New HSP genotypes and phenotypes - HSP Research Foundation

Research from South Korea, Finland, China, Spain, Turkey, Bahrain, Japan, Spain, Germany, Poland, Australia, Singapore, France, Taiwan, UK, Italy, India

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.

24 candidate HSP genes identified

Variability in HSP genetics across ethnic groups seems apparent, the more research is done.

This large Korean study of 82 clinically well-defined HSP families identified 88 variants in 54 genes using whole exome data. Whilst 56% (30) were known HSP genes, 44% (24) are candidate HSP genes not previously diagnosed in people with HSP. Regarding inheritance in these families, 48% is sporadic, 40% dominant and 12% recessive.

Abstract

Hereditary Spastic Paraplegias (HSP) are a group of rare inherited neurological disorders characterized by progressive loss of corticospinal motor-tract function. Numerous patients with HSP remain undiagnosed despite screening for known genetic causes of HSP. Therefore, identification of novel genetic variations related to HSP is needed.

In this study, we identified 88 genetic variants in 54 genes from whole-exome data of 82 clinically well-defined Korean HSP families. Fifty-six percent were known HSP genes, and 44% were composed of putative candidate HSP genes involved in the HSPome and originally reported neuron-related genes, not previously diagnosed in HSP patients. Their inheritance modes were 39, de novo; 33, autosomal dominant; and 10, autosomal recessive. Notably, ALDH18A1 showed the second highest frequency.

Fourteen known HSP genes were firstly reported in Koreans, with some of their variants being predictive of HSP-causing protein malfunction. SPAST and REEP1 mutants with unknown function induced neurite abnormality. Further, 54 HSP-related genes were closely linked to the HSP progression-related network. Additionally, the genetic spectrum and variation of known HSP genes differed across ethnic groups. These results expand the genetic spectrum for HSP and may contribute to the accurate diagnosis and treatment for rare HSP.

SOURCE: Genomics. 2021 Oct 27;113(6):4136-4148. doi: 10.1016/j.ygeno.2021.10.014. Online ahead of print. PMID: 34715294 Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

The emerging genetic diversity of hereditary spastic paraplegia in Korean patients

Jin Ok Yang 1 , Ji-Yong Yoon 2 , Duk Hyun Sung 3 , Sohyun Yun 2 , Jeong-Ju Lee 2 , Soo Young Jun 2 , Debasish Halder 2 , Su-Jin Jeon 4 , Eui-Jeon Woo 5 , Jin Myoung Seok 6 , Jin Whan Cho 7 , Ja-Hyun Jang 8 , Jung Kyoon Choi 9 , Byoung Joon Kim 10 , Nam-Soon Kim 11

1. Korea BioInformation Center (KOBIC), Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea; Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea.

2. Rare-disease Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea.

3. Department of Physical and Rehabilitation Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.

4. Rare-disease Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea; Department of Functional Genomics, University of Science and Technology (UST), Daejeon, Republic of Korea.

5. Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea; Department of Analytical Bioscience, University of Science and Technology (UST), Daejeon, Republic of Korea.

6. Department of Neurology, Soonchunhyang University College of Medicine, Soonchunhyang University Hospital Cheonan, Cheonan, Republic of Korea.

7. Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.

8. Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.

9. Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea.

10 Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.

11. Rare-disease Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea; Department of Functional Genomics, University of Science and Technology (UST), Daejeon, Republic of Korea.

Clinical exome sequencing cost-effective

Can significantly shorten time to confirmed diagnosis

This study established the cost effectiveness of using clinical exome sequencing (CES) as a first-choice diagnostic tool for people with difficult-to-diagnose neurological symptoms. In this study of 100 such people, CES yielded 27 diagnoses, with known variants in 14 cases and new, likely pathogenic variants in 13, across a range of conditions. An added advantage is the significant reduction in time getting a definitive diagnosis.

Objectives: Clinical diagnostics in adults with hereditary neurological diseases is complicated by clinical and genetic heterogeneity, as well as lifestyle effects. Here, we evaluate the effectiveness of exome sequencing and clinical costs in our difficult-to-diagnose adult patient cohort. Additionally, we expand the phenotypic and genetic spectrum of hereditary neurological disorders in Finland.

Methods: We performed clinical exome sequencing (CES) to 100 adult patients from Finland with neurological symptoms of suspected genetic cause. The patients were classified as myopathy (n = 57), peripheral neuropathy (n = 16), ataxia (n = 15), spastic paraplegia (n = 4), Parkinsonism (n = 3), and mixed (n = 5). In addition, we gathered the costs of prior diagnostic work-up to retrospectively assess the cost-effectiveness of CES as a first-line diagnostic tool.

Results: The overall diagnostic yield of CES was 27%. Pathogenic variants were found for 14 patients (in genes ANO5, CHCHD10, CLCN1, DES, DOK7, FKBP14, POLG, PYROXD1, SCN4A, TUBB3, and TTN) and likely pathogenic previously undescribed variants for 13 patients (in genes ABCD1, AFG3L2, ATL1, CACNA1A, COL6A1, DYSF, IRF2BPL, KCNA1, MT-ATP6, SAMD9L, SGCB, and TPM2). Age of onset below 40 years increased the probability of finding a genetic cause. Our cost evaluation of prior diagnostic work-up suggested that early CES would be cost-effective in this patient group, in which diagnostic costs increase linearly with prolonged investigations.

Conclusions: Based on our results, CES is a cost-effective, powerful first-line diagnostic tool in establishing the molecular diagnosis in adult neurological patients with variable symptoms. Importantly, CES can markedly shorten the diagnostic odysseys of about one third of patients.

Effectiveness of clinical exome sequencing in adult patients with difficult-to-diagnose neurological disorders

Markus T Sainio 1 , Juho Aaltio 1 , Virva Hyttinen 2 3 , Mika Kortelainen 2 4 , Simo Ojanen 5 , Anders Paetau 6 , Pentti Tienari 7 8 , Emil Ylikallio 1 7 , Mari Auranen 7 , Henna Tyynismaa 1 9 10

1. Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.

