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
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
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
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
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,
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.
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
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