New HSP genotypes & phenotypes

Research from Taiwan, Spain, China, France, USA, South Korea, Italy, Turkiye, India and Brazil

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.

RINT1 gene associated with SPG for the first time

Variants associated with early onset complex spastic paraplegia; impairment in lipid metabolism and mitochondrial function described.


The Rad50 interacting protein 1 (Rint1) is a key player in vesicular trafficking between the ER and Golgi apparatus. Biallelic variants in RINT1 cause infantile-onset episodic acute liver failure (ALF).

Here, we describe 3 individuals from 2 unrelated families with novel biallelic RINT1 loss-of-function variants who presented with early onset spastic paraplegia, ataxia, optic nerve hypoplasia, and dysmorphic features, broadening the previously described phenotype. Our functional and lipidomic analyses provided evidence that pathogenic RINT1 variants induce defective lipid-droplet biogenesis and profound lipid abnormalities in fibroblasts and plasma that impact both neutral lipid and phospholipid metabolism, including decreased triglycerides and diglycerides, phosphatidylcholine / phosphatidylserine ratios, and inhibited Lands cycle. Further, RINT1 mutations induced intracellular ROS production and reduced ATP synthesis, affecting mitochondria with membrane depolarization, aberrant cristae ultrastructure, and increased fission.

Altogether, our results highlighted the pivotal role of RINT1 in lipid metabolism and mitochondria function, with a profound effect in central nervous system development.

SOURCE:  J Clin Invest. 2023 Jul 17;133(14):e162836. doi: 10.1172/JCI162836. PMID: 37463447

RINT1 deficiency disrupts lipid metabolism and underlies a complex hereditary spastic paraplegia

Nathalie Launay  1   2 Montserrat Ruiz  1   2 Laura Planas-Serra  1   2 Edgard Verdura  1   2 Agustí Rodríguez-Palmero  1   3 Agatha Schlüter  1   2 Leire Goicoechea  1   2 Cristina Guilera  1   2 Josefina Casas  4   5 Felix Campelo  6 Emmanuelle Jouanguy  7   8   9 Jean-Laurent Casanova  7   8   9   10   11 Odile Boespflug-Tanguy  12   13 Maria Vazquez Cancela  14 Luis González Gutiérrez-Solana  2   15 Carlos Casasnovas  1   2   16 Estela Area-Gomez  17 Aurora Pujol  1   2   18

1. Neurometabolic Diseases Laboratory, Institut d’Investigació Biomèdica de Bellvitge (IDIBELL), Hospital Duran i Reynals, L’Hospitalet de Llobregat, Barcelona, Spain.

2. CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, ISCIII, Madrid, Spain.

3. Pediatric Neurology unit, Department of Pediatrics, Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona, Spain.

4. Research Unit on BioActive Molecules (RUBAM), Departament de Química Biomèdica, Institut de Química Avançada de Catalunya (IQAC-CSIC), Barcelona, Spain.

5. CIBEREHD, Centro de Investigación Biomédica en Red de Enfermedades heoaticas y digestivas, ISCIII, Madrid, Spain.

6. ICFO-Institut de Ciencies Fotoniques, The Barcelona Institute of Science and Technology, Castelldefels, Spain.

7. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale, UMR 1163, Necker Hospital for Sick Children, Paris, France.

8. University of Paris, Imagine Institute, Paris, France.

9. St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York, USA.

10. Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children, Paris, France.

11. Howard Hughes Medical Institute, New York, New York, USA.

12. CRMR Leukofrance Service de Neuropédiatrie, Hôpital Robert Debré AP-HP, Paris, France.

13. UMR1141 Neurodiderot Université de Paris Cité, Paris, France.

14. Pediatric Neurology Unit, Hospital Teresa Herrera, A Coruña, Spain.

15. Consulta de Neurodegenerativas, Sección de Neurología Pediátrica, Hospital, Infantil Universitario Niño Jesús, Madrid, Spain.

16. Neuromuscular Unit, Neurology Department, Hospital Universitari de Bellvitge, Universitat de Barcelona, L’Hospitalet de Llobregat, Barcelona, Spain.

17. Department of Neurology, Columbia University, New York, New York, USA.

18. Catalan Institution of Research and Advanced Studies (ICREA), Barcelona, Spain.

6 cases of SPG11 compared and with common clinical, radiological, electrodiagnostic and neuropsychological findings described

Background: To analyze the clinical phenotype of hereditary spastic paraplegia (HSP) caused by SPG11 mutations (SPG11-HSP).

