Clinical and molecular characterization of mitochondrial DNA disorders in a group of Argentinian pediatric patients.

Objective: To describe the clinical and molecular features of a group of Argentinian pediatric patients with mitochondrial DNA (mtDNA) disorders, and to evaluate the results of the implementation of a classical approach for the molecular diagnosis of mitochondrial diseases.

Methods: Clinical data from 27 patients with confirmed mtDNA pathogenic variants were obtained from a database of 89 patients with suspected mitochondrial disease, registered from 2014 to 2020. Clinical data, biochemical analysis, neuroimaging findings, muscle biopsy and molecular studies were analyzed.

HNRNPDL-related muscular dystrophy: expanding the clinical, morphological and MRI phenotypes.

Autosomal dominant limb girdle muscular dystrophy D3 HNRNPDL-related is a rare dominant myopathy caused by mutations in HNRNPDL. Only three unrelated families have been described worldwide, a Brazilian and a Chinese carrying the mutation c.1132G>A p.

'Dusty core disease' (DuCD): expanding morphological spectrum of RYR1 recessive myopathies.

Several morphological phenotypes have been associated to RYR1-recessive myopathies. We recharacterized the RYR1-recessive morphological spectrum by a large monocentric study performed on 54 muscle biopsies from a large cohort of 48 genetically confirmed patients, using histoenzymology, immunohistochemistry, and ultrastructural studies. We also analysed the level of RyR1 expression in patients' muscle biopsies.

Loss of Sarcomeric Scaffolding as a Common Baseline Histopathologic Lesion in Titin-Related Myopathies.

Titin-related myopathies are heterogeneous clinical conditions associated with mutations in TTN. To define their histopathologic boundaries and try to overcome the difficulty in assessing the pathogenic role of TTN variants, we performed a thorough morphological skeletal muscle analysis including light and electron microscopy in 23 patients with different clinical phenotypes presenting pathogenic autosomal dominant or autosomal recessive (AR) mutations located in different TTN domains. We identified a consistent pattern characterized by diverse defects in oxidative staining with prominent nuclear internalization in congenital phenotypes (AR-CM) (n = 10), ± necrotic/regenerative fibers, associated with endomysial fibrosis and rimmed vacuoles (RVs) in AR early-onset Emery-Dreifuss-like (AR-ED) (n = 4) and AR adult-onset distal myopathies (n = 4), and cytoplasmic bodies (CBs) as predominant finding in hereditary myopathy with early respiratory failure (HMERF) patients (n = 5).

[Dermatomyositis associated with anti-MDA5 autoantibody].

Dematomyositis is an idiopathic inflammatory myopathy with a variable clinical spectrum. In recent years, a number of myositis-specific antibodies have been identified including anti-MDA5, which is us eful for diagnosis, prognosis and classification of the diverse clinical forms of the disease. This antibody is associated with cutaneous ulcers, rapidly progressive interstitial lung disease, early mortality and poor prognosis, so the detection of this antibody in a suitable clinical context, raises the need for an aggressive immunosuppressive treatment.

[Argentine consensus on late-onset Pompe's disease].

Pompe's disease (PD) is an infrequent metabolic autosomic recessive disorder produced by the lack or deficiency of the acid alpha-glucosidase lysosomal enzyme in tissues of involved individuals. Delayed-onset PD is considered whenever symptoms onset start after one year of age. We present an update of the recommendations for the management of delayed-onset PD, taking as reference the guidelines from the Argentine Consensus for diagnosis, treatment and follow-up of PD published in 2013.

Intraneural perineuriomas: diagnostic value of magnetic resonance neurography.

Intraneural perineurioma (IP) is an under-recognized hypertrophic peripheral nerve tumor. It affects young patients involving frequently the sciatic nerve and its branches and presents with a progressive, painless and predominantly motor deficit. Magnetic resonance neurography (MRN) is a useful tool to localize the lesion, evaluate its extension, and discriminate between different etiologies.

CLN8 disease caused by large genomic deletions.

Background: The presence of deletions can complicate genetic diagnosis of autosomal recessive disease.

Method: The DNA of patients was analyzed in a diagnostic setting.

Results: We present three unrelated patients each carrying deletions that encompass the 37 kb gene and discuss their phenotype.

Muscle MRI in pediatrics: clinical, pathological and genetic correlation.

Pediatric myopathies comprise a very heterogeneous group of disorders that may develop at different ages and affect different muscle groups. Its diagnosis is sometimes difficult and must be confirmed by muscle biopsy and/or genetic analysis. In recent years, muscle involvement patterns observed on MRI have become a valuable tool, aiding clinical diagnosis and enriching pathological and genetic assessments.

