Reviews

Volume XLIV n. 1 - March 2025

Females with X-Linked Muscle Disorders: an underestimated patient population

Authors

Luisa Politano

Key words: Duchenne muscular dystrophy, Becker muscular dystrophy, Emery-Dreifuss muscular dystrophy, Myotubular Myopathy, X-chromosome inactivation, X-linked muscle disorders affected females
DOI: 10.36185/2532-1900-1096
Publication Date: 2025-03-28

Abstract

Carriers of genetic diseases including female carriers of X-linked disorders are traditionally believed to be asymptomatic due to the compensatory presence of the unmutated gene on the other allele. However, in recent decades numerous contributions have appeared in the literature showing how females carrying X-linked diseases can also present signs and symptoms linked to the specific gene defect. To explain the clinical manifestations observed in female carriers, several mechanisms leading to a reduced protein expression have been hypothesized, in particular the role of the X-chromosome inactivation (XCI). In this review, the focus will be on the relationship between skewed XCI and the development of muscle or cardiac symptoms in female carriers of the most frequent types of muscle disorders such as Duchenne and Becker muscular dystrophies, Emery-Dreifuss muscular dystrophy and Myotubular Myopathy. In all cases, there is a tendency for females with a more severe phenotype to have a skewed pattern of XCI, while females with an intermediate phenotype have a random pattern. Given the increasing recognition of important clinical presentations in females with X-linked muscle disorders and the recent availability of causal therapies for these diseases, specific guidelines are desirable and recommended that allow women to be properly recognized and have access to appropriate therapies.

Introduction

Muscle diseases are a heterogeneous group of disorders affecting skeletal muscles, characterised by progressive muscle wasting and weakness 1. According to the pattern of inheritance, they are classified in autosomal dominant and recessive disorders and in prevalent recessive X-linked muscle disorders 2.

The most frequent forms of X-linked recessive muscle disorders are dystrophinopathies, namely Duchenne (DMD) and Becker (BMD) muscular dystrophies, Emery-Dreifuss muscular Dystrophy (EDMD1) and myotubular myopathy (XLMTM).

Duchenne and Becker dystrophinopathies (DMD, OMIM #310200 and BMD, OMIM #302045) are caused by mutations in the dystrophin gene that lead to absent (DMD) or reduced (BMD) expression of the dystrophin protein in both skeletal and heart muscles 3.

DMD is the severe form of dystrophinopathy spectrum, with onset in early childhood and rapid progression such that by the age of 3-5 there is likely to be a waddling gait and positive Gowers’ sign 4. The incidence of DMD has been recently estimated in 1: 6.500 male births 5. In untreated boys, walking is lost by 12 years of age (mean 9.5 years). Respiratory failure and cardiomyopathy develop following the loss of ambulation and are the main cause of death 6-8. However, current standards of care considerably prolong independent ambulation and survival 9-11.

BMD, the benign form of dystrophinopathy, presents a broad spectrum of clinical severity, with onset of symptoms occurring from early childhood to as late as the sixth decade 12. The estimated prevalence of BMD in Europe ranges between 1:16,700-1:18,500 male births. Onset is usually in childhood typically after 7 years of age, but can be later. Presenting features in children include toe walking gait and/or exercise-related cramps with or without myoglobinuria. In older patients, cardiomyopathy may be the presenting feature. The condition is slowly progressive and about 40% of affected patients will eventually become wheelchair-dependent. Cardiac involvement leads to dilated cardiomyopathy, which can be disproportionate to skeletal muscle involvement 13. Life expectancy for patients can be normal but may be significantly shortened by dilated cardiomyopathy or, in wheelchair patients, by respiratory failure 14,15.

EDMD1 (OMIM #310300) is due to mutations in EDM gene and affects approximately 1:100,000 male births 16. It is characterised by the clinical triad of the Achilles, elbow and posterior neck tendons joint contractures, and cardiac anomalies (conduction defects, rhythm disturbances and dilated cardiomyopathy) that may lead to sudden cardiac death 16,17. Disease course and severity vary between and within families. Patients with severe forms of the disease may lose the capacity to walk, or may require intermittent nasal ventilation 18.

X-linked myotubular myopathy (XLMTM, OMIM #300415) is a severe congenital muscle disease caused by mutation in the MTM1 gene. MTM1 encodes myotubularin (MTM1), an endosomal phosphatase that acts to dephosphorylate key second messenger lipids PI3P and PI3.5P219. XLMTM is clinically characterized by profound muscle weakness, associated multiple disabilities (including ventilator and wheelchair dependence) and early death in most affected individuals. The estimated incidence of XLMTM is 1:50,000 male births worldwide 20.

Carriers of X-linked genetic muscle disorders

Usually, X-linked genetic disorders are passed to sons through unaffected carrier females. Affected males, who survive to reproduce, can have affected grandsons through their daughters, who are obligate carriers. Affected males cannot transmit the disorder to their sons.

Carriers of genetic diseases, including female carriers of X-linked disorders, are traditionally believed to be asymptomatic due to the compensatory presence of the unmutated gene on the other allele. However, in recent decades, numerous contributions have appeared in the literature showing how females carrying X-linked diseases can also present signs and symptoms linked to the specific gene defect.

To explain the clinical manifestations observed in female carriers, several mechanisms leading to a reduced protein expression have been hypothesized, in particular the role of the X-chromosome inactivation (XCI). X-chromosome inactivation, discovered by Mary Lyon in 196121, results in the random silencing of one X chromosome in female mammals as a form of dosage compensation to balance X-linked gene expression levels of the sexes 22. Skewed X chromosome inactivation describes the phenomenon whereby more than 75% of an individual’s cells choose one parent’s X chromosome as the inactive X 21,22.

