New HSP genotypes and phenotypes

Research from Italy, UK, Portugal, USA, Japan, Israel, the Netherlands, Turkey, Saudi Arabia, South Korea


New links between SPG7 HSP and ataxia


Large Italian study finds new variants


A huge study in Italy of 900 people with ataxia has shown that different types of an SPG7 HSP mutation accounted for about one in 40 cases. The type of inheritance enables prediction of the onset of symptoms and of disease progression, which is highly unusual amongst the HSPs.



BACKGROUND AND PURPOSE: Hereditary ataxias are heterogeneous groups of neurodegenerative disorders, characterized by cerebellar syndromes associated with dysarthria, oculomotor and corticospinal signs, neuropathy and cognitive impairment. Recent reports have suggested mutations in the SPG7 gene, causing the most common form of autosomal recessive spastic paraplegia (MIM#607259), as a main cause of ataxias. The majority of described patients were homozygotes or compound heterozygotes for the c.1529C>T (p.Ala510Val) change. We screened a cohort of 895 Italian patients with ataxia for p.Ala510Val in order to define the prevalence and genotype-phenotype correlation of this variant.

METHODS: We set up a rapid assay for c.1529C>T using restriction enzyme analysis after polymerase chain reaction amplification. We confirmed the diagnosis with Sanger sequencing.

RESULTS: We identified eight homozygotes and 13 compound heterozygotes, including two novel variants affecting splicing. Mutated patients showed a pure cerebellar ataxia at onset, evolving in mild spastic ataxia (alternatively) associated with dysarthria (~80% of patients), urinary urgency (~30%) and pyramidal signs (~70%). Comparing homozygotes and compound heterozygotes, we noted a difference in age at onset and Scale for the Assessment and Rating of Ataxia score between the two groups, supporting an earlier and more severe phenotype in compound heterozygotes versus homozygotes.

CONCLUSIONS: The SPG7 c.1529C>T (p.Ala510Val) mutants accounted for 2.3% of cerebellar ataxia cases in Italy, suggesting that this variant should be considered as a priority test in the presence of late-onset pure ataxia. Moreover, the heterozygous/homozygous genotype appeared to predict the onset of clinical manifestation and disease progression.

SOURCE: Eur J Neurol. 2018 Aug 11. doi: 10.1111/ene.13768. [Epub ahead of print] PMID: 30098094  © 2018 EAN.

Prevalence and phenotype of the c.1529C>T SPG7 variant in adult-onset cerebellar ataxia in Italy.

Mancini C1, Giorgio E1, Rubegni A2, Pradotto L3, Bagnoli S4, Rubino E5, Prontera P6, Cavalieri S1, Di Gregorio E1, Ferrero M1, Pozzi E1, Riberi E1, Ferrero P5, Nigro P7, Mauro A8, Zibetti M5, Tessa A2, Barghigiani M2, Antenora A9, Sirchia F10, Piacentini S4, Silvestri G11,12, De Michele G9, Filla A9, Orsi L5, Santorelli FM2, Brusco A1,13.

1 Department of Medical Sciences, University of Torino, Turin, Italy.

2 Molecular Medicine, IRCCS Fondazione Stella Maris, Pisa, Italy.

3 Division of Neurology and Neurorehabilitation, San Giuseppe Hospital, IRCCS Istituto Auxologico Italiano, Piancavallo, Italy.

4 Department of Neuroscience, Psychology, Drug Research and Child’s Health, University of Florence, Florence, Italy.

5 Department of Neuroscience and Mental Health, Città della Salute e della Scienza University Hospital, Turin, Italy.

6 Medical Genetics Unit, Hospital S. Maria della Misericordia, Perugia, Italy.

7 Clinica Neurologica, Azienda Ospedaliera – Università di Perugia, Perugia, Italy.

8 Department of Neurosciences, University of Torino, Turin, Italy.

9 Department of Neurosciences, Federico II University, Naples, Italy.

10 Institute for Maternal and Child Health – IRCCS Burlo Garofolo, Trieste, Italy.

11 Fondazione Policlinico Universitario IRCCS, A. Gemelli, Rome, Italy.

12 Università Cattolica del Sacro Cuore, Rome, Italy.

13 Medical Genetics Unit, Città della Salute e della Scienza Hospital, Turin, Italy.



MND gene now linked with HSP


3 brothers – 2 with ALS and 1 with HSP


In a family where the father developed a type of dementia in his mid-50s that progressed to motor neurone disease, his three sons all developed symptoms in their mid 20s, two of them with motor neurone disease and one with slowly progressive pure HSP.


