scholarly journals Familial ALS Type 25 – A Brazillian Case Serie

2021 ◽  
Author(s):  
José Marcos Vieira de Albuquerque Filho ◽  
Natália Merten Athayde ◽  
Alzira Alves de Siqueira Carvalho ◽  
Igor Braga Farias ◽  
Roberta Ismael Lacerda Machado ◽  
...  
Keyword(s):  
Female Patient ◽  
Age Of Onset ◽  
Genetic Diagnosis ◽  
Coiled Coil ◽  
Pathogenic Variant ◽  
Cortical Atrophy ◽  
Juvenile Form ◽  
Sporadic Als ◽  
Long Course ◽  
Age Range

Introduction: Familial Amyotrophic Lateral Sclerosis (fALS) represent 5-10% of ALS patients. Different mutations in the N-terminal motor or coiled-coil domains of the kinesin family member 5A (KIF5A) cause Hereditary Spastic Paraplegia Type 10 (HSP10), Charcot-Marie-Tooth 2 (CMT2), Neonatal Intractable Myoclonus and more recently described fALS Type 25. Previous described phenotypes are very similar to the sporadic type, except from the long course of disease. Methods: We describe four Brazillian patients, under clinical follow-up on two Neuromuscular services with genetic diagnosis of fALS25. Results: Four diferent fALS25 are described. Two brothers and two unrelated patients, with distinct features, three males and one female, age range from 72 to 24; age of onset ranged from 62 to 22. The genetic mutations were the following: simple heterozygous pathogenic variant c.1651C>G (p. Leu551Val), simple heterozygous pathogenic variant c.2953G>A (p. Gly985Ser) and pathogenic variant c.484C>T (p.Arg162Trp); all of KIF5A gene (fALS25). Only one patient presented with similar phenoptype and age of onset as sporadic ALS (sALS), the two brothers presented the symptoms at the ages of 28 and 30, the female patient at 22. All patients still walk without assistence after the diagnosis. All patients showed classic superior and inferior motor neuron involvement signs, but one brother had a mild limb ataxia. The three younger patients had MRI with no specific findings, except from subtle cortical atrophy in one brother, and mild vermis and corpus callosum atrophy on the other brother. Only the female patient had negative familiar history. Conclusions: fALS25 should be suspected in patient with fALS and longer course disease. Mutations KIF5A gene must be remembered either in juvenile form of ALS.

scholarly journals Blurred Lines – Is the distinction between CIDP and CMT always clear?

2021 ◽  
Author(s):  
Bruno de Mattos Lombardi Badia ◽  
Roberta Ismael Lacerda Machado ◽  
Wladimir Bocca Vieira de Rezende Pinto ◽  
Igor Braga Farias ◽  
José Marcos Vieira de Albuquerque Filho ◽  
...  
Keyword(s):  
Age Of Onset ◽  
Genetic Diagnosis ◽  
Clinical History ◽  
Pathogenic Variant ◽  
Charcot Marie Tooth Disease ◽  
Protein Levels ◽  
Immune Mediated ◽  
Slow Progression ◽  
Neurophysiological Studies ◽  
Age Range

Introduction: Charcot-Marie-Tooth disease (CMT) is a group of inherited sensorymotor neuropathies with variable age of onset, clinical and neurophysiological patterns but often with a chronic slow progression. Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an immune-mediated neuropathy with a relapsing clinical course and typically good response to corticosteroids or other therapies. The distinction between these two conditions can be made with aid of clinical history, neurophysiological studies and genetic testing in the vast majority of cases. However, an overlap between them can occur. Methods: We describe four Brazilian patients under clinical follow-up at our service with genetic diagnosis of CMT and clinical and neurophysiological features compatible with a concurrent CIDP diagnosis. Results: Four cases of different CMT subtypes with co-occurrence of an immunemediated neuropathy compatible with CIDP were reported. The patients were all unrelated, two males and two females, age range from 3 to 45 years. The genetic mutations were the following: hemizygous pathogenic variant c.514C>T (p.Pro172Ser) in GJB1 gene (CMT1X), duplication of PMP22 gene (CMT1A), simple heterozygous pathogenic variant c.188_190delCCT (p.Ser64del) in MPZ gene (CMT1B) and homozygous pathogenic variant c.122T>C (p.Ile41Thr) in FIG4 gene (CMT4J). All four patients presented with relapsing or subacute worsening of neurological symptoms, demyelinating non-uniform features in neurophysiological studies including conduction blocks and elevated cerebrospinal fluid (CSF) protein levels without pleocytosis. Three patients (3/4) improved after treatment with corticosteroids, immunoglobulin or cyclophosphamide with variable clinical response. Conclusion: CMT and CIDP are different conditions involving the peripheral nervous system and the distinction between them usually is possible with the appropriate assessment. The overlap between them is possible and we report four cases with this association.