It is estimated that 1.5-23% of females have skewed X inactivation 22-25. The degree of XCI skewing may influence the severity of some diseases including haemophilia B 26-27, dyskeratosis congenita 28, Fabry Disease 29-31, as well as Duchenne and Becker muscular dystrophies, Emery-Dreifuss muscular Dystrophy and Myotubular Myopathy, which will be the topic of this mini-review.

Duchenne/Becker carriers

About 2.5-18% of DMD/BMD carriers may present with varying degrees of muscle weakness, attributed to a reduced production of dystrophin in muscle cells. Beside muscle involvement, DMD/BMD carriers may develop cardiomyopathy after the age of 40, without significant differences in percentage 32. Myocardial damage shows the same behaviour already described in DMD/BMD patients 7 and progresses from preclinical to dilated cardiomyopathy, passing through stages of myocardial hypertrophy or dysrhythmias. The occurrence of cardiomyopathy increases significantly with age passing from about 50% in young carriers below the age of 16 to about 80-90% in older carriers 32. Dystrophin anomalies have been detected at the membrane level of the cardiomyocites on endomyocardial biopsy specimens 33.

We have shown that DMD and BMD symptomatic carriers had a preferential inactivation of the X-chromosome carrying the normal allele, while non-symptomatic carriers and healthy females showed a random XCI pattern 34,35. Moreover, when comparing muscle with heart symptomatic carriers, the former group showed a higher degree of skewing. Furthermore, no concordance in XCI was found between mothers and daughters, when symptomatic/asymptomatic mother-daughter pairs were analysed 34,35. Morover, the development of signs and symptoms of dystrophinopathy in carriers with X;autosome translocations involving the locus Xp21, was associated with non-random patterns of XCI 36.

Emery-Dreifuss Muscular Dystrophy carriers

EDMD1 female carriers are usually free of muscle symptoms but may present cardiac involvement after age 50, especially in the form of conduction tissue anomalies and/or arrhythmias. Intra-familial variability has been reported 37. Long-term cardiac follow-up of a large family with five affected males and seven carrier females revealed varying degrees of severity, ranging from tachycardia-bradycardia syndrome and variable bi-atrial and left ventricular dilatation to episodes of isolated symptomatic sustained ventricular tachycardia requiring device implantation 38. We first evaluated the relation between heart involvement in symptomatic EDMD1 carriers and XCI by studying its pattern in 30 EDMD1 female carriers subdivided according to the age (above or below 50 years) 39. We showed that 20% of them, 50% of whom were over 50 years old, had cardiac symptoms. No differences in XCI pattern between symptomatic and asymptomatic carriers were observed thus suggesting that arrhythmias in EDMD1 carriers poorly correlate with a skewed XCI analyzed on lymphocytes. We hypothesized that such a discordance may be due to (a) the different embryological origin of cardiac conduction tissue compared to lymphocytes or (b) the preferential loss of atrial cells replaced by fibrous tissue 39.

Myotubular Myopathy carriers

Female carriers of MTM1 mutations can also manifest symptoms that can vary from very mild to severe generalized congenital weakness 40,41. The symptomatic carriers typically have limb-girdle weakness, asymmetric muscle weakness and skeletal size, urinary incontinence, facial weakness, ptosis and ophthalmoplegia 40,41. Myalgias and muscle fatigue are common and debilitating symptoms 42. In its most severe form, manifesting carriers can have a severe motor impairment with wheelchair dependence and the need for respiratory support. Also for this group of female carriers, it has been proposed that skewed X inactivation is responsible for the affected phenotype. In partixular, by comparing XCI patterns in blood DNA with the phenotype in carriers of XL-MTM, Kristiansen et al. 43 reported that there was a tendency for females with a more severe phenotype to have a skewed pattern of XCI, while females with an intermediate phenotype had a random pattern 43.

Conclusions

In conclusion, there is a increasing recognition of important clinical presentations in affected girls and women with X-linked muscle disorders. However, despite several papers in literature document the role of skewed XCI in the development of symptoms, there is no consensus on this issue and measuring the degree of X inactivation is not currently considered as clinically helpful.

Therefore, greater awareness and close collaboration among healthcare professionals (pediatric and adult neurologists, clinical geneticists, cardiologists and general practitioners) regarding the possible clinical spectrum of women with X-linked muscle disorders and its impact on daily life is necessary, so that these patients can benefit from the same diagnostic and therapeutic options offered to affected males.

Given the recent availability of causal therapies for these pathologies, specific guidelines are desirable and recommended that allow women with X-linked muscle diseases to be adequately recognized and have access to appropriate therapies.

Acknowledgements

A special thanks to colleagues and patients and their families for their availability over the years.

Funding

None.

Conflicts of interest statement

The author declares no conflict of interest.

Ethical consideration

Not applicable.

Authors’ contributions

Not applicable.

History

Received: March 3, 2025

Accepted: March 19, 2025

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Luisa Politano - Cardiomyology and Medical Genetics, University of Campania Luigi Vanvitelli, Naples, Italy, 2024 Pisa Muscle Award Winner

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How to Cite
Politano, L. (2025). Females with X-Linked Muscle Disorders: an underestimated patient population. Acta Myologica, 44(1). https://doi.org/10.36185/2532-1900-1096
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