BACKGROUND: Rare disorders comprise of ~ 7500 different conditions affecting multiple systems. Diagnosis of rare diseases is complex due to dearth of specialized medical professionals, testing labs and limited therapeutic options. There is scarcity of data on the prevalence of rare diseases in different populations. India being home to a large population comprising of 4600 population groups, of which several thousand are endogamous, is likely to have a high burden of rare diseases. The present study provides a retrospective overview of a cohort of patients with rare genetic diseases identified at a tertiary genetic test centre in India.
RESULTS: Overall, 3294 patients with 305 rare diseases were identified in the present study cohort. These were categorized into 14 disease groups based on the major organ/ organ system affected. Highest number of rare diseases (D = 149/305, 48.9%) were identified in the neuromuscular and neurodevelopmental (NMND) group followed by inborn errors of metabolism (IEM) (D = 47/305; 15.4%). Majority patients in the present cohort (N = 1992, 61%) were diagnosed under IEM group, of which Gaucher disease constituted maximum cases (N = 224, 11.2%). Under the NMND group, Duchenne muscular dystrophy (N = 291/885, 32.9%), trinucleotide repeat expansion disorders (N = 242/885; 27.3%) and spinal muscular atrophy (N = 141/885, 15.9%) were the most common. Majority cases of β-thalassemia (N = 120/149, 80.5%) and cystic fibrosis (N = 74/75, 98.7%) under the haematological and pulmonary groups were observed, respectively. Founder variants were identified for Tay-Sachs disease and mucopolysaccharidosis IVA diseases. Recurrent variants for Gaucher disease (GBA:c.1448T > C), β-thalassemia (HBB:c.92.+5G > C), non-syndromic hearing loss (GJB2:c.71G > A), albinism (TYR:c.832 C > T), congenital adrenal hyperplasia (CYP21A2:c.29-13 C > G) and progressive pseudo rheumatoid dysplasia (CCN6:c.298T > A) were observed in the present study.
CONCLUSIONS: The present retrospective study of rare disease patients diagnosed at a tertiary genetic test centre provides first insight into the distribution of rare genetic diseases across the country. This information will likely aid in drafting future health policies, including newborn screening programs, development of target specific panel for affordable diagnosis of rare diseases and eventually build a platform for devising novel treatment strategies for rare diseases.

Dyspnea, the subjective sensation of breathlessness, is a distressing and potentially traumatic symptom. Dyspnea associated with mechanical ventilation may contribute to intensive care unit (ICU) associated post-traumatic stress disorder and impaired quality of life. Dyspnea is both difficult to alleviate and a cause of significant distress to patients, their loved ones, and care providers People living with neuromuscular disease, such as amyotrophic lateral sclerosis (ALS) or myasthenia gravis (MG), often rely on a ventilator at late stages of illness due to complications of progressive respiratory muscle weakness and paralysis. When unable to wean from the ventilator, conversations turn towards goals of care and release from the ventilator for comfort and end of life (EOL). Patients with and without neuromuscular disease have high risk for dyspnea at EOL upon ventilator liberation. Although limited recommendations have been published specific to patients with ALS, no guidelines currently exist for the terminal liberation from mechanical ventilation in patients experiencing respiratory muscle insufficiency from a neuromuscular disease. Further research on this topic is needed, including creation of a protocol for ventilator release in patients with neuromuscular disease. The following case reports detail the dissimilar EOL experiences of two patients with different forms of neuromuscular disease.

In order to understand abnormal gait, this article will first review normal gait, discuss how neuromuscular diseases disturb gait patterns and review orthotic interventions. In normal gait, concentric contractions accelerate and eccentric contractions decelerate the limb. Neuromuscular gait disorders can be grouped into (1) proximal weakness, (2) distal weakness, (3) nonlength-dependent or generalized weakness, (4) asymmetric weakness, and (5) sensory disorders. Identification of gait disturbance type in neuromuscular diseases leads to the appropriate orthotic prescription since orthotic strategies are grouped into (1) proximal weakness, (2) distal weakness, and (3) sensory disturbances. Orthotics is not indicated in all types of gait disturbance. Weakness in proximal hip musculature can be managed with gait aids such as walkers. In contrast, distal muscle weakness can be managed with orthotics. Preservation of gait assists in maintenance of daily function and integration in society.

Respiratory sequelae are a frequent cause of morbidity and mortality in children with NMD. Impaired cough strength and resulting airway clearance as well as sleep disordered breathing are the two main categories of respiratory sequelae. Routine clinical evaluation and diagnostic testing by pulmonologists is an important pillar of the multidisciplinary care required for children with NMD. Regular surveillance for respiratory disease and timely implementation of treatment including pulmonary clearance techniques as well as ventilation can prevent respiratory related morbidity including hospital admissions and improve survival. Additionally, novel disease modifying therapies for some NMDs are now available which has significantly improved the clinical trajectories of patients resulting in a paradigm shift in clinical care. Pulmonologists are \'learning\' the new natural history for these diseases and adjusting clinical management accordingly.

