New HSP genetics findings

From Japan, Greece, Belgium, Turkey, Italy, Canada


4 new mutations of the KIF1A gene (SPG30) identified


Recently, de novo KIF1A mutations were identified in patients with intellectual disability, spasticity and cerebellar atrophy and/or optic nerve atrophy. In this study, we analyzed a total of 62 families, including 68 patients with genetically unsolved childhood cerebellar atrophy, by whole-exome sequencing (WES).


We identified five de novo missense KIF1A mutations, including only one previously reported mutation (p.Arg316Trp). All the mutations are located in the motor domain of KIF1A. In all patients, initial symptom onset was during the infantile period, and included developmental delay in three patients and gait disturbance in two. Thereafter, they showed gait disturbances, exaggerated deep tendon reflexes, cerebellar symptoms and cerebellar atrophy on brain magnetic resonance imaging. Four patients showed lower limb spasticity, upper limb clumsiness and visual disturbances. Nerve conduction study revealed peripheral neuropathy in three patients.


This study further delineates clinical features of de novo KIF1A mutations. Genetic testing of KIF1A should be considered in children with developmental delay, cerebellar atrophy and pyramidal features.


SOURCE: Journal of Human Genetics , (10 September 2015) doi:10.1038/jhg.2015.108


De novo KIF1A mutations cause intellectual deficit, cerebellar atrophy, lower limb spasticity and visual disturbance


Chihiro Ohba, Kazuhiro Haginoya, Hitoshi Osaka, Kazuo Kubota, Akihiko Ishiyama, Takuya Hiraide, Hirofumi Komaki, Masayuki Sasaki, Satoko Miyatake, Mitsuko Nakashima, Yoshinori Tsurusaki, Noriko Miyake, Fumiaki Tanaka, Hirotomo Saitsu and Naomichi Matsumoto



11 new mutations identified in first-ever study of the Greek population


Frequency of occurrence of the major forms of HSP in the Greek population are very similar to those found in other populations.


Hereditary Spastic Paraplegia (HSP) is a syndrome characterised by lower limb spasticity, occurring alone or in association with other neurological manifestations, such as cognitive impairment, seizures, ataxia or neuropathy. HSP occurs worldwide, with different populations having different frequencies of causative genes.


The Greek population has not yet been characterised. The purpose of this study was to describe the clinical presentation and molecular epidemiology of the largest cohort of HSP in Greece, comprising 54 patients from 40 families. We used a targeted next-generation sequencing (NGS) approach to genetically assess a proband from each family. We made a genetic diagnosis in >50% of cases and identified 11 novel variants. Variants in SPAST and KIF5A were the most common causes of autosomal dominant HSP, whereas SPG11 and CYP7B1 were the most common cause of autosomal recessive HSP. We identified a novel variant in SPG11, which led to disease with later onset and may be unique to the Greek population and report the first nonsense mutation in KIF5A.


Interestingly, the frequency of HSP mutations in the Greek population, which is relatively isolated, was very similar to other European populations. We confirm that NGS approaches are an efficient diagnostic tool and should be employed early in the assessment of HSP patients.


SOURCE: European Journal of Human Genetics , (16 September 2015) doi:10.1038/ejhg.2015.200


Hereditary spastic paraplegia in Greece: characterisation of a previously unexplored population using next-generation sequencing


David S Lynch, Georgios Koutsis, Arianna Tucci, Marios Panas, Markella Baklou, Marianthi Breza, Georgia Karadima and Henry Houlden



Troyer syndrome (SPG20) variant discovered


Diagnosis improved with new technologies


A new variation of an SPG20 mutation, previously found only in the Amish population of North America, and in Oman, has now been discovered in a Turkish family. Whole exome sequencing and homozygosity mapping help to provide definitive diagnosis and much faster than previously available.


Troyer syndrome is an autosomal recessive form of complex hereditary spastic paraplegia. To date, the disorder has only been described in the Amish and in kindred from Oman. In Amish, all affected individuals have a homozygous one nucleotide deletion; c.1110delA. In the Omani kindred, all affected have a homozygous two nucleotides deletion; c.364_365delTA (p.Met122ValfsTer2).


Here we report the results of homozygosity mapping and whole exome sequencing in two siblings of a consanguineous Turkish family with mild intellectual disability, spastic paraplegia, and muscular dystrophy. We identified the same deletion that has been identified in the Omani kindred, but haplotype analysis suggests a recurrent event, and not a founder mutation.


We summarize current knowledge of Troyer syndrome, and propose wider use of whole exome sequencing in routine diagnostics. This applies in particular to nonspecific phenotypes with high heterogeneity, such as spastic paraplegia, intellectual disability, and muscular dystrophy, since in such cases the assignment of a definite diagnosis is frequently delayed.


SOURCE: Mol Cell Probes. 2015 Oct;29(5):315-8. doi: 10.1016/j.mcp.2015.05.006. Epub 2015 May 20. PMID: 26003402 [PubMed – in process] Copyright © 2015 Elsevier Ltd. All rights reserved.


Recurrent null mutation in SPG20 leads to Troyer syndrome.


Tawamie H1, Wohlleber E2, Uebe S1, Schmäl C3, Nöthen MM4, Abou Jamra R5.

1Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.

