New HSP genotypes & phenotypes

Research from China, Japan, Russia, USA, Turkey, Italy, Germany and Taiwan


What are genotypes and phenotypes?

The distinction between genotype and phenotype is the difference between an organism’s heredity (its genes or genotype) and what that heredity produces (the physical form and other characteristics, or phenotype).

The term “phenotype” refers to the observable physical properties of an organism, including people. These physical properties include appearance, development and behavior.

An organism’s phenotype is determined by its genotype, which is the set of genes the organism carries, as well as by environmental influences upon these genes. Due to the influence of environmental factors, organisms with identical genotypes, such as identical twins, ultimately express non-identical phenotypes because each organism encounters unique environmental influences as it develops.

Examples of phenotypes include height; eye, skin and hair color; shape and size. Phenotypes also include characteristics that can be observed or measured such as levels of hormones, blood type or behaviour.



New mutations causing SPG4, SPG3A and SPG1 found in large study in China.



Hereditary spastic paraplegias are heterogeneous disorders with diversified clinical manifestations, and genetic testing is important for the diagnosis and typing of hereditary spastic paraplegias. Gene panel sequencing containing 55 hereditary spastic paraplegias-related genes was performed to screen the pathogenic genes for hereditary spastic paraplegias. Sanger sequencing was adopted to validate if the family member carried the same pathogenic gene as the proband.

15 out of 53 patients carried mutation(s) in the screened hereditary spastic paraplegias-related genes. Among the 23 identified mutations, only one mutation had been previously reported as a pathogenic mutation. In the pedigree of case 6, the proband, his mother and uncle all carried the same novel deletion mutation (c.1459delA) at SPAST gene. Based on the pedigree, the disease was inherited in an AD pattern. In the pedigree of case 53, the family disease may be in an X-linked recessive inheritance pattern. The proband (case 53) carried two novel mutations in ALT1 gene and L1CAM gene (c.2511C>A), respectively. The L1CAM gene is the causative gene for the SPG1 X-linked recessive-hereditary spastic paraplegias.

Our data confirm the genetic heterogeneity of hereditary spastic paraplegias, and SPG4/SPAST were the most frequent forms. The pathogenicity of the novel mutations is worth to be further investigated.

SOURCE: Medicine (Baltimore). 2020 Jun 5;99(23):e20193. doi: 10.1097/MD.0000000000020193. PMID: 32501971

Genetic mutation analysis of hereditary spastic paraplegia: A retrospective study

Fang Cui 1LiuQing Sun 1Jie Qiao 2JianYong Li 1Mao Li 2SiYu Chen 2Bo Sun 2XuSheng Huang 2

1 Department of Neurology, Hainan Branch of Chinese PLA General Hospital.

2 Department of Neurology, Chinese PLA General Hospital, Beijing, China.



Another new mutation causing SPG4 found in a second study in China


Background: Hereditary spastic paraplegia is a heterogeneous group of clinically and genetically neurodegenerative diseases characterized by progressive gait disorder. Hereditary spastic paraplegia can be inherited in various ways, and all modes of inheritance are associated with multiple genes or loci. At present, more than 76 disease-causing loci have been identified in hereditary spastic paraplegia patients. Here, we report a novel mutation in SPAST gene associated with hereditary spastic paraplegia in a Chinese family, further enriching the hereditary spastic paraplegia spectrum.

Methods: Whole genomic DNA was extracted from peripheral blood of the 15 subjects from a Chinese family using DNA Isolation Kit. The Whole Exome Sequencing of the proband was analyzed and the result was identified in the rest individuals. RaptorX prediction tool and Protein Variation Effect Analyzer were used to predict the effects of the mutation on protein tertiary structure and function.

