New HSP genotypes and phenotypes

Posted - February 2020 in Research Highlights

Research from Russia, China, Japan, Poland, Italy, Canada, Czech Republic, Spain, the UK and Iran

 

56% of all genetically verified cases in this large study of 90 Russian families with 14 HSP types were SPG4 – a finding in line with similar studies elsewhere globally.

 

21 new mutations in SPAST were discovered amongst the 43 total SPAST mutations identified, adding significantly to the grand total of SPG4 disease associated mutations identified that now likely number around 400 or more.

 

Age of onset varied from 1 – 58 years, with a significant proportion of early-onset cases, particularly in males. Once again, this study identified marked differences within families with identical mutations regarding age of onset. Complications were present in a small number of cases including ataxia, epilepsy and mild cognitive impairment.

 

AIM: To investigate molecular, clinical and genealogical characteristics of SPG4 in a first representative Russian group, to estimate SPG4 proportion among all DNA-diagnosed spastic paraplegias.

MATERIAL AND METHODS: Fifty unrelated Russian families with SPG4 detected in the course of clinical and molecular studies of spastic paraplegias were studied. Clinical, genealogical and several molecular methods were used, i.e. Sanger sequencing of SPAST, massive parallel sequencing MPS (panel ‘hereditary paraplegias’) and multiplex ligation-dependent amplification MLPA.

RESULTS: SPG4 proportion was 56% among all DNA verified SPG cases (90 families/14 forms) and 68% in subgroup of dominant SPG. In 50 families, 43 different SPAST mutations were detected, of which 21 were novel; percentage of large rearrangements was 30% (13 mutations in 15 families). Four mutations were detected in two families each, nonsense mutation c.1291C>T (p.Arg431*) in 4 unrelated families. Proportion of familial cases was 68%, pedigrees with ‘missing’ disease in elderly carriers pointed to incomplete penetrance.

Age of onset varied from one year to 58 years, middle-age onset was common but the proportion of early-onset cases, particularly in male index cases, was also high. Onset age showed marked intrafamilial differences (more than 10 years in 14 pedigrees, up to 50 year in one) and between families with identical mutations. Insidious onset, slow development with most patients ambulant and ‘uncomplicated’ phenotype were typical.

Cases with additional signs were: a family with ataxia in both patients, two families with epilepsy in one of SPG4 patients; three families with mild mental deficiency in one of SPG4 patients. A case described separately is a 29-year-old male patient with indeterminate myalgia and no SPG signs in whom SPAST previously reported mutation p.Ala430Thr de novo was an unexpected MPS finding.

CONCLUSION: SPG4 substantially predomimates in SPG structure in Russian families as practically everywhere else. Half of 43 detected SPAST mutations are novel, the proportion of large rearrangements is 30% higher than in most of studies. Clinical inter- and intrafamilial variability concerns mostly age of onset. SPG4 is not exclusively adult-onset as was thought earlier.

SOURCE: Zh Nevrol Psikhiatr Im S S Korsakova. 2019;119(11):11-20. doi: 10.17116/jnevro201911911111. PMID: 31851166

Hereditary spastic paraplegia type 4 (SPG4) in Russian patients.

Rudenskaya GE1, Kadnikova VA1, Sidorova OP2, Beetz C3, Illarioshkin SN4, Dadaly EL1, Proskokova TN5, Ryzhkova OP1.

1 Research Centre for Medical Genetics, Moscow, Russia.

2 Vladimirsky Moscow Regional Clinical Institute.

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

4 Research Centre for Neurology, Moscow, Russia.

5 Far East State Medical University, Khabarovsk, Russia.

 


 

10 new mutations were discovered and the 2 different forms of Spastin, M1 and M87 were investigated in this large study of SPAST mutations in

150 HSPers with SPG4 type HSP in China.

 

BACKGROUND: Mutations in the SPAST gene are the most frequent cause of hereditary spastic paraplegia (HSP). We aim to extend the mutation spectrum of spastic paraplegia 4 (SPG4) and carried out experiment in vitro to explore the influence of the SPAST gene mutation on the function of corresponding protein.

METHODS: Whole-exome sequencing (WES) combined with multiplex ligation-dependent probe amplification (MLPA) were performed in a cohort of 150 patients clinically diagnosed with HSP. We focus on screening for mutations in SPAST gene and carrying out functional experiments to assess the effects of the novel variants.