Analysis of 226 exome-sequenced UK cases of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia identified 2 individuals who harbored a P497H and P506S UBQLN2 mutation, respectively (n = 0.9%). The P506S index case presented with behavioral variant frontotemporal dementia at the age of 54 years then progressed to ALS surviving 3 years. Three sons presented with (1) slowly progressive pure spastic paraplegia with an onset at 25 years and (2) ALS with disease onset of 25 years and survival of 2 years, and (3) ALS presenting symptoms at the age of 26 years, respectively. Analysis of postmortem tissue from the index case revealed frequent neuronal cytoplasmic UBQLN2-positive inclusions in the dentate gyrus and TDP-43-positive neuronal cytoplasmic inclusions in the frontal and temporal cortex and granular cell layer of the dentate gyrus of the hippocampus. Furthermore, a comprehensive analysis of published UBQLN2 mutations demonstrated that only proline-rich domain mutations contribute to a significantly earlier age of onset in male patients (p = 0.0026).


SOURCE: Neurobiol Aging. 2019 Jan;73:229.e5-229.e9. doi: 10.1016/j.neurobiolaging.2018.08.015. Epub 2018 Aug 24. PMID: 30348461

Striking phenotypic variation in a family with the P506S UBQLN2 mutation including amyotrophic lateral sclerosis, spastic paraplegia, and frontotemporal dementia.

Gkazi SA1, Troakes C1, Topp S1, Miller JW1, Vance CA1, Sreedharan J1, Al-Chalabi A1, Kirby J2, Shaw PJ2, Al-Sarraj S1, King A1, Smith BN1, Shaw CE3.

1 United Kingdom Dementia Research Institute Centre, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, Camberwell, London, UK.

2 Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK.

3 United Kingdom Dementia Research Institute Centre, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, Camberwell, London, UK. Electronic address: [email protected].



PLA2G6 gene now associated with HSP


Four Japanese families identified


383 HSP families in Japan who were screened for PLA2G6 mutations revealed the mutation in 4 families with clinical characteristics of HSP. The study was possible because of the registry that was created and is continuously developed by the Japan Spastic Paraplegia Research Consortium (JASPAC).



PLA2G6-associated neurodegeneration (PLAN) comprises heterogeneous neurodegenerative disorders, including infantile neuroaxonal dystrophy, neurodegeneration with brain iron accumulation 2B, and Parkinson disease 14 (PARK14). In addition, very recently, PLA2G6 mutations have been reported to represent a phenotype of hereditary spastic paraplegia (HSP).

In this study, we screened 383 HSP families to clarify the frequency of PLA2G6 mutations in the Japan Spastic Paraplegia Research Consortium, and revealed the clinical characteristics of HSP with PLA2G6 mutations. We found three families with compound heterozygous mutations of the PLA2G6 gene, c.517 C > T/c.1634A > G, c.662 T > C/c.991 G > T, and c.1187-2 A > G/c.1933C > T, and one family with a homozygous mutation of the PLA2G6 gene, c.1904G > A/c.1904G > A.

All three families with compound heterozygous mutations presented a uniform phenotype of a complicated form of HSP with infantile/child-onset spastic paraplegia, cerebellar ataxia, and mental retardation. On the other hand, the family with a homozygous mutation presented a late-onset complicated form of HSP with parkinsonism. This study may extend the clinical and genetic findings for PLAN.


SOURCE: J Hum Genet. 2018 Oct 9. doi: 10.1038/s10038-018-0519-7. [Epub ahead of print] PMID: 30302010

PLA2G6-associated neurodegeneration presenting as a complicated form of hereditary spastic paraplegia.

Koh K1, Ichinose Y1, Ishiura H2, Nan H1, Mitsui J3, Takahashi J4, Sato W5, Itoh Y6, Hoshino K7, Tsuji S3,8, Takiyama Y9; Japan Spastic Paraplegia Research Consotium.

