Phenotype Spectrum of TRPM3-Associated Disorders.

Objective: Monoallelic variants in the transient receptor potential melastatin-related type 3 gene (TRPM3) have been associated with neurodevelopmental manifestations, but knowledge on the clinical manifestations and treatment options is limited. We characterized the clinical spectrum, highlighting particularly the epilepsy phenotype, and the effect of treatments.

Methods: We analyzed retrospectively the phenotypes and genotypes of 43 individuals with TRPM3 variants, acquired from GeneMatcher and collaborations (n = 21), and through a systematic literature search (n = 22).

Exploring functional strength changes during nusinersen treatment in symptomatic children with SMA types 2 and 3.

The Hammersmith Functional Motor Scale-Expanded (HFMSE) is a validated outcome measure for monitoring changes in functional strength in patients with spinal muscular atrophy (SMA). The objective of this study was to explore changes in HFMSE item-scores in children with SMA types 2 and 3a treated with nusinersen over a period of six to twenty months. We stratified patients according to motor ability (sitting and walking), and calculated numbers and percentages for each specific improvement (positive score change) or decrease (negative score change) for the total group and each subgroup and calculated frequency distributions of specific score changes.

Monitoring Nusinersen Treatment Effects in Children with Spinal Muscular Atrophy with Quantitative Muscle MRI.

Background: Spinal muscular atrophy (SMA) is caused by deficiency of survival motor neuron (SMN) protein. Intrathecal nusinersen treatment increases SMN protein in motor neurons and has been shown to improve motor function in symptomatic children with SMA.

Objective: We used quantitative MRI to gain insight in microstructure and fat content of muscle during treatment and to explore its use as biomarker for treatment effect.

Longitudinal prospective cohort study to assess peripheral motor function with extensive electrophysiological techniques in patients with Spinal Muscular Atrophy (SMA): the SMA Motor Map protocol.

Background: Hereditary spinal muscular atrophy (SMA) is a motor neuron disorder with a wide range in severity in children and adults. Two therapies that alter splicing of the Survival Motor Neuron 2 (SMN2) gene, i.e.

Swallowing Problems in Spinal Muscular Atrophy Types 2 and 3: A Clinical, Videofluoroscopic and Ultrasound Study.

Background: Spinal muscular atrophy (SMA) is a hereditary motor neuron disorder, characterized by the degeneration of motor neurons and progressive muscle weakness. There is a large variability of disease severity, reflected by the classification of SMA types 1-4.

Objective: The aim of this cross-sectional study was to determine the nature of swallowing problems and underlying mechanisms in patients with SMA types 2 and 3, and the relationship between swallowing and mastication problems.

Lung function decline preceding chronic respiratory failure in spinal muscular atrophy: a national prospective cohort study.

Background: Progressive lung function decline, resulting in respiratory failure, is an important complication of spinal muscular atrophy (SMA). The ability to predict the need for mechanical ventilation is important. We assessed longitudinal patterns of lung function prior to chronic respiratory failure in a national cohort of treatment-naïve children and adults with SMA, hypothesizing an accelerated decline prior to chronic respiratory failure.

Randomized double-blind placebo-controlled crossover trial with pyridostigmine in spinal muscular atrophy types 2-4.

Hereditary proximal spinal muscular atrophy causes weakness and increased fatigability of repetitive motor functions. The neuromuscular junction is anatomically and functionally abnormal in patients with spinal muscular atrophy. Pharmacological improvement of neuromuscular transmission may therefore represent a promising additional treatment strategy.

Inflammatory markers in cerebrospinal fluid of paediatric spinal muscular atrophy patients receiving nusinersen treatment.

Spinal muscular atrophy (SMA) is a progressive motor neuron disease with onset during infancy or early childhood. Recent therapeutic advances targeting the genetic defect that underlies SMA improved survival in patients with infantile onset SMA (type 1) and improved motor function in SMA type 1-3. The most commonly used therapy for SMA, the antisense oligonucleotide nusinersen, is delivered by repeated intrathecal injections.