RESULTS: A total of 34 different mutations in the SPAST gene were identified, of which 10 were novel, including 1 missense (c.1479T > A), 1 nonsense (c.766G > T), 3 splicing (c.1413 + 1_1413+4delGTAA, c.1729-1G > A and c.1536+2T > G) and 5 frameshift mutations (c.1094delC, c.885dupA, c.517_518delAG, c.280delG and c.908dupC). For 7 novel non-splicing mutations, functional study showed that accumulated M1 spastin co-lcocalized with microtubules which was different from a uniformly diffused M87 spastin. While an impairment in severing activity was observed in both mutant M1 and mutant M87, except for c.280delG. All 3 novel splicing variants were predicted to affect splicing by using bioinformatic programs. However, only c.1536+2T > G had no influence on splice site in vitro, which conflicts with the in-silico analysis.

CONCLUSION: We genetically diagnosed 40 SPG4 patients. All the novel non-splicing mutations except for c.280delG were certified to exert an effect on the microtubule-severing and all the novel splicing mutations other than c.1536+2T > G would cause abnormal splicing of the spastin.

SOURCE: Parkinsonism Relat Disord. 2019 Dec;69:125-133. doi: 10.1016/j.parkreldis.2019.11.007. Epub 2019 Nov 6. PMID: 31751864 Copyright © 2019 Elsevier Ltd. All rights reserved.

Novel mutations in the SPAST gene cause hereditary spastic paraplegia.

Zhu Z1, Zhang C2, Zhao G3, Liu Q4, Zhong P5, Zhang M6, Tang W7, Zhan F8, Tian W9, Wang Y10, Yin K11, Huang X12, Jiang J13, Liu X14, Liu S15, Zhou H16, Luan X17, Tang H18, Wang Y19, Chen S20, Cao L21.

1 Department of Neurology and Institute of Neurology, Rui Jin Hospital & Rui Jin Hospital North, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: [email protected]

2 Department of Neurology and Institute of Neurology, Rui Jin Hospital & Rui Jin Hospital North, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Department of Neurology, Suzhou Hospital Affiliated to Anhui Medical University, Suzhou, China. Electronic address: [email protected]

3 Department of Neurology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Department of Neurology, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, China. Electronic address: [email protected]

4 Department of Neurology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China. Electronic address: [email protected]

5 Department of Neurology, Suzhou Hospital Affiliated to Anhui Medical University, Suzhou, China. Electronic address: [email protected]

6 Department of Neurology, Huainan First People’s Hospital Affiliated to Bengbu Medical College, Huainan, Anhui Province, China. Electronic address: [email protected]

7 Department of Neurology, Zhoushan Hospital, Zhoushan, Zhejiang Province, China. Electronic address: [email protected]

8 Department of Neurology and Institute of Neurology, Rui Jin Hospital & Rui Jin Hospital North, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: [email protected]

9 Department of Neurology and Institute of Neurology, Rui Jin Hospital & Rui Jin Hospital North, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: [email protected]

10 Department of Neurology and Institute of Neurology, Rui Jin Hospital & Rui Jin Hospital North, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Department of Neurology, Huainan First People’s Hospital Affiliated to Bengbu Medical College, Huainan, Anhui Province, China. Electronic address: [email protected]

11 McKusick-Zhang Center for Genetic Medicine and State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College (PUMC), Beijing, China. Electronic address: [email protected]

12 Department of Neurology and Institute of Neurology, Rui Jin Hospital & Rui Jin Hospital North, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: [email protected]

13 Department of Neurology and Institute of Neurology, Rui Jin Hospital & Rui Jin Hospital North, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: [email protected]

14 Department of Neurology and Institute of Neurology, Rui Jin Hospital & Rui Jin Hospital North, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Department of Neurology, Shanghai Fengxian District Central Hospital, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital South Campus, Shangha, China. Electronic address: [email protected]

15 Department of Neurology, Suzhou Hospital Affiliated to Anhui Medical University, Suzhou, China. Electronic address: [email protected]

16 Department of Neurology and Institute of Neurology, Rui Jin Hospital & Rui Jin Hospital North, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: [email protected]

17 Department of Neurology and Institute of Neurology, Rui Jin Hospital & Rui Jin Hospital North, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: [email protected]

18 Department of Neurology and Institute of Neurology, Rui Jin Hospital & Rui Jin Hospital North, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: [email protected]

19 Department of Neurology and Institute of Neurology, Rui Jin Hospital & Rui Jin Hospital North, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: [email protected]

20 Department of Neurology and Institute of Neurology, Rui Jin Hospital & Rui Jin Hospital North, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: [email protected]

21 Department of Neurology and Institute of Neurology, Rui Jin Hospital & Rui Jin Hospital North, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: [email protected]

 


 

Four new mutations in the KIAA0196 gene were discovered in this first-ever study of SPG8 type HSP in Italian people. Unlike previous reported cases, those with SPG8 in this study have a pure form of HSP and disease onset in the third or fourth decade of life, making it difficult to tell SPG8 and SPG4 apart in the clinic.

