New HSP genotypes and phenotypes

Research from Poland, Sudan, Spain, Iran, Korea, China, Czech Republic, Taiwan, Turkey, Mexico and Italy

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.

Case of SPG7 with ataxia and tremor of the soft palate


A 58-year-old woman presented with a 30-year history of progressive ataxia, dysarthria, and bilateral leg spasticity. Neurologic examination revealed involuntary movement of the uvula and soft palate at 2–3 Hz (video 1). Brain MRI showed only cerebellar atrophy (figure).

Targeted next-generation sequencing identified a pathogenic homozygous variant in the SPG7 gene (c.773_774delTG; p.V258Gfs*30) leading to the diagnosis of spastic paraplegia type 7. Palatal tremor may be present in a variety of acquired or familial disorders1 such as cerebrotendinous xanthomatosis, SCA20, POLG-related disorders, neuroferritinopathy, and Alexander disease, but it was reported in only one patient with SPG7 mutations.2 Our observation confirms that SPG7 screening should be considered in patients with palatal tremor and ataxia.

SOURCE: Neurology. 2020 May 12;94(19):e2074-e2075. doi: 10.1212/WNL.0000000000009409. Epub 2020 Apr 21. © 2020 American Academy of Neurology PMID: 32317346

Teaching Video NeuroImages: Palatal Tremor Associated With SPG7 Variants

Guido Primiano 1Ginevra Zanni 2Marta Nardella 2Serenella Servidei 2

1 From the UOC Neurofisiopatologia (G.P., S.S.), Fondazione Policlinico Universitario A. Gemelli IRCCS; Istituto di Neurologia (G.P., S.S.), Università Cattolica del Sacro Cuore; and Unit of Neuromuscular and Neurodegenerative Disorders (G.Z., M.N.), Department of Neurosciences, IRCCS, Bambino Gesù Research Hospital, Rome, Italy. [email protected].

2 From the UOC Neurofisiopatologia (G.P., S.S.), Fondazione Policlinico Universitario A. Gemelli IRCCS; Istituto di Neurologia (G.P., S.S.), Università Cattolica del Sacro Cuore; and Unit of Neuromuscular and Neurodegenerative Disorders (G.Z., M.N.), Department of Neurosciences, IRCCS, Bambino Gesù Research Hospital, Rome, Italy.

Recessive form of complex SPG4 described

Two affected siblings born to healthy parents



Hereditary spastic paraplegia (HSP or SPG) consists of a heterogeneous group of disorders, clinically divided into pure and complex forms. The former is characterized by neurological impairment limited to lower-extremity spasticity. The latter presents additional symptoms such as seizures, psychomotor impairment, cataract, deafness, and peripheral neuropathy. The genetic structure of HSP is diverse, with more than 72 loci and 55 genes identified so far. The most common type is SPG4, accounting for 40% of cases.

This case report describes 2 siblings presenting SPG4, one presumptive and one confirmed with a homozygous SPAST variant.


Two siblings born to third-degree consanguineous and healthy parents presented a SPG4 complex phenotype characterized by progressive psychomotor deterioration, mixed seizure patterns, corneal opacity, dysostotic bones, limb spasticity with extensor plantar responses, and axial hypotonia. After ruling out most inborn errors of metabolism in one of the patients, the complexity of the case derived from exome sequencing.

The identification of a homozygous variant in the SPAST gene established a diagnosis for SPG4. The phenotype-genotype did not correlate to classical manifestations, most likely due to the variant’s zygosity. Moreover, 34 patient’s relatives were identified with SPG4 clinical manifestations or asymptomatic with the same genetic variant in heterozygous state.


We described visual loss and seizures for SPG4 complex phenotype associated with a homozygous variant in the SPAST gene. This diagnosis will lead clinicians to consider it as a differential diagnosis providing adequate genetic counseling.

