New HSP genotypes & phenotypes

Research from Iran, Germany, Canada, Sweden, Sudan, France, China, South Korea, India

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.

NMNAT1 gene found to be a probable cause of HSP

The variant identified is linked with another disease (LCA9) but no NMNAT1 variant has ever been associated with a neurological disorder.


In the NAD biosynthetic network, the nicotinamide mononucleotide adenylyltransferase (NMNAT) enzyme fuels NAD as a co-substrate for a group of enzymes. Mutations in the nuclear-specific isoform, NMNAT1, have been extensively reported as the cause of Leber congenital amaurosis-type 9 (LCA9). However, there are no reports of NMNAT1 mutations causing neurological disorders by disrupting the maintenance of physiological NAD homeostasis in other types of neurons.

In this study, for the first time, the potential association between a NMNAT1 variant and hereditary spastic paraplegia (HSP) is described. Whole-exome sequencing was performed for two affected siblings diagnosed with HSP. Runs of homozygosity (ROH) were detected. The shared variants of the siblings located in the homozygosity blocks were selected. The candidate variant was amplified and Sanger sequenced in the proband and other family members. Homozygous variant c.769G>A:p.(Glu257Lys) in NMNAT1, the most common variant of NMNAT1 in LCA9 patients, located in the ROH of chromosome 1, was detected as a probable disease-causing variant. After detection of the variant in NMNAT1, as a LCA9-causative gene, ophthalmological and neurological re-evaluations were performed. No ophthalmological abnormality was detected and the clinical manifestations of these patients were completely consistent with pure HSP. No NMNAT1 variant had ever been previously reported in HSP patients. However, NMNAT1 variants have been reported in a syndromic form of LCA which is associated with ataxia.

In conclusion, our patients expand the clinical spectrum of NMNAT1 variants and represent the first evidence of the probable correlation between NMNAT1 variants and HSP.

SOURCE:  Neuromuscul Disord. 2023 Apr;33(4):295-301. doi: 10.1016/j.nmd.2023.02.001. Epub 2023 Feb 8. PMID: 36871412 Copyright © 2023 Elsevier B.V. All rights reserved.

NMNAT1 and hereditary spastic paraplegia (HSP): expanding the phenotypic spectrum of NMNAT1 variants

Zahra Sadr  1 Aida Ghasemi  1 Mohammad Rohani  2 Afagh Alavi  3

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. Genetics research center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran.

6 new variants and 1 known variant in BICD2 gene found in 7 people with this form of HSP

The BICD2 gene is also associated with a form of Spinal Muscular Atrophy (SMALED2)


BICD2 variants have been linked to neurodegenerative disorders like spinal muscular atrophy with lower extremity predominance (SMALED2) or hereditary spastic paraplegia (HSP). Recently, mutations in BICD2 were implicated in myopathies.

Here, we present one patient with a known and six patients with novel BICD2 missense variants, further characterizing the molecular landscape of this heterogenous neurological disorder. A total of seven patients were genotyped and phenotyped. Skeletal muscle biopsies were analyzed by histology, electron microscopy, and protein profiling to define pathological hallmarks and pathogenicity markers with consecutive validation using fluorescence microscopy. Clinical and MRI-features revealed a typical pattern of distal paresis of the lower extremities as characteristic features of a BICD2-associated disorder. Histological evaluation showed myopathic features of varying severity including fiber size variation, lipofibromatosis, and fiber splittings. Proteomic analysis with subsequent fluorescence analysis revealed an altered abundance and localization of thrombospondin-4 and biglycan.

Our combined clinical, histopathological, and proteomic approaches provide new insights into the pathophysiology of BICD2-associated disorders, confirming a primary muscle cell vulnerability. In this context, biglycan and thrombospondin-4 have been identified, may serve as tissue pathogenicity markers, and might be linked to perturbed protein secretion based on an impaired vesicular transportation.

