ABSTRACT
Spastic paraplegia type 4 (SPG4) is the most common type of autosomally inherited spastic paraplegia. Its main clinical features include typical simple hereditary spastic paraplegia, with neurological impairments limited to lower limb spasticity, hypertonic bladder dysfunction, and mild weakening of lower limb vibration sensation, without accompanying features such as nerve atrophy, ataxia, cognitive impairment, seizures, and muscle tone disorders. SPAST is the main pathogenic gene underlying SPG4, and various pathogenic SPAST variants have been discovered. This disease has featured a high degree of clinical heterogeneity, and the same pathogenic variant can have different age of onset and severity among different patients and even within the same family. There is a lack of systematic research on the correlation between the genotype and phenotype of SPG4, and the pathogenic mechanism has remained controversial. This article has provided a review for the clinical characteristics, pathogenic gene characteristics, correlation between the genotype and phenotype, and pathogenic mechanism of this disease, with an aim to provide reference for its clinical diagnosis and treatment.
Subject(s)
Humans , Spastic Paraplegia, Hereditary/genetics , Mutation , Spastin/genetics , Paraplegia/genetics , PhenotypeABSTRACT
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.
Subject(s)
Humans , Male , Female , East Asian People , Kinesins/genetics , Mutation , Pedigree , Spastic Paraplegia, Hereditary/geneticsABSTRACT
OBJECTIVE@#To analyze the clinical phenotype and genetic characteristics of a child with Hereditary spastic paraplegia (HSP).@*METHODS@#A child with HSP who was admitted to the Third Affiliated Hospital of Zhengzhou University on August 10, 2020 due to discovery of tiptoeing for 2 years was selected as the study subject, and relevant clinical data was collected. Peripheral blood samples of the child and her parents were collected for the extraction of genomic DNA. And trio-whole exome sequencing (trio-WES) was carried out. Candidate variants were verified by Sanger sequencing. Bioinformatic software was used to analyze the conservation of variant sites.@*RESULTS@#The child was a 2-year-and-10-month-old female with clinical manifestations including increased muscle tone of lower limbs, pointed feet, and cognitive language delay. Trio-WES results showed that she had harbored compound heterozygous variants of c.865C>T (p.Gln289*) and c.1126G>A (p.Glu376Lys) of the CYP2U1 gene. And the corresponding amino acid for c.1126G>A (p.Glu376Lys) is highly conserved among various species. Based on guidelines from the American College of Medical Genetics and Genomics, the c.865C>T was predicted as a pathogenic variant (PVS1+PM2_Supporting), and c.1126G>A was rated as a variant of uncertain significance (PM2_Supporting+PM3+PP3).@*CONCLUSION@#The child was diagnosed with HSP type 56 due to compound variants of the CYP2U1 gene. Above findings have enriched the mutation spectrum of the CYP2U1 gene.
Subject(s)
Female , Humans , Infant , Cytochrome P450 Family 2/genetics , Mutation , Pedigree , Phenotype , Spastic Paraplegia, Hereditary/geneticsABSTRACT
The hereditary spastic paraplegia (HSP) is a rare hereditary disease in nervous system due to the damage of corticospinal tract. HSP has various inheritance modes, including autosomal dominant inheritance, autosomal recessive inheritance, X-linked inheritance, and mitochondrial inheritance in some cases. At present, there are at least 80 subtypes of HSP. Hereditary spastic paraplegia type 11 (SPG11) is the most common subtype in autosomal recessive inheritance, and its pathogenic factor is KIAA1840 gene, which encodes spatacsin protein. A total of 52 SPG11 patients aged from 4-24 years old have been reported. Their initial symptoms were gait disturbance and/or mental retardation. As the disease develops, they may present with mental retardation, sphincter disturbance, decreased vision, ataxia, amyotrophy, pes arcuatus, ophthalmoplegia, peripheral neuropathy, and others. Except agenesis of the corpus callosum and periventricular white matter changes, patients might show cortical atrophy, ventricular dilation, and cerebellar atrophy, and so on. Chinese SPG11 patients manifested significant clinical and genetical heterogeneity and no obvious gender difference. Of them, 37 pathogenic mutations of KIAA1840 gene were detected, which all introduced truncated mutation of spatacsin protein. KIAA1840 gene frameshift mutation is the most common type of mutation.