Methods: Among the 17 patients with sporadic HSP who performed whole exome sequencing analysis, six were diagnosed with SPG11-HSP. The clinical and radiologic findings and the results of the electrodiagnostic and neuropsychologic tests were reviewed retrospectively.

Results: The median age at onset was 16.5 years (range, 13-38 years). Progressive spastic paraparesis was a core feature, and the median spastic paraplegia rating scale score was 24/52 (range, 16-31 points). Additional major symptoms were pseudobulbar dysarthria, intellectual disability, bladder dysfunction, and being overweight. Minor symptoms included upper limbs rigidity and sensory axonopathy. The median body mass index was 26.2 kg/m2 (range, 25.2-32.3 kg/m2). The thin corpus callosum (TCC) was predominant at the rostral body or anterior midbody, and the ears of the lynx sign was seen in all. The follow-up MRI showed the worsening of periventricular white matter (PVWM) signal abnormalities with ventricular widening or the extension of the TCC. Motor evoked potentials (MEP) to the lower limbs showed an absent central motor conduction time (CMCT) in all subjects. The upper limb CMCT was initially absent in three subjects, although it became abnormal in all at the follow-up. The mini-mental state examination median score was 27/30 (range, 26-28) with selective impairment of the attention/calculation domain. The median score of the full-scale intelligence quotient was 48 (range, 42-72) on the Wechsler Adult Intelligence Scale test.

Conclusion: Attention/calculation deficits and being overweight as well as pseudobulbar dysarthria were common additional symptoms in patients with SPG11-HSP. The rostral body and anterior midbody of the corpus callosum were preferentially thinned, especially in the early stage of the disease. The TCC, PVWM signal changes, and MEP abnormality worsened as the disease progressed.

SOURCE:  Front Neurol. 2023 Jun 15;14:1198728. doi: 10.3389/fneur.2023.1198728. eCollection 2023. PMID: 37396771 Copyright © 2023 Kang, Nam, Kim, Kang, Choi, Lee, Kim and Kim.

Clinical analysis in patients with SPG11 hereditary spastic paraplegia

You-Ri Kang  1 Tai-Seung Nam  1   2 Jae-Myung Kim  1 Kyung Wook Kang  1   2 Seong-Min Choi  1   2 Seung-Han Lee  1   2 Byeong C Kim  1   2 Myeong-Kyu Kim  1   2

1. Department of Neurology, Chonnam National University Hospital, Gwangju, Republic of Korea.

2. Department of Neurology, Chonnam National University Medical School, Gwangju, Republic of Korea.

New SPG54 variant identified

Clinical and brain imaging features of 3 patients compared

Objective: Hereditary spastic paraplegias (HSPs) are a group of inherited neurodegenerative disorders characterized by slowly progressive lower limb spasticity and weakness. HSP type 54 (SPG54) is autosomal recessively inherited and caused by mutations in the DDHD2 gene. This study investigated the clinical characteristics and molecular features of DDHD2 mutations in a cohort of Taiwanese patients with HSP.

Methods: Mutational analysis of DDHD2 was performed for 242 unrelated Taiwanese patients with HSP. The clinical, neuroimaging, and genetic features of the patients with biallelic DDHD2 mutations were characterized. A cell-based study was performed to assess the effects of the DDHD2 mutations on protein expression.

Results: SPG54 was diagnosed in three patients. Among them, two patients carried compound heterozygous DDHD2 mutations, p.[R112Q];[Y606*] and p.[R112Q];[p.D660H], and the other one was homozygous for the DDHD2 p.R112Q mutation. DDHD2 p.Y606* is a novel mutation, whereas DDHD2 p.D660H and p.R112Q have been reported in the literature. All three patients manifested adult onset complex HSP with additional cerebellar ataxia, polyneuropathy, or cognitive impairment. Brain proton magnetic resonance spectroscopy revealed an abnormal lipid peak in thalamus of all three patients. In vitro studies demonstrated that all the three DDHD2 mutations were associated with a considerably lower DDHD2 protein level.

Interpretation: SPG54 was detected in approximately 1.2% (3 of 242) of the Taiwanese HSP cohort. This study expands the known mutational spectrum of DDHD2, provides molecular evidence of the pathogenicity of the DDHD2 mutations, and underlines the importance of considering SPG54 as a potential diagnosis of adult-onset HSP.

SOURCE:  Ann Clin Transl Neurol. 2023 Jul 7. doi: 10.1002/acn3.51850. Online ahead of print. PMID: 37420318 © 2023 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.

