New HSP genetic findings - HSP Research Foundation

From Mali, Norway, Germany, Qatar, Italy, Turkey, Saudi Arabia, Pakistan, USA, Poland

New SPG10 mutation found in Mali family

Collaboration between Mali and the NIH

Hereditary spastic paraplegias (HSPs) are well-characterized disorders but rarely reported in Africa. We evaluated a Malian family in which three individuals had HSP and distal muscle atrophy and sensory loss. HSP panel testing identified a novel heterozygous missense mutation in KIF5A (c.1086G>C, p.Lys362Asn) that segregated with the disease (SPG10). Lys362 is highly conserved across species and Lys362Asn is predicted to be damaging. This study shows that HSPs are present in sub-Saharan Africa, although likely underdiagnosed. Increasing efficiency and decreasing costs of DNA sequencing will make it more feasible to diagnose HSPs in developing countries.

SOURCE: Ann Clin Transl Neurol. 2017 Mar 21;4(4):272-275. doi: 10.1002/acn3.402. eCollection 2017 Apr. PMID: 28382308

A novel mutation in KIF5A in a Malian family with spastic paraplegia and sensory loss.

Guinto CO1, Diarra S1, Diallo S2, Cissé L1, Coulibaly T1, Diallo SH2, Taméga A1, Chen KL3, Schindler AB3, Bagayoko K1, Simaga A4, Blackstone C3, Fischbeck KH3, Landouré G5.

1 Service de Neurologie Centre Hospitalier Universitaire du Point “G” Bamako Mali.

2 Service de Neurologie Centre Hospitalier Universitaire de Gabriel Touré Bamako Mali.

3 Neurogenetics Branch NINDS National Institutes of Health Bethesda Maryland.

4 Institut d’Ophtalmologie Tropicale de l’Afrique Bamako Mali.

5 Service de Neurologie Centre Hospitalier Universitaire du Point “G” Bamako Mali; Neurogenetics Branch NINDS National Institutes of Health Bethesda Maryland.

Genetic cause identified in 30/105 cases

Extensive previous investigations had failed

Hereditary ataxia and spastic paraplegia are heterogeneous monogenic neurodegenerative disorders. To date, a large number of individuals with such disorders remain undiagnosed. Here, we have assessed molecular diagnosis by gene panel sequencing in 105 early and late-onset hereditary ataxia and spastic paraplegia probands, in whom extensive previous investigations had failed to identify the genetic cause of disease.

Pathogenic and likely-pathogenic variants were identified in 20 probands (19%) and variants of uncertain significance in ten probands (10%). Together these accounted for 30 probands (29%) and involved 18 different genes. Among several interesting findings, dominantly inherited KIF1A variants, p.(Val8Met) and p.(Ile27Thr) segregated in two independent families, both presenting with a pure spastic paraplegia phenotype. Two homozygous missense variants, p.(Gly4230Ser) and p.(Leu4221Val) were found in SACS in one consanguineous family, presenting with spastic ataxia and isolated cerebellar atrophy. The average disease duration in probands with pathogenic and likely-pathogenic variants was 31 years, ranging from 4 to 51 years.

In conclusion, this study confirmed and expanded the clinical phenotypes associated with known disease genes. The results demonstrate that gene panel sequencing and similar sequencing approaches can serve as efficient diagnostic tools for different heterogeneous disorders. Early use of such strategies may help to reduce both costs and time of the diagnostic process.

SOURCE: PLoS One. 2017 Mar 31;12(3):e0174667. doi: 10.1371/journal.pone.0174667. eCollection 2017. PMID: 28362824

Targeted high throughput sequencing in hereditary ataxia and spastic paraplegia.

Iqbal Z1, Rydning SL1,2, Wedding IM1,2, Koht J2,3, Pihlstrøm L1,2, Rengmark AH1, Henriksen SP1, Tallaksen CM1,2, Toft M1.

1 Department of Neurology, Oslo University Hospital, Oslo, Norway.

2 Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.

3 Department of Neurology, Drammen Hospital, Vestre Viken Hospital Trust, Drammen, Norway.

Two new SPG30 mutations discovered

First finding outside the motor domain

This is the first evidence that KIF1A mutations outside the motor domain of the gene can cause HSP.

