A Novel Mutation (D395A) in Valosin-Containing Protein Gene Is Associated With Early Onset Frontotemporal Dementia in an Italian Family

Inclusion body myopathy (IBM) with Paget’s disease of bone (PDB) and/or frontotemporal dementia (FTD) (IBMPFD) was recently identified as rare autosomal dominant disorder due to mutations in VCP gene. However, VCP mutations have also been documented in patients with amyotrophic lateral sclerosis (ALS), Charcot-Marie-Tooth type 2 (CMT2) disease, and hereditary spastic paraplegia (HSP), underlining the heterogeneity of the phenotypes due to VCP mutations. In this study, we reported a novel missense heterozygous variant c.1184A > C (p.D395A) in exon 10 of VCP gene identified in three patients (two sisters and one brother) belonging to an Italian family. The patients underwent a detailed clinical evaluation including medical history, neurological examination, and neuropsychological assessment. Brain’s morphologic and functional analysis was also performed. The whole picture was consistent with the criteria of behavioral variant frontotemporal dementia (bvFTD) without IBM and PBD. Our report confirms the high degree of heterogeneity of VCP disease. A VCP analysis should be considered for the genetic screening of familial bvFTD with an early onset also in absence of IBM or PDB signs.

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SURPRISING GENOTYPE EXPRESSED AS A COMMON LIMB-GIRDLE MUSCULAR DYSTROPHY

Romanian Journal of Neurology ◽

10.37897/rjn.2017.2.6 ◽

2017 ◽

Vol 16 (2) ◽

pp. 71-73

Author(s):

Liviu Cozma ◽

◽

Maria Barsevschi ◽

Cristina Mitu ◽

Alexandra Bastian ◽

...

Keyword(s):

Muscular Dystrophy ◽

Clinical Picture ◽

Histopathological Examination ◽

Muscular Dystrophies ◽

Myofibrillar Myopathy ◽

Homozygous Variant ◽

Heterozygous Variant ◽

High Degree

Limb-girdle muscular dystrophies (LGMDs) comprise a phenotypical spectrum of muscular dystrophies with a high degree of genotypical variability. We describe the case of a 56-year-old male with a history and clinical picture sugestive for LGMD with skeletal and cardiologic involvement. Histopathological examination shows a severe dystrophic picture and geneting testing revealed a unique never reported genotype association: a homozygous variant in the DES gene, associated with myofibrillar myopathy type 1 and LGMD2R, as well as a heterozygous variant in the CRYAB gene, associated with myofibrillar myopathy type 2, both of which could be responsible for the clinical picture.

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Case Report: Early-Onset Behavioral Variant Frontotemporal Dementia in Patient With Retrotransposed Full-Length Transcript of Matrin-3 Variant 5

Frontiers in Neurology ◽

10.3389/fneur.2020.600468 ◽

2020 ◽

Vol 11 ◽

Author(s):

Madelyn Castro ◽

Nisha Venkateswaran ◽

Samuel T. Peters ◽

David R. Deyle ◽

Matthew Bower ◽

...

Keyword(s):

