Analysis of CYP2U1 gene variants in a child with Hereditary spastic paraplegia type 56 / 中华医学遗传学杂志

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.

Analysis of KIF1A gene variant in a Chinese pedigree affected with Spastic paraplegia type 30 / 中华医学遗传学杂志

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.

Identification of SPAST gene variant in a pedigree affected with hereditary spastic paraplegia type 4 / 中华医学遗传学杂志

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.

Clinical features and management of hereditary spastic paraplegia / Aspectos clinicos e manejo das paraplegias espasticas hereditarias

Hereditary spastic paraplegia (HSP) is a group of genetically-determined disorders characterized by progressive spasticity and weakness of lower limbs. An apparently sporadic case of adult-onset spastic paraplegia is a frequent clinical problem and a significant proportion of cases are likely to be of genetic origin. HSP is clinically divided into pure and complicated forms. The later present with a wide range of additional neurological and systemic features. To date, there are up to 60 genetic subtypes described. All modes of monogenic inheritance have been described: autosomal dominant, autosomal recessive, X-linked and mitochondrial traits. Recent advances point to abnormal axonal transport as a key mechanism leading to the degeneration of the long motor neuron axons in the central nervous system in HSP. In this review we aim to address recent advances in the field, placing emphasis on key diagnostic features that will help practicing neurologists to identify and manage these conditions.

Paraplegias espásticas hereditárias (PEH) constituem um grupo de desordens geneticamente determinadas caracterizadas por espasticidade e paraparesia de progressão insidiosa. Paraplegia espástica aparentemente esporádica de início no adulto constitui problema frequente na prática neurológica. Evidências recentes sugerem que uma proporção significativa destes casos é geneticamente determinada. O grupo das PEH é dividido clinicamente em formas puras e complicadas de acordo com a concomitância de outras manifestações clinicas e neurológicas. Até o momento 60 tipos genéticos foram identificados. Todos os modos de herança monogênica já foram descritos: autossômica dominante, autossômica recessiva, ligada ao X e mitocondrial. Avanços recentes indicam que alterações do transporte axonal estão implicadas na degeneração dos longos axônios motores no sistema nervoso central na PEH. Nesta revisão abordamos recentes avanços na área com ênfase nos aspectos clínicos chave que ajudam o neurologista geral no diagnóstico e manejo correto deste grupo de doenças.

Amplio espectro fenotípico de la SCA-3: paraparesia espástica hereditaria / The broad phenotypic spectrum of SCA-3: hereditary spastic paraplegia

La ataxia espinocerebelosa tipo 3 o enfermedad de Machado-Joseph (SCA-3/EMJ) es la forma más frecuente de ataxia espinocerebelosa autosómica dominante. Se caracteriza por una marcada variabilidad fenotípica, pudiendo causar formas no cerebelosas de presentación. En base a algunos casos comunicados, se ha propuesto una forma de presentación clínica similar a la de una paraparesia espástica hereditaria, con la presencia de signos de disfunción piramidal predominantes como la manifestación clínica inicial. Presentamos dos nuevos casos de SCA-3/EMJ con un cuadro clínico inicial sugerente de paraparesia espástica hereditaria y una revisión de los casos clínicos similares previamente informados. Nuestros hallazgos apoyan la propuesta de un subtipo de SCA-3/EMJ caracterizado por la presencia de marcada disfunción piramidal como manifestación inicial, simulando un cuadro clínico de paraparesia espástica hereditaria.

Machado-Joseph disease (MJD) is the most frequent dominantly inherited spinocerebellar ataxia. A marked phenotypic variability is a characteristic of this disorder that could involve non-cerebellar presentations. Based on several case reports describing pyramidal dysfunction as the main symptom at onset, a clinical form resembling hereditary spastic paraplegia has been proposed. We report here two further cases of MJD patients whose initial clinical presentation suggested hereditary spastic paraplegia, and a summary of the main findings of previously similar published reports. Our findings lent support to the proposal of a MJD subtype distinguished by a marked pyramidal dysfunction at onset, simulating a clinical picture of hereditary spastic paraplegia.

Uso de sugamadex em doença de Strumpell-Lorrain: relato de dois casos / Use of sugammadex in Strumpell-Lorrain disease: a report of two cases / Uso de sugamadex en enfermedad de Strumpell-Lorrain: relato de dos casos

CONTEÚDO: A doença de Strumpell-Lorrain, ou paraparesia espástica familiar (PEF), é uma doença hereditária neurológica rara, caracterizada principalmente por graus variáveis de rigidez e enfraquecimento dos músculos, com comprometimento cognitivo, surdez e ataxia nos casos mais graves. Descrevemos os casos de duas irmãs com PEF, agendadas para colecistectomia e colectomia subtotal, respectivamente. Também descrevemos o manejo anestésico em ambos os casos e revisamos a literatura sobre essa doença em relação à anestesia.

CONTENT: Strumpell-Lorrain disease - or familial spastic paraplegia (FSP) - is a rare hereditary neurological disorder, mainly characterized by variable degrees of stiffness and weakening of the muscles, with cognitive impairment, deafness, and ataxia in the more severe cases. We describe two female siblings with FSP programmed for cholecystectomy and subtotal colectomy, respectively, and also how we dealt with the anesthetic management in both cases and review the literature on this disease in relation to anesthesia.