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.

Differential diagnosis of Duchenne muscular dystrophy

2021 ◽  
Vol 2 (3) ◽  
pp. 159-166
Author(s):  
Alexey L. Kurenkov ◽  
Lyudmila M. Kuzenkova ◽  
Lale A. Pak ◽  
Bella I. Bursagova ◽  
Tatyana V. Podkletnova ◽  
...  
Keyword(s):  
Differential Diagnosis ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Muscle Damage ◽  
Genetic Diagnosis ◽  
Clinical Manifestations ◽  
Neuromuscular Diseases ◽  
Muscular Dystrophies ◽  
Juvenile Form ◽  
Pathogenic Variants

Duchenne muscular dystrophy (DMD) is a disease with an X-linked recessive type of inheritance, belonging to a group of disorders with primary muscle damage, caused by pathogenic variants in the DMD gene and associated with dysfunction of the dystrophin protein. Since DMD is manifested by the gradual development of progressive, mainly proximal muscle weakness, the differential diagnosis is primarily carried out in the group of diseases with muscle damage - myopathies. Among these diseases, the leading candidates for differential diagnosis are hereditary myopathies (limb-girdle muscular dystrophies, facioscapulohumeral dystrophy, congenital muscular dystrophies, glycogenoses - the most common juvenile form of glycogenosis type II (Pompe disease)) and, much less often, congenital myopathies and other conditions of neuromuscular diseases). When conducting a differential diagnosis in a child with suspected DMD, the age of the onset of the disease, early initial clinical manifestations and the development of symptoms as they grow, genealogical analysis, laboratory tests (the level of creatine kinase, aspartate aminotransferase, alanine aminotransferase in blood serum), instrumental (electromyography, magnetic resonance imaging of the brain and muscles) and molecular genetics (polymerase chain reaction, multiplex ligation-dependent probe amplification, next-generation sequencing, Sanger sequencing, etc.) of studies, and in some cases, muscle biopsy data. Knowledge of the nuances of the differential diagnosis allows establishing a genetic diagnosis of DMD as early as possible, which is extremely important for the formation of the prognosis of the disease and the implementation of all available treatment methods, including pathogenetic therapy, and is also necessary for medical and genetic counselling of families with DMD patients.

scholarly journals Evidence for polygenic and oligogenic basis of Australian sporadic amyotrophic lateral sclerosis

2020 ◽  
pp. jmedgenet-2020-106866 ◽  
Author(s):  
Emily P McCann ◽  
Lyndal Henden ◽  
Jennifer A Fifita ◽  
Katharine Y Zhang ◽  
Natalie Grima ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Genetic Variation ◽  
Genetic Analysis ◽  
Genetic Variants ◽  
Age Of Onset ◽  
Sporadic Amyotrophic Lateral Sclerosis ◽  
Whole Genome ◽  
Identity By Descent ◽  
Sporadic Als ◽  
Lateral Sclerosis

BackgroundAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with phenotypic and genetic heterogeneity. Approximately 10% of cases are familial, while remaining cases are classified as sporadic. To date, >30 genes and several hundred genetic variants have been implicated in ALS.MethodsSeven hundred and fifty-seven sporadic ALS cases were recruited from Australian neurology clinics. Detailed clinical data and whole genome sequencing (WGS) data were available from 567 and 616 cases, respectively, of which 426 cases had both datasets available. As part of a comprehensive genetic analysis, 853 genetic variants previously reported as ALS-linked mutations or disease-associated alleles were interrogated in sporadic ALS WGS data. Statistical analyses were performed to identify correlation between clinical variables, and between phenotype and the number of ALS-implicated variants carried by an individual. Relatedness between individuals carrying identical variants was assessed using identity-by-descent analysis.ResultsForty-three ALS-implicated variants from 18 genes, including C9orf72, ATXN2, TARDBP, SOD1, SQSTM1 and SETX, were identified in Australian sporadic ALS cases. One-third of cases carried at least one variant and 6.82% carried two or more variants, implicating a potential oligogenic or polygenic basis of ALS. Relatedness was detected between two sporadic ALS cases carrying a SOD1 p.I114T mutation, and among three cases carrying a SQSTM1 p.K238E mutation. Oligogenic/polygenic sporadic ALS cases showed earlier age of onset than those with no reported variant.ConclusionWe confirm phenotypic associations among ALS cases, and highlight the contribution of genetic variation to all forms of ALS.

