Posted - February 2017 in Research Highlights
From China, the Middle East, Italy and France
New causative SPG4 mutation found
Han Chinese family, Shandong province
Hereditary spastic paraplegias (HSPs) are a group of neurodegenerative disorders of highly clinical and genetic heterogeneity. SPG4 (SPAST) is the most common type of pure autosomal dominant hereditary spastic paraplegia (ADHSP) and its mutations account for 40% of all mutations associated with the ADHSP.
The purpose of this study was to identify the causative gene mutation and explore the genotype-phenotype correlation through the investigation of a Chinese Han family with ADHSP, which could lay solid foundation for further study of the pathogenesis and provide the basis for prenatal diagnosis for this disease.
Whole exome sequencing (WES) was performed on subjects with HSP from a Chinese family in Shandong Province. Systematic clinical analysis and 3.0T Magnetic resonance imaging (MRI) scans of brain and spinal cord on the affected proband were also accomplished. As a result, a novel nonsense SPG4 mutation, a single-nucleotide change from C to T which caused a substitution from glutamine to an immature stop codon at codon 536 (c.1606C>T, p.Gln536X), was identified. This mutation co-segregates with the HSP patients in this pedigree. MRI revealed no significant atrophy of spinal cord and brain in the proband.
In conclusion, our finding suggests that the novel nonsense mutation in SPG4 is causative to HSP and it’s of great significance in supplementing the mutational spectrum of the SPG4 and explaining the mechanism of HSPs. Our study also indicates that WES can be an efficient and rapid diagnostic tool for some complex and genetically heterogeneous diseases.
SOURCE: Int J Clin Exp Pathol 2016;9(10):10274-10281 www.ijcep.com /ISSN:1936-2625/IJCEP0034005
Whole exome sequencing identifies a novel SPG4 mutation in a Chinese family with hereditary spastic paraplegias
Shiguo Liu1*, Zhongcui Jing2*, Shien Liu3, Xueping Zheng4, Haiyan Wang2, Wenjian Xu3, Fengyuan Che5
1 Prenatal Diagnosis Center, The Affiliated Hospital of Qingdao University, Qingdao, China;
2 Department of Blood Transfusion, The Affiliated Hospital of Qingdao University, Qingdao, China;
3 Department of Radiology, The Affiliated Hospital of Qingdao University, Qingdao, China;
4 Department of Neurology, The Affiliated Hospital of Qingdao University, Qingdao, China;
5 Department of Neurology, Linyi People’s Hospital, Shandong University, Linyi, China.
New SPG23 mutation identified
Palestinian, Jordanian and Israeli families
This study identified a new SPG23 autosomal-recessive mutation associated with complex HSP in 10 members of three different families. Cellular studies based on skin biopsies revealed abnormalities in organelles, notably swollen mitochondria and vacuoles in the cytoplasm of melanocytes. This large study was carried out by a collaboration of researchers from England, Scotland, Japan, Taiwan, Israel, USA and Kuwait.
SPG23 is an autosomal-recessive neurodegenerative subtype of lower limb spastic paraparesis with additional diffuse skin and hair dyspigmentation at birth followed by further patchy pigment loss during childhood. Previously, genome-wide linkage in an Arab-Israeli pedigree mapped the gene to an approximately 25 cM locus on chromosome 1q24-q32.
By using whole-exome sequencing in a further Palestinian-Jordanian SPG23 pedigree, we identified a complex homozygous 4-kb deletion/20-bp insertion in DSTYK (dual serine-threonine and tyrosine protein kinase) in all four affected family members. DSTYK is located within the established linkage region and we also found the same mutation in the previously reported pedigree and another Israeli pedigree (total of ten affected individuals from three different families). The mutation removes the last two exons and part of the 3′ UTR of DSTYK. Skin biopsies revealed reduced DSTYK protein levels along with focal loss of melanocytes. Ultrastructurally, swollen mitochondria and cytoplasmic vacuoles were also noted in remaining melanocytes and some keratinocytes and fibroblasts. Cultured keratinocytes and fibroblasts from an affected individual, as well as knockdown of Dstyk in mouse melanocytes, keratinocytes, and fibroblasts, were associated with increased cell death after ultraviolet irradiation. Keratinocytes from an affected individual showed loss of kinase activity upon stimulation with fibroblast growth factor.
