Loss Of Ambulation Research Articles

Delivery challenges for CRISPR-Cas9 genome editing for Duchenne muscular dystrophy.

Duchene muscular dystrophy (DMD) is an X-linked neuromuscular disorder that affects about one in every 5000 live male births. DMD is caused by mutations in the gene that codes for dystrophin, which is required for muscle membrane stabilization. The loss of functional dystrophin causes muscle degradation that leads to weakness, loss of ambulation, cardiac and respiratory complications, and eventually, premature death. Therapies to treat DMD have advanced in the past decade, with treatments in clinical trials and four exon-skipping drugs receiving conditional Food and Drug Administration approval. However, to date, no treatment has provided long-term correction. Gene editing has emerged as a promising approach to treating DMD. There is a wide range of tools, including meganucleases, zinc finger nucleases, transcription activator-like effector nucleases, and, most notably, RNA-guided enzymes from the bacterial adaptive immune system clustered regularly interspaced short palindromic repeats (CRISPR). Although challenges in using CRISPR for gene therapy in humans still abound, including safety and efficiency of delivery, the future for CRISPR gene editing for DMD is promising. This review will summarize the progress in CRISPR gene editing for DMD including key summaries of current approaches, delivery methodologies, and the challenges that gene editing still faces as well as prospective solutions.

Characterization of spastic paraplegia in a family with a novel PSEN1 mutation.

Spastic paraparesis has been described to occur in 13.7% of PSEN1 mutations and can be the presenting feature in 7.5%. In this paper, we describe a family with a particularly young onset of spastic paraparesis due to a novel mutation in PSEN1 (F388S). Three affected brothers underwent comprehensive imaging protocols, two underwent ophthalmological evaluations and one underwent neuropathological examination after his death at age 29. Age of onset was consistently at age 23 with spastic paraparesis, dysarthria and bradyphrenia. Pseudobulbar affect followed with progressive gait problems leading to loss of ambulation in the late 20s. Cerebrospinal fluid levels of amyloid-β, tau and phosphorylated tau and florbetaben PET were consistent with Alzheimer's disease. Flortaucipir PET showed an uptake pattern atypical for Alzheimer's disease, with disproportionate signal in posterior brain areas. Diffusion tensor imaging showed decreased mean diffusivity in widespread areas of white matter but particularly in areas underlying the peri-Rolandic cortex and in the corticospinal tracts. These changes were more severe than those found in carriers of another PSEN1 mutation, which can cause spastic paraparesis at a later age (A431E), which were in turn more severe than among persons carrying autosomal dominant Alzheimer's disease mutations not causing spastic paraparesis. Neuropathological examination confirmed the presence of cotton wool plaques previously described in association with spastic parapresis and pallor and microgliosis in the corticospinal tract with severe amyloid-β pathology in motor cortex but without unequivocal disproportionate neuronal loss or tau pathology. In vitro modelling of the effects of the mutation demonstrated increased production of longer length amyloid-β peptides relative to shorter that predicted the young age of onset. In this paper, we provide imaging and neuropathological characterization of an extreme form of spastic paraparesis occurring in association with autosomal dominant Alzheimer's disease, demonstrating robust diffusion and pathological abnormalities in white matter. That the amyloid-β profiles produced predicted the young age of onset suggests an amyloid-driven aetiology though the link between this and the white matter pathology remains undefined.

Disease progression modeling of the North Star Ambulatory Assessment for Duchenne Muscular Dystrophy.

