Research from USA, Germany, Brazil, UK, China, Taiwan, Iran, Azerbaijan, Pakistan
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.
Severe and complex HSP results from sporadic SPG4 variants in children
Background: Familial hereditary spastic paraplegia (HSP)-SPAST (SPG4) typically presents with a pure HSP phenotype.
Objective: The aim of this study was to delineate the genotypic and phenotypic spectrum of children with de novo HSP-SPAST.
Methods: This study used a systematic cross-sectional analysis of clinical and molecular features.
Results: We report the clinical and molecular spectrum of 40 patients with heterozygous pathogenic de novo variants in SPAST (age range: 2.2-27.7 years). We identified 19 unique variants (16/40 carried the same recurrent variant, p.Arg499His). Symptom onset was in early childhood (median: 11.0 months, interquartile range: 6.0 months) with significant motor and speech delay, followed by progressive ascending spasticity, dystonia, neurogenic bladder dysfunction, gastrointestinal dysmotility, and epilepsy. The mean Spastic Paraplegia Rating Scale score was 32.8 ± 9.7 (standard deviation).
Conclusions: These results confirm that de novo variants in SPAST lead to a severe and complex form of HSP that differs from classic familial pure HSP-SPAST. Clinicians should be aware of this syndrome in the differential diagnosis for cerebral palsy.
SOURCE: Mov Disord. 2022 Sep 14. doi: 10.1002/mds.29225. Online ahead of print. PMID: 36103453 © 2022 International Parkinson and Movement Disorder Society.
Early-Onset and Severe Complex Hereditary Spastic Paraplegia Caused by De Novo Variants in SPAST
Alisa Mo 1 , Afshin Saffari 1 , Melanie Kellner 2 3 , Marion Döbler-Neumann 4 , Catherine Jordan 1 , Siddharth Srivastava 1 , Bo Zhang 1 5 , Mustafa Sahin 1 , John K Fink 6 , Linsley Smith 7 , Jennifer E Posey 8 , Katharine E Alter 9 , Camilo Toro 10 , Craig Blackstone 11 , Ariane G Soldatos 12 , Michelle Christie 7 , Rebecca Schüle 2 3 , Darius Ebrahimi-Fakhari 1 13 14 15
1. Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA.
2. Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research and Center of Neurology, University of Tübingen, Tübingen, Germany.
3. German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
4. Department of Pediatric Neurology, University Children’s Hospital, Tübingen, Germany.
5. ICCTR Biostatistics and Research Design Center, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA.
6. Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA.
7. Department of Neurology and Rehabilitation Medicine, Texas Scottish Rite Hospital, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
8. Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
9. Functional and Applied Biomechanics Section, Department of Rehabilitation Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA.
10. Undiagnosed Diseases Program, National Institutes of Health, Bethesda, Maryland, USA.
11. Movement Disorders Division, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
12. National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.
13. Movement Disorders Program, Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA.
14. The Manton Center for Orphan Disease Research, Boston Children’s Hospital, Boston, Massachusetts, USA.
15. Intellectual and Developmental Disabilities Research Center, Boston Children’s Hospital, Boston, Massachusetts, USA.
Arginase deficiency related to pathogenic variants in the ARG1 gene result in complicated HSP. This disease may represent a specific entity amongst the complicated HSPs.
Three previously unidentified variants discovered.
Introduction: Argininemia or arginase deficiency is a metabolic disorder caused by pathogenic variants in ARG1 and consists of a variable association of progressive spastic paraplegia, intellectual disability, and seizures. Hereditary spastic paraplegia (HSP) is a group of inherited diseases whose main feature is a progressive gait disorder characterized by lower limb spasticity. This study presents 7 patients with arginase 1 deficiency from 6 different families, all with an initial diagnosis of complicated HSP.
Methods: We evaluated the clinical data of 7 patients belonging to six independent families who were diagnosed with hyperargininemia in a neurogenetics outpatient clinic.
Results: All patients had lower limb spasticity and six had global developmental delay. Five individuals had intellectual disability and two had epilepsy. Psychiatric abnormalities were seen in two patients. In two participants of this study, MRI disclosed thinning of the corpus callosum. Molecular diagnosis was made by whole exome sequencing. All variants were present in homozygosis; we identified two novel missense variants, one novel frameshift variant, and one previously published missense variant.
