New HSP genotypes & phenotypes

Research from China, Mali, India, Taiwan, Russia, Saudi Arabia

What are genotypes and phenotypes?

The distinction between genotype and phenotype is the difference between someone’s heredity, the set of genes they carry, i.e. their genotype and what that set of genes produces, i.e. their physical and other characteristics or phenotype.

Physical characteristics (phenotype) are determined by the set of genes (genotype) someone has.

Physical characteristics include appearance, development and behaviour. Examples include height; eye, skin and hair colour; body shape and size. Phenotype also includes characteristics that can be observed or measured such as levels of hormones, blood type and behaviour.

Phenotype is determined as well as by environmental influences on the genes. Identical twins, who have identical genotypes, eventually develop some differences because each twin will encounter different environmental influences as they develop and age.

3 new HSP variants discovered

HSP population study in Mali

Background and purpose: Hereditary spastic paraplegia (HSP) is a group of neurodegenerative diseases divided into pure and complex forms, with spasticity in lower limbs only, or associated with other neurologic and non-neurologic manifestations, respectively. Although widely reported in other populations, very little data exist in sub-Saharan Africa.

Methods: Patients with neurodegenerative features were evaluated over a 19-month period at the Department of Neurology, Teaching Hospital of Point “G”, Bamako, Mali. The diagnosis of HSP was considered based on family history and the absence of other known non-genetic causes. Genetic analysis including candidate gene and whole exome sequencing was performed and variant pathogenicity was tested using prediction tools and ACMG guidelines.

Results: Of the 170 families with hereditary neurological disorders enrolled, 16 had features consistent with HSP, a frequency of 9%. The average age of onset was 14.7 years with 46% starting before age 6. The male/female ratio was 2.6:1. Complex forms were seen in 75% of cases, and pure forms in 25%. Pyramidal findings were present in all patients. Associated features included mental retardation, peripheral neuropathy, epilepsy, oculomotor impairment and urinary urgency. Most patients were treated with a muscle relaxant and physical therapy, and restorative surgery was done in one. Genetic testing identified novel variants in three families (19%).

Conclusion: This study confirms the clinical variability of HSPs and adds African data to the current literature.

SOURCE:  Acta Neurol Belg. 2022 Nov 17. doi: 10.1007/s13760-022-02113-w. Online ahead of print. PMID: 36396882 © 2022. The Author(s) under exclusive licence to Belgian Neurological Society.

Hereditary spastic paraplegia in Mali: epidemiological and clinical features

Salimata Diarra  1   2 Thomas Coulibaly  1   3 Kékouta Dembélé  3 Nyater Ngouth  4 Lassana Cissé  3 Seybou H Diallo  1   5 Madani Ouologuem  6 Salimata Diallo  5 Oumar Coulibaly  7 Koumba Bagayoko  1 Dramane Coulibaly  8 Assiatou Simaga  9 Hammadoun A Sango  10 Mahamadou Traoré  11 Steve Jacobson  4 Kenneth H Fischbeck  2 Guida Landouré  12   13   14 Cheick O Guinto  1   3 H3Africa consortium

1. Faculté de Médecine et d’Odontostomatologie, USTTB, Bamako, Mali.

2. Neurogenetics Branch, NINDS, NIH, Bethesda, MD, USA.

3. Service de Neurologie, CHU du Point “G”, Bamako, Mali.

4. Neuroimmunology Division, NINDS, NIH, Bethesda, MD, USA.

5. Service de Neurologie, CHU de Gabriel Touré, Bamako, Mali.

6. Service de Médecine, Hôpital du Mali, Bamako, Mali.

7. Service de Chirugie Pédiatrique, CHU de Gabriel Touré, Bamako, Mali.

8. Service de Médecine, CHU Mère-Enfant le “Luxembourg”, Bamako, Mali.

9. Institut d’Ophtalmologie Tropicale de l’Afrique (IOTA), Bamako, Mali.

10. DER de Santé Publique, Faculté de Médecine et d’Odontostomatologie, Bamako, Mali.

11. Service de Cytogénétique et de la Réproduction Biologique, INSP, Bamako, Mali.

12. Faculté de Médecine et d’Odontostomatologie, USTTB, Bamako, Mali.

13. Neurogenetics Branch, NINDS, NIH, Bethesda, MD, USA.

14. Service de Neurologie, CHU du Point “G”, Bamako, Mali.

Large study of SPG11 genotype and phenotype


Hereditary spastic paraplegia (HSP) is a rare hereditary disease in nervous system due to the damage of corticospinal tract. HSP has various inheritance modes, including autosomal dominant inheritance, autosomal recessive inheritance, X-linked inheritance, and mitochondrial inheritance in some cases. At present, there are at least 80 subtypes of HSP.

