Mutations in the Immunoglobulin Mu DNA Binding Protein 2 (IGHMBP2) gene cause Spinal Muscular Atrophy with Respiratory Distress type 1 (SMARD1), a rare, infantile, and fatal motor neuron disease, as well as the milder Charcot-Marie-Tooth disease type 2S (CMT2S). Gene therapy has emerged as a promising approach to correcting IGHMBP2 loss in SMARD1 models, but critical challenges remain. In this study, we compared the efficacy of two novel, optimized adeno-associated virus 9 (AAV9)-IGHMBP2 vectors, utilizing either the Chicken β-Actin (CBA) or a truncated form of the methyl-CpG-binding protein 2 (MeCP2) promoter (P546), in the SMARD1 murine model via intracerebroventricular delivery. Treated mice survival, histopathological and molecular profile were analyzed. Corroborating previous findings, both constructs effectively rescued the pathological phenotype, significantly improving survival, body weight, and motor function while preserving motor neurons and neuromuscular junctions. Notably, histopathological and RNA sequencing analyses revealed, for the first time, inflammatory marker alterations in the SMARD1 spinal cord, which resolved following treatment. A comparative analysis of the two vectors demonstrated superior long-term efficacy of the P546-promoter construct. ICV gene therapy approach can effectively rescue SMARD1 pathological hallmarks, including astrogliosis and microgliosis. Moreover, P546-promoter construct is superior in terms of safety profile and long-term therapeutic efficacy.

IGHMBP2-related disorders comprise a clinical spectrum from spinal muscular atrophy with respiratory distress type 1 (SMARD1) to Charcot-Marie-Tooth disease type 2S, with increasingly recognized atypical and overlapping phenotypes. We report four pediatric cases from three unrelated families with biallelic pathogenic variants in IGHMBP2. Case 1, a premature infant represents SMARD1. Case 2 had infantile-onset neuropathy without respiratory symptoms. Case 3 and 4, two siblings, presented with a Guillain-Barré syndrome-like phenotype, cauda equina enhancement on spinal neuroimaging, elevated cerebrospinal fluid protein, and electromyography revealing acute motor and sensory axonal neuropathy. Despite an initial response to intravenous immunoglobulin, previous symptoms in Case 3 led to consideration of an immune-mediated neuropathy superimposed on a genetic background. Genetic analysis identified a homozygous nonsense variant in Cases 1 and 2, and novel compound heterozygous missense variants in Case 3 and 4. Thus, the list of overlapping genetic and acquired neuropathies now also includes IGHMBP2-related CMT2S.

Motor Neuron Diseases (MNDs) such as Amyotrophic Lateral Sclerosis (ALS), Primary Lateral Sclerosis (PLS), Hereditary Spastic Paraplegia (HSP), Spinal Muscular Atrophy with Respiratory Distress Type 1 (SMARD1), Multisystem Proteinopathy (MSP), Spinal and Bulbar Muscular Atrophy (SBMA), and ALS associated to Frontotemporal Dementia (ALS-FTD), have traditionally been studied as distinct entities, each one with unique genetic and clinical characteristics. However, emerging research reveals that these seemingly disparate conditions converge on shared molecular mechanisms that drive progressive neuroaxonal degeneration. This narrative review addresses a critical gap in the field by synthesizing the most recent findings into a comprehensive, cross-disease mechanisms framework. By integrating insights into RNA dysregulation, protein misfolding, mitochondrial dysfunction, DNA damage, kinase signaling, axonal transport failure, and immune activation, we highlight how these converging pathways create a common pathogenic landscape across MNDs. Importantly, this perspective not only reframes MNDs as interconnected neurodegenerative models but also identifies shared therapeutic targets and emerging strategies, including antisense oligonucleotides, autophagy modulators, kinase inhibitors, and immunotherapies that transcend individual disease boundaries. The diagnostic and prognostic potential of Neurofilament Light Chain (NfL) biomarkers is also emphasized. By shifting focus from gene-specific to mechanism-based approaches, this paper offers a much-needed roadmap for advancing both research and clinical management in MNDs, paving the way for cross-disease therapeutic innovations.

Spinal muscular atrophy with respiratory distress type 1 (SMARD1) and Charcot-Marie-Tooth type 2S (CMT2S) typically present before age 10. Genetic factors account for up to 50 % of neuropathies, which often display varied symptoms. Mutations in the IGHMBP2 gene are associated with both CMT2S and SMARD1, resulting in a rare clinical condition marked by axonal neuropathy, spinal muscular atrophy, respiratory distress, and muscle weakness. Detailed family histories and medical data were collected. Segregation analysis was performed using Sanger sequencing and whole exome sequencing. Additionally, a review of molecularly confirmed patients was conducted. Protein tertiary structures expressed in the IGHMBP2 gene were tested for topological and conformational changes using modeling programs and in-silico tools. We identified a novel homozygous nonsense mutation (c.2568_2569del p.Gly857Alafs*27) in a family with a member showing neuropathy. This report details the clinical and genetic findings of the affected individuals, including a Turkish patient with neuropathy, and compares them with literature cases. Understanding the clinical impact of the (c.2568_2569del p.Gly857Alafs*27) mutation will enhance our knowledge of IGHMBP2 gene defects role in neuropathy. This study aims to highlight this severe recessive disease caused by pathogenic IGHMBP2 gene mutations and to examine the mutation spectrum and phenotype differences.

Spinal muscular atrophy with respiratory distress type 1 (SMARD1) and Charcot Marie Tooth type 2S (CMT2S) are due to mutations in immunoglobulin mu binding protein two (IGHMBP2). We generated the Ighmbp2-R604X mouse (R605X-humans) to understand how alterations in IGHMBP2 function impact disease pathology. The IGHMBP2-R605X mutation is associated with patients with SMARD1 or CMT2S. The impact of this mutation is substantial, Ighmbp2R604X/R604X mice have a decreased lifespan (6 days) and weight, and failure to thrive consistent with SMARD1 symptoms. Significant respiratory changes were present along with disease pathology of the phrenic nerve and diaphragm muscle fibers. Ighmbp2R604X/R604X mice also presented with signs of milk aspiration and lung pathology. Interestingly, P0 Ighmbp2R604X/R604X mice had visible milk spots, but demonstrated reduction of the milk spot by P3, indicating deficits in suckling. Alterations in hindlimb electrophysiology were consistent with the pathology of the sciatic nerve, hindlimb neuromuscular junction and muscle. Injection of the ssAAV9-WT-IGHMBP2 vector extended Ighmbp2R604X/R604X survival a few days. Ighmbp2R604X/R604X phenotypes are consistent with the most severe SMARD1 clinical symptoms and for the first time a Ighmbp2 mouse model demonstrates that milk aspiration and loss of the ability to suckle impact survival.