Previously, dominant mutations in DSTYK were implicated in congenital urological developmental disorders, but our study identifies different phenotypic consequences for a recurrent autosomal-recessive deletion mutation in revealing the genetic basis of SPG23.
SOURCE: Am J Hum Genet. 2017 Feb 2;100(2):364-370. doi: 10.1016/j.ajhg.2017.01.014. PMID: 28157540 PMCID: PMC5294675 [Available on 2017-08-02] Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved. [PubMed – in process]
Large Intragenic Deletion in DSTYK Underlies Autosomal-Recessive Complicated Spastic Paraparesis, SPG23.
Lee JY1, Hsu CK2, Michael M3, Nanda A4, Liu L5, McMillan JR5, Pourreyron C6, Takeichi T7, Tolar J8, Reid E9, Hayday T3, Blumen SC10, Abu-Mouch S11, Straussberg R12, Basel-Vanagaite L13, Barhum Y14, Zouabi Y15, Al-Ajmi H4, Huang HY16, Lin TC16, Akiyama M17, Lee JY16, McLean WH18, Simpson MA19, Parsons M3, McGrath JA20.
1 St John’s Institute of Dermatology, King’s College London (Guy’s Campus), London SE1 9RT, UK.
2 Department of Dermatology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan; Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan.
3 Randall Division of Cell and Molecular Biophysics, King’s College London (Guy’s Campus), London SE1 9RT, UK.
4 As’ad Al-Hamad Dermatology Center, Al-Sabah Hospital, Kuwait City 13001, Kuwait.
5 The National Diagnostic EB Laboratory, Viapath, St Thomas’ Hospital, London SE1 7EH, UK.
6 Jacqui Wood Cancer Centre, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK.
7 St John’s Institute of Dermatology, King’s College London (Guy’s Campus), London SE1 9RT, UK; Department of Dermatology, Nagoya University Graduate School of Medicine, Nagoya 466-8560, Japan.
8 Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN 55455, USA; Stem Cell Institute, University of Minnesota, Minneapolis, MN 55455, USA.
9 Cambridge Institute for Medical Research (CIMR), University of Cambridge, Cambridge CB2 0XY, UK; Department of Medical Genetics, Addenbrooke’s Hospital, University of Cambridge, Cambridge CB2 0QQ, UK.
10 Department of Neurology, Hillel Yaffe Medical Center, Hadera 38100, Israel; Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa 3525433, Israel.
11 Liver Unit, Department of Internal Medicine B, Hillel Yaffe Medical Center, Hadera 38100, Israel.
12 Neurogenetic Service, Neurology Institute, Schneider Children’s Medical Center, Petah Tikva 49202, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
13 Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel; Raphael Recanati Genetic Institute, Rabin Medical Center, Beilinson Campus, Petah Tikva 49100, Israel; Pediatric Genetics Unit, Schneider Children’s Medical Center, Petah Tikva 49202, Israel; Felsenstein Medical Research Center, Rabin Medical Center, Petah Tikva 4941492, Israel.
14 Laboratory of Clinical Neuroscience, Felsenstein Medical Research Center, Rabin Medical Center, Petah Tikva 4941492, Israel; Department of Neurology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
15 Neurogenetic Service, Neurology Institute, Schneider Children’s Medical Center, Petah Tikva 49202, Israel.
16 Department of Dermatology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan.
17 Department of Dermatology, Nagoya University Graduate School of Medicine, Nagoya 466-8560, Japan.
18 Centre for Dermatology and Genetic Medicine, Division of Molecular Medicine, University of Dundee, Dundee DD1 5EH, UK.