BACKGROUND AND PURPOSE:

Hereditary spastic paraplegia is a clinically and genetically heterogeneous group of rare, inherited disorders causing an upper motor neuron syndrome with (complex) or without (pure) additional neurological symptoms. Mutations in the KIF1A gene have already been associated with recessive and dominant forms of hereditary spastic paraplegia (SPG30) in a few cases.

METHODS:

All family members included in the study were examined neurologically. Whole-exome sequencing was used in affected individuals to identify the responsible candidate gene. Conventional Sanger sequencing was conducted to validate familial segregation.

RESULTS:

A family of Macedonian origin with two affected siblings, one with slowly progressive and the other one with a more complex and rapidly progressing hereditary spastic paraplegia is reported. In both affected individuals, two novel pathogenic mutations outside the motor domain of the KIF1A gene were found (NM_001244008.1:c.2909G>A, p.Arg970His and c.1214dup, p.Asn405Lysfs*40) that segregate with the disease within the family establishing the diagnosis of autosomal recessive SPG30.

CONCLUSIONS:

This report provides the first evidence that mutations outside the motor domain of the gene can cause (recessive) SPG30 and extends the genotype-phenotype association for KIF1A-related diseases.

Hereditary spastic paraplegia caused by compound heterozygous mutations outside the motor domain of the KIF1A gene.

Krenn M1, Zulehner G1, Hotzy C1, Rath J1, Stogmann E1, Wagner M2,3, Haack TB2, Strom TM2,4, Zimprich A1, Zimprich F1.

1 Department of Neurology, Medical University of Vienna, Vienna, Austria.

2 Institute of Human Genetics, Technical University Munich, Munich, Germany.

3 Institute of Neurogenomics, Helmholtz Zentrum München, Neuherberg, Germany.

4 Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.

New SPG45 HSP mutation found

Collaboration between Qatar and Cornell

BACKGROUND:

Hereditary Spastic Paraplegia (HSP) is a genetically heterogeneous group of neurodegenerative diseases. Thin Corpus Callosum (TCC) associated HSP is a distinguished subgroup of complex forms. Purines and pyrimidine, the basic DNA and RNA components, are regulating the cell metabolism, having roles in signal transduction, energy preservation and cellular repair. Genetic defects in nucleotide metabolism related genes have been only recently implicated in brain and neurodegenerative diseases’ pathogenesis.

CASE PRESENTATION:

We present a consanguineous Qatari family with two brothers, 9 and 3 years, who displayed a characteristic phenotype of early onset and markedly-severe spasticity with tiptoe walking, delayed dysarthric speech, persistent truncal hypotonia, and multiple variable-sized areas of brownish skin discoloration appearing at different places on the body. A clinical diagnosis suggestive of complex hereditary spastic paraplegia (HSP) was set after the family had the second affected child. Whole genome sequencing identified a novel homozygous NT5C2 splice site mutation (NM_012229.4/NM_001134373.2: c.1159 + 1G > T) that recessively segregated in family members. Brain MRI revealed dysgenic and thin corpus callosum (TCC) with peri-trigonal white matter cystic changes in both affected boys, whereas a well-developed corpus callosum with normal white matter was shown in their apparently normal brother, who found to be a carrier for the mutant variant. This mutation led to skipping of exon 14 with removal of 58 amino acid residues at the C-terminal half. The aberrantly spliced NT5C2 showed substantial reduction in expression level in the in-vitro study, indicating marked instability of the mutant NT5C2 protein.

CONCLUSION:

The present report expands the phenotypic spectrum of SPG45 and confirms NT5C2-SPG45 as a member of the rare TCC SPG-subtypes. Homozygous alteration in NT5C2 seems essential to produce central white matter developmental defects. The study highlights the importance of cytosolic II 5′-nucleotidase (NT5C2) in maintaining the normal balance of purines’ pool in the brain, which seems to play a pivotal role in the normal development of central white matter structures.

SOURCE: BMC Med Genet. 2017 Mar 21;18(1):33. doi: 10.1186/s12881-017-0395-6. PMID: 28327087

NT5C2 novel splicing variant expands the phenotypic spectrum of Spastic Paraplegia (SPG45): case report of a new member of thin corpus callosum SPG-Subgroup.

Elsaid MF1, Ibrahim K1, Chalhoub N2,3, Elsotouhy A4, El Mudehki N5, Abdel Aleem A6,7.

1 Pediatric Neurology Department, Hamad Medical Corporation, Doha, Qatar.

2 Neurogenetics Research program, Neurology Department, Weill Cornell Medical College, Qatar Foundation- Education City, 24144, Doha, Qatar.

