Clinical and biochemical spectrum of D-bifunctional protein deficiency.
ABSTRACT D-bifunctional protein deficiency is an autosomal recessive inborn error of peroxisomal fatty acid oxidation. Although case reports and small series of patients have been published, these do not give a complete and balanced picture of the clinical and biochemical spectrum associated with this disorder.
To improve early recognition, diagnosis, prognosis, and management of this disorder and to provide markers for life expectancy, we performed extensive biochemical studies in a large cohort of D-bifunctional protein-deficient patients and sent out questionnaires about clinical signs and symptoms to the responsible physicians.
Virtually all children presented with neonatal hypotonia and seizures and died within the first 2 years of life without achieving any developmental milestones. However, within our cohort, 12 patients survived beyond the age of 2 years, and detailed information on 5 patients with prolonged survival (> or =7.5 years) is provided.
Biochemical analyses showed that there is a clear correlation between several biochemical parameters and survival of the patient, with C26:0 beta-oxidation activity in cultured skin fibroblasts being the best predictive marker for life expectancy. Remarkably, three patients were identified without biochemical abnormalities in plasma, stressing that D-bifunctional protein deficiency cannot be excluded when all peroxisomal parameters in plasma are normal.
Article: Specific combination of compound heterozygous mutations in 17beta-hydroxysteroid dehydrogenase type 4 (HSD17B4) defines a new subtype of D-bifunctional protein deficiency.[show abstract] [hide abstract]
ABSTRACT: BACKGROUND: D-bifunctional protein (DBP) deficiency is typically apparent within the first month of life with most infants demonstrating hypotonia, psychomotor delay and seizures. Few children survive beyond two years of age. Among patients with prolonged survival all demonstrate severe gross motor delay, absent language development, and severe hearing and visual impairment. DBP contains three catalytically active domains; an N-terminal dehydrogenase, a central hydratase and a C-terminal sterol carrier protein-2-like domain. Three subtypes of the disease are identified based upon the domain affected; DBP type I results from a combined deficiency of dehydrogenase and hydratase activity; DBP type II from isolated hydratase deficiency and DBP type III from isolated dehydrogenase deficiency. Here we report two brothers (161/2 and 14 years old) with DBP deficiency characterized by normal early childhood followed by sensorineural hearing loss, progressive cerebellar and sensory ataxia and subclinical retinitis pigmentosa.Methods and resultsBiochemical analysis revealed normal levels of plasma VLCFA, phytanic acid and pristanic acid, and normal bile acids in urine; based on these results no diagnosis was made. Exome analysis was performed using the Agilent SureSelect 50Mb All Exon Kit and the Illumina HiSeq 2000 next-generation-sequencing (NGS) platform. Compound heterozygous mutations were identified by exome sequencing and confirmed by Sanger sequencing within the dehydrogenase domain (c.101C>T; p.Ala34Val) and hydratase domain (c.1547T>C; p.Ile516Thr) of the 17beta-hydroxysteroid dehydrogenase type 4 gene (HSD17B4). These mutations have been previously reported in patients with severe-forms of DBP deficiency, however each mutation was reported in combination with another mutation affecting the same domain. Subsequent studies in fibroblasts revealed normal VLCFA levels, normal C26:0 but reduced pristanic acid beta-oxidation activity. Both DBP hydratase and dehydrogenase activity were markedly decreased but detectable. CONCLUSIONS: We propose that the DBP phenotype seen in this family represents a distinct and novel subtype of DBP deficiency, which we have termed type IV based on the presence of a missense mutation in each of the domains of DBP resulting in markedly reduced but detectable hydratase and dehydrogenase activity of DBP. Given that the biochemical testing in plasma was normal in these patients, this is likely an underdiagnosed form of DBP deficiency.Orphanet Journal of Rare Diseases 11/2012; 7(1):90. · 5.83 Impact Factor
Article: MRI characterisation of adult onset alpha-methylacyl-coA racemase deficiency diagnosed by exome sequencing.[show abstract] [hide abstract]
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 alpha-methylacyl-coA racemase (AMACR) gene in both patients. The genetic diagnosis of alpha-methylacyl-coA racemase deficiency was confirmed by demonstrating markedly increased pristanic acid levels in blood (169 mumol/L, normal <1.5 mumol/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 alpha-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.Orphanet Journal of Rare Diseases 01/2013; 8(1):1. · 5.83 Impact Factor
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ABSTRACT: Molecular basis of D-bifunctional protein (D-BP) deficiency was studied with wild type and five disease-causing variants of 3R-hydroxyacyl-CoA dehydrogenase fragment of the human MFE-2 (multifunctional enzyme type 2) protein. Complementation analysis in vivo in yeast and in vitro enzyme kinetic and stability determinants as well as in silico stability and structural fluctuation calculations were correlated with clinical data of known patients. Despite variations not affecting the catalytic residues, enzyme kinetic performance (K(m), V(max) and k(cat)) of the recombinant protein variants were compromised to a varying extent and this can be judged as the direct molecular cause for D-BP deficiency. Protein stability plays an additional role in producing non-functionality of MFE-2 in case structural variations affect cofactor or substrate binding sites. Structure-function considerations of the variant proteins matched well with the available data of the patients.PLoS ONE 01/2013; 8(1):e53688. · 4.09 Impact Factor