19 Department of Medical and Molecular Genetics, King’s College London, School of Medicine, Guy’s Hospital, London SE1 9RT, UK.
20 St John’s Institute of Dermatology, King’s College London (Guy’s Campus), London SE1 9RT, UK; Centre for Dermatology and Genetic Medicine, Division of Molecular Medicine, University of Dundee, Dundee DD1 5EH, UK. Electronic address: [email protected].
New SPG39 variant causes cerebellar ataxia
Mutation discovered in Indian Parsi family
Autosomal-recessive cerebellar ataxias (ARCA) are clinically and genetically heterogeneous conditions primarily affecting the cerebellum. Mutations in the PNPLA6 gene have been identified as the cause of hereditary spastic paraplegia and complex forms of ataxia associated with retinal and endocrine manifestations in a field where the genotype-phenotype correlations are rapidly expanding.
We identified two cousins from a consanguineous family belonging to a large Zoroastrian (Parsi) family residing in Mumbai, India, who presented with pure cerebellar ataxia without chorioretinal dystrophy or hypogonadotropic hypogonadism. We used a combined approach of clinical characterisation, homozygosity mapping, whole-exome and Sanger sequencing to identify the genetic defect in this family. The phenotype in the family was pure cerebellar ataxia.
Homozygosity mapping revealed one large region of shared homozygosity at chromosome 19p13 between affected individuals. Within this region, whole-exome sequencing of the index case identified two novel homozygous missense variants in the PNPLA6 gene at c.3847G>A (p.V1283M) and c.3929A>T (p.D1310V) in exon 32. Both segregated perfectly with the disease in this large family, with only the two affected cousins being homozygous.
We identified for the first time PNPLA6 mutations associated with pure cerebellar ataxia in a large autosomal-recessive Parsi kindred. Previous mutations in this gene have been associated with a more complex phenotype but the results here suggest an extension of the associated disease spectrum.
SOURCE: Cerebellum. 2017 Feb;16(1):262-267. doi: 10.1007/s12311-016-0769-x. PMID: 26995604 PMCID: PMC5243903 [PubMed – in process]
Pure Cerebellar Ataxia with Homozygous Mutations in the PNPLA6 Gene.
Wiethoff S1,2,3, Bettencourt C4,5, Paudel R4, Madon P6, Liu YT4,7,8, Hersheson J4,9, Wadia N10, Desai J10, Houlden H4,9.
1 Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK. [email protected]
2 Center for Neurology and Hertie Institute for Clinical Brain Research, Eberhard-Karls-University, Tübingen, Germany. [email protected]
3 National Hospital for Neurology and Neurosurgery, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK. [email protected]
4 Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
5 Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, UK.
6 Department of Assisted Reproduction and Genetics, Jaslok Hospital and Research Centre, Mumbai, 400026, India.
7 Section of Epilepsy, Department of Neurology, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan.
8 National Yang-Ming University School of Medicine, Taipei, Taiwan.
9 National Hospital for Neurology and Neurosurgery, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
10 Department of Neurology, Jaslok Hospital and Research Centre, Mumbai, India.
New SPG11 mutation found in Hong Kong study
Adds to the 101 variants already found in SPG11
Hereditary spastic paraplegias (HSPs) are a group of heterogeneous neurodegenerative disorders, which are often presented with overlapping phenotypes such as progressive paraparesis and spasticity. To assist the diagnosis of HSP subtypes, next-generation sequencing is often used to provide supporting evidence.
In this study, we report the case of two probands from the same family with HSP symptoms, including bilateral lower limb weakness, unsteady gait, cognitive decline, dysarthria, and slurring of speech since the age of 14. Subsequent whole-genome sequencing revealed that the patients are compound heterozygous for variants in the SPG11 gene, including the paternally inherited c.6856C>T (p.Arg2286*) variant and the novel maternally inherited c.2316+5G>A splice-donor region variant. Variants in SPG11 are the common cause of autosomal recessive spastic paraplegia type 11.
