Machine learning-enhanced electrical impedance myography to diagnose and track spinal muscular atrophy progression.

To evaluate electrical impedance myography (EIM) in conjunction with machine learning (ML) to detect infantile spinal muscular atrophy (SMA) and disease progression.. Twenty-six infants with SMA and twenty-seven healthy infants had been enrolled and assessed with EIM as part of the NeuroNEXT SMA biomarker study.

The Answer ALS return of results study: Answering the duty to disclose.

The Return of Answer ALS Results (RoAR) Study was designed to provide a mechanism for participants in Answer ALS, a large, prospectively designed natural history and biorepository study to receive select clinical genetic testing results and study participants' experience with the results disclosure. Participants consented to receive results of five ALS genes () and/or 59 medically actionable genes as designated by the American College of Medical Genetics. Patient-reported genetic testing outcomes were measured via a post-disclosure survey.

Differential impact on motor unit characteristics across severities of adult spinal muscular atrophy.

Objective: To test the hypotheses that decomposition electromyography (dEMG) motor unit action potential (MUAP) amplitude and firing rate are altered in SMA; dEMG parameters are associated with strength and function; dEMG parameters are correlated with traditional electrophysiological assessments.

Methods: Ambulatory and non-ambulatory adults with SMA on nusinersen and healthy controls were enrolled. MUAPs were decomposed from multielectrode surface recordings during 30-s maximum contraction of the abductor digiti minimi (ADM).

Evidence-based consensus guidelines for ALS genetic testing and counseling.

Objective: Advances in amyotrophic lateral sclerosis (ALS) gene discovery, ongoing gene therapy trials, and patient demand have driven increased use of ALS genetic testing. Despite this progress, the offer of genetic testing to persons with ALS is not yet "standard of care." Our primary goal is to develop clinical ALS genetic counseling and testing guidelines to improve and standardize genetic counseling and testing practice among neurologists, genetic counselors or any provider caring for persons with ALS.

Heterogeneous splicing patterns resulting from KIF5A variants associated with amyotrophic lateral sclerosis.

Single-nucleotide variants (SNVs) in the gene encoding Kinesin Family Member 5A (KIF5A), a neuronal motor protein involved in anterograde transport along microtubules, have been associated with amyotrophic lateral sclerosis (ALS). ALS is a rapidly progressive and fatal neurodegenerative disease that primarily affects the motor neurons. Numerous ALS-associated KIF5A SNVs are clustered near the splice-site junctions of the penultimate exon 27 and are predicted to alter the carboxy-terminal (C-term) cargo-binding domain of KIF5A.

Identifying Biomarkers of Spinal Muscular Atrophy for Further Development.

Background: Spinal muscular atrophy (SMA) is caused by bi-allelic, recessive mutations of the survival motor neuron 1 (SMN1) gene and reduced expression levels of the survival motor neuron (SMN) protein. Degeneration of alpha motor neurons in the spinal cord causes progressive skeletal muscle weakness. The wide range of disease severities, variable rates of decline, and heterogenous clinical responses to approved disease-modifying treatment remain poorly understood and limit the ability to optimize treatment for patients.

Impaired motor unit recovery and maintenance in a knock-in mouse model of ALS-associated Kif5a variant.

Kinesin family member 5A (KIF5A) is an essential, neuron-specific microtubule-associated motor protein responsible for the anterograde axonal transport of various cellular cargos. Loss of function variants in the N-terminal, microtubule-binding domain are associated with hereditary spastic paraplegia and hereditary motor neuropathy. These variants result in a loss of the ability of the mutant protein to process along microtubules.

Psychometric evaluation of modified spinal muscular atrophy functional rating scale (SMAFRS) in adult patients using Rasch analysis.