Hereditary spastic paraplegia type 11 (SPG11) is the most common subtype in autosomal recessive inheritance, and its pathogenic factor is KIAA1840 gene, which encodes spatacsin protein. A total of 52 SPG11 patients aged from 4-24 years old have been reported. Their initial symptoms were gait disturbance and/or mental retardation. As the disease develops, they may present with mental retardation, sphincter disturbance, decreased vision, ataxia, amyotrophy, pes arcuatus, ophthalmoplegia, peripheral neuropathy, and others. Except agenesis of the corpus callosum and periventricular white matter changes, patients might show cortical atrophy, ventricular dilation, and cerebellar atrophy, and so on. Chinese SPG11 patients manifested significant clinical and genetical heterogeneity and no obvious gender difference. Of them, 37 pathogenic mutations of KIAA1840 gene were detected, which all introduced truncated mutation of spatacsin protein. KIAA1840 gene frameshift mutation is the most common type of mutation.

SOURCE: Journal of Central South University. Medical sciences. 2022 Dec 28;47(12):1729-1732. doi: 10.11817/j.issn.1672-7347.2022.190651.  PMID: 36748384

Research on clinical and molecular genetics of hereditary spastic paraplegia 11 patients in China

Juan DU  1

1. Department of Neurology, Xiangya Hospital, Central South University, Changsha 410078, China.

New frameshift variant in SPAST gene discovered

Cause of SPG4 in 10 members of a family over 4 generations with onset from 2 to 44 years and wide-ranging severity.

Objective: To clarify the pathogenicity and further explore the association between genotype and clinical phenotype of this variant, analyzing a novel variation of SPAST gene in hereditary spastic paraplegia (HSP) family from Changzhi city, Shanxi Province.

Methods: A family with HSP was tracked and collected in Neurology Department of Heping Hospital Affiliated to Changzhi Medical College in October 2019. Peripheral venous blood of 2 ml was extracted from the proband and 8 other members of the family, genomic DNA was extracted from the blood samples, and the genes of spastic paraplegia were screened by next-generation sequencing (NGS). HGMD, 1000G, OMIM databases and PolyPhen2, SIFT and other software were used for bioinformatics analysis of suspected mutations. Multiplex ligation-dependent probe amplification (MLPA) was used to further screen for total deletions/duplications in patients who remained negative after targeting NGS, and Sanger sequencing was performed to verify the suspected pathogenic mutation sites in the family to determine co-isolation of the mutation sites in the family members. Finally, it is necessary to refer to the latest version of The American College of Medical Genetics and Genomics (ACMG) sequence variation interpretation guidelines to interpret the mutation sites to determine pathogenicity.

Results: The HSP family consists of 47 members of 4 generations and 10 patients, with onset ages ranging from 2 to 44 years. The proband’s daughter only showed positive bilateral Babinski signs on physical examination, and the rest of the patients showed spasticity and weakness of lower limbs with varying severity on this basis. Preliminary screening by next-generation sequencing technology showed that the proband had frame-shift variation of SPAST gene c.1057_1058insCC (p.Leu354HisfsTer11) and missense variation of DCTN1 gene c.2213A>G (p.Gln738Arg). Then, Sanger sequencing was used for in-family verification, which showed SPAST gene c.1057_1058insCC (p.Leu354HisfsTer11) was detected in the affected members include father, brother, son and daughter, and not detected in the unaffected normal members, the proband’s wife, mother, sister and sister-in-law. However, the unaffected of mother detected missense variation of DCTN1 gene c.2213A>G (p.Gln738Arg), while the remaining members did not detect this variation. The results of MLPA showed that no large fragment variation was found.

Conclusions: The genetic pattern of the HSP family was autosomal dominant, and the clinical characteristics were consistent with hereditary spastic paraplegia type 4 (SPG4). Co-segregation of SPAST gene c.1057_1058insCC (p.Leu354HisfsTer11) was found in the HSP family and was the pathogenicity cause of this SPG4 family, and it was a newly discovered mutation locus.