Discussion: Clinical diagnosis of early onset complicated hereditary spastic paraplegia was made in all patients. Two patients were initially suspected of having SPG11 due to thinning of the corpus callosum. As argininemia may present with a highly penetrant phenotype of spastic paraplegia associated with additional symptoms, this disease may represent a specific entity amongst the complicated HSPs.
SOURCE: Cold Spring Harb Mol Case Stud. 2022 Sep 30;mcs.a006232. doi: 10.1101/mcs.a006232. Online ahead of print. PMID: 36180229
Arginase 1 deficiency presenting as complicated hereditary spastic paraplegia
Fernando Freua 1 , Mariana Espíndola de Castro Almeida 2 , Paulo Ribeiro Nóbrega 2 , Anderson Rodrigues Brandáo de Paiva 2 , Bruno Della-Ripa 2 , Paulina Cunha 2 , Lúcia Inês Macedo-Souza 2 , Clarissa Bueno 2 , David S Lynch 3 , Henry Houlden 3 , Leandro Tavares Lucato 4 , Fernando Kok 5
1. Neurogenetics Outpatient, Department of Neurology, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
2. Neurogenetics Outpatient, Department of Neurology, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
3. Department of Neuromuscular Disease, UCL Institute of Neurology, Queen Square, London, UK.
4. Department of Radiology, Hospital das Clínicas da Faculdade de Medicina da Universidade de Sáo Paulo, Sáo Paulo, Brazil.
5. Neurogenetics Outpatient, Department of Neurology, Hospital das Clínicas da Faculdade de Medicina da Universidade de Sáo Paulo, Sáo Paulo, Brazil.
Clinical and genetic spectrum of hereditary spastic paraplegia in Chinese children
Aim: To explore the clinical and genetic spectrum of hereditary spastic paraplegia (HSP) in Chinese children.
Method: This retrospective study was conducted between January 2014 and October 2021 in children clinically diagnosed with either pure HSP (pHSP) or complex HSP (cHSP).
Results: We investigated 45 children (32 males, 13 females; mean age [SD] at symptom onset 4 years [7 months]) clinically diagnosed with HSP and identified genetic causes in 35 patients. Most patients with autosomal dominant HSP had pHSP (16/18), whereas most patients with autosomal recessive HSP tended to have cHSP (14/16). SPG11 was the most common autosomal recessive subtype, followed by FA2H/SPG35, whereas SPAST/SPG4 was the most frequent cause of autosomal dominant HSP. Two patients with CPT1C mutations presented with a complex phenotype. Meanwhile, 10 patients were found to have likely pathogenic variants / variants of uncertain clinical significance in six genes related to HSP.
Interpretation: SPG11 and SPG4 were the most frequent subtypes in Chinese children with autosomal recessive HSP and autosomal dominant HSP. However, the prevalence of SPG4 was much lower than that in adults, which might be explained by the late onset of the disease. On the other hand, FA2H/SPG35 was common in our cohort, while it contributed to only a small proportion of adult cases, which might be explained by its rapid progression and early death in some patients. We also expanded the genetic and clinical spectra of SPG73.
SOURCE: Dev Med Child Neurol. 2022 Sep 15. doi: 10.1111/dmcn.15385. Online ahead of print. PMID: 36109173 © 2022 Mac Keith Press.
Clinical and genetic spectrum of hereditary spastic paraplegia in Chinese children
Jiaping Wang 1 , Fang Fang 1 , Changhong Ding 1 , Jiuwei Li 1 , Yun Wu 1 , Weihua Zhang 1 , Xinhua Bao 2 , Junlan Lv 1 , Xiaohui Wang 1 , Xiaotun Ren 1 , Paediatric Neurology Study Group
Collaborators – Paediatric Neurology Study Group: Jianbo Zhao, Hongmei Wang
1. Department of Neurology, Beijing Children’s Hospital, Capital Medical University, Beijing, China.
2. Department of Paediatric Neurology, Peking University First Hospital, Beijing, China.
Assessing the long-term course and mutational spectrum in SPG11
Not only frameshift and nonsense mutations but also splice mutations result in SPG11. Mutations are distributed throughout the spatacsin gene and are associated with severe motor and cognitive impairment.
