Journal of Neuromuscular Diseases

In recent years, treatments have been approved for certain neuromuscular diseases. In some cases, early pre-symptomatic treatment is necessary for optimal response, and thus newborn screening is critical.

To review the current status of newborn screening programs for neuromuscular diseases and early diagnosis through genetic testing.

Following the PRISMA guidelines, a literature search was performed on PubMed for screening of neuromuscular diseases; the search was conducted on literature available as of 1 May 2024.

Included were 77 articles on newborn screening for seven diseases: spinal muscular atrophy (19 studies), Duchenne muscular dystrophy (15), Pompe disease (20), X-linked adrenoleukodystrophy (14), Krabbe disease (6), metachromatic leukodystrophy (2), and myotonic dystrophy 1 (1). Ten articles on rapid genomic diagnosis were identified.

Since 2021, newborn screening programs for neuromuscular diseases have been established, notably in X-linked adrenoleukodystrophy, spinal muscular atrophy, Pompe disease, and Duchenne Muscular Dystrophy. Even in diseases where treatment is currently not life-changing, such as Krabbe disease, new newborn screening programs continue to be implemented, especially in the USA. The use of genetic diagnostic tests does not yet appear to be widespread or at least not widely reported. As new treatments become available, genomic newborn screening programs will need to be rapidly and broadly implemented.

A viral vector recombinant gene transfer therapy (GTT) has recently been approved by the FDA for males of all ages with Duchenne Muscular Dystrophy (DMD) without limitations regarding preexisting cardiac impairment. Acute myocarditis is a potential life-threatening short-term complication that has been reported following GTT. This immune mediated response can range from troponin elevation to rapid cardiovascular compromise and death, particularly in those with abnormal cardiac status at baseline. Early detection of cardiac compromise is essential to optimize outcomes.

The primary objective of this consensus statement is to advocate for caution with DMD GTT patient selection and to initiate preemptive monitoring for those who may be at increased risk for cardiac adverse events. Secondary objective is to deepen our understanding of short and long-term impact of DMD gene therapies on the heart.

A national learning network of pediatric cardiologists with expertise in DMD developed recommendations for cardiac surveillance of DMD males receiving GTT based on available evidence and expert consensus opinion. A monitoring and treatment plan for standard and high cardiac risk patients was developed.

Partnership of cardiologists with GTT prescribers is essential to identify patient-specific considerations that might influence risk for adverse cardiac events and alter post infusion monitoring and management plans. Consistency in cardiac surveillance practices across centers will expedite our knowledge regarding potential short- and long-term cardiac effects of GTT for DMD.

Improvement and maintenance of bulbar function are important goals of disease-modifying treatments (DMTs) for spinal muscular atrophy (SMA), but standardized and validated measures for assessing bulbar function do not exist, nor does a widely accepted definition of bulbar function in SMA. As such, the impact of DMTs on bulbar function has not yet been comprehensively evaluated.

We conducted a systematic literature review (SLR) to identify evidence about the impact of DMTs for SMA on bulbar function.

We used the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines to conduct this review. Embase^® and MEDLINE^® databases were searched through August 10, 2023. Eligible studies included patients with SMA who were treated with any DMT and reported bulbar function outcomes. Non-English studies were excluded.

We identified 51 studies (across 83 publications) that evaluated SMA DMTs and bulbar function for more than 1600 patients. The ability to feed orally, the ability to tolerate liquids, and the need for nutrition support were commonly reported. Most infants treated with any DMT before SMA symptom onset preserved bulbar function. Infants, children, and adults treated after SMA symptom onset experienced variable results in terms of bulbar function outcomes.

The definition and assessment of bulbar function are not standardized. Therefore, the tools, scales, methods, and timing used for bulbar function assessments varied among studies. Larger prospective studies using standardized and age-based assessments with longer follow-up periods are needed to assess the clinical stability of bulbar function for patients with SMA who receive DMTs.

Myasthenia gravis (MG) is a chronic autoimmune disease causing fluctuating muscle weakness. The MycarinG study showed that rozanolixizumab, a neonatal Fc receptor inhibitor, provided clinically meaningful improvements in MG outcomes in patients with acetylcholine receptor (AChR) and muscle-specific tyrosine kinase (MuSK) autoantibody-positive generalized MG (gMG).

We assessed efficacy and safety of 6-week rozanolixizumab treatment cycles in patients with gMG.

Following MycarinG, eligible patients enrolled in the open-label extension Phase 3 studies MG0004 (NCT04124965) to receive up to 52 weekly rozanolixizumab infusions or MG0007 (NCT04650854) to receive cycles of 6 weekly rozanolixizumab infusions (initiated on symptom worsening at investigators’ discretion). To assess the effect of repeated cyclical treatment, data were pooled across MycarinG, MG0004 (first 6 weeks) and MG0007 (interim analysis). Efficacy endpoints included change from baseline in Myasthenia Gravis Activities of Daily Living (MG-ADL), Myasthenia Gravis Composite (MGC) and Quantitative Myasthenia Gravis (QMG) assessed in patients who received ≥2 symptom-driven treatment cycles. Treatment-emergent adverse events (TEAEs) were assessed in patients who received ≥1 cycle and had an (up to) 8-week follow-up period.

