Distal Spinal Muscular Atrophy Research Articles

TRPV4 neuromuscular disease registry highlights bulbar, skeletal and proximal limb manifestations.

Dominant missense mutations of the calcium-permeable cation channel TRPV4 cause Charcot-Marie-Tooth disease (CMT) type 2C and two forms of distal spinal muscular atrophy. These conditions are collectively referred to as TRPV4-related neuromuscular disease and share features of motor greater than sensory dysfunction and frequent vocal fold weakness. Pathogenic variants lead to gain of ion channel function that can be rescued by TRPV4 antagonists in cellular and animal models. As small molecule TRPV4 antagonists have proven safe in trials for other disease indications, channel inhibition is a promising therapeutic strategy for TRPV4 patients. However, the current knowledge of the clinical features and natural history of TRPV4-related neuromuscular disease is insufficient to enable rational clinical trial design. To address these issues, we developed a TRPV4 patient database and administered a TRPV4-specific patient questionnaire. Here, we report demographic and clinical information, including CMT examination scores (CMTES), from 68 patients with known pathogenic TRPV4 variants, 40 of whom also completed the TRPV4 patient questionnaire. TRPV4 patients showed a bimodal age of onset, with the largest peak occurring in the first 2 years of life. Compared to CMT1A patients, TRPV4 patients showed distinct symptoms and signs, manifesting more ambulatory difficulties and more frequent involvement of proximal arm and leg muscles. Although patients reported fewer sensory symptoms, sensory dysfunction was often detected clinically. Many patients were affected by vocal fold weakness (55%) and shortness of breath (55%), and 11% required ventilatory support. Skeletal abnormalities were common, including scoliosis (64%), arthrogryposis (33%), and foot deformities. Strikingly, patients with infantile onset of disease showed less sensory involvement and less progression of symptoms. These results highlight distinctive clinical features in TRPV4 patients, including motor-predominant disease, proximal arm and leg weakness, severe ambulatory difficulties, vocal fold weakness, respiratory dysfunction, and skeletal involvement. In addition, patients with infantile onset of disease appeared to have a distinct phenotype with less apparent disease progression based on CMTES. These collective observations indicate that clinical trial design for TRPV4-related neuromuscular disease should include outcome measures that reliably capture non-length dependent motor dysfunction, vocal fold weakness, and respiratory disease.

Deep intronic variant causes aberrant splicing of ATP7A in a family with a variable occipital horn syndrome phenotype

Genetic variants in ATP7A are associated with a spectrum of X-linked disorders. In descending order of severity, these are Menkes disease, occipital horn syndrome, and X-linked distal spinal muscular atrophy. After 30 years of diagnostic investigation, we identified a deep intronic ATP7A variant in four males from a family affected to variable degrees by a predominantly skeletal phenotype, featuring bowing of long bones, elbow joints with restricted mobility which dislocate frequently, coarse curly hair, chronic diarrhoea, and motor coordination difficulties. Analysis of whole genome sequencing data from the Genomics England 100,000 Genomes Project following clinical re-evaluation identified a deep intronic ATP7A variant, which was predicted by SpliceAI to have a modest splicing effect. Using a mini-gene splicing assay, we determined that the intronic variant results in aberrant splicing. Sanger sequencing of patient cDNA revealed ATP7A transcripts with exon 5 skipping, or inclusion of a novel intron 4 pseudoexon. In both instances, frameshift leading to premature termination are predicted. Quantification of ATP7A mRNA transcripts using a qPCR assay indicated that the majority of transcripts (86.1 %) have non-canonical splicing, with 68.0 % featuring exon 5 skipping, and 18.1 % featuring the novel pseudoexon. We suggest that the variability of the phenotypes within the affected males results from the stochastic effects of splicing. This deep intronic variant, resulting in aberrant ATP7A splicing, expands the understanding of intronic variation on the ATP7A-related disease spectrum.

