Posted - September 2016 in Research Highlights
From Iran, Germany, China, Greece, Japan, Pakistan and Hungary
2 new mutations causing complicated, autosomal recessive SPG56 found in 2 Iranian HSPers.
Hereditary spastic paraplegia (HSP) is a heterogeneous condition characterized by progressive spasticity and weakness in the lower limbs. It is divided into two major groups, complicated and uncomplicated, based on the presence of additional features such as intellectual disability, ataxia, seizures, peripheral neuropathy and visual problems.
SPG56 is an autosomal recessive form of HSP with complicated and uncomplicated manifestations, complicated being more common. CYP2U1 gene mutations have been identified as responsible for SPG56. Intellectual disability, dystonia, subclinical sensory motor neuropathy, pigmentary degenerative maculopathy, thin corpus callosum and periventricular white-matter hyperintensities were additional features noted in previous cases of SPG56.
Here we identified two novel mutations in CYP2U1 in two unrelated patients by whole exome sequencing. Both patients had complicated HSP with activity-induced dystonia, suggesting dystonia as an additional finding in SPG56. Two out of 14 previously reported patients had dystonia, and the addition of our patients suggests dystonia in a quarter of SPG56 patients. Developmental regression has not been reported in SPG56 patients so far but both of our patients developed motor regression in infancy.
SOURCE: Eur J Paediatr Neurol. 2016 Sep;20(5):782-7. doi: 10.1016/j.ejpn.2016.05.013. Epub 2016 Jun 2. PMID: 27292318 [PubMed – in process] Copyright © 2016 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
CYP2U1 mutations in two Iranian patients with activity induced dystonia, motor regression and spastic paraplegia.
Kariminejad A1, Schöls L2, Schüle R3, Tonekaboni SH4, Abolhassani A5, Fadaee M5, Rosti RO6, Gleeson JG6.
1 Kariminejad-Najmabadi Pathology & Genetics Center, Tehran, Iran. Electronic address: [email protected]
2 Department for Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research, Hoppe-Seyler-Strasse 3, University of Tubingen, 72077, Tubingen, Germany; German Research Center for Neurodegenerative Diseases (DZNE), University of Tubingen, 72076, Tuebingen, Germany.
3 Department for Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research, Hoppe-Seyler-Strasse 3, University of Tubingen, 72077, Tubingen, Germany; German Research Center for Neurodegenerative Diseases (DZNE), University of Tubingen, 72076, Tuebingen, Germany; Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL, 33136, USA.
4 Pediatric Neurology Research Center, SBMU, Tehran, Iran.
5 Kariminejad-Najmabadi Pathology & Genetics Center, Tehran, Iran.
6 Howard Hughes Medical Institute, Laboratory for Pediatric Brain Diseases, University of California, San Diego, La Jolla, CA, 92093, USA.
2 new SPG 11 mutations found in a Chinese HSP family.
Autosomal recessive hereditary spastic paraplegia (ARHSP) with thin corpus callosum (TCC) is a complicated form of hereditary spastic paraplegia, characterized by progressive spastic paraplegia, weakness of the lower extremities and is usually accompanied by mental retardation. Mutations in the Spastic Paraplegia gene 11 (SPG11) account for a large proportion of ARHSP-TCC cases worldwide.
We describe a Chinese family with ARHSP-TCC. Two daughters of this family presented with a spastic gait and cognitive impairment. Brain imaging of the index patient revealed a thin corpus callosum. We performed detailed physical and auxiliary examinations and were able to exclude acquired causes of spastic paraplegia.
To determine the causative mutation, we took a candidate gene approach and screened the coding sequence and some flanking intronic sequence of SPG11 by direct Sanger sequencing. We identified two novel compound heterozygous mutations in SPG11 in affected individuals (c.1551_1552delTT, p.Cys518SerfsTer39 and c.5867-1G > T (IVS30-1G > T), p.Thr1956ArgfsTer15). Bioinformatic analysis predicts that these mutations would lead to a loss of protein function due to the truncation of the SPG11 protein.
The results of this case report indicate a broader approach to include screening for SPG11 mutations in ARHSP-TCC patients. Our findings enrich the phenotypic spectrum of SPG11 mutations.
SOURCE: BMC Neurol. 2016 Jun 3;16:87. doi: 10.1186/s12883-016-0604-5. PMID: 27256065 [PubMed – in process]
A case report of SPG11 mutations in a Chinese ARHSP-TCC family.
Zhang L1,2, McFarland KN2, Jiao J1, Jiao Y3.
1 Department of Neurology, China-Japan Friendship Hospital, 2 Yinghua Dongjie, Hepingli, 100029, Beijing, China.
2 McKnight Brain Institute and the Department of Neurology, College of Medicine, University of Florida, Gainesville, FL, 32610, United States of America.