SOURCE:  Int J Mol Sci. 2023 Apr 6;24(7):6808. doi: 10.3390/ijms24076808.  PMID: 37047781

Microscopic and Biochemical Hallmarks of BICD2-Associated Muscle Pathology toward the Evaluation of Novel Variants

Andreas Unger  1   2 Andreas Roos  3   4   5 Andrea Gangfuß  5 Andreas Hentschel  6 Dieter Gläser  7 Karsten Krause  3 Kristina Doering  8 Ulrike Schara-Schmidt  4 Sabine Hoffjan  8 Matthias Vorgerd  3 Anne-Katrin Güttsches  3

1. Department of Cardiovascular Medicine, Institute for Genetics of Heart Disease (IfGH), University Hospital Münster, 48149 Münster, Germany.

2. Institute of Physiology II, University of Münster, 48149 Münster, Germany.

3. Department of Neurology, Heimer Institute for Muscle Research, University Hospital Bergmannsheil, Ruhr University Bochum, 44789 Bochum, Germany.

4. Department of Pediatric Neurology, Centre for Neuromuscular Disorders, Centre for Translational Neuro- and Behavioral Sciences, University Duisburg-Essen, 45122 Essen, Germany.

5. Children’s Hospital of Eastern Ontario Research Institute, Ottawa, ON K1H 8L1, Canada.

6. Leibniz-Institut für Analytische Wissenschaften-ISAS-e.V., 44139 Dortmund, Germany.

7. Genetikum, Center for Human Genetics, 89231 Neu-Ulm, Germany.

8. Department of Human Genetics, Ruhr-University Bochum, 44801 Bochum, Germany.

Two rare autosomal recessive neurological disorders, leukoencephalopathy with ataxia and SPG56, were found in members of the same family.

Family report: Two rare autosomal recessive neurological disorders, leukoencephalopathy with ataxia and spastic paraplegia 56 (SPG56), were found in members of the same family. Two siblings presented with spastic paraplegia, cognitive impairment, bladder and bowel dysfunction and gait ataxia; their consanguineous parents were unaffected. Ophthalmological examination revealed chorioretinopathy. Brain MRI showed T2 hyperintensities and T1 hypointensities in the internal capsules, cerebral peduncles, pyramidal tracts and middle cerebellar peduncles. Both affected siblings were homozygous for CYP2U1 c.947A > T p.(Asp316Val), a known cause for SPG56. However, they were also homozygous for the novel variant CLCN2 c.607G > T, p.(Gly203Cys), classified as a variant of unknown significance. Testing of additional family members revealed homozygosity for both variants in an additional brother, whom we initially considered unaffected. Both male CLCN2 carriers were infertile, and review of the literature revealed one reported case with azoospermia, however the brother had no overt signs of SPG56. His testicular biopsy revealed incomplete maturation arrest in spermatogenesis; clinically we found mild memory impairment and hand tremor and MRI showed similar changes as his siblings. We consider CLCN2 c.607G > T pathogenic because of the neuroradiological and clinical findings, including azoospermia.

Conclusion: Considerable workup may be required to determine the pathogenicity of novel variants, and to unambiguously associate phenotype with genotype. In very rare disorders, highly specific clinical or biomarker combinations provide sufficient evidence for a variant’s pathogenicity. Phenotypic variation of monogenic disorders described in the literature may be attributed to a second co-occurring monogenic disorder, especially in consanguineous families. SPG56 may have reduced penetrance.

SOURCE:  Clin Park Relat Disord. 2023 Feb 22;8:100189. doi: 10.1016/j.prdoa.2023.100189. eCollection 2023. PMID: 36879630 © 2023 The Author(s).

Co-occurrence of CLCN2-related leukoencephalopathy and SPG56

Wejdan Almasoudi  1 Christer Nilsson  1 Ulrika Kjellström  2 Kevin Sandeman  3 Andreas Puschmann  1

1. Lund University, Skane University Hospital, Department of Clinical Sciences Lund, Neurology, Lund, Sweden.

2. Lund University, Skane University Hospital, Department of Clinical Sciences Lund, Ophthalmology, Lund, Sweden.

3. Department of Clinical Genetics and Pathology, Division of Laboratory Medicine, Office for Medical Services, Region Skåne, Sweden.

Clinical and genetic studies of 90 people from 38 unrelated Sudanese families yields 70% positive genetic test rate


Hereditary spinocerebellar degenerations (SCDs) is an umbrella term that covers a group of monogenic conditions that share common pathogenic mechanisms and include hereditary spastic paraplegia (HSP), cerebellar ataxia, and spinocerebellar ataxia. They are often complicated with axonal neuropathy and/or intellectual impairment and overlap with many neurological conditions, including neurodevelopmental disorders.