According to the ClinVar database, there are already 101 reported pathogenic variants in SPG11 that are associated with HSPs. To our knowledge, this is the first report of SPG11 variants in our local population. The novel splice variant identified in this study enriches the catalog of SPG11 variants, potentially leading to better genetic diagnosis of HSPs.
SOURCE: Cold Spring Harb Mol Case Stud. 2016 Nov;2(6):a001248. PMID: 27900367 PMCID: PMC5111012 [PubMed – in process]
Whole-genome sequencing of two probands with hereditary spastic paraplegia reveals novel splice-donor region variant and known pathogenic variant in SPG11.
Yu AC1, Chan AY2, Au WC3, Shen Y4, Chan TF5, Chan HE6.
1 School of Life Sciences, Faculty of Science, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR;; Partner State Key Laboratory of Agrobiotechnology, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR.
2 Division of Neurology, Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR.
3 Division of Neurology, Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR;; Gerald Choa Neuroscience Centre, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR.
4 School of Life Sciences, Faculty of Science, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR.
5 School of Life Sciences, Faculty of Science, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR;; Partner State Key Laboratory of Agrobiotechnology, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR;; Gerald Choa Neuroscience Centre, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR.
6 School of Life Sciences, Faculty of Science, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR;; Gerald Choa Neuroscience Centre, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR.
Two mutations discovered in SPG35 HSP Italian family
Compound heterozygous mutation from unrelated parents, previously seen only in the South Asian population.
Autosomal recessive spastic paraplegia form 35 (SPG35) is a rare form of Hereditary Spastic Paraplegia (HSP, MIM 18260) characterized by childhood onset of spasticity, cognitive decline and leukodystrophy . Additional clinical features such as seizures, dysphagia, dysarthria, dystonia, neuropathy and brain iron accumulation were also observed .
Mutations in the fatty acid 2-hydroxylase (FA2H) gene have been associated to the SPG35 form. FA2H encodes a nicotinamide adenine dinucleotide phosphate (NADPH)-dependent monooxygenase, involved in the synthesis of 2-hydroxy fatty acid galactolipids, that are the major component of myelin sheath .
SOURCE: J Neurol Sci. 2017 Jan 15;372:347-349. doi: 10.1016/j.jns.2016.11.069. Epub 2016 Dec 5. PMID: 28017243 [PubMed – in process]
Exome sequencing reveals two FA2H mutations in a family with a complicated form of Hereditary Spastic Paraplegia and psychiatric impairments.
Magariello A1, Russo C2, Citrigno L1, Züchner S3, Patitucci A1, Mazzei R1, Conforti FL1, Ferlazzo E2, Aguglia U4, Muglia M5.
1 Institute of Neurological Sciences, National Research Council, Mangone, CS, Italy.
2 Regional Epilepsy Centre, Bianchi-Melacrino-Morelli Hospital, Reggio Calabria, Italy.
3 Department of Human Genetics and Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
4 Regional Epilepsy Centre, Bianchi-Melacrino-Morelli Hospital, Reggio Calabria, Italy; Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy.
5 Institute of Neurological Sciences, National Research Council, Mangone, CS, Italy. Electronic address: [email protected].
New mutation of the REEP1 gene (SPG31).
Found in 64-year-old French woman
Hereditary spastic paraplegia (HSP) is a heterogeneous group of diseases little known in clinical practice due to its low prevalence, slow progression, and difficult diagnosis. This results in an underestimation of HSP leading to belated diagnosis and management. In depth diagnosis is based on clinical presentation and identification of genomic mutations. We describe the clinical presentation and pathogeny of HSP through a report of a case due to a novel mutation of the REEP1 gene (SPG31).
