Hereditary Muscle Disorders Research Articles

Ultra-Orphan drug development for GNE Myopathy: A synthetic literature review and meta-analysis

GNE myopathy is an autosomal recessive hereditary muscle disorder that has the following clinical characteristics: develops in early adulthood, gradually progresses from the distal muscles, and is relatively sparing of quadriceps until the advanced stages of the disease. With further progression, patients become non-ambulatory and need a wheelchair. There is growing concern about extra-muscular presentations such as thrombocytopenia, respiratory dysfunction, and sleep apnea syndrome. Pathologically, rimmed vacuoles and tubulofilamentous inclusions are observed in affected muscles. The cause of the disease is thought to be a sialic acid deficiency due to mutations of the GNE gene required for in vivo sialic acid biosynthesis. Sialic acid supplementation to a presymptomatic GNE myopathy mouse model was effective in preventing the development of the disease. Several clinical studies have been conducted to evaluate the safety and efficacy of sialic acid supplementation in humans. Based on the favorable results of these studies, an extended-release aceneuramic acid formulation was approved for treatment of GNE myopathy in Japan in March 2024. It is anticipated that it will be a significant step in the development of an effective treatment for GNE myopathy and other ultra-orphan diseases.

The importance of combining multiple genetic techniques to define recessive forms of myotonia congenita

Myotonia congenita (MC) is a hereditary skeletal muscle disorder characterized by muscle stiffness at the beginning of exercise (i.e. myotonia), alleviated by repetition of contraction (ie. warm-up effect). MC is caused by mutations in the CLCN1 gene, encoding the skeletal muscle voltage-gated chloride channel (ClC-1) and is traditionally classified as Thomsen (autosomal dominant) and Becker (autosomal recessive) diseases. We report here an Italian patient affected by diffuse muscle hypertrophy, predominant in lower limb, neck, and trapezius and difficulty in getting up from a chair after prolonged rest, suggestive of recessive MC. The combination of a specific next-generation sequencing panel for skeletal muscle channelopathies and multiplex ligation-dependent probe amplification for CLCN1, leaded to the detection of the known missense mutation p.G482R and a novel deletion of the last 3 exons of the CLCN1. This report demonstrates the importance of combining multiple genetic techniques to define recessive forms of MC.

The influence of genetic mutations on multilayer global longitudinal strain values in patients with hypertrophic cardiomyopaty

Abstract Background Hypertrophic cardiomyopathy (HCM) is a hereditary heart muscle disorder characterized by diverse genetic mutations. Multilayer global longitudinal strain (GLS) analysis has emerged as a valuable tool for assessing myocardial function. This study aimed to investigate the influence of genetic mutations on myocardial deformation patterns in HCM patients using multilayer GLS analysis. Methods A total of 83 adult patients diagnosed with HCM were included in the study. Genetic testing was performed to identify specific genetic mutations associated with HCM. Echocardiographic assessments were conducted to measure multilayer GLS values for endocardial, mid-myocardial, and epicardial layers. Patients were divided into gene-positive and gene-negative groups for comparative analysis. Results In the gene-negative group (n=41), the mean age was 57.1 ± 11.0 years, whereas in the gene-positive group (n=42), it was 55.5 ± 11.6 years (p=0.516). Significant differences were observed in endocardial (-16.1 ± 2.3 vs. -13.4 ± 3.2, p < 0.001) and mid-myocardial (-14.2 ± 2.1 vs. -12.3 ± 3.1, p = 0.002) GLS involvement between gene-negative and gene-positive HCM patients. However, no significant disparity in epicardial strain was detected. Conclusion The findings demonstrated a greater involvement of the endocardial and mid-myocardial layers in the group of HCM patients with positive genetic mutations. Multilayer GLS analysis has the potential to aid in the identification of subtle alterations in myocardial function associated with specific genetic mutations, contributing to refined risk assessment and personalized management strategies for HCM patients.

Dominantly inherited muscle disorders: understanding their complexity and exploring therapeutic approaches.

Treatments for disabling and life-threatening hereditary muscle disorders are finally close to becoming a reality. Research has thus far focused primarily on recessive forms of muscle disease. The gene replacement strategies that are commonly employed for recessive, loss-of-function disorders are not readily translatable to most dominant myopathies owing to the presence of a normal chromosome in each nucleus, hindering the development of novel treatments for these dominant disorders. This is largely due to their complex, heterogeneous disease mechanisms that require unique therapeutic approaches. However, as viral and RNA interference-based therapies enter clinical use, key tools are now in place to develop treatments for dominantly inherited disorders of muscle. This article will review what is known about dominantly inherited disorders of muscle, specifically their genetic basis, how mutations lead to disease, and the pathomechanistic implications for therapeutic approaches.