More than 200 genes and loci inherited through all modes of Mendelian inheritance are known. Autosomal recessive inheritance predominates in consanguineous communities; however, autosomal dominant and X-linked inheritance can also occur.

Sudan is inhabited by genetically diverse populations, yet it has high consanguinity rates. We used next-generation sequencing, genotyping, bioinformatics analysis, and candidate gene approaches to study 90 affected patients from 38 unrelated Sudanese families segregating multiple forms of SCDs. The age-at-onset in our cohort ranged from birth to 35 years; however, most patients manifested childhood-onset diseases (the mean and median ages at onset were 7.5 and 3 years, respectively).

We reached the genetic diagnosis in 63% and possibly up to 73% of the studied families when considering variants of unknown significance. Combining the present data with our previous analysis of 25 Sudanese HSP families, the success rate reached 52-59% (31-35/59 families). In this article we report candidate variants in genes previously known to be associated with SCDs or other phenotypically related monogenic disorders. We also highlight the genetic and clinical heterogeneity of SCDs in Sudan, as we did not identify a major causative gene in our cohort, and the potential for discovering novel SCD genes in this population.

SOURCE:  Eur J Hum Genet. 2023 Apr 3. doi: 10.1038/s41431-023-01344-6. Online ahead of print. PMID: 37012327 © 2023. The Author(s).

Clinical phenotyping and genetic diagnosis of a large cohort of Sudanese families with hereditary spinocerebellar degenerations

Ashraf Yahia  1   2   3   4 Ahlam A A Hamed  5 Inaam N Mohamed  5 Maha A Elseed  5 Mustafa A Salih  6   7 Sarah M El-Sadig  5 Hassab Elrasoul Siddig  8 Ali Elsir Musa Nasreldien  9 Mohamed Ahmed Abdullah  5 Maha Elzubair  5 Farouk Yassen Omer  10 Aisha Motwakil Bakhiet  5 Rayan Abubaker  11   12 Fatima Abozar  5 Rawaa Adil  5 Sara Emad  5 Mhammed Alhassan Musallam  5 Isra Z M Eltazi  13 Zulfa Omer  14 Hiba Malik  15 Mayada O E Mohamed  16 Ali A Elhassan  17 Eman O E Mohamed  5 Ahmed K M A Ahmed  18   19 Elhami A A Ahmed  5 Esraa Eltaraifee  5 Bidour K Hussein  20 Amal S I Abd Allah  5 Lina Salah  5 Mohamed Nimir  21   22   23 Omnia M Tag Elseed  5 Tasneem E A Elhassan  5 Abubakr Elbashier  5 Esraa S A Alfadul  5 Moneeb Fadul  5 Khalil F Ali  24 Shaimaa Omer M A Taha  25 Elfatih E Bushara  5 Mutaz Amin  26 Mahmoud Koko  20 Muntaser E Ibrahim  20 Ammar E Ahmed  5 Liena E O Elsayed  27 Giovanni Stevanin  28   29   30

1. Faculty of Medicine, University of Khartoum, Khartoum, Sudan.

2. Paris Brain Institute – ICM, CNRS UMR7225, INSERM 1127, Sorbonne University, F-75000, Paris, France.

3. Center of Neurodevelopmental Disorders (KIND), Centre for Psychiatry Research, Department of Women’s and Children’s Health, Karolinska Institutet and Stockholm Health Care Services, Region Stockholm, Stockholm, Sweden.

4. Astrid Lindgren Children’s Hospital, Karolinska University Hospital, Solna, Sweden.

5. Faculty of Medicine, University of Khartoum, Khartoum, Sudan.

6. Division of Pediatric Neurology, Department of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia.

7. College of Medicine, AlMughtaribeen University, Khartoum, Sudan.

8. Division of Neurology, Sudan Medical Council, Khartoum, Sudan.

9. Pediatric Neurology Department, Red Cross Memorial Children Hospital (RCWMCH), University of Cape Town (UCT), Cape Town, South Africa.