A 64-year-old woman presented gait disturbances due to spasticity of the lower limbs progressing since her third decade. Previous investigations failed to find any cause.
DNA analysis was performed to search for HSP causing mutations.
A novel heterozygote mutation (c.595 + 1G>A) of the REEP1 gene, within the splice site of intron 6, was discovered. This nucleotide change causes exon 6 skipping leading to frame shift and a truncated transcript identified by complementary DNA sequencing of reverse transcription polymerase chain reaction products.
REEP1 is a known protein predominantly located in the upper motor neurons. Mutation of REEP1 primary affects the longest axons explaining predominance of pyramidal syndrome on lower limbs.
Slow progressive pyramidal syndrome of the lower limbs should elicit a diagnosis of HSP. We describe a novel mutation of the REEP1 gene causing HSP. Pathogeny is based on resulting abnormal REEP1 protein, which is involved in the development of longest axons constituting the corticospinal tracts.
SOURCE: Medicine (Baltimore). 2017 Jan;96(3):e5911. doi: 10.1097/MD.0000000000005911. PMID: 28099355 PMCID: PMC5279100 [PubMed – in process]
Hereditary spastic paraplegia due to a novel mutation of the REEP1 gene: Case report and literature review.
Richard S1, Lavie J, Banneau G, Voirand N, Lavandier K, Debouverie M.
1 aDepartment of Neurology, University Hospital of Nancy, Nancy bDepartment of Neurology, Hospital of Bar-le-Duc, Bar-le-Duc cCentre d’Investigation Clinique Plurithématique CIC-P 1433, Inserm U1116, University Hospital of Nancy, Vandoeuvre-lès-Nancy dLaboratory of Rare Diseases: Genetic and Metabolism (MRGM), University Hospital Pellegrin, Bordeaux eDepartment of Genetics, Pitié-Salpêtrière Hospital, Public Hospital Network of Paris, Paris, France.
Two new SPG5 mutations discovered
Large study of 117 people in Italy with both HSP and MS
Autosomal recessive (AR) spastic paraplegia type 5 (SPG5) is due to mutations in the CYP7B1 gene, encoding for the cytochrome P450-7B1, responsible for oxysterols 7α-hydroxylation. Oxysterol/cholestenoic acids pool plays a role in motor neuron survival and immune response. SPG5 is characterized by white matter abnormalities at brain resonance imaging (MRI). In view of clinical presentation and MRI findings, multiple sclerosis (MS) is a possible differential diagnosis of SPG5. This study aimed to evaluate the frequency of CYP7B1 mutations in patients with MS.
117 MS patients with clinical spastic paraplegia or possible AR transmission were selected for the mutational screening.
Forty-three patients had primary progressive, 26 relapsing remitting, 26 secondary progressive, and 22 relapsing progressive MS clinical course. No CYP7B1 homozygous mutations were identified. Two novel variants and one pathogenic mutation were found at heterozygous state.
The two novel variants cosegregated with pyramidal signs and autoimmune diseases suggesting that they might be susceptibility factors. Reduced cytochrome P450-7B1 enzymatic activity could alter the balance among neurotoxic and neuroprotective oxysterols promoting motor neuron degeneration and/or immune response.
SOURCE: Acta Neurol Scand. 2016 Jun;133(6):410-4. doi: 10.1111/ane.12476. Epub 2015 Sep 15. PMID: 26370385 [PubMed – indexed for MEDLINE] © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
SPG5 and multiple sclerosis: clinical and genetic overlap?
Criscuolo C1, Carbone R1, Lieto M1, Peluso S1, Guacci A1, Filla A1, Quarantelli M2, Lanzillo R1, Morra VB1, De Michele G1.
1 Department of Neurosciences, Reproductive Sciences and Odontostomatology, ‘Federico II’ University of Naples, Naples, Italy.
2 Biostructure and Bioimaging Institute, National Research Council, Naples, Italy.