Female Duchenne Muscular Dystrophy Research Articles

Clinical, pathological, and genetic characterization in a large Chinese cohort with female dystrophinopathy

We aimed to investigate the clinical, pathological, and genetic characteristics of Chinese female dystrophinopathy and to identify possible correlations among them. One hundred forty genetically and/or pathologically confirmed female DMD variant carriers were enrolled, including 104 asymptomatic carriers and 36 symptomatic carriers. Twenty of 36 symptomatic and 16 of 104 asymptomatic carriers were sporadic with no family history. Muscle pathological analysis was performed in 53 carriers and X chromosome inactivation (XCI) analysis in 19 carriers. In asymptomatic carriers, the median age was 35.0 (range 2.0–58.0) years, and the serum creatine kinase (CK) level was 131 (range 60–15,745) IU/L. The median age, age of onset, and CK level of symptomatic carriers were 15.5 (range 1.8–62.0) years, 6.3 (range 1.0–54.0) years, and 6,659 (range 337–58,340) IU/L, respectively. Four female carriers with X-autosome translocation presented with a Duchenne muscular dystrophy (DMD) phenotype. Skewed XCI was present in 70.0% of symptomatic carriers. Compared to Becker muscular dystrophy (BMD)-like carriers, DMD-like carriers were more likely to have an early onset age, rapidly progressive muscle weakness, delayed walking, elevated CK levels, severe reduction of dystrophin, and skewed XCI. Our study reports the largest series of symptomatic female DMD carriers and suggests that delayed walking, elevated CK levels, severe reduction of dystrophin, X-autosome translocation, and skewed XCI pattern are associated with a severe phenotype in female dystrophinopathy.

Newborn screening for Duchenne muscular dystrophy: A two-year pilot study.

Duchenne muscular dystrophy (DMD) is an X-linked disorder resulting in progressive muscle weakness and atrophy, cardiomyopathy, and in late stages, cardiorespiratory impairment, and death. As treatments for DMD have expanded, a DMD newborn screening (NBS) pilot study was conducted in New York State to evaluate the feasibility and benefit of NBS for DMD and to provide an early pre-symptomatic diagnosis. At participating hospitals, newborns were recruited to the pilot study, and consent was obtained to screen the newborn for DMD. The first-tier screen measured creatine kinase-MM (CK-MM) in dried blood spot specimens submitted for routine NBS. Newborns with elevated CK-MM were referred for genetic counseling and genetic testing. The latter included deletion/duplication analysis and next-generation sequencing (NGS) of the DMD gene followed by NGS for a panel of neuromuscular conditions if no pathogenic variants were detected in the DMD gene. In the two-year pilot study, 36,781 newborns were screened with CK-MM. Forty-two newborns (25 male and 17 female) were screen positive and referred for genetic testing. Deletions or duplications in the DMD gene were detected in four male infants consistent with DMD or Becker muscular dystrophy. One female DMD carrier was identified. This study demonstrated that the state NBS program infrastructure and screening technologies we used are feasible to perform NBS for DMD. With an increasing number of treatment options, the clinical utility of early identification for affected newborns and their families lends support for NBS for this severe disease.

P.13 What is the future for female patients with childhood onset symptomatic Duchenne muscular dystrophy?

For female patients with childhood onset Duchenne muscular dystrophy (DMD) long-term disease course, specific female symptoms, the consequences for social participation, and with all this the exact need for care, are largely unknown. We aim to study a broad scope of symptoms, functional status, care management, and social participation in a relatively large cohort in order to support guideline development. A cohort of 12 patients was followed for a median period of 17.2 years. One patient deceased during follow-up due to cardiac failure. Fatigue, myalgia, lower back pain and arthralgia occurred in more than half of the patients. Functional status varied, and cardiac abnormalities were infrequent (3 out of 11 patients). Respiratory function, however, was decreased in 9 out of 11 patients, of whom only one had symptoms of hypoventilation. All patients experienced restrictions in education, sports, performing (paid) work and/ or household chores. These results show the wide phenotypic spectrum in female patients with childhood onset DMD, and the medical and social consequences. Respiratory and cardiac screening, but also rehabilitation care is recommended to improve health status and to support daily activities and participation for female DMD patients.

