New HSP genotypes and phenotypes

Posted - December 2017 in Research Highlights

From China, Japan, Italy, Brazil, UK, Korea, USA, Israel, Iran, Moldova, Greece, France, Belgium, Germany, UAE, Russia

 

SPG11 mutations most common in AR-HSP

Study of 36 ARHSP families in China

 

SPG11 was suspected to be the most common subtype of ARHSP in China, whereas SPG15, SPG5 or SPG7 are rare.

 

AIM OF THE STUDY:

To investigate the mutation frequency of SPG11, SPG15, SPG5 and SPG7 in China.

 

MATERIALS AND METHODS:

We have scanned the whole exons of KIAA1840, ZFYVE26, SPG7 and CYP7B1 genes in a group of 36 unrelated Chinese ARHSP families.

 

RESULTS:

SPG11 mutations were found in 33.33% (12/36) of ARHSP patients in our study, and no mutation was identified in SPG15, SPG5 or SPG7 genes. Among the SPG11 mutations detected, c.1755_1758delAGCA/p. P585PfsX623, c.29832984delTA/p.L934LfsX1010, c.1845_1848delGTCT/p.F617Lfs*5, c.6478+1G>T and c.3662_3665delTCAA/p.I1221RfsX1230 were novel mutations, they all introduced premature termination codons which were predicted to leading to the absence of the spastacsin protein in the patients’ cells. All the SPG11 patients in our study presented with spastic paraparesis and/or mental impairment at initial time, and most patients showed thin corpus callosum (TCC) and white matter abnormalities (WMA) in brain MRI. After years’ duration, they gradually manifested with dysarthria, dysphagia, peripheral neuropathy, amyotrophy, skeletal deformity, cerebellar signs, ophthalmoplegia, decreased vision, sphincter disturbance and tremor.

 

CONCLUSIONS:

SPG11 was suspected to be the most common subtype of ARHSP in China, whereas SPG15, SPG5 or SPG7 are rare. The core symptoms of Chinese SPG11 patients showed no difference when compared to SPG11 in western countries, and clinical heterogeneity also existed in our SPG11 patients. We suggested that ARHSP patients with mental impairment, especially combined with TCC, should be excluded SPG11 first in China.

 

SOURCE: Int J Neurosci. 2017 Oct 5:1-5. doi: 10.1080/00207454.2017.1378878. [Epub ahead of print] PMID: 28933964

 

Identification of novel SPG11 mutations in a cohort of Chinese families with hereditary spastic paraplegia.

 

Du J1, Hu YC1, Tang BS1,2,3, Jiang H1,2,3, Shen L1,2,3.

 

1a Department of Neurology , Xiangya Hospital , Central South University , Changsha , China.

2b The Key Laboratory of Hunan Province in Neurodegenerative Disorders , Central South University , Changsha , China.

3c The State Key Laboratory of Medical Genetics , Central South University , Changsha , China.

 


 

New SPAST variant studied in 7 families

Increases the breadth and diversity of SPG4 HSP

 

Mutations in SPG4/SPAST are the most frequent molecular aetiology in the autosomal dominant form of hereditary spastic paraplegia (HSP). Loss-of-function and haploinsufficiency in SPAST have been demonstrated and the pure form of spastic paraplegia is a main clinical manifestation.

 

This study is to explore the novel SPAST splice site donor variant, c.1004+3A>C, in seven patients from two families, one from Italy and the other from Japan. Exon 6 is skipped out by the variant, leading to a premature termination of translation, p.Gly290Trpfs*5. Measurement of SPAST transcripts in lymphocytes demonstrated a reduction through nonsense-mediated mRNA decay (NMD). Intra- and inter-familial phenotypic variations were observed, including age-at-onset, severity of spasticity, and scoliosis.

 

Our study demonstrated further evidence of allelic heterogeneity in SPG4, dosage effects through NMD, and broad clinical features of the SPAST mutation.

 

SOURCE: J Neurol Sci. 2017 Sep 15;380:92-97. doi: 10.1016/j.jns.2017.07.011. Epub 2017 Jul 9. PMID: 28870597

 

Spastic paraplegia type 4: A novel SPAST splice site donor mutation and expansion of the phenotype variability.

 

Kawarai T1, Montecchiani C2, Miyamoto R3, Gaudiello F4, Caltagirone C5, Izumi Y3, Kaji R3, Orlacchio A6.