SOURCE:  Chinese Journal of Internal Medicine. 2022 Dec 1;61(12):1343-1350. doi: 10.3760/cma.j.cn112138-20220912-00675. PMID: 36456515

A novel mutation of SPAST gene in a hereditary spastic paraplegia type 4 family

L P Zhang  1 Y F Wang  1

1. Department of Neurology, Heping Hospital Affiliated to Changzhi Medical College, Changzhi 046000,China.

Almost identical NIPA1 variants cause different phenotype

One causes pure SPG6, the other adolescent-onset complex SPG6

Objective: NIPA1 mutations have been implicated in hereditary spastic paraplegia (HSP) as the cause of spastic paraplegia type 6 (SPG6). The aim of this study was to investigate the clinical and genetic features of SPG6 in a Taiwanese HSP cohort.

Methods: We screened 242 unrelated Taiwanese patients with HSP for NIPA1 mutations. The clinical features of patients with a NIPA1 mutation were analyzed. Minigene-based splicing assay, RT-PCR analysis on the patients’ RNA, and cell-based protein expression study were utilized to assess the effects of the mutations on splicing and protein expression.

Results: Two patients were identified to carry a different heterozygous NIPA1 mutation. The two mutations, c.316G>A and c.316G>C, are located in the 3′ end of NIPA1 exon 3 near the exon-intron boundary and putatively lead to the same amino acid substitution, p.G106R. The patient harboring NIPA1 c.316G>A manifested spastic paraplegia, epilepsy and schizophrenia since age 17 years, whereas the individual carrying NIPA1 c.316G>C had pure HSP since age 12 years. We reviewed literature and found that epilepsy was present in multiple individuals with NIPA1 c.316G>A but none with NIPA1 c.316G>C. Functional studies demonstrated that both mutations did not affect splicing, but only the c.316G>A mutation was associated with a significantly reduced NIPA1 protein expression.

Interpretation: SPG6 accounted for 0.8% of HSP cases in the Taiwanese cohort. The NIPA1 c.316G>A and c.316G>C mutations are associated with adolescent-onset complex and pure form HSP, respectively. The different effects on protein expression of the two mutations may be associated with their phenotypic discrepancy.

SOURCE:  Ann Clin Transl Neurol. 2023 Jan 6. doi: 10.1002/acn3.51724. Online ahead of print. PMID: 36607129 © 2023 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.

Clinical and genetic characterization of NIPA1 mutations in a Taiwanese cohort with hereditary spastic paraplegia

Shih-Yu Fang  1   2 Ying-Tsen Chou  1 Kuo-Chou Hsu  3 Shao-Lun Hsu  1   2 Kai-Wei Yu  4 Yu-Shuen Tsai  5 Yi-Chu Liao  1   2   6 Pei-Chien Tsai  7 Yi-Chung Lee  1   2   6

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

2. Department of Neurology, National Yang Ming Chiao Tung University School of Medicine, Taipei, Taiwan.

3. Department of Medicine, Taipei Veterans General Hospital Yuanshan Branch, Yuanshan, Taiwan.

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

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

6. Brain Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan.

7. Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan.

New frameshift SPAST variant causing pure SPG4 identified

Introduction: Hereditary spastic paraplegias (HSPs) are genetic neurodegenerative diseases. The most common form of pure HSP that is inherited in an autosomal dominant manner is spastic paraplegia type 4 (SPG4), which is caused by mutations in the SPAST gene. Different theories have been proposed as the mechanism underlying SPAST-HSP for different types of genetic mutations, including gain- and loss-of-function mechanisms. To better understand the mutation mechanisms, we performed genetic analysis and investigated a truncating SPAST variant that segregated with disease in one family.

Objectives and methods: We described a pure HSP pedigree with family members across four generations. We performed genetic analysis and investigated a novel frameshift pathogenic variant (c.862_863dupAC, p. H289Lfs*27) in this family. We performed reverse transcription-polymerase chain reaction (RT-PCR), Sanger sequencing, and quantitative RT-PCR using total RNA from an Epstein-Barr virus-induced lymphoblastoid cell line produced from the proband. We also performed Western blotting on cell lysates to investigate if the protein expression of spastin is affected by this variant.

Results: This variant (c.862_863dupAC, p. H289Lfs*27) co-segregated with pure HSP in this family and is not registered in any public database. Measurement of SPAST transcripts in lymphoblasts from the proband demonstrated a reduction of SPAST transcript levels through likely nonsense-mediated mRNA decay. Immunoblot analyses demonstrated a reduction of spastin protein expression levels in lymphoblasts.