Biallelic DDHD2 mutations in patients with adult-onset complex hereditary spastic paraplegia

Ying-Tsen Chou #  1 Shao-Lun Hsu #  1   2 Yu-Shuen Tsai  3 Yi-Jiun Lu  4 Kai-Wei Yu  5 Hsiu-Mei Wu  5 Yi-Chu Liao  1   2   6 Yi-Chung Lee  1   2   6   7   8

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

4. Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan.

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

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

7. Department of Biological Science and Technology, College of Biological Science and Technology, National Yang Ming Chiao Tung University, Hsinchu, Taiwan.

8. Center for Intelligent Drug Systems and Smart Bio-devices (IDS2B), National Yang Ming Chiao Tung University, Hsinchu, Taiwan.

#. Contributed equally.

New variant causing SPG11 found

Neurodegeneration caused by protein trafficking and recycling defects described


We report a 49-year-old patient suffering from spastic paraplegia with a novel heterozygous mutation and analyzed the levels of heat shock proteins (hsp)-27, dopamine (DA), and its metabolites in their cerebrospinal fluid (CSF). The hsp27 protein concentration in the patient’s CSF was assayed by an ELISA kit, while DA levels and its metabolites in the CSF, 3,4-dihydroxyphenylacetic acid (DOPAC), Cys-DA, and Cys-DOPA were measured by HPLC. Whole exome sequencing demonstrated SPG-11 c.1951C>T and novel SYNJ1 c.2614G>T mutations, both heterozygous recessive.

The patient’s DA and DOPAC levels in their CSF were significantly decreased (53.0 ± 6.92 and 473.3 ± 72.19, p < 0.05, respectively) while no differences were found in their Cys-DA. Nonetheless, Cys-DA/DOPAC ratio (0.213 ± 0.024, p < 0.05) and hsp27 levels (1073.0 ± 136.4, p < 0.05) were significantly higher. To the best of our knowledge, the c.2614G>T SYNJ1 mutation has not been previously reported. Our patient does not produce fully functional spatacsin and synaptojanin-1 proteins. In this line, our results showed decreased DA and DOPAC levels in the patient’s CSF, indicating loss of DAergic neurons. Many factors have been described as being responsible for the increased cys-DA/DOPAC ratio, such as MAO inhibition and decreased antioxidant activity in DAergic neurons which would increase catecholquinones and consequently cysteinyl-catechols.

In conclusion, haploinsufficiency of spatacsin and synaptojanin-1 proteins might be the underlying cause of neurodegeneration produced by protein trafficking defects, DA vesicle trafficking/recycling processes, autophagy dysfunction, and cell death leading to hsp27 upregulation as a cellular mechanism of protection and/or to balance impaired protein trafficking.

SOURCE:  Genes (Basel). 2023 Jun 23;14(7):1320.  doi: 10.3390/genes14071320.  PMID: 37510225

Upregulation of Heat-Shock Protein (hsp)-27 in a Patient with Heterozygous SPG11 c.1951C>T and SYNJ1 c.2614G>T Mutations Causing Clinical Spastic Paraplegia

Juan Antonio García-Carmona  1   2 Joaquín Amores-Iniesta  3   4 José Soler-Usero  5 María Cerdán-Sánchez  1 Javier Navarro-Zaragoza  2   6 María López-López  1 Juan José Soria-Torrecillas  1 Ainhoa Ballesteros-Arenas  5 José Antonio Pérez-Vicente  1 Pilar Almela  2   6

1. Department of Neurology, Santa Lucia University Hospital, 30202 Cartagena, Spain.

2.  Group of Clinical & Experimental Pharmacology, Institute for Biomedical Research of Murcia (IMIB), 30120 Murcia, Spain.

3. Department of Animal Health, University of Murcia, 30100 Murcia, Spain.

4. Group of Mycoplasmosis, Epidemiology and Pathogen-Host Interaction, Institute for Biomedical Research of Murcia (IMIB), 30120 Murcia, Spain.

5. Department of Biology and Biochemistry, University of Castilla-León, 09001 Burgos, Spain.

6. Department of Pharmacology, University of Murcia, 30100 Murcia, Spain.

Micro-deletion discovered in PLP1 gene causing SPG2

Detailed disease-causing mechanism proposed

Objectives: Hereditary spastic paraplegia (HSP) is a genetically heterogeneous disease caused by over 70 genes, with a significant number of patients still genetically unsolved. In this study, we recruited a suspected HSP family characterized by spasticity, developmental delay, ataxia and hypomyelination, and intended to reveal its molecular etiology by whole exome sequencing (WES) and long-read sequencing (LRS) analyses.