SOURCE: Am J Case Rep. 2020 May 11;21:e919463. doi: 10.12659/AJCR.919463. PMID: 32389998

Clinical Characterization of 2 Siblings With a Homozygous SPAST Variant

Héctor Cruz-Camino 1Mercedes Vázquez-Cantú 2Diana Laura Vázquez-Cantú 3Jesús Santos-Guzmán 3Antonio Bandala-Jacques 3René Gómez-Gutiérrez 1Consuelo Cantú-Reyna 3

1 Medical Department, Genomi-k S.A.P.I. de C.V., Monterrey, Mexico.

2 Department of Medical Research, Cienciamed, Monterrey, Mexico.

3 School of Medicine and Health Sciences, Tecnologico de Monterrey, Monterrey, Mexico.

SPG31 complicated by second mutation

Complex HSP and cognitive impairment the result

A new mutation in the REEP1 gene causing SPG31 type pure HSP has been found in a Spanish family associated with a damaging mutation in another gene leading to intellectual disability, ADHD and foot deformity, thus highlighting the possibility of a dual genetic diagnosis in cases of presumed complex HSP and cognitive impairment.


Hereditary spastic paraplegias (HSPs) are a heterogeneous group of genetic disorders with spastic paraparesis as the main clinical feature. Complex forms may co-occur with other motor, sensory, and cognitive impairment. A growing number of loci and genes are being identified, but still more than 50% of the patients remain without molecular diagnosis.

We present a Spanish family with autosomal dominant HSP and intellectual disability (ID) in which we found a possible dual genetic diagnosis with incomplete penetrance and variable expressivity in the parents and three siblings: a heterozygous duplication of 15q11.2-q13.1 found by array CGH and a novel missense heterozygous change in REEP1 [c.73A>G; p.(Lys25Glu)] found by whole exome sequencing (WES). Following the standard genetic diagnosis approach in ID, array CGH analysis was first performed in both brothers affected by spastic paraparesis and ID from school age, and a heterozygous duplication of 15q11.2-q13.1 was found. Subsequently, the duplication was also found in the healthy mother and in the sister, who presented attention deficit/hyperactivity disorder (ADHD) symptoms from school age and pes cavus with mild pyramidal signs at 22 years of age.

Methylation analysis revealed that the three siblings carried the duplication unmethylated in the maternal allele, whereas their mother harbored it methylated in her paternal allele. Functional studies revealed an overexpression of UBE3A and ATP10A in the three siblings, and the slightest cognitive phenotype of the sister seems to be related to a lower expression of ATP10A. Later, searching for the cause of HSP, WES was performed revealing the missense heterozygous variant in REEP1 in all three siblings and the father, who presented subtle pyramidal signs in the lower limbs as well as the sister.

Our findings reinforce the association of maternally derived UBE3A overexpression with neurodevelopmental disorders and support that a spectrum of clinical severity is present within families. They also reveal that a dual genetic diagnosis is possible in patients with presumed complex forms of HSP and cognitive impairment.

SOURCE: Front Neurol. 2020 Feb 14;11:41. doi: 10.3389/fneur.2020.00041. eCollection 2020. Copyright © 2020 Aguilera-Albesa, de la Hoz, Ibarluzea, Ordóñez-Castillo, Busto-Crespo, Villate, Ibiricu-Yanguas, Yoldi-Petri, García de Gurtubay, Perez de Nanclares, Pereda and Tejada. PMID: 32117010

Hereditary Spastic Paraplegia and Intellectual Disability: Clinicogenetic Lessons From a Family Suggesting a Dual Genetics Diagnosis

Sergio Aguilera-Albesa 1 2Ana Belén de la Hoz 3 4Nekane Ibarluzea 3 4Andrés R Ordóñez-Castillo 5Olivia Busto-Crespo 6Olatz Villate 3 4 7María Asunción Ibiricu-Yanguas 2 8María E Yoldi-Petri 1 2Iñaki García de Gurtubay 2 8Guiomar Perez de Nanclares 9Arrate Pereda 9María Isabel Tejada 3 4 7

1 Paediatric Neurology Unit, Department of Paediatrics, Navarra Health Service Hospital, Pamplona, Spain.

2 Navarrabiomed Health Research Institute, Pamplona, Spain.

3 Biocruces Bizkaia Health Research Institute, Barakaldo, Spain.

4 Clinical Group Affiliated With the Centre for Biomedical Research on Rare Diseases (CIBERER), Valencia, Spain.

5 Department of Neurology, Navarra Health Service Hospital, Pamplona, Spain.

6 Department of Physical Medicine and Rehabilitation, Navarra Health Service, Pamplona, Spain.

7 Molecular Genetics Laboratory, Genetics Service, Cruces University Hospital, Osakidetza Basque Health Service, Barakaldo, Spain.

