Intrathecal Gene Therapy for Giant Axonal Neuropathy.

Background: Giant axonal neuropathy is a rare, autosomal recessive, pediatric, polysymptomatic, neurodegenerative disorder caused by biallelic loss-of-function variants in , the gene encoding gigaxonin.

Methods: We conducted an intrathecal dose-escalation study of scAAV9/JeT-GAN (a self-complementary adeno-associated virus-based gene therapy containing the transgene) in children with giant axonal neuropathy. Safety was the primary end point.

Electrical impedance myography in healthy volunteers.

Introduction/aims: Electrical impedance myography (EIM) is a noninvasive technique being used in clinical studies to characterize muscle by phase, reactance, and resistance after application of a low-intensity current. The aim of this study was to obtain 50-kHz EIM data from healthy volunteers (HVs) for use in future clinical and research studies, perform reliability tests on EIM outcome measures, and compare findings with muscle ultrasound variables.

Methods: Four arm and four leg muscles of HVs were evaluated using an EIM device with two sensors, P/N 20-0045 and P/N 014-009.

Noncoding variants alter GATA2 expression in rhombomere 4 motor neurons and cause dominant hereditary congenital facial paresis.

Hereditary congenital facial paresis type 1 (HCFP1) is an autosomal dominant disorder of absent or limited facial movement that maps to chromosome 3q21-q22 and is hypothesized to result from facial branchial motor neuron (FBMN) maldevelopment. In the present study, we report that HCFP1 results from heterozygous duplications within a neuron-specific GATA2 regulatory region that includes two enhancers and one silencer, and from noncoding single-nucleotide variants (SNVs) within the silencer. Some SNVs impair binding of NR2F1 to the silencer in vitro and in vivo and attenuate in vivo enhancer reporter expression in FBMNs.

MYH2-associated myopathy caused by a novel splice-site variant.

MYH2 encodes MyHCIIa, a myosin heavy chain found in fast type 2A fibers. Pathogenic variants in this gene have previously been implicated in dominant and recessive forms of myopathy. Three individuals reported here are part of a family in which four generations of individuals are affected by a slowly progressive, predominantly proximal myopathy in an autosomal dominant inheritance pattern.

Neuropathic symptoms with SARS-CoV-2 vaccination.

Background And Objectives: Various peripheral neuropathies, particularly those with sensory and autonomic dysfunction may occur during or shortly after acute COVID-19 illnesses. These appear most likely to reflect immune dysregulation. If similar manifestations can occur with the vaccination remains unknown.

Juvenile Amyotrophic Lateral Sclerosis: A Review.

Juvenile amyotrophic lateral sclerosis (JALS) is a rare group of motor neuron disorders with gene association in 40% of cases. JALS is defined as onset before age 25. We conducted a literature review of JALS and gene mutations associated with JALS.

TUBB3 Arg262His causes a recognizable syndrome including CFEOM3, facial palsy, joint contractures, and early-onset peripheral neuropathy.

Microtubules are formed from heterodimers of alpha- and beta-tubulin, each of which has multiple isoforms encoded by separate genes. Pathogenic missense variants in multiple different tubulin isoforms cause brain malformations. Missense mutations in TUBB3, which encodes the neuron-specific beta-tubulin isotype, can cause congenital fibrosis of the extraocular muscles type 3 (CFEOM3) and/or malformations of cortical development, with distinct genotype-phenotype correlations.

Giant axonal neuropathy: cross-sectional analysis of a large natural history cohort.

Giant axonal neuropathy (GAN) is an ultra-rare autosomal recessive, progressive neurodegenerative disease with early childhood onset that presents as a prominent sensorimotor neuropathy and commonly progresses to affect both the PNS and CNS. The disease is caused by biallelic mutations in the GAN gene located on 16q23.2, leading to loss of functional gigaxonin, a substrate specific ubiquitin ligase adapter protein necessary for the regulation of intermediate filament turnover.

Adult diagnosis of congenital serine biosynthesis defect: A treatable cause of progressive neuropathy.

A woman with ichthyosis, contractures, and progressive neuropathy represents the first case of phosphoserine aminotransferase deficiency diagnosed and treated in an adult. She has novel compound heterozygous mutations in the gene PSAT1. Treatment with high dose oral L-serine completely resolved the ichthyosis.

Differentiating Moebius syndrome and other congenital facial weakness disorders with electrodiagnostic studies.

Introduction: Congenital facial weakness (CFW) can result from facial nerve paresis with or without other cranial nerve and systemic involvement, or generalized neuropathic and myopathic disorders. Moebius syndrome is one type of CFW. In this study we explored the utility of electrodiagnostic studies (EDx) in the evaluation of individuals with CFW.