Methods: WES was performed on 13 individuals of the family to identify the causative mutations, including analyses of SNVs (single-nucleotide variants) and CNVs (copy number variants). Accurate circular consensus (CCS) long-read sequencing (LRS) was used to verify the findings of CNV analysis from WES.

Results: SNVs analysis identified a missense variant c.195G>T (p.E65D) of MORF4L2 at Xq22.2 co-segregating in this family from WES data. Further CNVs analysis revealed a microdeletion, which was adjacent to the MORF4L2 gene, also co-segregating in this family. LRS verified this microdeletion and confirmed the deletion range (chrX: 103,690,507-103,715,018, hg38) with high resolution at nucleotide level accuracy.

Interpretations: In this study, we identified an Xq22.2 microdeletion (about 24.5 kb), which contains distal enhancers of the PLP1 gene, as a likely cause of SPG2 in this family. The lack of distal enhancers may result in transcriptional repression of PLP1 in oligodendrocytes, potentially affecting its role in the maintenance of myelin, and causing SPG2 phenotype. This study has highlighted the importance of noncoding genomic alterations in the genetic etiology of SPG2.

SOURCE:  Ann Clin Transl Neurol. 2023 Jul 20. doi: 10.1002/acn3.51848. Online ahead of print.  PMID: 37475517 © 2023 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.

Microdeletion in distal PLP1 enhancers causes hereditary spastic paraplegia 2

Xun Zhou  1 Yige Wang  2 Runcheng He  2 Zhenhua Liu  2   3   4 Qian Xu  2   3   4 Jifeng Guo  2   3   4 Xinxiang Yan  2   3 Jinchen Li  1   2   3   5 Beisha Tang  1   2   3   4 Sheng Zeng  6 Qiying Sun  1   3   4

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

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

3. National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China.

4. Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, China.

5. Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, China.

6. Department of Geriatrics, The Second Xiangya Hospital, Central South University, Changsha, China.

SPG4 variant identified in 8 of 20 family members covering 4 generations

Background: Hereditary spastic paraplegia 4 (SPG4) caused by spastin (SPAST) gene mutations accounts for 40-45% of hereditary spastic paraplegia (HSP) cases. To search for more genetic evidences for the pathogenesis of HSP, the SPAST genotype and clinical phenotype of a Chinese Han SPG4 family were analysed in this study.

Methods: The clinical data of the proband and his family members were collected. Whole genomic DNA was extracted from peripheral blood, and the gene detection and pathogenicity analysis of mutations were conducted using whole-exome sequencing technology. Suspected pathogenic mutations were identified. Verification within this family was conducted by Sanger sequencing.

Results: Eight (4 males and 4 females) of 20 members in 4 generations had SPG4. All patients presented with the high feet arches (pes cavus), the abnormal gait, the active tendon reflexes of the upper limbs, the hyperreflexia of the lower limbs, and the positive ankle clonus and Babinski’s signs bilaterally. In the proband, we found a heterozygous mutation c.1495C > T in SPAST gene, which was associated with the autosomal dominant SPG4. Both the daughters and granddaughters of the proband in this family were verified to carry this mutation. The clinical characteristics of the SPG4 patients in this family are in line with the simple type of HSP. Heterozygous c.1495C > T is a pathogenic mutation in this family.

Conclusion: In this study, we identified a c.1495C > T mutation in the SPAST gene in a Han Chinese family, enriching the mutation spectrum of SPG4.

SOURCE:  Neurosci Lett. 2023 Aug 24;812:137399. doi: 10.1016/j.neulet.2023.137399. Epub 2023 Jul 19. PMID: 37473796 Copyright © 2023 Elsevier B.V. All rights reserved.

Identification of c.1495C > T mutation in SPAST gene in a family of Han Chinese with hereditary spastic paraplegia

Xiaohong Chen  1 Xinming Li  1 Yu Tan  1 Dejiang Yang  1 Lijun Lu  1 Youqing Deng  2 Renshi Xu  3

1. Department of Neurology, The First Hospital of Nanchang, Nanchang 330006, Jiangxi, China.

2. Department of Neurology, The First Hospital of Nanchang, Nanchang 330006, Jiangxi, China.

3. Department of Neurology, Jiangxi Provincial People’s Hospital, The Clinical College of Nanchang College, The First Affiliated Hospital of Nanchang College, Nanchang 330006, Jiangxi, China.