2. VATT Institute for Economic Research, Helsinki, Finland.

3. Department of Health and Social Management, University of Eastern Finland, Kuopio, Finland.

4. Department of Economics, Turku School of Economics, Turku, Finland.

5. Department of Veterinary Biosciences, Faculty of Veterinary Medicine, University of Helsinki, Helsinki, Finland.

6. Department of Pathology, HUSLAB and University of Helsinki, Helsinki, Finland.

7. Clinical Neurosciences, Neurology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

8. Translational Immunology Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.

9. Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland.

10. Neuroscience Center, Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland.

Emergence of dominant or sporadic SPG18 cases

Implications for gene testing and clinical practice

Objective: Hereditary spastic paraplegia (HSP) due to ERLIN2 gene mutations was designated as spastic paraplegia 18 (SPG18). To date, SPG18 families/cases are still rarely reported. All early reported cases shared the autosomal recessive (AR) inheritance pattern. Over the past 3 years, autosomal dominant (AD) or sporadic SPG18 cases had been continuously reported. Here, we reported the clinical and genetic features of the first autosomal dominant SPG18 pedigree in Chinese.

Methods: We conducted detailed medical history inquiry, neurological examinations of the proband and his family members, and charted the family tree. The proband underwent brain and cervical magnetic resonance imaging (MRI), electromyography (EMG), and whole exome sequencing. Sanger sequencing was performed to verify the genetic variation in the proband and some family members. A literature review of all reported SPG18 families/cases was carried out to summarize the clinical-genetic characteristics of SPG18 under different inheritance patterns.

Results: Four patients were clinically diagnosed as chronic spastic paraplegia in three consecutive generations with the autosomal dominant inheritance model. All the patients presented juvenile-adolescent onset and gradually worsening pure HSP phenotype. Clinical phenotypes were consistent within the family. Whole exome sequencing in the proband identified a previously reported heterozygous c.502G > A (p.V168M) mutation in exon 8 of ERLIN2 gene. This mutation was cosegregated with the phenotype in the family and was classified as likely pathogenic according to American College of Medical Genetics and Genomics (ACMG) guidelines. To date, eight AR-SPG18 families, five AD-SPG18 families, and three sporadic cases had been reported. Clinical phenotype of AD-SPG18 was juvenile-adolescent onset pure HSP, while the phenotype of AR-SPG18 was mostly complicated HSP with earlier onset and more severe conditions. In rare cases, the initial spastic paraplegia could evolve to rapidly progressive amyotrophic lateral sclerosis (ALS).

Conclusions: We reported the first autosomal dominant SPG18 pedigree in Chinese Han population, which added more pathogenic evidence for V168M mutation. As more SPG18 cases reported, the essentials of SPG18 need to be updated in clinical practice. Special attentions should be given in gene test for upper motor neuron disorders in case of missing heterozygous mutations in ERLIN2.

More autosomal dominant SPG18 cases than recessive? The first AD-SPG18 pedigree in Chinese and literature review

Shuai Chen 1 2 , Jin-Long Zou 1 2 , Shuang He 1 2 , Wei Li 1 , Jie-Wen Zhang 1 , Shu-Jian Li 1 2

1. Department of Neurology, Zhengzhou University People’s Hospital (Henan Provincial People’s Hospital), Zhengzhou, China.

2. Department of Neurology, Henan University People’s Hospital, Zhengzhou, China.

14 new variants found in 25 cases of HSP

Data supports the spasticity-ataxia phenotype (SAP) spectrum

Introduction: Hereditary spastic paraplegias (HSPs), a genetically heterogeneous group of neurodegenerative diseases, have an incidence of around 3 to 9 individuals every 100,000. Due to the broad clinical and genetic variability of HSPs, it is challenging to diagnose the disorder quickly and precisely. Hereditary spastic ataxias (HSAs) and HSPs are overlapping diseases, and their intersection has been gradually identified by next-generation sequencing. The idea of the spasticity-ataxia phenotype (SAP) spectrum is further substantiated by the similarities in phenotypes and underlying genes in ataxias and inherited spastic paraplegias and the related cellular processes and disease mechanisms these disorders exhibit.

Methods: Whole-exome sequencing was performed on the 25 spastic or spastic-ataxic gait patients.

Results: Twenty-two specific HSPs-HSAs-SAP mutations, including 14 novel mutations, were found in 25 cases from 18 Turkish and 2 Syrian families. This research discovers many novel hereditary spastic paraplegia (HSP) mutations and shows a robust genotype-phenotype heterogeneity in the disease.

Conclusions: This research helped expand the clinical and molecular scope of HSP and clarified the concept of the spasticity-ataxia phenotype, further enhancing our understanding of the complicated form of HSP and its association with ataxia. Our data broadens the spectrum of HSPs and HSAs related gene mutations and provides insights for genotype-phenotype correlations for HSPs and HSAs.

Hereditary spastic paraplegia: new insights into clinical variability and spasticity-ataxia phenotype, and novel mutations

Ibrahim Sahin 1 2 , Hanife Saat 3

1. Department of Medical Genetics, University of Health Sciences, Dışkapı Yıldırım Beyazıt Training and Research Hospital, Ankara, Turkey.

2. Department of Molecular Medicine, College of Medicine and Medical Sciences, Arabian Gulf University, Manama, Bahrain.

3. Department of Medical Genetics, University of Health Sciences, Dışkapı Yıldırım Beyazıt Training and Research Hospital, Ankara, Turkey.

6 adults with HSP found to have LYST gene variants

This study in Japan of 387 people with HSP identified six adults with variants in the LYST gene that is responsible for Chédiak-Higashi syndrome, where spastic paraplegia has rarely been reported.

Abstract

Hereditary spastic paraplegias (HSPs) comprise a group of neurodegenerative disorders characterized by weakness and leg spasticity. LYST is responsible for Chédiak-Higashi syndrome (CHS), which exhibits partial oculocutaneous albinism, primary immunodeficiency, and bleeding tendency in childhood. Although neurological symptoms of CHS also appear in adulthood, a phenotype of spastic paraplegia has rarely been reported in CHS.