Using virtual reality (VR) for Muscular Dystrophy (MD) rehabilitation promises to be a novel therapeutic approach, potentially enhancing motor learning, functional outcomes, and overall quality of life. This systematic review primarily aimed to provide a comprehensive summary of the current understanding regarding the application of VR in supporting MD rehabilitation. A systematic search was performed in PubMed, Scopus, Cochrane Library, and Web of Science to identify relevant articles. The inclusion criteria encompassed studies involving individuals diagnosed with MD who underwent VR interventions, with a primary focus on assessing functional improvement. Methodological quality of the studies was assessed by using the Physiotherapy Evidence Database (PEDro) scale. Seven studies, involving 440 individuals with Duchenne Muscular Dystrophy (DMD), were included in the review. Among these studies, six primarily explored the motor learning potential of VR, while one study investigated the impact of VR training on functional abilities. In conclusion, the qualitative synthesis supports VR-based interventions\' potential positive effects on motor learning, performance improvement, and functional outcomes in individuals with DMD. However, current usage mainly focuses on assessing the potential mechanisms\' benefits, suggesting the importance of expanding clinical adoption to harness their therapeutic potential for MD patients.

Anterior cruciate ligament (ACL) injury, particularly in increasingly young and active adolescents, continues to pose a clinical challenge with re-injury rates reported as high as 30%. Evidence also suggests that current standard-of-care ACL reconstruction (ACLR) does not mitigate post-traumatic osteoarthritis (PTOA) risk. Bridge- enhanced ACL restoration (BEAR) is a recently developed and tested ACL surgery that promotes primary healing of the native ACL with excellent early results. BEAR has shown to reduce signs of early PTOA compared to ACLR in an animal model. Here, we describe a theoretical framework related to re-innervation that can clarify why the outcomes of ACLR and BEAR surgeries differ. We also discuss how ongoing and new challenges in determining return-to-sport readiness following the competing surgeries may differ, and how emerging imaging tools and measures of neuromuscular function may aid in clinical decision-making to decrease the likelihood of re-injury and PTOA risk.

Cerebral palsy (CP) is the most common childhood-onset disability. The evolution of gait according to severity is well known amongst children and thought to peak between 8 and 12 years of age among those walking without assistive devices. However, among adults, clinical experience as well as scientific studies report, through clinical assessments, questionnaires and interviews, increasing walking difficulties leading to an increased dependency of assistive devices in everyday ambulation. For many individuals with CP, this change will occur around 30-40 years, with the risk of losing mobility increasing with age. This narrative review aims to first provide objective evidence of motor function and gait decline in adults with CP when ageing, and then to offer mechanistic hypotheses to explain those alterations. Many studies have compared individuals with CP to the typically developing population, yet the evolution with ageing has largely been understudied. Comorbid diagnoses comprise one of the potential determinants of motor function and gait decline with ageing in people with CP, with the first manifestations happening at an early age and worsening with ageing. Similarly, ageing appears to cause alterations to the neuromuscular and cardiovascular systems at an earlier age than their typically developing (TD) peers. Future studies should, however, try to better understand how the physiological particularities of CP change with ageing that could pave the way for better strategies for maintaining function and quality of life in people with CP.

