New HSP genotypes and phenotypes

Posted - September 2018 in Research Highlights

Research from China, Japan, Germany, Turkey and Australia

 

Sydney study finds new SPG7 mutation

 

Overlaps with Hereditary Cerebellar Ataxia

 

Dr. Kishore Kumar

Neurogeneticist Dr. Carolyn Sue

Dr Kishore Kumar and Prof Carolyn Sue, members of the HSP clinical trial team, are part of a broad consortium studying genetic diversity in the Hereditary Cerebellar Ataxias in Australia.

 

Abstract

Genetic testing strategies such as next-generation sequencing (NGS) panels and whole genome sequencing (WGS) can be applied to the hereditary cerebellar ataxias (HCAs), but their exact role in the diagnostic pathway is unclear. We aim to determine the yield from genetic testing strategies and the genetic and phenotypic spectrum of HCA in Australia by analysing real-world data. We performed a retrospective review on 87 HCA cases referred to the Neurogenetics Clinic at the Royal North Shore Hospital, Sydney, Australia. Probands underwent triplet repeat expansion testing; those that tested negative had NGS-targeted panels and WGS testing when available. In our sample, 58.6% were male (51/87), with an average age at onset of 37.1 years. Individuals with sequencing variants had a prolonged duration of illness compared to those with a triplet repeat expansion. The detection rate in probands for routine repeat expansion panels was 13.8% (11/80). NGS-targeted panels yielded a further 11 individuals (11/32, 34.4%), with WGS yielding 1 more diagnosis (1/3, 33.3%). NGS panels and WGS improved the overall diagnostic rate to 28.8% (23/80) in 14 known HCA loci. The genetic findings included novel variants in ANO10, CACNA1A, PRKCG and SPG7. Our findings highlight the genetic heterogeneity of HCAs and support the use of NGS approaches for individuals who were negative on repeat expansion testing. In comparison to repeat disorders, individuals with sequencing variants may have a prolonged duration of illness, consistent with slower progression of disease.

 

SOURCE: Cerebellum. 2018 Aug 4. doi: 10.1007/s12311-018-0969-7. [Epub ahead of print] PMID: 30078120

 

High Degree of Genetic Heterogeneity for Hereditary Cerebellar Ataxias in Australia.

Kang C1, Liang C2,3, Ahmad KE2,3, Gu Y2,3, Siow SF2,3, Colebatch JG4,5, Whyte S6, Ng K3, Cremer PD3, Corbett AJ7, Davis RL1,2, Roscioli T4,8, Cowley MJ9,10, Park JS2,11, Sue CM2,3, Kumar KR12,13,14.

1 Faculty of Medicine and Health, Kolling Institute of Medical Research, University of Sydney Northern Clinical School, St Leonards, Australia.

2 Department of Neurogenetics, Kolling Institute, University of Sydney and Northern Sydney Local Health District, St Leonards, Australia.

3 Department of Neurology, Royal North Shore Hospital, St Leonards, Australia.

4 Prince of Wales Clinical School and Neuroscience Research Australia, University of New South Wales, Randwick, Australia.

5 Institute of Neurological Sciences, Prince of Wales Hospital, Randwick, Australia.

6 Department of Neurology, Gosford Hospital, Gosford, Australia.

7 Department of Neurology, Concord Repatriation General Hospital, Concord, Australia.

8 Department of Clinical Genetics, Sydney Children’s Hospital, Randwick, Australia.

9 Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Darlinghurst, Australia.

10 St Vincent’s Clinical School, University of New South Wales, Darlinghurst, Australia.

11 Department of Experimental Animal Research, Seoul National University Hospital, Biomedical Research Institute, Seoul, Republic of Korea.

12 Department of Neurogenetics, Kolling Institute, University of Sydney and Northern Sydney Local Health District, St Leonards, Australia. [email protected]

13 Department of Neurology, Royal North Shore Hospital, St Leonards, Australia. [email protected]

14 Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Darlinghurst, Australia.