Duchenne muscular dystrophy (DMD) is a rare genetic disorder caused by decreased or absent dystrophin gene leading to progressive muscle degeneration and weakness in young boys. Disease progression models for the North Star Ambulatory Assessment (NSAA), a functional measurement widely used to assess outcomes in clinical trials, were developed using a longitudinal population modeling approach. The relationship between NSAA total score over time, loss of ambulation, and potential covariates that may influence disease progression were evaluated. Data included individual participant observations from an internal placebo-controlled phase II clinical trial and from the external natural history database for male patients with DMD obtained through the Cooperative International Neuromuscular Research Group (CINRG). A modified indirect response model for NSAA joined to a loss of ambulation (LOA) time-to-event model described the data well. Age was used as the independent variable because ambulatory function is known to vary with age. The NSAA and LOA models were linked using the dissipation rate constant parameter from the NSAA model by including the parameter as a covariate on the hazard equation for LOA. No covariates were identified. The model was then used as a simulation tool to explore various clinical trial design scenarios. This model contributes to the quantitative understanding of disease progression in DMD and may guide model-informed drug development decisions for ongoing and future DMD clinical trials.

High-Speed T2 -Corrected Multiecho Magnetic Resonance Spectroscopy for Quantitatively Detecting Skeletal Muscle Fatty Infiltration and Predicting the Loss of Ambulation in Patients With Duchenne Muscular Dystrophy.

High-speed T2 -corrected multiecho MRS (HISTO-MRS) is emerging as a quantitative modality for detecting muscle fat infiltration (MFF). However, the predictive value of HISTO-MRS for the loss of ambulation (LoA) in Duchenne muscular dystrophy (DMD) is unknown. To determine the feasibility of HISTO-MRS for assessing MFF in DMD and further identify the predictive value of HISTO-MRS for the LoA. Prospective. A total of 134 DMD boys (9.20 ± 2.43 years old) and 21 healthy boys (9.25 ± 2.10 years old). A 3 T, fast spin echo T1 -weighted imaging (T1 WI), two-point-Dixon gradient echo sequence (2-pt-Dixon) and HISTO-MRS. Subjective T1 WI fat grades by three radiologists, ROI analysis for MFF on 2pt-Dixon (Dixon MFF) and MFF on HISTO-MRS (HISTO MFF) by two radiologists. Clinical motor function: North Star Ambulatory Assessment, 10-m run/walk time, Gowers maneuver, and time to four-stairs climb and descend. Spearman rank correlation was used to assess the relation of fat filtration assessments and motor ability. Bland-Altman plots was performed to determine the agreement of HISTO MFF and Dixon MFF. Receiver operating characteristic (ROC) curves were analyzed to determine the discriminating ability of above MRI modalities for ambulatory and nonambulatory DMD. Logistic regression was used to identify the predictor of LoA. Variables with P < 0.05 in univariate logistic regression analysis were entered into the multivariate logistic regression model. HISTO MFF was significantly correlated with Dixon MFF. Bland-Altman plots show good agreement of HISTO MFF and Dixon MFF. ROC curves indicated that HISTO MFF show similar discrimination of LoA for DMD with Dixon MFF but better value than T1WI fat grades. Logistic regression showed that HISTO MFF was an independent predictor for LoA. HISTO-MRS is a potential quantitative method for assessing fat infiltration and shows predictive value for LoA in DMD patients. Stage 5.

An Overview of the Therapeutic Strategies for the Treatment of Spinal Muscular Atrophy.

Spinal muscular atrophy (SMA) is a recessive, neurodegenerative disorder. It is one of the most common genetic causes of infant mortality and is characterized by muscle weakness, loss of ambulation, and respiratory failure. SMA is primarily caused by a homozygous deletion or mutation of the survival motor neuron 1 (SMN1) gene. Humans possess a second, nearly identical copy of SMN, known as the SMN2 gene. Although the disease severity correlates inversely with the number of SMN2 copies present, it can never completely compensate for the loss of SMN1 in patients with SMA; SMN2 expresses only a fraction of the functional SMN transcript. The SMN protein is ubiquitous in human cells and plays several roles, ranging from assembling the spliceosome machinery to autophagy, RNA metabolism, signal transduction, cellular homeostasis, DNA repair, and recombination. Although the underlying mechanism remains unclear, anterior horn cells of the spinal cord gray matter are highly vulnerable to decreased SMN protein levels. To harness SMN2's ability to provide SMN function, two treatment strategies have been approved by the Food and Drug Administration (FDA), including an antisense oligonucleotide, nusinersen (Spinraza), and a small molecule, risdiplam (Evrysdi). Onasemnogene abeparvovec (Zolgensma) is an FDA-approved adeno-associated virus 9-mediated gene replacement therapy that creates a copy of the human SMN1 gene. In this review, we summarize the SMA etiology and FDA-approved therapies, and discuss the development of SMA therapeutic strategies and the challenges we faced.

