Highlights
- Fabry disease impacts women significantly, necessitating increased awareness and timely diagnosis.
- Multidisciplinary management and novel therapies are essential for improving outcomes in affected females.
Fabry Disease in Females: Overview and Genetics
Fabry disease (FD) is a rare X-linked lysosomal disorder caused by GLA gene mutations, leading to deficient α-galactosidase A activity and globotriaosylceramide accumulation. While traditionally considered a male disease, heterozygous females also exhibit a wide range of symptoms from asymptomatic to severe multisystem involvement due to X-chromosome inactivation (XCI) variability. Skewed XCI can cause females to have disease severity comparable to males, complicating diagnosis since enzyme assays may appear normal.
The disease affects multiple organs including the nervous system, kidneys, heart, and gastrointestinal tract. Diagnosis in females requires genetic testing combined with clinical evaluation and biomarkers like lyso-Gb3. Multidisciplinary management often includes enzyme replacement therapy (ERT) or pharmacologic chaperones such as migalastat.
Clinical Manifestations in Females
Females with FD experience diverse symptoms influenced by XCI, often with later onset and variable severity. Common features include:
- Neuropathic pain: Affects nearly half of female patients, presenting as burning pain and episodic crises that impair quality of life.
- Cerebrovascular events: Stroke and transient ischemic attacks occur in 5–27%, often later in life, with MRI showing white matter lesions.
- Renal involvement: Proteinuria is frequent, but progression to end-stage renal disease is less common than in males.
- Cardiac disease: Includes ventricular hypertrophy, valvular defects, and conduction abnormalities, sometimes mimicking hypertrophic cardiomyopathy.
- Gastrointestinal symptoms: Early abdominal pain and diarrhea are common.
Diagnosis Challenges and Approaches
Diagnosing FD in females is challenging due to normal or borderline α-Gal A enzyme levels caused by mosaic XCI. Genetic sequencing of the GLA gene is essential for confirmation, with lyso-Gb3 serving as a useful but sometimes variable biomarker. Diagnosis relies on combining clinical, biochemical, and genetic data within a multidisciplinary framework involving specialists in genetics, nephrology, cardiology, and neurology.
Disease Progression and Prognosis
Symptoms in females typically begin in adolescence or adulthood, with diagnosis often delayed until the third decade. Disease severity correlates with the degree of skewed XCI. Life expectancy is reduced by about 15 years compared to the general population, mainly due to cardiac complications. Renal pathology can progress gradually, emphasizing the need for early recognition and monitoring to prevent serious outcomes.
Treatment and Management
Management requires a multidisciplinary team approach. ERT with agalsidase alpha, beta, or pegunigalsidase alfa is the primary treatment, supplemented by migalastat for eligible mutations. Treatment initiation in females is based on clinical signs rather than genetics alone. Psychosocial support is critical, as fatigue, pain, and emotional challenges significantly impact quality of life.
Psychosocial Impact and Support
Women with FD often experience social functioning deficits, high rates of fatigue, and emotional distress related to chronic pain and systemic complications. Early psychosocial assessment and support improve coping and overall well-being. Specialized tools help evaluate neuropsychiatric symptoms and guide tailored interventions. Patient registries and support groups provide additional resources and community connection.
Importance of Early Detection and Awareness
Early diagnosis in females is vital to prevent irreversible organ damage and enable timely treatment. Due to variable symptoms and uninformative enzyme assays, genetic testing and awareness among healthcare providers are essential. Improved recognition facilitates family screening, genetic counseling, and better clinical outcomes.
Research and Future Directions
Research focuses on improving diagnostic biomarkers beyond enzyme assays, such as lyso-Gb3 and high-sensitive troponin T, and developing novel therapies including gene and stem cell treatments. Large registries like the Fabry Outcome Survey enhance understanding of disease variability and treatment effects in females. Ongoing efforts aim to tailor management to female-specific needs and improve prognosis.
The content is provided by Blake Sterling, Scopewires