Dihydropyridine receptor (DHPR, CACNA1S) congenital myopathy.

Muscle contraction upon nerve stimulation relies on excitation-contraction coupling (ECC) to promote the rapid and generalized release of calcium within myofibers. In skeletal muscle, ECC is performed by the direct coupling of a voltage-gated L-type Ca channel (dihydropyridine receptor; DHPR) located on the T-tubule with a Ca release channel (ryanodine receptor; RYR1) on the sarcoplasmic reticulum (SR) component of the triad. Here, we characterize a novel class of congenital myopathy at the morphological, molecular, and functional levels.

Bilateral foot-drop as predominant symptom in nebulin (NEB) gene related "core-rod" congenital myopathy.

Background: Congenital myopathies (CM) are a group of rare inherited muscle disorders characterized by particular histopathological alterations on muscle biopsy. Core-rod myopathy is a CM presenting with cores and rods as distinctive muscle morphological features.

Methods/results: We describe 3 young patients presenting congenital core-rod myopathy with bilateral foot-drop associated with autosomal recessive nebulin gene (NEB) mutations detected by exome sequencing.

Adult-onset autosomal dominant centronuclear myopathy due to BIN1 mutations.

Centronuclear myopathies are congenital muscle disorders characterized by type I myofibre predominance and an increased number of muscle fibres with nuclear centralization. The severe neonatal X-linked form is due to mutations in MTM1, autosomal recessive centronuclear myopathy with neonatal or childhood onset results from mutations in BIN1 (amphiphysin 2), and dominant cases were previously associated to mutations in DNM2 (dynamin 2). Our aim was to determine the genetic basis and physiopathology of patients with mild dominant centronuclear myopathy without mutations in DNM2.

Muscle histopathology in nebulin-related nemaline myopathy: ultrastrastructural findings correlated to disease severity and genotype.

Nemaline myopathy (NM) is a rare congenital myopathy characterised by hypotonia, muscle weakness, and often skeletal muscle deformities with the presence of nemaline bodies (rods) in the muscle biopsy. The nebulin (NEB) gene is the most commonly mutated and is thought to account for approximately 50% of genetically diagnosed cases of NM. We undertook a detailed muscle morphological analysis of 14 NEB-mutated NM patients with different clinical forms to define muscle pathological patterns and correlate them with clinical course and genotype.

Mutation update and genotype-phenotype correlations of novel and previously described mutations in TPM2 and TPM3 causing congenital myopathies.

Mutations affecting skeletal muscle isoforms of the tropomyosin genes may cause nemaline myopathy, cap myopathy, core-rod myopathy, congenital fiber-type disproportion, distal arthrogryposes, and Escobar syndrome. We correlate the clinical picture of these diseases with novel (19) and previously reported (31) mutations of the TPM2 and TPM3 genes. Included are altogether 93 families: 53 with TPM2 mutations and 40 with TPM3 mutations.

MM1+2C sporadic Creutzfeldt-Jakob disease presenting as rapidly progressive nonfluent aphasia.

We report a 77-year-old man, presenting with progressive aphasia as an initial symptom, who developed severe dementia over the course of 20 months. Frontal cortex PrPSc western blot was type 2 and codon 129 was MM; brain neuropathology showed cortical vacuoles with perivacuolar PrP immunostaining characteristic of MM2C. Cerebellum showed focal coarse, patchy staining in different sections of the molecular layer, diffuse fine punctuate and coarse PrP immunopositive deposits in the granule cell layer, and focal synaptic immunostaining in the molecular layer, suggestive of MM1+2C by histotyping.

Skeletal muscle biopsy analysis in reducing body myopathy and other FHL1-related disorders.

FHL1 mutations have been associated with various disorders that include reducing body myopathy (RBM), Emery-Dreifuss-like muscular dystrophy, isolated hypertrophic cardiomyopathy, and some overlapping conditions. We report a detailed histochemical, immunohistochemical, electron microscopic, and immunoelectron microscopic analyses of muscle biopsies from 18 patients carrying mutations in FHL1: 14 RBM patients (Group 1), 3 Emery-Dreifuss muscular dystrophy patients (Group 2), and 1 patient with hypertrophic cardiomyopathy and muscular hypertrophy (Group 2). Group 1 muscle biopsies consistently showed RBs associated with cytoplasmic bodies.

Gerstmann-Sträussler-Scheinker syndrome with variable phenotype in a new kindred with PRNP-P102L mutation.