A Scoping Review of the Recent Clinical Practice Regarding the Evaluation of Bone Mineral Density in Children and Adolescents with Neuromuscular Diseases

Introduction: Neuromuscular Diseases (NMD) are associated with decreased bone strength due to altered muscle-bone interaction. However, the evaluation of bone quality remains a certain challenge in these patients. The purpose of this scoping review is to investigate the recent literature regarding the assessment of Bone Mineral Density (BMD) in this population. Methods: An electronic search of the PubMed and Scopus database was performed considering studies published in the English literature after 2007 that evaluated BMD in pediatric and adolescent patients with NMD. We excluded studies that evaluated patients > 20 years, studies not involving humans, and studies investigating bone mineral density in various pediatric conditions, but without specific data on NMD. Results: Overall, 19 studies were included that evaluated BMD in 1983 patients with NMD. Duchenne Muscular Dystrophy was the most widely studied disease (n = 11 studies). Dual energy X-ray absorptiometry (DEXA) was the most common diagnostic modality for BMD evaluation, while the most frequent site for BMD measurement was the lumbar spine (89.4%, n = 17 studies), followed by total body BMD (68.4%, n = 13 studies). Low BMD in children with NMD was demonstrated in all studies, especially after loss of ambulation. Moreover, a positive correlation between lower BMD and older age was shown. Conclusions: BMD evaluation in NMD remains a clinical challenge, as indicated by the high heterogeneity regarding the optimal site and technique for the evaluation of bone quality in these patients. Although DXA is currently the diagnostic modality of choice, a consensus regarding the optimal site for BMD measurement, and the adjustment method for its obtained measurements for parameters such as age and height is needed.

Abstract 152: Relationship Between Gait Function And Damage To Descending Motor Pathways After Stroke

Introduction: Descending motor pathways, namely the corticospinal (CST) and corticoreticular tracts (CRT), are important for normal gait function and have been implicated in gait recovery after stroke. However, the relationship of structural injury to these tracts and gait function in the acute and chronic stage post-stroke remains unclear. Methods: Gait velocity was recorded the first week (acute) after stroke (n=127) and one year later (n= 50). CST and CRT injury were measured using weighted lesion load (wLL). The impact of CST and CRT injury on ambulation status (non-ambulatory vs. ambulatory) and gait velocity was assessed with multivariate logistic and linear regression models, respectively, acutely and chronically, controlling for wLL and lesion size. Results: Greater CRT injury resulted in a higher odds of ambulation loss acutely post-stroke (odds ratio [95% CI, p value]: CRT wLL, 1.06 [1.02-1.12, 0.007]; CST wLL 0.97 [0.95-0.99, 0.04]; lesion volume 1.00 [0.99-1.00, 0.96]). Conversely, greater CST injury had higher odds of ambulation loss at one-year (CST wLL, 1.09 [1.01-1.21, 0.04]; CRT wLL, 0.98 [0.84-1.13, 0.75]; lesion volume, 1.00 [0.99-1.00, 0.81]). For walkers (N=51 [acute] and 46 [chronic]), gait velocity was not significantly associated with CRT nor CST wLL at either time. Multicollinearity results denoted lesion measures provided independent information (maximum variance inflation factors 3.4 (acute), 4.2 (one-year)). Conclusion: Results suggest CRT injury is the dominant correlate of ambulation loss acutely, with CST the dominant correlate of persistent loss after one-year. Gait velocity is not well explained by damage to either tract. The results imply that the CRT may be the primary cortical projection for normal (pre-stroke) gait. Yet, the nervous system has sufficient redundancy to compensate for unilateral CRT injury, while CST injury may have a more enduring negative impact on gait function.

