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Heterozygous Mutations in HSD17B4 Cause Juvenile Peroxisomal D-Bifunctional Protein Deficiency

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Heterozygous Mutations in HSD17B4 Cause Juvenile Peroxisomal D-Bifunctional Protein Deficiency Heterozygous mutations in HSD17B4 cause juvenile peroxisomal D-bifunctional protein deficiency David J. Amor, MBBS, ABSTRACT PhD Objective: To determine the genetic cause of slowly progressive cerebellar ataxia, sensorineural Ashley P.L. Marsh, BSc deafness, and hypergonadotropic hypogonadism in 5 patients from 3 different families. Elsdon Storey, MBBS, Methods: The patients comprised 2 sib pairs and 1 sporadic patient. Clinical assessment included DPhil history, physical examination, and brain MRI. Linkage analysis was performed separately on the 2 Rick Tankard, BSc sets of sib pairs using single nucleotide polymorphism microarrays, followed by analysis of the Greta Gillies, MSci intersection of the regions. Exome sequencing was performed on 1 affected patient with variant Martin B. Delatycki, filtering and prioritization undertaken using these intersected regions. MBBS, PhD Kate Pope, BSc (Nursing) Results: Using a combination of sequencing technologies, we identified compound heterozygous HSD17B4 Catherine Bromhead, BSc mutations in in all 5 affected patients. In all 3 families, peroxisomal D-bifunctional Richard J. Leventer, protein (DBP) deficiency was caused by compound heterozygosity for 1 nonsense/deletion muta- MBBS, PhD tion and 1 missense mutation. Melanie Bahlo, PhD Conclusions: We describe 5 patients with juvenile DBP deficiency from 3 different families, bring- Paul J. Lockhart, PhD ing the total number of reported patients to 14, from 8 families. This report broadens and consol- idates the phenotype associated with juvenile DBP deficiency. Neurol Genet 2016;2:e114; doi: 10.1212/NXG.0000000000000114 Correspondence to Dr. Lockhart: [email protected] GLOSSARY CoA 5 coenzyme A; DBP 5 D-bifunctional protein; FSH 5 follicle-stimulating hormone; LH 5 luteinizing hormone; MPS 5 massively parallel sequencing; SNP 5 single nucleotide polymorphism; VLCFA 5 very long-chain fatty acid. Peroxisomal D-bifunctional protein (DBP) deficiency is an autosomal recessive disorder that compromises peroxisomal fatty acid oxidation. DBP is crucial to the b-oxidation of fatty acids in the peroxisome, catalyzing the second and third steps of this process which are performed, respectively, by a 2-enoyl-coenzyme A (CoA) hydratase unit and a 3-hydroxyacyl-CoA dehy- drogenase unit.1 DBP deficiency is typically associated with a severe clinical presentation com- prising neonatal hypotonia, seizures, and severely impaired psychomotor development.1 Dysmorphism, loss of hearing and vision, and CNS abnormalities also commonly occur. Infant onset DBP deficiency has been classified into 3 subgroups based on the relative impair- ment of the 2 DBP functions.2 Type I deficiency represents a total deficiency of both the hydratase and hydroxyacyl-CoA dehydrogenase activities. Type II is an isolated deficiency of the hydratase activity, and type III is an isolated deficiency of the hydroxyacyl-CoA dehydro- genase activity. The 3 subgroups share a similar spectrum of clinical features but differ in severity: nearly all infants with type I deficiency die in the first year of life, whereas those with types II and III often survive beyond 10 years.1 Recently, a less severe form of DBP has been described in 5 families3–7 and designated juvenile DBP deficiency,5 or alternatively DBP deficiency type IV6 or multifunctional protein From the Murdoch Childrens Research Institute (D.J.A., A.P.L.M., G.G., M.B.D., K.P., R.J.L., P.J.L.), Royal Children’s Hospital (D.J.A., M.B. D., R.J.L.), Parkville; Department of Paediatrics (D.J.A., A.P.L.M., M.B.D., C.B., R.J.L., P.J.L.), Department of Medical Biology (R.T., M.B.), The University of Melbourne; Department of Medicine (Neuroscience) (E.S.), Central Clinical School, Monash University; and Population Health and Immunity Division (R.T., M.B.), The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria, Australia. Funding information and disclosures are provided at the end of the article. Go to Neurology.org/ng for full disclosure forms. The Article Processing Charge was paid by the authors. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially. Neurology.org/ng © 2016 American Academy of Neurology 1 ª 2016 American Academy of Neurology. Unauthorized reproduction of this article is prohibited. ataxia syndrome.8 Here, we describe 5 affected C24:0/C22:0 ratio was 0.762 (reference 0.550– individuals from 3 new families affected by 1.115) and C26:0/C22:0 ratio was 0.020 (reference , juvenile DBP deficiency and expand the pub- 0.035). Plasma phytanic acid level was 0.1 mg/ , lished phenotypic spectrum for this disorder. 