Females with dystrophinopathy: A neglected patient population

R E F E R E N C E S 1. Frazier T, Dimitropoulos A, ArmstrongBrine M, Krakovic S, Shih A, Hardan A, Youngstrom E, Uljarevic M. The Autism Symptoms Dimensions Questionnaire: Development and psychometric evaluation of a new, opensource measure of autism symptomatology. Dev Med Child Neurol. 2023; 65: 1081– 92. 2. Donohue M, Childs A, Richards M, Robins D. Race influences parent report of concerns about symptoms of autism spectrum disorder. Autism. 2017; 23: 100– 111. 3. Zheng S, Kaat A, Farmer C, Thurm A, Burrows C, Kanne S, Georgiades S, Esler A, Lord C, Takahashi N, Nowell K, Will E, Roberts J, Bishop S. Bias in measurement of autism symptoms by spoken language level and nonverbal mental age in minimally verbal children with neurodevelopmental disorders. Front Psychol. 2022; 13: 927847. 4. Armstrong K, Duvall SW. Introductory editorial to the special issue: Assessment and diagnosis of autism spectrum disorder (ASD) and related clinical decision making in neuropsychological practice. Clin Neuropsychol. 2022; 36: 851– 855.

In human genetics, a gene carrier is an individual who carries a heterozygous gene that causes an inherited disease and who is essentially healthy at the time of the study. In the case of X-linked dystrophinopathies, including Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD), the term 'carrier' means a female who carries a mutation in the DMD gene.
It is a misconception that DMD/BMD carriers are always unaffected by the disease 1 simply because they usually present as asymptomatic. However, approximately 8% to 10% of carriers may experience muscle symptoms that vary in severity and age at onset, ranging from very mild muscle involvement but raised blood creatine kinase levels to severe myopathy, like that seen in affected males. 2 DMD gene carriers may also have severe myocardial involvement, in particular dilated cardiomyopathy characterized by significant left ventricular dilation and reduced ejection fraction. 3 However, the lack of natural history data and dedicated research have so far impaired the management of symptomatic females. In light of this, the paper by Houwen-van Opstal et al. 4 on the long-term outcome for females with early-onset dystrophinopathy is an interesting and appropriate contribution because it shows how 'females with early-onset dystrophinopathy experience a wide range of impairments, comorbidities, limitations in activities, and restrictions in social participation'. 4 To explain the onset of symptoms in BMD and DMD carriers, several mechanisms have been hypothesized; among them, the most cited is the preferential inactivation of the X chromosome (XCI) carrying the normal dystrophin allele. XCI is an epigenetic mechanism that equalizes X-linked gene dosage between males and females through the inactivation of one X chromosome in females. At the end of the process, females are a mosaic of two cell types expressing the maternal or paternal X chromosome. A random XCI indicates that cells present an equal (50:50) inactivation of the maternal or paternal X chromosome, while a skewed XCI indicates an unequal (>50%) inactivation between the two X chromosomes. The term 'extremely skewed' XCI indicates the preferential inactivation of one X chromosome in more than 90% to 95% of cells. Based on the degree of XCI in muscles or cardiac cells, DMD/BMD carriers may manifest different pictures of female dystrophinopathy.
Early-onset female dystrophinopathy is characterized by onset before 15 years and leads to severe muscle manifestations, while cardiomyopathy prevails in females aged more than 50 years. Cardiac symptoms may develop even in the absence of muscle weakness or occur in association with muscle involvement. Cardiomyopathy can develop de novo and/or its severity can progress over time if left untreated. Furthermore, an initially normal cardiac evaluation does not preclude subsequent development of symptoms. The course of cardiomyopathy may be silent or asymptomatic until the advanced stages and treatment is currently the same as for males with dystrophin-related left ventricular dysfunction. The course can be stabilized and/or improved by combining cardiac medications, while surveillance is necessary for an early diagnosis of cardiac, muscle, or respiratory involvement.
We studied the role of XCI in determining the onset of muscle or cardiac symptoms in females carrying pathogenic variants of the DMD gene and demonstrated a high degree of correlation between skewed or extremely skewed XCI and the DMD/BMD phenotype. 5 However, there is no consensus on this issue and measuring the degree of X inactivation is not currently considered as clinically helpful.
Increased awareness and close collaboration among health care professionals -adult and paediatric neurologists, clinical geneticists, cardiologists, and general practitioners -about the possible clinical spectrum of female dystrophinopathy and its impact on daily life ( Figure S1) is necessary for females to benefit from the same diagnostic and treatment options offered to affected males.
In the era of personalized medicine and recent availability of causative therapies for DMD (e.g. ataluren for nonsense mutations), the lack of specific guidelines prevents the issues of females with dystrophinopathies from being rightfully recognized as well as preventing females from accessing appropriate therapies.

AC K NOW L E D GE M E N T S
Open Access Funding provided by Universita degli Studi della Campania Luigi Vanvitelli within the CRUI-CARE Agreement.

DATA AVA I L A BI L I T Y S TAT E M E N T Not required
ORC I D Luisa Politano https://orcid.org/0000-0002-0925-7158

R E F E R E NC E S
Despite being essential components of high-quality patientcentered care, sexual health care and education are often inadequately provided to people with disabilities including those with spina bifida. [1][2][3] The reasons for this are many and include parental and provider discomfort, lack of provider knowledge of disability-specific sexual health needs of their patients, limited time in clinical encounters, the expectation that someone else will provide sexual health services, the need to focus on urgent clinical problems, and the misperceptions that individuals with disabilities are asexual. 2,3 All of these barriers are amenable to change.
Clinicians involved in the care of people with spina bifida, whether in a multidisciplinary clinic such as the site of the research conducted by Lutz et al. 3 or in outpatient clinical settings, should consider the sexual health needs of their patients just as they consider other health needs. The World Health Organization, American Academy of Pediatrics, and Spina Bifida Association all promote access to culturally responsive sexual health care. 2,4,5 Sexual education for people with spina bifida should be delivered in a longitudinal and developmentally appropriate manner. Clinicians should recognize that developing a healthy sexuality is a key component of growing up and should be considered in the context of our basic human desires for connectedness and intimacy, not something that is shameful and taboo. 2 Some parents may assume that providing