RARE DISEASE
Spinal muscular atrophy with respiratory distress type 1
Spinal muscular atrophy with respiratory distress type 1
Spinal muscular atrophy with respiratory distress type 1
Synonyms: Autosomal recessive distal spinal muscular atrophy type 1, Autosomal recessive spinal muscular atrophy with respiratory distress, Diaphragmatic spinal muscular atrophy, Distal hereditary motor neuropathy type 6, Distal-HMN type 6, SIANRF, SMARD1, Severe infantile axonal neuropathy with respiratory failure type 1, dHMN6, dSMA1
Synonyms: Autosomal recessive distal spinal muscular atrophy type 1, Autosomal recessive spinal muscular atrophy with respiratory distress, Diaphragmatic spinal muscular atrophy, Distal hereditary motor neuropathy type 6, Distal-HMN type 6, SIANRF, SMARD1, Severe infantile axonal neuropathy with respiratory failure type 1, dHMN6, dSMA1
Synonyms: Autosomal recessive distal spinal muscular atrophy type 1, Autosomal recessive spinal muscular atrophy with respiratory distress, Diaphragmatic spinal muscular atrophy, Distal hereditary motor neuropathy type 6, Distal-HMN type 6, SIANRF, SMARD1, Severe infantile axonal neuropathy with respiratory failure type 1, dHMN6, dSMA1
Drug discovery
1
drug
With orphan designation
Overview
Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is a rare autosomal recessive motor neuron disease caused by IGHMBP2 gene mutations. It manifests in infancy with life-threatening respiratory failure due to diaphragmatic paralysis, followed by rapidly progressive distal-to-proximal muscle weakness, autonomic dysfunction (e.g., arrhythmias, hyperhidrosis), and loss of deep tendon reflexes. Survival depends on lifelong mechanical ventilation, with most affected individuals dying before age two without intervention [1][2][5][17].
Burden
Mortality: >50% die within the first year without ventilation; prolonged survival requires 24/7 respiratory care [5][12][13].
Disability: Profound motor impairment (non-ambulatory), scoliosis, and contractures [8][9][14].
Psychosocial impact: High caregiver burden, recurrent hospitalizations, and limited access to specialized care [8][12][18].
Therapies
Respiratory support: Early tracheostomy/non-invasive ventilation for diaphragmatic paralysis [2][3][12].
Supportive care: Physical/occupational therapy, nutritional management, infection prevention (antibiotics/immunizations) [2][4][9].
Emerging therapies: Preclinical gene therapy targeting IGHMBP2 deficiency shows promise but remains investigational [3][11][15].
Categories: rare genetic diseases, rare neurological diseases
Research Papers
61 drug discovery papers about Spinal muscular atrophy with respiratory distress type 1, with 1 next-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
61 drug discovery papers about Spinal muscular atrophy with respiratory distress type 1, with 1 next-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2024-10-01 | Severe Metabolic Acidosis in a Patient with Spinal Muscular Atrophy
Introduction: Ketogenesis starts early after starvation in healthy individuals. However, ketoacidosis develops after ~2 weeks of starvation. We report a case of severe ketoacidosis after a short period of fasting in a patient with spinal muscular atrophy (SMA). Case Description: A 59-year-old wheelchair-bound male with SMA and a recent history of percutaneous cholecystostomy presented to the hospital with purulent drainage. His food intake mainly comprised ground vegetables and protein. The patient was nil per oral overnight on day 2 for cholecystostomy tube exchange and reported abdominal pain and vomiting on day 3 of admission. Home medications included baclofen and sertraline. Physical examination was noted for muscle atrophy without any distress. Blood pressure was 124/66 mm Hg, pulse rate was 85/min, respiratory rate was 22/min, and oxygen saturation was 98% on room air. Laboratory evaluation: serum bicarbonate 11 mmol/L, anion gap 22, pH 7.17 with partial pressure of carbon dioxide of 30 on day 3 of admission. Severe high anion gap metabolic acidosis (without adequate respiratory compensation) was confirmed with repeat tests. Sodium bicarbonate infusion was started due to severe acidosis while being further evaluated. Serum creatinine was 0.49 m/dl, and electrolytes were within range. Serum lactate was 0.8 mmol/L (0.5 to 2 mmol/L), osmolar gap was 4 (<10), serum ethanol, methanol, ethylene glycol, salicylate, and acetaminophen, respectively, were negative. The urine dipstick showed 2+ ketones, serum acetone was 20 mg/dL (0-5 m/dL), and serum beta-hydroxybutyrate was 8.52 mmol/L (0.28 mmol/L). His blood sugar was 93 mg/dl on day 1 and 63 mg/dl on day 3 of admission. Low-normal blood sugar and ketoacidosis in the setting of ~18 hours of fasting prompted a diagnosis of starvation ketoacidosis. Serum bicarbonate remained ~12 mmol/L on bicarbonate infusion. Dextrose infusion normalized bicarbonate (25 mmol/L) within four hours. Discussion: Starvation ketoacidosis is described within 12-24 hours of starvation in patients with SMA in isolated case reports. Poor ketone body consumption by low muscle mass is postulated to cause severe ketoacidosis in SMA patients upon a short period of starvation. Timely treatment and prevention with dextrose, including during fasting for procedures, are crucial to prevent this complication in SMA patients.