 

1 Department of Clinical Neuroscience, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, 770-0042, Japan. Electronic address: [email protected]

2 Laboratorio di Neurogenetica, Centro Europeo di Ricerca sul Cervello (CERC) – Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Santa Lucia, Rome, Italy; Dipartimento di Scienze Chirurgiche e Biomediche, Università di Perugia, Perugia, Italy.

3 Department of Clinical Neuroscience, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, 770-0042, Japan.

4 Laboratorio di Neurogenetica, Centro Europeo di Ricerca sul Cervello (CERC) – Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Santa Lucia, Rome, Italy.

5 Laboratorio di Neurologia Clinica e Comportamentale, IRCCS Santa Lucia, Rome, Italy; Dipartimento di Medicina dei Sistemi, Università di Roma “Tor Vergata”, Rome, Italy.

6 Laboratorio di Neurogenetica, Centro Europeo di Ricerca sul Cervello (CERC) – Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Santa Lucia, Rome, Italy; Dipartimento di Scienze Chirurgiche e Biomediche, Università di Perugia, Perugia, Italy. Electronic address: [email protected]

 


 

New REEP1 mutation discovered

High variability and diversity of REEP1 HSP mutations

 

Mutations in REEP1 have been identified in three types of neurological disorders, autosomal dominant form of Hereditary Spastic Paraplegia type 31 (SPG31), autosomal dominant distal hereditary motor neuronopathy type VB (HMN5B), and autosomal recessive form of congenital axonal neuropathy and diaphragmatic palsy. Previous studies demonstrated different molecular pathogenesis in SPG31, including loss-of-function, gain-of-function and haploinsufficiency.

 

A four-generation family from Japan, including 12 members, was investigated clinically and genetically. Seven affected members displayed pure spastic paraplegia. Impression of genetic anticipation was observed in the family, including tendency of earlier age-at-onset and increasing severity in subsequent generations. Genetic analysis revealed a heterozygous intronic variant, c.303+2T > A, in REEP1, which segregated with disease, and was also identified in one unaffected member. The variant causes exon 4 skipping leading to frame shift and a truncated transcript identified by complementary DNA sequencing of reverse transcription polymerase chain reaction products. Measurement of REEP1 transcripts in lymphocytes demonstrated a reduction through nonsense mediated mRNA decay (NMD).

 

Our study demonstrated further evidence of allelic heterogeneity in SPG31, mutant REEP1 mRNA dosage effects through NMD and intra-familial phenotype variability.

 

SOURCE: Parkinsonism Relat Disord. 2017 Oct 21. pii: S1353-8020(17)30383-8. doi: 10.1016/j.parkreldis.2017.10.012. [Epub ahead of print] PMID: 29107646

 

Spastic paraplegia type 31: A novel REEP1 splice site donor variant and expansion of the phenotype variability.

 

Kamada M1, Kawarai T2, Miyamoto R3, Kawakita R4, Tojima Y5, Montecchiani C6, D’Onofrio L7, Caltagirone C8, Orlacchio A6, Kaji R3.

 

1 Department of Neurological Intractable Disease Research, Kagawa University Faculty of Medicine, Kagawa, 761-0793, Japan.

2 Department of Clinical Neuroscience, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, 770-0042, Japan. Electronic address: [email protected]

3 Department of Clinical Neuroscience, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, 770-0042, Japan.

4 Department of Neurology, Kagawa University Hospital, Kagawa, 761-0793, Japan.

5 Faculty of Medicine, Tokushima University, Tokushima 770-0042, Japan.

6 Laboratorio di Neurogenetica, Centro Europeo di Ricerca sul Cervello (CERC) – Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Santa Lucia, Rome, Italy; Dipartimento di Scienze Chirurgiche e Biomediche, Università di Perugia, Perugia, Italy.

7 Laboratorio di Neurogenetica, Centro Europeo di Ricerca sul Cervello (CERC) – Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Santa Lucia, Rome, Italy.

8 Laboratorio di Neurologia Clinica e Comportamentale, IRCCS Santa Lucia, Rome, Italy; Dipartimento di Medicina dei Sistemi, Università di Roma “Tor Vergata”, Rome, Italy.