P.26 Motor and cognitive manifestations of young female carriers of Duchenne muscular dystrophy (DMD): a prospective natural history study

Clinical manifestations of Duchenne muscular dystrophy (DMD) have been well documented. However, less is known about the impact of DMD gene mutations for young female carriers. This cross-sectional study seeks to address the gap in understanding of the impact of carrier status on motor skill and cognitive functioning during formative years of development. We examined the motor abilities and neuropsychological functioning of genetically confirmed female DMD carriers in childhood and adolescence. Age appropriate functional and motor outcome assessments were administered including the Neuromuscular Gross Motor Outcome (GRO), 100-meter timed test (100m), Performance of Upper Limb (PUL), and others. Additionally, we assessed intelligence, executive functioning, visual motor integration, behavioral functioning and emotional regulation using standardized testing. To date, 8 subjects have been enrolled, average 11.7 years of age (range: 5–17 years) through the Nationwide Children's Hospital clinics. Gross motor performance was variable across the full cohort ranging between 71–100% of total score on the GRO, 10-95% of average predicted performance on the 100m, and 85-100% of total score on the PUL. Fine motor behavior and visual-motor integration tests indicate this cohort may experience a higher rate of motor coordination deficit and fine motor slowing, as evidenced by performance on norm-referenced assessments including the Grooved Pegboard Test (z-scores range: -0.75 to -5.61; N=7) and Beery Visual Motor Integration Scale (percentiles range: 0.7 – 63; N=7). Individual and group performance on motor outcome assessments and cognitive performance in areas related to attention, organization, working memory, arithmetic/mathematics, and verbal fluency to be presented. Subject enrollment, data collection, and analysis is ongoing.

A Paucisymptomatic HyperCKemia Patient Diagnosed with Manifesting Female Duchenne Muscular Dystrophy Carrier

A Paucisymptomatic HyperCKemia Patient Diagnosed with Manifesting Female Duchenne Muscular Dystrophy Carrier

A scalable, clinically severe pig model for Duchenne muscular dystrophy.

ABSTRACTLarge-animal models for Duchenne muscular dystrophy (DMD) are crucial for the evaluation of diagnostic procedures and treatment strategies. Pigs cloned from male cells lacking DMD exon 52 (DMDΔ52) exhibit molecular, clinical and pathological hallmarks of DMD, but die before sexual maturity and cannot be propagated by breeding. Therefore, we generated female DMD+/− carriers. A single founder animal had 11 litters with 29 DMDY/−, 34 DMD+/− as well as 36 male and 29 female wild-type offspring. Breeding with F1 and F2 DMD+/− carriers resulted in an additional 114 DMDY/− piglets. With intensive neonatal management, the majority survived for 3-4 months, providing statistically relevant cohorts for experimental studies. Pathological investigations and proteome studies of skeletal muscles and myocardium confirmed the resemblance to human disease mechanisms. Importantly, DMDY/− pigs displayed progressive myocardial fibrosis and increased expression of connexin-43, associated with significantly reduced left ventricular ejection fraction, at 3 months. Furthermore, behavioral tests provided evidence for impaired cognitive ability. Our breeding cohort of DMDΔ52 pigs and standardized tissue repositories provide important resources for studying DMD disease mechanisms and for testing novel treatment strategies.

Abstract 15784: Left Ventricular Structural Remodeling and Cardiomyopathy in Duchenne Muscular Dystrophy Carriers