VRK1 mutation associated with adult-onset spinal muscular atrophy and persistently elevated creatine kinase (P3-8.011)

<h3>Objective:</h3> NA <h3>Background:</h3> NA <h3>Design/Methods:</h3> We present a patient with persistently elevated creatinine kinase and a clinical syndrome consistent with adult-onset spinal muscular atrophy (dSMA) without pontocerebellar atrophy secondary to a vaccinia-related kinase 1 (VRK1) mutation. <h3>Results:</h3> A 46-year-old male presented for evaluation of persistently elevated creatinine kinase, leg weakness, and decreased balance for more than 5 years. He reported mild weakness mainly in the lower extremities and reduced calf size. The patient has had persistently elevated creatine kinase (CK) for the past 5 years, ranging from 580–7,000 units/L. On examination, he had bilateral high arches, calf fasciculations, and atrophy. Motor showed decreased strength in feet dorsiflexion and minimal bilateral hand interosseous weakness. Reflexes were normal except for the absent left ankle reflex. The rest of the neurologic examination was unremarkable. EMG/NCS showed reduced motor responses with diffuse neurogenic changes in the right arm and leg concerning for motor neuropathy. CK level remained elevated along with aldolase; otherwise negative myopathy labs. The neuropathy panel showed two pathogenic mutations of the VRK1 gene, variant c1072C&gt;T (p.Arg358) and c.356 A&gt;G (p.His119Arg), consistent with compound heterozygosity. <h3>Conclusions:</h3> VRK1 mutation is a rare cause of distal predominant spinal muscular atrophy. This disease is characterized by slowly progressive distal symmetric limb muscle weakness and atrophy, frequently leading to foot deformities such as pes cavus, with minimal or no sensory involvement. Mild elevations in CK can be seen in up to 50% of motor neuron disease cases. Our patient’s presentation was consistent with adult-onset spinal muscular atrophy. There was no pontocerebellar hypoplasia, which has also been described with this mutation. Creatine kinase level remained very elevated in our patient, beyond what has previously been described in the literature. Future investigation should be done to determine the significance of this, including whether there may be a myopathic component to this illness. <b>Disclosure:</b> Dr. Rodriguez-Hernandez has nothing to disclose. Dr. Carranza-Renteria has nothing to disclose. Dr. Faktorovich has a non-compensated relationship as a Board of Directors with Brother’s Brother Foundation that is relevant to AAN interests or activities.

A novel missense mutation in PLEKHG5 gene causing an intermediate form of autosomal-recessive Charcot–Marie–Tooth disease in an Iraqi family

BackgroundCharcot–Marie–Tooth disease comprises a large spectrum of clinically heterogeneous disorders. PLEKHG5 variants have shown an intermediate form of autosomal-recessive Charcot–Marie–Tooth disease C and distal spinal muscular atrophy IV. The purpose of this case study is to report a causative genetic defect associated with intermediate form of autosomal-recessive Charcot–Marie–Tooth disease C in an Iraqi consanguineous family.Case presentationWhole-exome and Sanger sequencing was used to identify probable gene defects in a 9-year-old male affected by CMTRIC. We found a new single mutation (c.1844C > A; p.T615N) in the PLEKHG5 gene, located in exon 17 (NM_020631.6), causing a missense mutation that has been changed one amino acid. The mutation was homozygous in the patient and heterozygous in his parents.ConclusionOur results expand the PLEKHG5 pathogenic mutation spectrum related to intermediate form of autosomal-recessive Charcot–Marie–Tooth disease C which is vital for screening and genetic diagnosis of the disease.