 

BACKGROUND: Spastic paraplegia type 8 (SPG8) is an autosomal-dominant form of hereditary spastic paraplegia (AD-HSP) caused by a mutation in the KIAA0196 gene. SPG8 accounts for 1% of less of all AD-HSP and the genotype-phenotype correlation remains poorly understood.

METHODS: We report the first clinical and genetic description of SPG8 disease in Italian patients. We identified four new mutations in KIAA0196 gene. These variants were identified using a multigene targeted resequencing HSP panel. We took this opportunity to review the pertinent literature.

RESULTS: Age at disease onset was in the third or fourth decade of life. Stiffness of the lower limb with spastic gait, walking impairment, and decreased vibration sense were common early symptoms. Subjects of two families had bladder control abnormalities. Unlike previous reported cases, Italian SPG8 subjects have pure form of spastic paraparesis without cranial nerve involvement, and onset is in adult life.

DISCUSSION: From a clinical point of view, it is hard to differentiate SPG8 from SPG4, in which bladder and vibration sense dysfunctions are frequent signs. The differential diagnosis with other forms of AD-HSPs seems relatively easier if one considers the early-onset manifestations in SPG3A and the peripheral nervous system and cerebellar involvement seen in SPG31.

SOURCE: Neurol Sci. 2019 Dec 9. doi: 10.1007/s10072-019-04180-z. [Epub ahead of print] PMID: 31814071

SPG8 mutations in Italian families: clinical data and literature review.

Ginanneschi F1, D’Amore A2,3, Barghigiani M2, Tessa A2, Rossi A4, Santorelli FM2.

1 Department of Medical, Surgical and Neurological Sciences, University of Siena, Policlinico Le Scotte. Viale Bracci 1, 53100, Siena, Italy. [email protected]

2 Molecular Medicine, IRCCS Fondazione Stella Maris, Pisa, Italy.

3 Department of Biology, University of Pisa, Pisa, Italy.

4 Department of Medical, Surgical and Neurological Sciences, University of Siena, Policlinico Le Scotte. Viale Bracci 1, 53100, Siena, Italy.

 


 

Two new mutations have been discovered in the SPG7 gene in someone affected by both ataxia and spastic paraplegia, once again highlighting the ambiguity surrounding inheritance patterns in this gene.

 

OBJECTIVE: To identify causative mutations in a patient affected by ataxia and spastic paraplegia.

METHODS: Whole-exome sequencing (WES) and whole-genome sequencing (WGS) were performed using patient’s DNA sample. RT-PCR and cDNA Sanger sequencing were performed on RNA extracted from patient’s fibroblasts, as well as western blot.

RESULTS: A novel missense variant in SPG7 (c.2195T> C; p.Leu732Pro) was first found by whole-exome sequencing (WES), while the second, also unreported, deep intronic variant (c.286 + 853A>G) was identified by whole-genome sequencing (WGS). RT-PCR confirmed the in silico predictions showing that this variant activated a cryptic splice site, inducing the inclusion of a pseudoexon into the mRNA sequence, which encoded a premature stop codon. Western blot showed decreased SPG7 levels in patient’s fibroblasts.

INTERPRETATION: Identification of a deep intronic variant in SPG7, which could only have been detected by performing WGS, led to a diagnosis in this HSP patient.

This case challenges the notion of an autosomal dominant inheritance for SPG7, and illustrates the importance of performing WGS subsequently or alternatively to WES to find additional mutations, especially in patients carrying one variant in a gene causing a predominantly autosomal recessive disease.

SOURCE: Ann Clin Transl Neurol. 2020 Jan;7(1):105-111. doi: 10.1002/acn3.50967. Epub 2019 Dec 18. PMID: 31854126 © 2019 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.

A deep intronic splice variant advises reexamination of presumably dominant SPG7 Cases.

