scholarly journals Elderly Onset of Weakness in Facioscapulohumeral Muscular Dystrophy

2012 ◽  
Vol 2012 ◽  
pp. 1-3
Author(s):  
Dominic B. Fee
Keyword(s):  
Genetic Testing ◽  
Family History ◽  
Muscular Dystrophy ◽  
Muscle Biopsy ◽  
Age Of Onset ◽  
Facioscapulohumeral Muscular Dystrophy ◽  
Elderly Onset ◽  
Phenotypic Features

A 77-year-old male is presented. He had onset of proximal weakness 10 years earlier. His course was slowly progressive. Despite having phenotypic features of facioscapulohumeral muscular dystrophy (FSH), genetic testing for this was delayed because of his age of onset, lack of family history, and benign appearing muscle biopsy. This case is one of the oldest onset of weakness in genetically confirmed FSH and highlights the recognized expansion in phenotype that has occurred since the advent of genetic testing.

scholarly journals Germinal defects of SDHx genes in patients with isolated pituitary adenoma

2020 ◽  
Vol 183 (4) ◽  
pp. 369-379
Author(s):  
Grégory Mougel ◽  
Arnaud Lagarde ◽  
Frédérique Albarel ◽  
Wassim Essamet ◽  
Perrine Luigi ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Pituitary Adenoma ◽  
Family History ◽  
Age Of Onset ◽  
Personal History ◽  
Pathogenic Variants ◽  
Predisposing Genes ◽  
History Of ◽  
New Gateway

Background: The ‘3PAs’ syndrome, associating pituitary adenoma (PA) and pheochromocytoma/paraganglioma (PPGL), is sometimes associated with mutations in PPGL-predisposing genes, such as SDHx or MAX. In ’3PAs’ syndrome, PAs can occur before PPGL, suggesting a new gateway into SDHx/MAX-related diseases. Objective: To determine the SDHx/MAX mutation prevalence in patients with isolated PAs and characterize PAs of patients with SDHx/MAX mutations. Design: Genes involved in PAs (AIP/MEN1/CDKN1B) or PPGLs (SDHx/MAX) were sequenced in patients with isolated PAs. We then conducted a review of cases of PA in the setting of ’3PAs’ syndrome. Results: A total of 263 patients were recruited. Seven (likely) pathogenic variants were found in AIP, two in MEN1, two in SDHA, and one in SDHC. The prevalence of SDHx mutations reached 1.1% (3/263). Of 31 reported patients with PAs harboring SDHx/MAX mutations (28 published cases and 3 cases reported here), 6/31 (19%) developed PA before PPGL and 8/31 (26%) had isolated PA. The age of onset was later than in patients with AIP/MEN1 mutations. PAs were mainly macroprolactinomas and showed intracytoplasmic vacuoles seen on histopathology. Conclusions: We discovered SDHx mutations in patients bearing PA who had no familial or personal history of PPGL. However, the question of incidental association remains unresolved and data to determine the benefit of SDHx/MAX screening in these patients are lacking. We recommend that patients with isolated PA should be carefully examined for a family history of PPGLs. A family history of PPGL, as well as the presence of intracytoplasmic vacuoles in PA, requires SDHx/MAX genetic testing of patients.

scholarly journals Prevalence of muscular dystrophy in patients with muscular disorders in Tehran, Iran

2018 ◽  
Vol 28 (2) ◽  
Author(s):  
Khadijeh Hajinaghi Tehrani ◽  
Maliheh Hajiloo ◽  
Elham Asadollahi ◽  
Fariba Paydar Lagini
Keyword(s):  
Family History ◽  
Muscular Dystrophy ◽  
Diagnostic Tests ◽  
Age Of Onset ◽  
Clinical Findings ◽  
Diagnostic Tools ◽  
Pathological Findings ◽  
Genetic Tests ◽  
Cross Sectional ◽  
Muscular Disorders

Muscular dystrophy is a group of diseases that is characterized by progressive muscle wasting and the weakness of variable distribution and severity. On the basis of the distribution of predominant muscle weakness, there are many different kinds of muscular dystrophy. Some dystrophies are especially frequent in certain populations. There are no studies on the prevalence of muscular dystrophy in Iran. This study was aimed to survey the prevalence of muscular dystrophy among Iranian patients with muscular disorders. This analytical cross-sectional study was conducted on 1000 patients with musculoskeletal disorders who visited the dystrophy association of Bou-Ali Hospital (Tehran) from June 2014 to June 2016. Patients’ data were extracted using a checklist that included age, gender, age of onset, family history, findings from clinical diagnostic tests and types of muscular dystrophy. The clinical findings were the results of genetic tests; EMG-NCV; para-clinical findings, including LDH and CPK; and pathological findings. All data were analyzed by SPSS V.22 (IBM Inc., NY) with Chi Square and One way ANOVA tests. All analyses were performed with P = 0.05 considered as the threshold of statistical significant. Out of the 337 patients studied, 262 (77.7%) were male and 75 (22.3%) were female. Subjects had a mean (± SD) age of 26.08 (± 11.86) years with an age range of 3 to 59 years. The most common types of muscular dystrophy were found to be Duchenne dystrophy (131 cases, 38.9%), limb-girdle dystrophy (91 cases, 27%), Becker dystrophy (58 cases, 17.2%), FSHD dystrophy (31 cases, 9.2%), and SMA (26 cases, 7.7%), respectively. The results showed that a statistically significant relationship between dystrophy types and gender, age, family history, age of diagnosis, CPK and LDH levels (P < 0.001). There were no statistical relationship between dystrophy types and pathological findings (P = 0.57), EMG-NCV test results (P = 0.062), and genetic findings (P = 0.06). Since muscular dystrophies often appear during the first decade of life, any information in regard to their prevalence can contribute to better planning and provisioning of required services, as well as better treatment or control of the condition. The results also showed that genetic tests, para-clinical tests, pathology analysis, and EMG-NCV tests can serve as good diagnostic tools for different varieties of dystrophy. Thus, facilitation of these diagnostic tests, particularly the genetic tests, can lead to a faster and more accurate diagnosis of dystrophy, especially in people with a family history of the disease.