10. Faculty of Medicine, Omdurman Islamic University, Khartoum, Sudan.

11. Sudanese Neurogenetics Research group, Faculty of Medicine, University of Khartoum, Khartoum, Sudan.

12. National University Biomedical Research Institute, National University, Khartoum, Sudan.

13. Neurology Department, Hamad Medical Corporation, Doha, Qatar.

14. Department of Hematology and Medical Oncology, University of Cincinnati Medical Center, Ohio, USA.

15. Department of Neurology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, CB2 0QQ, UK.

16. Division of Emergency Medicine, Sudan Medical Specialization Board, Khartoum, Sudan.

17. Sudan Neuroscience Projects, University of Khartoum, Khartoum, Sudan.

18. Department of Molecular Neuroscience, Graduate school of Medicine, Osaka University, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan.

19. WPI Immunology Frontier Research Center, Osaka University, 3-1, Yamadaoka, Suita, Osaka, 565-0871, Japan.

20. Institute of Endemic Diseases, University of Khartoum, Khartoum, Sudan.

21. Department of Pathology, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, UK.

22. Warwick Medical School, University of Warwick, Coventry, UK.

23. Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK.

24. Department of Cardiology, Royal Derby Hospital, Derby, UK.

25. Department of Radiology, Universal Hospital, Khartoum, Sudan.

26. Department of Biochemistry and Molecular Biology, Faculty of Medicine, Al-Neelain University, Khartoum, Sudan.

27. Department of Basic Sciences, College of Medicine, Princess Nourah bint Abdulrahman University, Riyadh, P.O.Box 84428, Riyadh, 11671, Saudi Arabia.

28. Paris Brain Institute – ICM, CNRS UMR7225, INSERM 1127, Sorbonne University, F-75000, Paris, France.

29. Univ. Bordeaux, CNRS, INCIA, UMR 5287, F-33000, Bordeaux, France.

30. EPHE, PSL Research university, CNRS, INCIA, UMR 5287, F-75000, Paris, France.

Two novel mutations, a frameshift mutation and a nonsense mutation were identified in the SPG11 gene


A 24-year-old man presented with insidious onset progressive gait disturbance and was finally diagnosed with autosomal recessive hereditary spastic paraplegia. Two novel mutations, including a frameshift mutation (c.5687_5691del) and a non-sense mutation (c.751C>T), were identified in the SPG11 gene of the patient through whole genome sequencing. The frameshift mutation of c.5687_5691del leads to a change in amino acid synthesis beginning with amino acid No. 1896 arginine and terminating at the 8th amino acid after the change (p. Arg1896MetfsTer8). The non-sense mutation (c.751C>T) causes the conversion of codon 251st encoding the amino acid Gln into a stop codon (p. Gln251Ter), resulting in premature termination of peptide synthesis. Although confirmation of compound-heterozygosity could not be performed, our findings enriched the phenotypic spectrum of SPG11 mutations related to hereditary spastic paraplegia.

SOURCE:  Front Integr Neurosci. 2023 Mar 24;17:1117617. doi: 10.3389/fnint.2023.1117617. eCollection 2023. PMID: 37035454 Copyright © 2023 Duan, Liu and Wu.

Case report: Novel mutations in the SPG11 gene in a case of autosomal recessive hereditary spastic paraplegia with a thin corpus callosum

Ji-Qing Duan  1 Hui Liu  1 Jia-Qiao Wu  2

1. Department of Intensive Care Unit, The Third People’s Hospital of Chengdu, Affiliated Hospital of Southwest Jiaotong University, Chengdu, China.

2. Department of Anesthesia, The Third People’s Hospital of Chengdu, Affiliated Hospital of Southwest Jiaotong University, Chengdu, China.

Rare autosomal-recessive form of SPG30 with mild symptoms; a new KIF1A variant identified


SPG30 is a newly categorized type of HSP caused by variants in the kinesin family member 1A gene (KIF1A). Advances in next-generation sequencing have resulted in a limited number of studies describing the clinical, electrophysiological, and radiological features of HSP, with variable manifestations. Most known pathogenic KIF1A variants affect the motor domain, although some rare pathogenic variants have been identified that affect the non-motor domain.

