Extrastriatal changes in patients with late-onset glutaric aciduria type I highlight the risk of long-term neurotoxicity

Abstract

BackgroundWithout neonatal initiation of treatment, 80–90% of patients with glutaric aciduria type 1 (GA1) develop striatal injury during the first six years of life resulting in a complex, predominantly dystonic movement disorder. Onset of motor symptoms may be acute following encephalopathic crisis or insidious without apparent crisis. Additionally, so-called late-onset GA1 has been described in single patients diagnosed after the age of 6 years. With the aim of better characterizing and understanding late-onset GA1 we analyzed clinical findings, biochemical phenotype, and MRI changes of eight late-onset patients and compared these to eight control patients over the age of 6 years with early diagnosis and start of treatment.ResultsNo late-onset or control patient had either dystonia or striatal lesions on MRI. All late-onset (8/8) patients were high excretors, but only four of eight control patients. Two of eight late-onset patients were diagnosed after the age of 60 years, presenting with dementia, tremor, and epilepsy, while six were diagnosed before the age of 30 years: Three were asymptomatic mothers identified by following a positive screening result in their newborns and three had non-specific general symptoms, one with additional mild neurological deficits. Frontotemporal hypoplasia and white matter changes were present in all eight and subependymal lesions in six late-onset patients. At comparable age a greater proportion of late-onset patients had (non-specific) clinical symptoms and possibly subependymal nodules compared to control patients, in particular in comparison to the four clinically and MR-wise asymptomatic low-excreting control patients.ConclusionsWhile clinical findings are non-specific, frontotemporal hypoplasia and subependymal nodules are characteristic MRI findings of late-onset GA1 and should trigger diagnostic investigation for this rare disease. Apart from their apparent non-susceptibility for striatal injury despite lack of treatment, patients with late-onset GA1 are not categorically different from early treated control patients. Differences between late-onset patients and early treated control patients most likely reflect greater cumulative neurotoxicity in individuals remaining undiagnosed and untreated for years, even decades as well as the higher long-term risk of high excretors for intracerebral accumulation of neurotoxic metabolites compared to low excretors.Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-017-0612-6) contains supplementary material, which is available to authorized users.

Pathogenesis of brain damage in glutaric acidemia type I: Lessons from the genetic mice model

“…These data suggest that the hypomyelination observed in the striatum of Gcdh −/− mice under high Lys chow is associated with endoplasmic reticulum stress and not to neuronal death, supporting distinct mechanisms for these processes. In line with these observations, a recent work showed decreased expression of galactocerebrosidase and myelin basic protein in 3D organotypic cell cultures prepared from Gcdh −/− brain that was accentuated by Lys exposure and may result from a reduction in the number of oligodendrocytes and/or a delayed myelination in the brain of these animals (Cudré-Cung et al, 2019), similarly to what is found in cerebral magnetic resonance imaging of GA I patients (Harting et al, 2009(Harting et al, , 2015Boy et al, 2017b). It was also demonstrated decreased density of neuronal fibers in axonal and dendrites of Gcdh −/− brain cell cultures that was further reduced by Lys exposure.…”

“…8. White matter injury in Gcdh −/− mice Diffuse white matter abnormalities with hypomyelination (delayed myelination) are commonly observed in GA I patients, especially in those affected by the late-onset or insidious forms that may not be accompanied by encephalopathic crises (Oguz et al, 2005;Strauss et al, 2007;Harting et al, 2009;Boy et al, 2017b). Gcdh −/− mice also present white matter changes.…”

A phenotypically severe, biochemically “silent” case of HIBCH deficiency in a newborn diagnosed by rapid whole exome sequencing and enzymatic testing

“…The concept of the cerebral organic acidurias is that the metabolites are more heavily enriched in the CNS compartments compared to the blood and the urine. The most well‐known example is the “low excretion” subset of individuals with glutaric acidemia Type I (Boy et al, ) who typically do not have high amounts of glutaric acid in their blood or urine but are at risk of striatal injury during metabolic crises. The most well‐known biochemically silent small molecule disease is tyrosinemia Type I, which can present with hepatocellular carcinoma without elevated succinylacetone or tyrosine (Blackburn et al, ).…”

Clinical and mutational spectrum of 4 Chinese families with glutaric aciduria type 1

“…Fortunately, diet control and drug treatment before encephalopathy could partially reduce extrapyramidal sequela caused by degenerated striate. Strict treatment management of protein diet (especially lysine and tryptophan acid), L-carnitine supplementation and vitamin B2 before 6 years old is considerably necessary [18] . When suffered from encephalopathy, patients should accept high energy treatment (glucose infusion and low dose insulin), then reduce or suspend the natural protein intake 1-2 days later, and accept intravenous supplementation of L-carnitine, meanwhile maintain electrolyte and acid-base balance.…”