New SPG76 genetic variants found amongst 3 families

Disease-causing mechanism and symptom profiles for SPG76 expanded by this study


Spastic paraplegia type 76 (SPG76) is a subtype of hereditary spastic paraplegia (HSP) caused by calpain-1 (CAPN1) mutations. Our study described the phenotypic and genetic characteristics of three families with spastic ataxia due to various CAPN1 mutations and further explored the pathogenesis of the two novel mutations. The three patients were 48, 39, and 48 years old, respectively. Patients 1 and 3 were from consanguineous families, while patient 2 was sporadic. Physical examination showed hypertonia, hyperreflexia, and Babinski signs in the lower limbs. Patients 2 and 3 additionally had dysarthria and depression.

CAPN1 mutations were identified by whole-exome sequencing, followed by Sanger sequencing and co-segregation analysis within the family. Functional examination of the newly identified mutations was further explored. Two homozygous mutations were detected in patient 1 (c.213dupG, p.D72Gfs*95) and patient 3 (c.1729+1G>A) with HSP, respectively. Patient 2 had compound heterozygous mutations c.853C>T (p.R285X) and c.1324G>A (p.G442S). Western blotting revealed the p.D72Gfs*95 with a smaller molecular weight than WT and p.G442S. In vitro, the wild-type calpain-1 is mostly located in the cytoplasm and colocalized with tubulin by immunostaining. However, p.D72Gfs*95 and p.G442S abnormally formed intracellular aggregation, with little colocalization with tubulin.

In this study, we identified three cases with SPG76, due to four various CAPN1 mutations, presenting lower limb spasticity and ataxia, with or without bulbar involvement and emotional disorder. Among these, c.213dupG and c.1324G>A are first identified in this paper. The genotype-phenotype correlation of the SPG76 cases reported worldwide was further summarized.

SOURCE:  Neurogenetics. 2023 Jul 19.  doi: 10.1007/s10048-023-00726-8. Online ahead of print. PMID: 37468791 © 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.

Spastic paraplegia type 76 due to novel CAPN1 mutations: three case reports with literature review

Zeyu Zhu #  1 Wenzhe Hou #  1   2 Yuwen Cao  1 Haoran Zheng  1   3 Wotu Tian  4 Li Cao  5

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.

3. School of Medicine, Anhui University of Science and Technology, Huainan, 232001, China.

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

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

#. Contributed equally.

SPAST variant causing pure SPG4 HSP not identified by whole exome sequencing (WES)

RNA sequencing did identify the variant and is recommended where WES fails

Objectives: To diagnose the molecular cause of hereditary spastic paraplegia (HSP) observed in a four-generation family with autosomal dominant inheritance.

Methods: Multiplex ligation-dependent probe amplification (MLPA), whole-exome sequencing (WES), and RNA sequencing (RNA-seq) of peripheral blood leukocytes were performed. Reverse transcription polymerase chain reaction (RT-PCR) and Sanger sequencing were used to characterize target regions of SPAST.

Results: A 121-bp AluYb9 insertion with a 30-bp poly-A tail flanked by 15-bp direct repeats on both sides was identified in the edge of intron 16 in SPAST that segregated with the disease phenotype.

Conclusions: We identified an intronic AluYb9 insertion inducing splicing alteration in SPAST causing pure HSP phenotype that was not detected by routine WES analysis. Our findings suggest RNA-seq is a recommended implementation for undiagnosed cases by first-line diagnostic approaches.

SOURCE: Mov Disord. 2023 Jul 2. doi: 10.1002/mds.29522. Online ahead of print. PMID: 37394769 © 2023 International Parkinson and Movement Disorder Society.

Alu Retrotransposition Event in SPAST Gene as a Novel Cause of Hereditary Spastic Paraplegia

Yi-Jun Chen  1   2   3 Meng-Wen Wang  1 Yu-Sen Qiu  1 Ru-Ying Yuan  1 Ning Wang  1   4 Xiang Lin  1   4 Wan-Jin Chen  1   4

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

2. Department of Geriatrics, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China.

3. Department of Geriatrics, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China.

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

New SPAST variant causing pure SPG4 found in several members of one family

Background: Hereditary spastic paraplegia (HSP) is a group of neurogenetic diseases of the corticospinal tract, accompanied by distinct spasticity and weakness of the lower extremities. Mutations in the spastic paraplegia type 4 (SPG4) gene, encoding the spastin protein, are the major cause of the disease. This study reported a Chinese family with HSP caused by a novel mutation of the SPG4 gene.

