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  • Updated 08.03.2021
  • Released 11.28.1994
  • Expires For CME 08.03.2024

Glutaric aciduria

Introduction

This article includes discussion of glutaric aciduria, glutaric acidemia, glutaric aciduria type I, glutaryl-CoA dehydrogenase deficiency. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.

Overview

Glutaric aciduria or acidemia type I is biochemically characterized by an accumulation of putatively neurotoxic glutaric and 3-hydroxyglutaric acid and nontoxic glutarylcarnitine. The majority of untreated individuals manifest dystonia due to striatal injury in infancy. Long-term observational studies, however, have demonstrated that one third of neonatally screened individuals still develop neurologic symptoms. Furthermore, progressive white matter abnormalities, subependymal nodules, malignant brain tumors, and chronic kidney disease have been reported in a subgroup of patients, raising concerns about the long-term disease outcome and highlighting the need for safer and more effective therapies. In this update, the author discusses the results of three studies explaining the formation of neurotoxic 3-hydroxyglutarate using side reactions of other mitochondrial enzymes, specifically medium chain acyl-CoA dehydrogenase and 3-methylglutaconyl-CoA hydratase. 2-Oxoadipate, the precursor of glutaryl-CoA, is accepted as a substrate by 2-oxoadipate and 2-oxoglutarate dehydrogenase complexes, showing substrate overlap, forming a hybrid 2-oxo acid dehydrogenase complex and, thus, explaining why inhibition of the 2-oxoadipate dehydrogenase complex has failed to rescue the biochemical and clinical phenotype in a mouse model of glutaric aciduria type I. Symptomatic individuals present with acute- or insidious-onset of dystonia. Both onset forms differ with regard to the extent of striatal lesions, the severity of dystonia, and the latency between detection of striatal lesions on MRI and clinical manifestation of symptoms.

Key points

• The precondition for preventing striatal injury is identifying patients during the newborn period when asymptomatic and starting metabolic treatment immediately.

• Intensified emergency treatment should be started without delay and before neurologic symptoms occur during each putatively threatening episode, such as infectious disease.

• Treatment should be initiated and patients should be followed by an interdisciplinary team of metabolic specialists, dieticians, psychologists, neurologists, physical therapists, and occupational therapists.

• In a neonatally screened population, quality of therapy becomes the major predictor of neurologic outcome and survival.

Historical note and terminology

Glutaric aciduria or acidemia type I (glutaryl-CoA dehydrogenase [GCDH] deficiency) was first described in 1975 (25) and is caused by inherited deficiency of GCDH (EC 1.3.8.6), an essential enzyme for the catabolism of lysine, hydroxylysine, and tryptophan (16; 19). The human GCDH gene was assigned to chromosome 19p13.13 (27).

First observational studies included patients from the Amish community (71; 70), Saulteaux/Ojibwa (Oji-Cree) First Nations (28), and European patients (35; 34; 14; 48). Meta-analysis evaluated published case reports of the prescreening era describe 115 post-symptomatically treated patients (05). An international cross-sectional study enrolling 279 patients investigated the impact of the diagnosis and mode of therapy on the neurologic outcome and survival (44). Development of tandem mass spectrometry-based programs for expanded neonatal screening has provided the opportunity to diagnose affected individuals before onset of irreversible striatal damage (52), and to start prospective follow-up studies (71; 43; 06; 31; 10).

At present, more than 700 patients have been reported worldwide. A guideline for diagnosis and management has been introduced (40) and revised twice (41; 11), and the beneficial effect of using this guideline has been confirmed (31; 10).

The EIMD Patient Registry is an international registry for intoxication type metabolic diseases and includes follow-up data for over 200 patients (46).

A variety of studies have focused on the pathogenetic mechanisms involved in acute neurodegeneration of this disease using in vitro and in vivo models, and have been reviewed by various authors (45; 36; 75). Gcdh-deficient mice, an animal model for this disease, have been developed and are still under investigation (38; 60; 59; 61; 79; 78; 18; 64).

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