scholarly journals Spastic paraplegia type 73: expanding phenotype of the first two Brazilian families

2021 ◽  
Author(s):  
Vinícius Lopes Braga ◽  
Wladimir Bocca Vieira de Rezende Pinto ◽  
Bruno de Mattos Lombardi Badia ◽  
José Marcos Vieira de Albuquerque Filho ◽  
Igor Braga Farias ◽  
...  
Keyword(s):  
De Novo ◽  
Current Knowledge ◽  
Spastic Paraparesis ◽  
Pathogenic Variant ◽  
Lower Limbs ◽  
Spastic Paraplegia ◽  
Pathogenic Variants ◽  
Genetic Features ◽  
Age Range ◽  
Late Stages

Context: Hereditary spastic paraplegias (HSPs) represent an expanding group of neurodegenerative diseases characterized mainly by progressive spastic paraparesis of the lower limbs. More than 80 different genetic loci have been associated with HSPs. In 2015, heterozygous pathogenic variants in the CPT1C gene were first associated with SPG73, not yet described in Brazilian patients. Objective: We present clinical, neuroimaging and genetic features of three Brazilian patients with SPG73. Cases reports: We report one male and two female patients, age range 36 to 78 years old. Case 1 presented with a 4-year-history of spasticity, predominantly crural tetraplegia, bladder incontinence, dysphagia and dysphonia. Family history disclosed a sister with epilepsy. Whole-exome sequencing (WES) disclosed a heterozygosis variant c.863G>A (p.Arg288His) in exon 9 of the CPT1C. Cases 2 and 3 are first degree relatives (mother and son). Both presented with long-standing slowly progressive spastic paraplegia. Case 3 presented bladder incontinence, constipation, dysphagia and dysphonia at late stages. Cases 2 and 3 WES disclosed the heterozygosis variant c.196T>G (p.Phe66Val) in exon 4 of the CPT1C. Discussion: Previous literature described six patients from an Italian family with pure HSPs phenotype and the pathogenic variant c.109C>G (p.Arg3. 7Cys) in CPT1C gene. Another group described three patients associated with pure HSPs phenotype and the pathogenic variant (c.226C>T) in the CPT1C gene. All previous reported cases had benign clinical course and bulbar involvement was not described before. One of our cases presented with a de novo variant and rapidly progressive motor and bulbar compromise. Conclusion: our cases expand the current knowledge about SPG73, including a rapidly progressive phenotype with bulbar involvement and cognitive compromise at late stages of disease course.

scholarly journals A Japanese hereditary spastic paraplegia family with a rare nonsynonymous variant in the SPAST gene

2021 ◽  
Vol 8 (1) ◽  
Author(s):  
Takuya Morikawa ◽  
Shiroh Miura ◽  
Takahisa Tateishi ◽  
Kazuhito Noda ◽  
Hiroki Shibata
Keyword(s):  
Molecular Diagnosis ◽  
Hereditary Spastic Paraplegia ◽  
Autosomal Dominant ◽  
Family Members ◽  
Pathogenic Variant ◽  
Lower Limbs ◽  
Spastic Paraplegia ◽  
Nonsynonymous Variant ◽  
Japanese Family ◽  
Functional Variants

AbstractSpastic paraplegia (SPG) type 4 is an autosomal dominant SPG caused by functional variants in the SPAST gene. We examined a Japanese family with three autosomal dominant SPG patients. These patients presented with typical symptoms of SPG, such as spasticity of the lower limbs. We identified a rare nonsynonymous variant, NM_014946.4:c.1252G>A [p.Glu418Lys], in all three family members. This variant has previously been reported in a Russian SPG family as a “likely pathogenic” variant.5 Ascertainment of additional patients carrying this variant in an unrelated Japanese SPG family further supports its pathogenicity. Molecular diagnosis of SPG4 in this family with hereditary spastic paraplegia is confirmed.