8 Department of Neurophysiology, Navarra Health Service Hospital, Pamplona, Spain.

9 Rare Diseases Research Group, Molecular (Epi)Genetics Laboratory, Bioaraba Health Research Institute, Araba University Hospital, Vitoria-Gasteiz, Spain.

New mutation discovered in SPG10

Hereditary spastic paraplegia (HSP) is a heterogeneous group of rare neurodegenerative diseases that are characterized by progressive weakness and spasticity of the lower limbs. Spastic paraplegia 10 (SPG10) is a autosomal dominant HSP with early onset that is caused by pathogenic variants of the kinesin family member 5A gene (KIF5A) that encodes the kinesin heavy chain (KHC).1

Here we report two SPG10 patients carrying a pathogenic missense variant (c.611G>A, p.Arg204Gln), which is a novel variation that has not been reported previously in Korea.

SOURCE: J Clin Neurol. 2020 Apr;16(2):347-348. doi: 10.3988/jcn.2020.16.2.347. PMID: 32319259

Hereditary Spastic Paraplegia With Axonal Sensorimotor Polyneuropathy in a Korean Family Caused by Pathogenic Variant of KIF5A (c.611G>A)

Hyungwoo Lee 1Yunkyung La 1Han Kyu Na 1Hongkyung Kim 2Saeam Shin 2Young Chul Choi 3

1 Department of Neurology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.

2 Department of Laboratory Medicine, Yonsei University College of Medicine, Seoul, Korea.

3 Department of Neurology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.

Most damaging SPG3A mutations identified

Potential application as biomarker in infants

The 5 most damaging mutations in SPG3A type HSP were identified using a range of computational analysis tools in this study. They have the potential to be used as genomic biomarkers in infants under 4 years of age, and may have a role in evaluating the response to any drug treatment.


Background: Hereditary spastic paraplegia type 3A (SPG3A) is a neurodegenerative disease inherited type of Hereditary spastic paraplegia (HSP). It is the second most frequent type of HSP which is characterized by progressive bilateral and mostly symmetric spasticity and weakness of the legs. SPG3A gene mutations and the phenotype-genotype correlations have not yet been recognized. The aim of this work was to categorize the most damaging single nucleotide polymorphisms (SNPs) in ATL1 gene and to predict their impact on the functional and structural levels by several computational analysis tools.

Methods: The raw data of ATL1 gene were retrieved from dbSNP database and then run into numerous computational analysis tools. Additionally we submitted the common six deleterious outcomes from the previous functional analysis tools to I-mutant 3.0 and MUPro, respectively, to investigate their effect on the structural level. The 3D structure of ATL1 was predicted by RaptorX and modeled using UCSF Chimera to compare the differences between the native and the mutant amino acids.

Results: Five nsSNPs out of 249 were classified as the most deleterious (rs746927118, rs979765709, rs119476049, rs864622269, and rs1242753115).

Conclusions: In this study, the impact of Non-synonymous single nucleotide polymorphisms (nsSNPs) in the ATL1 gene was investigated by various in silico tools that revealed five nsSNPs (V67F, T120I, R217Q, R495W, and G504E) are deleterious SNPs, which have a functional impact on ATL1 protein and, therefore, can be used as genomic biomarkers specifically before 4 years of age; also, it may play a key role in pharmacogenomics by evaluating drug response for this disabling disease.

SOURCE: Scientifica (Cairo). 2020 Apr 19;2020:8329286. doi: 10.1155/2020/8329286. eCollection 2020. Copyright © 2020 Mujahed I. Mustafa et al. PMID: 32322428

Extensive In Silico Analysis of ATL1 Gene : Discovered Five Mutations That May Cause Hereditary Spastic Paraplegia Type 3A

Mujahed I Mustafa 1Naseem S Murshed 2Abdelrahman H Abdelmoneim 3Miyssa I Abdelmageed 4Nafisa M Elfadol 5Abdelrafie M Makhawi 1

1 Department of Biotechnology, University of Bahri, Khartoum, Sudan.

2 Department of Microbiology, International University of Africa, Khartoum, Sudan.

3 Faculty of Medicine, Alneelain University, Khartoum, Sudan.

4 Department of Pharmacy, University of Khartoum, Khartoum, Sudan.

5 Department of Microbiology, National Ribat University, Khartoum, Sudan.

New mutations associated with SPG2 and SPG11 discovered

Study of clinical and genetic aspects of HSP in Turkey


Objectives: Hereditary spastic paraplegias (HSPs) are a heterogenous group of rare neurodegenerative disorders that present with lower limb spasticity. It is known as complicated HSP if spasticity is accompanied by additional features such as cognitive impairment, cerebellar syndrome, thin corpus callosum, or neuropathy.

