Posted - December 2016 in Research Highlights
From Hungary, Sudan, Australia and China
Nine new mutations found in 58 Hungarian HSPers in the SPAST, SPG7, SPG11, ATL1, NIPA1, and ABCD1 genes.
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 DOI: 10.1016/j.jns.2016.03.018
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].
Six new mutations have been discovered in a study of 25 HSP families in Sudan
Hereditary spastic paraplegias (HSP) are the second most common type of motor neuron disease recognized worldwide. We investigated a total of 25 consanguineous families from Sudan.
We used next-generation sequencing to screen 74 HSP-related genes in 23 families. Linkage analysis and candidate gene sequencing was performed in two other families. We established a genetic diagnosis in six families with autosomal recessive HSP (SPG11 in three families and TFG/SPG57, SACS and ALS2 in one family each). A heterozygous mutation in a gene involved in an autosomal dominant HSP (ATL1/SPG3A) was also identified in one additional family.
Six out of seven identified variants were novel. The c.64C>T (p.(Arg22Trp)) TFG/SPG57 variant (PB1 domain) is the second identified that underlies HSP, and we demonstrated its impact on TFG oligomerization in vitro. Patients did not present with visual impairment as observed in a previously reported SPG57 family (c.316C>T (p.(Arg106Cys)) in coiled-coil domain), suggesting unique contributions of the PB1 and coiled-coil domains in TFG complex formation/function and a possible phenotype correlation to variant location.
Some families manifested marked phenotypic variations implying the possibility of modifier factors complicated by high inbreeding. Finally, additional genetic heterogeneity is expected in HSP Sudanese families. The remaining families might unravel new genes or uncommon modes of inheritance.
SOURCE: Eur J Hum Genet. 2016 Sep 7. doi: 10.1038/ejhg.2016.108. [Epub ahead of print] PMID: 27601211 DOI: 10.1038/ejhg.2016.108
Hereditary spastic paraplegias: identification of a novel SPG57 variant affecting TFG oligomerization and description of HSP subtypes in Sudan.
Elsayed LE1,2,3, Mohammed IN3, Hamed AA3, Elseed MA3, Johnson A4, Mairey M1,2, Mohamed HE5,6, Idris MN3,6, Salih MA7, El-Sadig SM3,8, Koko ME9, Mohamed AY10, Raymond L1,2,11, Coutelier M1,2, Darios F1, Siddig RA12, Ahmed AK3, Babai AM3, Malik HM3, Omer ZM3, Mohamed EO3, Eltahir HB13, Magboul NA14, Bushara EE3, Elnour A15, Rahim SM14, Alattaya A16, Elbashir MI3, Ibrahim ME9, Durr A1,11, Audhya A4, Brice A1,11, Ahmed AE3,6, Stevanin G1,2,11.
1 Institut du Cerveau et de la Moelle épinière, INSERM U1127, CNRS UMR7225, Sorbonne Universités, UPMC Université Paris VI UMR_S1127, Paris, France.
2 Ecole Pratique des Hautes Etudes, EPHE, PSL université, Paris, France.
3 University of Khartoum, Khartoum, Sudan.
4 Department of Biomolecular Chemistry, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI, USA.
5 Alnelain Medical Center, Khartoum, Sudan.
6 Sudan Medical Council, Neurology, Sudan.
7 Division of Pediatric Neurology, Department of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
8 Department of Neurology, Soba University Hospital, Khartoum, Sudan.
9 Department of Molecular Biology, Institute of Endemic Diseases, University of Khartoum, Khartoum, Sudan.
10 Department of Biochemistry, Faculty of Medicine, National University, Khartoum, Sudan.
11 APHP Pitié-Salpêtrière Hospital, Department of genetics, Paris, France.
12 Neelain University, Khartoum, Sudan.
13 Department of Biochemistry, El Imam EL Mahdi University, Kosti, Sudan.
14 Department of Radiology, Alamal National Hospital, Khartoum, Sudan.
15 Department of Radiology, Ribat University Hospital, Khartoum, Sudan.
16 Antalya Medical Center, Khartoum, Sudan.
A new variant of the Atlastin gene (SPG3A HSP) is found in two members of one Australian family
Objective: To describe a family with a newly found ATL1 genetic variant and the associated phenotype.