Verdura E1,2, Schlüter A1,2, Fernández-Eulate G3,4,5, Ramos-Martín R1, Zulaica M3,4, Planas-Serra L1, Ruiz M1,2, Fourcade S1,2, Casasnovas C1,2,6, López de Munain A3,4,5,7, Pujol A1,2,8.

1 Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, Barcelona, Catalonia, Spain.

2 Centre for Biomedical Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain.

3 Biodonostia, Neurosciences Area, Neuromuscular diseases Laboratory, San Sebastian, Basque country, Spain.

4 CIBERNED, Instituto de Salud Carlos III, Ministry of Science, Innovation and Universities, Madrid, Spain.

5 Department of Neurology, Hospital Universitario Donostia, San Sebastian, Basque country, Spain.

6 Neuromuscular Unit, Neurology Department, Hospital Universitari de Bellvitge, L’Hospitalet de Llobregat, Barcelona, Catalonia, Spain.

7 Department of Neurosciences, Faculty of Medicine and Dentistry, UPV-EHU, San Sebastian, Basque country, Spain.

8 Catalan Institution of Research and Advanced Studies (ICREA), Barcelona, Catalonia, Spain.

 


 

Six new mutations, with two classified as disease-causing, were discovered in this study of 9 people with the most common autosomal recessive form of HSP, SPG11.

Genetic, clinical and electrophysiological overlap between SPG11 and autosomal recessive juvenile amyotrophic lateral sclerosis (ARJALS) was found, reinforcing the link between the two conditions that has previously been described.

 

BACKGROUND: Spastic paraplegia type 11 (SPG11) mutations are the most frequent cause of autosomal recessive hereditary spastic paraplegia (ARHSP). We are aiming to identify the causative mutations in SPG11 among families referred to our center with ARHSP in a Chinese population.

METHODS: Targeted next-generation sequencing was performed on the patients to identify disease-causing mutations. Variants were analyzed according to their predicted pathogenicity and their relevance to the clinical phenotypes. The segregation in the family members was validated by Sanger sequencing.

RESULTS: A total of 12 mutations in SPG11 gene from 9 index cases were identified, including 6 frameshift mutations, 3 missense mutations, 1 nonsense mutation, 1 splicing mutation, and 1 intron deletion mutation. In 6 of these patients, the mutations were homozygous, and the other 3 patients carried two compound heterozygous mutations.

Six mutations were novel; 2 were classified as pathogenic, 1 was considered as likely pathogenic, and the other 3 were variants of unknown significance. Additionally, 1 missense heterozygous variant we found was also carried by an amyotrophic lateral sclerosis (ALS) patient. Clinically and electrophysiologically, some of our ARHSP patients partially shared various features of autosomal-recessive juvenile amyotrophic lateral sclerosis (ARJALS), including combination of both UMN and LMN degeneration.

CONCLUSIONS: The results contribute to extending of the SPG11 gene mutation spectrum and emphasizing a putative link between ARHSP and ARJALS.

SOURCE: BMC Neurol. 2020 Jan 3;20(1):2. doi: 10.1186/s12883-019-1593-y. PMID: 31900114

Chinese families with autosomal recessive hereditary spastic paraplegia caused by mutations in SPG11.

Chen X1, Liu J1, Wei QQ1, Ou RW1, Cao B1, Yuan X1, Hou Y1, Zhang L1, Shang H2.

1 Department of Neurology, West China Hospital, Sichuan University, No. 37 Guoxue Xiang, Chengdu, 610041, Sichuan, China.

2 Department of Neurology, West China Hospital, Sichuan University, No. 37 Guoxue Xiang, Chengdu, 610041, Sichuan, China. [email protected]

 


 

This Canada-wide search of people with HSP for mutations in the ATP13A2 gene associated with SPG78 type HSP found three different, previously unreported mutations in three people. Apart from spastic paraplegia, all patients exhibited psychiatric symptoms.

 

BACKGROUND: Hereditary spastic paraplegias (HSP) are neurodegenerative disorders characterized by lower limb spasticity and weakness, with or without additional symptoms. Mutations in ATP13A2, known to cause Kufor-Rakeb syndrome (KRS), have been recently implicated in HSP.

METHODS: Whole-exome sequencing was done in a Canada-wide HSP cohort.