Introduction/aims: The Spinal Muscular Atrophy Functional Rating Scale (SMAFRS) was first developed as a secondary functional outcome measure to detect changes over time in patients with spinal muscular atrophy (SMA) in clinical trials. Its modified version evaluates 10 activities of daily living. The aim of the study was to analyze modified SMAFRS data using item response theory psychometric models.

CuATSM effectively ameliorates ALS patient astrocyte-mediated motor neuron toxicity in human in vitro models of amyotrophic lateral sclerosis.

Patient diversity and unknown disease cause are major challenges for drug development and clinical trial design for amyotrophic lateral sclerosis (ALS). Transgenic animal models do not adequately reflect the heterogeneity of ALS. Direct reprogramming of patient fibroblasts to neuronal progenitor cells and subsequent differentiation into patient astrocytes allows rapid generation of disease relevant cell types.

EphA4 targeting agents protect motor neurons from cell death induced by amyotrophic lateral sclerosis -astrocytes.

Amyotrophic lateral sclerosis (ALS) is a degenerative disease that progressively destroys motor neurons (MNs). Earlier studies identified EphA4, a receptor tyrosine kinase, as a possible disease-modifying gene. The complex interplay between the EphA4 receptor and its ephrin ligands in motor neurons and astrocytes has not yet been fully elucidated and includes a putative pro-apoptotic activity of the unbound receptor compared to ephrin-bound receptor.

Neurotoxic Astrocytes Directly Converted from Sporadic and Familial ALS Patient Fibroblasts Reveal Signature Diversities and miR-146a Theragnostic Potential in Specific Subtypes.

A lack of stratification methods in patients with amyotrophic lateral sclerosis (ALS) is likely implicated in therapeutic failures. Regional diversities and pathophysiological abnormalities in astrocytes from mice with SOD1 mutations (mSOD1-ALS) can now be explored in human patients using somatic cell reprogramming. Here, fibroblasts from four sporadic (sALS) and three mSOD1-ALS patients were transdifferentiated into induced astrocytes (iAstrocytes).

Premature delivery in the domestic sow in response to in utero delivery of AAV9 to fetal piglets.

Numerous pediatric neurogenetic diseases may be optimally treated by in utero gene therapy (IUGT); but advancing such treatments requires animal models that recapitulate developmental physiology relevant to humans. One disease that could benefit from IUGT is the autosomal recessive motor neuron disease spinal muscular atrophy (SMA). Current SMA gene-targeting therapeutics are more efficacious when delivered shortly after birth, however postnatal treatment is rarely curative in severely affected patients.

Neurofilament Levels in CSF and Serum in an Adult SMA Cohort Treated with Nusinersen.

Objective: To retrospectively evaluate the utility of serum and cerebrospinal fluid (CSF) levels of neurofilament light chain (NfL) and phosphorylated neurofilament heavy chain (pNfH) as biomarkers for spinal muscular atrophy (SMA) progression and response to nusinersen treatment.

Methods: NfL and pNfH levels were quantified using single molecular array (SIMOA) in CSF of 33 adult SMA patients (SMN copy number 3-5) before and in response to nusinersen treatment. In 11 of the patients, blood serum samples were also collected.

Continual cerebrospinal fluid sampling in the neonatal domestic piglet for biomarker and discovery studies.

Background: Longitudinal access to cerebrospinal fluid (CSF) is useful for biomarker discovery in neurological disorders or diseases affecting CSF composition. Here, we aim to test a new method for insertion of a permanent intrathecal catheter, facilitating longitudinal collection of CSF.

New Method: We surgically placed a permanent intrathecal catheter into the cisterna magna of anesthetized neonatal piglets.

Persistent neuromuscular junction transmission defects in adults with spinal muscular atrophy treated with nusinersen.

Objective: Spinal muscular atrophy (SMA) is a motor neuron disease caused by low levels of survival motor neuron (SMN) protein. Prior work in models and patients has demonstrated electrophysiological and morphological defects at the neuromuscular junction (NMJ). Therapeutic development has resulted in clinically available therapies to increase SMN protein levels in patients and improve muscle function.