In this study, we investigated LYST mutations in 387 HSP patients through the Japan Spastic Paraplegia Research Consortium to clarify the frequency of LYST mutations in HSP, finding six adult patients with LYST mutations in four HSP families. They exhibited intellectual disability, cerebellar ataxia, neuropathy, and pyramidal signs. Meanwhile, only 15 patients with CHS in childhood have been revealed in a decade by a nationwide survey in Japan. Thus, LYST mutations might indicate a HSP phenotype in a considerable number of adult patients with CHS.

Chédiak-Higashi syndrome presenting as a hereditary spastic paraplegia

Kishin Koh 1 , Mai Tsuchiya 1 , Hiroyuki Ishiura 2 , Haruo Shimazaki 3 4 , Takeshi Nakamura 5 , Hideo Hara 6 , Kohei Suzuyama 6 , Makio Takahashi 7 , Shoji Tsuji 8 9 , Yoshihisa Takiyama 10 , Japan Spastic Paraplegia Research Consortium

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

2. Department of Neurology, The University of Tokyo, Tokyo, Japan.

3. Faculty of Health & Medical Care, Saitama Medical University, Saitama, Japan.

4. Department of Neurology, Saitama Medical University Hospital, Saitama, Japan.

5. Department of Neurology, Kyoto Takeda Hospital, Kyoto, Japan.

6. Division of Neurology, Department of Internal Medicine, Saga University Faculty of Medicine, Saga, Japan.

7. Department of Neurology, Kitano Hospital Medical Research Institute, The Tazuke-Kofukai, Osaka, Japan.

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

9. Institute of Medical Genomics, International University of Health and Welfare, Chiba, Japan.

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

2 new SPG7 variants found

This study of 21 people with SPG7 established a mean age of onset at 37 years, with 57% showing spastic ataxia, 19% pure HSP and 19% complex cases.

Abstract

Spastic paraplegia type 7 (SPG7) is one of the most common hereditary spastic paraplegias. SPG7 mutations most often lead to spastic paraparesis (HSP) and/or hereditary cerebellar ataxia (HCA), frequently with mixed phenotypes. We sought to clinically and genetically characterize a Spanish cohort of SPG7 patients. Patients were recruited from our HCA and HSP cohorts.

We identified twenty-one patients with biallelic pathogenic SPG7 mutations. Mean age at onset was 37.4 years (SD ± 14.3). The most frequent phenotype was spastic ataxia (57%), followed by pure spastic paraplegia (19%) and complex phenotypes (19%). Isolated patients presented with focal or multifocal dystonia, subclinical myopathy or ophthalmoplegia. p.Ala510Val was the most frequent pathogenic variant encountered. Compound heterozygous for p.Ala510Val displayed younger onset (p < 0.05) and more complex phenotypes (p < 0.05) than p.Ala510Val homozygotes. Two novel variants were found: p.Lys559Argfs*33 and p.Ala312Glu.

In conclusion, spastic ataxia is the most common phenotype found in Spanish patients. Nonetheless, SPG7 analysis should also be considered in patients with less frequent clinical findings such as dystonia or ophthalmoplegia especially when these symptoms are associated with mild spastic ataxia.

Clinical and genetic characteristics of 21 Spanish patients with biallelic pathogenic SPG7 mutations

Raquel Baviera-Muñoz 1 , Marina Campins-Romeu 2 , Lidón Carretero-Vilarroig 3 , Isabel Sastre-Bataller 2 , Irene Martínez-Torres 2 , Juan F Vázquez-Costa 4 , Nuria Muelas 1 , Teresa Sevilla 5 , Juan J Vílchez 6 , Elena Aller 7 , Teresa Jaijo 7 , Luis Bataller 8 , Carmen Espinós 9

1. Department of Neurology, Hospital Universitari I Politècnic La Fe, Valencia, Spain; Neuromuscular and Ataxias Research Group, Instituto de Investigación Sanitaria La Fe, Valencia, Spain; Rare Diseases Joint Unit, CIPF-IIS La Fe, Valencia, Spain.

2. Department of Neurology, Hospital Universitari I Politècnic La Fe, Valencia, Spain; Rare Diseases Joint Unit, CIPF-IIS La Fe, Valencia, Spain.

3. Neuromuscular and Ataxias Research Group, Instituto de Investigación Sanitaria La Fe, Valencia, Spain; Rare Diseases Joint Unit, CIPF-IIS La Fe, Valencia, Spain; Cell Biology Department, University of Valencia, Valencia, Spain.

4. Department of Neurology, Hospital Universitari I Politècnic La Fe, Valencia, Spain; Neuromuscular and Ataxias Research Group, Instituto de Investigación Sanitaria La Fe, Valencia, Spain; Rare Diseases Joint Unit, CIPF-IIS La Fe, Valencia, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Spain.

5. Department of Neurology, Hospital Universitari I Politècnic La Fe, Valencia, Spain; Neuromuscular and Ataxias Research Group, Instituto de Investigación Sanitaria La Fe, Valencia, Spain; Rare Diseases Joint Unit, CIPF-IIS La Fe, Valencia, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Spain; Department of Medicine, University of Valencia, Valencia, Spain.

6. Neuromuscular and Ataxias Research Group, Instituto de Investigación Sanitaria La Fe, Valencia, Spain; Rare Diseases Joint Unit, CIPF-IIS La Fe, Valencia, Spain; Department of Medicine, University of Valencia, Valencia, Spain.

7. Rare Diseases Joint Unit, CIPF-IIS La Fe, Valencia, Spain; Department of Medicine, University of Valencia, Valencia, Spain; Department of Genetics, Hospital Universitari I Politècnic La Fe, Valencia, Spain.

8. Department of Neurology, Hospital Universitari I Politècnic La Fe, Valencia, Spain; Neuromuscular and Ataxias Research Group, Instituto de Investigación Sanitaria La Fe, Valencia, Spain; Rare Diseases Joint Unit, CIPF-IIS La Fe, Valencia, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Spain; Department of Medicine, University of Valencia, Valencia, Spain.