Inherited myopathy plus: Double-trouble from rare neuromuscular disorders

A rare disorder in the USA is one that affects <200,000 people, making inherited myopathies rare diseases. Increasing access to genetic testing has been instrumental for the diagnosis of inherited myopathies. Genetic findings, however, require clinical correlation due to variable phenotype, polygenic etiology of certain inherited disorders, and possible co-existing independent neuromuscular disorders. We searched the Mayo Clinic Rochester medical record (2004–2020) to identify adult patients carrying pathogenic variants or likely pathogenic variants in genes causative of myopathies and having a coexisting independent neuromuscular disorder classified as rare at https://rarediseases.info.nih.gov/. One additional patient was identified at Nationwide Children's hospital. Clinical and laboratory findings were reviewed. We identified 14 patients from 13 families fulfilling search criteria. Seven patients had a “double-trouble” inherited myopathy; two had an inherited myopathy with coexistent idiopathic myositis; three had an inherited myopathy with coexisting rare neuromuscular disorder of neurogenic type; a female DMD carrier had co-existing distal spinal muscular atrophy, which was featuring the clinical phenotype; and a patient with a MYH7 pathogenic variant had Sandhoff disease causing motor neuron disease. These cases highlight the relevance of correlating genetic findings, even when diagnostic, with clinical features, to allow precise diagnosis, optimal care, and accurate prognosis.

DNAJB2 c.184C>T mutation associated with distal hereditary motor neuropathy with rimmed vacuolar myopathy.

Distal hereditary motor neuropathy (dHMN), also known as distal spinal muscular atrophy (dSMA), comprises a group of inherited peripheral neuropathies with great clinical and genetic heterogeneity, mainly characterized by progressive atrophy and weakness of distal muscle without clinical or electrophysiological sensory abnormalities. Next-generation sequencing is widely applied as an effective diagnostic technique to discover pathogenic genes in patients with dHMN. To date, at least 23 causal genes have been identified to be associated with dHMN, several of which encode chaperones. Here, we report a dHMN patient due to a homozygous c.184C>T variant in the DNAJB2 gene with rare neuropathic and myopathic characteristics on pathological examination. These findings might broaden the mutational spectrum of DNAJB2 and expand the tissue involvement of DNAJB2-related presentations.

Multivalent DNA and nucleosome acidic patch interactions specify VRK1 mitotic localization and activity.

A key role of chromatin kinases is to phosphorylate histone tails during mitosis to spatiotemporally regulate cell division. Vaccinia-related kinase 1 (VRK1) is a serine–threonine kinase that phosphorylates histone H3 threonine 3 (H3T3) along with other chromatin-based targets. While structural studies have defined how several classes of histone-modifying enzymes bind to and function on nucleosomes, the mechanism of chromatin engagement by kinases is largely unclear. Here, we paired cryo-electron microscopy with biochemical and cellular assays to demonstrate that VRK1 interacts with both linker DNA and the nucleosome acidic patch to phosphorylate H3T3. Acidic patch binding by VRK1 is mediated by an arginine-rich flexible C-terminal tail. Homozygous missense and nonsense mutations of this acidic patch recognition motif in VRK1 are causative in rare adult-onset distal spinal muscular atrophy. We show that these VRK1 mutations interfere with nucleosome acidic patch binding, leading to mislocalization of VRK1 during mitosis, thus providing a potential new molecular mechanism for pathogenesis.

Muscle “islands”: An MRI signature distinguishing neurogenic from myopathic causes of early onset distal weakness

Muscle MRI has an increasing role in diagnosis of inherited neuromuscular diseases, but no features are known which reliably differentiate myopathic and neurogenic conditions. Using patients presenting with early onset distal weakness, we aimed to identify an MRI signature to distinguish myopathic and neurogenic conditions. We identified lower limb MRI scans from patients with either genetically (n = 24) or clinically (n = 13) confirmed diagnoses of childhood onset distal myopathy or distal spinal muscular atrophy. An initial exploratory phase reviewed 11 scans from genetically confirmed patients identifying a single potential discriminatory marker concerning the pattern of fat replacement within muscle, coined “islands”. This pattern comprised small areas of muscle tissue with normal signal intensity completely surrounded by areas with similar intensity to subcutaneous fat. In the subsequent validation phase, islands correctly classified scans from all 12 remaining genetically confirmed patients, and 12/13 clinically classified patients. In the genetically confirmed patients MRI classification of neurogenic/myopathic aetiology had 100% accuracy (24/24) compared with 65% accuracy (15/23) for EMG, and 79% accuracy (15/19) for muscle biopsy. Future studies are needed in other clinical contexts, however the presence of islands appears to highly suggestive of a neurogenic aetiology in patients presenting with early onset distal motor weakness.