RESULTS: Three additional patients with homozygous ATP13A2 mutations were identified, representing 0.7% of all HSP families. Spastic paraplegia was the predominant feature, all patients suffered from psychiatric symptoms, and one patient had developed seizures. Of the identified mutations, c.2126G>C;(p.[Arg709Thr]) is novel, c.2158G>T;(p.[Gly720Trp]) has not been reported in ATP13A2-related diseases, and c.2473_2474insAAdelC;p.[Leu825Asnfs*32]) has been previously reported in KRS but not in HSP. Structural analysis of the mutations suggested a disruptive effect, and enrichment analysis suggested the potential involvement of specific pathways.

CONCLUSION: Our study suggests that in HSP patients with psychiatric symptoms, ATP13A2 mutations should be suspected, especially if they also have extrapyramidal symptoms.

SOURCE: Mol Genet Genomic Med. 2020 Jan 15:e1052. doi: 10.1002/mgg3.1052. [Epub ahead of print] PMID: 31944623 © 2019 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.

Clinical and genetic analysis of ATP13A2 in hereditary spastic paraplegia expands the phenotype.

Estiar MA1,2, Leveille E3, Spiegelman D2,4, Dupre N5, Trempe JF6,7, Rouleau GA1,2,4, Gan-Or Z1,2,4.

1 Department of Human Genetics, McGill University, Montréal, QC, Canada.

2 Montreal Neurological Institute and Hospital, McGill University, Montréal, QC, Canada.

3 Faculty of Medicine, McGill University, Montréal, QC, Canada.

4 Department of Neurology and Neurosurgery, McGill University, Montréal, QC, Canada.

5 Department of Medicine, Faculty of Medicine, Université Laval, Quebec City, QC, Canada.

6 Department of Pharmacology & Therapeutics, McGill University, Montréal, QC, Canada.

7 Centre for Structural Biology, McGill University, Montréal, QC, Canada.

 


 

A large study of 664 families with HSP in Japan found four people in three families with new mutations in the VPS13D gene causing both pure and complicated forms of HSP. This gene is associated with several forms of neurodegenerative disease.

 

BACKGROUND: Alterations of vacuolar protein sorting-associated protein 13 (VPS13) family members including VPS13A, VPS13B, and VPS13C lead to chorea acanthocytosis, Cohen syndrome, and parkinsonism, respectively. Recently, VPS13D mutations were identified as a cause of VPS13D-related movement disorders, which show several phenotypes including chorea, dystonia, spastic ataxia, and spastic paraplegia.

METHODS: We applied whole-exome analysis for a patient with a complicated form of hereditary spastic paraplegia (HSP) and her unaffected parents. Then, we screened the candidate genes in 664 Japanese families with HSP in Japan.

RESULTS: We first found a compound heterozygote VPS13D mutation and a heterozygote ABHD4 variation in a sporadic patient with spastic paraplegia. Then, we found three patients with VPS13D mutations in two Japanese HSP families. The three patients with homozygous mutations (p.Thr1118Met/p.Thr1118Met and p.Thr2945Ala/p.Thr2945Ala) in the VPS13D showed an adult onset pure form of HSP. Meanwhile, the patient with a compound heterozygous mutation (p.Ser405Arg/p.Arg3141Ter) in the VPS13D showed a childhood onset complicated form of HSP associated with cerebellar ataxia, cervical dystonia, cataracts, and chorioretinal dystrophy.

CONCLUSION: In the present study, we found four patients in three Japanese families with novel VPS13D mutations, which may broaden the clinical and genetic findings for VPS13D-related disorders.

SOURCE: Mol Genet Genomic Med. 2019 Dec 26:e1108. doi: 10.1002/mgg3.1108. [Epub ahead of print] PMID: 31876103 © 2019 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.

VPS13D-related disorders presenting as a pure and complicated form of hereditary spastic paraplegia.

Koh K1, Ishiura H2, Shimazaki H3, Tsutsumiuchi M4,5, Ichinose Y1, Nan H1, Hamada S6, Ohtsuka T6, Tsuji S7,8, Takiyama Y1.

1 Department of Neurology, Graduate School of Medical Sciences, University of Yamanashi, Yamanashi, Japan.

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

3 Division of Neurology, Department of Internal Medicine, Jichi Medical University School of Medicine, Tochigi, Japan.

4 Department of Neurology, Jichi Medical University Saitama Medical Center, Omiya, Japan.

5 Department of Neurology, Toranomon Hospital, Tokyo, Japan.

6 Department of Biochemistry, Graduate School of Medical Sciences, University of Yamanashi, Yamanashi, Japan.

7 Department of Molecular Neurology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.

8 Department of Neurology, International University of Health and Welfare, Chiba, Japan.

 


 

A new mutation in the KIF1A gene, associated with SPG30 type HSP, was discovered in a 19-year-old boy who was first evaluated at 18 months with a slowly progressive complicated form of HSP.