2019-06-28 | Muscle fiber-type selective propensity to pathology in the nmd mouse model of SMARD1
Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is an autosomal recessive disease that causes distal limb muscle atrophy, due to motor neuron degeneration. Similar to other motor neuron diseases, SMARD1 shows differential vulnerability to denervation in various muscle groups, which is recapitulated in the nmd mouse, a model of SMARD1. In multiple neurodegenerative disease models, transcriptomic analysis has identified differentially expressed genes between vulnerable motor neuron populations, but the mechanism leading to susceptibility is largely unknown. To investigate if denervation vulnerability is linked to intrinsic muscle properties, we analyzed muscle fiber-type composition in muscles from motor units that show different degrees of denervation in nmd mice: gastrocnemius, tibialis anterior (TA), and extensor digitorum longus (EDL). Our results revealed that denervation vulnerability correlated with atrophy and loss of MyHC-IIb and MyHC-IIx muscle fiber types. Interestingly, increased vulnerability also correlated with an increased abundance of MyHC-I and MyHC-IIa muscle fibers. These results indicated that MyHC-IIx muscle fibers are the most vulnerable to denervation, followed by MyHC-IIb muscle fibers. Moreover, our data indicate that type MyHC-IIa and MyHC-IIb muscle fibers show resistance to denervation and compensate for the loss of MyHC-IIx and MyHC-IIb muscle fibers in the most vulnerable muscles. Taken together these results provide a basis for the selective vulnerability to denervation of specific muscles in nmd mice and identifies new targets for potential therapeutic intervention.
2017-04-13 | The Curse of Apneic Spells
A 6-year-old girl had reduced fetal movements, numerous apneic spells, muscle hypotonia, and developmental motor delay. Her muscle biopsy tissue showed variation in myofiber diameters, small minicores by electron microscopy, and near-uniformity of type I fibers. Although no mutations were detected in RYR1, SEPN1, and DMPK genes, the RAPSN gene revealed one known mutation, p.Asn88Lys, from the mother, and one novel mutation, p.Cys366Gly, from the father. Life-saving pyridostigmine treatment suppressed her apneic spells and improved her motor development.
2014-06-10 | Differentiation defects in primary motoneurons from a SMARD1 mouse model that are insensitive to treatment with low dose PEGylated IGF1
Muscle atrophy and diaphragmatic palsy are the clinical characteristics of spinal muscular atrophy with respiratory distress type 1 (SMARD1), and are well represented in the neuromuscular degeneration (Nmd2J) mouse, modeling the juvenile form of SMARD1. Both in humans and mice mutations in the IGHMBP2 gene lead to motoneuron degeneration. We could previously demonstrate that treatment with a polyethylene glycol-coupled variant of IGF1 (PEG-IGF1) improves motor functions accompanied by reduced fiber degeneration in the gastrocnemius muscle and the diaphragm, but has no beneficial effect on motoneuron survival. These data raised the question which cell autonomous disease mechanisms contribute to dysfunction and loss of Ighmbp2-deficient motoneurons. An analysis of primary Ighmbp2-deficient motoneurons exhibited differentiation deficits such as reduced spontaneous Ca2+ transients and altered axon elongation, which was not compensated by PEG-IGF1. This points to an IGF1 independent mechanism of motoneuron degeneration that deserves treatment approaches in addition to IGF1.
gene therapies
2025-12-31 | Phenotypic continuum in IGHMBP2-related disorders: a portfolio of cases from typical to Guillain-Barré syndrome-like presentation.
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.
2025-10-01 | Infantile Hypotonia and Respiratory Failure with Missense Variant in IGHMBP2 Gene: A Case of SMARD1 Disease
Background: Infantile-onset hypotonia could be due to genetic causes of neuromuscular diseases. We report an infant with spinal muscular atrophy with respiratory distress type 1 (SMARD1), which is a less-known, rare, severe, progressive congenital neuromuscular disease, manifesting after the initial months of life, with symmetrical distal limb weakness, muscle atrophy, and diaphragmatic paralysis. Clinical Description: A 9-month-old male, with developmental delay and failure to thrive, was referred for failure to wean from respiratory support. He had profound hypotonia, especially in the distal muscles of the lower limbs, with foot contracture and normal cranial nerves and other systems. Management and Outcome: Routine investigations and thyroid functions were normal. Chest X-ray showed eventration of diaphragm, magnetic resonance imaging revealed cerebral atrophy and cerebellar infarct. Electroneuromyography confirmed generalized sensory and motor axonal neuropathy. Whole exome sequencing detected a homozygous variant of uncertain significance in the IGHMBP2 gene. Considering the infantile onset, predominant distal muscle weakness, ventilator dependency, and diaphragmatic palsy, a diagnosis of SMARD was made. An elective tracheostomy was performed, and the child transitioned to bilevel positive airway pressure. Conclusion: This case creates awareness about SMARD1 disease, which may be considered a differential in infants with hypotonia and ventilator dependency, especially with distal muscle weakness and diaphragmatic palsy. Genetic analysis aids diagnosis.