Results: Spastic paraplegia has been inherited across at least four generations in this family, during which only four HSP patients were alive. The results obtained by analyzing the Whole Exome Sequencing of the proband exhibited a novel disease-associated in-frame deletion in the SPAST gene, and this mutation also existed in the other three HSP patients in this family. This in-frame deletion consists of three nucleotides deletion (c.1710_1712delGAA) within the exon 16, resulting in lysine deficiency at the position 570 of the protein (p.K570del). This novel mutation was also predicted to result in the synthesis of misfolded SPAST protein and have the deleterious effect on the function of SPAST protein.

Conclusion: In this case, we reported a novel mutation in the known SPAST gene that segregated with HSP disease, which can be inherited in each generation. Simultaneously, this novel discovery significantly enriches the mutation spectrum, which provides an opportunity for further investigation of genetic pathogenesis of HSP.

SOURCE: BMC Med Genet. 2020 Jun 3;21(1):123. doi: 10.1186/s12881-020-01053-7. PMID: 32493220

A novel SPAST gene mutation identified in a Chinese family with hereditary spastic paraplegia

Weiwei Yu 1Haiqiang Jin 1Jianwen Deng 1Ding Nan 1Yining Huang 2

1 Department of Neurology, Peking University First Hospital, 8 Xishiku Street Xicheng District, Beijing, 100034, China.

2 Department of Neurology, Peking University First Hospital, 8 Xishiku Street Xicheng District, Beijing, 100034, China.



New mutations in SPG4, SPG7 and SPG11 found in a third study in China


Objective: To explore the clinical and genetic characteristics of five pedigrees affected with hereditary spastic paraplegia (HSP).

Methods: Clinical data of the five pedigrees was collected, and high-throughput sequencing was carried out to detect potential variants. Sanger sequencing were used to verify the results.

Results: The probands of pedigree 1 and 2 were found to harbor heterozygous SPAST gene variants, namely c.1196C>T and c.1523T>A. The proband of pedigree 3 harbored compound heterozygous variants of FA2H gene (c.61G>C and c.688G>A). Proband from pedigree 4 harbored compound heterozygous variants of SPG11 gene (c.6812+4_6812+7delAGTA and c.915delT). The proband of pedigree 5 harbored compound heterozygous variants of SPG7 gene (c.1703_1704delAG and c.1937-1G>C). Based on the American College of Medical Genetics and Genomics (ACMG) guidelines, all variants were predicted to be likely pathogenic. Among these, SPAST gene c.1523T>A, FA2H gene c.61.G>C, SPG11 gene splicing region c.6812+4_6812+7delAGTA, c.915delT, SPG7 gene c.1703_1704delAG and splicing region c.1937-1G>C variants were unreported previously.

Conclusion: The probands of pedigrees 1 and 2 were diagnosed with autosomal dominant hereditary spastic paraplegia type 4, for which pedigree 2 showed incompletely penetrance. Pedigrees 3, 4, and 5 were diagnosed with autosomal recessive hereditary spastic paraplegia type 35, 11 and 7, respectively. Above result provided a reference for clinical diagnosis and genetic counseling for the affected pedigrees.

SOURCE: Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2020 Jul 10;37(7):709-712. doi: 10.3760/cma.j.issn.1003-9406.2020.07.002. PMID: 32619247

Clinical characteristics and variant analysis of five pedigrees with hereditary spastic paraplegia

Yanchuan Xie 1Yanjie XiaZongli SunLei GuZhouxian BaiXiangdong Kong

1 Department of Central Laboratory, the First Affiliated Hospital and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, Henan 471003, China.



New SPG4 mutation associated with cognitive impairment found in a fourth study in China


Brain damage was not restricted to the white matter, with widespread gray-matter damage found that may account for the disease progression, cognitive impairment and disease severity.


To determine the cortical mechanism that underlies the cognitive impairment and motor disability in hereditary spastic paraplegia (HSP), nine HSP patients from a Chinese family were examined using clinical evaluation, cognitive screening and genetic testing. Controls were matched healthy subjects. White-matter fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD; tract-based spatial statistics), cortical thickness (FreeSurfer), and subcortical gray matter (FIRST) based on T1-weighted MRI and diffusion tensor imaging were analyzed.