 

BACKGROUND: Pathogenic variants in KIF1A (kinesin family member 1A) gene have been associated with hereditary spastic paraplegia (HSP) type 30 (SPG30), encopassing autosomal dominant and recessive, pure and complicated forms.

CASE PRESENTATION: We report the long-term follow-up of a 19 year-old boy first evaluated at 18 months of age because of toe walking and unstable gait with frequent falls. He developed speech delay, mild intellectual disability, a slowly progressive pyramidal syndrome, microcephaly, bilateral optic subatrophy and a sensory axonal polyneuropathy. Brain MRI showed cerebellar atrophy, stable along serial evaluations (last performed at 18 years of age). Targeted NGS sequencing disclosed the de novo c.914C > T missense, likely pathogenic variant on KIF1A gene.

CONCLUSIONS: We report on a previously unpublished de novo heterozygous likely pathogenic KIF1A variant associated with slowly progressive complicated SPG30 and stable cerebellar atrophy on long-term follow-up, adding to current knowledge on this HSP subtype.

SOURCE: Ital J Pediatr. 2019 Dec 3;45(1):155. doi: 10.1186/s13052-019-0752-5. PMID: 31796088

Long-term follow-up until early adulthood in autosomal dominant, complex SPG30 with a novel KIF1A variant: a case report.

Spagnoli C1, Rizzi S2, Salerno GG2, Frattini D2, Fusco C2,3.

1 Neuropsichiatria Infantile, Presidio Ospedaliero Provinciale S. Maria Nuova, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy. [email protected]

2 Neuropsichiatria Infantile, Presidio Ospedaliero Provinciale S. Maria Nuova, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy.

3 SC Neuropsichiatria Infantile Laboratorio di Neurofisiologia dell’Età Evolutiva. Presidio Ospedaliero Provinciale S. Maria Nuova, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy.

 


 

A new mutation in the CAPN1 gene that causes SPG76 type HSP was discovered in a study of this gene in people with spinocerebellar ataxia (SCA) early-onset Parkinson’s disease (EOPD) and amyotrophic lateral sclerosis (ALS) as well as HSP. Those identified with mutations in this gene showed a complex phenotype including spastic paraplegia and ataxia, but no one with EOPD or ALS had disease-related mutations in CAPN1.

 

BACKGROUND: Mutations in CAPN1 have recently been reported to cause the spastic paraplegia 76 (SPG76) subtype of Hereditary Spastic Paraplegia (HSP). To investigate the role of CAPN1 in spastic paraplegia and other neurodegenerative diseases, including spinocerebellar ataxia (SCA), early-onset Parkinson’s disease (EOPD) and amyotrophic lateral sclerosis (ALS) we conducted a mutation analysis of CAPN1 in a cohort of Chinese patients with SPG, SCA, EOPD, and ALS.

METHODS: Variants of CAPN1 were detected in the three cohorts by Sanger or whole-exome sequencing, and all exons and exon-intron boundaries of CAPN1 were analysed.

RESULTS: A novel CAPN1 splicing variant (NM_001198868: c.338-1G > A) identified in a family with SPG/SCA showed a complex phenotype, including spastic paraplegia, ataxia, and extensor plantar response. This mutation was confirmed by Sanger sequencing and completely co-segregated with the phenotypes. Sequencing of the cDNA from the three affected patients detected a guanine deletion (c.340_340delG) that was predicted to result in an early stop codon after 61 amino acids (p. D114Tfs*62). No CAPN1 pathogenic mutation was found in the EOPD or ALS groups.

CONCLUSION: Our data reveal a novel CAPN1 mutation found in patients with SPG/SCA and emphasize the spastic and ataxic phenotypes of SPG76, but CAPN1 may not play a major role in EOPD and ALS.

SOURCE: J Neurol Sci. 2020 Jan 18;411:116691. doi: 10.1016/j.jns.2020.116691. [Epub ahead of print] PMID: 31982778 Copyright © 2020 Elsevier B.V. All rights reserved.

Mutation analysis of CAPN1 in Chinese populations with spastic paraplegia and related neurodegenerative diseases.

Xia ZC1, Liu ZH2, Zhou XX2, Liu Z2, Wang JL2, Hu ZM3, Tan JQ3, Shen L2, Jiang H2, Tang BS2, Lei LF4.