Subject(s)
Adolescent , Child , Child, Preschool , Humans , Young Adult , Atrophy , Intellectual Disability , Mutation , Proteins , Spastic Paraplegia, Hereditary/pathologyABSTRACT
OBJECTIVE@#To explore the genetic basis for a pedigree affected with hereditary spastic paraplegia type 4 (HSP4).@*METHODS@#Peripheral venous blood samples were taken from members of the four-generation pedigree and 50 healthy controls for the extraction of genomic DNA. Genes associated with peripheral neuropathy and hereditary spastic paraplegia were captured and subjected to targeted capture and next-generation sequencing. The results were confirmed by Sanger sequencing.@*RESULTS@#DNA sequencing suggested that the proband has carried a heterozygous c.1196C>G variant in exon 9 of the SPAST gene, which can cause substitution of serine by threonine at position 399 (p.Ser399Trp) and lead to change in the protein function. The same variant was also detected in other patients from the pedigree but not among unaffected individuals or the 50 healthy controls. Based on the ACMG 2015 guidelines, the variant was predicted to be possibly pathogenic.@*CONCLUSION@#The c.1196C>G variant of the SPAST gene probably underlay the HSP4 in this pedigree.
Subject(s)
Humans , Base Sequence , Mutation , Paraplegia/genetics , Pedigree , Sequence Analysis, DNA , Spastic Paraplegia, Hereditary/genetics , Spastin/geneticsABSTRACT
ABSTRACT Hereditary spastic paraplegias (HSP) are a group of genetic diseases characterized by lower limb spasticity with or without additional neurological features. Swallowing dysfunction is poorly studied in HSP and its presence can lead to significant respiratory and nutritional complications. Objectives: The aim of this study was to evaluate the frequency and clinical characteristics of dysphagia in different types of HSP. Methods: A two-center cross-sectional prevalence study was performed. Genetically confirmed HSP patients were evaluated using the Northwestern Dysphagia Patient Check Sheet and the Functional Oral Intake Scale. In addition, self-perception of dysphagia was assessed by the Eat Assessment Tool-10 and the Swallowing Disturbance Questionnaire. Results: Thirty-six patients with spastic paraplegia type 4 (SPG4), five with SPG11, four with SPG5, four with cerebrotendinous xanthomatosis (CTX), three with SPG7, and two with SPG3A were evaluated. Mild to moderate oropharyngeal dysphagia was present in 3/5 (60%) of SPG11 and 2/4 (50%) of CTX patients. A single SPG4 (2%) and a single SPG7 (33%) patient had mild oropharyngeal dysphagia. All other evaluated patients presented with normal or functional swallowing. Conclusions: Clinically significant oropharyngeal dysphagia was only present in complicated forms of HSP Patients with SPG11 and CTX had the highest risks for dysphagia, suggesting that surveillance of swallowing function should be part of the management of patients with these disorders.
