A Novel MYH14 Variant Presenting as a New Phenotype of MYH14-Associated Neuromuscular Disorders-Clinicohistologic Findings and Review of the Literature.

Background: Pathogenic variants in the nonmuscle myosin, MYH14, have been associated with several pathologic conditions including a complex phenotype with peripheral neuropathy, myopathy, hoarseness, and hearing loss. Since its first description in a large Korean kindred, this rare neuromuscular disorder has further been characterized in 1 American and 1 Canadian pedigree.

Case Presentation: Here, we describe a German patient with atypical MYH14-related neuromuscular disorder.

Quantitative whole-body muscle MRI in idiopathic inflammatory myopathies including polymyositis with mitochondrial pathology: indications for a disease spectrum.

Objective: Inflammatory myopathies (IIM) include dermatomyositis (DM), sporadic inclusion body myositis (sIBM), immune-mediated necrotizing myopathy (IMNM), and overlap myositis (OLM)/antisynthetase syndrome (ASyS). There is also a rare variant termed polymyositis with mitochondrial pathology (PM-Mito), which is considered a sIBM precursor. There is no information regarding muscle MRI for this rare entity.

GFPT1-Associated Congenital Myasthenic Syndrome Mimicking a Glycogen Storage Disease - Diagnostic Pitfalls in Myopathology Solved by Next-Generation-Sequencing.

GFPT1-related congenital myasthenic syndrome (CMS) is characterized by progressive limb girdle weakness, and less prominent involvement of facial, bulbar, or respiratory muscles. While tubular aggregates in muscle biopsy are considered highly indicative in GFPT1-associated CMS, excessive glycogen storage has not been described. Here, we report on three affected siblings with limb-girdle myasthenia due to biallelic pathogenic variants in GFPT1: the previously reported missense variant c.

Bi-allelic variants in CHKA cause a neurodevelopmental disorder with epilepsy and microcephaly.

The Kennedy pathways catalyse the de novo synthesis of phosphatidylcholine and phosphatidylethanolamine, the most abundant components of eukaryotic cell membranes. In recent years, these pathways have moved into clinical focus because four of ten genes involved have been associated with a range of autosomal recessive rare diseases such as a neurodevelopmental disorder with muscular dystrophy (CHKB), bone abnormalities and cone-rod dystrophy (PCYT1A) and spastic paraplegia (PCYT2, SELENOI). We identified six individuals from five families with bi-allelic variants in CHKA presenting with severe global developmental delay, epilepsy, movement disorders and microcephaly.

Cerebral Abnormalities in Spina Bifida: A Neuropathological Study.

Introduction: Spina bifida (SB) is the most common neural tube defect in humans. Here, we analyzed systematically the neuropathological findings of the brain in SB cases.

Methods: 79 cases with SB aperta (SBA) and 6 cases with SB occulta (SBO) autopsied at the Charité Neuropathology from 1974 to 2000 were re-evaluated retrospectively.

Expanding the phenotype of NUP85 mutations beyond nephrotic syndrome to primary autosomal recessive microcephaly and Seckel syndrome spectrum disorders.

Primary autosomal recessive microcephaly and Seckel syndrome spectrum disorders (MCPH-SCKS) include a heterogeneous group of autosomal recessive inherited diseases characterized by primary (congenital) microcephaly, the absence of visceral abnormalities, and a variable degree of cognitive impairment, short stature and facial dysmorphism. Recently, biallelic variants in the nuclear pore complex (NPC) component nucleoporin 85 gene (NUP85) were reported to cause steroid-resistant nephrotic syndrome (SRNS). Here, we report biallelic variants in NUP85 in two pedigrees with an MCPH-SCKS phenotype spectrum without SRNS, thereby expanding the phenotypic spectrum of NUP85-linked diseases.

Concurrent axon and myelin destruction differentiates X-linked adrenoleukodystrophy from multiple sclerosis.

Cerebral disease manifestation occurs in about two thirds of males with X-linked adrenoleukodystrophy (CALD) and is fatally progressive if left untreated. Early histopathologic studies categorized CALD as an inflammatory demyelinating disease, which led to repeated comparisons to multiple sclerosis (MS). The aim of this study was to revisit the relationship between axonal damage and myelin loss in CALD.

Systematic Classification of Spina Bifida.