1 Department of Neurology, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, PR China.

2 Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, PR China.

3 Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan 410078, PR China.

4 Department of Neurology, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, PR China. Electronic address: [email protected]

 


 

SPG31 type HSP is characterised by autosomal dominant inheritance of heterozygous mutations in the REEP1 gene, normally being associated with pure HSP. However, rare cases of severe, complicated HSP caused by recessively inherited REEP1 mutations have been described in the last few years.

This study presents another such case, expanding the possible symptom profiles from mild HSP through to severe spinal muscular atrophy (SMA).

 

Abstract

Heterozygous mutations in REEP1 (MIM #609139) encoding the receptor expression-enhancing protein 1 (REEP1) are a well-recognized and relatively frequent cause of autosomal dominant hereditary spastic paraplegia (HSP), SPG31. REEP1 localizes in the mitochondria and endoplasmic reticulum (ER) and facilitates ER-mitochondria interactions.

In addition to the HSP phenotype, REEP1 has been associated with an autosomal dominant spinal type of Charcot-Marie-Tooth disease in 2 families. More recently, a patient with a homozygous REEP1 mutation with a much more severe phenotype akin to spinal muscular atrophy with respiratory distress type 1 (SMARD1) was reported.

In this report, we present a patient with a homozygous mutation in REEP1 manifesting a severe congenital distal spinal muscular atrophy (SMA) with diaphragmatic paralysis, expanding the phenotype from mild autosomal dominant HSP through to severe recessive distal SMA pattern.

SOURCE: Neurol Genet. 2019 Nov 15;5(6):e379. doi: 10.1212/NXG.0000000000000379. eCollection 2019 Dec. PMID: 31872057

Further supporting evidence for REEP1 phenotypic and allelic heterogeneity.

Maroofian R1, Behnam M1, Kaiyrzhanov R1, Salpietro V1, Salehi M1, Houlden H1.

1 Department of Neuromuscular Disorders Institute of Neurology (R.M., R.K., V.S., H.H.), University College London, Queen Square; and Medical Genetics Laboratory of Genome (M.B., M.S.), Isfahan, Iran.

 


 

This Czech study investigated whether or not an ethnically specific, prevalent form of HSP might exist in the Czech Roma population. Eight Czech Roma people were identified in a large group with two of them being identified with SPG11 and SPG77 respectively, involving three newly discovered mutations.

There was some evidence that the SPG11 mutation could be a founder mutation in the Czech Roma population as the relevant mutation was found in the DNA of one individual from a large group of HSP-negative Czech Roma people.

 

Abstract

Hereditary spastic paraplegia (HSP or SPG) is a group of rare upper motor neuron diseases. As some ethnically-specific, disease-causing homozygous variants were described in the Czech Roma population, we hypothesised that some prevalent HSP-causing variant could exist in this population.

Eight Czech Roma patients were found in a large group of Czech patients with suspected HSP and were tested using gene panel massively parallel sequencing (MPS). Two of the eight were diagnosed with SPG11 and SPG77, respectively. The SPG77 patient manifests a pure HSP phenotype, which is unusual for this SPG type. Both patients are compound heterozygotes for two different variants in the SPG11 (c.1603-1G>A and del ex. 16-18) and FARS2 (c.1082C>T and del ex.1-2) genes respectively; the three variants are novel.

In order to find a potential ethnically-specific, disease-causing variant for HSP, we tested the heterozygote frequency of these variants among 130 anonymised DNA samples of Czech Roma individuals without clinical signs of HSP (HPS-negative). A novel deletion of ex.16-18 in the SPG11 gene was found in a heterozygous state in one individual in the HSP-negative group. Haplotype analysis showed that this individual and the patient with SPG11 shared the same haplotype. This supports the assumption that the identified SPG11 deletion could be a founder mutation in the Czech Roma population. In some Roma patients the disease may also be caused by two different biallelic pathogenic mutations.

SOURCE: Neurosci Lett. 2020 Jan 30;721:134800. doi: 10.1016/j.neulet.2020.134800. [Epub ahead of print] PMID: 32007496 Copyright © 2020 Elsevier B.V. All rights reserved.

Two types of recessive hereditary spastic paraplegia in Roma patients in compound heterozygous state; no ethnically prevalent variant found.

Meszarosova AU1, Seeman P2, Jencik J2, Drabova J3, Cibochova R4, Stellmachova J5, Safka Brozkova D2.