Objective: Hereditary spastic paraplegias (HSPs) comprise a heterogeneous group of neurodegenerative disorders resulting in progressive spasticity of the lower limbs. One form of autosomal recessive hereditary spastic paraplegia (ARHSP) with thin corpus callosum (TCC) was linked to chromosomal region 15q13-21 (SPG11) and associated with mutations in the spatacsin gene. We assessed the long-term course and the mutational spectrum of spatacsin-associated ARHSP with TCC.
Methods: Neurological examination, cerebral magnetic resonance imaging (MRI), 18fluorodeoxyglucose positron emission tomography (PET), nerve biopsy, linkage and mutation analysis are presented.
Results: Spastic paraplegia in patients with spatacsin mutations (n = 20) developed during the second decade of life. The Spastic Paraplegia Rating Scale (SPRS) showed severely compromised walking between the second and third decades of life (mean SPRS score, >30). Impaired cognitive function was associated with severe atrophy of the frontoparietal cortex, TCC, and bilateral periventricular white matter lesions. Progressive cortical and thalamic hypometabolism in the 18fluorodeoxyglucose PET was observed. Sural nerve biopsy showed a loss of unmyelinated nerve fibers and accumulation of intra-axonal pleomorphic membranous material. Mutational analysis of spatacsin demonstrated six novel and one previously reported frameshift mutation and two novel nonsense mutations. Furthermore, we report the first two splice mutations to be associated with SPG11.
Interpretation: We demonstrate that not only frameshift and nonsense mutations but also splice mutations result in SPG11. Mutations are distributed throughout the spatacsin gene and emerge as major cause for ARHSP with TCC associated with severe motor and cognitive impairment. The clinical phenotype and the ultrastructural analysis suggest a disturbed axonal transport of long projecting neurons.
SOURCE: Ann Neurol. 2007 Dec;62(6):656-65. doi: 10.1002/ana.21310. PMID: 18067136
Long-term course and mutational spectrum of spatacsin-linked spastic paraplegia
Ute Hehr 1 , Peter Bauer, Beate Winner, Rebecca Schule, Akguen Olmez, Wolfgang Koehler, Goekhan Uyanik, Anna Engel, Daniela Lenz, Andrea Seibel, Andreas Hehr, Sonja Ploetz, Josep Gamez, Arndt Rolfs, Joachim Weis, Thomas M Ringer, Michael Bonin, Gerhard Schuierer, Joerg Marienhagen, Ulrich Bogdahn, Bernhard H F Weber, Haluk Topaloglu, Ludger Schols, Olaf Riess, Juergen Winkler
1. Department of Human Genetics, University of Regensburg, Regensburg, Germany.
Novel variant and population study of KIF1A related HSP in Taiwan
SPG30 accounts for 1.2% (3/242) of patients in the Taiwanese HSP cohort, suggesting that it is an uncommon HSP subtype in Taiwan.
Background: Hereditary spastic paraplegia (HSP) is a heterogeneous group of inherited neurodegenerative disorders characterized by slowly progressive lower limbs spasticity and weakness. HSP type 30 (SPG30) is a HSP subtype caused by mutations in the kinesin family member 1A gene (KIF1A) and could be either autosomal dominantly or recessively inherited. The aim of this study was to investigate the clinical and genetic features of KIF1A mutations in a Taiwanese HSP cohort.
Methods: Mutational analysis of KIF1A was performed in 242 unrelated Taiwanese patients of Han Chinese ethnicity with clinically suspected HSP using targeted resequencing panel covering the entire coding regions of KIF1A. Clinical, electrophysiological and neuroimaging features of the HSP patients carrying a KIF1A mutation were characterized.
Results: Three different KIF1A mutations were identified in three patients with autosomal dominantly inherited HSP. Among them, KIF1A p.E19K was a novel mutation. The patient harboring KIF1A p.G321D presented with pure HSP, while the individuals carrying KIF1A p.E19K or p.R316Q manifested complex HSP with additional axonal sensorimotor polyneuropathy. The patients carrying KIF1A p.R316Q also had thoracic cord atrophy, thin corpus callosum and white matter hyperintensity.