Background: Mutations in the ATL1 gene are known to cause pure early onset autosomal dominant hereditary spastic paraplegia (SPG3A) and ulceromutilating sensory neuropathy, like HSN-1. We describe the detailed clinical and electrophysiological findings in the first family with ulceromutilating sensory neuropathy, along with spastic paraparesis, carrying the p.Ala354Pro likely pathogenic variant in ATL1.
Methods: Detailed clinical and electrophysiological studies were performed in affected and at risk family members. Motor and sensory conduction studies, were carried out on upper and lower limbs. Genetic analysis was carried out using a custom designed neurogenetic gene capture panel followed by massively parallel sequencing (MPS).
Results: Two affected family members were investigated, as well as one unaffected. Through the family history, 12 patients were found to have had the same phenotype, including three deceased family members. One affected family member was analysed by MPS, with the p.Ala354Pro likely pathogenic variant in ATL1 being the only significant finding. The second affected family member also carried the variant, while the unaffected family member did not.
The affected family members had characteristic history of a profound neuropathic pain syndrome, despite relative preservation of superficial sensory modalities. The patients also exhibited spastic paraparesis with hyper-reflexia. This resulted in recurrent painless foot ulcers and osteomyelitis. Nerve Conduction Studies (NCS) showed only a mild sensory neuropathy.
Conclusions: This novel ATL1 variant potentially expands the SPG3A phenotype. The combination of severe ulceromutilating neuropathy, a profound neuropathic pain syndrome, and only mild sensory neuropathy on NCS, along with spastic paraparesis, should prompt the screening for ATL1 mutations.
SOURCE: Neurology (2016) Volume: 86, Issue: 16 SUPPL. 1, Publisher: Lippincott Williams and Wilkins, Pages: no pagination ISBN: 0028-3878
Severe neuropathic pain syndrome, with ulceromutilating neuropathy and spastic paraparesis, associated with the P.ala354pro variant in atl1
Khade N., Ashton C., Davis M., Knezevic W.
A pure form of late-onset SPG18 HSP has been found in China
A Chinese HSPer has been found with new mutations in the ERLIN2 gene. Mutations in this gene cause SPG18 HSP, previously only found to be recessively inherited, early-onset and complicated.
Hereditary spastic paraplegia type 18 (HSP18) is a complicated form of autosomal recessive HSP characterized by progressive weakness and spasticity of the lower extremities, dysarthria, and cognitive decline. In 2011, HSP18, also known as Spastic Paraplegia 18 (SPG18), was firstly identified due to a candidate gene endoplasmic reticulum lipid raft-associated protein 2 (ERLIN2) on chromosome 8p11.2 in one Saudi family. During the past 5 years, another two families with SPG18 due to ERLIN2 mutations have been reported presenting with complicated phenotype. Here, we report a patient born in a non-consanguineous family who possessed an autosomal recessive pure form of HSP owing to novel mutations in ERLIN2. Patient was characterized by late-onset spasticity of lower extremities without significant speech involvement or cognitive disability.
We report a Chinese patient from a non-consanguineous family with a pure form of late-onset SPG18 HSP associated with compound heterozygous mutations in the ERLIN2 gene: c.538C>T and c.298+1G>T. She presented with late-onset progressive spasticity and weakness of the LLs without speech involvement or cognitive disability. Her son and daughter each carrying one of these mutations were not clinically affected.
In summary, we identified the first Chinese family with SPG18, a pure form of HSP, due to undocumented compound heterozygous novel mutations (c.538C>T and c.298+1G>T) in the ERLIN2 gene. This study expanded our knowledge of the phenotype of SPG18 and emphasized the importance of ERLIN2 gene screened for the patients manifesting as a pure form of late-onset HSP.
SOURCE: Chin Med J 2016; 129: 2759-61
Novel Mutations in Endoplasmic Reticulum Lipid Raft-associated Protein 2 Gene Cause Pure Hereditary Spastic Paraplegia Type 18
Tian WT, Shen JY, Liu XL, Wang T, Luan XH, Zhou HY, Chen SD, Huang XJ, Cao L.
1 Department of Neurology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
2 Institute of Neurology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China