3 Neurology Department, Weill Cornell Medical College, New York, USA.

4 Radiology Department, Hamad Medical Corporation, Doha, Qatar.

5 Physiotherapy Department, Hamad Medical Corporation, Doha, Qatar.

6 Neurogenetics Research program, Neurology Department, Weill Cornell Medical College, Qatar Foundation- Education City, 24144, Doha, Qatar. [email protected].

7 Neurology Department, Weill Cornell Medical College, New York, USA. [email protected].

New SPG2 HSP mutation found

Initial diagnosis was MS

Several single gene disorders can potentially be overlooked in the differential diagnostic evaluation of patients with multiple sclerosis (MS). Pelizaeus-Merzbacher disease and spastic paraplegia type 2 are allelic X-linked disorders associated with defective myelination of the central nervous system and mutations in PLP1. Neurological symptoms are occasionally observed in female carriers of these mutations. Two women – the proposita (Pt1) and her mother (Pt2) – reported walking difficulties since adolescence and showed progressive cognitive decline. Their neurological examinations revealed spastic gait, pyramidal tract involvement and distal muscle atrophy in the legs. Peripheral neuropathy and diffuse white matter (WM) changes on brain MRI were also observed. Both patients had a preliminary diagnosis of primary progressive MS. Using a targeted method in next generation sequencing, the novel heterozygous c.210T>G/p.Y70* in PLP1 was identified in Pt2. The same mutation was also found in Pt1 but not in five healthy relatives. The mutation showed moderate-to-severe skewed X inactivation in tissues, and Western blotting revealed a significant reduction of PLP1 and DM20 in the sural nerve of Pt2. In conclusion a mother and daughter presented an X-linked dominant disorder with skewed X inactivation. The authors suggest that PLP1 testing might be considered in the evaluation of women with spastic paraparesis, cognitive decline and WM changes.

SPG2 mimicking multiple sclerosis in a family identified using next generation sequencing.

Rubegni A1, Battisti C2, Tessa A1, Cerase A3, Doccini S1, Malandrini A2, Santorelli FM4, Federico A5.

1 Molecular Medicine, IRCCS Stella Maris, Pisa, Italy.

2 Unit of Neurology and Neurometabolic Disorders, Department of Medicine, Surgery and Neurosciences, University of Siena, Italy, Azienda Ospedaliera Universitaria Senese, Siena.

3 Unit NINT Neuroimaging and Neurointervention, Department of Neurological and Sensorineural Sciences, Azienda Ospedaliera Universitaria Senese, Siena, Italy.

4 Molecular Medicine, IRCCS Stella Maris, Pisa, Italy,. Electronic address: [email protected].

5 Unit of Neurology and Neurometabolic Disorders, Department of Medicine, Surgery and Neurosciences, University of Siena, Italy, Azienda Ospedaliera Universitaria Senese, Siena. Electronic address: [email protected].

PLA2G6 gene newly associated with HSP

Discovery made in Turkish siblings

PLA2G6-associated neurodegeneration (PLAN) and hereditary spastic paraplegia (HSP) are 2 groups of heterogeneous neurodegenerative diseases. In this study, we report PLA2G6 gene mutations in 3 families from Turkey, Morocco, and Romania. Two affected Turkish siblings presenting HSP adds the disease to PLAN phenotypes. They were homozygous for the PLA2G6 missense c.2239C>T, p.Arg747Trp variant and the ages of onset were 9 and 21. Parkinsonism, dystonia or cognitive decline were not the clinical elements in these patients contrary to the cases that has been previously reported with the same variant, however, iron accumulation was evident in their cranial magnetic resonance imaging. The Moroccan patient was homozygous for a novel missense c.1786C>T, p.Leu596Phe variant and the Romanian patient had 2 novel mutations; c.1898C>T, p.Ala633Val and c.1765_1768del, p.Ser589ThrfsTer76. Both of these patients conformed better to childhood onset PLAN with the age of onset at 4 and 7 years, respectively. Interestingly, all identified mutations were affecting the highly conserved patatin-like phospholipase domain of the PLA2G6 protein.

PLA2G6 mutations associated with a continuous clinical spectrum from neuroaxonal dystrophy to hereditary spastic paraplegia.