2025-05-12 | Clinical and Genetic Landscape of IGHMBP2 -Related Disorders: From Novel Variants to Phenotypic Insights.
Pathogenic variants in IGHMBP2 have been associated with spinal muscular atrophy with respiratory distress type 1 (SMARD1) and Autosomal Recessive Charcot-Marie-Tooth disease type 2S (AR-CMT2S), as well as a relatively wide spectrum of rare, atypical phenotypes. We describe clinical and molecular features of five patients who have diverse clinical findings associated with known and novel IGHMBP2 pathogenic variants. Genotype-phenotype correlations are evident, highlighting the association of specific variants with SMARD1 or AR-CMT2S. This study expands the spectrum of the IGHMBP2-related disease and highlights the necessity to study diverse populations to enhance diagnostic accuracy and refine genotype-phenotype correlations.
2024-10-26 | Clinical and Genetic Profiles of 5q- and Non-5q-Spinal Muscular Atrophy Diseases in Pediatric Patients.
Spinal muscular atrophy (SMA) is a genetic disease characterized by loss of motor neurons in the spinal cord and lower brainstem. The term "SMA" usually refers to the most common form, 5q-SMA, which is caused by biallelic mutations in SMN1 (located on chromosome 5q13). However, long before the discovery of SMN1, it was known that other forms of SMA existed. Therefore, SMA is currently divided into two groups: 5q-SMA and non-5q-SMA. This is a simple and practical classification, and therapeutic drugs have only been developed for 5q-SMA (nusinersen, onasemnogene abeparvovec, risdiplam) and not for non-5q-SMA disease. We conducted a non-systematic critical review to identify the characteristics of each SMA disease. Many of the non-5q-SMA diseases have similar symptoms, making DNA analysis of patients essential for accurate diagnosis. Currently, genetic analysis technology using next-generation sequencers is rapidly advancing, opening up the possibility of elucidating the pathology and treating non-5q-SMA. Based on accurate diagnosis and a deeper understanding of the pathology of each disease, treatments for non-5q-SMA diseases may be developed in the near future.
2024-09-13 | Real-world multidisciplinary outcomes of onasemnogene abeparvovec monotherapy in patients with spinal muscular atrophy type 1: experience of the French cohort in the first three years of treatment
Abstract Background Spinal muscular atrophy type 1 (SMA1) is the most severe and early form of SMA, a genetic disease with motor neuron degeneration. Onasemnogene abeparvovec gene transfer therapy (GT) has changed the natural history of SMA1, but real-world data are scarce. Methods A French national expert committee identified 95 newly diagnosed treatment-naive SMA1 patients between June 2019 and June 2022. We prospectively report on children treated with GT as the first and only therapy who had more than one-year of follow-up. Results Forty-six SMA1 patients received GT. Twelve patients received other treatments. Patients with respiratory insufficiency were oriented toward palliative care after discussion with families. Twenty-nine of the treated patients with more than 12 months of follow-up were included in the follow-up analysis. Among them, 17 had 24 months of follow-up. The mean age at treatment was 7.5 (2.1–12.5) months. Twenty-two patients had two SMN2 copies, and seven had three copies. One infant died in the month following GT due to severe thrombotic microangiopathy, and another died due to respiratory distress. Among the 17 patients with 24 months of follow-up, 90% required spinal bracing (15/17), three patients required nocturnal noninvasive ventilation, and two needed gastrostomy. Concerning motor milestones at the 24-month follow-up, all patients held their head, 15/17 sat for 30 s unassisted, and 12/17 stood with aid. Motor scores (CHOPINTEND and HINE-2) and thoracic circumference significantly improved in all patients. Conclusions Our study shows favorable motor outcomes and preserved respiratory and feeding functions in treatment-naive SMA1 infants treated by GT as the first and only therapy before respiratory and bulbar dysfunctions occurred. Nevertheless, almost all patients developed spinal deformities.
oligonucleotides
2026-07-02 | A class of deep intronic IGHMBP2 variants activate a shared cryptic splice donor, enabling correction of select variants with a single antisense oligonucleotide.
Biallelic disease-causing variants in IGHMBP2 cause spinal muscular atrophy with respiratory distress type I (SMARD1) and Charcot-Marie-Tooth type 2S (CMT2S). We present 12 unrelated patients with clinically suspected IGHMBP2-related-disease, each carrying a variant deep in intron 8 of IGHMBP2 (c.1235+1076G>A (n=6), c.1235+450G>A (n=5), and c.1235+894C>A (n=1)), along with a known deleterious variant in trans. To assess aberrant pathogenic splicing induced by these deep intronic variants in a relevant model, patient-derived induced pluripotent stem cells were differentiated into motor neurons (iMNs). Long-read RNA sequencing revealed introduction of different pseudoexons by each variant: c.1235+450G>A (626bp), c.1235+1076G>A (112bp and 77bp) and c.1235+894C>A (182bp). Although each variant utilizes a unique splice acceptor site, they all activate the same cryptic donor site, enabling a therapeutic approach to redirect aberrant splicing for all the variants using a single shared antisense oligonucleotide (ASO). Treatment of iMNs with this single ASO restored full-length IGHMBP2 protein in c.1235+894G>A and c.1235+1076G>A by decreasing the use of the novel acceptor site. In contrast, ASO treatment did not correct the splicing in c.1235+450G>A, suggesting that additional splice correction will be needed for this specific variant. A CRISPR interference screen of IGHMBP2 loss-of-function in iMNs identified ribonucleoprotein complex biogenesis (RNP), and rRNA and tRNA processing as top pathways implicated in motor neuron vulnerability. Proteomics and transcriptomics analysis of successfully treated patient iMNs revealed correction of RNP biogenesis and rRNA processing defects. This study highlights the importance of characterizing deep intronic variants in disease-relevant cells to assist the diagnostic process and inform therapeutics development.