RESUMO As paraparesias espásticas hereditárias (PEH) são um grupo de doenças genéticas caracterizado por espasticidade dos membros inferiores com ou sem características neurológicas adicionais. A disfunção da deglutição é pouco estudada nas PEH e sua presença pode levar a complicações respiratórias e nutricionais significativas. Objetivo: O objetivo deste estudo foi avaliar a frequência e a caracterização clínica da disfagia em diferentes tipos de PEH. Métodos: Foi realizado um estudo transversal em dois centros. Os pacientes com PEH confirmados geneticamente foram avaliados pelo Northwestern Dysphagia Patient Check Sheet e pela Escala Funcional de Ingestão Oral. Além disso, a autopercepção da disfagia foi avaliada pelo Eat Assessment Tool-10 e pelo Swallowing Disturbance Questionnaire. Resultados: Trinta e seis pacientes com paraplegia espástica tipo 4 (SPG4), cinco com SPG11, quatro com SPG5, quatro com xantomatose cerebrotendinosa (CTX), três com SPG7 e dois com SPG3A foram avaliados. Disfagia orofaríngea leve a moderada estava presente em 3/5 (60%) dos pacientes com SPG11 e 2/4 (50%) dos pacientes com CTX. Um único SPG4 (2%) e um único SPG7 (33%) apresentaram disfagia orofaríngea leve. Todos os outros pacientes avaliados apresentaram deglutição normal ou funcional. Conclusão: Disfagia orofaríngea clinicamente significativa estava presente apenas nas formas complicadas de PEH. A SPG11 e CTX apresentaram maiores riscos de disfagia, sugerindo que a avaliação da deglutição deve fazer parte do manejo dos pacientes com essas condições.
Subject(s)
Humans , Male , Female , Adult , Middle Aged , Aged , Spastic Paraplegia, Hereditary/epidemiology , Deglutition Disorders/epidemiology , Severity of Illness Index , Brazil/epidemiology , Spastic Paraplegia, Hereditary/physiopathology , Deglutition Disorders/physiopathology , Prevalence , Cross-Sectional Studies , Surveys and Questionnaires , Risk Factors , Sex Distribution , Age Distribution , Xanthomatosis, Cerebrotendinous/physiopathology , Xanthomatosis, Cerebrotendinous/epidemiologySubject(s)
Humans , Spastic Paraplegia, Hereditary , Deglutition Disorders , Prevalence , Deglutition , MutationSubject(s)
Humans , Child , Spastic Paraplegia, Hereditary , Brazil , Epidemiologic Studies , MutationABSTRACT
ABSTRACT Aims: To investigate hereditary spastic paraplegia (HSP) in a pediatric Brazilian sample. Methods: Epidemiological, clinical, radiological and laboratory data were analyzed in 35 patients. Results: Simple HSP (HSP-S) was detected in 12 patients, and complicated HSP (HSP-C) was detected in 23 patients. The mean age of onset of symptoms was 2.9 years in HSP-S and 1.6 years in HSP-C (p = 0.023). The disease was more severe in HSP-C. There were no differences in sex, ethnic background, or family history between groups. Intellectual disability was the most frequent finding associated with HSP-C. Peripheral axonal neuropathy was found in three patients. In the HSP-C group, MRI was abnormal in 13 patients. The MRI abnormalities included nonspecific white matter lesions, cerebellar atrophy, thinning of the corpus callosum and the "ear of the lynx sign". Conclusions: In children with spastic paraplegia, HSP must be considered whenever similar pathologies, mainly diplegic cerebral palsy, are ruled out.
RESUMO Objetivo: Investigar paraplegia espástica hereditária (PEH) em uma amostra brasileira de pacientes pediátricos. Métodos: Foram colhidos dados clínicos, epidemiológicos, radiológicos e laboratoriais de 35 pacientes. Resultados: Doze pacientes foram classificados como PEH simples (PEH-S), e 23 como PEH complicada (PEH-C). A média de idade de início dos sintomas foi de 2,9 anos na PEH-S e 1,6 anos na PEH-C (p = 0,023). A doença foi mais grave na PEH-C. Não houve diferença de sexo, etnia e histórico familial entre os dois grupos. Deficiência intelectual foi a associação clínica mais frequente na PEH-C. Neuropatia periférica axonal foi encontrada em três pacientes. A RM foi normal em 13 casos de PEH-C. Anormalidades de RM incluiram alterações inespecíficas da substância branca, atrofia de cerebelo, afilamento de corpo caloso e o "sinal da orelha de lince". Conclusões: PEH deve ser considerada em crianças com paraparesia espástica sempre que descartadas condições patológicas similares, principalmente paralisia cerebral.