A novel homozygous SLC39A14 variant in an infant with hypermanganesemia and a review of the literature.

Manganese (Mn) is an essential trace metal necessary for good health; however, excessive amounts in the body are neurotoxic. To date, three genes (SLC30A10, SLC39A8, and SLC39A14) have been discovered to cause inborn errors in Mn metabolism in humans. As very rare diseases, the clinical features require further clarification. A male Chinese patient who mainly presented with hypermanganesemia and progressive parkinsonism-dystonia was recruited for this study. We collected and analyzed clinical information, performed whole-exome sequencing (WES), and reviewed the relevant literature. The motor-developmental milestones of the patient were delayed at the age of 4 months, followed by rapidly progressive dystonia. The patient displayed elevated Mn concentrations in blood and urine, and brain magnetic resonance imaging (MRI) showed symmetrical hyperintensity on T1-weighted images and hypointensity on T2-weighted images in multiple regions. A novel homozygous variant of the SLC39A14 gene (c.1058T > G, p.L353R) was identified. The patient was treated with disodium calcium edetate chelation (Na2CaEDTA). Three months later, mild improvement in clinical manifestation, blood Mn levels, and brain MRI was observed. To date, 15 patients from 10 families have been reported with homozygous mutations of SLC39A14, with a mean age of onset of 14.9 months. The common initial symptom is motor regression or developmental milestone delay, with a disease course for nearly all patients involving development of progressive generalized dystonia and loss of ambulation before treatment. Additionally, hypermanganesemia manifests as Mn values ranging from 4- to 25-fold higher than normal baseline levels, along with brain MRI results similar to those observed in the recruited patient. Nine SLC39A14 variants have been identified. Seven patients have been treated with Na2CaEDTA, and only one patient achieved obvious clinical improvement. We identified a novel SLC39A14 mutation related to autosomal recessive hypermanganesemia with dystonia-2, which is a very rare disease. Patients present motor regression or delay of developmental milestones and develop progressive generalized dystonia. Chelation therapy with Na2CaEDTA appears to effectively chelate Mn and increase urinary Mn excretion in some cases; however, clinical response varies. The outcome of the disease was unsatisfactory. This study expands the genetic spectrum of this disease.

Pulmonary function tests for evaluating the severity of Duchenne muscular dystrophy disease.

In Duchenne muscular dystrophy (DMD), lung disease contributes significantly to morbidity and mortality. This study aimed to assess the usefulness of various pulmonary function tests in evaluating DMD severity. This retrospective study analysed lung function tests of patients with DMD-treated in the multidisciplinary respiratory neuromuscular clinic at Schneiders' Children Medical Center of Israel. Data were analysed according to age, ambulatory status and glucocorticoid treatment. Among 90 patients with DMD, 40/63 (63.5%) ambulatory patients and 22/27 (81.5%) nonambulatory patients successfully performed spirometry. Significant annual declines were demonstrated among nonambulatory patients, in percentile predicted forced vital capacity (3.8%) and in total lung capacity (5.5%) per year. The decline correlated with age and loss of ambulation but not with steroid treatment. Peak cough flow values were randomly distributed and did not correlate with age, ambulation or treatment. In nonambulatory patients, transcutaneous carbon dioxide measurement correlated significantly with age (r=0.55, p=0.02). Forced vital capacity, total lung capacity and transcutaneous carbon dioxide correlated with the clinical severity of disease in children with DMD. These measures may be useful in follow-up and clinical trials. A comparable correlation was not found for peak cough flow.