scholarly journals UNUSUAL PRESENTATIONS OF LMNA-ASSOCIATED LIPODYSTROPHY WITH COMPLEX PHENOTYPES AND GENERALIZED FAT LOSS: WHEN THE GENETIC DIAGNOSIS UNCOVERS NOVEL FEATURES

2020 ◽  
Vol 6 (2) ◽  
pp. e79-e85
Author(s):  
Natalia Xavier S. de Andrade ◽  
Suleyman Cem Adiyaman ◽  
Berna Demir Yuksel ◽  
Carla T. Ferrari ◽  
Abdelwahab Jalal Eldin ◽  
...  
Keyword(s):  
Genetic Diagnosis ◽  
Pathogenic Variant ◽  
The Body ◽  
Muscle Disease ◽  
Partial Lipodystrophy ◽  
Fat Loss ◽  
Pathogenic Variants ◽  
Complex Phenotypes ◽  
Familial Partial Lipodystrophy

Objective: Lipodystrophy represents a group of rare diseases characterized by loss of body fat. While patients with generalized lipodystrophy exhibit near-total lack of fat, partial lipodystrophy is associated with selective fat loss affecting certain parts of the body. Although classical familial partial lipodystrophy (FPLD) is a well-described entity, recent reports indicate phenotypic heterogeneity among carriers of LMNA pathogenic variants. Methods: We have encountered 2 unique cases with complex phenotypes, generalized fat loss, and very low leptin levels that made the distinction between generalized versus partial lipodystrophy quite challenging. Results: We present a 61-year-old female with generalized fat loss, harboring the heterozygous pathogenic variant p.R541P (c.1622G>C) on the LMNA gene. The discovery of the pathogenic variant led to correct clinical diagnosis of her muscle disease, identification of significant heart disease, and a recommendation for the implantation of a defibrillator. She was able to start metreleptin based on her generalized fat loss pattern and demonstration of the genetic variant. Secondly, we report a 40-year-old Turkish female with generalized fat loss associated with a novel heterozygous LMNA pathogenic variant p.K486E (c.1456A>G), who developed systemic B cell follicular lymphoma. Conclusion: Clinicians need to recognize that the presence of an LMNA variant does not universally lead to FPLD type 2, but may lead to a phenotype that is more complex and may resemble more closely generalized lipo-dystrophy. Additionally, providers should recognize the multisystem features of laminopathies and should screen for these features in affected patients, especially if the variant is not at the known hotspot for FPLD type 2.

scholarly journals Case Report: An Atypical Form of Familial Partial Lipodystrophy Type 2 Due to Mutation in the Rod Domain of Lamin A/C

2021 ◽  
Vol 12 ◽  
Author(s):  
Carolina Cecchetti ◽  
M. Rosaria D’Apice ◽  
Elena Morini ◽  
Giuseppe Novelli ◽  
Carmine Pizzi ◽  
...  
Keyword(s):  
Genetic Diagnosis ◽  
Coiled Coil ◽  
Missense Variant ◽  
Lamin A ◽  
Metabolic Complications ◽  
Partial Lipodystrophy ◽  
Atypical Form ◽  
Amino Terminal ◽  
Familial Partial Lipodystrophy