100 mL (reference 0.7). Urine bile acid profile was normal. Pedigree 2 includes 2 affected siblings, a male METHODS Standard protocol approvals, registrations, and patient consents. The study was approved by the Royal and a female, along with 3 unaffected female sib- Children’s Hospital Human Research Ethics Committee lings born to nonconsanguineous parents of Leba- (approval number 28097). Participants were recruited following nese descent. The male sib (II-2) presented at age review of clinical details obtained from medical records and family 29 years with a 5-year history of progressive ataxia. interviews. Each participant signed an informed consent docu- His workmates had noticed impaired balance and ment before enrollment. slurred speech, of which he was unaware. Increased Genetic analysis. Genetic studies were performed essentially as falls and deteriorating handwriting had been noted described previously.9 Genomic DNA isolated from the periph- for3years.Hehadnotnotedanyvisualorhearing eral blood and single nucleotide polymorphism (SNP) genotype impairment or sensory symptoms, and there was no data were generated. Parametric multipoint linkage analysis was erectile dysfunction. performed specifying a rare recessive disease model. Genomic DNA was analyzed by whole-exome capture (Illumina TruSeq Examination revealed a very broad-based ataxic capture kit, San Diego, CA), and massively parallel sequencing gait with mild cerebellar dysarthria. There was bilat- (MPS) was performed on a HiSeq2000 (Axeq Technologies, eral horizontal gaze-evoked nystagmus, but horizontal Macrogen, Seoul, Korea). Reads were aligned to the reference saccades appeared normal. Upward saccades were hy- genome with Novoalign, and variants were identified with pometric, and downward saccades hypermetric. Tone SAMtools and annotated by ANNOVAR. Variants were and power were normal in the limbs, and deep ten- filtered in a step-wise manner against exclusion criteria including linkage region, minor allele frequency (#0.01, don reflexes were reduced but present without 1000 Genomes10), and functional impact. Inclusion criteria enhancement. There was bilateral appendicular included predicted damaging effects on the protein using ataxia, with notably slow and hypermetric ballistic PolyPhen-2 and SIFT. Sanger sequence analysis of HSD17B4 tracking (“finger chase”) movements. Vibration and was performed by PCR amplification (primer sequences pinprick perception were intact distally, but 2-point available on request). Primary fibroblast cells were analyzed by discrimination was clearly impaired at the great toes Western blot as previously described11 using anti-HSD17B4 (2.5 cm). Brain MRI at age 25 years showed mild (1:1000 HPA021479; Sigma-Aldrich, St. Louis, MO) and anti–b-actin antibody (1:10000 A5441; Sigma-Aldrich). The cerebellar atrophy with vermal emphasis and normal reference sequences used for HSD17B4 were NG_008182.1, brainstem and cerebrum. Audiology showed moder- NM_000414.3, and NP_000405.1. ate high-frequency hearing loss. At follow-up assess- ment 1 year later, his testosterone, luteinizing RESULTS Clinical descriptions. The clinical details of hormone (LH), follicle-stimulating hormone (FSH), 5 affected individuals from 3 pedigrees are presented and sperm count were normal. He had naturally con- in table 1 and the family pedigrees in figure 1A. ceived 2 sons and a daughter. Five years later, he Pedigree 1, comprising 2 affected sisters of required a wheelchair for mobility outside the house. Italian descent (II-1 and II-2), was published previ- His vibration perception threshold was well below the ously under the designation “Cerebellar ataxia with fifth percentile for his age, but pinprick sensation hypergonadotropic hypogonadism” (OMIM remained intact. #605672),12 prior to the identification of The sister of the family proband (II-1) presented HSD17B4 mutations. Briefly, the sisters, aged 57 at age 31 years with a 4-year history of dysarthria and 63 years at the most recent follow-up, both and impaired balance, although she reported always presented with adult-onset progressive cerebellar sensing some imbalance. She had been referred to ataxia and secondary amenorrhea due to hypergo- an ENT specialist, who had discovered moderate nadotropic hypogonadism. Intellect was normal, high-frequency sensorineural hearing loss (figure peripheral sensory neuropathy was observed, and 2A). Ovarian failure had been diagnosed on investi- there was sensorineural deafness with vestibular hy- gation for primary amenorrhea. Examination revealed pofunction. Neurologic symptoms were observed in a mildly broad-based gait and mild cerebellar dysar- the third decade, and secondary
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