New HSP genetic findings

From Japan, Poland, England, China, Hungary, Morocco, Canada, Italy and the USA


A common theme emerging from the 9 research studies on HSP genetics reviewed below is that the pace and rate of discovery of new genetic causes of HSP is not slowing down despite the continuing stream of new discoveries that we report here each quarter. Also, the list of genetic variants of ‘unknown significance’, meaning that it is not clear if these mutations are disease-causing or not, grows longer and longer.


Similarly, the complexity of the HSP landscape continues to expand, not only within the confines of the condition but in the relationship and overlap with other conditions.



32 new mutations found in 16 main HSP genes

49 mutations found in 46 HSPers out of a total of 129 HSPers in this large Japanese study.

Hereditary spastic paraplegia (HSP) is one of the most genetically heterogeneous neurodegenerative disorders characterized by progressive spasticity and pyramidal weakness of lower limbs.

Because >30 causative genes have been identified, screening of multiple genes is required for establishing molecular diagnosis of individual patients with HSP. To elucidate molecular epidemiology of HSP in the Japanese population, we have conducted mutational analyses of 16 causative genes of HSP (L1CAM, PLP1, ATL1, SPAST, CYP7B1, NIPA1, SPG7, KIAA0196, KIF5A, HSPD1, BSCL2, SPG11, SPG20, SPG21, REEP1 and ZFYVE27) using resequencing microarrays, array-based comparative genomic hybridization and Sanger sequencing.

The mutational analysis of 129 Japanese patients revealed 49 mutations in 46 patients, 32 of which were novel. Molecular diagnosis was accomplished for 67.3% (33/49) of autosomal dominant HSP patients. Even among sporadic HSP patients, mutations were identified in 11.1% (7/63) of them. The present study elucidated the molecular epidemiology of HSP in the Japanese population and further broadened the mutational and clinical spectra of HSP.

SOURCE: J Hum Genet. 2014 Mar;59(3):163-72. doi: 10.1038/jhg.2013.139. Epub 2014 Jan 23. PMID: 24451228 [PubMed – indexed for MEDLINE]

Molecular epidemiology and clinical spectrum of hereditary spastic paraplegia in the Japanese population based on comprehensive mutational analyses.

Ishiura H1, Takahashi Y1, Hayashi T1, Saito K2, Furuya H3, Watanabe M4, Murata M5, Suzuki M6, Sugiura A7, Sawai S8, Shibuya K9, Ueda N10, Ichikawa Y1, Kanazawa I11, Goto J1, Tsuji S1.

1 Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

2 Institute of Medical Genetics, Tokyo Women’s Medical University, Tokyo, Japan.

3 Department of Neurology, Neuro-Muscular Center, National Omuta Hospital, Fukuoka, Japan.

4 Department of Neurology, Institute of Brain Science, Hirosaki University Graduate School of Medicine, Aomori, Japan.

5 Department of Neurology, National Center of Neurology and Psychiatry, Tokyo, Japan.

6 Department of Neurology, Higashisaitama Hospital, National Hospital Organization, Saitama, Japan.

7 Department of Neurology, Shizuoka Institute of Epilepsy and Neurological Disorders, Shizuoka, Japan.

8 1] Department of Molecular Diagnosis, Graduate School of Medicine, Chiba University, Chiba, Japan [2] Division of Laboratory Medicine and Clinical Genetics, Chiba University Hospital, Chiba, Japan.

9 Department of Neurology, Graduate School of Medicine, Chiba University, Chiba, Japan.

10 1] Department of Neurology, Chigasaki Municipal Hospital, Kanagawa, Japan [2] Department of Neurology, Yokohama City University School of Medicine, Kanagawa, Japan.

11 Graduate School, International University of Health and Welfare, Tokyo, Japan.



19 new HSP mutations found in Poland

Large study of the 3 main HSP genes

This large Polish study of 216 unrelated HSPers found 13 new mutations causing SPG4 HSP, 4 causing SPG3A and 2 causing SPG31.

Hereditary spastic paraplegias (HSPs) consist of a heterogeneous group of genetically determined neurodegenerative disorders. Progressive lower extremity weakness and spasticity are the prominent features of HSPs resulting from retrograde axonal degeneration of the corticospinal tracts. Three genetic types, SPG3 (ATL1), SPG4 (SPAST) and SPG31 (REEP1), appear predominantly and may account for up to 50% of autosomal dominant hereditary spastic paraplegias (AD-HSPs).

