title: MRI characterisation of adult onset alpha-methylacyl-coA racemase deficiency diagnosed by exome sequencing.
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.
authors.affiliation: Department of Neurology, Haukeland University Hospital, Bergen, Norway.
authors.forename: Kristoffer
authors.initials: K
authors.lastname: Haugarvoll
authors.forename: Stefan
authors.initials: S
authors.lastname: Johansson
authors.forename: Charalampos
authors.initials: C
authors.lastname: Tzoulis
authors.forename: Bjørn Ivar
authors.initials: BI
authors.lastname: Haukanes
authors.forename: Cecilie
authors.initials: C
authors.lastname: Bredrup
authors.forename: Gesche
authors.initials: G
authors.lastname: Neckelmann
authors.forename: Helge
authors.initials: H
authors.lastname: Boman
authors.forename: Per Morten
authors.initials: PM
authors.lastname: Knappskog
authors.forename: Laurence A
authors.initials: LA
authors.lastname: Bindoff
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D059472:Exome; D005260:Female; D005808:Genes, Recessive; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008661:Metabolism, Inborn Errors / Q000175:diagnosis* / Q000201:enzymology / Q000235:genetics; D008875:Middle Aged; D019998:Racemases and Epimerases / Q000235:genetics*; D035781:Siblings; D055815:Young Adult
chemical_list: D019998:Racemases and Epimerases; C108352:alpha-methylacyl-CoA racemase