1 Department of Neurology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi, Japan.

2 Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

3 Department of Molecular Neurology, The University of Tokyo, Tokyo, Japan.

4 Department of Pediatrics, National Mie Hospital, Mie, Japan.

5 Department of Immunology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.

6 Department of Neurology, Osaka City University, Osaka, Japan.

7 Department of Pediatrics, Minamiwakayama Medical Center, Wakayama, Japan.

8 International University of Health and Welfare Graduate School, Chiba, Japan.

9 Department of Neurology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi, Japan. [email protected].



New SPG52 HSP phenotype


Extremely rare genetic variant



Hereditary spastic paraplegias (HSPs) are a group of rare inherited neurodegenerative disorders that result from primary retrograde dysfunction of the long descending fibers of the corticospinal tract, causing lower limb spasticity and muscular weakness.

Spastic paraplegia type 52 (SPG52) is an autosomal recessive disease caused by AP4S1 mutations. The disease is characterized by neonatal hypotonia that progresses to hypertonia and spasticity in early childhood, developmental delay, mental retardation, and poor or absent speech. Febrile or afebrile seizures may also occur.2,4


AP4S1 encodes the small subunit of the adaptor protein complex-4 (AP4 complex).

The mutation found in the 4 yr old patient leads to the loss of exon 4, with predicted important consequences to the protein structure and the AP4 complex function. Anatomical changes similar to those observed in patients have been reported in an AP-4 complex knockout mouse model: enlargement of the lateral ventricles and thinning of the corpus callosum.7 Similar changes have also been seen in the patient described here, together with febrile and afebrile seizures.

The most recent neurologic evaluation revealed the presence of hypertonia in the left leg, associated with pyramidal signs, suggesting the possibility of future development of a spastic paraparesis, typical of this disease.

Here, we report a case of SPG52 associated with posterior perisylvian polymicrogyria, unexplained transitory hyperammonemia, and absence of facial dysmorphisms, which suggest an expansion of the disease phenotype.


SOURCE: Neurol Genet. 2018 Sep 19;4(5):e273. doi: 10.1212/NXG.0000000000000273. eCollection 2018 Oct. PMID: 30283821

AP4S1 splice-site mutation in a case of spastic paraplegia type 52 with polymicrogyria

Carmona S1, Marecos C1, Amorim M1, Ferreira AC1, Conceição C1, Brás J1, Duarte ST1, Guerreiro R1.

1 Department of Molecular Neuroscience (S.C., J.B., R.G.), UCL Institute of Neurology, University College London, United Kingdom; Paediatric Neurology Department (C.M., S.T.D.), Hospital Dona Estefânia, Centro Hospitalar de Lisboa Central; Genetics Department (M.A.), Hospital Dona Estefânia, Centro Hospitalar de Lisboa Central; Reference Center of Inherited Metabolic Diseases (A.C.F.), Centro Hospitalar de Lisboa Central; Neuroradiology Department (C.C.), Hospital Dona Estefânia, Centro Hospitalar de Lisboa Central, Lisbon, Portugal; UK Dementia Research Institute (J.B., R.G.), University College London, United Kingdom; and Department of Medical Sciences (J.B., R.G.), Institute of Biomedicine, iBiMED, University of Aveiro, Portugal.



New SPG77 HSP phenotype


Associated with new FARS2 mutation



Mutations in FARS2, the gene encoding the mitochondrial phenylalanine-tRNA synthetase (mtPheRS), have been linked to a range of phenotypes including epileptic encephalopathy, developmental delay, and motor dysfunction. We report a 9-year-old boy with novel compound heterozygous variants of FARS2, presenting with a pure spastic paraplegia syndrome associated with bilateral signal abnormalities in the dentate nuclei.

Exome sequencing identified a paternal nonsense variant (Q216X) lacking the catalytic core and anticodon-binding regions, and a maternal missense variant (P136H) possessing partial enzymatic activity. This case confirms and expands the phenotype related to FARS2 mutations with regards to clinical presentation and neuroimaging findings.


SOURCE: Ann Clin Transl Neurol. 2018 Aug 14;5(9):1128-1133. doi: 10.1002/acn3.598. eCollection 2018 Sep. PMID: 30250868

FARS2 mutations presenting with pure spastic paraplegia and lesions of the dentate nuclei.

Sahai SK1, Steiner RE2,3,4, Au MG5, Graham JM5, Salamon N6, Ibba M2,3,4, Pierson TM1,5,7.

1 Department of Neurology Cedars-Sinai Medical Center Los Angeles California.

2 Department of Microbiology Ohio State University Columbus Ohio 43210.

3 Center for RNA Biology Ohio State University Columbus Ohio 43210.

4 Ohio State Biochemistry Program Ohio State University Columbus Ohio 43210.

5 Department of Pediatrics Cedars-Sinai Medical Center Los Angeles California.

6 Department of Radiological Sciences David Geffen School of Medicine University of California Los Angeles Los Angeles California.

