Dr. Kolker of the Center of Pediatrics and Adolescent Medicine, University Hospital Heidelberg has no relevant financial relationships to disclose.)
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.
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.
• 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 (Goodman et al 1975) and is caused by inherited deficiency of GCDH (EC 184.108.40.206), an essential enzyme for the catabolism of lysine, hydroxylysine, and tryptophan (Christensen 1993; Fu et al 2004). The human GCDH gene was assigned to chromosome 19p13.13 (Greenberg et al 1994).
First observational studies included patients from the Amish community (Strauss et al 2003; Strauss et al 2007), Saulteaux/Ojibwa (Oji-Cree) First Nations (Greenberg et al 2002), and European patients (Hoffmann et al 1991; Hoffmann et al 1996; Busquets et al 2000; Kyllerman et al 2004). Meta-analysis evaluated published case reports of the prescreening era describe 115 post-symptomatically treated patients (Bjugstad et al 2000). An international cross-sectional study enrolling 279 patients investigated the impact of the diagnosis and mode of therapy on the neurologic outcome and survival (Kolker et al 2006). 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 (Lindner et al 2006), and to start prospective follow-up studies (Strauss et al 2003; Kolker et al 2007b; Boneh et al 2008; Heringer et al 2010; Boy et al 2018).
At present, more than 700 patients have been reported worldwide. A guideline for diagnosis and management has been introduced (Kolker et al 2007a) and revised twice (Kolker et al 2011; Boy et al 2017), and the beneficial effect of using this guideline has been confirmed (Heringer et al 2010; Boy et al 2018).
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 (Kolker et al 2004; Jafari et al 2011; Wajner 2019). Gcdh-deficient mice, an animal model for this disease, have been developed and are still under investigation (Koeller et al 2002; Sauer et al 2005; Sauer et al 2006; Sauer et al 2011; Zinnanti et al 2006; Zinnanti et al 2007; Danhauser et al 2012; Schmiesing et al 2018).
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