Most HSP families show autosomal dominant (AD) inheritance. On the other hand, autosomal recessive (AR) cases are also common because of the high frequency of consanguineous marriages in our country. This study aimed to investigate the clinical and genetic aetiology in a group of HSP patients.

Patients and methods: We studied 21 patients from 17 families. Six of them presented with recessive inheritance. All index patients were screened for ATL1 and SPAST gene mutations to determine the prevalence of the most frequent types of HSP in our cohort. Whole exome sequencing was performed for an AD-HSP family, in combination with homozygosity mapping for five selected AR-HSP families.

Results: Two novel causative variants were identified in PLP1 and SPG11 genes, respectively. Distribution of HSP mutations in our AD patients was found to be similar to European populations.

Conclusion: Our genetic studies confirmed that clinical analysis can be misleading when defining HSP subtypes. Genetic testing is an important tool for diagnosis and genetic counselling. However, in the majority of AR HSP cases, a genetic diagnosis is not possible.

SOURCE: Neurol Neurochir Pol. 2020;54(2):176-184. doi: 10.5603/PJNNS.a2020.0026. Epub 2020 Apr 3. PMID: 32242913

Clinical and Genetic Aspects of Hereditary Spastic Paraplegia in Patients From Turkey

Nihan H Akçakaya 1Burçak Özeş Ak 2Michael A Gonzalez 3Stefan Züchner 3Esra Battaloğlu 2Yeşim Parman 4

1 Istanbul University, Istanbul Medical Faculty, Department of Neurology, Istanbul, Turkey. [email protected].

2 Bogazici University, Department of Molecular Biology and Genetics, Istanbul, Turkey.

3 Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, United States.

4 Istanbul University, Istanbul Medical Faculty, Department of Neurology, Istanbul, Turkey.

Large study of SPG5 in Taiwan

3 new mutations and a ‘founder affect’ identified


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. 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. PMID: 32202070

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.

New mutation found in 8 family members with SPG80

This family had an older age at onset and fewer severe cases than average, due to the new mutation identified. Age at disease onset was not correlated with severity.


Hereditary spastic paraplegias (HSP) are a group of rare neurodegenerative diseases characterized by progressive spastic paraparesis. UBAP1 was recently found to induce a rare type of HSP (SPG80).

We identified a family with eight inherited spastic paraplegic patients carrying a novel heterozygous mutation c.279delG (p.S94Vfs*9) of UBAP1. We demonstrated a lack of functional UBAP1 in these patients, resulting in the neurological disorder caused by interceptions of the ESCRT pathway.

Extending from the older onset-age identified from this family, we found that comparing with the European and other populations, Asian patients displayed less proportion of severe patients and an older average age at onset. The origins of SPG80 patients associated with both their onset age and their disease severity, while the age at onset was not correlated with the disease severity.

SOURCE: Neurogenetics. 2020 Mar 28. doi: 10.1007/s10048-020-00608-3. Online ahead of print. PMID: 32222895

Autosomal Dominant Hereditary Spastic Paraplegia Caused by Mutation of UBAP1

Jianda Wang 1Yanqi Hou 2Lina Qi 3Shuang Zhai 4Liangwu Zheng 5Lin Han 2Yufan Guo 1Bijun Zhang 1Pu Miao 1Yuting Lou 1Xiaoxiao Xu 1Ye Wang 1Yanqi Ren 2Zhenhua Cao 2Jianhua Feng 6

1 Department of Pediatrics, The Second Affiliated Hospital of Zhejiang University School of Medicine, No.88 Jiefang Road, Hangzhou, 310009, Zhejiang Province, China.

2 RunningGene Inc., Beijing, 100083, China.

3 Department of Pediatrics, Yuhang Branch of The Second Affiliated Hospital of Zhejiang University, Hangzhou, 330110, Zhejiang Province, China.