Expert recommendations for magnetic resonance imaging of muscle disorders

Magnetic resonance (MRI) imaging of the skeletal muscles (muscle MRI for short) is increasingly being used in clinical routine for diagnosis and longitudinal assessment of muscle disorders. However, cross-centre standards for measurement protocol and radiological assessment are still lacking. The aim of this expert recommendation is to present standards for the application and interpretation of muscle MRI in hereditary and inflammatory muscle disorders. This work was developed in collaboration between neurologists, neuroradiologists, radiologists, neuropaediatricians, neuroscientists and MR physicists from different university hospitals in Germany. The recommendations are based on expert knowledge and afocused literature search. The indications for muscle MRI are explained, including the detection and monitoring of structural tissue changes and oedema in the muscle, as well as the identification of asuitable biopsy site. Recommendations for the examination procedure and selection of appropriate MRI sequences are given. Finally, steps for astructured radiological assessment are presented. The present work provides concrete recommendations for the indication, implementation and interpretation of muscle MRI in muscle disorders. Furthermore, it provides apossible basis for the standardisation of the measurement protocols at all clinical centres in Germany.

Expert recommendations for magnetic resonance imaging of muscle disorders

Magnetic resonance (MRI) imaging of the skeletal muscles (muscle MRI for short) is increasingly being used in clinical routine for diagnosis and longitudinal assessment of muscle disorders. However, cross-centre standards for measurement protocol and radiological assessment are still lacking. The aim of this expert recommendation is to present standards for the application and interpretation of muscle MRI in hereditary and inflammatory muscle disorders. This work was developed in collaboration between neurologists, neuroradiologists, radiologists, neuropaediatricians, neuroscientists and MR physicists from different university hospitals in Germany. The recommendations are based on expert knowledge and afocused literature search. The indications for muscle MRI are explained, including the detection and monitoring of structural tissue changes and oedema in the muscle, as well as the identification of asuitable biopsy site. Recommendations for the examination procedure and selection of appropriate MRI sequences are given. Finally, steps for astructured radiological assessment are presented. The present work provides concrete recommendations for the indication, implementation and interpretation of muscle MRI in muscle disorders. Furthermore, it provides apossible basis for the standardisation of the measurement protocols at all clinical centres in Germany.

Anoctamin 5 (ANO5) Muscle Disorders: A Narrative Review.

Anoctaminopathy-5 refers to a group of hereditary skeletal muscle or bone disorders due to mutations in the anoctamin 5 (ANO5)-encoding gene, ANO5. ANO5 is a 913-amino acid protein of the anoctamin family that functions predominantly in phospholipid scrambling and plays a key role in the sarcolemmal repairing process. Monoallelic mutations in ANO5 give rise to an autosomal dominant skeletal dysplastic syndrome (gnathodiaphyseal dysplasia or GDD), while its biallelic mutations underlie a continuum of four autosomal recessive muscle phenotypes: (1). limb–girdle muscular dystrophy type R12 (LGMDR12); (2). Miyoshi distal myopathy type 3 (MMD3); (3). metabolic myopathy-like (pseudometabolic) phenotype; (4). asymptomatic hyperCKemia. ANO5 muscle disorders are rare, but their prevalence is relatively high in northern European populations because of the founder mutation c.191dupA. Weakness is generally asymmetric and begins in proximal muscles in LGMDR12 and in distal muscles in MMD3. Patients with the pseudometabolic or asymptomatic hyperCKemia phenotype have no weakness, but conversion to the LGMDR12 or MMD3 phenotype may occur as the disease progresses. There is no clear genotype–phenotype correlation. Muscle biopsy displays a broad spectrum of pathology, ranging from normal to severe dystrophic changes. Intramuscular interstitial amyloid deposits are observed in approximately half of the patients. Symptomatic and supportive strategies remain the mainstay of treatment. The recent development of animal models of ANO5 muscle diseases could help achieve a better understanding of their underlying pathomechanisms and provide an invaluable resource for therapeutic discovery.