9. Rare Diseases Joint Unit, CIPF-IIS La Fe, Valencia, Spain; Department of Medicine, University of Valencia, Valencia, Spain; Laboratory of Rare Neurodegenerative Diseases, Centro de Investigación Príncipe Felipe (CIPF), Valencia, Spain.

Mutational hotspot associated with both SPG9A and CMT1A

A Japanese family includes five members with HSP type SPG9A and five members with Charcot-Marie-Tooth disease type 1A. The ALDH18A1 gene involved might easily undergo mutation with the HSP causing mutation newly occurring in the fourth-generation, with the particular mutation type having been found before in other families.

Background: ALDH18A1 mutations lead to delta-1-pyrroline-5-carboxylate-synthetase (P5CS) deficiency, which is a urea cycle-related disorder including SPG9A, SPG9B, autosomal dominant cutis laxa-3 (ADCL3), and autosomal recessive cutis laxa type 3A (ARCL3A). These diseases exhibit a broad clinical spectrum, which makes the diagnosis of P5CS deficiency difficult. We report here a rare Japanese family including both patients with an ALDH18A1 mutation (SPG9A) and ones with CMT1A.

Case presentation: A Japanese family included five patients with the CMT phenotype and five with the HSP phenotype in four generations. The patients with the HSP phenotype showed a pure or complicated form, and intrafamilial clinical variability was noted. Genetically, FISH analysis revealed that two CMT patients had a PMP22 duplication (CMT1A). Exome analysis and Sanger sequencing revealed five HSP patients had an ALDH18A1 heterozygous mutation of c.755G > A, which led to SPG9A. Haplotype analysis revealed that the ALDH18A1 mutation must have newly occurred. To date, although de novo mutations of ALDH18A1 have been described in ADCL3A, they were not mentioned in SPG9A in earlier reports. Thus, this is the first SPG9A family with a de novo mutation or the new occurrence of gonadal mosaicism of ALDH18A1. Analysis of serum amino acid levels revealed that two SPG9A patients and two unaffected family members had low citrulline levels and one had a low level of ornithine.

Conclusions: Since the newly occurring ALDH18A1 mutation, c.755G > A, is the same as that in two ADHSP families and one sporadic patient with SPG9A reported previously, this genomic site might easily undergo mutation. The patients with the c.755G > A mutation in our family showed clinical variability of symptoms like in the earlier reported two families and one sporadic patient with this mutation. Further studies are required to clarify the relationship between the amino acid levels and clinical manifestations, which will reveal how P5CS deficiency influences disease phenotypes including ARCL3A, ADCL3, SPG9B, and SPG9A.

SOURCE: BMC Neurol. 2021 Feb 11;21(1):64. doi: 10.1186/s12883-021-02087-x. PMID: 33573605

SPG9A with the new occurrence of an ALDH18A1 mutation in a CMT1A family with PMP22 duplication: case report

Kishin Koh 1 , Ryusuke Takaki 1 2 , Hiroyuki Ishiura 3 , Shoji Tsuji 4 5 , Yoshihisa Takiyama 6

1. Department of Neurology, Graduate School of Medical Sciences, University of Yamanashi, Yamanashi, 409-3898, Japan.

2. Department of Neurology, Iida Hospital, Nagano, 395-8505, Japan.

3. Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan.

4. Department of Molecular Neurology, University of Tokyo, Graduate School of Medicine, Tokyo, 113-8655, Japan.

5. Department of Neurology, International University of Health and Welfare, Chiba, 286-8686, Japan.

6. Department of Neurology, Graduate School of Medical Sciences, University of Yamanashi, Yamanashi, 409-3898, Japan.

New SPG23 variant discovered

Urinary problems the first sign

Introduction: DSTYK encodes dual serine/threonine and tyrosine protein kinase. DSTYK has been associated with autosomal-dominant congenital anomalies of the kidney and urinary tract and with autosomal-recessive hereditary spastic paraplegia type 23. Here, we report a father and his two dizygotic twin sons carrying a novel heterozygous missense variant in DSTYK, presenting with early onset lower urinary tract dysfunction due to dysfunctional voiding. Moreover, in the later course of the disease, both sons presented with bilateral spasticity in their lower limbs, brisk reflexes, and absence seizures.

Materials and methods: Exome sequencing in the affected father and his affected sons was performed. The sons presented clinically with urinary hesitancy, dysfunctional voiding, and night incontinence till adolescence, while the father reported difficulty in voiding. In the sons, cystoscopy excluded urethral valves and revealed hypertrophy of the bladder neck and trabeculated bladder. Additionally, both sons were diagnosed with absence epilepsy in early childhood. Filtering of exome data focused on rare (MAF < 0.01%), autosomal-dominant variants, predicted to be deleterious, residing in highly conserved regions of the exome.

Results: Exome analysis identified a novel, heterozygous missense variant (c.271C>A (p.Leu91Met)) in DSTYK segregating with the disease. In silico prediction analyses uniformly rated the variant to be deleterious suggesting the variant to be disease-causing in the family.

Conclusion: To the best of our knowledge, this is the first report of early onset dysfunctional voiding, seizures, and bilateral spasticity of the lower limbs associated with a novel heterozygous dominant missense variant in DSTYK.

Exome sequencing implicates a novel heterozygous missense variant in DSTYK in autosomal dominant lower urinary tract dysfunction and mild hereditary spastic paraparesis

Clara Vidic# 1 , Marcin Zaniew # 2 , Szymon Jurga 3 , Holger Thiele 4 , Heiko Reutter 5 , Alina C Hilger 6 7

1. Institute of Human Genetics, University of Bonn, Bonn, Germany.

2. Department of Pediatrics, University of Zielona Góra, Zielona Góra, Poland.

3. Department of Neurology, University of Zielona Góra, Zielona Góra, Poland.

4. Cologne Center for Genomics, University of Cologne, Cologne, Germany.

5. Department of Neonatology and Paediatric Intensive Care, University Hospital Erlangen, Erlangen, Germany.

6. Institute of Human Genetics, University of Bonn, Bonn, Germany.

7. Department of Pediatrics, Children’s Hospital, University of Bonn, Bonn, Germany.

# Contributed equally.

HSP mimic in children

Particular variant in the ADAR gene responsible

Background: The type 1 interferonopathy, Aicardi-Goutières syndrome 6 (AGS6), is classically caused by biallelic ADAR mutations whereas dominant ADAR mutations are associated with dyschromatosis symmetrica hereditaria (DSH). The unique dominant ADAR c.3019G>A variant is associated with neurological manifestations which mimic spastic paraplegia and cerebral palsy (CP).

