New HSP Genetics Findings

From Germany, Norway, Pakistan, China, Japan

2 new SPG5A mutations detected

The hereditary spastic paraplegias (HSPs) comprise a group of genetically heterogeneous neurodegenerative diseases. Here, we evaluated the spectrum and frequency of mutations in the CYP7B1, PNPLA6 and C19orf12 genes (causative for the subtypes SPG5A, SPG39 and SPG43, respectively) in a cohort of 63 unrelated HSP patients with suspected autosomal recessive inheritance. Two novel homozygous mutations (one frameshift and one missense mutation) were detected in CYP7B1 (SPG5A), while no disease-causing mutation was identified for SPG39 or SPG43.

SOURCE: Mol Cell Probes. 2016 Feb;30(1):53-5. doi: 10.1016/j.mcp.2015.12.001. Epub 2015 Dec 20. Copyright © 2015. Published by Elsevier Ltd. PMID: 26714052 [PubMed – in process]

Mutational analysis of the CYP7B1, PNPLA6 and C19orf12 genes in autosomal recessive hereditary spastic paraplegia.

Schubert SF1, Hoffjan S2, Dekomien G3.

1Department of Human Genetics, Ruhr-University Bochum, 44801 Bochum, Germany; University Witten/Herdecke, Faculty of Health, 58448 Witten, Germany; Center for Rare Diseases Ruhr (CeSER), 44791 Bochum, Germany.

2Department of Human Genetics, Ruhr-University Bochum, 44801 Bochum, Germany; Center for Rare Diseases Ruhr (CeSER), 44791 Bochum, Germany.

3Department of Human Genetics, Ruhr-University Bochum, 44801 Bochum, Germany; Center for Rare Diseases Ruhr (CeSER), 44791 Bochum, Germany. Electronic address: gabriele.dekomien@rub.de.

SPG 7 in Norway associated with both HSP and hereditary ataxia

Founder mutation identified
BACKGROUND AND PURPOSE:

SPG7 is one of the most common forms of autosomal recessive hereditary spastic paraplegia. The phenotype has been shown to be heterogeneous, varying from a complex spastic ataxia to pure spastic paraplegia or pure ataxia. The aim of this study was to clinically and genetically characterize patients with SPG7 in Norway.

METHODS:

Six Norwegian families with a clinical diagnosis of hereditary spastic paraplegia were diagnosed with SPG7 through Sanger sequencing and whole-exome sequencing. Haplotypes were established to identify a possible founder mutation. All patients were thoroughly examined and the clinical and molecular findings are described.

RESULTS:

The core phenotype was spastic paraparesis with ataxia, bladder disturbances and progressive external ophthalmoplegia. The variant p.H701P was identified in homozygous state in one family and in compound heterozygous state in three families. Haplotype analysis of seven surrounding single nucleotide polymorphisms supports that this variant resides on a founder haplotype. Four of the families were compound heterozygous for the previously well-described p.A510V variant.

CONCLUSION:

SPG7 is a common subgroup of hereditary spinocerebellar disorders in Norway. The broad phenotype in the Norwegian SPG7 population illustrates the challenges with the traditional dichotomous classification of hereditary spinocerebellar disorders into hereditary spastic paraplegia or hereditary ataxia. A Norwegian founder mutation p.H701P was identified in four out of six families, making it a major cause of SPG7 in Norway.

SOURCE: Eur J Neurol. 2016 Jan 12. doi: 10.1111/ene.12937. [Epub ahead of print] © 2016 EAN. PMID: 26756429 [PubMed – as supplied by publisher]

A founder mutation p.H701P identified as a major cause of SPG7 in Norway.

Rydning SL1,2, Wedding IM1,2, Koht J3, Chawla M4, Øye AM5, Sheng Y5, Vigeland MD5, Selmer KK5, Tallaksen CM1,2.

1Department of Neurology, Oslo University Hospital, Norway.

2Institute of Clinical Medicine, University of Oslo, Norway.

3Department of Neurology, Drammen Hospital, Vestre Viken Health Trust, Norway.

4Department of Radiology and Nuclear Medicine, Oslo University Hospital, Norway.

5Department of Medical Genetics, Oslo University Hospital and University of Oslo, Norway.