Case summary: A 44-year-old male was admitted to our hospital for long-term right lower limb weakness, leg stiffness, and unstable walking. His symptoms gradually worsened, while no obvious muscle atrophy in the lower limbs was found. Neurological examinations revealed that the muscle strength of the lower limbs was normal, and knee reflex hyperreflexia and bilateral positive Babinski signs were detected. Members of his family also had the same symptoms. Using mutation analysis, a novel heterozygous duplication mutation, c.1053dupA, p. (Gln352Thrfs*15), was identified in the SPG4 gene in this family.

Conclusion: A Chinese family with HSP had a novel mutation of the SPG4 gene, which is autosomal dominant and inherited as pure HSP. The age of onset, sex distribution, and clinical manifestations of all existing living patients in this family were analyzed. The findings may extend the current knowledge on the existing mutations in the SPG4 gene.

SOURCE:  World J Clin Cases. 2023 May 16;11(14):3288-3294. doi: 10.12998/wjcc.v11.i14.3288. PMID: 37274038 ©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.

Novel mutation of SPG4 gene in a Chinese family with hereditary spastic paraplegia: A case report

Jie Wang  1 Wei-Ting Bu  2 Mei-Jia Zhu  3 Ji-You Tang  3 Xiao-Min Liu  4

1. Department of Neurology, Shandong Provincial Qianfoshan Hospital, Shandong University of Traditional Chinese Medicine, Jinan 250014, Shandong Province, China.

2. Department of Neurology, Shandong Provincial Qianfoshan Hospital, Weifang Medical University, Jinan 250014, Shandong Province, China.

3. Department of Neurology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan 250014, Shandong Province, China.

4. Department of Neurology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan 250014, Shandong Province, China.

New FARS2 gene variant discovered in an 8 year old

This case of severe, complicated SPG77 is progressing rapidly, which is unexpectedly different from previously reported cases.


Defects in FARS2 are associated with either epileptic phenotypes or a spastic paraplegia subtype known as SPG77. Here, we describe an 8-year-old patient with severe and complicated spastic paraplegia, carrying a missense variant (p.Pro361Leu) and a novel intragenic deletion in FARS2. Of note, the disease is unexpectedly progressing rapidly and in a biphasic way differently from the previously reported cases.

Our study provides the first detailed molecular characterization of a FARS2 deletion and its underlying molecular mechanism, and demonstrates the need for combining different tools to improve the diagnostic rate.

SOURCE:  Front Genet. 2023 Apr 19;14:1130687. doi: 10.3389/fgene.2023.1130687. eCollection 2023. PMID: 37152989 Copyright © 2023 Panzeri, Citterio, Martinuzzi, Ancona, Martini and Bassi.

Case report: A novel FARS2 deletion and a missense variant in a child with complicated, rapidly progressive spastic paraplegia

Elena Panzeri  1 Andrea Citterio  1 Andrea Martinuzzi  2 Vera Ancona  2 Eleonora Martini  2 Maria Teresa Bassi  1

1. Laboratory of Molecular Biology, Scientific Institute IRCCS E. Medea, Bosisio Parini, Italy.

2. Department of Neurorehabilitation, Scientific Institute IRCCS E. Medea, Conegliano, Italy.

PYCR2 gene associated with HSP alone for the first time

Newly found variant responsible for childhood-onset HSP

Objectives: PYCR2 gene variants are extremely rare and associated with hypomyelinating leukodystrophy type 10 with microcephaly (HLD10). The aim of the present study is to report the clinical findings of patients having a novel PYCR2 gene variant that manifest Hereditary Spastic Paraplegia (HSP) as the only symptom, without hypomyelinating leukodystrophy. This is the first study that reports PYCR2 gene variants as a cause of HSP in late childhood. We believe it can contribute to expanding the spectrum of the phenotypes associated with PYCR2.

Methods: It is a retrospective study. Of the patients with similar clinical features from two related families, “patient 1” was designated as the index case, and was analyzed using Whole Exome Sequence analysis (WES). The detected variation was investigated in the index case’s parents, relatives, and sibling with a similar phenotype. Clinical, brain magnetic resonance (MR) images and MR spectroscopic findings of the patients were reported.