Ozes B1, Karagoz N2, Schüle R3,4, Rebelo A5, Sobrido MJ6, Harmuth F7, Synofzik M3,4, Pascual SIP8, Colak M2, Ciftci-Kavaklioglu B2, Kara B9, Ordóñez-Ugalde A6, Quintáns B6, Gonzalez MA5, Soysal A2, Zuchner S5, Battaloglu E1.

1 Department of Molecular Biology and Genetics, Bogazici University, Istanbul, Turkey.

2 Department of Neurology, Bakirkoy Training and Research Hospital for Psychiatry and Neurological Diseases, Istanbul, Turkey.

3 Department of Neurodegeneration, Hertie Institute for Clinical Brain Research and Centre of Neurology, Tuebingen, Germany.

4 University of Tuebingen, German Research Center for Neurodegenerative Diseases (DZNE), Tuebingen, Germany.

5 Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida.

6 Neurogenetics Group, FPGMX-IDIS, Santiago de Compostela, Spain.

7 Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Tuebingen, Germany.

8 Servicio de Neurologia Pediátrica, Hospital Universitario La Paz, Prof. Asociado Departamento de Pediatria, Universidad Autónoma de Madrid, Madrid, Spain.

9 Department of Radiology, Bakirkoy Dr. Sadi Konuk Training and Research Hospital, Istanbul, Turkey.

AR-HSP associated with KY gene mutation

New finding in Bedouin family

Twelve individuals of consanguineous Bedouin kindred presented with autosomal recessive progressive spastic paraplegia evident as of age 0-24 months, with spasticity of lower limbs, hyperreflexia, toe walking and equinus deformity. Kyphoscolisois was evident in older patients. Most had atrophy of the lateral aspects of the tongue and few had intellectual disability. Nerve conduction velocity, electromyography and head and spinal cord magnetic resonance imaging were normal in tested subjects. Muscle biopsy showed occasional central nuclei and fiber size variability with small angular fibers. Genome-wide linkage analysis identified a 6.7Mbp disease-associated locus on chromosome 3q21.3-3q22.2 (LOD score 9.02; D3S1290). Whole-exome sequencing identified a single homozygous variant within this locus, c.51_52ins(28); p.(V18fs56*) in KY, segregating in the family as expected and not found in 190 Bedouin controls. High KY transcript levels were demonstrated in muscular organs with lower expression in the CNS. The phenotype is reminiscent of kyphoscoliosis seen in Ky null mice. Two recent studies done independently and parallel to ours describe somewhat similar phenotypes in one and two patients with KY mutations. KY encodes a tranglutaminase-like peptidase, which interacts with muscle cytoskeletal proteins and is part of a Z-band protein complex, suggesting the disease mechanism may resemble myofibrillar myopathy. However, the mixed myopathic-neurologic features caused by human and mouse Ky mutations are difficult to explain by loss of KY sarcomere stabilizing function alone. KY transcription in CNS tissues may imply that it also has a role in neuromotor function, in line with the irregularity of neuromuscular junction in Ky null mutant mice.

SOURCE: Eur J Hum Genet. 2017 May 10. doi: 10.1038/ejhg.2017.85. [Epub ahead of print] PMID: 28488683

Progressive hereditary spastic paraplegia caused by a homozygous KY mutation.

Yogev Y1, Perez Y1, Noyman I2, Madegem AA3, Flusser H4, Shorer Z2, Cohen E5, Kachko L6, Michaelovsky A4, Birk R7, Koifman A8, Drabkin M1, Wormser O1, Halperin D1, Kadir R1, Birk OS1,8.

1 The Morris Kahn Laboratory of Human Genetics at the National Institute of Biotechnology in the Negev and Faculty of Health Sciences, Ben-Gurion University, Beer Sheva, Israel.

2 Department of Pediatric Neurology, Soroka University Medical Center, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel.

3 Department of Pediatrics, Beer Sheva, Clalit Health Services, Israel.

4 Zussman Child Development Center, Soroka University Medical Center, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel.