7 Board of Governors Regenerative Medicine Institute Cedars-Sinai Medical Center Los Angeles California.



Four new SPG74 HSP mutations found


Associated with new complicated phenotypes



Biallelic mutations in IBA57 cause a mitochondrial disorder with a broad phenotypic spectrum that ranges from severe intellectual disability to adolescent-onset spastic paraplegia. Only 21 IBA57 mutations have been reported, therefore the phenotypic spectrum of IBA57-related mitochondrial disease has not yet been fully elucidated.


In this study, we performed whole-exome sequencing on a Sepharadi Jewish and Japanese family with leukodystrophy. We identified four novel biallelic variants in IBA57 in the two families: one frameshift insertion and three missense variants. The three missense variants were predicted to be disease-causing by multiple in silico tools. The 29-year-old Sepharadi Jewish male had infantile-onset optic atrophy with clinically asymptomatic leukodystrophy involving periventricular white matter. The 19-year-old younger brother, with the same compound heterozygous IBA57 variants, had a similar clinical course until 7 years of age. However, he then developed a rapidly progressive spastic paraparesis following a febrile illness. A 7-year-old Japanese girl had developmental regression, spastic quadriplegia, and abnormal periventricular white matter signal on brain magnetic resonance imaging performed at 8 months of age. She had febrile convulsions at the age of 18 months and later developed epilepsy.


In summary, we have identified four novel IBA57 mutations in two unrelated families. Consequently, we describe a patient with infantile-onset optic atrophy and asymptomatic white matter involvement, thus broadening the phenotypic spectrum of biallelic IBA57 mutations.


SOURCE: J Hum Genet. 2018 Dec;63(12):1223-1229. doi: 10.1038/s10038-018-0516-x. Epub 2018 Sep 27. PMID: 30258207

Expanding the phenotype of IBA57 mutations: related leukodystrophy can remain asymptomatic.

Hamanaka K1, Miyatake S1,2, Zerem A3, Lev D4, Blumkin L3, Yokochi K5, Fujita A1, Imagawa E1, Iwama K1, Nakashima M6, Mitsuhashi S1, Mizuguchi T1, Takata A1, Miyake N1, Saitsu H6, van der Knaap MS7, Lerman-Sagie T3, Matsumoto N8.

1 Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.

2 Clinical Genetics Department, Yokohama City University Hospital, Yokohama, Japan.

3 Pediatric Neurology Unit, Metabolic-Neurogenetic Clinic, Wolfson Medical Center, Holon, and Sackler School of Medicine, Tel Aviv University, Tel-Aviv, Israel.

4 Institute of Medical Genetics, Metabolic-Neurogenetic Clinic, Wolfson Medical Center, Holon, and Sackler School of Medicine, Tel Aviv University, Tel-Aviv, Israel.

5 Department of Pediatric Neurology, Mikatahara General Hospital, Hamamatsu, Japan.

6 Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan.

7 Department of Child Neurology, VU University Medical Centre, Amsterdam, Netherlands.

8 Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan. [email protected].



New complex ataxia + HSP phenotype


SPG7 HSP and spinocerebellar ataxia genes


A coincidental sporadic spinocerebellar ataxia gene mutation combined with an SPG7 HSP mutation has resulted in a new complex phenotype, with both mutations impairing mitochondrial structure, dynamics and function.



Mitochondrial dynamics and quality control are crucial for neuronal survival and their perturbation is a major cause of neurodegeneration. m-AAA complex is an ATP-dependent metalloprotease located in the inner mitochondrial membrane and involved in protein quality control.

Mutations in the m-AAA subunits AFG3L2 and paraplegin are associated with autosomal dominant spinocerebellar ataxia (SCA28) and autosomal recessive hereditary spastic paraplegia (SPG7), respectively. We report a novel m-AAA-associated phenotype characterized by early onset optic atrophy with spastic ataxia and L-dopa-responsive parkinsonism.

The proband carried a de novo AFG3L2 heterozygous mutation (p.R468C) along with a heterozygous maternally inherited intragenic deletion of SPG7. Functional analysis in yeast demonstrated the pathogenic role of AFG3L2 p.R468C mutation shedding light on its pathogenic mechanism. Analysis of patient’s fibroblasts showed an abnormal processing pattern of OPA1, a dynamin-related protein essential for mitochondrial fusion and responsible for most cases of hereditary optic atrophy. Consistently, assessment of mitochondrial morphology revealed a severe fragmentation of the mitochondrial network, not observed in SCA28 and SPG7 patients’ cells.