scholarly journals Identification of UBAP1 mutations in juvenile hereditary spastic paraplegia in the 100,000 Genomes Project

2020 ◽  
Vol 28 (12) ◽  
pp. 1763-1768
Author(s):  
Thomas Bourinaris ◽  
◽  
Damian Smedley ◽  
Valentina Cipriani ◽  
Isabella Sheikh ◽  
...  
Keyword(s):  
Hereditary Spastic Paraplegia ◽  
De Novo ◽  
Age At Onset ◽  
Genetic Diagnosis ◽  
Spastic Paraplegia ◽  
Sequencing Data ◽  
Juvenile Form ◽  
Pathogenic Variants ◽  
Degenerative Disorders ◽  
Significant Gene

AbstractHereditary spastic paraplegia (HSP) is a group of heterogeneous inherited degenerative disorders characterized by lower limb spasticity. Fifty percent of HSP patients remain yet genetically undiagnosed. The 100,000 Genomes Project (100KGP) is a large UK-wide initiative to provide genetic diagnosis to previously undiagnosed patients and families with rare conditions. Over 400 HSP families were recruited to the 100KGP. In order to obtain genetic diagnoses, gene-based burden testing was carried out for rare, predicted pathogenic variants using candidate variants from the Exomiser analysis of the genome sequencing data. A significant gene-disease association was identified for UBAP1 and HSP. Three protein truncating variants were identified in 13 patients from 7 families. All patients presented with juvenile form of pure HSP, with median age at onset 10 years, showing autosomal dominant inheritance or de novo occurrence. Additional clinical features included parkinsonism and learning difficulties, but their association with UBAP1 needs to be established.

scholarly journals A Novel Missense Variant in the Gene PPP2R5D Causes a Rare Neurodevelopmental Disorder with Increased Phenotype

2021 ◽  
Vol 2021 ◽  
pp. 1-7
Author(s):  
Lulu Yan ◽  
Ru Shen ◽  
Zongfu Cao ◽  
Chunxiao Han ◽  
Yuxin Zhang ◽  
...  
Keyword(s):  
De Novo ◽  
Genetic Disorder ◽  
Neurodevelopmental Disorder ◽  
Three Dimensional ◽  
Missense Variant ◽  
Pathogenic Variant ◽  
Dimensional Structure ◽  
Chinese Family ◽  
Speech Impairment ◽  
Pathogenic Variants

PPP2R5D-related neurodevelopmental disorder, which is mainly caused by de novo missense variants in the PPP2R5D gene, is a rare autosomal dominant genetic disorder with about 100 patients and a total of thirteen pathogenic variants known to exist globally so far. Here, we present a 24-month-old Chinese boy with developmental delay and other common clinical characteristics of PPP2R5D-related neurodevelopmental disorder including hypotonia, macrocephaly, intellectual disability, speech impairment, and behavioral abnormality. Trio-whole exome sequencing (WES) and Sanger sequencing were performed to identify the causal gene variant. The pathogenicity of the variant was evaluated using bioinformatics tools. We identified a novel pathogenic variant in the PPP2R5D gene (c.620G>T, p.Trp207Leu). The variant is located in the variant hotspot region of this gene and is predicted to cause PPP2R5D protein dysfunction due to an increase in local hydrophobicity and unstable three-dimensional structure. We report a novel pathogenic variant of PPP2R5D associated with PPP2R5D-related neurodevelopmental disorder from a Chinese family. Our findings expanded the phenotypic and mutational spectrum of PPP2R5D-related neurodevelopmental disorder.