Myostatin and follistatin as monitoring and prognostic biomarkers in dysferlinopathy

Myostatin is a myokine which acts upon skeletal muscle to inhibit growth and regeneration. Myostatin is endogenously antagonised by follistatin. This study assessed serum myostatin and follistatin concentrations as monitoring or prognostic biomarkers in dysferlinopathy, an autosomal recessively inherited muscular dystrophy. Myostatin was quantified twice with a three-year interval in 76 patients with dysferlinopathy and 38 controls. Follistatin was quantified in 62 of these patients at the same timepoints, and in 31 controls. Correlations with motor function, muscle fat fraction and contractile cross-sectional area were performed. A regression model was used to account for confounding variables. Baseline myostatin, but not follistatin, correlated with baseline function and MRI measures. However, in individual patients, three-year change in myostatin did not correlate with functional or MRI changes. Linear modelling demonstrated that function, serum creatine kinase and C-reactive protein, but not age, were independently related to myostatin concentration. Baseline myostatin concentration predicted loss of ambulation but not rate of change of functional or MRI measures, even when relative inhibition with follistatin was considered. With adjustment for extra-muscular causes of variation, myostatin could form a surrogate measure of functional ability or muscle mass, however myostatin inhibition does not form a promising treatment target in dysferlinopathy.

Identification of vacuolar autophagic aggregates in the skeletal muscles of inbred C57BL/6NCrl mice.

A comprehensive pathological analysis of inbred strains is essential to define strain-specific spontaneous lesions and to understand whether a specific phenotype results from experimental intervention or reflects a naturally occurring disease. This study aimed to report and describe a novel condition affecting the skeletal muscles of an inbred C57BL/6NCrl mouse colony characterised by large sarcoplasmic vacuoles in the muscle fibres of male mice in the subsarcolemmal spaces and the intermyofibrillary network. There was no muscle weakness, loss of ambulation or cardiac/respiratory involvement. Post-mortem evaluation and histological analysis excluded the presence of pathological accumulations or lesions in other tissues and organs. Changes were seen in fibre size, with many hypotrophic and some slightly hypertrophic fibres. Histological, immunohistochemical and molecular analyses of the vacuolar content revealed dysregulation of the autophagy machinery while ruling out a morphologically similar condition marked by the accumulation of tubular aggregates.

Time to diagnosis of Duchenne muscular dystrophy in Austria and Germany

Duchenne muscular dystrophy (DMD) is an X-linked genetic disorder manifesting in early childhood with progressive muscular weakness and atrophy, and resulting in early loss of ambulation. The collection and evaluation of epidemiological data for this disease is crucial for an early diagnosis and disease management. In Germany, data are collected via the TREAT-NMD DMD patient registry (www.dmd-register.de). In contrast, data collection in Austria has not yet been performed systematically. For collecting data from Austrian DMD patients, an online survey of the patient’s caregivers was conducted. Data of 57 patients were collected entailing initial symptoms, diagnosis and therapeutic measures. Comparable data has been collected for Germany via the TREAT-NMD DMD patient registry. 57 DMD patients aged 4–34 years completed the Austrian survey. On average, first symptoms of the disease appeared at the age of 3.1 years. As the most frequent first symptom, 46% of the patients described problems in climbing stairs. In 40% of the patients, DMD was diagnosed early due to an accidentally detected hyperCKemia in infancy or early childhood. Corticosteroids represented the main therapeutic option in our cohort. At the time of the survey, only 52% of the patients were treated with corticosteroids. Patients from Germany reported that first symptoms appeared at the age of 3.06 years. Diagnosis was established by genetic testing or muscle biopsy. 47% of the patients were treated with corticosteroids. Time between first symptoms and diagnosis was 7 months in Austria, and 4.7 months in Germany, respectively. Compared to earlier international studies, the Austrian data show encouraging results regarding earlier start of corticosteroid therapy in a larger percentage of patients. Austrian and German data show a trend towards an earlier diagnosis of DMD, while the age at symptom onset was similar to previous studies. The collection and evaluation of epidemiological data of DMD patients is important and will hopefully contribute to accelerate DMD diagnosis and treatment access for the patients.

Functional and Clinical Outcomes Associated with Steroid Treatment among Non-ambulatory Patients with Duchenne Muscular Dystrophy1.