Population-based assessment of nusinersen efficacy in children with spinal muscular atrophy: a 3-year follow-up study.

Nusinersen (Spinraza®) improves survival of infants with hereditary proximal spinal muscular atrophy and motor function in children up to 12 years. Population-based assessments of treatment efficacy are limited and confined to select cohorts of patients. We performed a nationwide, population-based, single-centre cohort study in children with spinal muscular atrophy younger than 9.

Impaired activity of the fusogenic micropeptide Myomixer causes myopathy resembling Carey-Fineman-Ziter syndrome.

Skeletal muscle fibers contain hundreds of nuclei, which increase the overall transcriptional activity of the tissue and perform specialized functions. Multinucleation occurs through myoblast fusion, mediated by the muscle fusogens Myomaker (MYMK) and Myomixer (MYMX). We describe a human pedigree harboring a recessive truncating variant of the MYMX gene that eliminates an evolutionarily conserved extracellular hydrophobic domain of MYMX, thereby impairing fusogenic activity.

'This battle, between your gut feeling and your mind. Try to find the right balance': Parental experiences of children with spinal muscular atrophy during COVID-19 pandemic.

Aims: Parents of children with spinal muscular atrophy (SMA) often struggle with the all-consuming nature of the demands of caring for a child with substantial physical needs. Our aim was to explore experiences, challenges and needs of parents of a child with SMA in a COVID-19 pandemic situation.

Method: Nineteen parents of 21 children (15 months to 13 years of age) with SMA types 1-3 participated in semi-structured interviews in June to July 2020.

Genetic, biochemical, and clinical spectrum of patients with mitochondrial trifunctional protein deficiency identified after the introduction of newborn screening in the Netherlands.

Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) is included in many newborn screening (NBS) programs. Acylcarnitine-based NBS for LCHADD not only identifies LCHADD, but also the other deficiencies of the mitochondrial trifunctional protein (MTP), a multi-enzyme complex involved in long-chain fatty acid β-oxidation. Besides LCHAD, MTP harbors two additional enzyme activities: long-chain enoyl-CoA hydratase (LCEH) and long-chain ketoacyl-CoA thiolase (LCKAT).

Natural history of respiratory muscle strength in spinal muscular atrophy: a prospective national cohort study.

Background: Respiratory complications are the most important cause of morbidity and mortality in spinal muscular atrophy (SMA). Respiratory muscle weakness results in impaired cough, recurrent respiratory tract infections and eventually can cause respiratory failure. We assessed longitudinal patterns of respiratory muscle strength in a national cohort of treatment-naïve children and adults with SMA, hypothesizing a continued decline throughout life.

Prevalence of Bladder and Bowel Dysfunction in Duchenne Muscular Dystrophy Using the Childhood Bladder and Bowel Dysfunction Questionnaire.

Introduction: Lower urinary tract symptoms (LUTS) and gastrointestinal (GI) problems are common in Duchenne muscular dystrophy (DMD), but not systematically assessed in regular care. We aimed to determine the prevalence of bladder and bowel dysfunction (BBD) in DMD patients compared with healthy controls (HC).

Methods: The Childhood Bladder and Bowel Dysfunction Questionnaire (CBBDQ) based on the International Rome III criteria and the International Children's Continence Society was filled out by 57 DMD patients and 56 HC.

Mastication in Patients with Spinal Muscular Atrophy Types 2 and 3 is Characterized by Abnormal Efficiency, Reduced Endurance, and Fatigue.

Mastication problems can have a negative impact on the intake of food and quality of life. This cross-sectional study characterizes mastication problems using clinical and instrumental assessments in patients with spinal muscular atrophy (SMA) types 2 and 3 with self-reported bulbar problems. We included 27 patients (aged 13-67 years), 18 with SMA type 2 and 9 patients with SMA type 3 (of whom three were still ambulant) and applied a questionnaire, clinical mastication tests (TOMASS and 6-min mastication test), and muscle ultrasound of the mastication muscles.