Hospital based study on laboratory investigations on heriditary muscle disorders

Background: Myopathies are a group of neuro muscular diseases that cause muscle weakness, cramps, and spasms due to a primary defect of the muscle fiber. We undertook this study of hereditary muscle disorders to identify the clinical patterns and laboratory findings in these conditions and study the correlation between them, which will help in recognizing them early for adequate management with rehabilitation measures and for prognostication. Aim: To assess the correlation between the clinical and investigational profile in Hereditary muscle disorders. Methods: A cross sectional study was conducted among 44 patients with clinical features suggestive of hereditary muscle disorders who sort health care at Institute of neurology, Madras Medical college, Chennai using various investigation techniques like Serum CK measurement, Nerve conduction Study, Electromyography, Muscle biopsy. Results: CK elevation was found in all patients in our study, but the degree of elevation differs among various hereditary muscle disorders. It was maximal (>25 times normal) in patients with DMD (50%), BMD (40%) and in LGMD (4%). High degree of correlation between clinical diagnosis of hereditary muscle disorders and myopathic EMG was found. Myopathic pattern was observed in all patients of Muscular dystrophy, congenital myopathy and distal myopathy.

Genetic Appraisal of Hereditary Muscle Disorders In A Cohort From Mumbai, India.

Hereditary muscle disorders are clinically and genetically heterogeneous. Limited information is available on their genetic makeup and their prevalence in India. To study the genetic basis of prevalent hereditary myopathies. This is a retrospective study conducted at a tertiary care center. The study was approved by the institutional ethics board. The point of the collection was the genetic database. The genetic data of myopathy patients for the period of two and half years (2019 to mid-2021) was evaluated. Those with genetic diagnoses of DMD, FSHD, myotonic dystrophies, mitochondriopathies, and acquired myopathies were excluded. The main outcome measures were diagnostic yield and the subtype prevalence with their gene variant spectrum. The definitive diagnostic yield of the study was 39% (cases with two pathogenic variants in the disease-causing gene). The major contributing genes were GNE (15%), DYSF (13%), and CAPN3 (7%). Founder genes were documented in Calpainopathy and GNE myopathy. The uncommon myopathies identified were Laminopathy (0.9%), desminopathy (0.9%), and GMPPB-related myopathy (1.9%). Interestingly, a small number of patients showed pathogenic variants in more than one myopathy gene, the multigenic myopathies. This cohort study gives hospital-based information on the prevalent genotypes of myopathies (GNE, Dysferlinopathy, and calpainopathy), founder mutations, and also newly documents the curious occurrence of multigenicity in a small number of myopathies.

Hospital based study on demographic profile and clinical spectrum on hereditary muscle disorder

Background: Myopathies are disorders in which a primary functional or structural impairment of skeletal muscle. In general, Muscle disorders are classified into hereditary and acquired disorders. The approach to a patient with a suspected muscle disease is to determine the correct site of the lesion from history and physical examination. This will help to decide on management and prognostication issues. We undertook this study of hereditary muscle disorders to identify the demographic profile and clinical spectrum of hereditary muscle disorders. Aims and Objectives: To study the demographic profile of patients with hereditary muscle disorders and to study the clinical spectrum of hereditary muscle disorders. Methods and Materials: A cross sectional study was conducted on Institute of Neurology, Madras Medical College, Chennai during the period of July 2018 to February 2019 (8 months), among 44 patients (Males-32, Females-12), with clinical features suggestive of hereditary muscle disorders, with certain exclusion criteria’s. Clinical evaluation was done by detailed history taking followed by general and CNS examination, along with motor system examination. All the data were tabulated in Microsoft XL sheet, followed by analysis using SPSS software (version 20.0).

P 73 Muscle relaxation in myotonia and longitudinal nerve mobility in carpal tunnel syndrome as possible clinical applications for “dynamic” ultrasound shear-wave elastography