Evidence on the long-term efficacy of steroids in Duchenne muscular dystrophy (DMD) after loss of ambulation is limited. Characterize and compare disease progression by steroid treatment (prednisone, deflazacort, or no steroids) among non-ambulatory boys with DMD. Disease progression was measured by functional status (Performance of Upper Limb Module for DMD 1.2 [PUL] and Egen Klassifikation Scale Version 2 [EK] scale) and by cardiac and pulmonary function (left ventricular ejection fraction [LVEF], forced vital capacity [FVC] % -predicted, cough peak flow [CPF]). Longitudinal changes in outcomes, progression to key disease milestones, and dosing and body composition metrics were analyzed descriptively and in multivariate models. This longitudinal cohort study included 86 non-ambulatory patients with DMD (mean age 13.4 years; n = 40 [deflazacort], n = 29 [prednisone], n = 17 [no steroids]). Deflazacort use resulted in slower average declines in FVC % -predicted vs. no steroids (+3.73 percentage points/year, p < 0.05). Both steroids were associated with significantly slower average declines in LVEF, improvement in CPF, and slower declines in total PUL score and EK total score vs. no steroids; deflazacort was associated with slower declines in total PUL score vs. prednisone (all p < 0.05). Both steroids also preserved functional abilities considered especially important to quality of life, including the abilities to perform hand-to-mouth function and to turn in bed at night unaided (all p < 0.05 vs. no steroids). Steroid use after loss of ambulation in DMD was associated with delayed progression of important pulmonary, cardiac, and upper extremity functional deficits, suggesting some benefits of deflazacort over prednisone.

Spirometry correlates with physical activity in patients with Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is associated with progressive muscle weakness and respiratory decline. To date, studies have focused on respiratory decline and loss of ambulation as a metric of loss of skeletal muscle strength. However, new functional measures can assess skeletal muscle disease regardless of ambulatory status. The relationship between these tests and concurrent lung function is currently unexplored. To assess the correlation between spirometry measurements and functional muscle assessments such as accelerometry and quantitative muscle testing (QMT). Enrolled patients with DMD underwent accelerometry and QMT at study clinic visits. Any pulmonary function testing within 6 months of visit was obtained from the electronic medical record. The Spearman correlation coefficient was used to assess the relationship between spirometry and functional muscle testing. Forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1 ) demonstrated the strongest correlation with accelerometry. Both FVC and FEV1 showed a similar relationship to accelerometry when activity was divided into intensity categories, with low intensity and moderate-to-vigorous activity categories showing the strongest correlation. Maximal expiratory pressure (MEP) and FVC showed the most robust correlations with total QMT (p < 0.001 and p < 0.01, respectively). Lung function, specifically FVC percent predicted and FEV1 %p, shows a good correlation with upper and lower extremity skeletal muscle functional testing such as accelerometry and QMT.

Continuitiy of care with ataluren in Duchenne Muscular Dystrophy patients with nonsense mutations after loss of ambulation. Personal experience.

Duchenne Muscular Dystrophy (DMD) includes predictable phases requiring dedicated standard treatments. Therapeutic strategies feature corticosteroids or the more recent gene therapy/stop codon read-through. Ataluren (Translarna®) is an oral drug promoting the readthrough of premature stop codons caused by nonsense mutation (nm) in order to produce full-length dystrophin. It was licensed by EMA in 2014 for ambulatory patients with nmDMD aged ≥ 5 years. Our aim is to report data on long-term ataluren use in Italian patients with nmDMD, with emphasis on continuity of the treatment after loss of ambulation (LoA). Four DMD patients aged between 16 and 24 years who lost ambulation between 12 and 14 years continued to take ataluren after LoA. The oldest patient, aged 24 years, is still taking a few steps. Even in those experiencing motor decline, PUL-test performances were stable and respiratory function satisfactory in all; two patients developed severe cardiomyopathy, stable in one. Therapeutic continuity with ataluren should be offered to all nmDMD patients after LoA given its favourable safety and efficacy profile. However, further research is recommended to identify additional clinically meaningful outcomes and treatment goals following LoA.