Parents' perspectives on nusinersen treatment for children with spinal muscular atrophy.

Aim: To gain insight into parents' perspectives about their decision-making process concerning nusinersen treatment for their child, including perceived needs and concerns, and to explore factors that influence this process.

Method: This was an exploratory qualitative interview study among parents of children with spinal muscular atrophy types 1 to 3. Data were analysed using inductive thematic analysis.

Quantification of disease progression in spinal muscular atrophy with muscle MRI-a pilot study.

Objectives: Quantitative MRI (qMRI) of muscles is a promising tool to measure disease progression or to assess therapeutic effects in neuromuscular diseases. Longitudinal imaging studies are needed to show sensitivity of qMRI in detecting disease progression in spinal muscular atrophy (SMA). In this pilot study we therefore studied one-year changes in quantitative MR parameters in relation to clinical scores.

Deep intronic TIMMDC1 variant delays diagnosis of rapidly progressive complex I deficiency.

Complex I deficiency is the most common pediatric mitochondrial disease. It can cause a wide range of clinical disorders, including Leigh syndrome. TIMMDC1 encodes an assembly protein of complex I and has been recently associated with early onset mitochondrial disease in three unrelated families.

Quantitative MRI of skeletal muscle in a cross-sectional cohort of patients with spinal muscular atrophy types 2 and 3.

The aim of this study was to document upper leg involvement in spinal muscular atrophy (SMA) with quantitative MRI (qMRI) in a cross-sectional cohort of patients of varying type, disease severity and age. Thirty-one patients with SMA types 2 and 3 (aged 29.6 [7.

Relative hyperventilation in non-ventilated patients with spinal muscular atrophy.

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Feeding and Swallowing Problems in Infants with Spinal Muscular Atrophy Type 1: an Observational Study.

Background: Infantile hereditary proximal spinal muscular atrophy (SMA) type 1 is characterized by onset in the first 6 months of life and severe and progressive muscle weakness. Dysphagia is a common complication but has not been studied in detail.

Objective: To study feeding and swallowing problems in infants with SMA type 1, and to explore the relation between these problems and functional motor scores.

Assessment of motor unit loss in patients with spinal muscular atrophy.

Objective: To assess motor unit (MU) changes in patients with spinal muscular atrophy (SMA) using compound muscle action potential (CMAP) scans.

Methods: We performed CMAP scan recordings in median nerves of 24 treatment-naïve patients (median age 39; range 12-75 years) with SMA types 2-4. From each scan, we determined maximum CMAP amplitude (CMAP), a motor unit number estimate (MUNE), and D50 which quantifies the largest discontinuities within CMAP scans.

Natural history of lung function in spinal muscular atrophy.

Background: Respiratory muscle weakness is an important feature of spinal muscular atrophy (SMA). Progressive lung function decline is the most important cause of mortality and morbidity in patients. The natural history of lung function in SMA has, however, not been studied in much detail.

Population-based analysis of survival in spinal muscular atrophy.

Objective: To investigate probabilities of survival and its surrogate, that is, mechanical ventilation, in patients with spinal muscular atrophy (SMA).

Methods: We studied survival in a population-based cohort on clinical prevalence of genetically confirmed, treatment-naive patients with SMA, stratified for best acquired motor milestone (i.e.

Distinct effects on mRNA export factor GANP underlie neurological disease phenotypes and alter gene expression depending on intron content.

Defects in the mRNA export scaffold protein GANP, encoded by the MCM3AP gene, cause autosomal recessive early-onset peripheral neuropathy with or without intellectual disability. We extend here the phenotypic range associated with MCM3AP variants, by describing a severely hypotonic child and a sibling pair with a progressive encephalopathic syndrome. In addition, our analysis of skin fibroblasts from affected individuals from seven unrelated families indicates that disease variants result in depletion of GANP except when they alter critical residues in the Sac3 mRNA binding domain.