At data cut-off (July 8, 2022), 188/196 (95.9%) patients received ≥1 treatment cycle with a follow-up period (primary safety pool; MycarinG/MG0007) and 127 (64.8%) received ≥2 symptom-driven cycles (primary efficacy pool; MycarinG/MG0004 [first 6 weeks]/MG0007). Consistent and clinically meaningful improvements in MG-ADL, MGC and QMG scores, and high MG-ADL, MGC and QMG response rates, were observed at the end of the first symptom-driven cycle and subsequent cycles. TEAEs were experienced by 169/188 (89.9%) patients and were mostly mild to moderate. TEAEs did not increase with repeated cycles.

Repeated cycles of rozanolixizumab resulted in consistent, clinically meaningful improvements across cycles in MG-specific outcomes with an acceptable safety profile, supporting rozanolixizumab as a treatment option for adults with AChR and MuSK autoantibody-positive gMG.

Generalized myasthenia gravis (gMG) is a rare, chronic, fluctuating and heterogeneous autoimmune disease requiring lifelong treatment. The Phase 3 MycarinG study demonstrated the efficacy and safety of one 6-week cycle of weekly rozanolixizumab in adult patients with gMG. Open-label extension studies demonstrated consistent symptom improvement over additional treatment cycles.

To present findings from pooled analyses on the long-term safety of repeated cycles of rozanolixizumab.

Data from the Phase 3 randomized MycarinG study (NCT03971422) and the ongoing open-label extension study MG0007 (NCT04650854) were pooled to assess safety outcomes during cyclical treatment, including incidence of any treatment-emergent adverse events (TEAEs), severe TEAEs, serious TEAEs and TEAEs leading to discontinuations. Additional analyses were performed for TEAEs, including headache, infections, and hypersensitivity reactions.

At data cutoff (July 8, 2022), a total of 188 patients in MycarinG and MG0007 had received ≥1 treatment cycle with rozanolixizumab; total time in studies was 174.71 patient-years. Overall, 169/188 (89.9%) patients experienced any TEAE: 89/188 (47.3%) experienced any headache (including migraine, migraine with aura); 85/188 (45.2%) experienced an infection; 25/188 (13.3%) experienced a hypersensitivity reaction. One patient experienced an event of aseptic meningitis. The majority of AEs were mild-to-moderate in intensity, and incidence did not increase with repeated cyclic treatment. A total of 50/188 (26.6%) patients experienced severe TEAEs, the most common of which were MG worsening in 4/133 (3.0%) and 7/131 (5.3%) patients in the rozanolixizumab 7 mg/kg and rozanolixizumab 10 mg/kg groups, respectively, MG crisis in 0 and 4/131 (3.1%) patients, and headache in 1/133 (0.8%) and 7/131 (5.3%) patients.

These pooled results, representing 174.71 patient-years in the studies, demonstrate that treatment with rozanolixizumab in patients with gMG was well tolerated, and TEAEs were consistent and did not increase in incidence over repeated cycles in this patient population.

Oculopharyngeal muscular dystrophy (OPMD) is a rare, late-onset, slowly progressive neuromuscular disorder characterized by ptosis, dysphagia, and proximal limb weakness. Emerging clinical trials require rapidly accessible and sensitive biomarkers to evaluate OPMD disease progression and potential response to future treatments.

This cross-sectional study was designed to identify candidate circulating protein and imaging biomarkers of OPMD severity for future use in clinical trials.

Twenty-five individuals with OPMD (age 63.3 ± 10.5 years; GCN copy number of 13 in PABPN1) were assessed using the 7k SOMAScan assay to profile the plasma proteome, and MRI to quantify replacement of muscle by fat. OPMD severity was first categorized using the clinical presence/absence of limb weakness, and protein signals were considered distinguishing if they differed by more than 30% between subgroups and had statistically significant P-values after correcting for multiple comparisons. Distinguishing proteins were contrasted with age-matched controls (n = 10). OPMD severity was also treated as a continuous variable using fat fraction of the soleus muscle, and proteins were considered distinguishing if the slope of relationship between protein signal and soleus fat fraction differed significantly from zero after correcting for multiple comparisons. Pathway analyses were conducted using Metascape and the Database for Annotation, Visualization, and Integrated Discovery webtools.

Eighteen plasma proteins distinguished OPMD on both indicators of severity. Pathway analyses identified skeletal muscle tissue, phagocytosis/engulfment, and extracellular matrix organization as enriched ontology clusters in OPMD with limb weakness. The most distinguishing plasma protein signals (ACTN2, MYOM2, CA3, APOBEC2, MYL3, and PDLIM3) were over 200% higher in OPMD with limb weakness than OPMD without limb weakness as well as controls, and correlated strongly with percent of fatty replacement of soleus (r = 0.89 ± 0.04).