Here, we present the results of genetic testing of the three mentioned SPG genetic types in a group of 216 unrelated Polish patients affected with spastic paraplegia. Molecular evaluation was performed by multiplex ligation-dependent probe amplification (MLPA) and DNA sequencing.

Nineteen novel mutations: 13 in SPAST, 4 in ATL1 and 2 in REEP1, were identified among overall 50 different mutations detected in 57 families. Genetic analysis resulted in the identification of molecular defects in 54% of familial and 8.4% of isolated cases. Our research expanded the causative mutations spectrum of the three most common genetic forms of HSPs found in a large cohort of probands originating from Central Europe.

SOURCE: J Neurol Sci. 2015 Dec 15;359(1-2):35-9. doi: 10.1016/j.jns.2015.10.030. Epub 2015 Oct 17. PMID: 26671083 [PubMed – in process]

Molecular spectrum of the SPAST, ATL1 and REEP1 gene mutations associated with the most common hereditary spastic paraplegias in a group of Polish patients.

Elert-Dobkowska E1, Stepniak I1, Krysa W1, Rajkiewicz M1, Rakowicz M2, Sobanska A2, Rudzinska M3, Wasielewska A4, Pilch J5, Kubalska J1, Lipczynska-Lojkowska W6, Kulczycki J6, Kurdziel K7, Sikorska A8, Beetz C9, Zaremba J10, Sulek A11.

1 Department of Genetics, Institute of Psychiatry and Neurology, Warsaw, Poland.

2 Department of Clinical Neurophysiology, Institute of Psychiatry and Neurology, Warsaw, Poland.

3 Department of Neurology, Medical University of Silesia, Katowice, Poland.

4 Department of Neurology, University Hospital, Krakow, Poland.

5 Department of Pediatric Neurology, Medical University of Silesia, Katowice, Poland.

6 First Department of Neurology, Institute of Psychiatry and Neurology, Warsaw, Poland.

7 Department of Pediatric Neurology, St. Ludwig’s Children Hospital, Krakow, Poland.

8 Department of Genetics and Animal Breeding, University of Life Sciences, Poznan, Poland.

9 Department of Clinical Chemistry and Laboratory Diagnostics, Jena University Hospital, Jena, Germany.

10 Department of Genetics, Institute of Psychiatry and Neurology, Warsaw, Poland; Division Five of Medical Sciences, Polish Academy of Science, Warsaw, Poland.

11 Department of Genetics, Institute of Psychiatry and Neurology, Warsaw, Poland. Electronic address: [email protected].



Complex (complicated) HSP studied

In this large English study, 30/97 people with complex HSP (31%) were found to have SPG11 HSP. The next most common was SPG7 (5%), SPG35 (4%) and SPG15 (2%).

Some of the gene variants identified are usually associated with pure HSP. No genetic cause was identified in 51% of the people studied, suggesting as yet unidentified mutations.

The hereditary spastic paraplegias are a heterogeneous group of degenerative disorders that are clinically classified as either pure with predominant lower limb spasticity, or complex where spastic paraplegia is complicated with additional neurological features, and are inherited in autosomal dominant, autosomal recessive or X-linked patterns.

Genetic defects have been identified in over 40 different genes, with more than 70 loci in total. Complex recessive spastic paraplegias have in the past been frequently associated with mutations in SPG11 (spatacsin), ZFYVE26/SPG15, SPG7 (paraplegin) and a handful of other rare genes, but many cases remain genetically undefined. The overlap with other neurodegenerative disorders has been implied in a small number of reports, but not in larger disease series. This deficiency has been largely due to the lack of suitable high throughput techniques to investigate the genetic basis of disease, but the recent availability of next generation sequencing can facilitate the identification of disease-causing mutations even in extremely heterogeneous disorders.

We investigated a series of 97 index cases with complex spastic paraplegia referred to a tertiary referral neurology centre in London for diagnosis or management. The mean age of onset was 16 years (range 3 to 39). The SPG11 gene was first analysed, revealing homozygous or compound heterozygous mutations in 30/97 (30.9%) of probands, the largest SPG11 series reported to date, and by far the most common cause of complex spastic paraplegia in the UK, with severe and progressive clinical features and other neurological manifestations, linked with magnetic resonance imaging defects. Given the high frequency of SPG11 mutations, we studied the autophagic response to starvation in eight affected SPG11 cases and control fibroblast cell lines, but in our restricted study we did not observe correlations between disease status and autophagic or lysosomal markers.

