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

Haugarvoll Kristoffer, Johansson Stefan, Tzoulis Charalampos, Haukanes, Bredrup Cecilie, Neckelmann Gesche, Boman Helge, Knappskog, Bindoff

Description

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.

Sujets

• Epileptic seizure
• Ataxia
• Peroxisomal disorder
• Inborn error of metabolism
• Trémor
• Peripheral neuropathy
• Retinitis pigmentosa

Informations

• Publié par: biomed
• Publié le: 01 janvier 2013
• Nombre de lectures: 9
• Langue: English
• Poids de l'ouvrage: 3 Mo

Extrait

Haugarvollet al. Orphanet Journal of Rare Diseases2013,8:1 http://www.ojrd.com/content/8/1/1

R E S E A R C HOpen Access MRI characterisation of adult onset alphamethylacylcoA racemase deficiency diagnosed by exome sequencing 1,2 3,41,2 33,5 Kristoffer Haugarvoll, Stefan Johansson, Charalampos Tzoulis, Bjørn Ivar Haukanes , Cecilie Bredrup, 6 2,32,3 1,2* Gesche Neckelmann , Helge Boman, Per Morten Knappskogand Laurence A Bindoff

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 theαmethylacylcoA racemase (AMACR)gene in both patients. The genetic diagnosis ofαmethylacylcoA racemase deficiency was confirmed by demonstrating markedly increased pristanic acid levels in blood (169μmol/L, normal <1.5μmol/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. Keywords:AMACRgene, Seizures, Next generation sequencing, Ataxia, Peroxisomal disorders, Metabolic disorders, Tremor, Peripheral neuropathy, Pigmentary retinopathy

Background Highthroughput sequence capture methods and next generation sequencing (NGS) technologies make exome sequencing an effective method to identify the cause of Mendelian disorders [13]. Exome sequencing has primar ily been applied to identify novel genetic causes of disease although it is increasingly being used in the diagnostic

* Correspondence: laurence.bindoff@helsebergen.no 1 Department of Neurology, Haukeland University Hospital, Bergen, Norway 2 Department of Clinical Medicine, University of Bergen, Bergen, Norway Full list of author information is available at the end of the article

setting, particular in disorders displaying locus heterogen eity such as ataxias, CharcotMarieTooth disease (CMT), hereditary spastic paraplegias (HSP) and retinitis pigmen tosa [35]. Large genes containing numerous mutations may also be effectively screened by NGS. In addition, exo me sequencing may be an important tool for correctly diagnosing rare disorders, [6] particularly when they ma nifest phenotypic heterogeneity. We used exome sequencing to diagnoseαmethylacyl coA racemase deficiency (MIM 614307), an autosomal recessive peroxisomal disorder with accumulation of

© 2013 Haugarvoll et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.