 


 

KIF1A mutation causes complicated HSP

Autism Spectrum Disorder (ASD) found

 

A sporadic, dominant mutation in the KIF1A gene has been found for the first time to be associated with Autism Spectrum Disorder (ASD) in a complicated phenotype with HSP.

 

Abstract

Mutations in the kinesin family member 1A (KIF1A) gene have been associated with a wide range of phenotypes including recessive mutations causing hereditary sensory neuropathy and hereditary spastic paraplegia and de novo dominant mutations causing a more complex neurological disorder affecting both the central and peripheral nervous system.

 

We identified by exome sequencing a de novo dominant missense variant, (c.38G>A, p.R13H), within an ATP binding site of the kinesin motor domain in a patient manifesting a complex phenotype characterized by autism spectrum disorder (ASD), spastic paraplegia and axonal neuropathy. The presence of ASD distinguishes this case from previously reported patients with de novo dominant mutations in KIF1A.

 

SOURCE: J Peripher Nerv Syst. 2017 Aug 23. doi: 10.1111/jns.12235. [Epub ahead of print] PMID: 28834584

 

A de novo dominant mutation in KIF1A associated with axonal neuropathy, spasticity and autism spectrum disorder.

 

Tomaselli PJ1,2, Rossor AM1, Horga A1, Laura M1, Blake JC1, Houlden H3, Reilly MM1.

 

1 MRC Centre for Neuromuscular Diseases and National Hospital for Neurology and Neurosurgery, UCL Institute of Neurology, London, UK.

2 Department of Neuromuscular Disorders, Clinical Hospital of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil.

3 Department of Neurogenetics, The National Hospital for Neurology and Neurosurgery, UCL Institute of Neurology, London, UK.

 


 

Another KIF1A mutation causes complicated HSP

Mild intellectual disability with language delay

 

A new, second, sporadic, dominant mutation in the KIF1A gene has been discovered. It is associated with mild intellectual disability with language delay and a range of other complications.

 

KIF1A is a brain-specific anterograde motor protein that transports cargoes towards the plus-ends of microtubules. Many variants of the KIF1A gene have been associated with neurodegenerative diseases and developmental delay. Homozygous mutations of KIF1A have been identified in a recessive subtype of hereditary spastic paraplegia (HSP), SPG30. In addition, KIF1A mutations have been found in pure HSP with autosomal dominant inheritance.

 

Here we report the first case of familial complicated HSP with a KIF1A mutation transmitted in autosomal dominant inheritance. A heterozygous p.T258M mutation in KIF1A was found in a Korean family through targeted exome sequencing. They displayed phenotypes of mild intellectual disability with language delay, epilepsy, optic nerve atrophy, thinning of corpus callosum, periventricular white matter lesion, and microcephaly. A structural modeling revealed that the p.T258M mutation disrupted the binding of KIF1A motor domain to microtubules and its movement along microtubules. Assays of peripheral accumulation and proximal distribution of KIF1A motor indicated that the KIF1A motor domain with p.T258M mutation has reduced motor activity and exerts a dominant negative effect on wild-type KIF1A.

 

These results suggest that the p.T258M mutation suppresses KIF1A motor activity and induces complicated HSP accompanying intellectual disability transmitted in autosomal dominant inheritance.

 

SOURCE: Sci Rep. 2017 Oct 2;7(1):12527. doi: 10.1038/s41598-017-12999-9. PMID: 28970574

 

Autosomal dominant transmission of complicated hereditary spastic paraplegia due to a dominant negative mutation of KIF1A, SPG30 gene.

 

Cheon CK1,2, Lim SH3, Kim YM4, Kim D5, Lee NY3, Yoon TS3, Kim NS3, Kim E5,6, Lee JR7.

 

1 Department of Pediatrics, Pusan National University Children’s Hospital, Yangsan, Korea. [email protected]

2 Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan, Korea. [email protected]

3 Rare Disease Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea.

4 Department of Pediatrics, Pusan National University Children’s Hospital, Yangsan, Korea.

5 Center for Synaptic Brain Dysfunctions, Institute for Basic Science (IBS), Daejeon, Korea.

6 Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Korea.

7 Rare Disease Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea. [email protected].

 


 

Mutation ‘hot spot’ identified in KIF1A gene

Associated with dominant SPG30 HSP

 

Autosomal recessive KIF1A missense mutations cause hereditary spastic paraplegia (HSP) type SPG30, while recessive truncations lead to sensory and autonomic neuropathy (HSN2C) and many de novo missense mutations are associated with cognitive impairment. Here, we describe family members across three generations with pure HSP.