Shear wave elastography (SWE) is an emerging modality in clinical ultrasound. Using acoustic radiation force impulses to generate transversal shear waves and fast imaging to track their propagation, it enables the non-invasive estimation of two-dimensional maps of tissue elasticity. Various applications in neuromuscular medicine have been investigated, e.g., altered muscle elasticity has been reported in muscular dystrophy and inflammatory myopathies, and elasticity of the median nerve at the wrist has been shown to be increased in carpal tunnel syndrome. Currently available SWE systems have a temporal resolution of about 1/second, making “dynamic”, functional assessments of nerve or muscle possible; we propose two such possible applications: (1) Myotonia describes delayed muscle relaxation in rare hereditary muscle disorders. In six patients with different myotonic muscle disorders and six controls, we performed SWE of the flexor digitorum superficialis muscle in the forearm with a frequency of one measurement per second. From measurements before, during and after brief voluntary contraction, the relaxation time to 10% of normalized shear wave velocity (RT0.1) was determined. 46 imaging sequences were acquired, with a mean RT0.1 of 7.38 s in patients and 1.36 s in control subjects, which is comparable to data obtained by mechanical dynamometry. (2) In carpal tunnel syndrome, reduced nerve mobility mostly in the lateral plane, but also longitudinally, has been described. Wrist and elbow movements, in healthy subjects, are known to alter median nerve tension and, thus, elasticity as detectable by SWE. We present a protocol to investigate whether entrapment at the carpal tunnel affects these posture-induced changes, an effect that might similarly occur in other compressive or traumatic neuropathies. These applications demonstrate how resolving functional manoeuvres by “dynamic” ultrasound SWE may be utilized for clinical diagnostic assessments.

Surgical septal myectomy for hypertrophic cardiomyopathy. The Iranian experience.

Hypertrophic obstructive cardiomyopathy (HOCM) is a hereditary heart muscle disorder characterized by significant myocardial hypertrophy. we assessed perioperative and long-term follow-up data of Iranian HOCM patients who underwent SM in 2 pioneering centers. Clinical data of patients with HOCM septal myectomy are collected. Thirty-day outcome and long-term follow-up data for recurrence of gradient and mortality are reported. Ninety-six patients in two different centers enrolled in the study. Most patients of 52 patients in center 1 were male (34/52 [65.3%]).and the mean age was of 36.7 ± 19 years. Syncope before admission was reported in 5.7%, the mean left ventricular ejection fraction on admission was 53 ± 8%, the mean left ventricular outflow tract gradient was 66.3 ± 20.4 mm Hg, and the mean preoperativeseptal thickness was 25.4 ± 6.7 mm. A redo SM was performed in 3 patients (5.8%), mitral valve repair in 5 patients (9.6%), and atrioventricular repair in 5 patients (9.6%). A residual systolic anterior motion was detected in 4 patients (7.7%), the mean postoperative septal thickness was 19 ± 6 mm (25.1% septal thickness reduction), and in-hospital mortality was 5.8% (n = 3). A longer-term follow-up showed death in 3 patients (5.8%) and late recurrent left ventricular outflow tract obstruction in 1 patient. Transaortic myectomy is an effective surgery with acceptable early and late mortality rates. Improvements in functional status are seen in almost all patients. Appropriate SM is crucial to a good clinical outcome. Long-term survival is excellent and cardiac sudden death is extremely rare after a good surgical treatment.

Gain-of-Function STIM1 L96V Mutation Causes Myogenesis Alteration in Muscle Cells From a Patient Affected by Tubular Aggregate Myopathy.

Tubular Aggregate Myopathy (TAM) is a hereditary ultra-rare muscle disorder characterized by muscle weakness and cramps or myasthenic features. Biopsies from TAM patients show the presence of tubular aggregates originated from sarcoplasmic reticulum due to altered Ca2+ homeostasis. TAM is caused by gain-of-function mutations in STIM1 or ORAI1, proteins responsible for Store-Operated-Calcium-Entry (SOCE), a pivotal mechanism in Ca2+ signaling. So far there is no cure for TAM and the mechanisms through which STIM1 or ORAI1 gene mutation lead to muscle dysfunction remain to be clarified. It has been established that post-natal myogenesis critically relies on Ca2+ influx through SOCE. To explore how Ca2+ homeostasis dysregulation associated with TAM impacts on muscle differentiation cascade, we here performed a functional characterization of myoblasts and myotubes deriving from patients carrying STIM1 L96V mutation by using fura-2 cytofluorimetry, high content imaging and real-time PCR. We demonstrated a higher resting Ca2+ concentration and an increased SOCE in STIM1 mutant compared with control, together with a compensatory down-regulation of genes involved in Ca2+ handling (RyR1, Atp2a1, Trpc1). Differentiating STIM1 L96V myoblasts persisted in a mononuclear state and the fewer multinucleated myotubes had distinct morphology and geometry of mitochondrial network compared to controls, indicating a defect in the late differentiation phase. The alteration in myogenic pathway was confirmed by gene expression analysis regarding early (Myf5, Mef2D) and late (DMD, Tnnt3) differentiation markers together with mitochondrial markers (IDH3A, OGDH). We provided evidences of mechanisms responsible for a defective myogenesis associated to TAM mutant and validated a reliable cellular model usefull for TAM preclinical studies.