Rapidly Progressive Multisutural Craniosynostosis in a Patient With Jackson-Weiss Syndrome and a De Novo FGFR2 Pathogenic Variant

2019 ◽  
Vol 56 (10) ◽  
pp. 1386-1392
Author(s):  
Karel-Bart Celie ◽  
Melissa Yuan ◽  
Christopher Cunniff ◽  
Jarrod Bogue ◽  
Caitlin Hoffman ◽  
...  
Keyword(s):  
Clinical Outcomes ◽  
Early Treatment ◽  
Clinical Presentation ◽  
De Novo ◽  
Pathogenic Variant ◽  
Medical Complications ◽  
3 Dimensional ◽  
Constitutive Activation ◽  
Pathogenic Variants ◽  
Dimensional Modeling

Little is currently known about the mechanisms by which pathogenic variants of FGFR2 produce changes in the FGFR protein and influence the clinical presentation of affected individuals. We report on a patient with a de novo pathogenic variant of FGFR2 and a phenotype consistent with Jackson-Weiss syndrome who presented with delayed, rapidly progressive multisutural craniosynostosis and associated medical complications. Using 3-dimensional modeling of the FGFR protein, we provide evidence that this variant resulted in abnormal dimerization and constitutive activation of FGFR, leading to the Jackson-Weiss phenotype. Knowledge regarding the correlation between genotype and phenotype of persons with FGFR2-related craniosynostosis has the potential to allow for anticipation of medical complications, institution of early treatment, and improved clinical outcomes.

scholarly journals Coffin-Lowry preprint 2018

2018 ◽  
Author(s):  
Paolo Moretti
Keyword(s):  
Family History ◽  
Clinical Features ◽  
De Novo ◽  
Severe Disease ◽  
Immunosuppressive Treatment ◽  
Pathogenic Variant ◽  
First Degree Relatives ◽  
Pathogenic Variants ◽  
History Of ◽  
Psychiatric Manifestations

Coffin-Lowry syndrome is an X-linked disease caused by pathogenic variants in RPS6KA3. The disease generally causes severe neurologic and non-neurologic abnormalities in males, and more variable phenotypes in females, including psychiatric manifestations. The majority of cases occur in the absence of known family history of the disease, and women carrying a de novo pathogenic variant may be undiagnosed due to the absence of severe disease manifestations or typically affected first-degree relatives. We describe the clinical features of a woman of normal intellect carrying a novel RPS6KA3 pathogenic variant in whom psychiatric manifestations and encephalopathy responded to immunosuppressive treatment.

Heterozygous KIF1A variants underlie a wide spectrum of neurodevelopmental and neurodegenerative disorders

2020 ◽  
pp. jmedgenet-2020-107007
Author(s):  
Francesco Nicita ◽  
Monia Ginevrino ◽  
Lorena Travaglini ◽  
Stefano D'Arrigo ◽  
Giovanna Zorzi ◽  
...  
Keyword(s):  
Early Onset ◽  
Wide Spectrum ◽  
Spastic Paraparesis ◽  
Pathogenic Variants ◽  
Novel Variants ◽  
Early Onset Ataxia ◽  
Genetic Features ◽  
Caucasian Patients ◽  
Group 2 ◽  
Complex Forms

BackgroundDominant and recessive variants in the KIF1A gene on chromosome 2q37.3 are associated with several phenotypes, although only three syndromes are currently listed in the OMIM classification: hereditary sensory and autonomic neuropathy type 2 and spastic paraplegia type 30, both recessively inherited, and mental retardation type 9 with dominant inheritance.MethodsIn this retrospective multicentre study, we describe the clinical, neuroradiological and genetic features of 19 Caucasian patients (aged 3–65 years) harbouring heterozygous KIF1A variants, and extensively review the available literature to improve current classification of KIF1A-related disorders.ResultsPatients were divided into two groups. Group 1 comprised patients with a complex phenotype with prominent pyramidal signs, variably associated in all but one case with additional features (ie, epilepsy, ataxia, peripheral neuropathy, optic nerve atrophy); conversely, patients in group 2 presented an early onset or congenital ataxic phenotype. Fourteen different heterozygous missense variants were detected by next-generation sequencing screening, including three novel variants, most falling within the kinesin motor domain.ConclusionThe present study further enlarges the clinical and mutational spectrum of KIF1A-related disorders by describing a large series of patients with dominantly inherited KIF1A pathogenic variants ranging from pure to complex forms of hereditary spastic paraparesis/paraplegias (HSP) and ataxic phenotypes in a lower proportion of cases. A comprehensive review of the literature indicates that KIF1A screening should be implemented in HSP regardless of its mode of inheritance or presentations as well as in other complex neurodegenerative or neurodevelopmental disorders showing congenital or early onset ataxia.

