Glutaric aciduria type 1: Clinical, biochemical and molecular findings in patients from Israel

Abstract

Glutaric aciduria type 1 (GA1) is a rare cerebral organic aciduria which typically manifests as an acute encephalopathic crisis followed by profound long-term neurological handicap. We report the diagnosis of 12 new patients from a single laboratory in Israel during a 5-year period. Eleven of the 12 were of Palestinian origin, and only two were related. One patient was asymptomatic whilst one was mildly, one moderately and nine severely affected, two of whom had unusual MRI findings. Two patients had normal glutaric acid excretion and normal blood glutarylcarnitine levels yet glutarylcarnitine excretion was increased, indicating its utility as a diagnostic marker. Four novel GCDH mutations (Thr193_Arg194insHis, Asn329Ser, Thr341Pro, Met405Val) and five previously reported mutations (Ser119Leu, Leu283Pro, Ala293Thr, Gly390Arg and Thr416Ile) were identified. Severely and mildly affected or even asymptomatic patients shared the same genotypes (Thr416Ile/Thre416Ile and Aal293Thr/Thr193_Arg194insHis). Knowledge of the responsible mutation enabled successful prenatal diagnosis on chorionic villous DNA in three families.

In conclusion, GA1 is genetically heterogeneous and has a relatively high incidence in the Palestinian population, reflecting the historical tradition of marriages within extended kindreds, particularly in isolated villages. Additional genetic and/or environmental factors must account for the phenotypic heterogeneity in patients with the same genotype. The diagnosis was not suspected in the majority of cases despite typical clinical and/or neuroimaging features, suggesting that glutaric aciduria may be under-diagnosed. Greater awareness of glutaric aciduria amongst pediatricians, neonatologists and radiologists is the key to identifying the disorder in the presymptomatic phase and preventing its catastrophic consequences.

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.