A novel mutation in the SPAST gene (NM_014946.3, c.1321+2T>C) was detected. Patients had motor disability and low Montreal Cognitive Assessment (MoCA) scores. Patients showed significantly decreased total gray- and white-matter volumes, corpus callosum volume, cortical thickness, and subcortical gray-matter volume as well as significantly lower FA and AD values and significantly higher MD and RD values in the corpus callosum and corticospinal tract. Cortical thickness, subcortical gray-matter volume, and MoCA score were negatively correlated with disease duration. Cortical thickness in the right inferior frontal cortex was negatively correlated with Spastic Paraplegia Rating Scale score. Cortical thickness and right hippocampus volume were positively correlated with the MoCA score and subscores. In conclusion, brain damage is not restricted to the white matter in SPG4-HSP patients, and widespread gray-matter damage may account for the disease progression, cognitive impairment, and disease severity in SPG4-HSP.

SOURCE: Front Neurol.  2020 May 27;11:399.  doi: 10.3389/fneur.2020.00399. eCollection 2020. PMID: 32536902 Copyright © 2020 Lin, Zheng, Ma, Wang, Fan, Wu, Wang, Zhang and Zhan.

Cortical Damage Associated With Cognitive and Motor Impairment in Hereditary Spastic Paraplegia: Evidence of a Novel SPAST Mutation

Jian-Zhong Lin 1Hong-Hua Zheng 2Qi-Lin Ma 3Chen Wang 3Li-Ping Fan 3Han-Ming Wu 3Dan-Ni Wang 3Jia-Xing Zhang 4Yi-Hong Zhan 3

  1. Magnetic Resonance Center, The Affiliated Zhongshan Hospital of Xiamen University, Xiamen, China.
  2. Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, School of Medicine, Xiamen University, Xiamen, China.
  3. Department of Neurology, The First Affiliated Hospital of Xiamen University, Xiamen, China.
  4. Institute of Brain Diseases and Cognition, School of Medicine, Xiamen University, Xiamen, China.



New SPG4 mutation identified in 62 year old woman with recurrent urinary tract infections


We present a 62-year-old woman who developed recurrent urinary tract infections in her early fifties and, after an evaluation by an infectious disease physician, was referred for a neurological consultation. Her history and neurological examination were consistent with spastic paraparesis and there was significant family history of a variety of neurological diagnoses suggesting a genetic disorder.

Whole exome genetic testing revealed a novel change, a c.508 C > T variant in the SPAST gene. Our genetic and protein modeling analysis suggest that this is a disease-producing mutation confirming the diagnosis of hereditary spastic paraplegia type 4 (SPG4). This patient expands the spectrum of mutations that can cause this disorder and demonstrate the importance of recognizing the role of neurological disorders in causing neurogenic bladder and recurrent urinary tract infections.

SOURCE: Journal of Community Hospital Internal Medicine Perspectives (JCHIMP). Jul/Aug2020, Vol. 10 Issue 4, p369-370. 2p.

Complicated SPG4 presenting with recurrent urinary tract infection.

Oberoi, Kinsi1, Grewal, Kabir S.2,3, Reddy Peddareddygari, Leema3,4

1 Clarivate Analytics, Life Sciences Division, Philadelphia, PA, USA
2 School of Arts and Sciences, University of Rochester, Rochester, NY, USA
3 Dynamic Biologics Inc., R&D department, Monmouth Junction, NJ, USA
4 Neuroscience Institute, Saint Francis Medical Center, Trenton, NJ, USA



Sporadic case of pure SPG4 confirmed with infantile onset


Spastic paraplegia type 4 (SPG4) is caused by mutations of the SPAST gene and is the most common form of autosomal-dominantly inherited pure hereditary spastic paraplegia (HSP). We herein report a Japanese patient with SPG4 with a confirmed de novo mutation of SPAST. On exome sequencing and Sanger sequencing, we identified the heterozygous missense mutation p.R460L in the SPAST gene. This mutation was absent in the parents, and the paternity and maternity of the parents were both confirmed. The patient showed a pure SPG4 phenotype with an infantile onset. This study may expand the clinical and genetic findings for SPG4.