3 Department of Neurology, China-Japan Friendship Hospital, 2 Yinghua Dongjie, Hepingli, 100029, Beijing, China. [email protected].
2 new SPG11 HSP mutations found in a 30-year-old female from Greece
SPG11 belongs to the autosomal recessive hereditary spastic paraplegias (HSP) and presents during childhood or puberty with a complex clinical phenotype encompassing learning difficulties, ataxia, peripheral neuropathy, amyotrophy, and mental retardation.
We hereby present the case of a 30-year-old female patient with complex autosomal recessive HSP with thinning of the corpus callosum (TCC) and dementia that was compound heterozygous with two novel mutations in the SPG11 gene.
Sequence analysis of the SPG11 gene revealed two novel mutations in a compound heterozygous state in the index patient (c.2431C>T/p.Gln811Ter and c.6755_6756insT/p.Glu2252Aspfs*88). MRI showed abnormal TCC, white matter (WM) hyperintensities periventricularly, and the ‘ears of the lynx’ sign. Diffusion tensor imaging showed a mild-to-moderate decrease in fractional anisotropy and an increase in mean diffusivity in WM compared to age-matched controls, while magnetic resonance spectroscopy showed abnormal findings in affected WM with a decrease in N-acetyl-aspartate in WM regions of interest. This is the first SPG11 kindred from the Greek population to be reported in the medical literature.
SOURCE: Neurodegener Dis. 2016 Jun 18;16(5-6):373-381. [Epub ahead of print] PMID: 27318863 [PubMed – as supplied by publisher] © 2016 S. Karger AG, Basel.
Novel Compound Heterozygous Spatacsin Mutations in a Greek Kindred with Hereditary Spastic Paraplegia SPG11 and Dementia.
Fraidakis MJ1, Brunetti M, Blackstone C, Filippi M, Chiò A.
1 NEURORARE Centre for Rare and Genetic Neurological and Neuromuscular Diseases and Neurogenetics, Athens, Greece.
First case of SPG28 HSP identified in Japan with a new mutation detected.
Spastic paraplegia (SPG) type 28 is an autosomal recessive SPG caused by mutations in the DDHD1 gene. We examined a Japanese 54-years-old male patient with autosomal recessive SPG. His parents were consanguineous. He needed a wheelchair for transfer due to spastic paraplegia. There was a history of operations for bilateral hallux valgus, thoracic ossification of the yellow ligament, bilateral carpal tunnel syndrome, bilateral ankle contracture, and lumbar spinal canal stenosis.
He noticed gait disturbance at age 14. He used a cane for walking in his 40s. On neurological examination, he showed hyperreflexia, spasticity, and weakness in the lower extremities and bilateral Babinski reflexes. Urinary dysfunctions and impaired vibration sense in the lower limbs were observed.
By exome sequencing analysis using Agilent SureSelect and Illumina MiSeq, we identified 17,248 homozygous nucleotide variants in the patient. Through the examination of 48 candidate genes known to be responsible for autosomal recessive SPG, we identified a novel homozygous 4-bp deletion, c.914_917delGTAA, p.Ser305Ilefs*2 in exon2 of the DDHD1 gene encoding phosphatidic acid-preferring phospholipase A1 (PA-PLA1). The mutation is expected to cause a frameshift generating a premature stop codon 3-bp downstream from the deletion. In consequence, the DDHD domain that is known to be critical for PLA1 activity is completely depleted in the mutated DDHD1 protein, predicted to be a functionally null mutation of the DDHD1 gene.
By Sanger sequencing, we confirmed that both parents are heterozygous for the mutation. This variation was not detected in 474 Japanese control subjects as well as the data of the 1,000G Project. We conclude that the novel mutation in DDHD1 is the causative variant for the SPG28 patient that is the first record of the disease in Japanese population.
SOURCE: Eur J Med Genet. 2016 Aug;59(8):413-6. doi: 10.1016/j.ejmg.2016.05.010. Epub 2016 May 20. PMID: 27216551 [PubMed – in process] Copyright © 2016 Elsevier Masson SAS. All rights reserved.
A novel frameshift mutation of DDHD1 in a Japanese patient with autosomal recessive spastic paraplegia.
Miura S1, Morikawa T2, Fujioka R3, Kosaka K2, Yamada K2, Hattori G4, Motomura M5, Taniwaki T6, Shibata H2.
1 Division of Respirology, Neurology, and Rheumatology, Department of Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka 830-0011, Japan. Electronic address: [email protected]
2 Division of Genomics, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
3 Department of Food and Nutrition, Beppu University Junior College, 82 Kitaishigaki, Beppu, Oita 874-8501, Japan.
4 Department of Neurosurgery, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka 830-0011, Japan.
5 Department of Internal Medicine, Nagasaki Yurino Hospital, 1155-2 Motomuragou, Togitsu, Nagasaki 851-2103, Japan.
6 Division of Respirology, Neurology, and Rheumatology, Department of Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka 830-0011, Japan.