5 Department of Orthopaedics, Soroka University Medical Center, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel.

6 Department of Pathology, Soroka University Medical Center, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel.

7 Department of Nutrition, Faculty of Health Sciences, Ariel University, Ariel, Israel.

8 Genetics Institute, Soroka University Medical Center, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel.

New infantile ascending HSP mutation found

Severe HSP form in Pakistani child

Infantile onset ascending spastic paralysis (IAHSP) is a type of recessively inherited spastic paraplegia. We investigated the clinical and genetic cause of a recessively inherited disorder in two siblings manifesting severe spasticity in the lower limbs, which hindered their gait. A novel homozygous nonsense mutation c.1918 C > T (p.Arg640*) was identified after whole-exome sequencing within ALS2 in the DNA of both patients. The obligate carriers were heterozygous for the mutation and other unaffected members were homozygous for the wild type allele. The variant was absent from 100 control chromosomes and all public databases. This report extends the allelic heterogeneity of ALS2 mutations and emphasizes the importance of genetic testing for diagnosis of pediatric disorders.

SOURCE: J Neurogenet. 2017 May 13:1-4. doi: 10.1080/01677063.2017.1324441. [Epub ahead of print]

A novel mutation in ALS2 associated with severe and progressive infantile onset of spastic paralysis.

Tariq H1, Mukhtar S2, Naz S1.

1 a School of Biological Sciences , University of the Punjab , Lahore , Pakistan.

2 b Punjab Institute of Neurosciences , Lahore General Hospital , Lahore , Pakistan.

New SPG72 HSP mutation found

Rare, autosomal dominant, pure HSP

Alterations in proteins that regulate endoplasmic reticulum morphology are common causes of hereditary spastic paraplegia (SPG1-78, plus others). Mutations in the REEP1 gene that encodes an endoplasmic reticulum-shaping protein are well-known causes of SPG31, a common autosomal dominant spastic paraplegia. A closely-related gene, REEP2, is mutated in SPG72, with both autosomal and recessive inheritances. Here, we report a patient with a pure hereditary spastic paraplegia due to a de novo missense mutation (c.119T > G, p.Met40Arg) in REEP2 at a highly-conserved residue very close to another known pathogenic missense change. This represents only the second autosomal dominant SPG72 missense mutation reported.

SOURCE: Ann Clin Transl Neurol. 2017 Apr 11;4(5):347-350. doi: 10.1002/acn3.404. eCollection 2017 May. PMID: 28491902

De novo REEP2 missense mutation in pure hereditary spastic paraplegia.

Roda RH1,2, Schindler AB2, Blackstone C2.

1 Neuromuscular Medicine Department of Neurology Johns Hopkins University School of Medicine Baltimore Maryland.

2 Neurogenetics Branch National Institute of Neurological Disorders and Stroke National Institutes of Health Bethesda Maryland.

New SPG10 mutation found

Considerably different phenotype from normal

The KIF5A gene (OMIM 602821) encodes a neuron-specific kinesin heavy chain involved in intracellular transport of mitochondria and other cargoes. KIF5A protein comprises the N terminal motor domain, the stalk domain and the C-terminal cargo binding domain. The binding between KIF5A and its cargoes is mediated by kinesin adaptor proteins such as TRAK1 and TRAK2. Numerous missense KIF5A mutations in the motor and stalk domains cause spastic paraplegia type 10 (SPG10, OMIM 604187). Conversely, the role of loss-of-function mutations, especially those affecting the cargo binding domain, is unclear. We describe a novel de novo KIF5A p.Ser974fs/c.2921delC mutation found by whole exome sequencing in a patient with a congenital severe disease characterized by myoclonic seizures and progressive leukoencephalopathy. Since this phenotype differs considerably from the KIF5A/SPG10 disease spectrum we propose that the KIF5A p.Ser974fs and possibly other mutations which lead to truncation of the C-terminal tail of the protein cause a novel disorder. We speculate that the unique effect of the C-terminal truncating KIF5A mutations may result from the previously described complex role of this protein domain in binding of the TRAK2 and possibly other kinesin adaptor protein(s).

KIF5A de novo mutation associated with myoclonic seizures and neonatal onset progressive leukoencephalopathy.

Rydzanicz M1, Jagła M2, Kosinska J1, Tomasik T2, Sobczak A2, Pollak A3, Herman-Sucharska I4, Walczak A1, Kwinta P2, Płoski R1.

1 Department of Medical Genetics, Medical University of Warsaw, Warsaw, Poland.

2 Department of Pediatrics, Chair of Pediatrics, Institute of Pediatrics, Jagiellonian University, Medical College, Cracow, Poland.

3 Department of Genetics, Institute of Physiology and Pathology of Hearing, Warsaw, Poland.

4 Department of Electroradiology, Jagiellonian University, Cracow, Poland.