2 new mutations found in ALS2 gene in Pakistani families

Associated with infantile-onset ascending HSP

Biallelic mutations of ALS2 cause a clinical spectrum of overlapping autosomal recessive neurodegenerative disorders: infantile-onset ascending hereditary spastic paralysis (IAHSP), juvenile primary lateral sclerosis (JPLS), and juvenile amyotrophic lateral sclerosis (ALS2). We report on eleven individuals affected with IAHSP from two consanguineous Pakistani families.

A combination of linkage analysis with homozygosity mapping and targeted sequencing identified two novel ALS2 mutations, a c.194T > C (p.Phe65Ser) missense substitution located in the first RCC-like domain of ALS2/alsin and a c.2998delA (p.Ile1000*) nonsense mutation.

This study of extended families including a total of eleven affected individuals suggests that a given ALS2 mutation may lead to a phenotype with remarkable intra-familial clinical homogeneity.

SOURCE: Amyotroph Lateral Scler Frontotemporal Degener. 2016 Jan 11:1-6. [Epub ahead of print] PMID: 26751646 [PubMed – as supplied by publisher]

Identification of two novel ALS2 mutations in infantile-onset ascending hereditary spastic paraplegia.

Daud S1, Kakar N2,3,4, Goebel I2,5, Hashmi AS1, Yaqub T1,6, Nürnberg G7, Nürnberg P7,8,9, Morris-Rosendahl DJ10,11, Wasim M1, Volk AE2,5, Kubisch C2,5, Ahmad J4, Borck G2.

1a Institute of Biochemistry and Biotechnology (IBBt), UVAS , Lahore , Pakistan

2b Institute of Human Genetics, University of Ulm , Ulm , Germany

3c International Graduate School in Molecular Medicine Ulm, University of Ulm , Ulm , Germany

4d Department of Biotechnology and Informatics , BUITEMS , Quetta , Pakistan

5e Institute of Human Genetics, University Medical Center Hamburg-Eppendorf , Hamburg , Germany

6f Department of Microbiology , UVAS , Lahore , Pakistan

7g Cologne Center for Genomics (CCG), University of Cologne , Cologne , Germany

8h Center for Molecular Medicine Cologne (CMMC), University of Cologne , Cologne , Germany

9i Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne , Cologne , Germany

10j Clinical Genetics and Genomics, Royal Brompton Hospital , London , United Kingdom

11k National Heart and Lung Institute, Imperial College London , London , United Kingdom.8

First case of pure SPG14 HSP found

Previously only complicated forms had been identified

The first-ever case of pure SPG 14 HSP has been reported in a research study of a Chinese family with no interbreeding. Previously, SPG 14 HSP had only ever been found in the complicated form, and that was in Italian families.

Hereditary spastic paraplegia (HSP) is a clinical and genetic heterogeneity group of neurodegenerative disorders which is characterized by progressive weakness and spasticity of the lower limbs. More than 70 genetic types of HSP have been described so far.

Here we describe a Chinese non-consanguineous family with two affected siblings manifesting early-onset autosomal recessive HSP in pure forms.

To identify genotype and characterize phenotype, CytoScan HD array analysis was performed on the two siblings. A run of homozygosity (ROH) shared by the two patients was detected on chromosome 3q28-q29. The ROH region, about 7.7Mb on the chromosome 3:190172058-197851260 partially overlapped with the ROH region of SPG14 previously reported. Subsequently, microsatellite analysis confirmed this ROH and whole-exome sequencing was carried out while no causative mutations were found in the exons of known HSP genes and 68 candidate genes in that region.

In conclusion, our data suggest the ROH in this region may play a pivotal role in SPG14 pathogenesis. This is the first clinical description of a pure form spastic paraplegia in a non-consanguineous family associated with the SPG14 locus.

SOURCE: J Neurol Sci. 2015 Dec 15;359(1-2):351-5. doi: 10.1016/j.jns.2015.10.057. Epub 2015 Nov 4. Copyright © 2015 Elsevier B.V. All rights reserved. PMID: 26671141 [PubMed – in process]

Microarray analysis unmasked two siblings with pure hereditary spastic paraplegia shared a run of homozygosity region on chromosome 3q28-q29.