Conclusion: We report an SPG4 family with a novel heterozygous frameshift variant p.H289Lfs*27 in SPAST. Our study implies haploinsufficiency as the pathogenic mechanism for this variant and expands the known mutation spectrum of SPAST.

SOURCE:  Front Neurol. 2022 Nov 14;13:1005544. doi: 10.3389/fneur.2022.1005544. eCollection 2022. PMID: 36452170 Copyright © 2022 Nan, Chu, Liu, Xie and Wu.

A novel truncating variant of SPAST associated with hereditary spastic paraplegia indicates a haploinsufficiency pathogenic mechanism

Haitian Nan  1 Min Chu  1 Li Liu  1 Kexin Xie  1 Liyong Wu  1

1. Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China.

Rare case of pure, adult-onset SPG15


Hereditary spastic paraplegia (HSP) 15 is an autosomal recessive neurodegenerative disease caused by homozygous or heterozygous point mutations in the ZFYVE26 gene that encodes the spastizin protein, located on chromosome 14q22-q24. Hereditary spastic paraplegia has been rarely reported in Saudi Arabia.

In this article, we report a rare case of adult-onset HSP 15 with a pure form of the disease in a Saudi patient with a compound heterozygous variant in the ZFYVE26 gene. The present case suggests that a compound heterozygous mutation in the ZFYVE26 may be associated with a later-onset disease and a milder phenotype.

Given the low prevalence of the disease as well as heterogenicity and variability of its presenting symptoms, HSP 15 may be difficult to diagnose. However, early diagnosis is important to prevent unnecessary extensive investigations, facilitate early symptomatic management and provide genetic counseling for family planning to those affected and their first and second-degree relatives.

SOURCE:  Maedica (Bucur). 2022 Sep;17(3):730-734. doi: 10.26574/maedica.2022.17.3.730.  PMID: 36540605

Adult-Onset Hereditary Spastic Paraplegia 15 in a Saudi Patient with A Compound Heterozygous Variant in the ZFYVE26 Gene

Hussein Algahtani  1   2   3 Bader Shirah  4 Rahaf Aljohani  3 Amjad Alshehri  3 Maryam Alqassas  3 Angham Abdulrhman Abdulkareem  5 Muhammad Imran Naseer  5   6

1. Department of Medicine, King Abdulaziz Medical City, Jeddah, Saudi Arabia.

2. King Abdullah International Medical Research Center, Jeddah, Saudi Arabia.

3. College of Medicine, King Saud bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia.

4. Department of Neuroscience, King Faisal Specialist Hospital & Research Centre, Jeddah, Saudi Arabia.

5. Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah, Saudi Arabia.

6. Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia.

New variants in HACE1 gene discovered

Gross deletion associated with HSP in 2 yr old boy


Spastic paraplegia and psychomotor retardation with or without seizures (SPPRS, OMIM 616756) is a rare genetic disease caused by biallelic pathogenic variants in the HACE1 gene. Originally, these mutations have been reported to be implicated in tumor predisposition. Nonetheless, via whole exome sequencing in 2015, HACE1 mutations were suggested to be the cause of a new autosomal recessive neurodevelopmental disorder, which is characterized by spasticity, muscular hypotonia, and intellectual disability. To date, 14 HACE1 pathogenic variants have been described; these variants have a loss-of-function effect that leads to clinical presentations with variable severities. However, gross deletions in the HACE1 gene have not yet been mentioned as a cause of spastic paraplegia.

Here, we report a clinical case involving a 2-year-old male presenting with spasticity, mainly affecting the lower limbs, and developmental delay. Exome sequencing, chromosomal microarray analysis, and mRNA analysis were used to identify the causative gene. We revealed that the clinical findings were due to previously undescribed HACE1 biallelic deletions. We identified the deletion of exon 7: c.(534+1_535-1)_(617+1_618-1)del (NM_020771.4) and the gross deletion in the 6q16.3 locus, which affected the entire HACE1 gene: g.105018931_105337494del, (GRCh37). A comprehensive diagnostic approach for the patients with originally homozygous mutations in HACE1 is required since false homozygosity results are possible. More than 80% of the described mutations were reported to be homozygous. Initial hemizygosity is hard to detect by quantitative methods, and this may challenge molecular diagnostic identification in patients with spastic paraplegia.