2Institute of Human Genetics, University of Bonn, Bonn, Germany; Humangenetik Freibrug, Freiburg, Germany.

3Institute of Human Genetics, University of Bonn, Bonn, Germany.

4Institute of Human Genetics, University of Bonn, Bonn, Germany; Department of Genomics, Life and Brain Center, University Bonn, Bonn, Germany.

5Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; Centogene, Rostock, Germany. Electronic address: [email protected].



New SPG7 mutation discovered


High variability in symptoms found in the family


We report the clinical description and genetic analyses of a Greek family with four individuals affected with a complicated form of hereditary spastic paraplegia (HSP) and a recessive pattern of inheritance. Exome sequencing of all affected individuals led to the identification of a homozygous 25 bp deletion predicted to lead to a frameshift and premature stop codon in the SPG7 gene, encoding paraplegin.


This deletion, which is located in the first exon of the SPG7 gene, has not been previously reported and likely lead to the complete absence of the SPG7 protein. Interestingly, this family shows significant phenotypic heterogeneity further highlighting the clinical variability associated with SPG7 mutations. Our findings emphasize the clinical utility of whole exome sequencing for the molecular diagnosis of HSPs.


SOURCE: Eur J Med Genet. 2015 Nov;58(11):573-7. doi: 10.1016/j.ejmg.2015.08.001. Epub 2015 Aug 7. PMID: 26260707 [PubMed – in process] Copyright © 2015 Elsevier Masson SAS. All rights reserved.


Identification of a novel homozygous SPG7 mutation by whole exome sequencing in a Greek family with a complicated form of hereditary spastic paraplegia.


Daoud H1, Papadima EM2, Ouled Amar Bencheikh B1, Katsila T2, Dionne-Laporte A1, Spiegelman D1, Dion PA1, Patrinos GP2, Orrù S3, Rouleau GA4.

1Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.

2University of Patras School of Health Sciences, Department of Pharmacy, University Campus, Patras, Greece.

3Genetica Medica, Dipartimento di Scienze Mediche, Università di Cagliari, Cagliari, Italy.

4Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada. Electronic address: [email protected].



Four SPG30 mutations identified from 192 HSPers


Large genetic screening study in Italy


KIF1A gene encodes the kinesin 1a protein, an axonal motor protein working in cargo transport along neurites. Variants in KIF1A were identified in different forms of neurodegenerative diseases with dominant and recessive inheritance. Homozygous recessive mutations were found in the hereditary sensory and autonomic neuropathy type 2, HSAN2 and in a recessive subtype of hereditary spastic paraparesis, SPG30. De novo heterozygous dominant variants were found both in a dominant form of SPG30 (AD-SPG30) with one single family reported and in patients with different forms of progressive neurodegenerative diseases.


We report the results of a genetic screening of 192 HSP patients, with the identification of four heterozygous variants in KIF1A in four cases, two of whom with family history for the disease. Three of the four variants fall within the motor domain, a frequent target for variants related to the AD-SPG30 subtype. The fourth variant falls downstream the motor domain in a region lacking any functional domain. The KIF1A-related patients show clinical pictures overlapping the known AD-SPG30 phenotype including pure and complicated forms with few differences.


Of note, one of the families, originating from the Sicily island, carries the same variant p.S69L detected in the first AD-SPG30 family of Finnish origin reported; differently from the first one, the latter family shows a wide intra-familial phenotype variability. Overall, these data reveal a very low frequency of the AD-SPG30 subtype while confirming the presence of amino acid residues in the motor domain representing preferential targets for mutations, thereby supporting their functional relevance in kinesin 1a activity.


SOURCE: J Neurol. 2015 Dec;262(12):2684-90. doi: 10.1007/s00415-015-7899-9. Epub 2015 Sep 26. PMID: 26410750 [PubMed – in process]


Variants in KIF1A gene in dominant and sporadic forms of hereditary spastic paraparesis.


Citterio A1, Arnoldi A1, Panzeri E1, Merlini L2, D’Angelo MG3, Musumeci O4, Toscano A4, Bondi A5, Martinuzzi A6, Bresolin N1,7, Bassi MT8.

1Laboratory of Molecular Biology, Scientific Institute IRCCS E. Medea, Via D. L. Monza 20, 23842, Bosisio Parini, Lecco, Italy.

2SC Laboratory of Musculoskeletal Cell Biology, Istituto Ortopedico Rizzoli, IRCCS, Bologna, Italy.

3Neuromuscular Disorders Unit, Scientific Institute IRCCS E. Medea, 23842, Bosisio Parini, Lecco, Italy.

4Department of Neurosciences, University of Messina, Messina, Italy.

5Department of Rizzoli-Sicilia, Istituto Ortopedico Rizzoli, 90011, Palermo, Italy.

6Conegliano Research Center, Scientific Institute IRCCS E. Medea, Conegliano, Italy.

7Neurology Unit, IRCCS Ca’ Granda, Ospedale Maggiore Policlinico Foundation, Dino Ferrari Centre, Department of Physiopathology and Transplantation, Universita’ di Milano, Milan, Italy.

8Laboratory of Molecular Biology, Scientific Institute IRCCS E. Medea, Via D. L. Monza 20, 23842, Bosisio Parini, Lecco, Italy. [email protected].









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