BACKGROUND: Neuromuscular blockade (NMB) agents are a critical component of balanced anesthesia. NMB reversal methods can include spontaneous reversal, sugammadex, or neostigmine and the choice of reversal strategy can depend on various factors. Unanticipated changes to clinical practice emerged due to the COVID-19 pandemic, and a better understanding of how NMB reversal trends were affected by the pandemic may help provide insight into how providers view the tradeoffs in the choice of NMB reversal agents.
OBJECTIVE: We aim to analyze NMB reversal agent use patterns for US adult inpatient surgeries before and after the COVID-19 outbreak to determine whether pandemic-related practice changes affected use trends.
METHODS: A retrospective longitudinal analysis of a large all-payer national electronic US health care database (PINC AI Healthcare Database) was conducted to identify the use patterns of NMB reversal during early, middle, and late COVID-19 (EC, MC, and LC, respectively) time periods. Factors associated with NMB reversal choices in inpatient surgeries were assessed before and after the COVID-19 pandemic reached the United States. Multivariate logistic regression assessed the impact of the pandemic on NMB reversal, accounting for patient, clinical, procedural, and site characteristics. A counterfactual framework was used to understand if patient characteristics affected how COVID-19-era patients would have been treated before the pandemic.
RESULTS: More than 3.2 million inpatients experiencing over 3.6 million surgical procedures across 931 sites that met all inclusion criteria were identified between March 1, 2017, and December 31, 2021. NMB reversal trends showed a steady increase in reversal with sugammadex over time, with the trend from January 2018 onwards being linear with time (R2>0.99). Multivariate analysis showed that the post-COVID-19 time periods had a small but statistically significant effect on the trend, as measured by the interaction terms of the COVID-19 time periods and the time trend in NMB reversal. A slight increase in the likelihood of sugammadex reversal was observed during EC relative to the pre-COVID-19 trend (odds ratio [OR] 1.008, 95% CI 1.003-1.014; P=.003), followed by negation of that increase during MC (OR 0.992, 95% CI 0.987-0.997; P<.001), and no significant interaction identified during LC (OR 1.001, 95% CI 0.996-1.005; P=.81). Conversely, active reversal (using either sugammadex or neostigmine) did not show a significant association relative to spontaneous reversal, or a change in trend, during EC or MC (P>.05), though a slight decrease in the active reversal trend was observed during LC (OR 0.987, 95% CI 0.983-0.992; P<.001).
CONCLUSIONS: We observed a steady increase in NMB active reversal overall, and specifically with sugammadex compared to neostigmine, during periods before and after the COVID-19 outbreak. Small, transitory alterations in the NMB reversal trends were observed during the height of the COVID-19 pandemic, though these alterations were independent of the underlying NMB reversal time trends.

Neuromuscular fatigue induces superior migration of the humeral head in individuals with subacromial pain. This has been attributed to weakness of rotator cuff muscles and overactive deltoid muscles. Investigation of common inputs to motoneuron pools of the rotator cuff and deltoid muscles offers valuable insight into the underlying mechanisms of neuromuscular control deficits associated with subacromial pain. This study aims to investigate intermuscular coherence across the rotator cuff and deltoid muscles during a sustained submaximal isometric fatiguing contraction in individuals with and without subacromial pain. Twenty symptomatic and 18 asymptomatic young adults participated in this study. Surface EMG was recorded from the middle deltoid (MD) and infraspinatus (IS). Intramuscular EMG was recorded with fine-wire electrodes in the supraspinatus (SS). Participants performed an isometric fatiguing contraction of 30° scaption at 25% MVC until endurance limit. Pooled coherence of muscle pairs (SS-IS, SS-MD, IS-MD) in the 2-5 Hz (delta), 5-15 Hz (alpha) and 15-35 Hz (beta) frequency bands during the initial and final 30s of the fatigue task were compared. SS-IS and SS-MD delta-band coherence increased with fatigue in the asymptomatic group, but not the symptomatic group. In the alpha and beta bands, SS-IS and SS-MD coherence increased with fatigue in both groups. IS-MD beta-band coherence was greater in the symptomatic than the asymptomatic group. Individuals with subacromial pain failed to increase common drive across rotator cuff and deltoid muscles and have altered control strategies during neuromuscular fatigue. This may contribute to glenohumeral joint instability and subacromial pain experienced by these individuals.

BACKGROUND: The causative genes for over 60% of inherited peripheral neuropathy (IPN) remain unidentified. This study endeavours to enhance the genetic diagnostic rate in IPN cases by conducting screenings focused on non-coding repeat expansions.
METHODS: We gathered data from 2424 unrelated Japanese patients diagnosed with IPN, among whom 1555 cases with unidentified genetic causes, as determined through comprehensive prescreening analyses, were selected for the study. Screening for CGG non-coding repeat expansions in LRP12, GIPC1 and RILPL1 genes was conducted using PCR and long-read sequencing technologies.
RESULTS: We identified CGG repeat expansions in LRP12 from 44 cases, establishing it as the fourth most common aetiology in Japanese IPN. Most cases (29/37) exhibited distal limb weakness, without ptosis, ophthalmoplegia, facial muscle weakness or bulbar palsy. Neurogenic changes were frequently observed in both needle electromyography (97%) and skeletal muscle tissue (100%). In nerve conduction studies, 28 cases primarily showed impairment in motor nerves without concurrent involvement of sensory nerves, consistent with the phenotype of hereditary motor neuropathy. In seven cases, both motor and sensory nerves were affected, resembling the Charcot-Marie-Tooth (CMT) phenotype. Importantly, the mean CGG repeat number detected in the present patients was significantly shorter than that of patients with LRP12-oculopharyngodistal myopathy (p<0.0001). Additionally, GIPC1 and RILPL1 repeat expansions were absent in our IPN cases.
CONCLUSIONS: We initially elucidate LRP12 repeat expansions as a prevalent cause of CMT, highlighting the necessity for an adapted screening strategy in clinical practice, particularly when addressing patients with IPN.