2025-08-14 | Neuroaxonal Degeneration as a Converging Mechanism in Motor Neuron Diseases (MNDs): Molecular Insights into RNA Dysregulation and Emerging Therapeutic Targets.
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.
2024-04-08 | The contribution and therapeutic implications of IGHMBP2 mutations on IGHMBP2 biochemical activity and ABT1 association.
Mutations within immunoglobulin mu DNA binding protein (IGHMBP2), an RNA-DNA helicase, result in SMA with respiratory distress type I (SMARD1) and Charcot Marie Tooth type 2S (CMT2S). The underlying biochemical mechanism of IGHMBP2 is unknown as well as the functional significance of IGHMBP2 mutations in disease severity. Here we report the biochemical mechanisms of IGHMBP2 disease-causing mutations D565N and H924Y, and their potential impact on therapeutic strategies. The IGHMBP2-D565N mutation has been identified in SMARD1 patients, while the IGHMBP2-H924Y mutation has been identified in CMT2S patients. For the first time, we demonstrate a correlation between the altered IGHMBP2 biochemical activity associated with the D565N and H924Y mutations and disease severity and pathology in patients and our Ighmbp2 mouse models. We show that IGHMBP2 mutations that alter the association with activator of basal transcription (ABT1) impact the ATPase and helicase activities of IGHMBP2 and the association with the 47S pre-rRNA 5' external transcribed spacer. We demonstrate that the D565N mutation impairs IGHMBP2 ATPase and helicase activities consistent with disease pathology. The H924Y mutation alters IGHMBP2 activity to a lesser extent while maintaining association with ABT1. In the context of the compound heterozygous patient, we demonstrate that the total biochemical activity associated with IGHMBP2-D565N and IGHMBP2-H924Y proteins is improved over IGHMBP2-D565N alone. Importantly, we demonstrate that the efficacy of therapeutic applications may vary based on the underlying IGHMBP2 mutations and the relative biochemical activity of the mutant IGHMBP2 protein.
2018-10-01 | SMA CLINICAL DATA, OUTCOME MEASURES AND REGISTRIES
This study explored the utility of ACTIVE scaled workspace volume scores to quantify meaningful change in individuals with spinal muscular atrophy (SMA) due to disease progression or treatment. ACTIVE, a 65-second custom designed video game, uses a skeletal tracking algorithm to quantify the volume of space (m3) the player can interact with while reaching in three dimensions to squish spiders or dig for jewels. Sixty-two individuals with SMA type 2 or 3 (age 10.5y +/-5y) and 362 age-matched controls (age 10.7y +/-3.5y) participated. Individuals seen in our clinic (n=37) also completed traditional assessments including the PROMIS self-report of upper extremity function, Hammersmith Functional Motor Scale Expanded (HFMSE), and revised upper limb module (RULM). The remainder were tested at a CureSMA meeting (ACTIVE only n=25). ACTIVE differentiated between patients with varying severity of SMA, as defined by their Brooke level, and from healthy controls (Jonckheere-Terpstra test for trend P<0.0001). ACTIVE significantly correlated with the HFMSE and the RULM (Rho=0.8-0.9, p<0.01). Relevance to patients and families was established by strong correlations to self and parent measures of upper extremity ability (Rho=0.6-0.7, p<0.01). Nine individuals (age 9.4y +/- 4.8y) in this cohort received Spinraza. Responsiveness to change was demonstrated by significant changes pre and post treatment (Median change = 28 pts, Wilcoxon signed rank test p=0.02). Two methods were used to calculate a minimal clinically important difference (MCID). Using the more conservative of the 2 estimates (14.5 pts), all but one Spinraza-treated patient exceeded the MCID, suggesting a robust change not due to random fluctuation. In contrast, no SMA patients in our natural history cohort improved greater than the MCID. Our results validate ACTIVE for use in an SMA cohort and suggest meaningful functional change post-treatment can be readily detected using ACTIVE in individuals with SMA types 2 and 3.