 

A heterozygous p.Ser69Leu KIF1A mutation segregates with those afflicted. The same variant was previously reported in a Finnish father and son with pure HSP as well as four members of a Sicilian kindred with more intrafamilial phenotypic variability. This further validates the pathogenicity of the p.Ser69Leu mutation and suggests that it may represent a mutation hot spot.

 

SOURCE: Ann Clin Transl Neurol. 2017 Oct 14;4(11):821-824. doi: 10.1002/acn3.452. eCollection 2017 Nov. PMID: 29159194

 

Multigeneration family with dominant SPG30 hereditary spastic paraplegia.

 

Roda RH1,2, Schindler AB2, Blackstone C2.

 

1 Department of Neurology Neuromuscular Medicine 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 mutation type found in NT5C2 gene

Associated with SPG45 and SPG65 HSP types

 

SPG45 is a rare form of autosomal recessive spastic paraplegia associated with mental retardation. Detailed phenotyping and mutation analysis was undertaken in three individuals with SPG45 from a consanguineous family of Arab Muslim origin. Using whole-exome sequencing, we identified a novel homozygous missense mutation in NT5C2 (c.1379T>C; p.Leu460Pro). Our data expand the molecular basis of SPG45, adding the first missense mutation to the current database of nonsense, frameshift, and splice site mutations. NT5C2 mutations seem to have a broad clinical spectrum and should be sought in patients manifesting either as uncomplicated or complicated HSP.

 

SOURCE: Am J Med Genet A. 2017 Nov;173(11):3109-3113. doi: 10.1002/ajmg.a.38414. Epub 2017 Sep 8. PMID: 28884889

 

Novel homozygous missense mutation in NT5C2 underlying hereditary spastic paraplegia SPG45.

 

Straussberg R1,2, Onoufriadis A3, Konen O2,4, Zouabi Y1,2, Cohen L2,5, Lee JYW3, Hsu CK3, Simpson MA6, McGrath JA3.

 

1 Neurogenetic Clinic, Neurology Institute, Schneider Children’s Medical Center, Petah Tikva, Israel.

2 Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

3 St John’s Institute of Dermatology, Division of Genetics and Molecular Medicine, King’s College London, London, UK.

4 Radiology Institute, Schneider Children’s Medical Center, Petah Tikva, Israel.

5 Genetic Institute, Schneider Children’s Medical Center, Petah Tikva, Israel.

6 Department of Medical and Molecular Genetics, Division of Genetics and Molecular Medicine, King’s College London, Guy’s Hospital, London, UK.

 


 

New exon rearrangement identified in NT5C2 gene

Associated with complex SPG45/65 HSP

 

Hereditary spastic paraplegias are a rare group of clinically and genetically heterogeneous neurodegenerative diseases, with upper motor neuron degeneration and progressive lower limb spasticity as their main phenotypic features. Despite that 76 distinct loci have been reported and some casual genes identified, most of the underlying causes still remain unidentified. Moreover, a wide range of clinical manifestations is present in most hereditary spastic paraplegias subtypes, adding further complexity to their differential clinical diagnoses.

 

Here, we describe the first exon rearrangement reported in the SPG45/SPG65 (NT5C2) loci in a family featuring a complex hereditary spastic paraplegias phenotype. This study expands both the phenotypic and mutational spectra of the NT5C2-associated disease.

 

SOURCE: NPJ Genom Med. 2017;2. pii: 20. doi: 10.1038/s41525-017-0022-7. Epub 2017 Jun 1. PMID: 29123918

 

Whole genome sequencing identifies a novel homozygous exon deletion in the NT5C2 gene in a family with intellectual disability and spastic paraplegia.

 

Darvish H1, Azcona LJ2, Tafakhori A3, Ahmadi M3, Ahmadifard A1, Paisán-Ruiz C4,5,6.

 

1 Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

2 Department of Neurosciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.

3 Department of Neurology, School of Medicine, Imam Khomeini Hospital and Iranian Center of Neurological Research, Tehran University of Medical Sciences, Tehran, Iran.

4 Departments of Neurology, Psychiatry, and Genetics and Genomic sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.

5 Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.

6 Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.