Introduction: Duchenne muscular dystrophy (DMD) is an X-linked neuromuscular disorder. DMD-associated cardiomyopathy is the primary mode of premature death in the majority of male DMD patients, but the prevalence of cardiomyopathy and its clinical significance in female DMD carriers is less well characterized. Hypothesis: We hypothesized that a significant proportion of DMD carriers develop maladaptive left ventricular (LV) structural remodeling and cardiomyopathy over time. Methods: A cross-sectional study was undertaken comparing cardiac magnetic resonance imaging (cMRI) and cardiopulmonary stress test (CPX) parameters between DMD carriers and healthy age- and sex-matched controls from the Dallas Heart Study (DHS). Demographic data, cMRI parameters, and CPX parameters were collected retrospectively on 30 consecutive DMD carriers and 26 control DHS subjects. Results: Overall, DMD carriers had a significantly lower LVEF compared to DHS controls (58+8% vs 70+7%, p< 0.0001). The overall prevalence of reduced LVEF in DMD carriers (defined as LVEF <60%) was 63% compared to 8% in DHS controls. The volumetric variables indexed to body surface area (LVEDVi and LVESVi) were significantly higher in DMD carriers compared to control subjects (72+14 ml/m 2 vs 58+7, p< 0.0001; 31+10 ml/m 2 vs 17+5, p< 0.0001; respectively). LV concentricity was also significantly lower among all DMD carriers compared to DHS controls (3.10+0.65 g/mL 0.67 vs 3.73+0.79, p =0.002). LV concentricity was significantly lower in DMD carriers with reduced EF compared to controls (3.09+0.51 g/mL 0.67 vs 3.73+0.79, p = 0.012), while DMD carriers with preserved EF also had reduced concentricity compared to controls (3.12+0.86 vs 3.73+0.79, p = 0.054). Finally, peak VO 2 was lower in DMD carriers compared to DHS controls (23+6 ml/kg/min vs 25+4, p =0.076), though this difference did not reach statistical significance. Conclusions: Collectively, the data suggest that middle-aged female DMD carriers are at greater risk of developing left ventricular systolic dysfunction and cardiomyopathy associated with decreased exercise capacity. A possible mechanism driving the development of this cardiomyopathy is progressive, maladaptive left ventricular dilatation and cardiac atrophy.

Enhanced dimethylarginine degradation improves coronary flow reserve and exercise tolerance in Duchenne muscular dystrophy carrier mice.

Duchenne muscular dystrophy (DMD) is an X-linked disease caused by null mutations in dystrophin and characterized by muscle degeneration. Cardiomyopathy is common and often prevalent at similar frequency in female DMD carriers irrespective of whether they manifest skeletal muscle disease. Impaired muscle nitric oxide (NO) production in DMD disrupts muscle blood flow regulation and exaggerates postexercise fatigue. We show that circulating levels of endogenous methylated arginines including asymmetric dimethylarginine (ADMA), which act as NO synthase inhibitors, are elevated by acute necrotic muscle damage and in chronically necrotic dystrophin-deficient mice. We therefore hypothesized that excessive ADMA impairs muscle NO production and diminishes exercise tolerance in DMD. We used transgenic expression of dimethylarginine dimethylaminohydrolase 1 (DDAH), which degrades methylated arginines, to investigate their contribution to exercise-induced fatigue in DMD. Although infusion of exogenous ADMA was sufficient to impair exercise performance in wild-type mice, transgenic DDAH expression did not rescue exercise-induced fatigue in dystrophin-deficient male mdx mice. Surprisingly, DDAH transgene expression did attenuate exercise-induced fatigue in dystrophin-heterozygous female mdx carrier mice. Improved exercise tolerance was associated with reduced heart weight and improved cardiac β-adrenergic responsiveness in DDAH-transgenic mdx carriers. We conclude that DDAH overexpression increases exercise tolerance in female DMD carriers, possibly by limiting cardiac pathology and preserving the heart's responses to changes in physiological demand. Methylated arginine metabolism may be a new target to improve exercise tolerance and cardiac function in DMD carriers or act as an adjuvant to promote NO signaling alongside therapies that partially restore dystrophin expression in patients with DMD.NEW & NOTEWORTHY Duchenne muscular dystrophy (DMD) carriers are at risk for cardiomyopathy. The nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) is released from damaged muscle in DMD and impairs exercise performance. Transgenic expression of dimethylarginine dimethylaminohydrolase to degrade ADMA prevents cardiac hypertrophy, improves cardiac function, and improves exercise tolerance in DMD carrier mice. These findings highlight the relevance of ADMA to muscular dystrophy and have important implications for therapies targeting nitric oxide in patients with DMD and DMD carriers.

Functional performance and muscular strength in symptomatic female carriers of Duchenne muscular dystrophy.

To investigate the motor and functional impairments of 10 female patients with dystrophinopathy diagnosed with clinical, pathological, genetic and immunohistochemical studies. A descriptive study of a sample of symptomatic female carriers of DMD mutations. The studied variables were muscular strength and functional performance. The prevalence was 10/118 (8.4%) symptomatic female carriers. Deletions were found in seven patients. The age of onset of symptoms in female carriers of DMD was quite variable. Pseudohypertrophy of calf muscles, muscular weakness, compensatory movements and longer timed performance on functional tasks were observed in most of the cases. Differently from males with DMD, seven female patients showed asymmetrical muscular weakness. The asymmetric presentation of muscle weakness was frequent and affected posture and functionality in some cases. The functional performance presents greater number of compensatory movements. Time of execution of activities was not a good biomarker of functionality for this population, because it does not change in the same proportion as the number of movement compensations. Clinical manifestation of asymmetrical muscle weakness and compensatory movements, or both can be found in female carriers of DMD mutations, which can adversely affect posture and functional performance of these patients.