4 The Children’s Hospital, Zhejiang University School of Medicine, Hangzhou, 310052, Zhejiang Province, China.

5 The People’s Hospital of Jiangshan, Jiangshan, 324100, Zhejiang Province, China.

6 Department of Pediatrics, The Second Affiliated Hospital of Zhejiang University School of Medicine, No.88 Jiefang Road, Hangzhou, 310009, Zhejiang Province, China.

New mutation found in ERLIN2 gene

Pure autosomal dominant form of HSP found in 5 family members

Hereditary spastic paraplegia (HSP) is a heterogeneous inherited disorder that manifests with lower extremity weakness and spasticity. HSP can be inherited by autosomal dominant, autosomal recessive, and X-linked inheritance patterns. Recent studies have shown that, although rare, mutations in a single gene can lead to multiple patterns of inheritance of HSP.

We enrolled the HSP family showing autosomal dominant inheritance and performed genetic study to find the cause of phenotype in this family. We recruited five members of a Korean family as study participants. Four of the five family members had pure HSP. Part of the family members underwent whole-exome sequencing (WES) to identify the causative mutation.

As the result of WES and Sanger sequencing analysis, a novel missense mutation (c.452 C > T, p.Ala151Val) of ERLIN2 gene was identified as the cause of the autosomal dominant HSP in the family.

Our study suggests that the ERLIN2 gene leads to both autosomal recessive and autosomal dominant patterns of inheritance in HSP. Moreover, autosomal dominant HSP caused by ERLIN2 appears to cause pure HSP in contrast to autosomal recessive ERLIN2 related complicated HSP (SPG18).

SOURCE: Sci Rep. 2020 Feb 24;10(1):3295. doi: 10.1038/s41598-020-60374-y. PMID: 32094424

An Autosomal Dominant ERLIN2 Mutation Leads to a Pure HSP Phenotype Distinct From the Autosomal Recessive ERLIN2 Mutations (SPG18)

Jin-Mo Park 1Byeonghyeon Lee 2 3Jong-Heun Kim 2 3Seong-Yong Park 2 3Jinhoon Yu 2 3Un-Kyung Kim 4 5Jin-Sung Park 6

1 Department of Neurology, Dongguk University College of Medicine, Dongguk Unversity Gyeongju Hospital, Gyeongju, Republic of Korea.

2 Department of Biology, College of Natural Sciences, Kyungpook National University, Daegu, Republic of Korea.

3 School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu, Republic of Korea.

4 Department of Biology, College of Natural Sciences, Kyungpook National University, Daegu, Republic of Korea.

5 School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu, Republic of Korea

6 Department of Neurology, School of medicine, Kyungpook National University, Kyungpook National University Chilgok hospital, Daegu, Republic of Korea.

New mutation found in CAPN1 gene

Complex SPG76 HSP and spinocerebellar ataxia


Background: Mutations in CAPN1 have recently been reported to cause the spastic paraplegia 76 (SPG76) subtype of hereditary spastic paraplegia (HSP). To investigate the role of CAPN1 in spastic paraplegia and other neurodegenerative diseases, including spinocerebellar ataxia (SCA), early-onset Parkinson’s disease (EOPD), and amyotrophic lateral sclerosis (ALS) we conducted a mutation analysis of CAPN1 in a cohort of Chinese patients with SPG, SCA, EOPD, and ALS.

Methods: Variants of CAPN1 were detected in the three cohorts by Sanger or whole-exome sequencing, and all exons and exon-intron boundaries of CAPN1 were analysed.

Results: A novel CAPN1 splicing variant (NM_001198868: c.338-1G > A) identified in a familial SPG/SCA showed a complex phenotype, including spastic paraplegia, ataxia, and extensor plantar response. This mutation was confirmed by Sanger sequencing and completely co-segregated with the phenotypes. Sequencing of the cDNA from the three affected patients detected a guanine deletion (c.340_340delG) that was predicted to result in an early stop codon after 61 amino acids (p. D114Tfs*62). No CAPN1 pathogenic mutation was found in the EOPD or ALS groups.

Conclusion: Our data reveal a novel CAPN1 mutation found in patients with SPG/SCA and emphasize the spastic and ataxic phenotypes of SPG76, but CAPN1 may not play a major role in EOPD and ALS.