 


 

Two new variants found in AP4M1A gene

Associated with SPG50 HSP Cerebral Palsy Quadriplegia

 

BACKGROUND:

Autosomal recessive hereditary spastic paraplegia (HSP) due to AP4M1 mutations is a very rare neurodevelopmental disorder reported for only a few patients.

 

METHODS:

We investigated a Greek HSP family using whole exome sequencing (WES).

 

RESULTS:

A novel AP4M1A frameshift insertion, and a very rare missense variant were identified in all three affected siblings in the compound heterozygous state (p.V174fs and p.C319R); the unaffected parents were carriers of only one variant. Patients were affected with a combination of: (a) febrile seizures with onset in the first year of life (followed by epileptic non-febrile seizures); (b) distinctive facial appearance (e.g., coarse features, bulbous nose and hypomimia); (c) developmental delay and intellectual disability; (d) early-onset spastic weakness of the lower limbs; and (e) cerebellar hypoplasia/atrophy on brain MRI.

 

CONCLUSIONS:

We review genotype-phenotype correlations and discuss clinical overlaps between different AP4-related diseases. The AP4M1 belongs to a complex that mediates vesicle trafficking of glutamate receptors, being likely involved in brain development and neurotransmission.

 

SOURCE: Orphanet J Rare Dis. 2017 Nov 2;12(1):172. doi: 10.1186/s13023-017-0721-2. PMID: 29096665

 

Genotype-phenotype correlations and expansion of the molecular spectrum of AP4M1-related hereditary spastic paraplegia.

 

Bettencourt C1,2, Salpietro V3, Efthymiou S4,5, Chelban V4,6, Hughes D4, Pittman AM4, Federoff M4,7, Bourinaris T8, Spilioti M9, Deretzi G8, Kalantzakou T8, Houlden H10,11, Singleton AB7, Xiromerisiou G8.

 

1 Department of Molecular Neuroscience, Institute of Neurology, University College London, London, WC1N 3BG, UK. [email protected]

2 Department of Clinical and Experimental Epilepsy, Institute of Neurology, University College London, London, WC1N 3BG, UK. [email protected]

3 Department of Molecular Neuroscience, Institute of Neurology, University College London, London, WC1N 3BG, UK. [email protected]

4 Department of Molecular Neuroscience, Institute of Neurology, University College London, London, WC1N 3BG, UK.

5 Department of Clinical and Experimental Epilepsy, Institute of Neurology, University College London, London, WC1N 3BG, UK.

6 Department of Neurology, Medical State University N, Testemitanu, Chisinau, Moldova.

7 Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, 20892, USA.

8 Department of Neurology, Papageorgiou Hospital, Thessaloniki, Greece.

9 Neurology Department of Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki, Greece.

10 Department of Molecular Neuroscience, Institute of Neurology, University College London, London, WC1N 3BG, UK. [email protected]

11 National Hospital for Neurology and Neurosurgery, University College London Hospitals, London, WC1N 3BG, UK. [email protected].

 


 

New SPG56 mutations found

Enzyme test tells bad from harmless mutations

 

Genetic testing reports sometimes identify variants (mutations) as being of ‘uncertain clinical significance’ (VUS). This means that it is not known whether or not a particular variant does or does not cause HSP. There are various ways to predict pathogenicity of a variant. The researchers in this study developed an enzyme test that can be used clinically to evaluate pathogenicity of variants in the CYP2U1 gene.

 

Abstract

Hereditary spastic paraplegia (HSP) is an inherited disorder of the central nervous system mainly characterized by gradual spasticity and weakness of the lower limbs.

 

SPG56 is a rare autosomal recessive early onset complicated form of HSP caused by mutations in CYP2U1. The CYP2U1 enzyme was shown to catalyze the hydroxylation of arachidonic acid.

 

Here, we report two further SPG56 families carrying three novel CYP2U1 missense variants and the development of an in vitro biochemical assay to determine the pathogenicity of missense variants of uncertain clinical significance.

 

We compared spectroscopic, enzymatic, and structural (from a 3D model) characteristics of the over expressed wild-type or mutated CYP2U1 in HEK293T cells. Our findings demonstrated that most of the tested missense variants in CYP2U1 were functionally inactive because of a loss of proper heme binding or destabilization of the protein structure.