Leukoencephalopathy and conduction blocks in PLEKHG5-associated intermediate CMT disease

Biallelic variants in PLEKHG5 have been reported so far associated with different clinical phenotypes including Lower motor neuron disease (LMND) [also known as distal hereditary motor neuropathies (dHMN or HMN) or distal spinal muscular atrophy (DSMA4)] and intermediate Charcot-Marie-Tooth disease (CMT). We report four patients from two families presenting with intermediate CMT and atypical clinical and para-clinical findings. Patients presented with predominant distal weakness with none or mild sensory involvement and remain ambulant at last examination (22–36 years). Nerve conduction studies revealed, in all patients, intermediate motor nerve conduction velocities, reduced sensory amplitudes and multiple conduction blocks in upper limbs, outside of typical nerve compression sites. CK levels were strikingly elevated (1611–3867 U/L). CSF protein content was mildly elevated in two patients. Diffuse bilateral white matter lesions were detected in one patient. Genetic analysis revealed three novel frameshift variants c.1835_1860del and c.2308del (family 1) and c.104del (family 2). PLEKHG5-associated disease ranges from pure motor phenotypes with predominantly proximal involvement to intermediate CMT with predominant distal motor involvement and mild sensory symptoms. Leukoencephalopathy, elevated CK levels and the presence of conduction blocks associated with intermediate velocities in NCS are part of the phenotype and may arise suspicion of the disease, thus avoiding misdiagnosis and unnecessary therapeutics in these patients.

Associations between Neurological Diseases and Mutations in the Human Glycyl-tRNA Synthetase

Aminoacyl-RNA synthetases (aaRSs) are among the key enzymes of protein biosynthesis. They are responsible for conducting the first step in the protein biosynthesis, namely attaching amino acids to the corresponding tRNA molecules both in cytoplasm and mitochondria. More and more research demonstrates that mutations in the genes encoding aaRSs lead to the development of various neurodegenerative diseases, such as incurable Charcot–Marie–Tooth disease (CMT) and distal spinal muscular atrophy. Some mutations result in the loss of tRNA aminoacylation activity, while other mutants retain their classical enzyme activity. In the latter case, disease manifestations are associated with additional neuron-specific functions of aaRSs. At present, seven aaRSs (GlyRS, TyrRS, AlaRS, HisRS, TrpRS, MetRS, and LysRS) are known to be involved in the CMT etiology with glycyl-tRNA synthetase (GlyRS) being the most studied of them.

Novel TRPV4 mutation in a large Chinese family with congenital distal spinal muscular atrophy, skeletal dysplasia and scaly skin

Mutations in the transient receptor potential vanilloid 4 (TRPV4) gene, encoding a polymodal Ca2+ permeable channel, have been associated with a spectrum of dominantly inherited skeletal dysplasias and neuropathies. The clinical manifestations of TRPV4-associated disorders are highly heterogeneous. This study describes a large Chinese family with a novel mutation in the TRPV4 gene. Nineteen individuals from this family were investigated. Clinical, electrophysiological, and radiographic examinations were performed. The proband and other four affected family members showed signs of congenital distal spinal muscular atrophy, skeletal abnormalities including osteonecrosis of the femoral head, and scaly skin. Based on whole-exome sequencing analysis, a novel heterozygous mutation was identified in the proband in the TRPV4 gene at position c.2355G > T, resulting in a tryptophan to cysteine substitution at amino acid 785 (p.Trp785Cys) of TRPV4. Furthermore, the mutation co-segregated with disease in this family. Thus, our findings further contributed to expansion of the clinical and phenotypic spectrum of TRPV4-associated disorders.