Subject(s)
Humans , Male , Female , Infant , Child, Preschool , Child , Adolescent , Spastic Paraplegia, Hereditary/pathology , Spastic Paraplegia, Hereditary/epidemiology , Time Factors , Brazil/epidemiology , Magnetic Resonance Imaging , Spastic Paraplegia, Hereditary/diagnostic imaging , Sex Distribution , Age of Onset , Age Distribution , Statistics, Nonparametric , Corpus Callosum/pathology , Corpus Callosum/diagnostic imagingABSTRACT
This article reports the clinical features and C12orf65 gene mutations of a girl with autosomal recessive spastic paraplegia-55. The 8-year-old girl experienced disease onset at the age of 5 years and had optic atrophy as the main clinical manifestation, with slow movements in standing up and a slight duck-shaped gait. Peripheral blood DNA samples were collected from this child and her parents and brother to perform high-throughput whole-exome sequencing and high-throughput mitochondrial genome sequencing. Sanger sequencing was performed for verification. The results showed two compound heterozygous mutations, c.394C>T and c.447_449delGGAinsGT, in the C12orf65 gene. The former mutation came from her father and was a known pathogenic mutation, and the latter came from her mother and was a novel mutation which had not been reported in literature. This study expands the mutation spectrum of the C12orf65 gene and thus provides a molecular basis for the etiological diagnosis of the child and the genetic counseling of the family.
Subject(s)
Child , Female , Humans , Male , High-Throughput Nucleotide Sequencing , Mitochondrial Proteins , Genetics , Mutation , Pedigree , Peptide Termination Factors , Genetics , Spastic Paraplegia, Hereditary , GeneticsABSTRACT
OBJECTIVE@#To identify pathogenic mutation in a Chinese family affected with hereditary spastic paraplegia (HSP) through genetic testing and a follow-up survey.@*METHODS@#Whole exome sequencing was performed on DNA samples of two patients and one unaffected member to screen candidate mutations. Sanger sequencing was used to validate the suspected mutations in all ten family members.@*RESULTS@#Four patients and three asymptomatic members (under 25 years old) carried a c.1771T>C mutation of the KIAA0196, while the other three asymptomatic members (over 40 years old) did not carry the mutation. The mutation was predicted to be "affect protein function", "probably damaging" and "disease causing" by SIFT, PolyPhen-2 and Mutation Taster, respectively. Three asymptomatic carriers were followed up and one of them developed HSP one year later, while the other two had no signs of the disease yet.@*CONCLUSION@#The clinical phenotype of the c.1771T>C mutation of KIAA0196 has a considerable heterogeneity and this mutation may be a common pathogenic site of KIAA0196 mutations among Chinese patients with hereditary spastic paraplegia.
Subject(s)
Adult , Humans , Asian People , Heterozygote , Mutation , Pedigree , Phenotype , Proteins , Genetics , Spastic Paraplegia, Hereditary , GeneticsABSTRACT
OBJECTIVE@#To detect pathogenic variation in a pedigree affected with hereditary spastic paraplegia type 31 and explore its molecular pathogenesis.@*METHODS@#Customized Roche NimbleGen capture probes were used to capture all exons of the target genes in relation with hereditary spastic paraplegia. The DNA samples were also assayed with fluorescent quantitative PCR as well as chromosomal microarray analysis using CytoScan HD chip.@*RESULTS@#The proband and her father and grandfather were found to carry a deletion for position 85 992 693-86 842 693 on chromosome 2, which spanned approximately 900 kb and encompassed the REEP1 gene. The latter has been specifically associated with hereditary spastic paraplegia type 31. The same deletion was not found in her mother who is phenotypically normal.@*CONCLUSION@#The deletional variation of the REEP1 gene probably underlies the disease in this pedigree.