 

We also showed that functional data do not necessarily correlate with in silico predictions of variants pathogenicity, using different bioinformatic phenotype prediction tools. Our results therefore highlight the importance to use biological tools, such as the enzymatic test set up in this study, to evaluate the effects of newly identified variants in clinical settings.

 

SOURCE: Hum Mutat. 2017 Oct 16. doi: 10.1002/humu.23359. [Epub ahead of print] PMID: 29034544

 

CYP2U1 activity is altered by missense mutations in hereditary spastic paraplegia 56.

 

Durand CM1, Dhers L2, Tesson C3,4, Tessa A5, Fouillen L6, Jacqueré S1, Raymond L3,4, Coupry I1, Benard G1, Darios F3, El-Hachimi KH3,4, Astrea G5, Rivier F7, Banneau G8, Pujol C3, Lacombe D1,9, Durr A3,8, Babin PJ1, Santorelli FM5, Pietrancosta N2,10, Boucher JL2, Mansuy D2, Stevanin G3,4,8, Goizet C1,9.

 

1 INSERM U1211, Laboratoire Maladies Rares: Génétique et Métabolisme. Bordeaux University, Bordeaux, France.

2 UMR 8601 CNRS, University Paris Descartes, Paris Sorbonne Cité, Paris, France.

3 Institut du Cerveau et de la Moelle épinière, INSERM U1127, Sorbonne Universités, UPMC UMR_S 1127, CNRS UMR 7225, Paris, France.

4 Ecole Pratique des Hautes Etudes, EPHE, PSL Research University, Paris, France.

5 IRCCS Fondazione Stella Maris, Molecular Medicine, Calambrone, Italy.

6 Laboratoire de Biogenèse Membranaire-UMR 5200, CNRS, Bordeaux University, Bordeaux, France.

7 Département de Neuropédiatrie – CR Maladies Neuromusculaires AOC, CHU de Montpellier, U1046 INSERM UMR9214 CNRS, Montpellier University, Montpellier, France.

8 APHP, Department of Genetics, Pitié-Salpêtrière University Hospital, Paris, France.

9 Service de Génétique Médicale, CHU Pellegrin, Bordeaux, France.

10 Team Chemistry & Biology, Modeling & Immunology for Therapy, CBMIT, 2MI Platform, Paris, France.

 


 

Three new FARS2 mutations discovered

FARS2 mutations associated with SPG77 HSP or epilepsy

 

Mutations in FARS2 are known to cause dysfunction of mitochondrial translation due to deficient aminoacylation of the mitochondrial phenylalanine tRNA. Here, we report three novel mutations in FARS2 found in two patients in a compound heterozygous state. The missense mutation c.1082C>T (p.Pro361Leu) was detected in both patients. The mutations c.461C>T (p.Ala154Val) and c.521_523delTGG (p.Val174del) were each detected in one patient.

 

We report abnormal in vitro aminoacylation assays as a functional validation of the molecular genetic findings. Based on the phenotypic data of previously reported subjects and the two subjects reported here, we conclude that FARS2 deficiency can be associated with two phenotypes: (i) an epileptic phenotype, and (ii) a spastic paraplegia phenotype.

 

SOURCE: Mol Genet Metab. 2017 Oct 12. pii: S1096-7192(17)30410-9. doi: 10.1016/j.ymgme.2017.10.004. [Epub ahead of print] PMID: 29126765

 

New insights into the phenotype of FARS2 deficiency.

 

Vantroys E1, Larson A2, Friederich M2, Knight K2, Swanson MA2, Powell CA3, Smet J1, Vergult S4, De Paepe B1, Seneca S5, Roeyers H6, Menten B4, Minczuk M3, Vanlander A1, Van Hove J2, Van Coster R7.

 

1 Department of Pediatric Neurology and Metabolism, Ghent University Hospital, Ghent, Belgium.

2 Department of Pediatrics, Section of Clinical Genetics and Metabolism, University of Colorado School of Medicine, Aurora, CO, USA.

3 MRC Mitochondrial Biology Unit, University of Cambridge, Hills Road, Cambridge CB2 0XY, UK.

4 Center for Medical Genetics Ghent, Ghent University, Ghent, Belgium.

5 Center for Medical Genetics, UZ Brussel and Reproduction Genetics and Regenerative Medicine, Vrije Universiteit Brussel, Brussels, Belgium.