scholarly journals Diagnostic Value of Dystrophin Immunostaining in the Diagnosis of Duchenne and Becker Muscular Dystrophy Patients

2021 ◽  
Vol 9 (A) ◽  
pp. 1137-1141
Author(s):  
Shinta Andi Sarasati ◽  
Kristy Iskandar ◽  
Maria Alethea Septianastiti ◽  
Rusdy Ghazali Malueka ◽  
Ery Kus Dwianingsih
Keyword(s):  
Genetic Testing ◽  
Muscular Dystrophy ◽  
Muscle Biopsy ◽  
Predictive Value ◽  
False Negative ◽  
High Sensitivity ◽  
Becker Muscular Dystrophy ◽  
Diagnostic Value ◽  
Diagnostic Tools ◽  
Sensitivity Specificity

Background: Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are X-linked recessive muscular disorders caused by the absence or reduction of the muscle cytoskeletal protein dystrophin. Standard procedures to detect deletion and duplication of the DMD gene use Multiplex Ligation-Dependent Probe Amplification (MLPA). However, genetic testing, such as MLPA, is not covered by the national insurance scheme in Indonesia. Immunohistochemical (IHC) staining of dystrophin from muscle biopsy in the form of Formalin-Fixed Paraffin-Embedded (FFPE) specimens can be an alternative method to detect dystrophin expression in protein levels to establish the diagnosis of DMD or BMD. Objectives: To determinate sensitivity, specificity and accuracy of IHC analysis of dystrophin in DMD/BMD patient in comparison with the standard genetic testing, MLPA. Methods: Twenty-six patients enrolled in this study were clinically diagnosed as DMD/BMD in Dr. Sardjito Hospital and Universitas Gadjah Mada Academic Hospital. Genomic DNA was isolated from 3 mL of EDTA-peripheral whole blood samples. The deletion and duplication of DMD genes were detected by MLPA. IHC examination was performed using a specific antibody dystrophin (DYS2). Complete loss of dystrophin staining indicated DMD, while partial loss of dystrophin staining indicated BMD. MLPA result was used as the gold standard to determine sensitivity, specificity, and accuracy of IHC technique using a 2x2 table. Results: MLPA results revealed 18 (18/26; 69.3%) patients with deletion and 3 (3/26; 11.5%) patients with duplication. Five (5/26; 19.2%) patients who showed no deletion nor duplication were excluded from the analysis. Among 21 patients with deletion or duplication, 18 (18/21; 85.7%) patients were out-of-frame (DMD) and 3 (3/21; 14.3%) patients were in-frame (BMD). Six patients showed a discrepancy between the IHC and MLPA results with 9.5% (2/21) false positive and 19% (4/21) false negative. The sensitivity of dystrophin IHC was 77.78%, specificity 33.33%, positive predictive value 87.5%, negative predictive value 20%, and accuracy 71.43%. Conclusion: Muscle biopsy followed by IHC can be one of the diagnostic tools to diagnose BMD or DMD, with high sensitivity. The protein-based strategy is probably the most efficient way to approach the diagnosis of Duchenne and Becker muscular dystrophy in limited health care settings.

Frequency and characterization of mutations in genes in a large cohort of patients referred to MODY registry

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Emily Breidbart ◽  
Liyong Deng ◽  
Patricia Lanzano ◽  
Xiao Fan ◽  
Jiancheng Guo ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Exome Sequencing ◽  
Large Scale ◽  
Age Of Onset ◽  
Family Members ◽  
Ethnically Diverse ◽  
Monogenic Diabetes ◽  
Diabetes Diagnosis ◽  
Pathogenic Variants ◽  
Atypical Diabetes

