Original articleGlutaric aciduria type 1: Clinical, biochemical and molecular findings in patients from Israel
Introduction
The neurometabolic disorder glutaric aciduria type 1 (GA1, OMIM ♯231670) is an autosomal recessively inherited defect in the pathway of lysine, hydroxylysine and tryptophan catabolism caused by deficiency of glutaryl-CoA dehydrogenase (EC 1.3.99.7) encoded by the GCDH gene. It is one of the cerebral organic acidurias, a distinctive subgroup of organic acidurias which manifests predominantly as an encephalopathy rather than an acute disturbance in systemic metabolic homeostasis.
The clinical phenotype of GA1 has been summarized in a number of patient cohort descriptions.1, 2, 3, 4 It typically presents in a developmentally normal infant towards the first birthday as an acute encephalopathic crisis following an intercurrent illness, with permanent residual sequelae including dystonia-dyskinesia, seizures and developmental regression or delay. The biochemical diagnosis of GA1 is based on detection of large quantities of glutaric acid (GA) and 3-hydroxyglutaric acid (3-HGA) excreted in the urine and elevated levels of glutarylcarnitine in the blood. Some patients, however, have normal GA excretion and only slightly elevated 3-HGA excretion5 and may also have normal glutarylcarnitine levels.6
A number of hypotheses have been proposed to explain the pathogenesis of the disorder and the stroke-like acute striatal necrosis that underlies the encephalopathic crisis. These include NMDA receptor-mediated excitotoxicity induced by 3-HGA7 or by the kynurenine pathway product quinolinic acid,8 glutaconyl-CoA-mediated neurotoxicity9 and disruption of vascular endothelial integrity by 3-HGA.10 Recently, striatal injury was induced in a GCDH knockout mouse model by administration of a high-protein or high-lysine diet and was attributed to extremely high levels of GA accumulating in the brain,11 a finding also observed in human post-mortem studies.12
Once the encephalopathic crisis has occurred, management of GA1 patient is limited to conservative measures as the striatal damage is irreversible. If the diagnosis can be made in the presymptomatic phase, appropriate management can prevent the catastrophic neurological deterioration in the majority of cases.1, 4, 13 This prophylactic management involves administration of carnitine supplements, restriction of dietary lysine and/or protein intake and adherence to an emergency regimen protocol designed to reverse the catabolic state during acute febrile or vomiting episodes by administering intravenous fluids with high glucose concentration as well as lipids and carnitine.
We present the clinical features and the biochemical and neuroimaging findings of a series of GA1 patients from Israel and report recurrent and novel GCDH mutations identified in these patients. Our findings indicate that GA1 is relatively common in the Palestinian population but that the diagnosis is often delayed or missed due to lack of familiarity with this disorder amongst pediatricians and allied professionals.
Section snippets
Patients
This study comprises all GA1 patients diagnosed by the metabolic laboratory at Hadassah—Hebrew University Medical Center during a 5-year period ending in mid-2004. Patient ♯1 has been previously reported.14, 15
Biochemical analyses
Qualitative analysis of urine organic acids was performed by gas chromatography – mass spectrometry (GC-MS) following a standard ethyl acetate/diethyl ether extraction and trimethylsilyl derivatization. GA concentration in urine was determined by GC-MS using a stable isotope dilution
Results
The clinical, biochemical and molecular findings in the patients are summarized in Table 1.
Discussion
In a period of 5 yr, our laboratory made a diagnosis of GA1 in 12 new patients, 11 of whom were of Palestinian descent. Considering that three additional laboratories in Israel perform diagnostic investigations for inborn errors of metabolism and that the awareness of GA1 and access to diagnostic facilities in the medical services in the Palestinian Territories is limited, we believe that the true number of patients in this population might be considerably higher. By comparison, only 28 patients
Acknowledgements
The authors thank Birthe Roos, Ulbe Holwerda and Erwin E Janssen for excellent metabolite analysis.
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Update current understanding of neurometabolic disorders related to lysine metabolism
2023, Epilepsy and BehaviorIdentification of novel pathogenic variants in the GCDH gene and assessment of neurodevelopmental outcomes in 24 children with glutaric aciduria type 1
2022, European Journal of Paediatric NeurologyCitation Excerpt :The most frequent missense variant was p.Arg294Gln(c.881G>A) in exon 9, found in six patients. In contrast, most common mutation in the European population has been p.Arg402Trp (c.1204C>T) in exon 10 [21]. Children with the variant p.Arg294Gln in our cohort presented with acute encephalopathy (66%), macrocephaly (66%), prior developmental delay (33%) and seizures (33%).
Glutaric aciduria type 1: Genetic and phenotypic spectrum in 53 patients
2020, European Journal of Medical GeneticsCitation Excerpt :Instant recognition and accurate diagnosis of the significant symptoms of GA1, such as encephalopathic crisis, are crucial to reduce the amount of damage and prevent recurrences. At that point, tandem mass spectrometry is essential to screen asymptomatic newborns (Lindner et al., 2006; Korman et al., 2007). In our study, the C5DC values were elevated in approximately 90% of the GA1 patients, ranging from 0.30 to 3.69 μmol/L (normal; 0–0.3 μmol/L).
Malignant brain tumors in patients with glutaric aciduria type I
2018, Molecular Genetics and MetabolismCitation Excerpt :In addition, prospective measurement of the concentrations of 3-OHGA in extracted tumor tissues, when available, may shed important light on the metabolic etiology of these brain tumors. Neuroimaging is used in the follow up of patients with GA I for 1) detecting space occupying lesions such as subdural hematomas (which have been reported since as early as 1993 [7,26], 2) characterizing ancillary CNS changes such as arachnoid cysts/temporal pole hypoplasia (which have been reported since as early as 1991 [27–29]) or, subependymal mass lesions [3–6], 3) monitoring white matter progression in spite of a stable neurological status, even though recent recommendations do not considered essential brain MRI for the clinical follow-up [1]. We propose that brain MRI should be used also for the detection of malignant brain tumors in patients with GA I.
Arachnoid cysts in glutaric aciduria type I (GA-I)
2017, Arachnoid Cysts: Epidemiology, Biology, and Neuroimaging