Conclusion: SPG30 accounts for 1.2% (3/242) of patients in the Taiwanese HSP cohort, suggesting that it is an uncommon HSP subtype in Taiwan. This study delineates the clinical and genetic features of SPG30 in Taiwan and provides useful information for the diagnosis and management of SPG30, especially in patients of Han Chinese descent.
SOURCE: Parkinsonism Relat Disord. 2022 Oct;103:144-149. doi: 10.1016/j.parkreldis.2022.09.001. Epub 2022 Sep 16. PMID: 36155026 Copyright © 2022 Elsevier Ltd. All rights reserved.
Investigating KIF1A mutations in a Taiwanese cohort with hereditary spastic paraplegia
Shao-Lun Hsu 1 , Yi-Chu Liao 2 , Kon-Ping Lin 1 , Po-Yu Lin 3 , Kai-Wei Yu 4 , Yu-Shuen Tsai 5 , Yuh-Cherng Guo 6 , Yi-Chung Lee 7
1. Department of Neurology, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Neurology, National Yang Ming Chiao Tung University School of Medicine, Taipei, Taiwan.
2. Department of Neurology, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Neurology, National Yang Ming Chiao Tung University School of Medicine, Taipei, Taiwan; Brain Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan.
3. Department of Neurology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, 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. Department of Neurology, China Medical University Hospital, Taichung, Taiwan; School of Medicine, China Medical University, Taichung, Taiwan; Neuroscience and Brain Disease Center, College of Medicine, China Medical University, Taichung, Taiwan.
7. Department of Neurology, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Neurology, National Yang Ming Chiao Tung University School of Medicine, Taipei, Taiwan; Brain Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan.
New HSP variants in SPG9 and SPG11 discovered
Hereditary spastic paraplegia is an uncommon inherited neurological disorder with heterogeneous clinical expressions. ALDH18A1 (located on 10q24.1) gene-related spastic paraplegias (SPG9A and SPG9B) are rare metabolic disorders caused by dominant and recessive mutations that have been found recently.
Autosomal recessive hereditary spastic paraplegia is a common and clinical type of familial spastic paraplegia linked to the SPG11 locus (locates on 15q21.1). There are different symptoms of spastic paraplegia, such as muscle atrophy, moderate MR, short stature, balance problem, and lower limb weakness.
Our first proband involves a 45 years old man and our second proband involves a 20 years old woman both are affected by spastic paraplegia disease. Genomic DNA was extracted from the peripheral blood of the patients, their parents, and their siblings using a filter-based methodology and quantified and used for molecular analysis and sequencing. Sequencing libraries were generated using Agilent SureSelect Human All ExonV7 kit, and the qualified libraries are fed into NovaSeq 6000 Illumina sequencers. Sanger sequencing was performed by an ABI prism 3730 sequencer.
Here, for the first time, we report two cases, the first one which contains likely pathogenic NM_002860: c.475C>T: p.R159X mutation of the ALDH18A1 and the second one has likely pathogenic NM_001160227.2: c.5454dupA: p.Glu1819Argfs Ter11 mutation of the SPG11 gene and also was identified by the whole-exome sequencing and confirmed by Sanger sequencing. Our aim with this study was to confirm that these two novel variants are direct causes of spastic paraplegia.
SOURCE: Genomics Inform. 2022 Sep;20(3):e30. doi: 10.5808/gi.22030. Epub 2022 Sep 30. PMID: 36239107
Two novel mutations in ALDH18A1 and SPG11 gene found by whole-exome sequencing in spastic paraplegia disease patients in Iran