The candidate biomarkers identified contribute to the ongoing search for sensitive and accessible biomarkers of OPMD progression, prognosis, and monitoring.

Spinal Muscular Atrophy (SMA) leads to motor neuron loss, with progressive muscle weakness and wasting. Nationwide registries for neuromuscular diseases are pivotal for assessing epidemiology, preparing for clinical trials, and for adopting standardized management guidelines.

This paper aims to present data gathered during the establishment of Pakistan's inaugural registry for genetically confirmed SMA cases.

In this retrospective study, 215 participants with genetically confirmed SMA were recruited. Telephonic interviews were conducted to collect data for the Muscular Disease Registry of Pakistan that was analyzed using STATA version 17.0.

SMA type 1 was the most common type (71.2%, n = 153). Amongst patients who were tested for survival motor neuron (SMN2) copies, the majority (84.4%, n = 168) had two SMN2 copies. SMA types were significantly associated with the ability to sit (p < 0.001) and walk (p < 0.001), and usage of a wheelchair (p = 0.0054). SMN2 copy numbers were significantly associated with the ability to sit (p = 0.020) and walk (p = 0.031).

This study highlights the high prevalence of SMA genotypes and phenotypes associated with severe disease in our population. Our findings reiterate the challenging prognosis for Pakistani children with SMA and underscore the necessity of the development of nationwide newborn screening programs and making treatments available.

Glycogenosis type 11 or deficiency in lactate dehydrogenase A (LDHA) (OMIM: 612933) is an ultra-rare condition of perturbed glycogen metabolism, first described in 1980 in a Japanese patient, and quite rare outside Japan. There are very few cases described in the literature and there is limited awareness of this condition that can easily be misdiagnosed or remain undiagnosed.

To report on an ultra-rare form of glycogenosis stressing the association with cutaneous features and raise awareness for this rare condition. We report a novel pathogenic variant and aim to contribute to the understanding of the myopathophysiological mechanisms of disease by proteomics.

We report the clinical, histopathological, magnetic resonance, genetic and proteomic features of a 19-year-old male of North African background that presented from infancy episodes of muscle pain, contractures and high CK levels immediately after moderate to high-intensity exercise. The patient was followed for several years prior to our observation due to severe acne that involved mostly the back and was resistant to treatment.

The phenotype of this patient is similar to the ones previously described with muscle and skin involvement. The MRI functional studies, interrupted at 2’30’’ due to muscle pain, allowed us to confirm the presence of a metabolic disturbance of the muscles. The histological features of the muscle were quite subtle consisting mainly in rare subsarcolemmal vacuoles also identified at ultra-structural level. Immunostaining with the antibody targeting LDHA showed intracytoplasmic aggregates of the protein unlike the normal control that presented a diffuse staining. Exome analysis revealed a novel bi-allelic frameshifting deletion in exon 7 of the LDHA gene; c.766_767delGT. Proteomic findings accord with loss of functional LDHA and provide significant insights into the pathobiochemistry of the disease.

Our combined data expand the current genetic landscape of LDHA-related disease, confirms the concept of a metabolic-driven vacuolar myopathy and provides insights into the biochemical nature of myopathology.

Congenital myopathies are a group of heterogenous inherited muscle diseases. With advances in genetics, newer genes with novel features are being described. Pyridine nucleotide-disulfide oxidoreductase domain 1 (PYROXD1) related myopathy is an ultrarare congenital myopathy. Only few cases have been reported worldwide till now. We report the first interesting case of PYROXD1 related myopathy from India.

This is a retrospective study done from a quaternary neurology referral centre from southern India. All clinical, laboratory and electrophysiological data were collected from the medical records. Institutional ethics approval and informed consent from patient were obtained.

A 9 year-old-boy of non-consanguineous parentage presented with progressive fatigable proximo-distal weakness of upper and lower limbs with facial weakness from the age of 4 years. This was followed by chewing and swallowing difficulty. However speech was normal. There was profound proximal and distal joint hyperextensibility along with hip and ankle contractures. There was facial dysmorphism with high arched palate and retrognathism. Investigations showed normal serum creatine kinase levels. Nerve conduction studies showed axonal sensorimotor neuropathy. There was significant decremental response in tibialis anterior. Muscle biopsy showed both myopathic and neurogenic changes with novel findings of mitochondrial aggregates in subsarcolemmal and perinuclear regions. Next generation sequencing revealed a missense variant NM_024854.5:c.394C > T (NP_079130.2:p.Arg132Cys) of uncertain significance in exon 4 of PYROXD1 gene.

This is the first report of PYROXD1 related myopathy from India. There were novel features of muscle fatigability, contractures, novel muscle biopsy features and a variant of uncertain significance expanding the phenotypic and genotypic spectrum of this rare myopathy.