Muscle Ultrasound Shear Wave Elastography as a Non-Invasive Biomarker in Myotonia.

Myotonia, i.e., delayed muscle relaxation in certain hereditary muscle disorders, can be assessed quantitatively using different techniques ranging from force measurements to electrodiagnostics. Ultrasound shear wave elastography (SWE) has been proposed as a novel tool in biomechanics and neuromuscular medicine for the non-invasive estimation of muscle elasticity and, indirectly, muscle force. The aim of this study is to provide ‘proof-of-principle’ that SWE allows a quantitative measurement of the duration of delayed muscle relaxation in myotonia in a simple clinical setting. In six myotonic muscle disorder patients and six healthy volunteers, shear wave velocities (SWV) parallel to the fiber orientation in the flexor digitorum superficialis muscle in the forearm were recorded with a temporal resolution of one per second during fist-clenching and subsequent relaxation; the relaxation time to 10% of normalized shear wave velocity (RT0.1) was calculated. Forty-six SWE imaging sequences were acquired, yielding a mean RT0.1 of 7.38 s in myotonic muscle disorder patients, significantly higher than in healthy volunteers (1.36 s), which is comparable to data obtained by mechanical dynamometry. SWV measurements during the baseline relaxation and voluntary contraction phases did not differ significantly between groups. We conclude that SWE is a promising, non-invasive, widely available tool for the quantitative assessment of myotonia to aid in diagnosis and therapeutic monitoring.

Changes in Resurgent Sodium Current Contribute to the Hyperexcitability of Muscles in Patients with Paramyotonia Congenita.

Paramyotonia congenita (PMC) is a rare hereditary skeletal muscle disorder. The major symptom, muscle stiffness, is frequently induced by cold exposure and repetitive exercise. Mutations in human SCN4A gene, which encodes the α-subunit of Nav1.4 channel, are responsible for PMC. Mutation screening of SCN4A gene from two PMC families identified two missense mutations, p.T1313M and p.R1448H. To elucidate the electrophysiological abnormalities caused by the mutations, the p.T1313M, p.R1448H, and wild-type (WT) SCN4A genes were transient expressed on Chinese hamster ovary (CHO-K1) cells. The detailed study on the gating defects of the mutant channels using the whole-cell patch clamping technique was performed. The mutant Nav1.4 channels impaired the basic gating properties with increasing sustained and window currents during membrane depolarization and facilitated the genesis of resurgent currents during repolarization. The mutations caused a hyperpolarization shift in the fast inactivation and slightly enhanced the slow inactivation with an increase in half-maximal inactivation voltage. No differences were found in the decay kinetics of the tail current between mutant and WT channels. In addition to generating the larger resurgent sodium current, the time to peak in the mutant channels was longer than that in the WT channels. In conclusion, our results demonstrated that the mutations p.T1313M and p.R1448H in Nav1.4 channels can enhance fast inactivation, slow inactivation, and resurgent current, revealing that subtle changes in gating processes can influence the clinical phenotype.

CONGENITAL MYOPATHIES 1 – NEMALINE: P.25 Autosomal recessive congenital myopathy with splicing mutation (c.21522+3A>G) of NEB gene

Congenital myopathies are a heterogeneous group of hereditary primary muscle disorders that are present from birth, although their onset may be delayed until later in infancy or early childhood. The most common of these rare disorders are nemaline myopathy, central core disease, centronuclear (myotubular) myopathies, and congenital fiber type disproportion. Among them, nemaline myopathy, a rare congenital myopathy, is characterized by generalized muscle weakness, respiratory insufficiency, and the presence of rod structures on muscle biopsy, which is caused by mutations in at least 13 known genes.

Distal myopathy due to TCAP variants in four unrelated Chinese patients.