Case summaries: We report three cases of spastic paraplegia or CP diagnosed with AGS6 caused by the ADAR c.3019G>A variant. Two children inherited the variant from an asymptomatic parent, and each child had a different clinical course. The youngest case demonstrated relentless progressive symptoms but responded to immunomodulation using steroids and ruxolitinib.

Conclusion: The ADAR c.3019G>A variant has incomplete penetrance and is a likely underrecognized imitator of spastic paraplegia and dystonic CP. A high level of clinical suspicion is required to diagnose this form of AGS, and disease progression may be ameliorated by immunomodulatory treatment with selective Janus kinase inhibitors.

SOURCE: Brain Dev. 2021 Oct 23;S0387-7604(21)00185-6. doi: 10.1016/j.braindev.2021.10.001. Online ahead of print. PMID: 34702576 Copyright © 2021 The Japanese Society of Child Neurology. All rights reserved.

Autosomal dominant ADAR c.3019G>A (p.(G1007R)) variant is an important mimic of hereditary spastic paraplegia and cerebral palsy

Hannah F Jones 1 , Marion Stoll 2 , Gladys Ho 3 , Dugald O’Neill 4 , Velda X Han 5 , Simon Paget 6 , Kirsty Stewart 6 , Jennifer Lewis 6 , Kavitha Kothur 4 , Christopher Troedson 4 , Yanick J Crow 7 , Russell C Dale 8 , Shekeeb S Mohammad 9

1. Neurology Department, The Children’s Hospital at Westmead Clinical School, Faculty of Medicine and Health, University of Sydney, New South Wales, Australia; Starship Hospital, Centre for Brain Research, Faculty of Medical and Health Sciences, University of Auckland, New Zealand.

2. Molecular Medicine Laboratory, Concord Repatriation General Hospital, NSW Health Pathology, Australia.

3. Molecular Genetics Department, The Children’s Hospital at Westmead, Australia; Discipline of Child & Adolescent Health, University of Sydney, Sydney, New South Wales 2006, Australia; Discipline of Genetic Medicine, University of Sydney, Sydney, New South Wales 2006, Australia.

4. Neurology Department, The Children’s Hospital at Westmead Clinical School, Faculty of Medicine and Health, University of Sydney, New South Wales, Australia.

5. Khoo-Teck Puat-National University Children’s Medical Institute, National University Health System, Singapore.

6. Kids Rehab, The Children’s Hospital at Westmead, New South Wales, Australia.

7. MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom; Laboratory of Neurogenetics and Neuroinflammation, Institute Imagine, Université de Paris, Paris, France.

8. Neurology Department, The Children’s Hospital at Westmead Clinical School, Faculty of Medicine and Health, University of Sydney, New South Wales, Australia; Discipline of Child & Adolescent Health, University of Sydney, Sydney, New South Wales 2006, Australia.

9. Neurology Department, The Children’s Hospital at Westmead Clinical School, Faculty of Medicine and Health, University of Sydney, New South Wales, Australia; Discipline of Child & Adolescent Health, University of Sydney, Sydney, New South Wales 2006, Australia.

Unknown genetic causes of suspected HSP

ABCD1 gene worth checking

Background: Adrenoleukodystrophy (ALD) is an X-linked peroxisomal disorder caused by mutations in the ABCD1 gene. The clinical manifestations of ALD vary widely with some patients presenting with adrenomyeloneuropathy (AMN) that resembles the phenotype of hereditary spastic paraplegia (HSP). The aim of this study is to investigate the frequency, spectrum, and clinical features of ABCD1 mutations in Taiwanese patients with HSP phenotype.

Methods: Mutational analysis of the ABCD1 gene was performed in 230 unrelated Taiwanese patients with clinically suspected HSP by targeted resequencing. Clinical, electrophysiological, and neuroimaging features of the patients carrying an ABCD1 pathogenic mutation were characterized.

Results: Ten different ABCD1 mutations were identified in eleven patients, including two novel mutations (p.Q177Pfs*17 and p.Y357*) and eight ever reported in ALD cases of other ethnicities. All patients were male and exhibited slowly progressive spastic paraparesis with onset ages ranging from 21 to 50 years. Most of them had additional non-motor symptoms, including autonomic dysfunction in nine patients, sensory deficits in seven, premature baldness in seven, skin hyperpigmentation in five, psychiatric symptoms in one and cerebellar ataxia in one. Seven of the ten patients who ever received nerve conduction studies showed axonal polyneuropathy. Magnetic resonance imaging (MRI) revealed diffuse spinal cord atrophy in seven patients, cerebral white matter hyperintensity in one patient, and cerebellar involvement in one patient.

Conclusions: ABCD1 mutations account for 4.8% (11/230) of the cases with HSP phenotype in Taiwan. This study highlights the importance to consider ABCD1 mutations in patients with clinically suspected HSP of unknown genetic causes.

Investigating ABCD1 mutations in a Taiwanese cohort with hereditary spastic paraplegia phenotype

Shao-Lun Hsu 1 , Ying-Hao Chen 2 , Cheng-Ta Chou 3 , Ying-Tsen Chou 4 , Yu-Shuen Tsai 5 , Cheng-Tsung Hsiao 1 , Yi-Chu Liao 6 , Yi-Chung Lee 7

1. Department of Neurology, Taipei Veterans General Hospital, Taipei, Taiwan; Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.

2. Department of Neurology, Ditmanson Medical Foundation Chia-Yi Christian, Hospital, Taiwan.

3. Department of Neurology, Neurological Institute, Taichung Veterans General Hos-pital, Taichung, Taiwan.

4. Department of Neurology, Taipei Veterans General Hospital, Taipei, Taiwan.

5. Center for Systems and Synthetic Biology, National Yang Ming Chiao Tung University, Taipei, Taiwan.

6. Department of Neurology, Taipei Veterans General Hospital, Taipei, Taiwan; Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan; Brain Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan.