This case suggests that coincidental mutations in both components of the mitochondrial m-AAA protease may result in a complex phenotype and reveals a crucial role for OPA1 processing in the pathogenesis of neurodegenerative disease caused by m-AAA defects.


SOURCE: Hum Mutat. 2018 Dec;39(12):2060-2071. doi: 10.1002/humu.23658. Epub 2018 Oct 10. PMID: 30252181

Concurrent AFG3L2 and SPG7 mutations associated with syndromic parkinsonism and optic atrophy with aberrant OPA1 processing and mitochondrial network fragmentation.

Magri S1, Fracasso V1, Plumari M1, Alfei E2, Ghezzi D1,3, Gellera C1, Rusmini P4, Poletti A4, Di Bella D1, Elia AE5, Pantaleoni C2, Taroni F1.

1 Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.

2 Unit of Developmental Neurology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.

3 Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, Università degli Studi di Milano, Milan, Italy.

4 Dipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Centro di Eccellenza sulle Malattie Neurodegenerative, Università degli Studi di Milano, Milan, Italy.

5 Unit of Neurology 1, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.



New SPG35 HSP mutation identified


Associated with recessive, complex HSP


Here, we report an HSP type 35 case of Turkish origin with a novel homozygous mutation in FA2H gene, presented with progressive gait disturbance and cognitive impairment.


A 16-years-old boy was admitted to our hospital because of progressive difficulty in walking, unsteady gait, cognitive impairment, and hand tremor. He had normal motor and intellectual development until the age of 10 years when gait disturbance and balance problems first appeared. Five years later, he began to show deterioration in academic skills. The patient was diagnosed with cerebral palsy because of these complaints in another hospital. The parents were consanguineous, and there was no family history of neurologic disease. He was born at term and had no neonatal problems. He had healthy two older sisters.

We identified a novel missense homozygous mutation at the FA2H gene (c.130C>T p. Pro44Ser p. P44S) which has not been reported previously.

In conclusion, SPG35 should be included in the differential diagnosis of lower limb spasticity and weakness when additional ataxia, mild cognitive deficits, and extrapyramidal involvement are present.


SOURCE: Ann Indian Acad Neurol 2018;21:335-9

Hereditary spastic paraplegia type 35 with a novel mutation in fatty acid 2-hydroxylase gene and literature review of the clinical features

Faruk Incecik1Seyda Besen1Sevcan Tug Bozdogan2

1 Department of Pediatric Neurology, Faculty of Medicine, Cukurova University, Adana, Turkey

2 Department of Medical Genetics, Faculty of Medicine, Cukurova University, Adana, Turkey



Complicated SPG11 HSP family history


Four mutations produce multiple impairments



The interaction of multiple genetic factors, as opposed to monogenic inheritance, has been suspected to play a role in many diseases. This interaction has been described as an oligogenic inheritance model, which may be a useful tool in explaining certain clinical observations.

The purpose of this study was to search for novel genetic defects among members of a family with traits that include mental retardation, short stature, osteopetrosis, calcification of basal ganglia, and thinning of the corpus callosum.

In the index case (111-4), we identified four homozygous mutations: chromosome 8, intron2 (c.232+1G>A) at CA2 gene; chromosome 15, exon 32 (c.6100C>T) at the SPG11; chromosome 5, exon 11 (c.1015G>A) at the MCCC2; and chromosome 9, exon 9 (C.1193g>t) at the LARP gene. The mutations were confirmed by Sanger sequencing, and both parents were observed to be heterozygous for the four mutations. A moderately affected sister of the index case was homozygous for only three mutations in CA2, LARP, and Mccc2, while a non-affected sister was heterozygous for three mutations in CA2, LARP, and MCCC2 and negative for SPG11.

The clinical features of the two affected sisters can be explained distinctively by each homozygous mutation in an oligogenic pattern of inheritance. This family represents an example of an oligogenic pattern of inheritance of mental retardation, short stature, spastic paraparesis, and osteopetrosis.