In the remaining cases, next generation sequencing was carried out revealing variants in a number of other known complex spastic paraplegia genes, including five in SPG7 (5/97), four in FA2H (also known as SPG35) (4/97) and two in ZFYVE26/SPG15. Variants were identified in genes usually associated with pure spastic paraplegia and also in the Parkinson’s disease-associated gene ATP13A2, neuronal ceroid lipofuscinosis gene TPP1 and the hereditary motor and sensory neuropathy DNMT1 gene, highlighting the genetic heterogeneity of spastic paraplegia. No plausible genetic cause was identified in 51% of probands, likely indicating the existence of as yet unidentified genes.

SOURCE: DOI: aww111 First published online: 23 May 2016 © The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain.

Genetic and phenotypic characterization of complex hereditary spastic paraplegia

Eleanna Kara, Arianna Tucci, Claudia Manzoni, David S. Lynch, Marilena Elpidorou, Conceicao Bettencourt, Viorica Chelban, Andreea Manole, Sherifa A. Hamed, Nourelhoda A. Haridy, Monica Federoff, Elisavet Preza, Deborah Hughes, Alan Pittman, Zane Jaunmuktane, Sebastian Brandner, Georgia Xiromerisiou, Sarah Wiethoff, Lucia Schottlaender, Christos Proukakis, Huw Morris, Tom Warner, Kailash P. Bhatia, L.V. Prasad Korlipara, Andrew B. Singleton, John Hardy, Nicholas W. Wood, Patrick A. Lewis, Henry Houlden.



2 new SPG 11 mutations found

Targeted exome capture technology used


Hereditary spastic paraplegia (HSP) is a neurodegenerative disease that is characterized by progressive weakness and spasticity of the lower extremities; HSP can present as complicated forms with additional neurological signs. More than 70 disease loci have been described with different modes of inheritance.


In this study, nine subjects from a Chinese family that included two individuals affected by HSP were examined through detailed clinical evaluations, physical examinations, and genetic tests. Targeted exome capture technology was used to identify gene mutations.


Two novel compound heterozygous mutations in the SPG 11 gene were identified, c.4001_4002insATAAC and c.4057C>G. The c.4001_4002insATAAC mutation leads to a reading frame shift during transcription, resulting in premature termination of the protein product. The missense mutation c.4057C>G (p.H1353D) is located in a highly conserved domain and is predicted to be a damaging substitution.


Based on the results described here, we propose that these novel compound heterozygous mutations in SPG 11 are the genetic cause of autosomal recessive HSP in this Chinese family.

SOURCE: Can J Neurol Sci. 2016 Mar 28:1-8. [Epub ahead of print] PMID: 27018819 [PubMed – as supplied by publisher]

Novel SPG 11 Mutations in Hereditary Spastic Paraplegia With Thin Corpus Callosum in a Chinese Family.

Tian X1, Wang M1, Zhang K2, Zhang X1.

1 Department of Neurology,Xuan Wu Hospital,Capital Medical University,Beijing 100053,China.

2 Department of Radiology,Xuan Wu Hospital,Capital Medical University,Beijing 100053,China.



CAPN1 gene – SPG76 HSP link confirmed

Worms, fruit flies and zebrafish studied in this collaboration between scientists in Canada and Morocco.

Biologists have identified gene mutations that cause hereditary spastic paraplegia (HSP), a group of inherited disorders that cause progressive weakness and stiffness of the leg muscles. The discovery can potentially improve genetic screening and therapy.

More than 70 genes are suspected to be responsible for HSP, but their exact roles in this disease remain unknown.

By sequencing the genomes of individuals living with HSP, the scientists from McGill University, Canada, and Mohammed V University, Morocco, homed in on mutations in a gene known as CAPN1 that encodes calpain 1, a calcium-activated protein widely found in the brain1.

One of these mutations eventually leads to a buildup of inactive calpain 1 in the brain.

Inactivating genes similar to CAPN1 in worms, fruit flies, and zebrafish embryos produced the effects of HSP in these animals, confirming the link between CAPN1 gene mutations and HSP.

Discovery of HSP-related genes opens up possibilities for selecting healthy embryos through genetic diagnosis in affected families, the researchers say.

“Besides the prospect of [improved] therapies and the CAPN1’s roles in HSP, this research highlights the importance of calpains in the nervous system,” says Ziv Gan-Or, the lead author of the study.

SOURCE: Published online 26 May 2016 doi:10.1038/nmiddleeast.2016.80

Rogue gene implicated in hereditary spastic paraplegia

Biplab Das



New mutation in SPG56 HSP discovered

Recessively inherited, complicated HSP

We describe a novel sporadic case of SPG56, a rare complicated form of HSP that expands the clinical and molecular spectrum of the disease, being associated to novel mutations in CYP2U1 and showing as novel feature dorsal hydromyelia at spinal cord MRI.