Sajad Rafiee Komachali 1 2 3 , Zakieh Siahpoosh 3 , Mansoor Salehi 1 2
1. Cellular, Molecular and Genetics Research Center, Isfahan University of Medical Sciences, Isfahan, Iran.
2. Medical Genetics Research Center of Genome, Isfahan University of Medical Sciences, Isfahan, Iran.
3. Dept of Biology, Faculty of Science, University of Sistan and Baluchestan, Zahedan, Iran.
New frame shift variant in SPG51 identified
AP-4-associated hereditary spastic paraplegia (HSP), also known as AP-4 deficiency syndrome, is a genetically diverse group of neurologic disorders defined by complex spastic paraplegia. Different forms of AP-4-associated HSP are classified by chromosomal locus or causative gene. Spastic paraplegia 51 (SPG51) is a neurodevelopmental condition that is caused by autosomal recessive mutations in the adaptor protein complex 4 complex subunit 1 (AP4E1) gene. Further, previous studies described an autosomal dominant mutation in the AP4E1 gene has also been linked to persistent stuttering.
Here, we describe a patient from a consanguineous marriage who manifested severe intellectual disability (ID), absent speech, microcephaly, seizure, and movement disorders. Exome sequencing identified a novel homozygous frame-shift variant (NM_007347.5:c.3214_3215del, p.Leu1072AlafsTer10) in the AP4E1 gene, which was confirmed by Sanger sequencing. In this study, we also reviewed the phenotype of the former cases. Our findings added to the knowledge of little-studied homozygous AP4E1 mutation.
SOURCE: J Genet. 2022;101:40. PMID: 36226339
Spastic paraplegia 51: phenotypic spectrum related to novel homozygous AP4E1 mutation
Jamal Manoochehri 1 , Hamed Reza Goodarzi, Seyed Mohammad Bagher Tabei
1. Department of Genetics, Marvdasht Branch, Islamic Azad University, Marvdasht, Iran.
Range of SPG47 clinical features described
Background: Hereditary spastic paraplegias (HSP) are a group of neurodegenerative diseases that present with weakness and stiffness in the lower limb muscles and lead to progressive neurological decline. Bi-allelic loss-of-function variants in genes that encode subunits of the adaptor protein complex 4 (AP-4) lead to complex HSP. This study aimed to identify causative genetic variants in consanguineous families with HSP from Azerbaijan and Pakistan.
Methods: We performed a thorough clinical and neuroradiological characterization followed by exome sequencing in 7 patients from 3 unrelated families. Segregation analysis was subsequently performed by Sanger sequencing.
Results: We describe 7 patients (4 males, 2-31 years of age) with developmental delay and spasticity. Similar to the previously reported cases with AP4B1-associated HSP, cases in the present report besides spasticity in the lower limbs had additional features including microcephaly, facial dysmorphism, infantile hypotonia, and epilepsy. The imaging findings included thin corpus callosum, white matter loss, and ventriculomegaly.
Conclusion: In this study, we report 7 novel cases of HSP caused by bi-allelic variants in AP4B1 in Azerbaijani and Pakistani families. Our observations will help clinicians observe and compare common and unique clinical features of AP4B1-associated HSP patients, further improving our current understanding of HSP.
SOURCE: Eur J Med Genet. 2022 Nov;65(11):104620. doi: 10.1016/j.ejmg.2022.104620. Epub 2022 Sep 16. PMID: 36122674 Copyright © 2022 Elsevier Masson SAS. All rights reserved.
AP4B1-associated hereditary spastic paraplegia: Expansion of clinico-genetic phenotype and geographic range
Kamran Salayev 1 , Clarissa Rocca 2 , Rauan Kaiyrzhanov 2 , Ulviyya Guliyeva 3 , Sughra Guliyeva 3 , Aytan Mursalova 4 , Fatima Rahman 5 , Najwa Anwar 5 , Faisal Zafar 6 , Farida Jan 7 , Nuzhat Rana 6 , Shazia Maqbool 5 , SYNAPS Study Group 2 ; QUEEN SQUARE Genomics 2 ; Stephanie Efthymiou 2 , Henry Houlden 8
1. Azerbaijan Medical University, Department of Neurology, Baku, AZ, 1010, Azerbaijan.
2. University College London, Institute of Neurology, Department of Neuromuscular Disorders, Queen Square, WC1N 3BG, London, UK.
