Glutaric acidemia type 1: Treatment and outcome of 168 patients over three decades

Kevin A Strauss,Katie B Williams,Vincent J Carson,Laura Poskitt,Lauren E Bowser,Millie Young,Donna L Robinson,Christine Hendrickson,Keturah Beiler,Cora M Taylor,Barbara Haas-Givler,Jennifer Hailey,Stephanie Chopko,Erik G Puffenberger,Karlla W Brigatti,Freeman Miller,D Holmes Morton

doi:10.1016/j.ymgme.2020.09.007

Abstract

Glutaric acidemia type 1 (GA1) is a disorder of cerebral organic acid metabolism resulting from biallelic mutations of GCDH. Without treatment, GA1 causes striatal degeneration in >80% of affected children before two years of age. We analyzed clinical, biochemical, and developmental outcomes for 168 genotypically diverse GA1 patients managed at a single center over 31 years, here separated into three treatment cohorts: children in Cohort I (n = 60; DOB 2006–2019) were identified by newborn screening (NBS) and treated prospectively using a standardized protocol that included a lysine-free, arginine-enriched metabolic formula, enteral l-carnitine (100 mg/kg•day), and emergency intravenous (IV) infusions of dextrose, saline, and l-carnitine during illnesses; children in Cohort II (n = 57; DOB 1989–2018) were identified by NBS and treated with natural protein restriction (1.0–1.3 g/kg•day) and emergency IV infusions; children in Cohort III (n = 51; DOB 1973–2016) did not receive NBS or special diet. The incidence of striatal degeneration in Cohorts I, II, and III was 7%, 47%, and 90%, respectively (p < .0001). No neurologic injuries occurred after 19 months of age. Among uninjured children followed prospectively from birth (Cohort I), measures of growth, nutritional sufficiency, motor development, and cognitive function were normal. Adherence to metabolic formula and l-carnitine supplementation in Cohort I declined to 12% and 32%, respectively, by age 7 years. Cessation of strict dietary therapy altered plasma amino acid and carnitine concentrations but resulted in no serious adverse outcomes. In conclusion, neonatal diagnosis of GA1 coupled to management with lysine-free, arginine-enriched metabolic formula and emergency IV infusions during the first two years of life is safe and effective, preventing more than 90% of striatal injuries while supporting normal growth and psychomotor development. The need for dietary interventions and emergency IV therapies beyond early childhood is uncertain.

Highlights

Glutaric acidemia type 1 (GA1; OMIM #231670) is a disorder of cerebral organic acid metabolism caused by biallelic variants of GCDH, which encodes a mitochondrial flavin-dependent glutaryl-coenzyme A (CoA) dehy drogenase (GCDH) that mediates degradation of lysine and tryptophan (Fig. 1)
Ninety-one (54%) patients were homozygous for the c.1262C > T (p.Ala421Val) variant, 46 (27%) were homozygous or compound heterozygous for other GCDH alleles, and 31 (18%) had no molecular testing but a compelling clinical and biochemical GA1 phenotype, including elevated C5DC concentrations in plasma, elevations of both C5DC and 3-hydroxyglutaric acid (3HGA) in urine, congenital or infantile-onset macrocephaly, and characteristic middle cranial fossa fluid collections detected by magnetic resonance imaging [6,15]
Among 43 remaining pa tients in Cohort I, dried filter paper blood spots were collected at a median of 2 postnatal days and results were reported through state newborn screening (NBS) at a later median age of 8 days (p < .0001)

Summary

Introduction

Glutaric acidemia type 1 (GA1; OMIM #231670) is a disorder of cerebral organic acid metabolism caused by biallelic variants of GCDH, which encodes a mitochondrial flavin-dependent glutaryl-CoA dehy drogenase (GCDH) that mediates degradation of lysine and tryptophan (Fig. 1). Neuronal GCDH deficiency results in proximal accumulation of glutaryl-coenzyme A (CoA) and its dicarboxylic acid derivatives, glu taric acid (GA) and 3-hydroxyglutaric acid (3HGA). These metabolites become concentrated in the brain due to its limited capacity to form 5‐carbon carnitine and glycine conjugates from glutaryl-CoA [1,2] or export medium-chain dicarboxylates [3,4]. Encephalopathic crises strike during an infectious illness within the first 24 months of life but rarely occur without apparent provocation and may even happen in utero [9,10] Regardless of their timing or me chanism, striatal lesions result in a complex extrapyramidal movement disorder that is the principal determinant of outcome.

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Results

Conclusion