SOURCE: Intern Med. 2020 Jun 9. doi: 10.2169/internalmedicine.4599-20. Online ahead of print. PMID: 32522921

A Japanese SPG4 Patient with a Confirmed De Novo Mutation of the SPAST Gene

Haitian Nan 1Kensho Okamoto 2Lihua Gao 1Yuto Morishima 1Yuta Ichinose 1Kishin Koh 1Masaki Hashiyada 3Noboru Adachi 4Yoshihisa Takiyama 1

  1. Department of Neurology, Graduate School of Medical Sciences, University of Yamanashi, Japan.
  2. Department of Neurology, Ehime Prefectural Central Hospital, Japan.
  3. Department of Legal Medicine, Kansai Medical University, Japan.
  4. Department of Legal Medicine, Graduate School of Medical Sciences, University of Yamanashi, Japan.



Large SPG30 HSP study in Russia


Autosomal dominant SPG30 HSP was found to occur in 10 unrelated families out of a total of 118, making it the third most common form of HSP detected. Four new mutations were discovered; the clinical variability described, and the importance of AD SPG30 established.


Background: Spastic paraplegia type 30 (SPG30) caused by KIF1A mutations was first reported in 2011 and was initially considered a very rare autosomal recessive (AR) form. In the last years, thanks to the development of massive parallel sequencing, SPG30 proved to be a rather common autosomal dominant (AD) form of familial or sporadic spastic paraplegia (SPG), with a wide range of phenotypes: pure and complicated. The aim of our study is to detect AD SPG30 cases and to examine their molecular and clinical characteristics for the first time in the Russian population.

Methods: Clinical, genealogical and molecular methods were used. Molecular methods included massive parallel sequencing (MPS) of custom panel ‘spastic paraplegias’ with 62 target genes complemented by familial Sanger sequencing. One case was detected by the whole exome sequencing.

Results: AD SPG30 was detected in 10 unrelated families, making it the 3rd (8.4%) most common SPG form in the cohort of 118 families. No AR SPG30 cases were detected. In total, 9 heterozygous KIF1A mutations were detected, with 4 novel and 5 known mutations. All the mutations were located within KIF1A motor domain. Six cases had pure phenotypes, of which 5 were familial, where 2 familial cases demonstrated incomplete penetrance, early onset and slow relatively benign SPG course. All 4 complicated cases were caused by novel mutations without familial history. The phenotypes varied from severe in two patients (e.g. lack of walking, pronounced mental retardation) to relatively mild non-disabling symptoms in two others.

Conclusion: AD SPG30 is one of the most common forms of SPG in Russia, the disorder has pronounced clinical variability while pure familial cases represent a significant part.

SOURCE: BMC Neurol.  2020 Aug 3;20(1):290.  doi: 10.1186/s12883-020-01872-4. PMID: 32746806

KIF1A-related autosomal dominant spastic paraplegias (SPG30) in Russian families

G E Rudenskaya 1V A Kadnikova 2O P Ryzhkova 1L A Bessonova 1E L Dadali 1D S Guseva 1T V Markova 1D N Khmelkova 3A V Polyakov 1

  1. Federal State Budgetary Scientific Institution “Research Centre for Medical Genetics” (RCMG), Moscow, Russia.
  2. Federal State Budgetary Scientific Institution “Research Centre for Medical Genetics” (RCMG), Moscow, Russia.
  3. “Genomed” Ltd, Moscow, Russia.