PurposeFamilial partial lipodystrophy type 2 (FPLD2) patients generally develop a wide variety of severe metabolic complications. However, they are not usually affected by primary cardiomyopathy and conduction system disturbances, although a few cases of FPLD2 and cardiomyopathy have been reported in the literature. These were all due to amino-terminal heterozygous lamin A/C mutations, which are considered as new forms of overlapping syndromes.Methods and ResultsHere we report the identification of a female patient with FPLD2 due to a heterozygous missense variant c.604G>A in the exon 3 of the LMNA gene, leading to amino acid substitution (p.Glu202Lys) in the central alpha-helical rod domain of lamin A/C with a high propensity to form coiled-coil dimers. The patient’s cardiac evaluations that followed the genetic diagnosis revealed cardiac rhythm disturbances which were promptly treated pharmacologically.ConclusionsThis report supports the idea that there are “atypical forms” of FPLD2 with cardiomyopathy, especially when a pathogenic variant affects the lamin A/C head or alpha-helical rod domain. It also highlights how increased understanding of the genotype-phenotype correlation could help clinicians to schedule personalized monitoring of the lipodystrophic patient, in order to prevent uncommon but possible devastating manifestations, including arrhythmias and sudden death.

scholarly journals Enzyme-inducing antiseizure drugs associate with low bone mineral density in men with epilepsy

2021 ◽  
Author(s):  
Aline de Fátima Dias ◽  
Lucas Scárdua Silva ◽  
Rafael Batista João ◽  
Amanda Canal Rigotti ◽  
Gabriel Ferri Baltazar ◽  
...  
Keyword(s):  
Bone Mineral Density ◽  
Bone Mineral ◽  
Age Of Onset ◽  
Young Group ◽  
Categorical Variables ◽  
Mineral Density ◽  
Chi Square ◽  
T Score ◽  
Age Range ◽  
The Impact

Introduction: Little is known about the impact of enzyme-inducing antiseizure drugs (EI-ASD) on the reduction of Bone Mineral Density (BMD) in men with epilepsy (MWE). Objectives: To evaluate the BMD in MWE exposed to EI-ASDs (phenytoin, carbamazepine and phenobarbital) and its relationship with the duration of epilepsy. Methods: We evaluated BMD from 74 consecutive MWE (median age (range), 52.5 (25- 74) years) exposed to previous or current EI-ASDs, followed at UNICAMP-Brazil. Individuals were split into two groups (young-group, 31 individuals [25-49 years]; older group, 43 subjects, [50-74 years]). The BMD test evaluated t-score indexes from the femoral neck, whole femur and lumbar spine. Osteopenia was defined with t-score of - 1.0 to -2.4; osteoporosis, with T-scores lower than -2.5. Data were extracted from medical records. We analyzed data with SPSS22, performed chi-square tests for categorical variables and applied a partial correlation test (controlled for age) between BD scores and duration of epilepsy. Results: BMD was reduced in 49/74 men (66.2%). Both groups presented equivalent proportions of BMD abnormalities (p=0.087) (young-group [14/41 normal (45%), 12/31 osteopenia (39%), 5/31 osteoporosis (16%)]; older-group [11/43 normal (26%), 16/43 osteopenia (37%), 16/43 osteoporosis (37%)]. BMD did not correlate with the duration of disease or age of onset. Conclusion: BMD reduction is highly prevalent in MWE exposed to EI-ASD, including young individuals. Data suggest that exposure to EI-ASD may associate with early BMD reduction, which evolve to osteopenia and osteoporosis. BMD evaluation in MWE and appropriate treatment may be necessary to reduce fractures’ risk.

scholarly journals Long-read sequencing identified a causal structural variant in an exome-negative case and enabled preimplantation genetic diagnosis

2018 ◽  
Author(s):  
Hefan Miao ◽  
Jiapeng Zhou ◽  
Qi Yang ◽  
Fan Liang ◽  
Depeng Wang ◽  
...  
Keyword(s):  
Preimplantation Genetic Diagnosis ◽  
Genetic Diagnosis ◽  
Glycogen Storage Disease Type ◽  
Pathogenic Variant ◽  
Mendelian Disease ◽  
Vitro Fertilization ◽  
Alu Elements ◽  
Negative Case ◽  
Long Read