Results: A novel homozygous missense (NM_013328: c.383T > C, p.V128A) variant in the PYCR2 gene is detected in 5 patients from 2 related families. All the patients were male, their ages ranges from 6 to 26 years (15.58 ± 8.33 yrs). Developmental milestones were normal without dysmorphic features. 4 patients (%80) exhibit mild intention tremor, which started at the age of approximately 6 years. 4 patients (%80) had gait difficulty and progressive lower limb spasticity, which are started at the age of 8-12 years. White matter myelination was normal in all patients. Glycine peaks were detected on the MR spectroscopy in all patients.

Conclusion: Some variants of the PYCR2 gene are responsible for causing clinical features of HSP without hypomyelinating leukodystrophy in pediatric patients.

SOURCE:  Eur J Paediatr Neurol. 2023 May;44:51-56. doi: 10.1016/j.ejpn.2023.04.002. Epub 2023 Apr 28. PMID: 37141741 © 2023 Published by Elsevier Ltd on behalf of European Paediatric Neurology Society.

Pyrroline-5-carboxylate reductase 2 (PYCR2) deficiency causes hereditary spastic paraplaegia in late childhood

Gunes Sager  1 Ayberk Türkyilmaz  2 Hediye Pınar Günbey  3 İbrahim Taş  4 Fatih Ozhelvaci  5 Yasemin Akin  6

1. Department of Pediatric Neurology, Kartal Dr. Lutfi Kirdar City Hospital, Istanbul, Turkiye

2. Department of Medical Genetics, Karadeniz Technical University Faculty of Medicine, Trabzon, Turkiye.

3. Department of Radiology, Kartal Dr. Lutfi Kirdar City Hospital, Istanbul, Turkiye.

4. Department of Pediatric Metabolism, Umraniye Training and Research Hospital, Istanbul, Turkiye.

5. Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland.

6. Department of Pediatrics, Kartal Dr. Lutfi Kirdar City Hospital, Istanbul, Turkiye.

Case report of 53-year-old with SPG48


Hereditary spastic paraplegias (HSP) are inherited neurodegenerative disorders characterized by progressive paraplegia and spasticity in the lower limbs. SPG48 represents a rare genotype characterized by mutations in AP5Z1, a gene playing a role in intracellular membrane trafficking. This study describes a case of a 53-year-old male patient with SPG48 presenting spastic paraplegia, infertility, hearing impairment, cognitive abnormalities and peripheral neuropathy. The Sanger sequencing revealed a homozygous deletion in the chr 7:4785904-4786677 region causing a premature stop codon in exon 10. The patient’s brother was heterozygous for the mutation. The brain magnetic resonance imaging found a mild brain atrophy and white matter lesions. In the analysis of the auditory thresholds, we found a significant hearing decrease in both ears.

SOURCE:  Front Neurol. 2023 Apr 3;14:1156100. doi: 10.3389/fneur.2023.1156100. eCollection 2023. PMID: 37077568 Copyright © 2023 Jin, Wang, Nian, Wang and Fu.

Hereditary spastic paraplegia (SPG 48) with deafness and azoospermia: A case report

Ping Jin  1 Yu Wang  1 Na Nian  1 Gong-Qiang Wang  1 Xiao-Ming Fu  1   2

1. Department of Neurology, The Affiliated Hospital of Institute of Neurology, Anhui University of Chinese Medicine, Hefei, China.

2. Institute of Neurology, Anhui University of Chinese, Hefei, China.

New sporadic variant in FAR1 gene identified, causing complex HSP


FAR1 (MIM *616107) is required for the reduction of fatty acyl CoAs to fatty alcohols which is important for plasmalogen biosynthesis. Recently, heterozygous de novo variants in FAR1 have been associated with cataracts, spastic paraparesis, and speech delay (MIM# 619338). Three different heterozygous de novo variants, all located in the same codon, causing substitution of arginine at position 480 into cysteine, histidine, or leucine, were reported in patients with the latter disorder. Here, the authors have identified a novel substitution in the same Arg480 position into serine. The authors also provide in silico docking analysis of the mutant protein.

SOURCE:  Indian J Pediatr. 2023 Jun 19. doi: 10.1007/s12098-023-04652-3. Online ahead of print. PMID: 37335441 © 2023. The Author(s), under exclusive licence to Dr. K C Chaudhuri Foundation.

Complex Hereditary Spastic Paraparesis Caused by de novo p.Arg480Ser in FAR1

Arya Shambhavi  1 Amita Moirangthem  1 Manmohan Pandey  1 Shubha R Phadke  2

1. Department of Medical Genetics, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Raebareli Road, Lucknow, Uttar Pradesh, 226014, India.