Report of a Patient with Multiple Mutations Leading to CharcotMarie-Tooth Disease and Distal Spinal Muscular Atrophy: A Case Report

The Charcot-Marie-Tooth disease is a group of progressive disorders that affects the peripheral nerves and results in loss of sensation and atrophy of muscles in lower limbs. There are several types of Charcot-Marie-Tooth and multiple genes are associated with this disease. Distal spinal muscular atrophy is an extremely rare disorder characterized by progressive pure lower motor neuron involvement. A 24 yr old woman using wheelchair referred to Farhud Genetic Clinic, Tehran, Iran in 2019, with progressive muscular atrophy, pain and Electromyography test suggesting Charcot-Marie-tooth. Both feet and hands were involved. Whole exome sequencing was performed on extracted DNA from her blood sample. We report the first case of a patient with different types of CharcotMarie-Tooth and distal spinal muscular atrophy simultaneously, which are as a result of mutations in multiple genes; this case is very uncommon.

GARS-related disease in infantile spinal muscular atrophy: Implications for diagnosis and treatment.

The majority of patients with spinal muscular atrophy (SMA) identified to date harbor a biallelic exonic deletion of SMN1. However, there have been reports of SMA-like disorders that are independent of SMN1, including those due to pathogenic variants in the glycyl-tRNA synthetase gene (GARS1). We report three unrelated patients with de novo variants in GARS1 that are associated with infantile-onset SMA (iSMA). Patients were ascertained during inpatient hospital evaluations for complications of neuropathy. Evaluations were completed as indicated for clinical care and management and informed consent for publication was obtained. One newly identified, disease-associated GARS1 variant, identified in two out of three patients, was analyzed by functional studies in yeast complementation assays. Genomic analyses by exome and/or gene panel and SMN1 copy number analysis of three patients identified two previously undescribed de novo missense variants in GARS1 and excluded SMN1 as the causative gene. Functional studies in yeast revealed that one of the de novo GARS1 variants results in a loss-of-function effect, consistent with other pathogenic GARS1 alleles. In sum, the patients' clinical presentation, assessments of previously identified GARS1 variants and functional assays in yeast suggest that the GARS1 variants described here cause iSMA. GARS1 variants have been previously associated with Charcot-Marie-Tooth disease (CMT2D) and distal SMA type V (dSMAV). Our findings expand the allelic heterogeneity of GARS-associated disease and support that severe early-onset SMA can be caused by variants in this gene. Distinguishing the SMA phenotype caused by SMN1 variants from that due to pathogenic variants in other genes such as GARS1 significantly alters approaches to treatment.

ATP7A Clinical Genetics Resource – A comprehensive clinically annotated database and resource for genetic variants in ATP7A gene

ATP7A is a critical copper transporter involved in Menkes Disease, Occipital horn Syndrome and X-linked distal spinal muscular atrophy type 3 which are X linked genetic disorders. These are rare diseases and their genetic epidemiology of the diseases is unknown. A number of genetic variants in the genes have been reported in published literature as well as databases, however, understanding the pathogenicity of variants and genetic epidemiology requires the data to be compiled in a unified format. To this end, we systematically compiled genetic variants from published literature and datasets. Each of the variants were systematically evaluated for evidences with respect to their pathogenicity and classified as per the American College of Medical Genetics and the Association of Molecular Pathologists (ACMG-AMP) guidelines into Pathogenic, Likely Pathogenic, Benign, Likely Benign and Variants of Uncertain Significance. Additional integrative analysis of population genomic datasets provides insights into the genetic epidemiology of the disease through estimation of carrier frequencies in global populations. To deliver a mechanistic explanation for the pathogenicity of selected variants, we also performed molecular modeling studies. Our modeling studies concluded that the small structural distortions observed in the local structures of the protein may lead to the destabilization of the global structure. To the best of our knowledge, ATP7A Clinical Genetics Resource is one of the most comprehensive compendium of variants in the gene providing clinically relevant annotations in gene.

Incidence and Clinical Features of TRPV4-Linked Axonal Neuropathies in a USA Cohort of Charcot-Marie-Tooth Disease Type 2.

