VMA21-X-linked myopathy in Peru: characterization of three families.

VMA21-X-Linked related myopathy is a rare neuromuscular disease characterized by a wide phenotypic spectrum ranging from neonatal forms with severe muscular weakness and respiratory failure, to mild childhood or adult-onset forms with slowly progressive muscular weakness and variably elevated serum creatine kinases. This condition is also called X-linked myopathy with excessive autophagy (XMEA) due to the presence of autophagic vacuoles with sarcolemmal proteins. Here we describe the clinical, muscle imaging, and genetic findings of six VMA21-X-Linked related myopathy patients belonging to three unrelated Peruvian families.

: Unveiling the Function of a Novel Gene Associated with Hereditary Myopathy.

Unlabelled: was identified as a novel candidate gene for autosomal dominant centronuclear myopathy-4 (CNM4) approximately ten years ago. However, to date, only one family has been described, and the function of CCDC78 remains unclear. Here, we analyze for the first time a family harboring a nonsense mutation to better understand the role of CCDC78 in muscle.

Sex influences clinical phenotype in valosin-containing protein mutations: A case family report and systematic literature review.

Objective: Mutations in the valosin-containing protein (VCP) gene cause autosomal dominant multisystem proteinopathy 1 (MSP1), characterized by a variable combination of inclusion body myopathy (IBM), Paget's disease of bone (PDB), and frontotemporal dementia (FTD). Here we report a novel VCP missense mutations in an Italian family with FTD as the prevalent manifestation and compare our results with those described in the literature.

Methods: We described the clinical, molecular, and imaging data of the studied family.

A Schematic Approach to Defining the Prevalence of COL VI Variants in Five Years of Next-Generation Sequencing.

Objective: To define the prevalence of variants in collagen VI genes through a next-generation sequencing (NGS) approach in undiagnosed patients with suspected neuromuscular disease and to propose a diagnostic flowchart to assess the real pathogenicity of those variants.

Methods: In the past five years, we have collected clinical and molecular information on 512 patients with neuromuscular symptoms referred to our center. To pinpoint variants in COLVI genes and corroborate their real pathogenicity, we sketched a multistep flowchart, taking into consideration the bioinformatic weight of the gene variants, their correlation with clinical manifestations and possible effects on protein stability and expression.

Expanding the clinical-pathological and genetic spectrum of RYR1-related congenital myopathies with cores and minicores: an Italian population study.

Mutations in the RYR1 gene, encoding ryanodine receptor 1 (RyR1), are a well-known cause of Central Core Disease (CCD) and Multi-minicore Disease (MmD). We screened a cohort of 153 patients carrying an histopathological diagnosis of core myopathy (cores and minicores) for RYR1 mutation. At least one RYR1 mutation was identified in 69 of them and these patients were further studied.

The Diagnostic Approach to Mitochondrial Disorders in Children in the Era of Next-Generation Sequencing: A 4-Year Cohort Study.

Mitochondrial diseases (MDs) are a large group of genetically determined multisystem disorders, characterized by extreme phenotypic heterogeneity, attributable in part to the dual genomic control (nuclear and mitochondrial DNA) of the mitochondrial proteome. Advances in next-generation sequencing technologies over the past two decades have presented clinicians with a challenge: to select the candidate disease-causing variants among the huge number of data provided. Unfortunately, the clinical tools available to support genetic interpretations still lack specificity and sensitivity.

Early Findings in Neonatal Cases of -Related Congenital Myopathies.

Ryanodine receptor type 1-related congenital myopathies are the most represented subgroup among congenital myopathies (CMs), typically presenting a central core or multiminicore muscle histopathology and high clinical heterogeneity. We evaluated a cohort of patients affected with Ryanodine receptor type 1-related congenital myopathy (-RCM), focusing on four patients who showed a severe congenital phenotype and underwent a comprehensive characterization at few months of life. To date there are few reports on precocious instrumental assessment.