DMD carrier model with mosaic dystrophin expression in the heart reveals complex vulnerability to myocardial injury.

Duchenne muscular dystrophy (DMD) is a devastating neuromuscular disease that causes progressive muscle wasting and cardiomyopathy. This X-linked disease results from mutations of the DMD allele on the X-chromosome resulting in the loss of expression of the protein dystrophin. Dystrophin loss causes cellular dysfunction that drives the loss of healthy skeletal muscle and cardiomyocytes. As gene therapy strategies strive toward dystrophin restoration through micro-dystrophin delivery or exon skipping, preclinical models have shown that incomplete restoration in the heart results in heterogeneous dystrophin expression throughout the myocardium. This outcome prompts the question of how much dystrophin restoration is sufficient to rescue the heart from DMD-related pathology. Female DMD carrier hearts can shed light on this question, due to their mosaic cardiac dystrophin expression resulting from random X-inactivation. In this work, a dystrophinopathy carrier mouse model was derived by breeding male or female dystrophin-null mdx mice with a wild type mate. We report that these carrier hearts are significantly susceptible to injury induced by one or multiple high doses of isoproterenol, despite expressing ~57% dystrophin. Importantly, only carrier mice with dystrophic mothers showed mortality after isoproterenol. These findings indicate that dystrophin restoration in approximately half of the heart still allows for marked vulnerability to injury. Additionally, the discovery of divergent stress-induced mortality based on parental origin in mice with equivalent dystrophin expression underscores the need for better understanding of the epigenetic, developmental, and even environmental factors that may modulate vulnerability in the dystrophic heart.

What is the Ocular phenotype associated with a dystrophin deletion of exons 12-29?

Duchenne muscular dystrophy (DMD) is a result of a X-linked recessive inherited mutation of the DMD gene which contains 79 exons. This rare disease is passed on by the mother who is called a carrier. Primarily it affects boys, but in rare cases it can affect girls. Dystrophin protein is mostly located in skeletal and cardiac muscles, which explains muscular and cardiac manifestations in symptomatic female DMD-carriers. Dystrophin is also present in extramuscular tissues. Some dystrophin isoforms are exclusively or predominantly expressed in the brain or the retina. It has been reported that DMD patients and DMD-carriers present normal visual acuity, but abnormal electroretinographic findings. As symptomatic female DMD are very rare, ophthalmic screening of the female patient with deletions of exons 12- 29 is valuable. Studying the functional relationship between ocular symptoms and related different deletions of exons dystrophin gene may further elucidate the pathophysiology in DMD.

Abstract 415: Transgenic Expression of Dimethylarginine Dimethylaminohydrolase Attenuates Exercise-induced Fatigue in Duchenne Muscular Dystrophy Carrier Mice

Duchenne muscular dystrophy (DMD) is an X-linked disease caused by mutations in dystrophin and characterized by muscle degeneration, cardiomyopathy, and impaired muscle nitric oxide (NO) production that disrupts muscle blood flow regulation and leads to excessive post-exercise fatigue. Interestingly, circulating levels of the endogenous NO synthase inhibitor asymmetric dimethylarginine (ADMA) are elevated in dystrophin-deficient subjects. Therefore, we hypothesized that excessive circulating ADMA impairs muscle NO production and thus negatively impacts exercise tolerance in DMD. The objectives of this study were to determine whether increased circulating ADMA is itself sufficient to affect exercise performance, and whether transgenic modulation of ADMA metabolism could improve exercise-induced fatigue in the mdx mouse model of DMD. Although infusion of exogenous ADMA did impair exercise performance in healthy, wild-type mice, transgenic expression of dimethylarginine dimethylaminohydrolase 1 (DDAH), the enzyme that degrades ADMA, did not affect exercise-induced fatigue in dystrophin-deficient male mdx mice. Surprisingly, DDAH transgene expression did attenuate exercise-induced fatigue in dystrophin-heterozygous female mdx carrier mice. This improvement in exercise tolerance was associated with reduced heart weight, improved cardiac contractile function, and improved chronotropic responsiveness to beta-adrenergic stimulation in DDAH-transgenic female mdx carriers. In contrast, DDAH transgene expression did not significantly affect skeletal muscle pathology in female mdx carriers. We conclude that DDAH transgene expression improves exercise tolerance in dystrophin-heterozygous females, possibly by limiting pathological cardiac remodeling and helping to maintain heart performance. These findings emphasize the importance of methylated arginines to the development of cardiomyopathy in female DMD carriers, and have interesting implications for current genetic therapies that may only partially restore dystrophin expression in the hearts of male DMD patients.