SOURCE:  Genes (Basel). 2022 Nov 23;13(12):2186. doi: 10.3390/genes13122186. PMID: 36553453

Previously Undescribed Gross HACE1 Deletions as a Cause of Autosomal Recessive Spastic Paraplegia

Valeriia A Kovalskaia  1 Victoriia V Zabnenkova  1 Marina S Petukhova  1 Zhanna G Markova  1 Vyacheslav Yu Tabakov  1 Oxana P Ryzhkova  1

1. Research Centre for Medical Genetics, 115522 Moscow, Russia.

New variants identified in SPG76

“Ear of the Lynx” MRI found for the first time in SPG76

Background: Hereditary Spastic Paraparesis (HSP) are a group of genetically inherited disorders, clinically and genetically heterogenous and characterized by degeneration of corticospinal tracts, manifesting with progressive spasticity and lower limbs weakness. Most HSPs have an autosomal dominant inheritance. “Ear of the Lynx” sign describes the characteristic abnormality in the forceps minor region of the corpus callosum (CC) on MRI brain. These bear a striking resemblance to the ears of a lynx. This finding has previously been described with hereditary spastic paraparesis 11 and 15, both of which are autosomal recessive HSPs.

Cases: We describe this finding in two siblings with novel mutations causing HSP76, an extremely rare autosomal recessive HSP (less than 50 cases described worldwide), which has not been reported previously.

Conclusion: This sign suggests the presence of pathogenic genetic mutations and is likely indicative of autosomal recessive HSPs.

SOURCE:  Mov Disord Clin Pract. 2022 Nov 17;10(1):120-123. doi: 10.1002/mdc3.13606. eCollection 2023 Jan. PMID: 36704071

“Ear of the Lynx” Sign in Hereditary Spastic Paraparesis (HSP) 76

Ayush Agarwal  1 Rahul Oinam  1 Vinay Goel  2 Pooja Sharma  3 Mohd Faruq  3 Ajay Garg  2 Achal K Srivastava  1

1. Department of Neurology All India Institute of Medical Sciences New Delhi India.

2. Department of Neuroradiology All India Institute of Medical Sciences New Delhi India.

3. Department of Genomics and Molecular Medicine CSIR Institute of Genomics and Integrative Biology New Delhi India.

New SPG2 variant found in study of 8 people in 3 families

Inter and intra-family range of clinical features described

Objective: Spastic paraplegia type 2 (SPG2) is an X-linked recessive (XLR) form of hereditary spastic paraplegia (HSP) caused by mutations in proteolipid protein 1 (PLP1) gene. We described the clinical and genetic features of three unrelated families with PLP1 mutations and reviewed PLP1-related cases worldwide to summarize the genotype-phenotype correlations.

Methods: The three probands were 23, 26, and 27 years old, respectively, with progressively aggravated walking difficulty as well as lower limb spasticity. Detailed physical examination showed elevated muscle tone, hyperreflexia, and Babinski signs in lower limbs. Brain MRI examinations were investigated for all cases. PLP1 mutations were identified by whole exome sequencing, followed by Sanger sequencing, family co-segregation, and phenotypic re-evaluation.

Results: A total of eight patients with SPG2 were identified in these three families. The probands additionally had cognitive impairment, urinary or fecal incontinence, ataxia, and white matter lesions (WML) in periventricular regions, with or without kinetic tremor. Three hemizygous mutations in PLP1 were identified, including c.453+159G>A, c.834A>T (p.*278C), and c.434G>A (p.W145*), of which c.834A>T was first associated with HSP.

Interpretation: We identified three families with complicated SPG2 due to three PLP1 mutations. Our study supports the clinical inter-and intra-family heterogeneity of SPG2. The periventricular region WML and cognitive impairment are the most common characteristics. The kinetic tremor in upper limbs was observed in 2/3 families, suggesting the spectrum of PLP1-related disorders is still expanding.

SOURCE:  Ann Clin Transl Neurol. 2023 Jan 9. doi: 10.1002/acn3.51722. Online ahead of print. PMID: 36622199

PLP1 gene mutations cause spastic paraplegia type 2 in three families

Li Yao  1   2 Zeyu Zhu  1 Chao Zhang  2 Wotu Tian  1 Li Cao  1  

1. Department of Neurology, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China.

2  Suzhou Hospital of Anhui Medical University, Suzhou Municipal Hospital of Anhui Province, Suzhou, 234000, China.

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