2018-10-01 | SMA CLINICAL DATA, OUTCOME MEASURES AND REGISTRIES
Spinal muscular atrophy (SMA) is a devastating neuromuscular disorder characterized by paralysis and muscle weakness and can affect both children and adults. The first FDA approved SMA therapeutic, Spinraza, improves SMA patients' symptoms and motor function. It is expected that increased lifespan will lead to a shift from the severe infantile SMA population to a milder SMA adult population. It is unknown whether such lifespan extension will reveal new, previously unknown defects that could arise with age, as mild mouse models of SMA are currently lacking. We generated a new mouse model, the Smn2B/-;SMN2+/- mice, which present with nearly normal lifespan and very subtle SMA features. We have characterized canonical features of SMA as well as examined non-neuronal organs over the course of an aging study (18 months). The Smn2B/-;SMN2+/- mice are mildly weaker on motor tests and start losing weight at around 12 months of age. Histologically, Smn2B/-;SMN2+/- mice displayed reduced muscle fiber size and increased central nucleation while motor neuron counts seemed spared. Muscle-nerve electrophysiological assessment of the soleus revealed a significant motor neuron/NMJ component as nerve stimulation lead to lower force production than direct muscle stimulation. Interestingly, female mice appear less affected. Many parameters of the twitch and tetanic force production were also altered. Ultrastructural analysis of the sciatic nerve is underway. Thus far, there is no significant impairment in the lymphoid organs, liver and heart, where defects were previously identified in more severe models. Altogether, this study will shed light on future potential obstacles we may face in our changing SMA population. Being proactive in understanding this aspect will ensure timely development of additional therapeutics and ensure sustained quality of life for SMA patients throughout their lifespan.
small molecules
2024-10-01 | Severe Metabolic Acidosis in a Patient with Spinal Muscular Atrophy
Introduction: Ketogenesis starts early after starvation in healthy individuals. However, ketoacidosis develops after ~2 weeks of starvation. We report a case of severe ketoacidosis after a short period of fasting in a patient with spinal muscular atrophy (SMA). Case Description: A 59-year-old wheelchair-bound male with SMA and a recent history of percutaneous cholecystostomy presented to the hospital with purulent drainage. His food intake mainly comprised ground vegetables and protein. The patient was nil per oral overnight on day 2 for cholecystostomy tube exchange and reported abdominal pain and vomiting on day 3 of admission. Home medications included baclofen and sertraline. Physical examination was noted for muscle atrophy without any distress. Blood pressure was 124/66 mm Hg, pulse rate was 85/min, respiratory rate was 22/min, and oxygen saturation was 98% on room air. Laboratory evaluation: serum bicarbonate 11 mmol/L, anion gap 22, pH 7.17 with partial pressure of carbon dioxide of 30 on day 3 of admission. Severe high anion gap metabolic acidosis (without adequate respiratory compensation) was confirmed with repeat tests. Sodium bicarbonate infusion was started due to severe acidosis while being further evaluated. Serum creatinine was 0.49 m/dl, and electrolytes were within range. Serum lactate was 0.8 mmol/L (0.5 to 2 mmol/L), osmolar gap was 4 (<10), serum ethanol, methanol, ethylene glycol, salicylate, and acetaminophen, respectively, were negative. The urine dipstick showed 2+ ketones, serum acetone was 20 mg/dL (0-5 m/dL), and serum beta-hydroxybutyrate was 8.52 mmol/L (0.28 mmol/L). His blood sugar was 93 mg/dl on day 1 and 63 mg/dl on day 3 of admission. Low-normal blood sugar and ketoacidosis in the setting of ~18 hours of fasting prompted a diagnosis of starvation ketoacidosis. Serum bicarbonate remained ~12 mmol/L on bicarbonate infusion. Dextrose infusion normalized bicarbonate (25 mmol/L) within four hours. Discussion: Starvation ketoacidosis is described within 12-24 hours of starvation in patients with SMA in isolated case reports. Poor ketone body consumption by low muscle mass is postulated to cause severe ketoacidosis in SMA patients upon a short period of starvation. Timely treatment and prevention with dextrose, including during fasting for procedures, are crucial to prevent this complication in SMA patients.
2019-06-28 | Muscle fiber-type selective propensity to pathology in the nmd mouse model of SMARD1
Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is an autosomal recessive disease that causes distal limb muscle atrophy, due to motor neuron degeneration. Similar to other motor neuron diseases, SMARD1 shows differential vulnerability to denervation in various muscle groups, which is recapitulated in the nmd mouse, a model of SMARD1. In multiple neurodegenerative disease models, transcriptomic analysis has identified differentially expressed genes between vulnerable motor neuron populations, but the mechanism leading to susceptibility is largely unknown. To investigate if denervation vulnerability is linked to intrinsic muscle properties, we analyzed muscle fiber-type composition in muscles from motor units that show different degrees of denervation in nmd mice: gastrocnemius, tibialis anterior (TA), and extensor digitorum longus (EDL). Our results revealed that denervation vulnerability correlated with atrophy and loss of MyHC-IIb and MyHC-IIx muscle fiber types. Interestingly, increased vulnerability also correlated with an increased abundance of MyHC-I and MyHC-IIa muscle fibers. These results indicated that MyHC-IIx muscle fibers are the most vulnerable to denervation, followed by MyHC-IIb muscle fibers. Moreover, our data indicate that type MyHC-IIa and MyHC-IIb muscle fibers show resistance to denervation and compensate for the loss of MyHC-IIx and MyHC-IIb muscle fibers in the most vulnerable muscles. Taken together these results provide a basis for the selective vulnerability to denervation of specific muscles in nmd mice and identifies new targets for potential therapeutic intervention.