CONTENIDO: La enfermedad de Strumpell-Lorrain, o paraparesia espástica familiar (PEF), es una enfermedad hereditaria neurológica rara, caracterizada principalmente por grados variables de rigidez y debilitamiento de los músculos, con el compromiso cognitivo, la sordera y la ataxia en los casos más graves. Describimos aquí dos casos de dos hermanas con PEF, citadas para colecistectomía y colectomía subtotal respectivamente. Describimos también el manejo anestésico en ambos casos y revisamos la literatura sobre esa enfermedad con relación a la anestesia.

Paraplegia espástica familiar: atualização / Familiar spastic paraplegia: update

A Paraplegia Espástica Familiar (PEF) é uma doença hereditária com apresentações diversas, que variam desde a forma pura de apresentação clínica, caracterizada por fraqueza nos membros inferiores, espasticidade, aumento dos reflexos tendíneos, podendo apresentar clônus ou sinal de Babinski, urgência urinária e diminuição da sensibilidade vibratória nas extremidades dos membros inferiores, e a forma complexa de apresentação, que consiste no tipo puro acrescido de outros sinais e sintomas neurológicos. A forma de transmissão é por herança genética autossômica dominante, autossômica recessiva ou ligada ao cromossomo X, e o diagnóstico definitivo da forma clínica depende da realização dos testes genéticos, que identificam os alelos mutantes e suas respectivas proteínas transcritas, as quais participam no processo fisiopatológico da doença. O objetivo deste trabalho é de revisar as características clínicas e genéticas na PEF, as vias fisiopatológicas e o aconselhamento genético. Para isso, foi realizada uma revisão de 82 trabalhos que abordam temas relevantes sobre o assunto.

The Hereditary Spastic Paraplegia (HSP) is a degenerative disease with various presentations, ranging from the pure form of clinical presentation, characterized by weakness in the lower limbs, spasticity, increase of tendineous reflexes and clonus, Babinski sign, urinary urgency and diminished distal lower limbs vibratory sensation. There are two different forms of presentation: the pure form and other with different neurological symptoms and signs in addition to spastic paraplegia. The means of transmission is by genetic inheritance autosomal dominant, autosomal recessive or X cromosome-linked and the definitive diagnosis depends on the performance of genetic tests that identify mutant alleles and their proteins transcribed, participating in a major pathophysiological process of the disease. The purpose of this work is to review the clinical and genetics features in HSP, the pathophysiologic pathways and the genetic counseling. In order to learn more about this disease we reviewed data of 82 works that discuss relevant topics on this subject.

Hereditary spastic paraplegia associated with thin corpus callosum

Autosomal recessive hereditary spastic paraplegia (AR-HSP) associated with thin corpus callosum was recently described in Japan, and most families were linked to chromosome 15q13-15. We report two patients from two different Brazilian families with progressive gait disturbance starting at the second decade of life, spastic paraparesis, and mental deterioration. One patient presented cerebellar ataxia. Magnetic resonance imaging (MRI) of the head of both patients showed a thin corpus callosum. AR-HSP with a thin corpus callosum is a rare disorder, mainly described in Japanese patients. We found only 4 Caucasian families with AR-HSP with thin corpus callosum described in the literature. Further studies including additional Caucasian families of AR-HSP with thin corpus callosum are required to delineate the genetic profile of this syndrome in occidental countries

Machado-Joseph disease versus hereditary spastic paraplegia: case report

Machado-Joseph disease (MJD) is the most common autosomal dominant spinocerebellar ataxia and presents great phenotypic variability. MJD presenting with spastic paraparesis was recently described in Japanese patients. We report the case of 41-year-old woman with the phenotype of complicated hereditary spastic paraplegia. Her father died at the age of 56 years due to an undiagnosed progressive neurological disease that presented parkinsonism. She had an expanded allele with 66 CAG repeats and a normal allele with 22 repeats in the gene of MJD. MJD should be considered in the differential diagnosis of autosomal dominant complicated HSP. A patient with the phenotype of complicated HSP and relatives with other clinical features of a neurodegenerative disease should raise the suspicion of MJD

Paraplejía Espástica Familiar y Artritis Reumatoidea / Familial spastic paraplegia and rheumatoid arthritis

Se informan los hallazgos clínicos y de laboratorio en una paciente con paraplejía espástica familiar (PEF) en su forma pura, asociada con una artritis reumatoidea. Los primeros síntomas de la PEF aparecieron durante la adolescencia la cual admite un modo de herencia autosómica dominante. La artritis reumatoidea se caracterizó por afectación poliarticular, factor reumatoideo positivo, velocidad de sedimientación elevada y fenotipo SZ de alfa-1 antitripsina. Se concluye que la asociación entre ambas entidades pudiera obedecer a un defecto genético primario localizado en el brazo largo del cromosoma 14

Familial spastic paraplegia.

Familial spastic paraplegia (FSP) was recorded in three families. The pattern of familial transmission and the onset in the second and third decade of life strongly suggested autosomal dominant inheritance. FSP in this series showed the consistent, classical, clinical features with some inconstant findings (nystagmus, dysarthria, posterior column involvement). Baclofen for the treatment of spasticity is beneficial in this condition and genetic counselling should be considered.