Yu W1, You X2, Wang D1, Dong K1, Su J3, Li C3, Liu J1, Zhang Q1, You F1, Wang X1, Huang J1, Qiao B4, Duan W5.

1Institute of Cardiovascular Disease, General Hospital of Jinan Military Region, 8 Lashan Road, Jinan 250022, China.

2Division of Quality Management, Shandong Center for Disease Control and Prevention, 16992 Jingshi Road, Jinan 250014, China.

3Department of Neurology, General Hospital of Jinan Military Region, 25 Shifan Road, Jinan 250031, China.

4Institute of Cardiovascular Disease, General Hospital of Jinan Military Region, 8 Lashan Road, Jinan 250022, China. Electronic address: cijnmd@outlook.com.

5Institute of Cardiovascular Disease, General Hospital of Jinan Military Region, 8 Lashan Road, Jinan 250022, China. Electronic address: dwy2115@126.com.

New SPAST (SPG4) and SPG3A mutations found

Linkage analysis a powerful tool in gene discovery

We studied four Chinese families with pure hereditary spastic paraplegia (HSP) to investigate the clinical features and associated genetic mutations.

Linkage analysis was performed for all families to map the disease locus onto autosomal chromosomes, and related loci involved in HSP on the X chromosome were also examined. Polymerase chain reaction (PCR) sequencing was used to detect gene mutations. To confirm the influence of a splice-site mutation on mRNA, we used reverse transcription-PCR and direct sequencing. Linkage analysis and ATL1 gene sequencing of amniocytes were performed for prenatal genetic diagnosis.

One missense variant (c.1517T>A) and a splice-site mutation (c.1245+1G>A) in SPAST, and two missense variants (c.715C>T, c.1204T>G) in ATL1 were identified. The c.1245+1G>A mutation caused a deletion of exon 9 in the SPAST gene. Prenatal genetic diagnosis showed that fetus did not carry the ALT1 c.1204T>G mutation. Follow-up was maintained for 5 years, and the negative result was confirmed by evidence of a healthy growing boy.

We identified two novel mutations and two previously reported mutations in SPAST and ATL1, respectively. The family with the ATL1 c.1204T>G mutation exhibited male-lethality, female infancy-onset, and pseudo- X-linked dominant transmission, which had never been previously reported for HSP. Characteristic facial features were also noticed. The boy on whom prenatal gene diagnosis was performed is healthy and without an unusual face, suggesting that the c.1204T>G mutation might be related to these features. The results extend the genetic spectrum of HSP and suggest that linkage analysis remains a powerful tool in gene discovery studies.

SOURCE: Genet Mol Res. 2015 Nov 23;14(4):14690-7. doi: 10.4238/2015.November.18.33. PMID: 26600529 [PubMed – in process]

Mutation analysis of four Chinese families with pure hereditary spastic paraplegia: pseudo- X-linked dominant inheritance and male lethality due to a novel ATL1 mutation.

Zhao N1, Sui Y1, Li XF1, Liu W1, Lu YP1, Feng WH1, Ma C1, Wang YW2, Bao HX2, Huang F2, Wang H2, Yi DX2, Han WT1, Jiang M1.

1Key Laboratory of Reproductive Health and Medical Genetics, National Health and Family Planning Commission, Shenyang, China.

2Affiliated Hospital of Liaoning Provincial Research Institute, National Health and Family Planning Commission, Shenyang, China.

New SPG11 mutation identified in Japan

We identified a novel homozygous mutation in the splice site donor (SSD) of intron 30 (c.5866+1G>A) in consanguineous Japanese SPG11 siblings showing late-onset spastic paraplegia using the whole-exome sequencing.

Phenotypic variability was observed, including age-at-onset, dysarthria and pes cavus. Coding DNA sequencing revealed that the mutation affected the recognition of the constitutive SSD of intron 30, splicing upstream onto a nearby cryptic SSD in exon 30. The use of constitutive splice sites of intron 29 was confirmed by sequencing. The mutant transcripts are mostly subject to degradation by the nonsense-mediated mRNA decay system. SPG11 transcripts, escaping from the nonsense-mediated mRNA decay pathway, would generate a truncated protein (p.Tyr1900Phefs5X) containing the first 1899 amino acids and followed by 4 aberrant amino acids.

