Dr. Kolker of University Children's 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 patients manifests with acute- or insidious-onset dystonia due to striatal injury in infancy. The natural disease course can be changed by newborn screening and presymptomatic start of combined metabolic therapy. The long-term disease course, however, remains less clear. In this update, the author discusses the results of 3 studies demonstrating that individuals with (near-) loss of enzyme activity (so-called high excreters) and those not following recommended dietary treatment or being diagnosed with significant delay seem to be at increased risk of progressive white matter changes and subependymal nodules in cranial MRI. Three individuals in this group developed malignant brain tumors, raising the question of whether glutaric aciduria type I might be a predisposing condition, similar to L-2-hydroxyglutaric aciduria. Enhanced glutarylation of mitochondrial proteins in glial cells and disturbed glutamate and glutamine metabolism are candidate mechanisms for impaired metabolic crosstalk between neurons and astrocytes, fostering long-term pathologic changes.
• The precondition for preventing striatal injury is identifying patients 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.
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 22.214.171.124), an essential enzyme for the catabolism of lysine, hydroxylysine, and tryptophan (Christensen 1993; Fu et al 2004).
Retrospective and prospective studies include patients from 2 North American genetic isolates with a high carrier frequency: the Amish Community (Strauss et al 2003; Strauss et al 2007) and the Saulteaux/Ojibwa (Oji-Cree) Indians (Greenberg et al 2002) as well as European patients (Hoffmann et al 1991; Hoffmann et al 1996; Busquets et al 2000; Kyllerman et al 2004). A metaanalysis of this disease evaluating 42 published case reports describing 115 patients has been reported (Bjugstad et al 2000). An international cross-sectional study enrolling 279 patients has also been published (Kolker et al 2006). A guideline for diagnosis and management has been introduced (Kolker et al 2007a), and the beneficial effect of using this guideline has been confirmed (Heringer et al 2010). Guideline recommendations have since been updated (Kolker et al 2011). A revision of the proposed recommendations has confirmed the previous recommendations for diagnosis, therapy, and care (Boy et al 2017). The EIMD Patient Registry is an international registry for intoxication type metabolic diseases and includes follow-up data for over 200 patients (Kolker et al 2015).
These reports greatly broadened the clinical spectrum of glutaric aciduria type I to include children with nonprogressive extrapyramidal syndromes and even biochemically affected but clinically normal children with glutaric aciduria type I. At present, more than 700 patients have been reported worldwide. As a result, glutaric aciduria is now recognized as 1 of the most common identifiable inborn errors of metabolism associated with progressive or nonprogressive extrapyramidal disease. Development of tandem mass spectrometry-based programs for expanded neonatal screening has provided the opportunity to diagnose a variety of children before onset of acute encephalopathy (Lindner et al 2006) and to start prospective follow-up studies (Strauss et al 2003; Kolker et al 2007b; Bijarnia et al 2008; Boneh et al 2008).
The human GCDH gene was assigned to chromosome 19p13.13 (Greenberg et al 1994).
A variety of studies have focused on the pathogenetic mechanisms involved in acute neurodegeneration of this disease using in vitro and in vivo models (Kolker et al 2004). 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).
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