New mutation discovered in a Pakistani female with recessive SPG35 HSP
Autosomal recessive Hereditary spastic paraplegias (HSPs) are more frequent in consanguineous populations with a prevalence of 0.6/100,000 in Norway and up to 5.75/100,000 in Tunisia. The prevalence of all hereditary spastic paraplegia (HSPs, SPGs) ranges between 4.3 and 9.8/100,000.
The key symptom of the HSP of lower limbs can be complicated by a variety of signs and symptoms including cognitive impairment, optic atrophy, cerebellar ataxia or peripheral nerve involvement. Most of the HSPs (about 70%) are caused by mutations in SPAST (SPG4), ATL1 (SPG3A) and REEP1 (SPG31) genes. Nineteen of the HSPs follow an autosomal dominant (most in SPG4 and SPG3 genes), 27 an autosomal recessive (most in SPG11 gene), 3 X-linked mode of transmission ((L1CAM (SPG1), PLP1 (SPG2), and SLC16A2 (SPG22) genes): and one a maternal trait of inheritance.
Mutations in genes like (NIPA1), (SPG6), KIAA0196 (SPG8), KIF5A (SPG10), RNT2 (SPG12), SPGD1 (SPG13), BSCL2, (SPG17), REEP1 (SPG31), ZFYVE27 (SPG33) and SLC33A1 (SPG42) are reported like autosomal dominant inheritances of the HSPs. Furthermore genes (CYP7B1 (SPG5), SPG7 (SPG7), ZFYVE26 (SPG15), ERLIN2, (SPG18), SPG20, (SPG20), ACP33 (SPG21), KIF1A (SPG30), FA2H (SPG35), NTE (SPG39), GJA12/GJC2 (SPG44), KIAA0415 (SPG48) and 4 more genes encoding for the AP4-complex (SPG47) are associated with rare autosomal recessive causes of SPG.
HSP type 35 (MIM#612319) is an autosomal recessive form of the HSPs caused by mutations in the FA2H gene (MIM#611026) at 16q21-q23 chromosome, that encodes fatty acid 2-hydroxylase, spanning 372 amino acids and 7 exons: it contains a cytochrome b5 heme-binding domain, and a fatty acid hydroxylase domain encoded by exons 5 through 7. FA2H is involved in the synthesis of 2-hydroxy fatty acid galactolipids, major component of the myelin sheath. Hereditary spastic paraplegias are clinically and genetically highly heterogeneous group of neurodegenerative disorders. The autosomal recessive HSPs are often associated with complex phenotype, and one of the most frequent forms is caused by mutations in the SPG11/KIAA1840 gene.
- Case presentation
We report the clinical, neurophysiological, and molecular findings of a patient with a new FA2H variant, detected by NGS (Next Generation Sequencing) technologies.
Since age 3y, the patient presented alterations in psychomotor development. Lower limb spasticity and optic atrophy was noted. This patient has one brother with similar clinical characteristic and disease progression. Her parents were Pakistani cousins but have no symptoms of HSP.
The main clinical features were exposed at neurological and psychomotor development. There was no evidence of cranial, pulmonary or abdominal alterations. Brain MRI only showed atrophy of the cerebellar vermis. The patient presented mild mental retardation and a mildly decreased muscle tone in upper limbs. No more clinical data were available.
- Materials and methods
After receiving parents’ informed consent, DNA was extracted from peripheral blood by organic Phenol:Chloroform:Isoamyl Alcohol procedure. Extracted DNA was quantified by a 0.8%agarose gel. In a first analysis Sanger sequencing was performed in PLP1 gene, secondly NGS in all genes related to autosomal dominant, recessive and X-linked patterns of HSP were analysed. NGS was performed following protocols of HaloPlex Target Enrichment System for Illumina sequencing (ultrasequencing in MiSeq (Illumina) platform) and analysed by DNAnexus software. Reference sequences were used from data of HGMD (The Human Gene Mutation Database) for each of the analysed genes.
PLP1 gene has been included after doctor’s recommendations but no relevant data has been found in the analysis of this gene. For that reason we performed a NGS analysis. However, there were no point mutations results in most of the genes analysed by NGS (SPG3A, BSCL2, HSPD1, KIF5A, NIPA1, REEP1, RTN2, SLC33A1, SNTB1, SPAST, ZFYVE27, AP4B1, AP4E1, AP4M1, AP4S1, AP5Z1, C120RF65, CYP2U1, CYP7B1, DDHD2, ERUN2, GJC2, KIF1A, PNPLA6, ALS2, ZFYVE27, SPG11, SPG20, SPG21, SPG7, TECPR2, VPS37A, L1CAM, PLP1, SLC16A2 and KDM5C). There was only relevant data of NGS at FA2H gene.