Spina bifida (SB) is an umbrella term for multiple conditions characterized by misclosure of vertebral arches. Neuropathologic findings in SB cases are often reported with imprecise and overlapping terminology. In view of the increasing identification of SB-associated genes and pathomechanisms, the precise description of SB subtypes is highly important.

Congenital microcephaly-linked CDK5RAP2 affects eye development.

Biallelic mutations in the cyclin-dependent kinase 5 regulatory subunit-associated protein 2 gene CDK5RAP2 cause autosomal recessive primary microcephaly type 3 (MCPH3). MCPH is characterized by intellectual disability and microcephaly at birth, classically without further organ involvement. Only recently, congenital cataracts were reported in four patients of one pedigree with MCPH3.

Microglia damage precedes major myelin breakdown in X-linked adrenoleukodystrophy and metachromatic leukodystrophy.

X-linked adrenoleukodystrophy (X-ALD) and metachromatic leukodystrophy (MLD) are two relatively common examples of hereditary demyelinating diseases caused by a dysfunction of peroxisomal or lysosomal lipid degradation. In both conditions, accumulation of nondegraded lipids leads to the destruction of cerebral white matter. Because of their high lipid content, oligodendrocytes are considered key to the pathophysiology of these leukodystrophies.

The congenital clubfoot - immunohistological analysis of the extracellular matrix.

Purpose: Congenital clubfoot is one of the most common limb disorders in humans and its etiology is still unclear. In order to better understand the pathogenesis of patients with primary clubfoot, we examined whether there are quantitative changes in the extracellular matrix (ECM; based on common interstitial collagens [C] like CI and CIII, microfilamentous collagens like CVI, noncollagenous proteins like undulin, and enzymes like matrixmetalloproteinase [MMP]-2 and tissue inhibitor of matrixmetalloproteinase [TIMP]-2 that are known to play a role in fibrogenesis and fibrolysis) of muscles involved in the foot deformity of patients with primary clubfoot corresponding to fibrosis.

Patients And Methods: Thirty patients (age ranging from 4 months to 5 years and 7 months) with primary clubfoot were examined (23 male and 7 female patients), among whom 18 patients were affected on one side and 12 affected on both sides.

Immunomodulatory placental-expanded, mesenchymal stromal cells improve muscle function following hip arthroplasty.

Background: No regenerative approach has thus far been shown to be effective in skeletal muscle injuries, despite their high frequency and associated functional deficits. We sought to address surgical trauma-related muscle injuries using local intraoperative application of allogeneic placenta-derived, mesenchymal-like adherent cells (PLX-PAD), using hip arthroplasty as a standardized injury model, because of the high regenerative and immunomodulatory potency of this cell type.

Methods: Our pilot phase I/IIa study was prospective, randomized, double blind, and placebo-controlled.

CDK5RAP2 Is Required to Maintain the Germ Cell Pool during Embryonic Development.

Gene products linked to microcephaly have been studied foremost for their role in brain development, while their function in the development of other organs has been largely neglected. Here, we report the critical role of Cdk5rap2 in maintaining the germ cell pool during embryonic development. We highlight that infertility in Cdk5rap2 mutant mice is secondary to a lack of spermatogenic cells in adult mice as a result of an early developmental defect in the germ cells through mitotic delay, prolonged cell cycle, and apoptosis.

Synthetic niche to modulate regenerative potential of MSCs and enhance skeletal muscle regeneration.

Severe injury to the skeletal muscle often results in the formation of scar tissue, leading to a decline in functional performance. Traditionally, tissue engineering strategies for muscle repair have focused on substrates that promote myogenic differentiation of transplanted cells. In the current study, the reported data indicates that mesenchymal stromal cells (MSCs) transplanted via porous alginate cryogels promote muscle regeneration by secreting bioactive factors that profoundly influence the function of muscle progenitor cells.

Experimental investigation and histopathological identification of acute thermal damage in skeletal porcine muscle in relation to whole-body SAR, maximum temperature, and CEM43 °C due to RF irradiation in an MR body coil of birdcage type at 123 MHz.

Purpose: This study is an investigation of the relationship between several characteristic parameters and acute thermal damage in porcine skeletal muscle.

Material And Methods: Fourteen pigs under injection anaesthesia were placed into a magnetic resonance body coil and exposed for different time durations to different specific energy absorption rate (SAR) levels at 123 MHz. Local temperatures were measured using four temperature sensors.