Here, we report a Korean family with a rare homozygous autosomal-recessive form of SPG30. A 59-year-old man and his father presented with an uncomplicated, mild SPG30 phenotype, characterized by a progressive, spastic gait. Familial co-segregation analysis revealed a pathogenic c.2751_2753delGGA KIF1A variant that affects the non-motor domain. Our case broadens the genetic and clinical variability of SPG30, warranting similar studies to consolidate the pathogenicity of SPG30.

SOURCE:  Gene. 2023 Jun 20;870:147403. doi: 10.1016/j.gene.2023.147403. Epub 2023 Mar 30. PMID: 37001573 Copyright © 2023 Elsevier B.V. All rights reserved.

Identification of an in-frame homozygous KIF1A variant causing a mild SPG30 phenotype in a Korean family

Byeonghyeon Lee  1 Ha Hyun Song  2 Ye-Ri Kim  3 Jong-Heun Kim  4 Seong Tae Cho  2 Jeong Ho Lee  2 Un-Kyung Kim  5 Jin-Sung Park  6

1. New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation (KMEDI-hub), Daegu, Republic of Korea.

2. Department of Biology, College of Natural Sciences, Kyungpook National University, Daegu, Republic of Korea; School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu, Republic of Korea.

3. Department of Biology, College of Natural Sciences, Kyungpook National University, Daegu, Republic of Korea; Adcanced Bio-Resource Research Center, Kyungpook National University, Daegu, Republic of Korea.

4. Department of Biology, College of Natural Sciences, Kyungpook National University, Daegu, Republic of Korea; School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu, Republic of Korea; Preclinical Research Center, Daegu-Gyeongbuk Medical Innovation Foundation (KMEDI-hub), Daegu, Republic of Korea.

5. Department of Biology, College of Natural Sciences, Kyungpook National University, Daegu, Republic of Korea; 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 DDHD2 gene variant, not previously predicted as pathogenic, how found to cause SPG54

Introduction: Spastic paraplegia type 54 (SPG54) is an autosomal recessive disorder, caused by bi-allelic mutations in the DDHD2 gene. Worldwide, over 24 SPG54 families and 24 pathogenic variants have been reported. Our study aimed to describe the clinical and molecular findings of a pediatric patient from a consanguineous Iranian family with significant motor development delay, walking problems, paraplegia and optic atrophy.

Methods: The patient was a 7-year-old boy with severe neurodevelopmental and psychomotor problems. Neurological examinations, laboratory tests, electroencephalography (EEG), computed tomography (CT) scan, and brain magnetic resonance scan (MRI) were carried out for clinical evaluation. Whole-exome sequencing (WES) and in silico analysis were undertaken to identify the genetic cause of the disorder.

Results: The neurological examination showed developmental delay, spasticity in the lower extremities, ataxia, foot contractures and deep tendon reflexes (DTR) in the extremities. CT scan was normal, but MRI revealed corpus callosum thinning (TCC) with atrophic changes in the white matter.

The genetic study reported a homozygous variant (c.856 C>T, p.Gln286Ter) in the DDHD2 gene. The homozygous state was confirmed by direct sequencing in the proband and his 5-year-old brother. This variant was not reported as a pathogenic variant in literature or genetic databases and was predicted to affect the function of the DDHD2 protein.

Conclusion: The clinical symptoms in our cases were similar to the previously reported phenotype of SPG54. Our results deepen the molecular and clinical spectrum of SPG54 to facilitate future diagnoses.

SOURCE:  Neurodegener Dis. 2023 Mar 28. doi: 10.1159/000530375. Online ahead of print.  PMID: 36977391

Clinical manifestations associated with the domain-containing protein 2 (DDHD2) gene mutation in an Iranian family with Spastic Paraplegia 54

Abolfazl YariShokoofeh EtesamShannaz ZarifiSepideh ParvizpourEbrahim Miri-Moghaddam

New sporadic KIF1A gene variant probable cause of SPG30

Objective: To explore the genetic basis for a Chinese pedigree affected with hereditary spastic paraplegia type 30 (HSP30).

Methods: A proband presented at the Second Hospital of Shanxi Medical University in August 2021 was selected as the study subject. The proband was subjected to whole exome sequencing, and candidate variant was verified by Sanger sequencing and bioinformatic analysis.