2017-04-13 | The Curse of Apneic Spells
A 6-year-old girl had reduced fetal movements, numerous apneic spells, muscle hypotonia, and developmental motor delay. Her muscle biopsy tissue showed variation in myofiber diameters, small minicores by electron microscopy, and near-uniformity of type I fibers. Although no mutations were detected in RYR1, SEPN1, and DMPK genes, the RAPSN gene revealed one known mutation, p.Asn88Lys, from the mother, and one novel mutation, p.Cys366Gly, from the father. Life-saving pyridostigmine treatment suppressed her apneic spells and improved her motor development.
2014-06-10 | Differentiation defects in primary motoneurons from a SMARD1 mouse model that are insensitive to treatment with low dose PEGylated IGF1
Muscle atrophy and diaphragmatic palsy are the clinical characteristics of spinal muscular atrophy with respiratory distress type 1 (SMARD1), and are well represented in the neuromuscular degeneration (Nmd2J) mouse, modeling the juvenile form of SMARD1. Both in humans and mice mutations in the IGHMBP2 gene lead to motoneuron degeneration. We could previously demonstrate that treatment with a polyethylene glycol-coupled variant of IGF1 (PEG-IGF1) improves motor functions accompanied by reduced fiber degeneration in the gastrocnemius muscle and the diaphragm, but has no beneficial effect on motoneuron survival. These data raised the question which cell autonomous disease mechanisms contribute to dysfunction and loss of Ighmbp2-deficient motoneurons. An analysis of primary Ighmbp2-deficient motoneurons exhibited differentiation deficits such as reduced spontaneous Ca2+ transients and altered axon elongation, which was not compensated by PEG-IGF1. This points to an IGF1 independent mechanism of motoneuron degeneration that deserves treatment approaches in addition to IGF1.
gene therapies
2025-12-31 | Phenotypic continuum in IGHMBP2-related disorders: a portfolio of cases from typical to Guillain-Barré syndrome-like presentation.
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.
2025-10-01 | Infantile Hypotonia and Respiratory Failure with Missense Variant in IGHMBP2 Gene: A Case of SMARD1 Disease
Background: Infantile-onset hypotonia could be due to genetic causes of neuromuscular diseases. We report an infant with spinal muscular atrophy with respiratory distress type 1 (SMARD1), which is a less-known, rare, severe, progressive congenital neuromuscular disease, manifesting after the initial months of life, with symmetrical distal limb weakness, muscle atrophy, and diaphragmatic paralysis. Clinical Description: A 9-month-old male, with developmental delay and failure to thrive, was referred for failure to wean from respiratory support. He had profound hypotonia, especially in the distal muscles of the lower limbs, with foot contracture and normal cranial nerves and other systems. Management and Outcome: Routine investigations and thyroid functions were normal. Chest X-ray showed eventration of diaphragm, magnetic resonance imaging revealed cerebral atrophy and cerebellar infarct. Electroneuromyography confirmed generalized sensory and motor axonal neuropathy. Whole exome sequencing detected a homozygous variant of uncertain significance in the IGHMBP2 gene. Considering the infantile onset, predominant distal muscle weakness, ventilator dependency, and diaphragmatic palsy, a diagnosis of SMARD was made. An elective tracheostomy was performed, and the child transitioned to bilevel positive airway pressure. Conclusion: This case creates awareness about SMARD1 disease, which may be considered a differential in infants with hypotonia and ventilator dependency, especially with distal muscle weakness and diaphragmatic palsy. Genetic analysis aids diagnosis.
2025-05-12 | Clinical and Genetic Landscape of IGHMBP2 -Related Disorders: From Novel Variants to Phenotypic Insights.
Pathogenic variants in IGHMBP2 have been associated with spinal muscular atrophy with respiratory distress type 1 (SMARD1) and Autosomal Recessive Charcot-Marie-Tooth disease type 2S (AR-CMT2S), as well as a relatively wide spectrum of rare, atypical phenotypes. We describe clinical and molecular features of five patients who have diverse clinical findings associated with known and novel IGHMBP2 pathogenic variants. Genotype-phenotype correlations are evident, highlighting the association of specific variants with SMARD1 or AR-CMT2S. This study expands the spectrum of the IGHMBP2-related disease and highlights the necessity to study diverse populations to enhance diagnostic accuracy and refine genotype-phenotype correlations.
2024-10-26 | Clinical and Genetic Profiles of 5q- and Non-5q-Spinal Muscular Atrophy Diseases in Pediatric Patients.
Spinal muscular atrophy (SMA) is a genetic disease characterized by loss of motor neurons in the spinal cord and lower brainstem. The term "SMA" usually refers to the most common form, 5q-SMA, which is caused by biallelic mutations in SMN1 (located on chromosome 5q13). However, long before the discovery of SMN1, it was known that other forms of SMA existed. Therefore, SMA is currently divided into two groups: 5q-SMA and non-5q-SMA. This is a simple and practical classification, and therapeutic drugs have only been developed for 5q-SMA (nusinersen, onasemnogene abeparvovec, risdiplam) and not for non-5q-SMA disease. We conducted a non-systematic critical review to identify the characteristics of each SMA disease. Many of the non-5q-SMA diseases have similar symptoms, making DNA analysis of patients essential for accurate diagnosis. Currently, genetic analysis technology using next-generation sequencers is rapidly advancing, opening up the possibility of elucidating the pathology and treating non-5q-SMA. Based on accurate diagnosis and a deeper understanding of the pathology of each disease, treatments for non-5q-SMA diseases may be developed in the near future.