6 Department of Experimental Clinical and Health Psychology, Ghent University, Ghent, Belgium.

7 Department of Pediatric Neurology and Metabolism, Ghent University Hospital, Ghent, Belgium. Electronic address: [email protected].

 


 

REEP1 mutations also cause Charcot-Marie-Tooth (CMT) disease type 2

Loss or gain of function the big difference

 

Single-nucleotide variants that abolish the stop codon (“nonstop” alterations) are a unique type of substitution in genomic DNA. Whether they confer instability of the mutant mRNA or result in expression of a C-terminally extended protein depends on the absence or presence of a downstream in-frame stop codon, respectively. Of the predicted protein extensions, only few have been functionally characterized.

 

In a family with autosomal dominant Charcot-Marie-Tooth disease type 2, that is, an axonopathy affecting sensory neurons as well as lower motor neurons, we identified a heterozygous nonstop variant in REEP1. Mutations in this gene have classically been associated with the upper motor neuron disorder hereditary spastic paraplegia (HSP). We show that the C-terminal extension resulting from the nonstop variant triggers self-aggregation of REEP1 and of several reporters. Our findings support the recently proposed concept of 3’UTR-encoded “cryptic amyloidogenic elements.” Together with a previous report on an aggregation-prone REEP1 deletion variant in distal hereditary motor neuropathy, they also suggest that toxic gain of REEP1 function, rather than loss-of-function as relevant for HSP, specifically affects lower motor neurons. A search for similar correlations between genotype, phenotype, and effect of mutant protein may help to explain the wide clinical spectra also in other genetically determined disorders.

 

SOURCE: Hum Mutat. 2017 Nov 9. doi: 10.1002/humu.23369. [Epub ahead of print] PMID: 29124833

 

A nonstop variant in REEP1 causes peripheral neuropathy by unmasking a 3’UTR-encoded, aggregation-inducing motif.

 

Bock AS1, Günther S1, Mohr J2, Goldberg LV1, Jahic A1, Klisch C3, Hübner CA4, Biskup S2, Beetz C1.

 

1 Department of Clinical Chemistry and Laboratory Medicine, Jena University Hospital, Jena, Germany.

2 CeGaT GmbH und Praxis für Humangenetik, Tübingen, Germany.

3 Neurologische Praxis Klisch, Erfurt, Germany.

4 Department of Human Genetics, Jena University Hospital, Jena, Germany.

 


 

New SPG7 cause of complicated HSP discovered

SPG7 mutations possible where ataxia is present

 

Autosomal recessive hereditary spastic paraparesis is rare. We present 4 patients with slowly progressive predominantly lower limb spasticity and ataxia. Only one patient had family history of ataxia but without any underlying diagnosis. All of them proved negative for the mutation of Spinocerebellar ataxia genes SCA 1,2,3 and 6. All had mutation in the SPG7 gene suggestive of autosomal recessive hereditary spastic paraparesis. One of the heterozygous mutants showed a novel c1617delC ,p(Val540fs) frameshift mutation in exon 12 of the SPG7 gene. SPG7 mutation accounts for 1.5-7% of all the HSP but it is the cause of undiagnosed ataxia in 18.6% in a recent case series.

 

SPG7 mutation should be remembered as an important cause of undiagnosed ataxia especially where next generation sequencing is not widely available or affordable.

 

SOURCE: Neurosciences (Riyadh). 2017 Oct;22(4):303-307. doi: 10.17712/nsj.2017.4.20170253. PMID: 29057857

 

Case series of autosomal recessive hereditary spastic paraparesis with novel mutation in SPG 7 gene.

 

Bhattacharjee S1, Beauchamp N, Murray BE, Lynch T.

 

1 Department of Neurology, Plymouth Hospital NHS Trust, Plymbridge Lane, United Kingdom. E-mail: [email protected].

 


 

New mutation found in Spartin gene

Associated with complicated SPG20 HSP

 

Troyer Syndrome (TRS) is a rare autosomal recessive complicated spastic paraplegia disorder characterized by various neurological and musculoskeletal manifestations. Pathogenicity stems from mutations in SPG20 which encodes Spartin, a multifunctional protein that is thought to be essential for neuron viability.