Cognitive and Behavioral Profile of Egyptian Children with Duchenne Muscular Dystrophy

Background Duchenne Muscular Dystrophy (DMD) is a progressive neuromuscular disorder that could be associated with cognitive and behavioral disorders. Aim To evaluate the cognitive abilities and behavioral disorders in children with DMD and possible relation to various clinical characteristics. Subjects and methods 50 boys with DMD aged 6–14 years and an age-matched 50 boys as a control were included in the study. Assessment of cognitive function was the done using Arabic version of Stanford Binet intelligence test fourth edition, and behavioral assessment was done using the Arabic version of child behavior checklist. Results There was statistically significant difference between both groups regarding the total as well as all subscales of IQ test, cases showed lower scores on total and subscales IQ in comparison to controls. There was statistically significant difference between the mean scores in cases and control in all scales; internalizing problems, externalizing problems, other problems, as well as the total score. More children in the clinical and borderline categories in all domains were observed in the cases as compared to the control group. Positive relation was detected between internalizing behavioral problems and ambulatory state, duration of disease, associated conditions and cognitive abilities. Also, positive relation was observed between IQ and ambulatory state. Conclusion Cognitive and behavioral problems are common in DMD. Cognitive impairment have an association with the progression of muscular deterioration and loss of ambulation. Internalizing problems are more common with prolonged duration of illness, loss of ambulation, presence of associated conditions and cognitive abilities.

Uloga gena modifikatora na klinički tok Dišenove mišićne distrofije

Duchenne muscular dystrophy is the most common inherited muscle disease in childhood, which has a progressive clinical course with a fatal outcome that most often occurs between the second and fourth decade of life. The disease is inherited X-linked, recessively, and in two-thirds of patients, it is transmitted from the mother, while in the remaining third of patients, it is a de novo mutation. Mutations in the dystrophin gene (DMD gene) such as deletions, duplications and small mutations can be found throughout the entire length of the gene. The disease begins between the third and fifth year of life, and the initial muscle weaknesses are clinically manifested as slower running, difficulty climbing stairs or difficulty getting up from squats. Sometimes, accidentally discovered, elevated keratin kinase values or delayed early psychomotor development milestones in a child with hypertrophic calves can initiate a diagnostic procedure in the direction of Duchenne muscular dystrophy. The disease usually has a uniform clinical course and implies a clear time sequence of events. Muscle weakness leads to loss of ambulation, then the function of the upper extremities, to complete immobility, with the evolution of dilated cardiomyopathy and respiratory insufficiency, which are the main causes of death. Certain patients show deviations from the above in terms of longer functionality and later loss of independent ambulation, later cardiomyopathy and respiratory insufficiency and vice versa. It is believed that in addition to the application of modern standards of care and treatment of patients, the clinical course is influenced by genes independent of the causal DMD gene, which affects processes in dystrophic muscle, primarily inflammation, fibrosis and fatty infiltration, through specific signaling pathways. So far, six genes have been described whose variants modify the course of Duchenne muscular dystrophy. The secreted phosphoprotein 1 (SPP1) is the first described gene whose G allele in the variant rs28357094 is associated with an earlier age of gait loss. In addition, variants in the genes described are LTBP4 (latent transforming growth factor-b binding protein 4), CD40, ACTN3 (actinin 3), THBS1 (thrombospondin 1) and TCTEX1D1 (Tctex1 domain containing 1). The aim of this paper is to present already-known genes that modify Duchenne muscular dystrophy and their influence on the clinical course of the disease.