2024-09-13 | Real-world multidisciplinary outcomes of onasemnogene abeparvovec monotherapy in patients with spinal muscular atrophy type 1: experience of the French cohort in the first three years of treatment
Abstract Background Spinal muscular atrophy type 1 (SMA1) is the most severe and early form of SMA, a genetic disease with motor neuron degeneration. Onasemnogene abeparvovec gene transfer therapy (GT) has changed the natural history of SMA1, but real-world data are scarce. Methods A French national expert committee identified 95 newly diagnosed treatment-naive SMA1 patients between June 2019 and June 2022. We prospectively report on children treated with GT as the first and only therapy who had more than one-year of follow-up. Results Forty-six SMA1 patients received GT. Twelve patients received other treatments. Patients with respiratory insufficiency were oriented toward palliative care after discussion with families. Twenty-nine of the treated patients with more than 12 months of follow-up were included in the follow-up analysis. Among them, 17 had 24 months of follow-up. The mean age at treatment was 7.5 (2.1–12.5) months. Twenty-two patients had two SMN2 copies, and seven had three copies. One infant died in the month following GT due to severe thrombotic microangiopathy, and another died due to respiratory distress. Among the 17 patients with 24 months of follow-up, 90% required spinal bracing (15/17), three patients required nocturnal noninvasive ventilation, and two needed gastrostomy. Concerning motor milestones at the 24-month follow-up, all patients held their head, 15/17 sat for 30 s unassisted, and 12/17 stood with aid. Motor scores (CHOPINTEND and HINE-2) and thoracic circumference significantly improved in all patients. Conclusions Our study shows favorable motor outcomes and preserved respiratory and feeding functions in treatment-naive SMA1 infants treated by GT as the first and only therapy before respiratory and bulbar dysfunctions occurred. Nevertheless, almost all patients developed spinal deformities.
oligonucleotides
2026-07-02 | A class of deep intronic IGHMBP2 variants activate a shared cryptic splice donor, enabling correction of select variants with a single antisense oligonucleotide.
Biallelic disease-causing variants in IGHMBP2 cause spinal muscular atrophy with respiratory distress type I (SMARD1) and Charcot-Marie-Tooth type 2S (CMT2S). We present 12 unrelated patients with clinically suspected IGHMBP2-related-disease, each carrying a variant deep in intron 8 of IGHMBP2 (c.1235+1076G>A (n=6), c.1235+450G>A (n=5), and c.1235+894C>A (n=1)), along with a known deleterious variant in trans. To assess aberrant pathogenic splicing induced by these deep intronic variants in a relevant model, patient-derived induced pluripotent stem cells were differentiated into motor neurons (iMNs). Long-read RNA sequencing revealed introduction of different pseudoexons by each variant: c.1235+450G>A (626bp), c.1235+1076G>A (112bp and 77bp) and c.1235+894C>A (182bp). Although each variant utilizes a unique splice acceptor site, they all activate the same cryptic donor site, enabling a therapeutic approach to redirect aberrant splicing for all the variants using a single shared antisense oligonucleotide (ASO). Treatment of iMNs with this single ASO restored full-length IGHMBP2 protein in c.1235+894G>A and c.1235+1076G>A by decreasing the use of the novel acceptor site. In contrast, ASO treatment did not correct the splicing in c.1235+450G>A, suggesting that additional splice correction will be needed for this specific variant. A CRISPR interference screen of IGHMBP2 loss-of-function in iMNs identified ribonucleoprotein complex biogenesis (RNP), and rRNA and tRNA processing as top pathways implicated in motor neuron vulnerability. Proteomics and transcriptomics analysis of successfully treated patient iMNs revealed correction of RNP biogenesis and rRNA processing defects. This study highlights the importance of characterizing deep intronic variants in disease-relevant cells to assist the diagnostic process and inform therapeutics development.
2025-08-14 | Neuroaxonal Degeneration as a Converging Mechanism in Motor Neuron Diseases (MNDs): Molecular Insights into RNA Dysregulation and Emerging Therapeutic Targets.
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.
2024-04-08 | The contribution and therapeutic implications of IGHMBP2 mutations on IGHMBP2 biochemical activity and ABT1 association.