7. Department of Neurology, Taipei Veterans General Hospital, Taipei, Taiwan; Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan; Brain Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan.

New SPTAN1 variant associated with complicated HSP

Both pure and complicated HSP now linked with recessive inheritance of SPTAN1 gene mutations

Abstract

Heterozygous mutations in SPTAN1 are associated with a broad phenotypical spectrum ranging from axonal neuropathy phenotypes to neurodevelopmental phenotypes with or without epilepsy. Recently, biallelic mutations in SPTAN1 were reported as a potential cause of autosomal recessive pure hereditary spastic paraplegia (HSP). However, no further HSP cases with biallelic SPTAN1 mutations have been reported.

Herein, we report the clinical and genetic findings of a patient with complicated HSP likely caused by a novel homozygous SPTAN1 mutation. A patient with complicated HSP from a consanguineous family was recruited. The proband underwent detailed neurological examinations. Homozygosity mapping was performed in the proband and her healthy sister. Whole exome sequencing was performed in the proband. Our patient had early onset motor symptoms with upper motor neuron paralysis and intellectual disability, which is compatible with complicated HSP. Genetic analysis identified a rare homozygous missense mutation in SPTAN1 (c.4162A>G, p.I1388V), which was predicted to be deleterious by in silico tools. Her healthy parents and sister all carried the heterozygous mutation. Our results provided further support for the association of biallelic SPTAN1 variants with HSP and suggested that screening for the SPTAN1 gene should be considered not only in patients with pure HSP but also in patients with complicated HSP.

SPTAN1 variants likely cause autosomal recessive complicated hereditary spastic paraplegia

Fei Xie 1 2 , Shuqi Chen 2 , Peng Liu 2 , Xinhui Chen 2 , Wei Luo 3

1. Department of Neurology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.

2. Department of Neurology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.

3. Department of Neurology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.

New SPG7 mutation linked to early onset degenerative parkinsonism

Abstract

A 43-year-old man presented with ataxia and stiffness of lower limbs for approximately the last 10 years. The clinical examination revealed bilateral parkinsonism. The magnetic resonance imaging of the brain and spine showed no structural abnormality to explain his symptoms. However, the dopamine transporter scan showed abnormal tracer uptake in both basal ganglia, suggestive of degenerative parkinsonism.

The next generation sequencing of spastic paraparesis gene panel revealed a probably pathogenic novel mutation in the SPG7 gene. Though the exact mechanism of parkinsonism in SPG7 mutation is unclear, mitochondrial dysfunction and oxidative stress seem to play a key role. SPG7 mutation should be considered as a cause of early onset degenerative parkinsonism when no alternative explanation can be found.

SOURCE: Neurol India. Jul-Aug 2021;69(4):1051-1052. doi: 10.4103/0028-3886.325330. PMID: 34507444

Early Onset Degenerative Parkinsonism – Consider SPG7 Mutation

Shakya Bhattacharjee 1 , Muhammad Noushad 1 , Martin Sadler 1

1. Department of Neurology, Plymouth Hospital NHS Trust, Plymouth, United Kingdom.

Sporadic SPAST variant causing infantile-onset, complicated HSP

16 other cases with the same variant have been reported, with variable phenotype.

Background: Spastic paraplegia type 4 (SPG4) is caused by mutations in the SPAST gene, is the most common form of autosomal-dominant pure hereditary spastic paraplegias (HSP), and is rarely associated with a complicated form that includes ataxia, epilepsy, and cognitive decline. To date, the genotype-phenotype correlation has not been substantially established for SPAST mutations.

Case presentation: We present a Japanese patient with infantile-onset HSP and a complex form with coexisting ataxia and epilepsy. The sequencing of SPAST revealed a de novo c.1496G > A (p.R499H) mutation. A review of the literature revealed 16 additional patients with p.R499H mutations in SPAST associated with an early-onset complicated form of HSP. We found that the complicated phenotype of patients with p.Arg499His mutations could be mainly divided into three subgroups: (1) infantile-onset ascending hereditary spastic paralysis, (2) HSP with severe dystonia, and (3) HSP with cognitive impairment. Moreover, the c.1496G > A mutation in SPAST may occur as a de novo variant at noticeably high rates.

Conclusion: We reviewed the clinical features of the patients reported in the literature with the p.Arg499His mutation in SPAST and described the case of a Japanese patient with this mutation presenting a new complicated form. Accumulating evidence suggests a possible association between infantile-onset complicated HSP and the p.Arg499His mutation in SPAST. The findings of this study may expand the clinical spectrum of the p.Arg499His mutation in SPAST and provide an opportunity to further study the genotype-phenotype correlation of SPG4.

A p.Arg499His mutation in SPAST is associated with infantile-onset complicated spastic paraplegia: a case report and review of the literature

Haitian Nan 1 , Hiroshi Shiraku 2 , Tomoko Mizuno 3 , Yoshihisa Takiyama 4

1. Department of Neurology, Graduate School of Medical Sciences, University of Yamanashi, Yamanashi, 409-3898, Japan.

2. Department of Pediatrics, JA Toride Medical Center, Ibaraki, 302-0022, Japan.

3. Department of Pediatrics, Tokyo Medical and Dental University, Tokyo, 113-8510, Japan.

4. Department of Neurology, Graduate School of Medical Sciences, University of Yamanashi, Yamanashi, 409-3898, Japan.

New SPG6 mutation discovered

Sporadic case in a 39-year-old

Abstract

SPG6 accounts for 1% of autosomal dominant Hereditary Spastic Paraplegia (HSP) and is caused by pathogenic variants in NIPA1, which encodes a magnesium transporter located in plasma membrane and early endosomes, implicated in neuronal development and maintenance.