SOURCE: J Neurol Sci. 2020 Apr 15;411:116691. doi: 10.1016/j.jns.2020.116691. Epub 2020 Jan 18. Copyright © 2020 Elsevier B.V. All rights reserved. PMID: 31982778

Mutation Analysis of CAPN1 in Chinese Populations With Spastic Paraplegia and Related Neurodegenerative Diseases

Zheng-Cai Xia 1Zhen-Hua Liu 2Xiao-Xia Zhou 2Zhen Liu 2Jun-Ling Wang 2Zheng-Mao Hu 3Jie-Qiong Tan 3Lu Shen 2Hong Jiang 2Bei-Sha Tang 2Li-Fang Lei 4

1 Department of Neurology, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, PR China.

2 Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, PR China.

3 Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan 410078, PR China.

4 Department of Neurology, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, PR China.

Another new mutation found in CAPN1 gene

Causes pure form of SPG76

The range of phenotypes associated with mutations in the CAPN1 gene continue to expand as this study finds another mutation in this gene associated with a pure form of HSP, adding to the complicated and spastic-ataxia phenotypes previously found.


Purpose: SPG76 is one of the rare forms of hereditary spastic paraplegia (HSP) caused by mutations in the CAPN1 gene. The mode of inheritance of SPG76 is autosomal recessive (AR) and so far, only 24 families and 25 mutations in this gene have been reported worldwide. These mutations have been associated with a spectrum of disorders from pure HSP to spastic ataxia.

HSP genetically is one of the most heterogeneous neurological disorders and to date, 79 types of HSP (SPG1-SPG79) have been identified, however, it has been suggested that many HSP-genes, particularly in AR-HSPs, remained unknown. AR-HSPs clinically overlap with other neurodegenerative disorders, making an accurate diagnosis of the disease difficult. Therefore, in addition to clinical examination, a high throughout genetic method like whole exome sequencing (WES) may be necessary for the diagnosis of this type of neurodegenerative disorders.

Methods and Results: Herein, we present the clinical features and results of WES in the first Iranian family with a novel CAPN1 variant, c.C853T:p.R285* and pure HSP.

Conclusion: Some of the previous studies have mentioned that the “spasticity-ataxia phenotype might be conducive to the diagnosis of SPG76” but recently the number of pure HSP patients with CAPN1 mutation is increasing. The present study also expands the mutation spectrum of pure CAPN1-related SPG76; emphasizing that CAPN1 screening is required in both pure HSP and spasticity-ataxia phenotypes. As noted in some other literature, we suggest the clinical spectrum of this disorder to be considered as “CAPN1-associated neurodegeneration”.

SOURCE: Int J Neurosci. 2020 May 13;1-13. doi: 10.1080/00207454.2020.1763344. Online ahead of print. PMID: 32352326

CAPN1 and Hereditary Spastic Paraplegia: A Novel Variant in an Iranian Family and Overview of the Genotype-Phenotype Correlation

Mohammad Masoud Rahimi Bidgoli 1Leila Javanparast 1Mohammad Rohani 2Hossein Najmabadi 1Babak Zamani 3Afagh Alavi 1

1 Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran.

2 Department of Neurology, Iran University of Medical Sciences, Hazrat Rasool Hospital, Tehran, Iran.

3 Neurology Department, Firoozgar hospital, Iran University of Medical Sciences, Tehran, Iran.

The 3 references following are about HSP types related to Adaptor Protein Complex 4 (AP-4)

New mutation discovered in SPG46


Hereditary spastic paraplegia (HSP) is a neurodegenerative disorder characterized by pyramidal weakness and spasticity of the lower limbs. SPG46, one of autosomal recessive HSP, is clinically characterized by spasticity and pyramidal weakness of the lower limbs, cognitive impairment, congenital bilateral cataract, thin corpus callosum, and hypogonadism in males. Mutations in the non-lysosomal glucosylceramidase β2 (GBA2) gene have been identified in patients with SPG46.

A Japanese woman was identified with bilateral cataracts when she was in an elementary school. She felt falling easily, speaking unclearness, and difficulty in walking and raising her left leg in her 30s. Her neurological examination at the age of 44 revealed dysarthria, spasticity in the upper and lower extremities, increased jaw jerk and tendon reflexes in the extremities, bilateral extensor plantar reflexes, ataxia, and pollakiuria. Magnetic resonance imaging showed thinning of the corpus callosum body as well as atrophy in the pons and cerebellum.