AbstractFor a proportion of individuals judged clinically to have a recessive Mendelian disease, only one pathogenic variant can be found from clinical whole exome sequencing (WES), posing a challenge to genetic diagnosis and genetic counseling. Here we describe a case study, where WES identified only one pathogenic variant for an individual suspected to have glycogen storage disease type Ia (GSD-Ia), which is an autosomal recessive disease caused by bi-allelic mutations in the G6PC gene. Through Nanopore long-read whole-genome sequencing, we identified a 7kb deletion covering two exons on the other allele, suggesting that complex structural variants (SVs) may explain a fraction of cases when the second pathogenic allele is missing from WES on recessive diseases. Both breakpoints of the deletion are within Alu elements, and we designed Sanger sequencing and quantitative PCR assays based on the breakpoints for preimplantation genetic diagnosis (PGD) for the family planning on another child. Four embryos were obtained after in vitro fertilization (IVF), and an embryo without deletion in G6PC was transplanted after PGD and was confirmed by prenatal diagnosis, postnatal diagnosis, and subsequent lack of disease symptoms after birth. In summary, we present one of the first examples of using long-read sequencing to identify causal yet complex SVs in exome-negative patients, which subsequently enabled successful personalized PGD.

scholarly journals Subacute Sclerosing Panencephalltis: Clinical and Laboratory Manifestations

2019 ◽  
Vol 32 (5-6) ◽  
pp. 107-17
Author(s):  
Hardiono D. Pusponegoro ◽  
Jimmy Passat ◽  
M. Hardjono Abdoerachman
Keyword(s):  
Age Of Onset ◽  
Subacute Sclerosing Panencephalitis ◽  
Clinical Manifestations ◽  
Social Contact ◽  
Cortical Atrophy ◽  
Laboratory Findings ◽  
Immunization Programme ◽  
Positive Antibody ◽  
Burst Pattern ◽  
History Of

We reviewed clinical and laboratory findings of 12 cases of Subacute sclerosing panencephalitis (SSPE) hospitalized at our department from 1985 to 1991. All cases were diagnosed and hospitalized at the 2nd stage. The principal clinical manifestations were mental changes, myoclonus, and frequent falls. Other clinical manifestations were ocular changes, involuntary movements, loss of social contact, and spasticity. Diagnosis was based on suppression-burst pattern in EEG and positive antibody titer to measles in serum and cerebrospinal fluid. CT scan was not diagnotic, since it was either normal or showed only non-specific cortical atrophy. Eleven patients (91, 7%) recalled a history of measles in the past. Age of onset of SSPE varied among cases and was difficult to specify precisely due to its subtle nature. None of the cases had been vaccinated against measles. SSPE is a rare disease, but is almost always fatal with prolonged suffering of the patient. Based on our experience with SSPE patients, we recommend to broaden the immunization programme against measles.

Age of Menarche in Females of Al-Ramadi City/Iraq

2019 ◽  
Vol 10 (01) ◽  
Author(s):  
Rafal Mustafa Murshid
Keyword(s):  
Life Stress ◽  
Age Of Onset ◽  
Cross Sectional Study ◽  
Psychological Status ◽  
Cross Sectional ◽  
Early Menarche ◽  
The Family ◽  
School Girls ◽  
Age Range ◽  
Age Of Menarche

Aim of the study: Estimate the age of menarche in females of Al-Ramadi city/Iraq. Methodology: This is a retrospective descriptive cross sectional study carried out in Al Ramadi city from the 1stof March to the 1st of May 2017. Data were collected from 404 secondary school girls selected randomly from different secondary schools according to the population density of Ramadi city areas. Age of menarche divided in to early menarche (8- less thN 11 years age), normal menarche (11-14 years), and late menarche (14-16 years). Questionnaire was filled by the family and included female's age, age of onset of her menarche, father and mother's job, education, residency, economic, psychological status and the level of stress the family during onset of menarche. Results: The age range of the studied females was 12 to 18 years. Their mean age of menarche was 13.25 years. About 89% of the respondents were found to be within normal age of menarche, 10.3% of late menarche, and 0.5% had early menarche. The most frequent age of starting menarche was at 13 years (39.1%) followed by 14 years. Normal age menarche was found to be more prevalent among urban dwellers, females of house wife mothers, employed fathers, educated parents, living in their owned houses, and of less life stress. Conclusion: The mean age of menarche in Ramadi city was 13.25 and was higher than age recorded in Baghdad and consistent with ages recoded in many other neighboring and far countries. Keyword: Menarche, Ramadi; Females.

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