 


 

19 new mutations found a large Chinese study

 

Main HSP genes the same as found elsewhere globally

 

Abstract

Hereditary spastic paraplegia (HSP) is a heterogeneous group of neurodegenerative diseases characterized by progressive weakness and spasticity of lower limbs. To clarify the genetic spectrum and improve the diagnosis of HSP patients, targeted next-generation sequencing (NGS) was applied to detect the culprit genes in 55 Chinese HSP pedigrees. The classification of novel variants was based on the American College of Medical Genetics and Genomics (ACMG) standards and guidelines. Patients remaining negative following targeted NGS were further screened for gross deletions/duplications by multiplex ligation-dependent probe amplification (MLPA).

 

We made a genetic diagnosis in 61.8% (34/55) of families and identified 33 mutations, including 14 known mutations and 19 novel mutations. Of them, one was de novo mutation (NIPA1: c.316G>A). SPAST mutations (22/39, 56.4%) are the most common in Chinese AD-HSP followed by ATL1 (4/39, 10.3%). Moreover, we identified the third BSCL2 mutation (c.1309G>C) related to HSP by further functional studies and first reported the KIF1A mutation (c.304G>A) in China. Our findings broaden the genetic spectrum of HSP and improve the diagnosis of HSP patients. These results demonstrate the efficiency of targeted NGS to make a more rapid and precise diagnosis in patients with clinically suspected HSP.

 

KEY MESSAGES: We made a genetic diagnosis in 61.8% of families and identified 33 mutations. SPAST mutations are the most common in Chinese AD-HSP followed by ATL1. Our findings broaden the genetic spectrum and improve the diagnosis of HSP.

 

SOURCE: J Mol Med (Berl). 2018 Jul;96(7):701-712. doi: 10.1007/s00109-018-1655-4. Epub 2018 Jun 11. PMID: 29934652

 

Targeted next-generation sequencing improves diagnosis of hereditary spastic paraplegia in Chinese patients.

Lu C1,2, Li LX1, Dong HL1, Wei Q1, Liu ZJ3, Ni W1, Gitler AD4, Wu ZY5,6.

1 Department of Neurology and Research Center of Neurology in Second Affiliated Hospital, and Key Laboratory of Medical Neurobiology of Zhejiang Province, Zhejiang University School of Medicine, 88 Jiefang Road, Hangzhou, 310009, China.

2 Department of Neurology and Institute of Neurology, First Affiliated Hospital, Fujian Medical University, Fuzhou, China.

3 Department of Neurology and Institute of Neurology, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China.

4 Department of Genetics, Stanford University School of Medicine, Stanford, USA.

5 Department of Neurology and Research Center of Neurology in Second Affiliated Hospital, and Key Laboratory of Medical Neurobiology of Zhejiang Province, Zhejiang University School of Medicine, 88 Jiefang Road, Hangzhou, 310009, China. [email protected]

6 Joint Institute for Genetics and Genome Medicine Between Zhejiang University and University of Toronto, Zhejiang University, Hangzhou, China.

 


 

First report of SPG9 in non-Caucasians

 

New mutation and complicated HSP identified

 

Abstract

Hereditary spastic paraplegias (HSPs) are characterized by various inherited disorders in which weakness and spasticity of the lower extremities are the predominant symptoms. Recently, HSP caused by ALDH18A1 mutations has been reported as SPG9 with autosomal dominant (SPG9A) and autosomal recessive (SPG9B) transmission. In this study, we obtained clinical and genetic findings in two Japanese families with SPG9B. One family had a novel compound heterozygous mutation (c.1321 C > T/c.1994G > A) in the ALDH18A1 gene. The other family had a homozygous mutation (c.383 G > A/c.383 G > A) in the ALDH18A1 gene.

 

To date, only two SPG9B families with ALDH18A1 mutations have been reported. This is the first report of SPG9 in non-Caucasians. Furthermore, we found cerebellar ataxia in one family, although cerebellar ataxia has not been reported in SPG9B so far. SPG9B might involve a complicated HSP including cerebellar ataxia and cognitive impairment. This study expands the clinical and genetic spectrum of ALDH18A1-related disorders.

