NDLI: MRI characterisation of adult onset alpha-methylacyl-coA racemase deficiency diagnosed by exome sequencing

Content Provider	Springer Nature : BioMed Central
Author	Haugarvoll, Kristoffer Johansson, Stefan Tzoulis, Charalampos Haukanes, Bjørn Ivar Bredrup, Cecilie Neckelmann, Gesche Boman, Helge Knappskog, Per Morten Bindoff, Laurence A
Abstract	Background Correct diagnosis is pivotal to understand and treat neurological disease. Herein, we report the diagnostic work-up utilizing exome sequencing and the characterization of clinical features and brain MRI in two siblings with a complex, adult-onset phenotype; including peripheral neuropathy, epilepsy, relapsing encephalopathy, bilateral thalamic lesions, type 2 diabetes mellitus, cataract, pigmentary retinopathy and tremor. Methods We applied clinical and genealogical investigations, homozygosity mapping and exome sequencing to establish the diagnosis and MRI to characterize the cerebral lesions. Results A recessive genetic defect was suspected in two siblings of healthy, but consanguineous parents. Homozygosity mapping revealed three shared homozygous regions and exome sequencing, revealed a novel homozygous c.367 G>A [p.Asp123Asn] mutation in the α-methylacyl-coA racemase (AMACR) gene in both patients. The genetic diagnosis of α-methylacyl-coA racemase deficiency was confirmed by demonstrating markedly increased pristanic acid levels in blood (169 μmol/L, normal <1.5 μmol/L). MRI studies showed characteristic degeneration of cerebellar afferents and efferents, including the dentatothalamic tract and thalamic lesions in both patients. Conclusions Metabolic diseases presenting late are diagnostically challenging. We show that appropriately applied, homozygosity mapping and exome sequencing can be decisive for establishing diagnoses such as late onset α-methylacyl-coA racemase deficiency, an autosomal recessive peroxisomal disorder with accumulation of pristanic acid. Our study also highlights radiological features that may assist in diagnosis. Early diagnosis is important as patients with this disorder may benefit from restricted dietary phytanic and pristanic acid intake.
Related Links	https://ojrd.biomedcentral.com/counter/pdf/10.1186/1750-1172-8-1.pdf
Ending Page	10
Page Count	10
Starting Page	1
File Format	HTM / HTML
ISSN	17501172
DOI	10.1186/1750-1172-8-1
Journal	Orphanet Journal of Rare Diseases
Issue Number	1
Volume Number	8
Language	English
Publisher	BioMed Central
Publisher Date	2013-01-03
Access Restriction	Open
Subject Keyword	Medicine Public Health Pharmacology Toxicology Human Genetics AMACR gene Seizures Next generation sequencing Ataxia Peroxisomal disorders Metabolic disorders Tremor Peripheral neuropathy Pigmentary retinopathy Medicine/Public Health Pharmacology/Toxicology
Content Type	Text
Resource Type	Article
Subject	Pharmacology (medical) Genetics (clinical)
Journal Impact Factor	3.4/2023
5-Year Journal Impact Factor	3.9/2023

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