SOURCE: Published 8 November 2018 Volume 2018:11 Pages 129134

Potential oligogenic disease of mental retardation, short stature, spastic paraparesis and osteopetrosis

Abdulaziz Alsemari,1 Mohanned Alsuhaibani,2 Rawabi Alhathlool,1 Bayan Mamdouh Ali1

1Department of Neurosciences, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia; 2Department of Radiology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia



New SPG10 HSP mutation discovered


Axonal neuropathy also present



Kinesins are a family of proteins for anterograde transport of the molecules from the neuronal cell body. Their impairment has been widely associated with neurodegeneration of the motor neurons. KIF5A gene causes autosomal dominant spastic paraplegia 10, a neurological disorder characterized by spasticity and weakness of the lower limbs (SPG10).

We carried out a screening of KIF5A gene in 50 subjects affected by HSP negative to diagnostic test for SPG4, ATL1 and REEP1. We identified a novel variation p.Ile255Met in a 58-year-old man who developed progressive gait disturbance due to spastic paraparesis complicated by axonal neuropathy.


SOURCE: Acta Neurol Belg. 2018 Dec;118(4):643-646. doi: 10.1007/s13760-018-1039-0. Epub 2018 Nov 9. PMID: 30411208

Kinesins in neurological inherited diseases: a novel motor-domain mutation in KIF5A gene in a patient from Southern Italy affected by hereditary spastic paraplegia.

Citrigno L1, Magariello A1, Pugliese P2, Di Palma G1, Conforti FL1, Petrone A2, Muglia M3.

1 Institute of Neurological Sciences, National Research Council, 87050, Mangone (Cosenza), Italy.

2 Neurology Unit, Annunziata Hospital, Cosenza, Italy.

3 Institute of Neurological Sciences, National Research Council, 87050, Mangone (Cosenza), Italy. [email protected].



New SPAST HSP mutation identified


Mother and son from South Korea



A 45-year-old male presented with progressive gait impairment that had first appeared several years previously. We performed a genetic study of the patient and his mother, whom he reported as having similar gait difficulty.

Molecular genetic studies revealed that both the patient and his mother had a heterozygous c.1413+4A>G (IVS11+4A>G) variant in SPAST. A reverse-transcription polymerase chain reaction (RT-PCR) revealed an aberrant splicing product, and the skipping of SPAST exon 11 [r.1322_1413del92 (p.Asp441Glyfs*7)] identified as likely pathogenic.

In the present patient we discovered a novel likely pathogenic variant of SPAST causing exon-11 skipping, which may affect the function of the AAA domain.


SOURCE:  J Clin Neurol. 2018 Jan;14:e60.

Novel Pathogenic Variant of SPAST (c.1413+4A>G) in a Patient with Hereditary Spastic Paraplegia.

Yang J#1, Seo JY#2, Lee KW1, Park HM3.

1 Department of Neurology, Gil Medical Center, Gachon University College of Medicine, Incheon, Korea.

2 Department of Laboratory Medicine, Gil Medical Center, Gachon University College of Medicine, Incheon, Korea.

3 Department of Neurology, Gil Medical Center, Gachon University College of Medicine, Incheon, Korea. [email protected].

# Contributed equally



New SPG5 HSP mutation discovered


In first Japanese person with SPG5 HSP



SPG5 is a rare subtype of autosomal recessive hereditary spastic paraplegia caused by a homozygous mutation in the oxysterol-7a-hydroxylase gene, CYP7B1. We describe the first Japanese patient with SPG5 with a novel mutation in the CYP7B1 gene. On exome sequencing, we identified a homozygous frameshift mutation, c.741delA, p.K247fs, in exon 3 of the CYP7B1 gene. The patient showed spastic paraparesis with white matter hyperintensities in the bilateral corona radiata and periventricular and subcortical regions on brain magnetic resonance imaging.

The present study expands the mutation spectrum of CYP7B1 and provides an opportunity to study the genotype-phenotype correlation in SPG5.


SOURCE: Intern Med. 2018 Oct 17. doi: 10.2169/internalmedicine.1839-18. [Epub ahead of print] PMID: 30333426

Exome Sequencing Reveals a Novel Homozygous Frameshift Mutation in the CYP7B1 Gene in a Japanese Patient with SPG5.

Nan H1, Shimozono K1, Ichinose Y1, Tsuchiya M1, Koh K1, Hiraide M2, Takiyama Y1.

1 Department of Neurology, Graduate School of Medical Sciences, University of Yamanashi, Japan.

2 Department of Neurology, Kyonan Hospital, Japan.


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