Gerstmann-Sträussler-Scheinker syndrome (GSS) is a dominantly inherited disorder belonging to the group of transmissible human spongiform encephalopathies or prion diseases. Several families affected by GSS with patients carrying mutations in the prion protein gene have been described worldwide. We report clinical, genealogical, neuropathology and molecular study results from two members of the first Argentine kindred affected by GSS.

Hereditary myopathy with early respiratory failure: occurrence in various populations.

Objective: Several families with characteristic features of hereditary myopathy with early respiratory failure (HMERF) have remained without genetic cause. This international study was initiated to clarify epidemiology and the genetic underlying cause in these families, and to characterise the phenotype in our large cohort.

Methods: DNA samples of all currently known families with HMERF without molecular genetic cause were obtained from 12 families in seven different countries.

Morphological spectrum and clinical features of myopathies with tubular aggregates.

Tubular aggregates (TAs) are aggregates of densely packed tubules in human skeletal muscle fibers with particular histochemical and ultrastructural features that most probably arise from the sarcoplasmic reticulum. Some studies have shown an additional mitochondrial origin of TAs. We studied the histopathological spectrum and clinical features in a large cohort of patients with TAs in their muscle biopsy (106 biopsies), derived from our muscle biopsy archive (15,412 biopsies in total).

Pompe disease, the must-not-miss diagnosis: A report of 3 patients.

Introduction: Pompe disease is a progressive and debilitating neuromuscular disorder that presents with a heterogeneous array of signs and symptoms including proximal muscle weakness, respiratory insufficiency, and/or elevated creatine kinase levels. It mimics other neuromuscular disorders, making its diagnosis challenging and often significantly delayed, thereby increasing morbidity and early mortality of the disease.

Methods: Three Pompe disease patients are discussed to highlight the challenging path to diagnosis and the common cluster of symptoms that could lead to timely and accurate diagnosis.

Diagnosis of mitochondrial disorders applying massive pyrosequencing.

Mitochondrial disorders are a frequent cause of neurological disability affecting children and adults. Traditionally, molecular diagnosis of mitochondrial diseases was mostly accomplished by the use of Sanger sequencing and PCR-RFLP. However, there are particular drawbacks associated with the use of these methods.

Creutzfeldt-Jakob disease surveillance in Argentina, 1997-2008.

Background: Epidemiological data on Creutzfeldt-Jakob disease (CJD) from Latin America are limited. We present a comprehensive epidemiological survey on CJD patients in Argentina based on systematic surveillance between 1997 and 2008.

Methods: A CJD Surveillance Referral Center (SRC) was established in Argentina in 1997; previously a Neuropathology Referral Center was used from 1983 to 1996.

Genetic prion disease with codon 196 PRNP mutation: clinical and pathological findings.

Ten percent to 15% of all human transmissible spongiform encephalopathy are characterized by a mutation in prion protein gene (PRNP). They are distinct with respect to clinical signs, disease onset, disease duration, and diagnostic findings. During our surveillance activities in Germany, we identified 7 patients with the rare mutation E196K in PRNP gene, thereof 4 patients belonging to 2 families.

Early onset collagen VI myopathies: Genetic and clinical correlations.

Objective: Mutations in the genes encoding the extracellular matrix protein collagen VI (ColVI) cause a spectrum of disorders with variable inheritance including Ullrich congenital muscular dystrophy, Bethlem myopathy, and intermediate phenotypes. We extensively characterized, at the clinical, cellular, and molecular levels, 49 patients with onset in the first 2 years of life to investigate genotype-phenotype correlations.

Methods: Patients were classified into 3 groups: early-severe (18%), moderate-progressive (53%), and mild (29%).

Abnormal distribution of inositol 1,4,5-trisphosphate receptors in human muscle can be related to altered calcium signals and gene expression in Duchenne dystrophy-derived cells.

Inositol 1,4,5-trisphosphate (IP(3)) receptors (IP(3)Rs) drive calcium signals involved in skeletal muscle excitation-transcription coupling and plasticity; IP(3)R subtype distribution and downstream events evoked by their activation have not been studied in human muscle nor has their possible alteration in Duchenne muscular dystrophy (DMD). We studied the expression and localization of IP(3)R subtypes in normal and DMD human muscle and in normal (RCMH) and dystrophic (RCDMD) human muscle cell lines. In normal muscle, both type 1 IP(3)Rs (IP(3)R1) and type 2 IP(3)Rs (IP(3)R2) show a higher expression in type II fibers, whereas type 3 IP(3)Rs (IP(3)R3) show uniform distribution.