2. Department of Medical Genetics, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Raebareli Road, Lucknow, Uttar Pradesh, 226014, India.

2 new SPG45 variants discovered in 5-year-old child


In hereditary spastic paraplegias (HSPs), magnetic resonance imaging (MRI) scans of the brain typically show the involvement of the anterior part of the corpus callosum with abnormalities in the white matter fibers of the forceps minor (“ears of the lynx” sign). However, these imaging findings are particularly associated with spastic paraplegia type 11 (SPG11) or spastic paraplegia type 15 (SPG15). 1

A child with spastic gait achieved independent walking at the age of 2 years, and 3 years later was referred to our service for investigation. A brain MRI demonstrated corpus callosum dysgenesis and peritrigonal white matter abnormality. Whole exome sequencing revealed compound heterozygosity for two novel likely pathogenic variants in NT5C2 (p.[Leu468Pro] and p.[Gln542Argfs*71]), consistent with SPG45, of the SPG subtypes with thin corpus callosum. 2

SOURCE: Arq Neuropsiquiatr. 2023 Mar;81(3):322-323.  doi: 10.1055/s-0043-1763299. Epub 2023 Apr 14. PMID: 37059441

Dysgenesis of the posterior segment of the corpus callosum: don’t miss SPG45!

Daniel de Faria Guimarães  1   2 Ana Luiza Viegas de Almeida  3 Felipe Alba Scortegagna  1   2 Renato Hoffmann Nunes  1   2 Simone Consuelo Amorim  3 Felipe Torres Pacheco  1   2 Fernando Kok  4   5 Antonio José da Rocha  1   2

1. Santa Casa de Misericórdia de São Paulo, Faculdade de Ciências Médicas, Departamento de Radiologia, São Paulo SP, Brazil.

2. Grupo DASA São Paulo, Departamento de Radiologia, São Paulo SP, Brazil.

3. Clínica Vita, Departamento de Neurologia Pediátrica, São Paulo SP, Brazil.

4. Universidade de São Paulo, Faculdade de Medicina, Departamento de Neurologia, São Paulo SP, Brazil.

5. Mendelics Análise Genômica, São Paulo SP, Brazil.

2 new GBA2 gene variants suspected of causing SPG46

Sporadic case of HSP in 21-year-old with phenotype described

Objective: To present a case of Hereditary Spastic Paraplegia (HSP) 46 with distinct imaging and clinical findings, with two novel variants in GBA2, previously classified as variants of undetermined significance (VUS).

Background: HSP is an uncommon cause of lower extremity spasticity and weakness. There have been many genetic etiologies identified with various clinical features. HSP 46 is an autosomal recessive, slowly progressive form of HSP caused by biallelic pathogenic variants in GBA2.

Design/Methods: NA (Case report)

Results: A 21-year-old man presented with progressive lower extremity weakness and ambulatory dysfunction. Symptom onset was in second grade, when he was found to have difficulty walking and inversion of the right foot. His ambulatory dysfunction continued to progress. Extensive serologic testing was negative, as was MRI of his spinal cord. Brain MRI demonstrated thinning of the corpus collosum. Examination approximately 12 years after his initial presentation was notable for diffuse hyperreflexia, bilateral lower extremity spasticity, and bilateral Hoffmann and Babinski signs. He had excessive lower extremity circumduction in swing phase, hyperextension at the knees, and internal rotation at the hips; consistent with a scissoring gait. There were no cranial neuropathies, sensory deficits, or cerebellar ataxia. The family history was negative. Genetic testing via whole-exome sequencing demonstrated compound heterozygous GBA2 variants, both classified as VUS: c.1820 A>G (p.N607S) and c.472 G>A (p.G158R).

Conclusions: Considering the distinctive clinical features, MRI finding of dysgenesis of the corpus collosum, and absence of an alternative explanation, we propose that the GBA2 variants found in this patient may be causative. Functional studies and/or messenger ribonucleic acid sequencing may confirm our hypothesis.

SOURCE:  Neurology Apr 2023, 100 (17 Supplement 2) 3171 doi: 10.1212/WNL.0000000000203075

A Rare Case of Hereditary Spastic Paraplegia 46 With Novel Compound Heterozygous GBA2 gene variants (P3-8.013)

Sandeep Gill, Sukhraj Gill, Madeline Williamson, J. David Avila

Geisinger Medical Center, Pennsylvania USA

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