Update on Biomarkers in Spinal Muscular Atrophy.

The availability of disease modifying therapies for spinal muscular atrophy (SMA) has created an urgent need to identify clinically meaningful biomarkers. Biomarkers present a means to measure and evaluate neurological disease across time. Changes in biomarkers provide insight into disease progression and may reveal biologic, physiologic, or pharmacologic phenomena occurring prior to clinical detection.

Safety, Tolerability, and Effect of Nusinersen Treatment in Ambulatory Adults With 5q-SMA.

To determine the safety and tolerability of nusinersen treatment in ambulatory adults with spinal muscular atrophy (SMA) and investigate the treatment effect on muscle strength, physical function, and motor unit physiology. Individuals aged 18 years or older with genetically confirmed 5q SMA, three or more copies of the SMN2 gene, and the ability to ambulate 30 feet were enrolled. Safety outcomes included the number of adverse events and serious adverse events, clinically significant vital sign or laboratory parameter abnormalities.

Amyotrophic lateral sclerosis alters the metabolic aging profile in patient derived fibroblasts.

Aging is a major risk factor for neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). As metabolic alterations are a hallmark of aging and have previously been observed in ALS, it is important to examine the effect of aging in the context of ALS metabolic function. Here, using a newly established phenotypic metabolic approach, we examined the effect of aging on the metabolic profile of fibroblasts derived from ALS cases compared to controls.

A review and analysis of the clinical literature on Charcot-Marie-Tooth disease caused by mutations in neurofilament protein L.

Charcot-Marie-Tooth disease (CMT) is one of the most common inherited neurological disorders and can be caused by mutations in over 100 different genes. One of the causative genes is NEFL on chromosome 8 which encodes neurofilament light protein (NEFL), one of five proteins that co-assemble to form neurofilaments. At least 34 different CMT-causing mutations in NEFL have been reported which span the head, rod, and tail domains of the protein.

Safety, Tolerability, and Effect of Nusinersen in Non-ambulatory Adults With Spinal Muscular Atrophy.

Investigation of the safety, tolerability, and treatment effect of nusinersen treatment in non-ambulatory adults with spinal muscular atrophy (SMA). Non-ambulatory individuals, aged 18 years or older with genetically confirmed 5q SMA were enrolled. In participants with spinal fusion, fluoroscopy guided cervical C1-C2 lateral approach was used.

Searching Far and Genome-Wide: The Relevance of Association Studies in Amyotrophic Lateral Sclerosis.

Genome-wide association studies (GWAS) and rare variant association studies (RVAS) are applied across many areas of complex disease to analyze variation in whole genomes of thousands of unrelated patients. These approaches are able to identify variants and/or biological pathways which are associated with disease status and, in contrast to traditional linkage studies or candidate gene approaches, do so without requiring multigenerational affected families, prior hypotheses, or known genes of interest. However, the novel associations identified by these methods typically have lower effect sizes than those found in classical family studies.

Nanochannel-Based Poration Drives Benign and Effective Nonviral Gene Delivery to Peripheral Nerve Tissue.

While gene and cell therapies have emerged as promising treatment strategies for various neurological conditions, heavy reliance on viral vectors can hamper widespread clinical implementation. Here, the use of tissue nanotransfection as a platform nanotechnology to drive nonviral gene delivery to nerve tissue via nanochannels, in an effective, controlled, and benign manner is explored. TNT facilitates plasmid DNA delivery to the sciatic nerve of mice in a voltage-dependent manner.

Longitudinal natural history of type I spinal muscular atrophy: a critical review.

Background: The advent of new therapies in spinal muscular atrophy (SMA) has highlighted the need to have natural history data for comparison. Natural history studies using structured assessments in type I however are very limited. We identified and reviewed all the existing longitudinal history data in infants with type I SMA first assessed before the age of 7 months with the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND).