Don’t Forget About Fabry Disease


A rare genetic disorder may have unrecognized psychological consequences.



Fabry disease is a rare genetic disorder, so rare that its psychiatric consequences remain poorly understood. Although there have been studies evaluating psychological and psychiatric issues among patients with Fabry disease, very little has been written about individuals challenged by the burdensome symptoms associated with the disease, or about the emotional distress that can result from living with a chronic condition. It is crucial that health care providers are equipped to recognize potential psychological or psychiatric challenges and are able to refer patients with Fabry disease for an appropriate assessment. A better understanding of anxiety and depression in Fabry patients has important implications for health service planning, evaluation of therapeutic treatments, and clinical management.

Causes and Consequences

Fabry disease is a pan-ethnic, X-linked lysosomal storage disorder caused by a deficiency of the enzyme α-galactosidase A (α-GAL); that results in the progressive accumulation of globotriaosylceramide, or Gb3.1-3 Classic Fabry disease mutations are seen in approximately 1:22,000 to 1:40,000 males, and atypical presentations are associated with about 1:1000 to 1:3000 males and 1:6000 to 1:40,000 females with a spectrum of phenotypes.4 Phenotypes vary from the classic phenotype, to a later-onset, predominantly cardiac phenotype. Manifestations are diverse in female patients in part due to variations in residual enzyme activity and X chromosome inactivation patterns. Newborn screening (NBS) studies revealed frequencies of the classic and later-onset phenotypes of up to 1 in 22,570 males and 1 in 1390 males, respectively.5

As Fabry disease progresses, it results in a multisystemic disease affecting the renal, cardiac, pulmonary, ocular, and dermal systems, as well as the peripheral and central nervous systems (CNS).6 Consequently, as substrate continues to build up, cellular dysfunction triggers organ impairment and eventually system damages. This can lead to substantial morbidity and reduced life expectancy, especially for patients who are untreated.7

Fabry disease encompasses a spectrum of phenotypes ranging from the severe classic phenotype to atypical forms. The effective management of Fabry disease requires a multidisciplinary approach. It can be treated with bimonthly infusions of enzyme replacement therapy (ERT) to replace deficient α-galactosidase A, oral chaperone therapy, conventional medical treatment, or adjunct therapies.

CNS involvement precipitates cerebral micro and macro angiopathy leading to stroke at an early age, with an estimated prevalence of 6.9% in male and 4.3% in female Fabry disease patients.8,9 CNS alterations reported include increased occurrence of white matter lesions (WML), dilation and tortuosity of the larger intracranial arteries, signal enhancement of the lateral pulvinar on T1 weighted images, and hippocampal atrophy.10-12 In non-Fabry cohorts, WMLs have frequently been related to processing speed, memory, and executive functioning deficits.13 In Fabry disease, cognitive deficits have been described primarily in attention, executive functions, and psychomotor performance.1,14

Autopsy studies in Fabry disease patients have repeatedly shown severe globotriosylceramide (Gb3) accumulation in the neurons and ganglion cells of the hippocampus, which could ultimately lead to functional deterioration of the cells, compromised energy metabolism, oxidative stress, and cellular death.15 Gb3 deposition in Fabry disease is the result of the inherited reduction of α-Galactosidase and causes clinical manifestation in early childhood, with a slight delay in girls.9 Early accumulation of Gb3 in the lysosomes of cells and subsequent cellular death could thus be responsible for such early hippocampal atrophy, as observed in some studies. Neuropathic pain and major depression have also been shown to be strongly related to reduced hippocampal volume (HV) in otherwise healthy subjects.16 Given that pain and depression are frequent symptoms in Fabry disease, the impact of both on HV decline seems expected, but research is variable. Depressive symptoms naturally fluctuate over the course of time due to symptom variability and progression of the disease.17 Placebo-controlled studies are needed to address antidepressant treatment options in patients with Fabry disease, as depression can be a major burden on the lives of patients and families.17

Clinical Manifestations Over a Lifespan

In Fabry disease, the presence of substrate accumulation can be traced back to the prenatal period; however, symptoms generally do not develop before early childhood.18 Affected children may experience acute and chronic neuropathic pain, described as a burning sensation and tingling in the hands and feet (acroparesthesia). They may also present with sweating abnormalities (anhidrosis, hypohidrosis) that make it difficult to exercise and perform physical activities. Abdominal pain and diarrhea have also been reported. During adolescence, gastrointestinal problems may increase in severity and frequency, and proteinuria can become elevated. Fabry crisis, manifested as severe pain radiating from the hands and feet, may occur spontaneously as a response to various environmental conditions like heat, cold, stress, and fatigue. Swelling of the affected areas (lymphedema) and redness may also be present and are predictors of future heart and renal dysfunctions. Vascular skin lesions (angiokeratomas) can appear, clustering around the umbilicus and swim trunk areas. With advancing age, patients may present with respiratory problems, cardiac and cerebrovascular manifestations, and hearing loss or tinnitus. Late disease is characterized by life-threatening renal failure, stroke, and severe cardiac problems.19

Psychological Issues

Depression is common and underdiagnosed in Fabry disease. Previous research found that 60% of the patients enrolled in a study presented with clinical depression compared to healthy controls.14 Overall, depression is by far the most frequently reported psychiatric complication of Fabry disease, ranging from 15% to 62.5% in all series. Despite its prevalence, depression is not often discussed at clinic visits (Table 1). Although depression and anxiety are often reported, referrals to psychologists or psychiatrists are limited, and mental health professionals are rarely involved as part of the care team.

Table. Research Findings of Psychological Symptoms in Fabry

Table. Research Findings of Psychological Symptoms in Fabry

Studies past and present have indicated that depressive symptoms in Fabry disease can be related to pain as well as social factors, including economic status.3,6 Conversely, the relationship between depressive symptoms and renal, cardiac, or cerebral involvement is generally less prominent; subjective health perception plays a more active role.3,6,7 Differences in coping might influence the psychological well-being of Fabry patients. In a recent study, it was found that coping styles that involve avoiding emotional distress led to more depressive symptoms, while positivity and problem solving led to less depressive symptoms.3 Given the chronic multisystemic manifestations—pain, lack of sleep, and crippling fatigue—it would be extraordinary if individuals living with Fabry disease did not have to manage any psychological challenges.

Determining the importance of different factors related to depressive symptoms can aid in the identification of patients at risk and act as a starting point for specific psychological interventions to prevent or treat depressive symptoms.

Importance of Psychological and Psychiatric Evaluation

Over the past 20 years of working with patients diagnosed with Fabry disease, it has been troubling to see that common themes of depression, anxiety, uncertainty, and frustration are often reported before interventions for psychological difficulties are considered. In my practice, it is apparent that many individuals living with chronic conditions find it difficult to advocate for themselves. During an appointment, patients may report that they are exhausted, misunderstood, or cannot face being judged if they mention that they experience depression or anxiety. Patients often worry that telling their health care provider that they are depressed or anxious may require an additional appointment, causing them to feel overburdened. This discouragement can result in feelings of self-doubt, anger, and fear that serve to worsen depression. Also, depression associated with a chronic medical illness often aggravates the condition, especially if the illness causes pain and fatigue, or limits the ability to interact with others.

It is critical that patients with Fabry disease have the support and resources they need to understand the physical manifestations and the psychological challenges that the condition can cause. Building a broader understanding of these issues can improve quality of life, as patients no longer have to define themselves by their illness. Learning how to process and explore these issues can provide a normalizing and gratifying opportunity to be happier and enjoy more success.

There are many steps a care team can take to screen for psychological issues. Primary care encounters are often the only opportunities for patients with Fabry disease to address emotional challenges and obtain the professional attention they require. For clinicians, forging empathetic partnerships with patients, prescribing appropriate treatments, and closely monitoring symptoms and therapeutic progress are invaluable for optimal management of both affective and medical disorders.

Cognitive behavioral therapy is often considered the most effective therapy for depression and anxiety. If patients are continuously thinking about negative outcomes, they begin to have a generalized feeling of hopelessness that can lead to a depressed or anxious mood. It can be beneficial for health care providers to help patients with Fabry explore ways to manage the disease. The common approach is to challenge negative thoughts and prompt the patient to explain the basis of their negative health perceptions.

Behavioral activation is just as important as the cognitive components of therapy. To help improve mood, patients should be encouraged to set goals and regularly partake in activities that they enjoy. In addition, many patients with depression and anxiety feel empowered when they can help choose the treatment approach used to manage their disease. Having a role in deciding how treatment is approached can also help support adherence, which is critical when coping with severe symptoms.

While data on the impact of depression treatment for patients with Fabry disease are limited, a recent pilot study examined the effects of psychological counseling on depression, adaptive functioning (AF), quality of life (QOL), and subjective pain experience. Subjects completed 6 months of in-person or telecounseling with the same health psychologist, followed by 6 months without counseling. Self-report measures of depression, AF, QOL, and subjective pain were completed every 3 months. All subjects experienced improvements in depression, which were sustained during the follow-up period.20 Study findings support the efficacy of psychological treatment for depression in individuals with Fabry disease, with additional benefits achieved when health psychologists aligned closely with lysosomal storage disease treatment centers in the patient management continuum.

Concluding Thoughts

Patients with depression and chronic illnesses such as Fabry disease are challenging to treat, but they are exactly the type of patient that can benefit from expert care.21 A growing body of evidence supports the view that chronic medical conditions and depression are interrelated. Collaborative care for psychological challenges is a treatment model that uses a multimodal, biopsychosocial, structured, evidence-based approach, involving nonmedical specialists. It is critical that care teams work with patients to develop a shared definition of potential issues, provide education and support, target treatment goals, develop a specific treatment plan, and provide follow-up.

Dr Bjoraker is a pediatric neuropsychologist with specialized training and expertise in rare genetic and neurodegenerative diseases. She served as faculty at the University of Minnesota and at the University of Colorado-Denver/Children’s Hospital Colorado where she participated in the neurometabolic, neurogenetic and neuromuscular clinic care teams. Dr Bjoraker is known nationally and internationally for her expertise in lysosomal storage diseases and other inborn errors of metabolism and neurodegenerative diseases. She is a presenter and researcher with extended publications in rare genetic diseases and experience in clinical trial development. Dr Bjoraker is also a consultant in Minneapolis, Minnesota.


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