A novel homozygous c.1838A > G (p.D613G) missense mutation was detected at exon 12 in GBA2. We diagnosed her illness as an autosomal-recessive form of hereditary SPG46. The clinical features matched previously reported phenotype of SPG46. This is the first report of a Japanese patient with SPG46 with a novel mutation in GBA2. We presume that the novel GBA2 missense mutation found in our patient would cause loss of GBA2 activity, resulting in the neurological manifestations of SPG46.

SOURCE: eNeurologicalSci. 2020 Apr 2;19:100238. doi: 10.1016/j.ensci.2020.100238. eCollection 2020 Jun. © 2020 The Authors. PMID: 32280793

A Novel Mutation in the GBA2 Gene in a Japanese Patient With SPG46: A Case Report

Keiko Nakamura-Shindo 1Kenjiro Ono 1 2Kishin Koh 3Hiroyuki Ishiura 4Shoji Tsuji 5 6Yoshihisa Takiyama 3Masahito Yamada 1

1 Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Sciences, 13-1 Takara-machi, Kanazawa, Japan.

2 Division of Neurology, Department of Internal Medicine, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, Japan.

3 Department of Neurology, Graduate School of Medical Sciences, University of Yamanashi, 1110 Shimokato, Chuou-city, Yamanashi, Japan.

4 Department of Neurology, The University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan.

5 Department of Molecular Neurology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan.

6 Institute of Medical Genomics, International University of Health and Welfare, 4-3 Kozunomori, Narita-city, Chiba, Japan.

Founder mutation in AP-4 HSP Polish families identified

New SPG47 phenotype described


Biallelic mutations in the AP4B1 gene, encoding adaptor-related protein complex 4 beta-1 subunit, have been recognized as an important cause of a group of conditions leading to adaptor-related protein complex 4 (AP4)-associated hereditary spastic paraplegia (SPG47).

We describe a homozygous, known variant c.1160_1161delCA (p.Thr387fs) that was found in the largest ever group of patients coming from four families. The patients exhibited early hypotonia progressing to spastic paraplegia, microcephaly, epilepsy, and central nervous system (CNS) defects and global developmental delay that are consistent with the nature of SPG47.

Our findings expand phenotypic spectrum of SPG47 to include polymorphic seizures, mild/moderate intellectual disability, and intracerebral cysts as well as point to founder mutation in AP4 deficiency disorders in apparently non-consanguineous Polish families without shared ancestry.

SOURCE: J Appl Genet. 2020 May;61(2):213-218. doi: 10.1007/s13353-020-00552-w. Epub 2020 Mar 12. PMID: 32166732

AP4B1-associated Hereditary Spastic Paraplegia: Expansion of Phenotypic Spectrum Related to Homozygous p.Thr387fs Variant

Krzysztof Szczałuba 1Hanna Mierzewska 2Robert Śmigiel 3Joanna Kosińska 1Agnieszka Koppolu 1 4Anna Biernacka 1 4Piotr Stawiński 1 5Agnieszka Pollak 1Małgorzata Rydzanicz 1Rafał Płoski 6

1 Department of Medical Genetics, Medical University of Warsaw, ul. Pawinskiego 3c, 02-106, Warsaw, Poland.

2 Department of Child and Adolescent Neurology, Institute of Mother and Child, Warsaw, Poland.

3 Department of Paediatrics, Division of Paediatric Propaedeutics and Rare Disorders, Wroclawa Medical University, Wroclaw, Poland.

4 Postgraduate School of Molecular Medicine, Warsaw, Poland.

5 Department of Genetics, Institute of Physiology and Pathology of Hearing, Warsaw, Poland.

6 Department of Medical Genetics, Medical University of Warsaw, ul. Pawinskiego 3c, 02-106, Warsaw, Poland.

New mutation discovered in SPG47

Case description expands the phenotype



Introduction: The AP4B1 gene encodes a subunit of adaptor protein complex-4 (AP4), a component of intracellular transportation of proteins that play important roles in neurons. Bi-allelic mutations in AP4B1 cause autosomal recessive spastic paraplegia-47 (SPG47).

Case presentation: Here we present a Chinese patient with spastic tetraplegia, moderate psychomotor development delay and febrile seizures plus. Brain MRIs showed dilated supratentorial ventricle, thin posterior and splenium part of corpus callosum. The patient had little progress through medical treatments and rehabilitating regimens.