 

SOURCE: J Hum Genet. 2018 Jun 18. doi: 10.1038/s10038-018-0477-0. [Epub ahead of print] PMID: 29915212

 

Novel mutations in the ALDH18A1 gene in complicated hereditary spastic paraplegia with cerebellar ataxia and cognitive impairment.

Koh K1, Ishiura H2, Beppu M3, Shimazaki H4, Ichinose Y1, Mitsui J2, Kuwabara S5, Tsuji S2,6, Takiyama Y7; Japan Spastic Paraplegia Research Consortium.

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

2 Department of Neurology, The University of Tokyo Hospital, Tokyo, Japan.

3 Department of Molecular Diagnosis, Chiba University Graduate School of Medicine, Chiba, Japan.

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

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

6 International University of Health and Welfare, Chiba, Japan.

7 Department of Neurology, Graduate School of Medical Sciences, University of Yamanashi, Yamanashi, Japan. [email protected].

 


 

Potentially new HSP gene identified

 

GPT2 mutation & autosomal recessive, complicated HSP

 

Abstract

Various genetic defects can cause intellectual and developmental disabilities (IDDs). Often IDD is a symptom of a more complex neurodevelopmental or neurodegenerative syndrome. Identifying syndromic patterns is substantive for diagnostics and for understanding the pathomechanism of a disease.

 

Recessive glutamate pyruvate transaminase (GPT2) mutations have recently been associated with IDD in 4 families. Here, we report a novel recessive GPT2 stop mutation p.Gln24* causing a complex IDD phenotype in a homozygous state in 5 patients from 2 consanguineous Arab families. By compiling clinical information of these individuals and previously described GPT2 patients, a recognizable neurodevelopmental and potentially neurodegenerative phenotype can be assigned consisting of intellectual disability, pyramidal tract affection with spastic paraplegia, microcephaly and frequently epilepsy. Because of the consistent presence of pyramidal tract affection in GPT2 patients, we further suggest that GPT2 mutations should be considered in cases with complex hereditary spastic paraplegia.

 

SOURCE: Clin Genet. 2018 Jun 7. doi: 10.1111/cge.13390. [Epub ahead of print] PMID: 29882329

 

GPT2 mutations cause developmental encephalopathy with microcephaly and features of complicated hereditary spastic paraplegia.

Hengel H1,2, Keimer R3, Deigendesch W3, Rieß A4, Marzouqa H3, Zaidan J3, Bauer P4, Schöls L1,2.

1 Department of Neurology and Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.

2 German Center of Neurodegenerative Diseases (DZNE), Tübingen, Germany.

3 Caritas Baby Hospital, Bethlehem, Palestine.

4 Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.

 


 

New SPG11 HSP mutation found

 

May indicate broader phenotype

 

Abstract

We describe the cases of two sisters with spastic paraplegia 11 (SPG11). The younger sister developed relapsing lesions in the brain white matter with enhancement during the acute phase that mimicked multiple sclerosis (MS). The elevation of myelin basic protein in the CSF suggested demyelination, but a normal IgG index, the absence of oligoclonal bands, and the ineffectiveness of steroid treatment indicate that an autoimmune mechanism may not have been involved.

 

In these affected sisters, we identified novel compound heterozygous mutations in the SPG11 gene. Our cases indicate the possible existence of a broader phenotypic spectrum of SPG11 mutations.

 

SOURCE: Intern Med. 2018 Jun 6. doi: 10.2169/internalmedicine.0976-18. [Epub ahead of print] PMID: 29877287

 

Novel SPG11 Mutations in a Patient with Symptoms Mimicking Multiple Sclerosis.

Mukai M1, Koh K2, Ohnuki Y3, Nagata E1, Takiyama Y2, Takizawa S1.

1 Departments of Neurology and Molecular Life Science, Tokai University School of Medicine, Japan.

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

3 Department of Molecular Life Science, Basic Medical Science and Molecular Medicine, Tokai University School of Medicine, Japan.

 


 

First reported childhood onset of SPG8 HSP

 

New SPG8 gene mutation identified

 

Abstract

RATIONALE: We report a case of Spastic paraplegia 8 (SPG8) with a novel mutation of KIAA0196 gene.

