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

Orphanet Journal of Rare Diseases

Stefan Kölker¹  Jana Heringer¹  Nikolas Boy¹  Renate Brackmann²  Inga Harting³  Angelika Seitz³  Olaf Bodamer⁴ 

[1] Centre for Child and Adolescent Medicine, Clinic I, Division of Neuropaediatrics and Metabolic Medicine, University Hospital Heidelberg;Department of Child and Adolescent Medicine, Klinikum Herford;Department of Neuroradiology, University Hospital Heidelberg;Division of Genetics and Genomics, Boston Children’s Hospital;

关键词: Glutaric aciduria type I;    Late-onset;    Long-term disease course;    Subependymal nodules;    Frontotemporal hypoplasia;    High excretor;   

DOI  :  10.1186/s13023-017-0612-6

来源: DOAJ

【 摘 要 】

Abstract Background Without 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. Results No 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. Conclusions While 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.

【 授权许可】

Unknown