Abstract Objectives There have been few large-scale studies utilizing exome sequencing for genetically undiagnosed maturity onset diabetes of the young (MODY), a monogenic form of diabetes that is under-recognized. We describe a cohort of 160 individuals with suspected monogenic diabetes who were genetically assessed for mutations in genes known to cause MODY. Methods We used a tiered testing approach focusing initially on GCK and HNF1A and then expanding to exome sequencing for those individuals without identified mutations in GCK or HNF1A. The average age of onset of hyperglycemia or diabetes diagnosis was 19 years (median 14 years) with an average HbA1C of 7.1%. Results Sixty (37.5%) probands had heterozygous likely pathogenic/pathogenic variants in one of the MODY genes, 90% of which were in GCK or HNF1A. Less frequently, mutations were identified in PDX1, HNF4A, HNF1B, and KCNJ11. For those probands with available family members, 100% of the variants segregated with diabetes in the family. Cascade genetic testing in families identified 75 additional family members with a familial MODY mutation. Conclusions Our study is one of the largest and most ethnically diverse studies using exome sequencing to assess MODY genes. Tiered testing is an effective strategy to genetically diagnose atypical diabetes, and familial cascade genetic testing identified on average one additional family member with monogenic diabetes for each mutation identified in a proband.

scholarly journals Novel SCN5A p.Val1667Asp Missense Variant Segregation and Characterization in a Family with Severe Brugada Syndrome and Multiple Sudden Deaths

2021 ◽  
Vol 22 (9) ◽  
pp. 4700
Author(s):  
Michelle M. Monasky ◽  
Emanuele Micaglio ◽  
Giuseppe Ciconte ◽  
Ilaria Rivolta ◽  
Valeria Borrelli ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Family History ◽  
Risk Stratification ◽  
Brugada Syndrome ◽  
Electrophysiological Study ◽  
Functional Characterization ◽  
The Family ◽  
Novel Variant ◽  
History Of ◽  
Scn5a Gene

Genetic testing in Brugada syndrome (BrS) is still not considered to be useful for clinical management of patients in the majority of cases, due to the current lack of understanding about the effect of specific variants. Additionally, family history of sudden death is generally not considered useful for arrhythmic risk stratification. We sought to demonstrate the usefulness of genetic testing and family history in diagnosis and risk stratification. The family history was collected for a proband who presented with a personal history of aborted cardiac arrest and in whom a novel variant in the SCN5A gene was found. Living family members underwent ajmaline testing, electrophysiological study, and genetic testing to determine genotype-phenotype segregation, if any. Patch-clamp experiments on transfected human embryonic kidney 293 cells enabled the functional characterization of the SCN5A novel variant in vitro. In this study, we provide crucial human data on the novel heterozygous variant NM_198056.2:c.5000T>A (p.Val1667Asp) in the SCN5A gene, and demonstrate its segregation with a severe form of BrS and multiple sudden deaths. Functional data revealed a loss of function of the protein affected by the variant. These results provide the first disease association with this variant and demonstrate the usefulness of genetic testing for diagnosis and risk stratification in certain patients. This study also demonstrates the usefulness of collecting the family history, which can assist in understanding the severity of the disease in certain situations and confirm the importance of the functional studies to distinguish between pathogenic mutations and harmless genetic variants.

Combined Muscle Biopsy and Comprehensive Electrophysiology in General Anesthesia is Valuable in Diagnosis of Neuromuscular Disease in Children

2021 ◽  
Author(s):  
Christina E. Hoei-Hansen ◽  
Marie L. B. Tygesen ◽  
Morten Dunø ◽  
John Vissing ◽  
Martin Ballegaard ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Muscle Biopsy ◽  
Neuromuscular Disease ◽  
Genetic Diagnosis ◽  
Congenital Myasthenic Syndrome ◽  
Diagnostic Quality ◽  
Pathogenic Variants ◽  
Combined Use ◽  
Myasthenic Syndrome ◽  
Size Variability

Abstract Aim The diagnostic workup in patients with delayed motor milestones suspected of having either myopathy or a congenital myasthenic syndrome is complex. Our hypothesis was that performance of a muscle biopsy and neurophysiology including stimulated single-fiber electromyography during an anesthetic procedure, combined with genetic testing has a high diagnostic quality. Materials and Methods Clinical and paraclinical data were retrospectively collected from 24 patients aged from 1 month to 10 years (median: 5.2 years). Results Neurophysiology examination was performed in all patients and was abnormal in 11 of 24. No patients had findings suggestive of a myasthenic syndrome. Muscle biopsy was performed in 21 of 24 and was normal in 16. Diagnostic findings included nemaline rods, inclusion bodies, fiber size variability, and type-II fiber atrophy. Genetic testing with either a gene panel or exome sequencing was performed in 18 of 24 patients, with pathogenic variants detected in ACTA1, NEB, SELENON, GRIN2B, SCN8A, and COMP genes. Conclusion Results supporting a neuromuscular abnormality were found in 15 of 24. In six patients (25%), we confirmed a genetic diagnosis and 12 had a clinical neuromuscular diagnosis. The study suggests that combined use of neurophysiology and muscle biopsy in cases where genetic testing does not provide a diagnosis can be useful in children with delayed motor milestones and clinical evidence of a neuromuscular disease.

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