SPG30 HSP study in Italy


Similar to the Russian study described above, this study of the gene responsible for SPG30 HSP, KIF1A, also found dominant inheritance to be important. Various conditions related to mutations in this gene were described in three new mutations were found.


Background: Dominant and recessive variants in the KIF1A gene on chromosome 2q37.3 are associated with several phenotypes, although only three syndromes are currently listed in the OMIM classification: hereditary sensory and autonomic neuropathy type 2 and spastic paraplegia type 30, both recessively inherited, and mental retardation type 9 with dominant inheritance.

Methods: In this retrospective multicentre study, we describe the clinical, neuro-radiological and genetic features of 19 Caucasian patients (aged 3-65 years) harboring heterozygous KIF1A variants, and extensively review the available literature to improve current classification of KIF1A-related disorders.

Results: Patients were divided into two groups. Group 1 comprised patients with a complex phenotype with prominent pyramidal signs, variably associated in all but one case with additional features (ie, epilepsy, ataxia, peripheral neuropathy, optic nerve atrophy); conversely, patients in Group 2 presented an early onset or congenital ataxic phenotype. Fourteen different heterozygous missense variants were detected by next-generation sequencing screening, including three novel variants, most falling within the kinesin motor domain.

Conclusion: The present study further enlarges the clinical and mutational spectrum of KIF1A-related disorders by describing a large series of patients with dominantly inherited KIF1A pathogenic variants ranging from pure to complex forms of hereditary spastic paraparesis/paraplegias (HSP) and ataxic phenotypes in a lower proportion of cases. A comprehensive review of the literature indicates that KIF1A screening should be implemented in HSP regardless of its mode of inheritance or presentations as well as in other complex neurodegenerative or neurodevelopmental disorders showing congenital or early onset ataxia.

SOURCE: J Med Genet. 2020 Jul 31;jmedgenet-2020-107007. doi: 10.1136/jmedgenet-2020-107007. Online ahead of print. PMID: 32737135 © Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.

Heterozygous KIF1A variants underlie a wide spectrum of neurodevelopmental and neurodegenerative disorders

Francesco Nicita # 1Monia Ginevrino # 2 3Lorena Travaglini 4Stefano D’Arrigo 5Giovanna Zorzi 6Renato Borgatti 7 8Gaetano Terrone 9Michela Catteruccia 4Gessica Vasco 10Vesna Brankovic 11Sabrina Siliquini 12Silvia Romano 13Chiara Veredice 14Marina Pedemonte 15Michelina Armando 10Donatella Lettori 10Fabrizia Stregapede 4 16Luca Bosco 4Antonella Sferra 4Valeria Tessarollo 5Romina Romaniello 17Giovanni Ristori 13Enrico Bertini 4Enza Maria Valente 8 18Ginevra Zanni 4

  1. Unit of Neuromuscular and Neurodegenerative Diseases, Department of Neuroscience and Neurorehabilitation, IRCCS Bambino Gesù Children’s Hospital, Roma, Italy [email protected].
  2. Istituto di Medicina Genomica, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, Roma, Italy.
  3. Laboratory of Medical Genetics, IRCCS, Bambino Gesù Children’s Hospital, Roma, Italy.
  4. Unit of Neuromuscular and Neurodegenerative Diseases, Department of Neuroscience and Neurorehabilitation, IRCCS Bambino Gesù Children’s Hospital, Roma, Italy.
  5. Department of Developmental Neurology, Fondazione IRCCS, Istituto Neurologico Carlo Besta, Milano, Italy.
  6. Child Neuropsychiatry Unit, Fondazione IRCCS, Istituto Neurologico Carlo Besta, Milano, Italy.
  7. Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy.
  8. IRCCS Mondino Foundation, Pavia, Italy.
  9. Department of Translational Medicine, Section of Pediatrics, Child Neurology Unit, Universita degli Studi di Napoli Federico II, Napoli, Campania, Italy.
  10. Unit of Neurorehabilitation, Department of Neuroscience and Neurorehabilitation, IRCCS Bambino Gesù Children’s Hospital, Roma, Italy.
  11. Clinic for Child Neurology and Psychiatry, University of Belgrade, Belgrade, Serbia.
  12. Child Neuropsychiatry Unit, Pediatric Hospital G. Salesi, Ospedali Riuniti, Ancona, Italy.
  13. Neurosciences, Mental Health, and Sensory Organs (NESMOS) Department, Center for Experimental Neurological Therapies, S. Andrea Hospital Site, Sapienza University of Rome, Rome, Italy.
  14. Child Neurology and Psychiatry, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, Rom, Italy.
  15. Unit of Pediatric Neurology and Muscle Diseases, IRCCS Istituto Giannina Gaslini, Genova, Italy.
  16. Department of Sciences, Roma Tre University, Rom, Italy.
  17. Neuropsychiatry and Neurorehabilitation Unit, Scientific Institute, IRCCS Eugenio Medea, Lecco, Italy.
  18. Department of Molecular Medicine, University of Pavia, Pavia, Italy.