Long-Term Pathological Follow-Up of Myocardium in a Carrier of Duchenne Muscular Dystrophy With Dilated Cardiomyopathy

Duchenne muscular dystrophy (DMD) is a fatal X-linked disorder, with an incidence of ≈1 in 3600 to 6000 male births. DMD is caused by mutations in the dystrophin gene located at Xp21.2 and is clinically characterized by progressive muscle degeneration and dilated cardiomyopathy (DCM). Some female DMD carriers show a variety of clinical manifestations, ranging from creatine kinase elevation to severe muscle weakness. DCM has been reported in 8% to 18% of female DMD carriers and sometimes results in a lethal course. Here, we describe long-term follow-up observations of myocardial changes in a DMD carrier with DCM. A 29-year-old female presented with progressive shortness of breath, increasing ankle edema, and orthopnea after a full-term normal delivery. A chest X ray showed cardiomegaly and bilateral pleural effusions, and echocardiography showed a severely reduced left ventricular ejection fraction of 24%, with a markedly increased left ventricular end-diastolic diameter of 71 mm. She was admitted for heart failure, and her symptoms improved with furosemide and inotropes. There were no symptoms to suggest myopathy, and blood analysis revealed no elevation of creatine kinase (60 U/L). Her newborn boy showed extreme elevation of creatine kinase (105 868 U/L) and was diagnosed with DMD …

Myocardial Fibrosis and Left Ventricular Dysfunction in Duchenne Muscular Dystrophy Carriers Using Cardiac Magnetic Resonance Imaging.

The goal of our study was to characterize the degree of myocardial fibrosis and left ventricular dysfunction in our cohort of Duchenne muscular dystrophy (DMD) carriers using cardiac magnetic resonance imaging (CMR). Seventy percent of males with DMD have mothers who are carriers of the Xp21 mutation. Carrier phenotypic characteristics range from asymptomatic to left ventricular (LV) dysfunction and cardiomyopathy. The true prevalence of cardiac involvement in DMD carriers is unknown. We performed a retrospective observational study. All female DMD carriers who underwent clinical CMR studies at Cincinnati Children's Hospital Medical Center from December 6, 2006, to August 28, 2013, were evaluated. Patients underwent standard CMR assessment with LV function assessment and late gadolinium enhancement (LGE). In addition, offline feature tracking strain analysis was performed on the basal, mid, and apical short axis. Twenty-two patients were studied, of which 20 underwent adequate testing for myocardial LGE. Four of 22 patients (18 %) were found to have LV dysfunction (ejection fraction <55 %). Seven of 20 DMD carriers (35 %) were found to have LGE. The patients with evidence of LGE had an overall trend to lower absolute deformation parameters; however, this did not meet statistical significance when correcting for multiple comparisons. Our study demonstrates a high rate of LGE as well as LV dysfunction in DMD carriers. Cardiovascular and musculoskeletal symptoms were not statistically different between those with and without cardiac involvement. This study demonstrates the importance of surveillance CMR evaluation of DMD carriers.

Muscle-specific discordant skewing of X-chromosome inactivation leads to different clinical phenotypes of Duchenne muscular dystrophy in two monozygotic female twins

Background: Mutations within the DMD gene leading to the absence or vast reduction of dystrophin cause Duchenne muscular dystrophy (DMD). The majority of female heterozygous carriers of X-linked recessive DMD mutations are asymptomatic or mildly affected due to the balanced X-inactivation. However, in rare cases of female DMD carriers skewed X-inactivation leads to clinical symptoms.

