Abstract
BackgroundCorrect 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.MethodsWe applied clinical and genealogical investigations, homozygosity mapping and exome sequencing to establish the diagnosis and MRI to characterize the cerebral lesions.ResultsA 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.ConclusionsMetabolic 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.
Highlights
Correct diagnosis is pivotal to understand and treat neurological disease
We used exome sequencing to diagnose α-methylacylcoA racemase deficiency (MIM 614307), an autosomal recessive peroxisomal disorder with accumulation of pristanic acid, in two adult siblings. α-methylacyl-coA racemase deficiency has previously been reported in eight adult patients worldwide and the disorder has been associated with heterogeneous clinical presentations (Table 1) [7,8,9,10,11,12,13,14]
At age 39 years, a demyelinating peripheral neuropathy was diagnosed and a glucose tolerance test was consistent with type 2 diabetes mellitus
Summary
Correct diagnosis is pivotal to understand and treat neurological disease. 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. We used exome sequencing to diagnose α-methylacylcoA racemase deficiency (MIM 614307), an autosomal recessive peroxisomal disorder with accumulation of pristanic acid, in two adult siblings. Α-methylacyl-coA racemase deficiency has previously been reported in eight adult patients worldwide and the disorder has been associated with heterogeneous clinical presentations (Table 1) [7,8,9,10,11,12,13,14]. In peroxisomal disorders affecting breakdown of branched-chain fatty acids, phytanic acid and pristanic acid accumulate [16]. Phytanic acid and pristanic acid are degradation products from the chlorophyll sidechain phytol. Peroxisomal SED include X-linked adrenoleukodystrophy (MIM 300100) , Refsum disease (MIM 266500), α-methylacyl-coA racemase (AMACR) deficiency (MIM 614307), sterol carrier protein X (SCPx) deficiency (MIM 613724) and D-bifunctional protein (DBP) deficiency (MIM 261515) [9,15,19]
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