#Contributed equally.



New mutation found in SPG48



We describe an additional patient with spastic paraplegia 48 (SPG48). A 52-year-old woman with gradually increasing gait disturbance was admitted to our hospital. When she was 47 years old, acquaintances noted a shuffling gait. Gait worsening was evident at 48 years. Spastic gait was apparent at 50, and she required a walking stick at 54. Her elder brother had similar gait disturbance. No consanguinity was known. Neurologic examination at 52 disclosed spasticity and moderate weakness in the lower limbs with spasticity and brisk reflexes in all limbs.

Laboratory studies including HTLV-1 titer detected no abnormalities. MRI demonstrated mild corpus callosum narrowing and prominent anterior periventricular hyperintensities in fluid attenuation inversion recovery images. In limb muscles, electromyography (EMG) showed a chronic neurogenic pattern including reduced interference.

Gene analysis identified compound homozygosity in exon 7 of adaptor-related protein complex 5 subunit zeta 1 (AP5Z1), including a novel frameshift mutation, c.1662_1672del;p.Glu554Hfs*15 in the patient, and a heterozygous missense mutation in asymptomatic family members, including her mother, two siblings, and a daughter. The frameshift mutation is considered a pathogenic variant according to American College of Medical Genetics and Genomics standards and guidelines.

Based on clinical features, imaging findings and genetic abnormalities, we diagnosed this patient with SPG48. Mutations in AP5Z1, which encodes the ζ subunit of AP-5, underlie SPG48. The AP-5 adaptor protein complex, which is mutated in SPG48, binds to both spastizin and spatacsin. While hereditary spastic paraplegias generally are clinically and genetically heterogenous, SPG48, SPG11, and SPG15 are clinically similar.

SOURCE: Rinsho Shinkeigaku. 2020 Aug 7;60(8):543-548. doi: 10.5692/ Epub 2020 Jul 7. PMID: 32641631

A case of spastic paraplegia 48 with a novel mutation in the AP5Z1 gene

Kyoko Maruta 1Masahiro Ando 2Takanobu Otomo 3Hiroshi Takashima 2

1 Department of Neurology, National Hospital Organization Minamikyushu National Hospital.

2 Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medicine and Dental Sciences.

3 Department of Molecular and Genetic Medicine, Kawasaki Medical School.



New compound heterozygous variants discovered in SPG46 in two sisters


Cervical dystonia, a painful condition in which the neck muscles contract involuntarily, causing the head to twist or turn to one side, is also a new finding.



GBA2 associated spastic paraplegia type 46 (SPG46) is an autosomal-recessive disorder associated with a clinical presentation of spastic gait, muscle weakness as well as an array of clinical symptoms including pseudobulbar palsy and progressive cognitive decline. Several neurological and non-neurological symptoms are associated with GBA2 mutations. An initial presentation with dystonia has not been reported so far.