scholarly journals Janus-faced spatacsin (SPG11): involvement in neurodevelopment and multisystem neurodegeneration

Brain ◽  
2020 ◽  
Vol 143 (8) ◽  
pp. 2369-2379
Author(s):  
Tatyana Pozner ◽  
Martin Regensburger ◽  
Tobias Engelhorn ◽  
Jürgen Winkler ◽  
Beate Winner
Keyword(s):  
Clinical Symptoms ◽  
Current Knowledge ◽  
Clinical Manifestations ◽  
Lower Limbs ◽  
Pathogenic Variants ◽  
Structural Abnormalities ◽  
Neuronal Systems ◽  
And Function ◽  
The Impact

Abstract Hereditary spastic paraplegia (HSP) is a heterogeneous group of rare motor neuron disorders characterized by progressive weakness and spasticity of the lower limbs. HSP type 11 (SPG11-HSP) is linked to pathogenic variants in the SPG11 gene and it represents the most frequent form of complex autosomal recessive HSP. The majority of SPG11-HSP patients exhibit additional neurological symptoms such as cognitive decline, thin corpus callosum, and peripheral neuropathy. Yet, the mechanisms of SPG11-linked spectrum diseases are largely unknown. Recent findings indicate that spatacsin, the 280 kDa protein encoded by SPG11, may impact the autophagy-lysosomal machinery. In this update, we summarize the current knowledge of SPG11-HSP. In addition to clinical symptoms and differential diagnosis, our work aims to link the different clinical manifestations with the respective structural abnormalities and cellular in vitro phenotypes. Moreover, we describe the impact of localization and function of spatacsin in different neuronal systems. Ultimately, we propose a model in which spatacsin bridges between neurodevelopmental and neurodegenerative phenotypes of SPG11-linked disorders.

scholarly journals Genomic diagnosis for children with intellectual disability and/or developmental delay

2016 ◽  
Author(s):  
Kevin M. Bowling ◽  
Michelle L. Thompson ◽  
Michelle D. Amaral ◽  
Candice R. Finnila ◽  
Susan M. Hiatt ◽  
...  
Keyword(s):  
Neurological Disease ◽  
Large Scale ◽  
De Novo ◽  
Pathogenic Variant ◽  
Research Progress ◽  
Degree Relative ◽  
Identification Rate ◽  
Pathogenic Variants ◽  
First Choice ◽  
Uncertain Significance

ABSTRACTBackgroundDevelopmental disabilities have diverse genetic causes that must be identified to facilitate precise diagnoses. We describe genomic data from 371 affected individuals, 309 of which were sequenced as proband-parent trios.MethodsWhole exome sequences (WES) were generated for 365 individuals (127 affected) and whole genome sequences (WGS) were generated for 612 individuals (244 affected).ResultsPathogenic or likely pathogenic variants were found in 100 individuals (27%), with variants of uncertain significance in an additional 42 (11.3%). We found that a family history of neurological disease, especially the presence of an affected 1st degree relative, reduces the pathogenic/likely pathogenic variant identification rate, reflecting both the disease relevance and ease of interpretation of de novo variants. We also found that improvements to genetic knowledge facilitated interpretation changes in many cases. Through systematic reanalyses we have thus far reclassified 15 variants, with 11.3% of families who initially were found to harbor a VUS, and 4.7% of families with a negative result, eventually found to harbor a pathogenic or likely pathogenic variant. To further such progress, the data described here are being shared through ClinVar, GeneMatcher, and dbGAP.ConclusionOur data strongly support the value of large-scale sequencing, especially WGS within proband-parent trios, as both an effective first-choice diagnostic tool and means to advance clinical and research progress related to pediatric neurological disease.