Mutations in TRPV4 are linked to a group of clinically distinct, but also overlapping axonal neuropathies, including Charcot-Marie-Tooth disease type 2C (CMT2C), scapuloperoneal spinal muscular atrophy, and congenital distal spinal muscular atrophy. The incidence of TRPV4-linked cases ranges from 0 to 7% in overall axonal neuropathy cohorts from European countries and Australia. However, the data from other areas remain largely unknown. In this study, we screened for TRPV4 mutations in a well-characterized USA cohort of 62 unrelated CMT2 patients without mutations in MFN2, GARS, NEFL, and GDAP1. All 15 coding exons of TRPV4 were analyzed by Sanger-sequencing. Clinical features of TRPV4-linked patients were compared with those lacking TRPV4 mutations. We identified two TRPV4 mutations in two patients. A TRPV4-R316C was identified in a patient with family history, while a TRPV4-R269C in an apparently sporadic case. Marked clinical variations were observed in the patients with TRPV4 mutations. Our data suggest that TRPV4-linked CMT2C accounts for a sizable fraction in this USA cohort of CMT2; it has a wide phenotypic spectrum, and vocal cord paralysis, scapular weakness and wasting, skeletal dysplasia, and hearing loss are suggestive signs for TRPV4-linked CMT2C.

Occupation-based hand therapy in a baker with monomelic amyotrophy (distal segmental spinal muscular atrophy or Hirayama disease)

The aim of this case report is twofold: the very rare Hirayama disease is discussed, including the impact on the patient’s functioning. The unique way to solve an orthesis problem is described, by observing patient’s performance meticulously. Various hand function assessments were used to cover every level of the International Classification of Functioning model. An occupation-based approach was followed by performing a working visit during which the essence of his treatment problem became apparent. The development of a new adjustable brace is described. Combining two sorts of wrist positions in one splint is a novel approach that could be helpful for patients with other conditions. A work visit was helpful to focus on the participation level. The occupation-based intervention resulted in the patient’s ability to resume work.

In Silico analysis of SIGMAR1 gene causing distal hereditary motor neuropathy in a Pakistani family

Distal hereditary motor neuropathy (dHMN), also known as distal spinal muscular atrophy (distal SMA), comprises of a group of progressive neurological diseases resulting in degeneration of lower motor neurons with weakness and atrophy in distal muscles. In the present study, we investigated a large multigenerational family from Pakistan with multiple individuals showing distal muscle wasting and weakness of the upper and lower limbs. Our genomic studies identified a previously reported splice-site sequence variant of SIGMAR1 gene in this family (NM_005866.3 c.151+1G>T;c.92_151del; p.31_50del), which has been commonly implicated in a broad spectrum of motor neuron conditions.Structural annotation of human SIGMAR1 protein identified one signal peptide domain, and a single trans-membrane domain. Putative post-translational modifications revealed several generic phosphorylation sites in SIGMAR1, and the protein was predicted to interact with endoplasmic reticulum mono‑oxygenases, CYP51A1 and MSMO1. Our results entail the first report of SIGMAR1 mutation associated with dHMN from Pakistan, and provide the basis for further studies on structural variations and biological pathways involving SIGMAR1 in hereditary motor neuropathies.