Results: The proband was found to have harbored a heterozygous c.110T>C variant in exon 3 of the KIF1A gene, which can cause substitution of isoleucine by threonine at position 37 (p.I37T) and alter the function of its protein product. The same variant was not found in his parents, elder brother and elder sister, suggesting that it has a de novo origin. Based on the guidelines of the American College of Medical Genetics and Genomics (ACMG), the variant was rated as likely pathogenic (PM2_Supporting+PP3+PS2).

Conclusion: The c.110T>C variant of the KIF1A gene probably underlay the HSP30 in the proband. Above finding has enable genetic counseling for this family.

SOURCE:  Chinese Journal of Medical Genetics. 2023 Apr 10;40(4):419-422. doi: 10.3760/cma.j.cn511374-20220718-00475. PMID: 36972935

Analysis of KIF1A gene variant in a Chinese pedigree affected with Spastic paraplegia type 30

Gang Xu  1 Jianwei LiZhanjin DengYuan XiaTao WangYan BaiYan QiYong An Zhou

1. The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi 030001, China.

New gene variant causing SPG81 identified

Background: Hereditary spastic paraplegia 81 is a recently identified, rare autosomal recessive disease, caused by biallelic pathogenic variants in the SELENOI gene, with only two families reported to date. The features documented in the two previous affected families include sensorineural deafness, blindness, cleft palate, delayed motor development, regression of motor skills, impaired intellectual development, poor speech and language acquisition, spasticity, hyperreflexia, white matter abnormalities and cerebral and cerebellar atrophy.

Methods: In the present study, we performed exome sequencing analysis in a single family with two affected siblings to identify the genetic cause of complicated hereditary spastic paraplegia. The results were further confirmed by Sanger sequencing, cDNA analysis and 3D protein modelling.

Results: Exome sequencing identified a homozygous, synonymous variant in the SELENOI gene (NM_033505.4:c.126G>A:p.(Lys42Lys)) in both of the siblings. Sanger sequencing confirmed the heterozygous status in both parents consistent with the autosomal recessive inheritance. This variant has been found to disrupt normal splicing and lead to skipping of exon 2, causing in-frame deletion of SELENOI N-terminal 23 amino acids [NM_033505.4:c.57_126del:p.(Tyr20_Lys42del)] and further leading to structural changes in the protein.

Conclusions: We report a novel homozygous synonymous variant in the SELENOI gene causing abnormal splicing in two patients affected with hereditary spastic paraplegia 81. This report further expands the phenotypic and genotypic spectrum of hereditary spastic paraplegia 81.

SOURCE:  J Gene Med. 2023 Mar 21;e3501. doi: 10.1002/jgm.3501. Online ahead of print. PMID: 36942482 © 2023 John Wiley & Sons Ltd.

A novel homozygous synonymous splicing variant in SELENOI gene causes spastic paraplegia 81

Asodu Sandeep Sarma  1   2 Bathula Siddardha  1 Pragna Lakshmi T  1 Prajnya Ranganath  3 Ashwin Dalal  1

1. Diagnostics Division, Centre for DNA Fingerprinting and Diagnostics, Hyderabad, Telangana, India.

2. Graduate Studies, Regional Centre for Biotechnology, Faridabad, Haryana, India.

3. Department of Medical Genetics, Nizam’s Institute of Medical Sciences, Hyderabad, Telangana, India.

35% positive genetic tests for HSP in a study of 54 people with clinical HSP diagnosis

Background: Hereditary spastic paraplegia (HSP) constitutes a group of clinically and genetically rare neurodegenerative diseases characterized by progressive corticospinal tract degeneration. The phenotypes and genotypes of HSP are still expanding. In this study, we aimed to analyse the differential diagnosis, clinical features, and genetic distributions of a Chinese HSP patients in a 14-year cohort and to improve our understanding of the disease.

Methods: The clinical data of patients with a primary diagnosis of HSP at the initial visit to the Department of the Neurology, Peking University Third Hospital, from 2008 to 2022 were retrospectively collected. Next-generation sequencing gene panels (NGS) combined with a multiplex ligation-amplification assay (MLPA) were conducted. Epidemiological and clinical features and candidate variants in HSP-related genes were analyzed and summarized.