Biallelic loss of function variants in SYT2 cause a treatable congenital onset presynaptic myasthenic syndrome.

Synaptotagmins are integral synaptic vesicle membrane proteins that function as calcium sensors and regulate neurotransmitter release at the presynaptic nerve terminal. Synaptotagmin-2 (SYT2), is the major isoform expressed at the neuromuscular junction. Recently, dominant missense variants in SYT2 have been reported as a rare cause of distal motor neuropathy and myasthenic syndrome, manifesting with stable or slowly progressive distal weakness of variable severity along with presynaptic NMJ impairment.

Electrical impedance myography (EIM) in a natural history study of mutation carriers.

Electrical Impedance Myography (EIM) was used to evaluate disease progression in subjects with expansion mutations and to assess correlations with Medical Research Council (MRC) Scale and revised ALS Functional Rating Scale (ALSFRS-R) measurements. Four types of clinical presentations were assessed; Amyotrophic Lateral Sclerosis (ALS), Frontotemporal dementia (FTD) or other dementia, ALS-FTD, and asymptomatic (ASYMP). Subjects were divided into an ALS Group (ALS/ALS-FTD) and non-ALS Group (FTD/ASYMP) based on initial visit and evaluated at 0, 6, 18, and 30 months with EIM of 4 arm and 4 leg muscles, ALSFRS-R, and MRC scales.

Neurological manifestations of Erdheim-Chester Disease.

Objective: To characterize the spectrum of neurologic involvement in Erdheim-Chester Disease (ECD), a treatable inflammatory neoplasm of histiocytes.

Methods: Sixty-two patients with ECD were prospectively enrolled in a natural history study that facilitated collection of clinical, imaging, laboratory, neurophysiologic, and pathologic data.

Results: Ninety-four percent of the patients had neurologic abnormalities on examination or imaging, and 22% had neurologic symptoms as the initial presentation of ECD.

A novel frameshift mutation in SOX10 causes Waardenburg syndrome with peripheral demyelinating neuropathy, visual impairment and the absence of Hirschsprung disease.

Waardenburg syndrome (WS) is a group of genetic disorders associated with varying components of sensorineural hearing loss and abnormal pigmentation of the hair, skin, and eyes. There exist four different WS subtypes, each defined by the absence or presence of additional features. One of the genes associated with WS is SOX10, a key transcription factor for the development of neural crest-derived lineages.

Utility and practice of electrodiagnostic testing in the pediatric population: An AANEM consensus statement.

Nerve conduction studies and needle electromyography, collectively known as electrodiagnostic (EDX) studies, have been available for pediatric patients for decades, but the accessibility of this diagnostic modality and the approach to testing vary significantly depending on the physician and institution. The maturation of molecular diagnostic approaches and other diagnostic technologies such as neuromuscular ultrasound indicate that an analysis of current needs and practices for EDX studies in the pediatric population is warranted. The American Association of Neuromuscular & Electrodiagnostic Medicine convened a consensus panel to perform literature searches, share collective experiences, and develop a consensus statement.

Safe marginal resection of atypical neurofibromas in neurofibromatosis type 1.

Objective: Patients with neurofibromatosis type 1 (NF1) are predisposed to visceral neurofibromas, some of which can progress to premalignant atypical neurofibromas (ANFs) and malignant peripheral nerve sheath tumors (MPNSTs). Though subtotal resection of ANF may prevent malignant transformation and thus deaths with no neural complications, local recurrences require reoperation. The aim of this study was to assess the surgical morbidity associated with marginal resection of targeted ANF nodules identified via preoperative serial volumetric MRI and 18F-FDG-PET imaging.

Clinical Evaluation of Melorheostosis in the Context of a Natural History Clinical Study.

Melorheostosis is a rare dysostosis involving cortical bone overgrowth that affects the appendicular skeleton. Patients present with pain, deformities, contractures, range of motion limitation(s), and limb swelling. It has been described in children as well as adults.

Haploinsufficiency of the brain-derived neurotrophic factor gene is associated with reduced pain sensitivity.

Rare pain-insensitive individuals offer unique insights into how pain circuits function and have led to the development of new strategies for pain control. We investigated pain sensitivity in humans with WAGR (Wilms tumor, aniridia, genitourinary anomaly, and range of intellectual disabilities) syndrome, who have variably sized heterozygous deletion of the 11p13 region. The deletion region can be inclusive or exclusive of the brain-derived neurotrophic factor (BDNF) gene, a crucial trophic factor for nociceptive afferents.