonatal deaths. Almost all patients were born to consanguineous parents. Organic acidopathies (OA) were diagnosed in 48 out of 248 cases (19%), which constitute the second largest group of IEM found in this cohort after lysosomal storage disease. Among OA patients, three cases from two families were found to have glutaric aciduria type I. The estimated incidence of this disorder in the present cohort is 2 in 100,000 live births. The authors concluded that data obtained from this study underestimate the true figures of various IEM in the region. Therefore, there is an urgent need for centralized newborn screening program that utilizes tandem mass spectrometry, and offers genetic counseling for these families.
Al-Shamsi et al. (2014) undertook a study to calculate the birth prevalence of IEMs among Emiratis in the UAE by taking into consideration all neonates born with an inherited metabolic condition at Tawam Hospital between 1995 and 2012. A total of 37 distinct IEMs were found in Emirati neonates in this study, providing an estimated IEM birth prevalence of 75.24 per 100,000 live births. Type I Glutaric Aciduria was found to have a birth prevalence of between 1.1 and 1.9 per 100,000. Three mutations were identified in the GCDH gene among the affected patients.
[See also: Oman > CAGS Work Group, 2006].