Alpha-sarcoglycanopathy presenting as myalgia and hyperCKemia in two adults with a long-term follow-up. Case reports.

Two patients with a paucisymptomatic hyperckemia underwent a skeletal muscle biopsy and massive gene panel to investigate mutations associated with inherited muscle disorders. In the SGCA gene, sequence analyses revealed a homozygous c.850C > T/p.

Protein aggregates and autophagy involvement in a family with a mutation in Z-band alternatively spliced PDZ-motif protein.

Z-band alternatively spliced PDZ-motif protein (ZASP) is a sarcomeric component expressed both in cardiac and skeletal muscles. Mutations in the LDB3/ZASP gene cause cardiomyopathy and myofibrillar myopathy. We describe a c.

Evaluation of Chromosome Microarray Analysis in a Large Cohort of Females with Autism Spectrum Disorders: A Single Center Italian Study.

Autism spectrum disorders (ASD) encompass a heterogeneous group of neurodevelopmental disorders resulting from the complex interaction between genetic and environmental factors. Thanks to the chromosome microarray analysis (CMA) in clinical practice, the accurate identification and characterization of submicroscopic deletions/duplications (copy number variants, CNVs) associated with ASD was made possible. However, the widely acknowledged excess of males on the autism spectrum reflects on a paucity of CMA studies specifically focused on females with ASD (f-ASD).

Respiratory muscle involvement in LGMD D3 muscular dystrophy: an extensive clinical description of the first Italian patient.

Limb girdle muscular dystrophy is a genetically inherited condition that primarily affects skeletal muscle leading to progressive, predominantly proximal muscle weakness at presentation. Autosomal dominant LGMD represent 10% of all LGMDs. -related muscular dystrophy, LGMD1G/LGMD D3 (MIM#609115), is an extremely rare autosomal dominant adult onset myopathy described in a handful of families.

MYH2 myopathy, a new case expands the clinical and pathological spectrum of the recessive form.

Background: Hereditary myosin myopathies are a group of rare muscle disorders, caused by mutations in genes encoding for skeletal myosin heavy chains (MyHCs). MyHCIIa is encoded by MYH2 and is expressed in fast type 2A and 2B muscle fibers. MYH2 mutations are responsible for an autosomal dominant (AD) progressive myopathy, characterized by the presence of rimmed vacuoles and by a reduction in the number and size of type 2A fibers, and a recessive early onset myopathy characterized by complete loss of type 2A fibers.

Next-generation sequencing approach to hyperCKemia: A 2-year cohort study.

Objective: Next-generation sequencing (NGS) was applied in molecularly undiagnosed asymptomatic or paucisymptomatic hyperCKemia to investigate whether this technique might allow detection of the genetic basis of the condition.

Methods: Sixty-six patients with undiagnosed asymptomatic or paucisymptomatic hyperCKemia, referred to tertiary neuromuscular centers over an approximately 2-year period, were analyzed using a customized, targeted sequencing panel able to investigate the coding exons and flanking intronic regions of 78 genes associated with limb-girdle muscular dystrophies, rhabdomyolysis, and metabolic and distal myopathies.

Results: A molecular diagnosis was reached in 33 cases, corresponding to a positive diagnostic yield of 50%.

VARS2-linked mitochondrial encephalopathy: two case reports enlarging the clinical phenotype.

Background: Mitochondrial respiratory chain consists of five complexes encoded by nuclear and mitochondrial genomes. Mitochondrial aminoacyl-tRNA synthetases are key enzymes in the synthesis of such complexes. Bi-allelic variants of VARS2, a nuclear gene encoding for valyl-tRNA (Val-tRNA) synthetase, are associated to several forms of mitochondrial encephalopathies or cardiomyoencephalopathies.

Complex multisystem phenotype associated with the mitochondrial DNA m.5522G>A mutation.