3. MediClub Hospital, 45, Uzeyir Hajibeyli Str., Baku, AZ, 1010, Azerbaijan.
4. Baku City Gerontologic Centre, Azadliq Ave., Baku, Azerbaijan.
5. Development and Behavioral Pediatrics Department, Institute of Child Health and the Children Hospital, Lahore, 54000, Pakistan.
6. Department of Paediatric Neurology, Children’s Hospital and Institute of Child Health, Multan, Pakistan.
7. Department of Paediatrics and Child Health, Aga Khan University Hospital, Karachi, Pakistan.
8. University College London, Institute of Neurology, Department of Neuromuscular Disorders, Queen Square, WC1N 3BG, London, UK.
New variant discovered causing childhood-onset SPG54
Background: Spastic paraplegia type 54 (SPG54) is a rare inherited autosomal recessive disorder, and a complex hereditary spastic paraplegia (HSP) caused by mutations in the phospholipase DDHD2 gene. SPG54 is characterized by early onset of spastic paraplegia, intellectual disability and dysplasia of corpus callosum.
Case presentation: We report a 9 years and 5 months old Chinese girl with progressive spasm of the lower limbs, muscle weakness and intellectual disability. Brain magnetic resonance imaging (MRI) showed periventricular leukomalacia and thinning of the corpus callosum. According to the Wechsler Intelligence Scale, her IQ is 42. By whole exome sequencing, novel compound heterozygous missense mutations in the DDHD2 gene [c.168G>C, p.(Trp56Cys) and c.1505T>C, p.(Phe502Ser)] were identified in the proband. Comparative amino acid sequence alignment across different species revealed that Trp56 and Phe502 in the DDHD2 protein were highly conserved during evolution. And multiple in silico prediction tools suggested that both mutations were deleterious.
Conclusions: Our study reports a very rare case of complicated HSP caused by two novel compound heterozygous mutations in the DDHD2 gene. Our findings expand the genetic spectrum of SPG54.
SOURCE: Front Pediatr. 2022 Aug 26;10:997274. doi: 10.3389/fped.2022.997274. eCollection 2022. PMID: 36090575 Copyright © 2022 Xu, Lu, Du, Zhao, Li, Zhang and Tang.
Case report: Novel compound heterozygous missense mutations in the DDHD2 gene in a Chinese patient associated with spastic paraplegia type 54
Xin Xu 1 , Fen Lu 1 , Senjie Du 1 , Xiaoke Zhao 1 , Hongying Li 1 , Li Zhang 1 , Jian Tang 1
1 Department of Rehabilitation, Children’s Hospital of Nanjing Medical University, Nanjing, China.
New RNF170 variant found to cause adolescent-onset SPG85
Hereditary spastic paraplegia (HSP) is a heterogeneous group of inherited neurodegenerative disease characterized by progressive lower limb spasticity. Recent studies revealed that biallelic variants in RNF170 gene cause autosomal recessive complicated HSP with infancy onset.
Here, we report an adolescent-onset HSP patient from a consanguineous Chinese family, with lower extremity stiffness, spastic gait, and unstable straight-line walking as the main manifestations. Whole-exome sequencing identifies a novel RNF170 mutation c.190C>T (p.R64*), which co-segregates with the disease in this pedigree. Functional analysis, including quantitative real-time PCR (RT-qPCR) and Western blot, indicates that both the mRNA and protein levels of mutant RNF170 are significantly reduced, which confirms the loss-of-function mechanism.
Our study expands the spectrum of RNF170-associated HSP, while the RNF170 protein-involved degradation of the inositol 1,4,5-trisphosphate receptor in neurodegenerative motor neuron disorders deserves further investigation.
SOURCE: Clin Genet. 2022 Aug 31. doi: 10.1111/cge.14219. Online ahead of print. PMID: 36046950 © 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
Novel stop-gain RNF170 variation detected in a Chinese family with adolescent-onset hereditary spastic paraplegia
Jing-Xin Fu 1 , Qiao Wei 1 , Yu-Lan Chen 1 2 , Hong-Fu Li 1 2 3
1. Department of Neurology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
2. Department of Medical Genetics, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
3. MOE Frontier Science Center for Brain Research and Brain-Machine Integration, Zhejiang University, Hangzhou, China.