Mutations within immunoglobulin mu DNA binding protein (IGHMBP2), an RNA-DNA helicase, result in SMA with respiratory distress type I (SMARD1) and Charcot Marie Tooth type 2S (CMT2S). The underlying biochemical mechanism of IGHMBP2 is unknown as well as the functional significance of IGHMBP2 mutations in disease severity. Here we report the biochemical mechanisms of IGHMBP2 disease-causing mutations D565N and H924Y, and their potential impact on therapeutic strategies. The IGHMBP2-D565N mutation has been identified in SMARD1 patients, while the IGHMBP2-H924Y mutation has been identified in CMT2S patients. For the first time, we demonstrate a correlation between the altered IGHMBP2 biochemical activity associated with the D565N and H924Y mutations and disease severity and pathology in patients and our Ighmbp2 mouse models. We show that IGHMBP2 mutations that alter the association with activator of basal transcription (ABT1) impact the ATPase and helicase activities of IGHMBP2 and the association with the 47S pre-rRNA 5' external transcribed spacer. We demonstrate that the D565N mutation impairs IGHMBP2 ATPase and helicase activities consistent with disease pathology. The H924Y mutation alters IGHMBP2 activity to a lesser extent while maintaining association with ABT1. In the context of the compound heterozygous patient, we demonstrate that the total biochemical activity associated with IGHMBP2-D565N and IGHMBP2-H924Y proteins is improved over IGHMBP2-D565N alone. Importantly, we demonstrate that the efficacy of therapeutic applications may vary based on the underlying IGHMBP2 mutations and the relative biochemical activity of the mutant IGHMBP2 protein.
2018-10-01 | SMA CLINICAL DATA, OUTCOME MEASURES AND REGISTRIES
This study explored the utility of ACTIVE scaled workspace volume scores to quantify meaningful change in individuals with spinal muscular atrophy (SMA) due to disease progression or treatment. ACTIVE, a 65-second custom designed video game, uses a skeletal tracking algorithm to quantify the volume of space (m3) the player can interact with while reaching in three dimensions to squish spiders or dig for jewels. Sixty-two individuals with SMA type 2 or 3 (age 10.5y +/-5y) and 362 age-matched controls (age 10.7y +/-3.5y) participated. Individuals seen in our clinic (n=37) also completed traditional assessments including the PROMIS self-report of upper extremity function, Hammersmith Functional Motor Scale Expanded (HFMSE), and revised upper limb module (RULM). The remainder were tested at a CureSMA meeting (ACTIVE only n=25). ACTIVE differentiated between patients with varying severity of SMA, as defined by their Brooke level, and from healthy controls (Jonckheere-Terpstra test for trend P<0.0001). ACTIVE significantly correlated with the HFMSE and the RULM (Rho=0.8-0.9, p<0.01). Relevance to patients and families was established by strong correlations to self and parent measures of upper extremity ability (Rho=0.6-0.7, p<0.01). Nine individuals (age 9.4y +/- 4.8y) in this cohort received Spinraza. Responsiveness to change was demonstrated by significant changes pre and post treatment (Median change = 28 pts, Wilcoxon signed rank test p=0.02). Two methods were used to calculate a minimal clinically important difference (MCID). Using the more conservative of the 2 estimates (14.5 pts), all but one Spinraza-treated patient exceeded the MCID, suggesting a robust change not due to random fluctuation. In contrast, no SMA patients in our natural history cohort improved greater than the MCID. Our results validate ACTIVE for use in an SMA cohort and suggest meaningful functional change post-treatment can be readily detected using ACTIVE in individuals with SMA types 2 and 3.
2018-10-01 | SMA CLINICAL DATA, OUTCOME MEASURES AND REGISTRIES
Spinal muscular atrophy (SMA) is a devastating neuromuscular disorder characterized by paralysis and muscle weakness and can affect both children and adults. The first FDA approved SMA therapeutic, Spinraza, improves SMA patients' symptoms and motor function. It is expected that increased lifespan will lead to a shift from the severe infantile SMA population to a milder SMA adult population. It is unknown whether such lifespan extension will reveal new, previously unknown defects that could arise with age, as mild mouse models of SMA are currently lacking. We generated a new mouse model, the Smn2B/-;SMN2+/- mice, which present with nearly normal lifespan and very subtle SMA features. We have characterized canonical features of SMA as well as examined non-neuronal organs over the course of an aging study (18 months). The Smn2B/-;SMN2+/- mice are mildly weaker on motor tests and start losing weight at around 12 months of age. Histologically, Smn2B/-;SMN2+/- mice displayed reduced muscle fiber size and increased central nucleation while motor neuron counts seemed spared. Muscle-nerve electrophysiological assessment of the soleus revealed a significant motor neuron/NMJ component as nerve stimulation lead to lower force production than direct muscle stimulation. Interestingly, female mice appear less affected. Many parameters of the twitch and tetanic force production were also altered. Ultrastructural analysis of the sciatic nerve is underway. Thus far, there is no significant impairment in the lymphoid organs, liver and heart, where defects were previously identified in more severe models. Altogether, this study will shed light on future potential obstacles we may face in our changing SMA population. Being proactive in understanding this aspect will ensure timely development of additional therapeutics and ensure sustained quality of life for SMA patients throughout their lifespan.
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Drug Discovery Landscape
1 orphan drug designation for Spinal muscular atrophy with respiratory distress type 1.
1 orphan drug designation for Spinal muscular atrophy with respiratory distress type 1.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Single-stranded, non-replicating recombinant adeno-associated viral vector serotype 9 containing the human immunoglobulin u-binding protein 2 cDNA | gene therapies | FDA | Abigail Wexner Research Institute, Nationwide Children’s Hospital |
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