Mitochondrial tRNAs are responsible for more than half of pathogenic point mutations in the mitochondrial genome (mtDNA). Different mutations give rise to widely differing phenotypes, ranging from isolated organ-specific diseases to multisystem conditions. Herein, we report a 40-year-old woman presenting with a complex multisystem phenotype including sensorineural hearing loss, retinopathy, severe dilated cardiomyopathy, non-insulin dependent diabetes mellitus, and renal failure.

Clinical and neuroimaging features of the m.10197G>A mtDNA mutation: New case reports and expansion of the phenotype variability.

Complex I (CI) is the largest component of the mitochondrial respiratory chain (MRC) and it is made up of 7 mitochondrial DNA (mtDNA)-encoded and at least 38 nuclear DNA-encoded subunits. Isolated CI deficiency is the most common single enzyme deficiency in the heterogeneous group of MRC disorders and it is a relatively common etiology of Leigh-like syndrome (LS). With a few exceptions, descriptions of the clinical spectrum of specific mutations in CI are scarce.

Broad phenotypic spectrum and genotype-phenotype correlations in GMPPB-related dystroglycanopathies: an Italian cross-sectional study.

Background: Dystroglycanopathy (α-DG) is a relatively common, clinically and genetically heterogeneous category of congenital forms of muscular dystrophy (CMD) and limb-girdle muscular dystrophy (LGMD) associated with hypoglycosylated α-dystroglycan. To date, mutations in at least 19 genes have been associated with α-DG. One of them, GMPPB, encoding the guanosine-diphosphate-mannose (GDP-mannose) pyrophosphorylase B protein, has recently been associated with a wide clinical spectrum ranging from severe Walker-Warburg syndrome to pseudo-metabolic myopathy and even congenital myasthenic syndromes.

Congenital myopathies: clinical phenotypes and new diagnostic tools.

Congenital myopathies are a group of genetic muscle disorders characterized clinically by hypotonia and weakness, usually from birth, and a static or slowly progressive clinical course. Historically, congenital myopathies have been classified on the basis of major morphological features seen on muscle biopsy. However, different genes have now been identified as associated with the various phenotypic and histological expressions of these disorders, and in recent years, because of their unexpectedly wide genetic and clinical heterogeneity, next-generation sequencing has increasingly been used for their diagnosis.

Neutral Lipid Storage Diseases: clinical/genetic features and natural history in a large cohort of Italian patients.

Background: A small number of patients affected by Neutral Lipid Storage Diseases (NLSDs: NLSD type M with Myopathy and NLSD type I with Ichthyosis) have been described in various ethnic groups worldwide. However, relatively little is known about the progression and phenotypic variability of the disease in large specific populations. The aim of our study was to assess the natural history, disability and genotype-phenotype correlations in Italian patients with NLSDs.

MYH7-related myopathies: clinical, histopathological and imaging findings in a cohort of Italian patients.

Background: Myosin heavy chain 7 (MYH7)-related myopathies are emerging as an important group of muscle diseases of childhood and adulthood, with variable clinical and histopathological expression depending on the type and location of the mutation. Mutations in the head and neck domains are a well-established cause of hypertrophic cardiomyopathy whereas mutation in the distal regions have been associated with a range of skeletal myopathies with or without cardiac involvement, including Laing distal myopathy and Myosin storage myopathy. Recently the spectrum of clinical phenotypes associated with mutations in MYH7 has increased, blurring this scheme and adding further phenotypes to the list.

Dolichol-phosphate mannose synthase depletion in zebrafish leads to dystrophic muscle with hypoglycosylated α-dystroglycan.

Defective dolichol-phosphate mannose synthase (DPMS) complex is a rare cause of congenital muscular dystrophy associated with hypoglycosylation of alpha-dystroglycan (α-DG) in skeletal muscle. We used the zebrafish (Danio rerio) to model muscle abnormalities due to defects in the subunits of DPMS. The three zebrafish ortholog subunits (encoded by the dpm1, dpm2 and dpm3 genes, respectively) showed high similarity to the human proteins, and their expression displayed localization in the midbrain/hindbrain area and somites.