Here we report a 39-year-old woman affected by progressive gait disturbance associated to absence seizures episodes within childhood. Clinical exome sequencing identified a likely pathogenic de novo heterozygous variant in NIPA1 (NM_144599.5 c.249 C > G; p.Asn83Lys). Molecular modelling was performed to evaluate putative functional consequence of the NIPA1 protein. Indeed, the Asn83Lys modification is predicted to induce a significant perturbation of the protein structure, altering signal transduction or small-molecule transport by modulating the length of the second transmembrane domain.

This is the first study reporting a SPG6-affected patient harboring the NIPA1 p.Asn83Lys mutation.

SOURCE: J Hum Genet. 2021 Jun 9. doi: 10.1038/s10038-021-00941-x. Online ahead of print. PMID: 34108639

A novel de novo NIPA1 missense mutation associated to hereditary spastic paraplegia

Dora Fabbro 1 , Catia Mio 2 , Federico Fogolari 3 , Giuseppe Damante 1 4

1. Istituto di Genetica Medica, Azienda Sanitaria Universitaria Friuli Centrale, Udine, Italy.

2. Dipartimento di Area Medica, Università degli Studi di Udine, Udine, Italy.

3. Dipartimento di Scienze Matematiche, Informatiche e Fisiche, Università degli Studi di Udine, Udine, Italy.

4. Dipartimento di Area Medica, Università degli Studi di Udine, Udine, Italy.

2 new variants found causing AR SPG9B

SPG9B in the family involved had milder symptoms, later onset and without cognitive impairment, in contrast to SPG9A.

SPG9A is autosomal dominant (AD) causing complicated HSP. SPG9B can be either autosomal dominant or autosomal recessive (AR) causing pure or complicated forms of HSP respectively.

Background: Hereditary spastic paraplegia (HSP) caused by mutations in ALDH18A1 have been reported as spastic paraplegia 9 (SPG9), with autosomal dominant and autosomal recessive transmission (SPG9A and SPG9B). SPG9 is rare and has shown phenotypic and genotypic heterogeneity in previous reports.

Methods: This study screened ALDH18A1 mutations in autosomal recessive HSP patients using combined whole exome sequencing and RNA splicing analysis. We conducted in silico investigations, co-segregation analysis, and ELISA-based analysis of P5CS (Δ1-pyrroline-5-carboxylate synthetase; encoded by ALDH18A1) concentration to validate the pathogenicity of the detected ALDH18A1 variants. All previously reported bi-allelic ALDH18A1 mutations and cases were reviewed to summarize the genetic and clinical features of ALDH18A1-related HSP.

Results: A novel missense mutation c.880T>C, p.S294P and an intronic splicing mutation c.-28-13A>G were both detected in ALDH18A1 in an autosomal recessive family presenting with a complicated form of HSP. ELISA assays revealed significantly decreased P5CS concentration in the proband’s plasma compared with that in the healthy controls. Moreover, review of previously reported recessive cases showed that SPG9B patients in our cohort presented with milder symptoms, i.e., later age at onset and without cognitive impairment.

Conclusion: The present study expands the genetic and clinical spectrum of SPG9B caused by ALDH18A1 mutation. Our work defines new genetic variants to facilitate future diagnoses, in addition to demonstrating the highly informative value of splicing mutation prediction in the characterization of disease-related intronic variants.

SOURCE: Front Neurol. 2021 May 19;12:627531. doi: 10.3389/fneur.2021.627531. eCollection 2021. PMID: 34093392 Copyright © 2021 Chen, Zhang, Wang, Qiu, Yuan, Dong, Zhao, Zhou, Wang, Chen and Lin.

Novel Compound Missense and Intronic Splicing Mutation in ALDH18A1 Causes Autosomal Recessive Spastic Paraplegia

Yi-Jun Chen 1 , Zai-Qiang Zhang 2 , Meng-Wen Wang 1 , Yu-Sen Qiu 1 , Ru-Ying Yuan 1 , En-Lin Dong 1 , Zhe Zhao 3 , Hai-Tao Zhou 4 , Ning Wang 1 5 , Wan-Jin Chen 1 5 , Xiang Lin 1 5

1. Department of Neurology and Institute of Neurology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China.

2. Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.

3. Department of Neuromuscular Disorders, The Third Hospital of Hebei Medical University, Shijiazhuang, China.

4. Department of Neurology, Luoyang Central Hospital Affiliated to Zhengzhou University, Luoyang, China.

5. Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, China.

A case of SPG51 in a newborn

Severe form of this complicated HSP type associated with a newly identified mutation.

Background: Autosomal recessive mutations in the AP-4 (adaptor protein complex 4) complex subunit ϵ – 1 (AP-4E1) gene on chromosome 15q21.2 are known to cause spastic paraplegia 51 (SPG51). The exact phenotype of SPG51 remains poorly characterized, because only a few families have been reported as carriers of the mutation. In addition, a previous study identified an autosomal dominant mutation in the AP4E1 gene as being associated with persistent stuttering. The aim of the current study was to characterize the phenotype of a paediatric patient with an identified novel AP4E1 mutation presenting with significant psychomotor retardation, intellectual disability and paraplegia.

Methods: Magnetic resonance imaging was used to identify hypoplasia of the corpus callosum. The DNA sample was tested using multiplex ligation-dependent probe amplification (MLPA) and array comparative genomic hybridization (aCGH). In addition, next-generation sequencing (NGS) was performed using the patient’s DNA, and Sanger sequencing was performed using that of his family members.

Results: The phenotype was identified to be associated with a novel pathogenic variant c.942_943 + 3delinsCC in the AP4E1 gene. The patient manifested severely delayed psychomotor development, impaired global physical development and general illness. Movement disorders were evident during the neonatal period.

Conclusions: The present study identifies a previously unknown disease-inducing AP4E1 gene mutation.

SOURCE: BMC Med Genomics. 2021 May 18;14(1):131. doi: 10.1186/s12920-021-00980-5. PMID: 34006278

A new family with spastic paraplegia type 51 and novel mutations in AP4E1

Izabela Winkler 1 2 , Paweł Miotła 3 , Monika Lejman 4 , Aleksandra Pietrzyk 5 , Magdalena Kacprzak 5 , Marcin Kubiak 6 , Agnieszka Sobczyńska-Tomaszewska 5 , Maciej Skrzypczak 3 , Ilona Jaszczuk 4 7

1. 2nd Department of Gynaecology, St. Johns Centre Oncology, Lublin Oncology Centre, 7 Jaczewski Street, 20-090, Lublin, Poland.