This study showed a successful clinical application of whole-exome sequencing in spastic paraplegia and demonstrated a further evidence of allelic heterogeneity in SPG11. The confirmation of aberrant transcript by splice site mutation is a prerequisite for a more precise molecular diagnosis.

SOURCE: J Neurol Sci. 2015 Dec 15;359(1-2):250-5. doi: 10.1016/j.jns.2015.10.045. Epub 2015 Oct 30. Copyright © 2015 Elsevier B.V. All rights reserved. PMID: 26671123 [PubMed – in process]

Late-onset spastic paraplegia: Aberrant SPG11 transcripts generated by a novel splice site donor mutation.

Kawarai T1, Miyamoto R2, Mori A3, Oki R4, Tsukamoto-Miyashiro A5, Matsui N6, Miyazaki Y7, Orlacchio A8, Izumi Y9, Nishida Y10, Kaji R11.

1Department of Clinical Neuroscience, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan. Electronic address: tkawarai@tokushima-u.ac.jp.

2Department of Clinical Neuroscience, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan. Electronic address: ninigii@gmail.com.

3Department of Clinical Neuroscience, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan. Electronic address: noa@tokushima-u.ac.jp.

4Department of Clinical Neuroscience, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan. Electronic address: okkey19840323@gmail.com.

5Department of Clinical Neuroscience, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan. Electronic address: amiyashiro818@tokushima-u.ac.jp.

6Department of Clinical Neuroscience, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan. Electronic address: naoko@tokushima-u.ac.jp.

7Department of Clinical Neuroscience, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan. Electronic address: miyazaki@tokushima-u.ac.jp.

8Laboratorio di Neurogenetica, CERC-IRCCS Santa Lucia, Rome, Italy; Dipartimento di Medicina dei Sistemi, Università di Roma “Tor Vergata”, Rome, Italy. Electronic address: a.orlacchio@hsantalucia.it.

9Department of Clinical Neuroscience, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan. Electronic address: yizumi@tokushima-u.ac.jp.

10Itsuki Hospital, Tokushima 770-0852, Japan. Electronic address: ynishida@shirt.ocn.ne.jp.

11Department of Clinical Neuroscience, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan. Electronic address: rkaji@tokushima-u.ac.jp.

New SPG3A mutation found

Demonstrates that mutations in the Atlastin gene can cause recessive as well as dominant inheritance.

Hereditary spastic paraplegia (HSP) is an extremely heterogeneous disease caused by mutations of numerous genes leading to lower limb spasticity (pure forms) that can be accompanied by neurological symptoms (complex forms). Despite recent advances, many causal mutations in patients remain unknown.

We identified a consanguineous family with the early-onset HSP. Whole-exome sequencing revealed homozygosity for a novel Atlastin GTPase 1 gene stop mutation in three affected siblings. Heterozygous parents and siblings were unaffected.

This was unexpected as mutations in the Atlastin 1 gene are known to cause autosomal dominant HSP. But our study showed that Atlastin 1 mutations may cause autosomal recessively inherited paraplegia with an underlying loss-of-function mechanism. Hence, patients with recessive forms of HSP should also be tested for the Atlastin 1 gene.

SOURCE: J Hum Genet. 2016 Feb 18. doi: 10.1038/jhg.2016.6. [Epub ahead of print] PMID: 26888483 [PubMed – as supplied by publisher]

Homozygous mutation in Atlastin GTPase 1 causes recessive hereditary spastic paraplegia.

Willkomm L1,2, Heredia R3, Hoffmann K4, Wang H1,2, Voit T5, Hoffman EP3, Cirak S1,2,3,6.

1Institute of Human Genetics, University Hospital Cologne, Cologne, Germany.

2Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.

3Research Center for Genetic Medicine, Children’s National Medical Center, Washington, DC, USA.

4Institute of Human Genetics, Martin-Luther-University Halle-Wittenberg, Halle an der Saale, Germany.

5Institute of Myology, Pierre and Marie Curie University, UPMC-INSERM UMR 974, Paris, France.

6Department of Peadiatrics, University Hospital Cologne, Cologne, Germany.