Results: 54 cases (probands from 25 different pedigrees and 29 sporadic cases) from 95 patients with a primary diagnosis of HSP were finally confirmed to have a clinical diagnosis of HSP based on clinical criteria, including their clinical findings, family history and long-term follow-up.

Earlier disease onset was associated with longer diagnostic delay and longer disease duration and was associated with a lower risk of loss of ability to walk independently. In addition, 20 candidate variants in reported HSP-related genes were identified in these clinically diagnosed HSP patients, including variants in SPAST, ALT1, WASHC5, SPG11, B4GALNT1, and REEP1. The genetic diagnostic rate in these 54 patients was 35.18%.

Conclusion: Hereditary spastic paraplegia has high clinical and genetic heterogeneity and is prone to misdiagnosis. Long-term follow-up and genetic testing can partially assist in diagnosing HSP. Our study summarized the clinical features of Chinese HSP patients in a 14-year cohort, expanded the genotype spectrum, and improved our understanding of the disease.

SOURCE:  Front Genet. 2023 Feb 27;14:1085442.  doi: 10.3389/fgene.2023.1085442. eCollection 2023. PMID: 36923789 Copyright © 2023 Yu, He, Liu, Wu, Cai, Zhang, Liu and Fan.

Clinical features and genetic spectrum of Chinese patients with hereditary spastic paraplegia: A 14-year study

Weiyi Yu  1   2   3 Ji He  1   2   3 Xiangyi Liu  1   2   3 Jieying Wu  1   2   3 Xiying Cai  4 Yingshuang Zhang  1   2   3 Xiaoxuan Liu  1   2   3 Dongsheng Fan  1   2   3

1. Department of Neurology, Peking University Third Hospital, Beijing, China.

2. Beijing Municipal Key Laboratory of Biomarker and Translational Research in Neurodegenerative Diseases, Beijing, China.

3. Key Laboratory for Neuroscience, National Health Commission, Ministry of Education, Peking University, Beijing, China.

4. School of Basic Medical Sciences, Peking University, Beijing, China.

New SPAST variant causing SPG4 discovered

Only male members in the subject family were affected


Hereditary spastic paraplegia (HSP) comprises a group of hereditary and neurodegenerative diseases that are characterized by axonal degeneration or demyelination of bilateral corticospinal tracts in the spinal cord; affected patients exhibit progressive spasticity and weakness in the lower limbs. The most common manifestation of HSP is spastic paraplegia type 4 (SPG4), which is caused by mutations in the spastin (SPAST) gene.

The present study reports the clinical characteristics of affected individuals and sequencing analysis of a mutation that caused SPG4 in a family. All affected family members exhibited spasticity and weakness of the lower limbs and, notably, only male members of the family were affected. Whole‑exome sequencing revealed that all affected individuals had a novel c.1785C>A (p. Ser595Arg) missense mutation in SPAST. Bioinformatics analysis revealed changes in both secondary and tertiary structures of the mutated protein.

The novel missense mutation in SPAST supported the diagnosis of SPG4 in this family and expands the spectrum of pathogenic mutations that cause SPG4. Analysis of SPAST sequences revealed that most pathogenic mutations occurred in the AAA domain of the protein, which may have a close relationship with SPG4 pathogenesis.

SOURCE:  Mol Med Rep. 2023 Apr;27(4):79. doi: 10.3892/mmr.2023.12966. Epub 2023 Feb 24. PMID: 36825575

A novel missense mutation in SPAST causes hereditary spastic paraplegia in male members of a family: A case report

Xing-Chen Wang #  1 Rui-Han Liu #  2 Ting Wang  3 Yanling Wang  3 Yan Jiang  4 Dan-Dan Chen  4 Xin-Yu Wang  4 Tong-Shu Hou  5 Qing-Xia Kong 1

1. Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, P.R. China.

2. Department of Pediatrics, Affiliated Hospital of Jining Medical University, Jining, Shandong 272000, P.R. China.

3. Department of Nursing, Affiliated Hospital of Jining Medical University, Jining, Shandong 272000, P.R. China.

4. Clinical Medical College, Jining Medical University, Jining, Shandong 272000, P.R. China.

5. Second Clinical Medical College, Binzhou Medical University, Binzhou, Shandong 256600, P.R. China.

#. Contributed equally.

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