Personalized treatment options for spinal muscular atrophy

<p>Spinal muscular atrophy (SMA) is an autosomal recessive disease leading to progressive muscle weakness and atrophy, in severe cases also affecting the bulbar and respiratory muscles.The clinical spectrum of the disease is extremely variable, in the most severe cases resulting in perinatal death, while at the least severe end of the spectrum causing some motor deficits in old age without the loss of ambulation. Spinal muscular atrophy care has changed dramatically in recent years due to the availability of new therapeutic options.&nbsp;<br>The FDA approved nusinersen in 2016, this was followed by the approval of onasemnogene abeparvovec in 2019 and risdiplam in 2020. The EMA approved all three therapies a year later. Two of the threapies work at the pre-mRNA level, one at the DNA level. The clinical studies leading to the approval of the three drugs included patients of different ages and clinical conditions, and utilised partly different motor and functional scales. Therefore, direct comparison of these clinical studies is not possible. However, an increasing amount of real-world data contribute to the better understanding of the efficacy of the different therapies for patients of different ages and clinical conditions, in a real-world setting. Thus, the question may arise &ldquo;Which is the best SMA therapy?&rdquo;. This is an impossible question to answer. Indeed the question &ldquo;Which therapy is the most suitable for a certain patient at a certain time?&rdquo; is much more realistic. Here, we provide a brief overview of the objectively measurable results of the three therapies to date and an outlook into future therapeutic avenues.&nbsp;</p>.

Long-term Observation in Patients with Duchenne Muscular Dystrophy with Early Introduction of a Standing Program Using Knee-ankle-foot Orthoses.

This study investigated the outcomes of the early introduction of a standing program for patients with Duchenne muscular dystrophy (DMD). This was a retrospective observational study of 41 outpatients with DMD aged 15-20 years. We introduced the standing program using knee-ankle-foot orthoses (KAFO) to slow the progression of scoliosis when ankle dorsiflexion became less than 0° in the ambulatory period. Thirty-two patients with DMD were offered the standing program with KAFO; 12 continued the program until the age of 15 years (complete group) and 20 discontinued the program before the age of 15 years (incomplete group). The non-standing program group included 9 patients. The standing program with KAFO was significantly associated with the Cobb angle at the age of 15 years after adjustment for the duration of corticosteroid use and DMD mutation type (P=0.0004). At the age of 15 years, significant correlations were found between the ankle dorsiflexion range of motion (ROM) and non-ambulatory period (P=0.0010), non-ambulatory period and Cobb angle (P<0.0001), Cobb angle and percent predicted forced vital capacity (P=0.0004), and ankle dorsiflexion ROM and Cobb angle (P=0.0066). In the complete group, the age at ambulation loss (log-rank P=0.0015), scoliosis progression (log-rank P=0.0032), and pulmonary dysfunction (log-rank P=0.0006) were significantly higher than in the non-standing program group. The early introduction of a standing program for DMD patients may prolong the ambulation period and slow the progression of scoliosis and pulmonary dysfunction.

Genotype-phenotype correlation and natural history study of dysferlinopathy: a single-centre experience from India.

Dysferlinopathies are a group of limb-girdle muscular dystrophies causing significant disability in the young population. There is a need for studies on large cohorts to describe the clinical, genotypic and natural history in our subcontinent. To describe and correlate the clinical, genetic profile and natural history of genetically confirmed dysferlinopathies. We analysed a retrospective cohort of patients with dysferlinopathy from a single quaternary care centre in India. A total of 124 patients with dysferlinopathy were included (40 females). Median age at onset and duration of illness were 21years (range, 13-50) and 48months (range, 8-288), respectively. The average follow-up period was 60months (range, 12-288). Fifty-one percent had LGMD pattern of weakness at onset; 23.4% each had Miyoshi and proximo-distal type while isolated hyperCKemia was noted in 1.6%. About 60% were born to consanguineous parents and 26.6% had family history of similar illness. Twenty-three patients (18.6%) lost ambulation at follow-up; the median time to loss of independent ambulation was 120months (range, 72-264). Single-nucleotide variants (SNVs) constituted 78.2% of patients; INDELs 14.5% and 7.3% had both SNVs and INDELs. Earlier age at onset was noted with SNVs. There was no correlation between the other clinical parameters and ambulatory status with the genotype. Thirty-seven (45.7%) novel pathogenic/likely pathogenic (P/LP) variants were identified out of a total of 81 variations. The c.3191G > A variant was the most recurrent mutation. Our cohort constitutes a clinically and genetically heterogeneous group of dysferlinopathies. There is no significant correlation between the clinico-genetic profile and the ambulatory status.