 

Here we report on the clinical and molecular characterization of TRS in five patients from an extended consanguineous family in the United Arab Emirates. Molecular analysis involved Whole Exome Sequencing and Sanger sequencing for identification and confirmation of the causative variant respectively. In silico tools including CADD and Polyphen-2 were used to assess pathogenicity of the variant. The clinical description of these patients included spastic paraparesis, motor and cognitive delay, gait abnormalities, musculoskeletal features, as well as white matter abnormalities and emotional lability.

 

Molecular analysis revealed a novel homozygous missense mutation in SPG20 (c.1324G > C; p.Ala442Pro) occurring at an evolutionarily conserved residue in the Plant-Related Senescence domain of Spartin. The mutation segregated with the clinical phenotype in all patients. In silico algorithms predict the mutation to be disease causing, and the variant had not been previously reported in public or ethnic specific variant repositories.

 

SOURCE: Metab Brain Dis. 2017 Dec;32(6):2155-2159. doi: 10.1007/s11011-017-0104-3. Epub 2017 Sep 5. PMID: 28875386

 

Novel SPG20 mutation in an extended family with Troyer syndrome.

 

Bizzari S1, Hamzeh AR2, Nair P2, Mohamed M3, Saif F3, Aithala G3, Al-Ali MT2, Bastaki F3.

 

1 Centre for Arab Genomic Studies, P.O. Box 22252, Dubai, United Arab Emirates. [email protected].

2 Centre for Arab Genomic Studies, P.O. Box 22252, Dubai, United Arab Emirates.

3 Pediatric Department, Latifa Hospital, Dubai Health Authority, Dubai, United Arab Emirates.

 


 

New SPAST mutation found

Some complications and brain alterations identified

 

Highlights

  • We present a 39 year old woman with hereditary spastic paraparesis and cognitive impairment.
  • Impairment is present in the domains of attention, memory, executive function as well as behavior dysregulation and apraxia of speech.
  • This is associated with a novel deletion of exons 9–12 of the SPAST gene, also called SPG4.
  • Novel findings on FDG-PET include hypometabolism in the frontal areas, precuneus, cerebellum and anterior thalamus.

 

SOURCE: J Neurol Sci. 2016 Aug 15;367:131-2. doi: 10.1016/j.jns.2016.05.057. Epub 2016 May 31. PMID: 27423575

 

A case report of a woman with young onset cognitive impairment associated with hereditary spastic paraplegia due to a mutation in the SPAST gene.

 

Tisher A1, Salardini A2.

 

1 Yale Department of Neurology, 800 Howard Avenue, New Haven, CT 06511, United States. Electronic address: [email protected]

2 Yale Department of Neurology, 800 Howard Avenue, New Haven, CT 06511, United States. Electronic address: [email protected]

 


 

Two new SPAST mutations found

52 HSP families from Bashkortostan region Russia

 

Hereditary spastik paraplegias (HSP) are a group of neurodegenerative disorders with primary lesion of the pyramidal tract. The most frequent autosomal dominant form of the disease in Europeans is HSP associated with mutations in the spastin gene (SPG4). Analysis of the gene SPG4 was carried out in 52 unrelated families with HSP from Bashkortostan by SSCP and following sequencing.

 

Previously undescribed frameshift mutations c.322del29 (p.Val108SerfsX18) and c.885del10 (p.Thr295ThrfsX16) were detected in two unrelated families. Clinical studies have shown that, in both families, the disease corresponds to an uncomplicated form of hereditary spastic paraplegia, a main feature of which is the lower spastic paraparesis without any other symptoms.

 

SOURCE: Russian Journal of Genetics, June 2016, Volume 52, Issue 6, pp 603–607 Akhmetgaleyeva, A.F., Khidiyatova, I.M., Saifullina, E.V. et al. Russ J Genet (2016) 52: 603. https://doi.org/10.1134/S1022795416060028

 

Two novel mutations in gene SPG4 in patients with autosomal dominant spastic paraplegia

Akhmetgaleyeva 1, I. M. Khidiyatova 1,2, E. V. Saifullina 2, R. F. Idrisova 4, R. V. Magzhanov 3, E. K. Khusnutdinova 1,2

 

  1. Institute of Biochemistry and Genetics, Ufa Scientific Center, Russian Academy of Sciences,Ufa, Russia
  2. Bashkir State University,Ufa, Russia
  3. Bashkir State Medical University,Ufa, Russia
  4. Kuvatov Republican Clinic Hospital,Ufa, Russia

 

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