2. 2nd Department of Gynaecology, Lublin Medical University, 8 Jaczewski Street, 20-954, Lublin, Poland.

3. 2nd Department of Gynaecology, Lublin Medical University, 8 Jaczewski Street, 20-954, Lublin, Poland.

4. Department of Paediatric Haematology, Oncology and Transplantology, Children Clinical Hospital, II Dept. of Paediatrics, Medical University, A. Gebali 6, 20-093, Lublin, Poland.

5. MedGen Medical Centre, Wiktorii Wiedeńskiej 9a Street, 02-954, Warsaw, Poland.

6. Department of Surgery, St. Johns Centre Oncology, 7 Jaczewski Street, 20-090, Lublin, Poland.

7. Department of Cancer Genetics with Cytogenetic Laboratory, Medical University of Lublin, Radziwiłłowska 11, 20-080, Lublin, Poland.

Case of SPG46 in a 2-year-old

Complicated HSP associated with 2 different mutations – one already known and one new

Introduction: Spastic paraplegia type 46 (SPG46) is a rare autosomal recessive hereditary spastic paraplegia, caused by mutations in the non-lysosomal glucosylceramidase β2 (GBA2) gene. Worldwide, approximately twenty SPG46 families have been identified so far.

Case report: We describe a compound heterozygous Italian patient carrying a novel (p.Arg879Gln) and a recurrent (p.Arg399 *) GBA2 gene variant. The patient presented unsteady gait at age 2, and progressively manifested spastic-ataxia, scoliosis, mild intellectual decline, and bilateral cataract.

Discussion: Clinical manifestations associated with GBA2 gene variants encompass a spectrum of overlapping phenotypes including cerebellar ataxia, spastic paraplegia, and Marinesco-Sjogren-like syndrome. We review previously reported cases of SPG46 and discuss possible genetic differential diagnosis.

Spastic paraplegia type 46: novel and recurrent GBA2 gene variants in a compound heterozygous Italian patient with spastic ataxia phenotype

Marta Gatti 1 , Stefania Magri 1 , Daniela Di Bella 1 , Elisa Sarto 1 , Franco Taroni 1 , Caterina Mariotti 2 , Lorenzo Nanetti 1

1. Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, Via Celoria, 11, 20133, Milan, Italy.

2. Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, Via Celoria, 11, 20133, Milan, Italy.

New mutation identified in child with SPG56

Complicated form of HSP with onset from infancy in this case

Abstract

Spastic paraplegia-56 is a rare autosomal recessive disorder, caused by homozygous or compound heterozygous mutations in the CYP2U1 gene, located on chromosome 4. To date, only 28 patients with this disorder have been reported in the literature. We report a new case of CYP2U1-related spastic paraplegia-56. We also reviewed previously published patients with this condition from various databases.

Next-generation sequencing in the index child detected a novel homozygous two base pair deletion in exon 2 of the CYP2U1 gene that results in a frameshift and premature truncation of the protein 19 amino-acid downstream to codon 361. Together with the presented case, 29 were available for analysis. The mean age at the diagnosis was 17.84 ± 6.86 years. Intellectual disability/cognitive dysfunction and delayed walking or gait disturbance were the most common presenting features. Around half of the patients had neuroregression in between 1 and 2 years. It is clinically imperative to suspect this disease in children with early-onset spastic paraparesis, especially in cases accompanied by baseline development delay or cognitive impairment and consanguinity.

Spastic Paraplegia-56 due to a Novel CYP2U1 Truncating Mutation in an Indian Boy: A New Report and Literature Review

Indar K Sharawat 1 , Prateek Kumar Panda 1 , Lesa Dawman 2

1. Pediatric Neurology Division, Department of Pediatrics, All India Institute of Medical Sciences (AIIMS), Rishikesh, Uttarakhand, India.

2. Department of Pediatrics, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.

2 new variants causing SPG80 in 2 families

Pure form of HSP with dominant inheritance

Abstract

Hereditary spastic paraplegias (HSPs) are a group of rare neurodegenerative disorders. HSPs are complex disorders and are clinically and genetically heterogeneous. To date, more than 80 genes or genetic loci have been reported to be responsible for HSPs in a Mendelian-dependent manner.

Most recently, ubiquitin-associated protein 1 (UBAP1) has been recognized to be involved in HSP. Here, we identified novel protein truncating variants in two families with a pure form of HSP. A novel deletion (c.468_469delTG) in the UBAP1 gene was found in the first family, whereas a nonsense variant (c.512T>G) was ascertained in the second family. The variants were confirmed in all patients but were not detected in unaffected family members. The mutations resulted in truncated proteins of UBAP1. The variants did not result in different subcellular localizations in neuro-2a cells. However, each of the two variants impaired neurite outgrowth. Taken together, our findings expand the pathogenic spectrum of UBAP1 variants in HSP.

SOURCE: PLoS One. 2021 Jun 30;16(6):e0253871. doi: 10.1371/journal.pone.0253871. eCollection 2021. PMID: 34191852

Two novel truncating variants in UBAP1 are responsible for hereditary spastic paraplegia

Xinchao Bian 1 , Guangying Cheng 2 , Xinbo Sun 1 , Hongkun Liu 3 , Xiangmao Zhang 1 , Yu Han 1 , Bo Li 3 , Ning Li 3

1. Department of Neurosurgery, Zibo Central Hospital, Shandong University, Zibo, China.

2. Department of Gynecology, Zibo Central Hospital, Shandong University, Zibo, China.

3. Department of Integrated Traditional Chinese and Western Medicine Orthopedics, Zibo Central Hospital, Shandong University, Zibo, China.

Research from South Korea, Finland, China, Spain, Turkey, Bahrain, Japan, Spain, Germany, Poland, Australia, Singapore, France, Taiwan, UK, Italy, India

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