Distal myopathies are a group of clinically and genetically heterogeneous hereditary muscle disorders characterized by progressive muscular weakness starting in the distal parts of the limbs. The most common subtype of distal myopathy is GNE myopathy, a rare muscle disease with autosomal recessive inheritance. Limb-girdle muscular dystrophy 2G (LGMD2G) is a rare autosomal recessive subtype of LGMDs caused by TCAP variant. Patients with LGMD2G can present with distal myopathy and rimmed vacuoles on muscle pathology. Thus far, the most reported TCAP mutations related to LGMD2G were recessive frameshift or nonsense variants. Here, we described four Chinese patients from unrelated families with LGMD2G due to TCAP mutations. The clinical symptoms of our patients were similar to those previously reported in LGMD2G patients. Three different pathogenic TCAP variants were identified in these patients, including two frameshift variants and one intronic variant. Autophagolysosomes have been observed in one patient by electron microscopy. Our research expands the genetic spectrum of TCAP mutations in China, indicating c.165-166insG is likely the common pathogenic variant. We also provide evidences that autophagy may be involved in the pathophysiology of LGMD2G.

Investigation of hereditary muscle disorders in the genomic era

Investigation of hereditary muscle disorders in the genomic era

Translocation of molecular chaperones to the titin springs is common in skeletal myopathy patients and affects sarcomere function

SummaryMyopathies encompass a wide variety of acquired and hereditary disorders. The pathomechanisms include structural and functional changes affecting, e.g., myofiber metabolism and contractile properties. In this study, we observed increased passive tension (PT) of skinned myofibers from patients with myofibrillar myopathy (MFM) caused by FLNC mutations (MFM-filaminopathy) and limb-girdle muscular dystrophy type-2A due to CAPN3 mutations (LGMD2A), compared to healthy control myofibers. Because the giant protein titin determines myofiber PT, we measured its molecular size and the titin-to-myosin ratio, but found no differences between myopathies and controls. All-titin phosphorylation and site-specific phosphorylation in the PEVK region were reduced in myopathy, which would be predicted to lower PT. Electron microscopy revealed extensive ultrastructural changes in myofibers of various hereditary myopathies and also suggested massive binding of proteins to the sarcomeric I-band region, presumably heat shock proteins (HSPs), which can translocate to elastic titin under stress conditions. Correlative immunofluorescence and immunoelectron microscopy showed that two small HSPs (HSP27 and αB-crystallin) and the ATP-dependent chaperone HSP90 translocated to the titin springs in myopathy. The small HSPs, but not HSP90, were upregulated in myopathic versus control muscles. The titin-binding pattern of chaperones was regularly observed in Duchenne muscular dystrophy (DMD), LGMD2A, MFM-filaminopathy, MFM-myotilinopathy, titinopathy, and inclusion body myopathy due to mutations in valosin-containing protein, but not in acquired sporadic inclusion body myositis. The three HSPs also associated with elastic titin in mouse models of DMD and MFM-filaminopathy. Mechanical measurements on skinned human myofibers incubated with exogenous small HSPs suggested that the elevated PT seen in myopathy is caused, in part, by chaperone-binding to the titin springs. Whereas this interaction may be protective in that it prevents sarcomeric protein aggregation, it also has detrimental effects on sarcomere function. Thus, we identified a novel pathological phenomenon common to many hereditary muscle disorders, which involves sarcomeric alterations.

Reliability and validity analyses of the North Star Ambulatory Assessment in Brazilian Portuguese

The North Star Ambulatory Assessment measures motor performance in ambulatory boys with Duchenne muscular dystrophy, a hereditary and degenerative muscle disorder. To use the North Star Ambulatory Assessment in Brazilian boys, we performed the cross-cultural adaptation to the Portuguese language spoken in Brazil and evaluated the reliability and validity of the instrument. Cross-cultural adaptation included: independent translations, synthesis, committee review, pre-testing in 12 boys, back-translation and comparison with the original instrument. Thirty-five boys with Duchenne muscular dystrophy and 38 healthy age-matched controls were recruited for further analyses. Reliability was assessed by internal consistency and reproducibility. Validity studies included face, content, construct and known-groups analyses. Cross-cultural adaptation resulted in an adequate instrument. Reliability studies demonstrated high internal consistency (Cronbach's alpha = 0.935) and adequate intra and inter-rater reproducibility (intraclass correlation coefficient = 0.988 and 0.962). Validation analyses indicated satisfactory content, face and convergent construct validities, with positive correlations with the Motor Function Measure total score (r = 0.863) and the 6-minute walk test (r = 0.433). The known group validity was demonstrated by higher scores in younger boys with Duchenne muscular dystrophy (p = 0.005). North Star Ambulatory Assessment in Brazilian Portuguese is a reliable and valid instrument to measure functional capacity in boys with Duchenne muscular dystrophy.