PATIENT CONCERNS: A 12-year-old boy presented as ankle sprained, lower limb stiffness, abnormal gait since he was 5 years old.

DIAGNOSES: The next generation sequence showed a novel c.1128delG (p.L376fs) mutation in KIAA0196 gene, the electromyography showed the pyramidal tract conduction dysfunction and deep sensory conduction abnormalities of lower limbs without motor neuron damage. The diagnosis was SPG8.

INTERVENTIONS: Patient was given Baclofen treatment (30 mg/day, orally).

OUTCOMES: At one year follow up, his symptoms didn’t improve.

LESSONS: We describe a novel KIAA0196 c.1128del.G (p.L376fs) mutation in a Chinese patient with SPG8. To our knowledge, it’s the first frame deletion mutation causing shift mutation of KIAA0196 gene, resulting in the earliest onset of SPG8 in the world. Gene sequencing is a powerful diagnostic tool to identify a causal mutation in genetically heterogeneous HSP.

 

SOURCE: Medicine (Baltimore). 2018 May;97(20):e10760. doi: 10.1097/MD.0000000000010760. PMID: 29768361

 

A novel KIAA0196 mutation in a Chinese patient with spastic paraplegia 8: A case report.

Ma L1, Shi Y2, Chen Z2, Li S2, Qin W2, Zhang J2.

1 Department of Neurology, People’s Hospital of Zhengzhou University.

2 Department of Neurology, Henan Provincial People’s Hospital, Zhengzhou, China.

 


 

Three new HSP mutations identified

 

Two in SPG4 and one in SPG3A

 

A study of 23 HSPers from 6 families in Turkey found a new SPG3A mutation in 6 HSPers and two new SPG4 mutations in 5 HSPers.

 

Abstract

Hereditary spastic paraparesis (HSP) constitutes both genetic and clinically heterogeneous group of upper motor neuron diseases. Half of the individuals with autosomal dominant (AD) HSP have mutations in SPAST, ATL1, and REEP1 genes. This study was conducted to elucidate the genetic etiology of patients with the pure type AD-HSP diagnosis. The patient group consisted of 23 individuals from 6 families in Turkey. In the first step of work, Sanger sequencing (SS) was performed in ATL1, SPAST, and REEP1 genes and the second phase whole-exome sequencing (WES) was performed following SS analysis for the patients with no detected mutations in these genes.

 

The results of this study revealed that in ATL1, 6 patients have previously reported c.776C > A mutation and 6 patients have novel c.470 T > C mutation. In SPAST, 3 patients have novel c.1072G > C mutation and 2 patients have novel c.1099-1G > C mutation.

 

WES was performed in three patients, who had no detected mutation in these genes with SS analysis. In this approach, as previously reported c.1859 T > C mutation in KIAA0196 was detected, and it was confirmed with the patient’s relatives by SS. In three patients, no HSP-associated variant could be identified in SS and WES.

 

With this study, the molecular genetic etiology in 20 of 23 (87%) individuals that were included in this study with the utilization of SS and WES was elucidated. Utilization of SS and WES methods have enabled the identification of genetic etiology of HSP further with appropriate genetic counseling that was provided to the patients.

 

SOURCE: Neurol Sci. 2018 Jun 16. doi: 10.1007/s10072-018-3454-7. [Epub ahead of print] PMID: 29907907

 

Three novel mutations in 20 patients with hereditary spastic paraparesis.

Duz MB1, Dasdemir S1, Kalayci Yigin A1, Akalin MA2, Seven M3.

1 Department of Medical Genetics, Cerrahpaşa Medical School, Istanbul University-Cerrahpaşa, 34098, Fatih, Istanbul, Turkey.

2 Department of Neurology, Cerrahpaşa Medical School, Istanbul University-Cerrahpaşa, 34098, Fatih, Istanbul, Turkey.

3 Department of Medical Genetics, Cerrahpaşa Medical School, Istanbul University-Cerrahpaşa, 34098, Fatih, Istanbul, Turkey. [email protected].

 

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