1 DNA Laboratory, Department of Paediatric Neurology, 2nd Faculty of Medicine Charles University and University Hospital Motol, Prague, Czech Republic. Electronic address: [email protected]

2 DNA Laboratory, Department of Paediatric Neurology, 2nd Faculty of Medicine Charles University and University Hospital Motol, Prague, Czech Republic.

3 Department of Biology and Medical Genetics, 2nd Faculty of Medicine Charles University and University Hospital Motol, Prague, Czech Republic.

4 Department of Paediatric Neurology, 2nd Faculty of Medicine Charles University and University Hospital Motol, Prague, Czech Republic.

5 Department of Medical Genetics, Palacky University Hospital, Olomouc, Czech Republic.

 


 

Two compound heterozygous mutations, one of which is newly discovered, were identified in the C12orf65 gene of an 8 year old girl with autosomal recessive SPG55 type HSP. Disease onset occurred at 5 years of age with impaired vision caused by degeneration of the optic nerve being the main feature, a common symptom of this HSP type. The known HSP-causing mutation came from the child’s father, with the new mutation from the mother.

 

Abstract

This article reports the clinical features and C12orf65 gene mutations of a girl with autosomal recessive spastic paraplegia-55. The 8-year-old girl experienced disease onset at the age of 5 years and had optic atrophy as the main clinical manifestation, with slow movements in standing up and a slight duck-shaped gait.

Peripheral blood DNA samples were collected from this child and her parents and brother to perform high-throughput whole-exome sequencing and high-throughput mitochondrial genome sequencing. Sanger sequencing was performed for verification. The results showed two compound heterozygous mutations, c.394C>T and c.447_449delGGAinsGT, in the C12orf65 gene. The former mutation came from her father and was a known pathogenic mutation, and the latter came from her mother and was a novel mutation that had not been reported in the literature.

This study expands the mutation spectrum of the C12orf65 gene and thus provides a molecular basis for the etiological diagnosis of the child and the genetic counseling of the family.

SOURCE: Zhongguo Dang Dai Er Ke Za Zhi. 2019;21(11):1094–1098. PMID: 31753091

Clinical Features and C12orf65 Mutations of Autosomal Recessive Spastic paraplegia-55: A Case Report

Shuang-Zhu Lin 1Xian-Ting SunHong-Wei Ma

1 Diagnosis and Treatment Center for Children, Affiliated Hospital of Changchun University of Chinese Medicine, Changchun 130021, China.

 


 

A new mutation in the SPAST gene responsible for SPG4 type HSP was discovered in a large Polish family with a history of gait problems. Despite the identical mutation, affected individuals showed a range of HSP profiles that varied in their severity.

 

BACKGROUND: Hereditary spastic paraplegia is a large group of degenerative, neurological disorders characterized by progressive lower limb spasticity and weakness. The disease was investigated precisely but still clinicians often make incorrect or late diagnosis. Our aim was to investigate the genetic background and clinical phenotype of spastic paraplegia in large Polish family.

CASE PRESENTATION: A 37 years old woman presented with 4-year history of walking difficulties. On neurological examination, she had signs of upper motor lesion in lower extremities. She denied sphincter dysfunction and her cognition was normal. Her family history was positive for individuals with gait problems. The initial diagnosis was familial spastic paraplegia. Genetic testing identified a novel mutation in SPAST gene.

All available family members were examined and had genetic testing. The same mutation in SPAST gene was identified in other affected family members. All patients carrying the mutation presented with different phenotypes.

CONCLUSION: This study presents a family with spastic paraplegia due to a novel mutation c.1390G›T(p.Glu464Term) in SPAST gene. Affected individuals showed a range of phenotypes that varied in their severity. This case report demonstrates, the signs of hereditary spastic paraplegia can be often misdiagnosed with other diseases. Therefore genetic testing should always be considered in patients with lower limb spasticity and positive family history in order to help to establish the correct diagnosis.

SOURCE: BMC Neurol. 2019 Dec 14;19(1):322. doi: 10.1186/s12883-019-1561-6. PMID: 31837705

Case report on novel mutation in SPAST gene in Polish family with spastic paraplegia.

Klimkowicz-Mrowiec A1, Dziubek A2, Sado M2, Karpiński M2, Gorzkowska A3.

1 Department of Neurology, Jagiellonian University, School of Medicine, 31-503 Krakow, Botaniczna 3, Krakow, Poland. [email protected]

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

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

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