Whole exome sequencing identified novel compound heterozygous truncating variants c.1207C > T (p.Gln403*) and c.52_53delAC (p.Cys18Glnfs*7) in AP4B1 gene. Causal mutations in AP4B1 have been reported in 29 individuals from 22 families so far, most of which are homozygous mutations.

Conclusions: Our study enriches the genetic and phenotypic spectrum of SPG47. Early discovery, diagnosis and proper treatment on the conditions generally increase chances of improvement in the quality of life for patients.

SOURCE: BMC Med Genet. 2020 Mar 14;21(1):51. doi: 10.1186/s12881-020-0988-3. PMID: 32171285

Novel Variants in AP4B1 Cause Spastic Tetraplegia, Moderate Psychomotor Development Delay and Febrile Seizures in a Chinese Patient: A Case Report

Wen-Cong Ruan 1Jia Wang 2Yong-Lin Yu 1Yue-Ping Che 1Li Ding 1Chen-Xi Li 1Xiao-Dong Wang 3Hai-Feng Li 4

1 Department of Rehabilitation, The Children’s Hospital, Zhejiang University School of Medicine, Zhejiang, 310052, China.

2 Cipher Gene, LLC, Beijing, 100080, China.

3 Cipher Gene, LLC, Beijing, 100080, China. [email protected].

4 Department of Rehabilitation, The Children’s Hospital, Zhejiang University School of Medicine, Zhejiang, 310052, China.

Combined SPG11 and juvenile MND identified

Features of both conditions found in 8 patients

This study suggests recognising a combined diagnosis of SPG11 HSP and Juvenile amyotrophic lateral sclerosis, a form of motor neuron disease, as all eight patients in the study had features present in both conditions. As well, two new mutations in SPG11 were found.


Background: SPG11 mutations can cause autosomal recessive hereditary spastic paraplegia (ARHSP) and juvenile amyotrophic lateral sclerosis (JALS). Because these diseases share some clinical presentations and both can be caused by SPG11 mutations, it was considered that definitive diagnosis may not be straight forward.

Methods: The DNAs of referred ARHSP and JALS patients were exome sequenced. Clinical data of patients with SPG11 mutations were gathered by interviews and neurological examinations including electrodiagnosis (EDX) and magnetic resonance imaging (MRI).

Results: Eight probands with SPG11 mutations were identified. Two mutations are novel. Among seven Iranian probands, six carried the p.Glu1026Argfs*4-causing mutation. All eight patients had features known to be present in both ARHSP and JALS. Additionally and surprisingly, presence of both thin corpus callosum (TCC) on MRI and motor neuronopathy were also observed in seven patients. These presentations are, respectively, key suggestive features of ARHSP and JALS.

Conclusion: We suggest that rather than ARHSP or JALS, combined ARHSP/JALS is the appropriate description of seven patients studied. Criteria for ARHSP, JALS, and combined ARHSP/JALS designations among patients with SPG11 mutations are suggested. The importance of performing both EDX and MRI is emphasized. Initial screening for p.Glu1026Argfs*4 may facilitate SPG11 screenings in Iranian patients.

SOURCE: Mol Genet Genomic Med. 2020 May 8;e1240. doi: 10.1002/mgg3.1240. Online ahead of print. © 2020 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC. PMID: 32383541

Description of Combined ARHSP/JALS Phenotype in Some Patients With SPG11 Mutations

Marzieh Khani 1Hosein Shamshiri 2Farzad Fatehi 2Mohammad Rohani 3Bahram Haghi Ashtiani 4Fahimeh Haji Akhoundi 4Afagh Alavi 5Hamidreza Moazzeni 1Hanieh Taheri 1Mina Tolou Ghani 1Leila Javanparast 5Seyyed Saleh Hashemi 5Ramona Haji Seyed Javadi 6Matineh Heidari 4Shahriar Nafissi 2Elahe Elahi 1

1 School of Biology, College of Science, University of Tehran, Tehran, Iran.

2 Department of Neurology, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran.

3 Department of Neurology, Hazrat Rasool Hospital, Iran University of Medical Sciences, Tehran, Iran.

4 Department of Neurology, Firoozgar Hospital, Iran University of Medical Sciences, Tehran, Iran.

5 Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran.

6 Department of Radiation Oncology, Emory University School of Medicine, Atlanta, GA, USA.

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