Mutations in PTRH2 cause novel infantile-onset multisystem disease with intellectual disability, microcephaly, progressive ataxia, and muscle weakness.

Objective: To identify the cause of a so-far unreported phenotype of infantile-onset multisystem neurologic, endocrine, and pancreatic disease (IMNEPD).

Methods: We characterized a consanguineous family of Yazidian-Turkish descent with IMNEPD. The two affected children suffer from intellectual disability, postnatal microcephaly, growth retardation, progressive ataxia, distal muscle weakness, peripheral demyelinating sensorimotor neuropathy, sensorineural deafness, exocrine pancreas insufficiency, hypothyroidism, and show signs of liver fibrosis.

Phenotype of matrin-3-related distal myopathy in 16 German patients.

Objective: To characterize the phenotype of patients with distal myopathy with vocal cord and pharyngeal weakness due to the p.S85C mutation in the matrin-3 gene (MATR3, Mendelian Inheritance in Man 164015). Recently, it has been suggested that patients with this mutation may suffer from familial amyotrophic lateral sclerosis.

Eosinophils in hereditary and inflammatory myopathies.

It is not known whether eosinophilic myositis is a specific histopathological feature of limb girdle muscular dystrophy 2A (LGMD2A). Number and location of eosinophils in skeletal muscle biopsies (n=100) was analysed by Giemsa and modified hematoxylin/eosin staining in patients with genetically confirmed myopathies (LGMD2A, LGMD2B, LGMD2L, facioscapulohumeral muscular dystrophy, dystrophinopathy), histologically confirmed idiopathic inflammatory myopathies (sporadic inclusion body myositis (sIBM), dermatomyositis (DM), polymyositis), amyotrophic lateral sclerosis (neurogenic control), and normal controls. The number of eosinophils/mm² was significantly higher in LGMD2A, PM, DM, and sIBM compared to controls but not significantly higher than other myopathies.

Noninvasive monitoring of training induced muscle adaptation with 31P-MRS: fibre type shifts correlate with metabolic changes.

Purpose: To evaluate training induced metabolic changes noninvasively with (31)P magnetic resonance spectroscopy ((31)P-MRS) for measuring muscle fibre type adaptation.

Methods: Eleven volunteers underwent a 24-week training, consisting of speed-strength, endurance, and detraining (each 8 weeks). Prior to and following each training period, needle biopsies and (31)P-MRS of the resting gastrocnemius muscle were performed.

Polymyositis with cytochrome C oxidase negative fibers--a pathological and clinical challenge.

Polymyositis (PM) with cytochrome C oxidase negative fibers also referred to as PM with mitochondrial pathology (PM-Mito) is characterized by the symptoms of inclusion body myositis (IBM) and by the myopathological findings of PM except for an increase of muscle fibers with insufficient mitochondrial cytochrome C oxidase activity. Few PM-Mito cases are published; mitochondrial ultrastructure has not been studied in these patients. We report 2 PM-Mito patients with later onset than usually seen in IBM and poor responsiveness to glucocorticoids.

CDK5RAP2 expression during murine and human brain development correlates with pathology in primary autosomal recessive microcephaly.

Homozygous mutations in the cyclin-dependent kinase-5 regulatory subunit-associated protein 2 gene CDK5RAP2 cause primary autosomal recessive microcephaly (MCPH). MCPH is characterized by a pronounced reduction of brain volume, particularly of the cerebral cortex, and mental retardation. Though it is a rare developmental disorder, MCPH has moved into the spotlight of neuroscience because of its proposed central role in stem-cell biology and brain development.

Systemic inflammation disrupts the developmental program of white matter.

Objective: Perinatal inflammation is a major risk factor for neurological deficits in preterm infants. Several experimental studies have shown that systemic inflammation can alter the programming of the developing brain. However, these studies do not offer detailed pathophysiological mechanisms, and they rely on relatively severe infectious or inflammatory stimuli that most likely do not reflect the levels of systemic inflammation observed in many human preterm infants.

Time course of skeletal muscle regeneration after severe trauma.

Background And Purpose: Animal models of skeletal muscle injury should be thoroughly described and should mimic the clinical situation. We established a model of a critical size crush injury of the soleus muscle in rats. The aim was to describe the time course of skeletal muscle regeneration using mechanical, histological, and magnetic resonance (MR) tomographic methods.