The patient presented an early-onset, slowly progressive paraparesis associated with mild mental retardation. Neurological assessments included the Spastic Paraplegia Rating Scale (SPRS), Mental Deterioration Battery (MDB), and Wechsler Adult Intelligence Scale (WAIS), neurophysiological and neuroimaging studies.

Targeted next-generation sequencing panels for the whole set of genes associated with HSP were performed in the proband and her relatives. Neuroimaging studies showed dorsal hydromyelia but no brain MRI abnormalities. Targeted next-generation identified two novel mutations: the c.5C > A/p.S2* on the maternal allele in compound heterozygosity with the paternally-inherited c.1288+5G > C in CYP2U1. Both mutations predict early protein truncation and a loss of function.

So far, only few SPG56 cases have been reported. This case expands and further characterize the clinical and molecular spectrum of SPG56. In this regard, in consideration of the putative gene function in neurodevelopment, we suggest a causal association between CYP2U1 mutations and hydromyelia in our patient.

SOURCE: Eur J Paediatr Neurol. 2016 May;20(3):444-8. doi: 10.1016/j.ejpn.2016.02.001. Epub 2016 Feb 18. Copyright © 2016 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved. PMID: 26936192 [PubMed – in process]

Hereditary spastic paraplegia: Novel mutations and expansion of the phenotype variability in SPG56.

Masciullo M1, Tessa A2, Perazza S3, Santorelli FM2, Perna A4, Silvestri G5.

1 IRCCS Fondazione Santa Lucia, Rome, Italy.

2 IRCCS Stella Maris, Pisa, Italy.

3 IRCCS Stella Maris, Pisa, Italy; Advanced Sciences and Technologies in Rehabilitation Medicine and Sports, Tor Vergata University (SP), Rome, Italy.

4 Department of Geriatrics, Neurosciences and Orthopedics, Institute of Neurology, Catholic University of Sacred Heart, Rome, Italy.

5 Department of Geriatrics, Neurosciences and Orthopedics, Institute of Neurology, Catholic University of Sacred Heart, Rome, Italy. Electronic address: [email protected].



9 new HSP mutations in 5 genes

Hungarian study discovery

In the first comprehensive genetic study of HSP in Hungary, researchers have discovered 9 new HSP causing mutations in 5 genes – SPG7, SPG11, ATL1, NIPA1 and ABCD1.


Hereditary spastic paraplegias (HSPs) are a clinically and genetically heterogeneous group of neurodegenerative diseases with progressive lower limb spasticity and weakness. The aim of this study is to determine the frequency of different SPG mutations in Hungarian patients, and to provide further genotype-phenotype correlations for the known HSP causing genes.


We carried out genetic testing for 58 probands with clinical characteristics of HSP. For historical reasons, three different approaches were followed in different patients: 1) Sanger sequencing of ATL1 and SPAST genes, 2) whole exome, and 3) targeted panel sequencing by next generation sequencing.


Genetic diagnosis was established for 20 probands (34.5%). We detected nine previously unreported mutations with high confidence for pathogenicity. The most frequently affected gene was SPAST with pathogenic or likely pathogenic mutations in 10 probands. The most frequently detected variant in our cohort was the SPG7 p.Leu78*, observed in four probands. Altogether five probands were diagnosed with SPG7. Additional mutations were detected in SPG11, ATL1, NIPA1, and ABCD1.


This is the first comprehensive genetic epidemiological study of patients with HSP in Hungary. Next generation sequencing improved the yield of genetic diagnostics in this disease group even when the phenotype was atypical. However, considering the frequency of the HSP-causing gene defects, SPG4, the most common form of the disease, should be tested first to be cost effective in this economic region.

SOURCE: J Neurol Sci. 2016 May 15;364:116-21. doi: 10.1016/j.jns.2016.03.018. Epub 2016 Mar 12. Copyright © 2016 Elsevier B.V. All rights reserved. PMID: 27084228 [PubMed – in process]

Genetic background of the hereditary spastic paraplegia phenotypes in Hungary – An analysis of 58 probands.

Balicza P1, Grosz Z1, Gonzalez MA2, Bencsik R1, Pentelenyi K1, Gal A1, Varga E3, Klivenyi P3, Koller J1, Züchner S2, Molnar JM4.