A novel case of congenital spinocerebellar ataxia 5: further support for a specific phenotype associated with the p.(Arg480Trp) variant in SPTBN2

2020 ◽  
Vol 13 (12) ◽  
pp. e238108
Author(s):  
Andrea Zonta ◽  
Alessandro Brussino ◽  
Patrizia Dentelli ◽  
Alfredo Brusco
Keyword(s):  
De Novo ◽  
Brain Mri ◽  
Spastic Paraparesis ◽  
Lower Limbs ◽  
Normal Brain ◽  
Hereditary Ataxia ◽  
Missense Change ◽  
History Of ◽  
Brain Ventricle ◽  
Vermian Hypoplasia

A 4-year-old girl was referred to the geneticist with a history of ataxia associated with intention tremor of the hands, strabismus and hypermetropy. Her symptoms presented about 2 years earlier with inability to walk unaided and lower limbs hypotonia. Cognitive functions were normal. Brain MRI showed a cerebellar and vermian hypoplasia with enlargement of both the cerebrospinal fluid spaces and the IV brain ventricle. Family history was unremarkable. A genetic screening using a 42-gene panel for hereditary ataxia/spastic paraparesis identified a de novo c.1438C>T - p.(Arg480Trp) missense change in the SPTBN2 gene (NM_006946.2). This variant is reported to be associated with congenital ataxia, later evolving into ataxia and intellectual disability. This case further supports the existence of a specific SPTBN2 p.(Arg480Trp)-associated phenotype, with a de novo recurrence of this variant in the heterozygous state.

scholarly journals A de novo frameshift pathogenic variant in TBR1 identified in autism without intellectual disability

2020 ◽  
Vol 14 (1) ◽  
Author(s):  
Laurie-Anne Sapey-Triomphe ◽  
Julie Reversat ◽  
Gaëtan Lesca ◽  
Nicolas Chatron ◽  
Marina Bussa ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Magnetic Resonance ◽  
Brain Development ◽  
Language Impairment ◽  
De Novo ◽  
Genetic Alterations ◽  
Autism Spectrum ◽  
Pathogenic Variant ◽  
Pathogenic Variants ◽  
Patient Reported

Abstract Background In order to be able to provide accurate genetic counseling to patients with Autism Spectrum Disorder (ASD), it is crucial to identify correlations between heterogeneous phenotypes and genetic alterations. Among the hundreds of de novo pathogenic variants reported in ASD, single-nucleotide variations and small insertions/deletions were reported in TBR1. This gene encodes a transcription factor that plays a key role in brain development. Pathogenic variants in TBR1 are often associated with severe forms of ASD, including intellectual disability and language impairment. Methods Adults diagnosed with ASD but without intellectual disability (diagnosis of Asperger syndrome, according to the DSM-IV) took part in a genetic consultation encompassing metabolic assessments, a molecular karyotype and the screening of a panel of 268 genes involved in intellectual disability, ASD and epilepsy. In addition, the patient reported here went through a neuropsychological assessment, structural magnetic resonance imaging and magnetic resonance spectroscopy measurements. Results Here, we report the case of a young adult male who presents with a typical form of ASD. Importantly, this patient presents with no intellectual disability or language impairment, despite a de novo heterozygous frameshift pathogenic variant in TBR1, leading to an early premature termination codon (c.26del, p.(Pro9Leufs*12)). Conclusion Based on this case report, we discuss the role of TBR1 in general brain development, language development, intellectual disability and other symptoms of ASD. Providing a detailed clinical description of the individuals with such pathogenic variants should help to understand the genotype-phenotype relationships in ASD.

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