We report clinical, genetic and brain imaging findings in two siblings with hereditary spastic paraparesis. One sister presented with juvenile-onset leg spasticity and progressed to spastic tetraparesis, cervical and jaw opening dystonia, pseudobulbar symptoms and dementia. The other sister initially developed cervical dystonia in adulthood followed by gait spasticity and cognitive decline in the disease course. Molecular genetic testing revealed novel compound heterozygous variants in GBA2 in both sisters. The initial presentation with cervical dystonia and the differing clinical disease progression expand the clinical phenotype of GBA2 associated SPG46.

SOURCE: Eur J Med Genet. 2020 Sep;63(9):103992.  doi: 10.1016/j.ejmg.2020.103992. Epub 2020 Jun 24. PMID: 32590105 Copyright © 2020 Elsevier Masson SAS. All rights reserved.

Dystonia as initial presentation of compound heterozygous GBA2 mutations: Expanding the phenotypic spectrum of SPG46

Katja Kloth 1Claudia Cozma 2Maxim Bester 3Christian Gerloff 4Saskia Biskup 5Simone Zittel 6

  1. Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  2. Centogene AG, Department of Biomarker Research and Development, Rostock, Germany.
  3. Department of Neuroradiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  4. Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  5. Praxis für Humangenetik Tuebingen, Paul-Ehrlich-Str. 23, 72076, Tuebingen, Germany.
  6. Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.



New mutation causing SPG3A HSP found in 4 year old girl with abnormal spine MRI



Hereditary/Familial spastic paraparesis (HSP) or Strumpell-Lorrain syndrome constitutes a heterogeneous group of neurodegenerative disorders involving predominantly the corticospinal tracts and dorsal columns.[1]

We saw a 4-year-old girl with toe-walking, abnormal gait, and frequent falls for the past two and a half years. The symptoms were non-progressive and she continued ambulation with difficulty. She also showed motor and mild language delay. Father had similar complaints since early childhood and had undergone several surgical procedures for gait improvement. He was currently employed and ambulatory with a waddling gait. Remaining family members were not affected and normal.

On examination, she had signs of vitamin D deficiency (frontal bossing and wrist widening), a single café-au-lait macule over the left side of the trunk, platynychia, unclear speech, bilateral talipes varus, spastic paraparesis, diminished vibration sense, extensor plantar, ankle contractures, waddling gait, normal head size, and absence of organomegaly. Father also demonstrated toe-walking, spastic paraparesis, and knee and ankle contractures. Clinical diagnoses of familial, inherited spastic paraparesis, or neurometabolic disorders such as arginase deficiency, biotinidase deficiency, and abetalipoproteinemia were considered. Magnetic resonance imaging (MRI) of the spine revealed hydromyelia with mild spinal cord atrophy. MRI brain in the child was normal. MRI spine of father was normal. Tandem mass spectrometry, gas chromatography-mass spectrometry, serum ammonia, lipid profile, nerve conduction, and electromyography studies were normal.

Whole exome sequencing for the child revealed an autosomal-dominant, heterozygous, missense, pathogenic variation in exon 8 (NM_015915) of ATL1 gene (chr14:51081116.c.T749A/p. Leu250Gln), which was confirmed by Sanger sequencing. Parental testing was not done due to financial constraints. She was offered supportive care and anti-spasticity drugs.

SPG3A/Atlastin-1 mutations represent approximately 30–50% of autosomal dominant HSP cases and are the most frequent cause of HSP with onset before the age of 10 years.[3] The reported genetic variations are predominantly of missense type, as in the index patient. However, this was a novel mutation, which has not been observed in 1000 genome database and ExAC database.

In pure forms, MRI spine can be normal; however, spinal cord atrophy and hydromyelia has been reported in cases with SPG56 variation.[5] We propose that hydromyelia seen in the index child may be an incidental finding and cannot explain the entire spectrum of clinical symptoms seen in this child. Hence, it probably is not the cause of spastic paraparesis in the index child.