1 Institute of Genomic Medicine and Rare Disorders, Semmelweis University, Tömő Street 25-29, 1083 Budapest, Hungary.

2 Dr John T. Macdonald Foundation Department of Human Genetics, John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, 1501 NW 10 Ave, Miami, FL 33136, USA.

3 Department of Neurology, University of Szeged, Semmelweis street 6, 6720 Szeged, Hungary.

4 Institute of Genomic Medicine and Rare Disorders, Semmelweis University, Tömő Street 25-29, 1083 Budapest, Hungary. Electronic address: [email protected].



New mutation found for SPG8 HSP

Japanese discovery by exome sequencing

This Japanese study took the number of known SPG8 mutations causing HSP to 11 and expanded the range of associated symptoms, with mild upper limb symptoms observed.

Exome sequencing revealed a novel missense mutation (c.2152G>A, p.E713K) in the KIAA0196 gene in a Japanese patient with SPG8. To date, only 10 mutations in the KIAA0196 gene have been reported in the world.

We describe the clinical and genetic findings in our patient with SPG8, which is a rare dominant hereditary spastic paraplegia. Notably, our patient showed mild upper limb ataxia, which is a relatively atypical symptom of SPG8. Thus, our patient showed a wide clinical spectrum of SPG8.

SOURCE: Clin Neurol Neurosurg. 2016 May;144:36-8. doi: 10.1016/j.clineuro.2016.02.031. Epub 2016 Mar 4. Copyright © 2016 Elsevier B.V. All rights reserved. PMID: 26967522 [PubMed – in process]

Exome sequencing reveals a novel missense mutation in the KIAA0196 gene in a Japanese patient with SPG8.

Ichinose Y1, Koh K1, Fukumoto M1, Yamashiro N1, Kobayashi F1, Miwa M1, Nagasaka T1, Shindo K1, Ishiura H2, Tsuji S2, Takiyama DY3.

1 Department of Neurology, Graduate School of Medical Science, University of Yamanashi, Yamanashi 409-3898, Japan.

2 Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

3 Department of Neurology, Graduate School of Medical Science, University of Yamanashi, Yamanashi 409-3898, Japan. Electronic address: [email protected].



2 new sporadic SPG30 HSP mutations found

Mutations in the KIF1A gene causing SPG30 HSP can be inherited dominantly, recessively or without precedent (de novo) in a family. The resultant HSP can be either pure or complicated, making this form of HSP one of the broadest in terms of how it occurs and how it presents.

Hereditary spastic paraplegias are a clinically and genetically heterogeneous group of disorders characterized by lower extremity spasticity and weakness.

Recently, the first de novo mutations in KIF1A were identified in patients with an early-onset severe form of complicated hereditary spastic paraplegia.

We report two additional patients with novel de novo mutations in KIF1A, hereby expanding the genetic spectrum of KIF1A-related hereditary spastic paraplegia. Both children presented with spastic paraplegia and additional findings of optic nerve atrophy, structural brain abnormalities, peripheral neuropathy, cognitive/language impairment, and never achieved ambulation. In particular, we highlight the progressive nature of cerebellar involvement as captured on sequential magnetic resonance images (MRIs), thus linking the neurodegenerative and spastic paraplegia phenotypes. Exome sequencing in patient 1 and patient 2 identified novel heterozygous missense mutations in KIF1A at c.902G>A (p.R307Q) and c.595G>A (p.G199 R) respectively. Therefore, our report contributes to expanding the genotypic and phenotypic spectrum of hereditary spastic paraplegia caused by mutations in KIF1A.

SOURCE: J Child Neurol. 2016 Mar 31. pii: 0883073816639718. [Epub ahead of print] © The Author(s) 2016. PMID: 27034427 [PubMed – as supplied by publisher]

Novel De Novo Mutations in KIF1A as a Cause of Hereditary Spastic Paraplegia With Progressive Central Nervous System Involvement.

Hotchkiss L1, Donkervoort S2, Leach ME3, Mohassel P2, Bharucha-Goebel DX3, Bradley N2, Nguyen D2, Hu Y2, Gurgel-Giannetti J4, Bönnemann CG5.

1 National Institutes of Health, Bethesda, MD, USA Weill Cornell Medical College, New York, NY, USA.

2 National Institutes of Health, Bethesda, MD, USA.

3 National Institutes of Health, Bethesda, MD, USA Children’s National Medical Center, Washington, DC, USA.

4 Universidade Federal de Minas Gerais, Belo Horizonte-MG, Brazil.

5 National Institutes of Health, Bethesda, MD, USA [email protected].

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