Frontotemporal Dementia ◽

Early Onset ◽

Messenger Rna ◽

Dna Analysis ◽

Novel Mutation ◽

Full Length ◽

Incomplete Penetrance ◽

Significant Past Medical History ◽

Degree Relative ◽

Matrin 3

Frontotemporal dementia (FTD) rarely occurs in individuals under the age of 30, and genetic causes of early-onset FTD are largely unknown. The current report follows a 27 year-old patient with no significant past medical history presenting with two years of progressive changes in behavior, rushed speech, verbal aggression, and social withdrawal. MRI and FDG-PET imaging of the brain revealed changes maximally in the frontal and temporal lobes, which along with the clinical features, are consistent with behavioral variant FTD. Next generation sequencing of a panel of 28 genes associated with dementia and amyotrophic lateral sclerosis (ALS) initially revealed a duplication of exon 15 in Matrin-3 (MATR3). Whole genome sequencing determined that this genetic anomaly was, in fact, a sequence corresponding with full-length MATR3 variant 5 inserted into chromosome 12, indicating retrotransposition from a messenger RNA intermediate. To our knowledge, this is a novel mutation of MATR3, as the majority of mutations in MATR3 linked to FTD-ALS are point mutations. Genomic DNA analysis revealed that this mutation is also present in one unaffected first-degree relative and one unaffected second-degree relative. This suggests that the mutation is either a disease-causing mutation with incomplete penetrance, which has been observed in heritable FTD, or a benign variant. Retrotransposons are not often implicated in neurodegenerative diseases; thus, it is crucial to clarify the potential role of this MATR3 variant 5 retrotransposition in early-onset FTD.

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A Novel Mutation ofSMAD3Identified in a Chinese Family with Aneurysms-Osteoarthritis Syndrome

BioMed Research International ◽

10.1155/2015/968135 ◽

2015 ◽

Vol 2015 ◽

pp. 1-6

Author(s):

Wenwen Zhang ◽

Min Zhou ◽

Cheng Liu ◽

Chen Liu ◽

Tong Qiao ◽

...

Keyword(s):

Signal Transduction ◽

Early Onset ◽

Autosomal Dominant ◽

Novel Mutation ◽

Mutation Spectrum ◽

Chinese Family ◽

Phenotype Correlation ◽

Autosomal Dominant Disorder ◽

Arterial Tree ◽

Craniofacial Features

Aneurysms-osteoarthritis syndrome (AOS) is a recently delineated autosomal dominant disorder characterized by aneurysms, dissections, and tortuosity throughout the arterial tree in association with early onset osteoarthritis, mild craniofacial features, and skeletal and cutaneous anomalies. Previous studies have demonstrated that mutations inSMAD3, a key regulator of TGF-βsignal transduction, contribute to AOS. Here, we investigated a family of three generations affected by AOS. A novelSMAD3mutation, c.266G>A (p.C89Y), was identified and cosegregated with the affected individuals in this family. Our finding expands the mutation spectrum ofSMAD3gene and further strengthens the connection between the presence of aneurysms-osteoarthritis phenotype andSMAD3mutations, which facilitates the understanding of the genotype-phenotype correlation of AOS.

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Expanding the Phenotype of Frontotemporal Lobar Degeneration With FUS-Positive Pathology (FTLD-FUS)

Journal of Neuropathology & Experimental Neurology ◽

10.1093/jnen/nlaa045 ◽

2020 ◽

Vol 79 (7) ◽

pp. 809-812 ◽

Cited By ~ 1

Author(s):

Karina Chornenka ◽

Veronica Hirsch-Reinshagen ◽

Mari Perez-Rosendahl ◽

Howard Feldman ◽

Freddi Segal-Gidan ◽

...

Keyword(s):

Frontotemporal Dementia ◽

Language Impairment ◽

Early Onset ◽

Frontotemporal Lobar Degeneration ◽

Age Of Onset ◽

Fused In Sarcoma ◽

Behavioral Abnormalities ◽

Early Memory ◽

High Degree

Abstract Atypical frontotemporal lobar degeneration with ubiquitin-positive inclusions (aFTLD-U) is an uncommon cause of frontotemporal dementia characterized by fused in sarcoma-positive inclusions. It is classified as a subtype of frontotemporal lobar degeneration with FUS pathology. Cases with aFTLD-U pathology typically display an early onset of symptoms and severe psychobehavioral changes in the absence of significant aphasia, cognitive-intellectual dysfunction or motor features. This phenotype is regarded as being sufficiently unusual and consistent as to allow antemortem diagnosis with a high degree of accuracy. In this report, we describe 2 cases with aFTLD-U pathology that broaden the associated phenotype to include later age of onset, milder behavioral abnormalities and early memory and language impairment.

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