Subject(s)
Female , Humans , Membrane Transport Proteins , Paraplegia , Pedigree , Sequence Deletion , Spastic Paraplegia, Hereditary , GeneticsABSTRACT
OBJECTIVE@#To explore the genetic basis for a pedigree affected with X-linked adrenoleukodystrophy presenting as spastic paraplegia of the lower limbs.@*METHODS@#Genomic DNA was extracted from peripheral blood samples of the patient and his mother. Potential variant was detected with a panel for genes associated with spastic paraplegia. Candidate variant was verified by PCR and Sanger sequencing.@*RESULTS@#Both the proband and his mother presented with walking difficulty. A previously known variant, c.623T to A (p.V208E), was identified in the ABCD1 gene mapped on chromosome X in both.@*CONCLUSION@#X-link adrenoleukodystrophy should be taken into account as a possible diagnosis for this pedigree.
Subject(s)
Female , Humans , Male , ATP Binding Cassette Transporter, Subfamily D, Member 1 , Genetics , Adrenoleukodystrophy , Genetics , Genetic Testing , Pedigree , Spastic Paraplegia, HereditaryABSTRACT
ABSTRACT Motor and non-motor manifestations are common and disabling features of hereditary spastic paraplegia (HSP). Botulinum toxin type A (Btx-A) is considered effective for spasticity and may improve gait in these patients. Little is known about the effects of Btx-A on non-motor symptoms in HSP patients. Objective To assess the efficacy of Btx-A on motor and non-motor manifestations in HSP patients. Methods Thirty-three adult patients with a clinical and molecular diagnosis of HSP were evaluated before and after Btx-A injections. Results Mean age was 41.7 ± 13.6 years and there were 18 women. Most patients had a pure phenotype and SPG4 was the most frequent genotype. The Btx-A injections resulted in a decrease in spasticity at the adductor muscles, and no other motor measure was significantly modified. In contrast, fatigue scores were significantly reduced after Btx-A injections. Conclusion Btx-A injections resulted in no significant functional motor improvement for HSP, but fatigue improved after treatment.
RESUMO Manifestações motoras e não motoras são comuns e incapacitantes nas paraparesias espásticas hereditárias (PEH). Toxina botulínica do tipo A (TB-A) é considerada eficaz no tratamento da espasticidade e pode melhorar a marcha nesses pacientes. Pouco se sabe sobre os efeitos da TB-A sobre sintomas não-motores. Objetivo avaliar a eficácia da TB-A sobre manifestações motoras e não-motoras nas PEH. Método trinta e três pacientes adultos com PEH foram avaliados antes e depois das aplicações de TB-A. Resultados A média de idade foi 41,7 ± 13,6 anos e havia 18 mulheres. A maioria dos pacientes portava a forma pura e o genótipo mais comum foi SPG4. Houve diminuição da espasticidade dos músculos adutores da coxa sem melhora da marcha. A pontuação da fadiga reduziu após as injeções. Conclusão As aplicações de TB-A não melhoraram a marcha nos pacientes mas a redução da fadiga foi significativa após o tratamento.
Subject(s)
Humans , Male , Female , Adult , Middle Aged , Spastic Paraplegia, Hereditary/physiopathology , Spastic Paraplegia, Hereditary/drug therapy , Botulinum Toxins, Type A/therapeutic use , Motor Disorders/physiopathology , Motor Disorders/drug therapy , Neuromuscular Agents/therapeutic use , Reproducibility of Results , Treatment Outcome , Age of Onset , Muscle Fatigue/drug effects , Muscle Fatigue/physiology , Gait/drug effects , Gait/physiology , Injections, Intramuscular , Muscle Spasticity/drug therapyABSTRACT
ABSTRACT The authors have constructed a brief timeline of major clinical research related to hereditary spastic paraplegia (HSP). This timeline summarizes the evolution of HSP research, from the first clinical descriptions by Adolf von Strümpell in 1880 to the present day, with the transformation of these diseases into a rapidly-growing and heterogeneous group of neurogenetic diseases.
RESUMO Os autores constroem uma breve linha do tempo com as principais pesquisas clinicas relacionadas as paraplegias espásticas hereditárias. Desde a descrição clínica inicial em 1880, feita por Adolf von Strümpell, até os dias atuais com a transformação dessas doenças em um grupo de doenças neurogenéticas com grande variabilidade na apresentação fenotípica e genotípica.