P.107 - SMA registry in Russia

Spinal muscular atrophy (SMA) is a rare neuromuscular disorder with progressive loss of motor neurons in anterior horns of the spinal cord and progressive muscle wasting that leads to early death due to respiratory failure. We present SMA registry in Russian Federation that was hold by SMA Family Foundation and Russian Children Neuromuscular Center. To the date registry includes data of 370 patients with SMA. By the types they distributed as follows: type 1 (Werdnig-Hoffmann disease) – 96 patients, type 2 (Dubowitz disease) – 180 patients, type 3 (Kugelberg-Welander disease)– 74 patients and distal SMA – 20 patients. 18 patients with distal SMA are not genotyped. All patients with SMN1 SMA are confirmed genetically with the deletion of exon 7, but only 70 of them are tested for number of copies of SMN2 gene. There was found an exon 7 deletion of SMN1 gene and a point mutation in another SMN1 gene in 7 patients. So there are 18 patients with SMA I type (10 patients has 2 copies and 8 has 3 copies); 37 patients with SMA II type (1 patient has 1 copy, 4 has 2 copies, 26 has 3 copies, 6 has 4 copies); 15 patients with SMA III type (1 patient with 2 copies, 7 with 3 copies, 4 has 4 copies, 3 has 5 copies). We have 51 patients with SMA I/II types who have tracheostomy and are using invasive ventilation support, 24 patients are using BiPAP frequently and 43 patients are using cough assist devices. Motor development in SMA patients in Russian Children Neuromuscular Center is usually assessed with validation functional scales: CHOP INTEND for SMA type I and Hammersmith Functional Motor Scale for patients with SMA types II and III. SMA Family Foundation provides standards of care for patients with SMA. Great number of SMA patients in Russia may be of great interest to pharmaceutical companies who develops new drugs to treat spinal muscular atrophy.

Motor neuronal repletion of the NMJ organizer, Agrin, modulates the severity of the spinal muscular atrophy disease phenotype in model mice.

Spinal muscular atrophy (SMA) is a common and often fatal neuromuscular disorder caused by low levels of the Survival Motor Neuron (SMN) protein. Amongst the earliest detectable consequences of SMN deficiency are profound defects of the neuromuscular junctions (NMJs). In model mice these synapses appear disorganized, fail to mature and are characterized by poorly arborized nerve terminals. Given one role of the SMN protein in orchestrating the assembly of spliceosomal snRNP particles and subsequently regulating the alternative splicing of pre-mRNAs, a plausible link between SMN function and the distal neuromuscular SMA phenotype is an incorrectly spliced transcript or transcripts involved in establishing or maintaining NMJ structure. In this study, we explore the effects of one such transcript-Z+Agrin-known to be a critical organizer of the NMJ. We confirm that low SMN protein reduces motor neuronal levels of Z+Agrin. Repletion of this isoform of Agrin in the motor neurons of SMA model mice increases muscle fiber size, enhances the post-synaptic NMJ area, reduces the abnormal accumulation of intermediate filaments in nerve terminals of the neuromuscular synapse and improves the innervation of muscles. While these effects are independent of changes in SMN levels or increases in motor neuron numbers they nevertheless have a significant effect on the overall disease phenotype, enhancing mean survival in severely affected SMA model mice by ∼40%. We conclude that Agrin is an important target of the SMN protein and that mitigating NMJ defects may be one strategy in treating human spinal muscular atrophy.

Trk receptor signaling and sensory neuron fate are perturbed in human neuropathy caused by Gars mutations

Charcot-Marie-Tooth disease type 2D (CMT2D) is a peripheral nerve disorder caused by dominant, toxic, gain-of-function mutations in the widely expressed, housekeeping gene, GARS The mechanisms underlying selective nerve pathology in CMT2D remain unresolved, as does the cause of the mild-to-moderate sensory involvement that distinguishes CMT2D from the allelic disorder distal spinal muscular atrophy type V. To elucidate the mechanism responsible for the underlying afferent nerve pathology, we examined the sensory nervous system of CMT2D mice. We show that the equilibrium between functional subtypes of sensory neuron in dorsal root ganglia is distorted by Gars mutations, leading to sensory defects in peripheral tissues and correlating with overall disease severity. CMT2D mice display changes in sensory behavior concordant with the afferent imbalance, which is present at birth and nonprogressive, indicating that sensory neuron identity is prenatally perturbed and that a critical developmental insult is key to the afferent pathology. Through in vitro experiments, mutant, but not wild-type, GlyRS was shown to aberrantly interact with the Trk receptors and cause misactivation of Trk signaling, which is essential for sensory neuron differentiation and development. Together, this work suggests that both neurodevelopmental and neurodegenerative mechanisms contribute to CMT2D pathogenesis, and thus has profound implications for the timing of future therapeutic treatments.