The sequence analysis of the FA2H gene revealed the novel nonsense mutation c.565 (c.565 C>T) in homozygosis; this mutation generates an Arginine to Stop Codon (p.R189X) exchange. These kinds of mutations are classified as pathogenic because they encode a truncated protein by a premature stop codon of the protein: so they are considered good clinical tools for diagnosis and genetic counseling.
SOURCE: J Neurol Sci. 2015 Oct 15;357(1-2):332-4. doi: 10.1016/j.jns.2015.07.042. Epub 2015 Aug 29.
Novel FA2H mutation in a girl with familial spastic paraplegia
Aguirre-Rodríguez FJ1, Lucenilla MI1, Alvarez-Cubero MJ2, Mata C3, Entrala-Bernal C3, Fernandez-Rosado F3.
1 Complejo Hospitalario Torrecárdenas, Calle Hermandad de Donantes de Sangre s/n, 04009, Almeria, Spain.
2 LORGEN G.P., S.L., Business Innovation Center – BIC/CEEL, Technological area of Health Science, Av. de la Innovación 1, Granada 18016, Spain; Genetic Identification Laboratory, Legal Medicine and Toxicology Department, Medicine Faculty, University of Granada, Avda. de Madrid 11, Granada 18071, Spain; GENYO (Pfizer-University of Granada-Andalusian Government Centre for Genomics and Oncological Research), Granada, Spain. Electronic address: [email protected]
3 LORGEN G.P., S.L., Business Innovation Center – BIC/CEEL, Technological area of Health Science, Av. de la Innovación 1, Granada 18016, Spain.
2 new SPAST (SPG4) HSP mutations discovered in Hungary
Hereditary spastic paraplegia (HSP) is heterogeneous group of genetically inherited disorders mainly characterized by spastic gait impairment. It affects approximately 1.2-9.6 out of 100,000 individuals.
There are more than 50 mutations which can be responsible for the development of uncomplicated or complicated (spastic paraplegia associated with additional neurologic or systemic abnormalities) forms, and there are several modes of inheritance. The most common causes of autosomal dominantly inherited cases, which account for 70-80% of all HSP forms in the Western countries, are mutations in the SPAST gene mapped to 2p22.
All types of mutations (missense, nonsense, splicing site, deletions and insertions) have been detected in the SPAST gene at numerous loci with wide age range of onset. The gene product, spastin possesses 2 main structural domains: the microtubule interacting and trafficking domain (MIT) in the N-terminus, which is responsible for the association of spastin with microtubules, and the catalytic AAA domain at the C-terminus with ATPase activity. The spastin-mediated severing of microtubules is particularly involved in axonal transport and axonal branching. The haploinsufficiency of spastin – mainly caused by mutations in the AAA domain – is responsible for the progressive retrograde degeneration preferentially affecting long corticospinal axons with the consequential development of characteristic symptoms.
The aim of this study is to present the detailed clinical phenotype of a previously unpublished novel mutation site in the SPAST gene, and furthermore to report a de novo mutation leading to the development of characteristic symptoms in early childhood.
SOURCE: Clin Neurol Neurosurg. 2015 Sep;136:82-5. doi: 10.1016/j.clineuro.2015.05.009. Epub 2015 Jun 6.
The clinical manifestations of two novel SPAST mutations.
Zádori D1, Máté A2, Róna-Vörös K1, Gergev G3, Zimmermann A4, Nagy N5, Széll M5, Vécsei L6, Sztriha L4, Klivényi P7.
1 Department of Neurology, Faculty of Medicine, Albert Szent-Györgyi Clinical Centre, University of Szeged, Szeged, Hungary.
2 Department of Neurosurgery, Faculty of Medicine, Albert Szent-Györgyi Clinical Centre, University of Szeged, Szeged, Hungary.
3 Department of Pediatrics and Pediatric Health Care Centre, Faculty of Medicine, Albert Szent-Györgyi Clinical Centre, University of Szeged, Szeged, Hungary; 2nd Department of Pediatrics, Semmelweis University, Budapest, Hungary.
4 Department of Pediatrics and Pediatric Health Care Centre, Faculty of Medicine, Albert Szent-Györgyi Clinical Centre, University of Szeged, Szeged, Hungary.
5 Department of Medical Genetics, Faculty of Medicine, Albert Szent-Györgyi Clinical Centre, University of Szeged, Szeged, Hungary.
6 Department of Neurology, Faculty of Medicine, Albert Szent-Györgyi Clinical Centre, University of Szeged, Szeged, Hungary; MTA-SZTE Neuroscience Research Group, Szeged, Hungary.
7 Department of Neurology, Faculty of Medicine, Albert Szent-Györgyi Clinical Centre, University of Szeged, Szeged, Hungary. Electronic address: [email protected]