In conclusion, in any child presenting with early onset toe-walking and spasticity with similar family history, a differential diagnosis of autosomal-dominant HSP due to ATL1 (SPG3A) must be considered. Timely diagnosis will help to initiate early rehabilitation and prevent unnecessary diagnostic evaluations.

SOURCE: Ann Indian Acad Neurol. May-Jun 2020;23(3):386-387. doi: 10.4103/aian.AIAN_424_19. Epub 2020 Jun 10. PMID: 32606547

Familial Spastic Paraparesis: A Novel Mutation in a 4-Year-Old Girl

Bhanudeep Singanamalla 1Shivan Kesavan 1Arushi G Saini 1

1 Pediatric Neurology Unit, Department of Pediatrics, Advanced Pediatrics Centre, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.



3 new mutations causing SPG5 HSP amongst 19 individuals from 17 families in Taiwan.


Objectives: To investigate the clinical, electrophysiological, neuroimaging characteristics and genetic features of SPG5 in Taiwan.

Methods: Mutational analysis of the coding regions of CYP7B1 was performed by utilizing targeted resequencing analysis of the 187 unrelated Taiwanese HSP patients. The diagnosis of SPG5 was ascertained by the presence of biallelic CYP7B1 mutations. The SPG5 patients received clinical, electrophysiological, and neuroimaging evaluations. Disease severity was assessed by using the Spastic Paraplegia Rating Scale (SPRS) and the disability score. Two microsatellite markers as well as 18 single-nucleotide polymorphism (SNP) markers flanking CYP7B1 were genotyped to assess the founder effect of the CYP7B1 p.R112* mutation.

Results: Nineteen SPG5 patients from 17 families were identified. They typically presented an insidious onset progressive spastic paraparesis with proprioception involvement beginning at age 8 to 40 years. Their MRIs often showed white matter abnormalities in bilateral occipito-parietal regions, spinal cord atrophy, and mild cerebellar atrophy. Six different mutations in CYP7B1 were recognized, including three novel ones (p.N131Ifs*4, p.A295V, and p.L439R). CYP7B1 p.R112* was the most common mutation and present in 88.2% of the 17 SPG5 pedigrees. The patients with homozygous CYP7B1 p.R112* mutations had a milder clinical severity. Detailed haplotype analyses demonstrated a shared haplotype in the 25 individuals carrying at least one single allele of CYP7B1 p.R112*, suggesting a founder effect.

Interpretation: This study delineates the distinct clinical and genetic features of SPG5 in Taiwan and provides useful information for the diagnosis and management of SPG5, especially in patients of Chinese descent.

SOURCE: Ann Clin Transl Neurol. 2020 Apr;7(4):486-496. PMID: 32202070  doi: 10.1002/acn3.51019. Epub 2020 Mar 22. © 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.

Clinical characteristics of Taiwanese patients with Hereditary spastic paraplegia type 5

Cheng-Ta Chou 1 2Bing-Wen Soong 3 4Kon-Ping Lin 3 5Yu-Shuen Tsai 6Kang-Yang Jih 3 5Yi-Chu Liao 3 5 7Yi-Chung Lee 3 5 7

  1. Institute of Clinical Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.
  2. Department of Neurology, Neurological Institute, Taichung Veterans General Hospital, Taichung, Taiwan.
  3. Department of Neurology, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan.
  4. Department of Neurology, Taipei Neuroscience Institute, Taipei Medical University-Shuang Ho Hospital, Taipei, Taiwan.
  5. Department of Neurology, National Yang-Ming University School of Medicine, Taipei, Taiwan.
  6. Center for Systems and Synthetic Biology, National Yang-Ming University, Taipei, Taiwan.
  7. Brain Research Center, National Yang-Ming University School of Medicine, Taipei, Taiwan.






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