The use of cffDNA in fetal sex determination during the first trimester of pregnancy of female DMD carriers

Chorionic villus sampling (CVS) or amniocentesis for fetal sex determination is generally the first step in the prenatal diagnosis of X-linked genetic disorders such as Duchenne muscular dystrophy (DMD). However, non-invasive prenatal diagnostic (NIPD) techniques such as measurement of cell-free fetal DNA (cffDNA) in maternal plasma are preferable given the procedure-related miscarriage rate of CVS. We determined fetal sex during the first trimester using a quantitative real-time polymerase chain reaction (PCR) assay of cffDNA in pregnant carriers of DMD. The fetal sex was confirmed by amniocentesis karyotype analysis and multiplex ligation-dependent probe amplification (MLPA) at 16 weeks. This procedure may avoid unnecessary CVS or amniocentesis of female fetuses.

Three Cases of Manifesting Female Carriers in Patients with Duchenne Muscular Dystrophy

Duchenne muscular dystrophy usually affects males. However, females are also affected in rare instances. Approximately 8% of female Duchenne muscular dystrophy (DMD) carriers are manifesting carriers and have muscle weakness to some extent. We investigated the clinical features of 3 female patients with dystrophinopathy diagnosed by clinical, pathological, and genetic studies at our neuromuscular disease clinic. The onset age of manifesting symptoms varied (8-28 years). Muscle weakness grade varied as follows: patient 1 showed asymmetrical bilateral proximal upper and lower extremities weakness, patient 2 showed asymmetrical bilateral upper extremities weakness similar to scapulohumoral muscular dystrophy, and patient 3 had only bilateral asymmetric proximal lower extremities weakness. Two patients had familial histories of DMD (their sons were diagnosed with DMD), but the 1 remaining patient had no familial history of DMD. The serum creatine kinase level was elevated in all patients, but it was not correlated with muscular weakness. An electromyography study showed findings of myopathy in all patients. One patient was diagnosed with a DMD carrier by a muscle biopsy with an immunohistochemical stain (dystrophin). The remaining 2 patients with familial history of DMD were diagnosed by multiplex ligation-dependent probe amplification (MLPA). There were inconsistent clinical features in the female carriers. An immunohistochemical analysis of dystrophin could be useful for female carrier patients. Also, multiplex ligation-dependent probe amplification is essential for the diagnosis of a manifesting female carrier DMD in female myopathic patients because conventional multiplex PCR could not detect the duplication and is less accurate compared to MLPA.

Diagnostic utility of cardiac magnetic resonance for detection of cardiac involvement in female carriers of Duchenne muscular dystrophy

BackgroundCardiac involvement is a recognised complication in female carriers of Duchenne muscular dystrophy (DMD). Since segmental or global left ventricle (LV) wall motion abnormalities in DMD carriers can arise even...

Homozygous female Becker muscular dystrophy

We report, for the first time, on a female Becker muscular dystrophy (BMD) patient with homozygous dystrophin deletion. The 14-year-old patient, product of consanguineous parents, presented with a 7-year history of exercise intolerance and recurrent myoglobinuria. Although CK was elevated to 1,800 U/L, no muscle weakness, atrophy, or hypertrophy was seen on examination. Muscle pathology demonstrated a minimal dystrophic change and faint dystrophin staining pattern. Semi-quantitative PCR of dystrophin revealed a homozygous dystrophin deletion of exons 45-55, which is predicted to remove 593 amino acids without frame shifting. Western blot analysis of skeletal muscle for dystrophin showed a 306 kDa band; thus, we made a diagnosis of female BMD. We confirmed identical deletion in both father and mother, in hemizygous and heterozygous modes, respectively. Neither female Duchenne muscular dystrophy (DMD) nor BMD due to homozygous dystrophin mutation has ever been identified although female DMD has been found in patients with Turner syndrome or unilateral parental disomy for X chromosome. Our results indicate that dystrophinopathy can also be caused in females by homozygosity, albeit rare.

Co-occurrence of mutations in both dystrophin- and androgen-receptor genes is a novel cause of female Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder. Here, we report a novel mechanism for the occurrence of DMD in females. In a Vietnamese DMD girl, conventional PCR amplification analysis disclosed a deletion of exons 12-19 of the dystrophin gene on Xp21.2, with a karyotype of 46, XY. Furthermore, a novel mutation in the androgen-receptor gene on Xq11.2-q12 was identified in this girl, which led to male pseudohermaphroditism. Co-occurrence of mutations of these two genes constitutes a novel mechanism underlying female DMD.