Review of Mechanisms, Pharmacological Management, Psychosocial Implications, and Holistic Treatment of Pain in Fabry Disease

Abstract

Fabry disease is a progressive X-linked lysosomal storage disease caused by a mutation in the GLA gene, encoding the lysosomal hydrolase α-galactosidase A. The consequent reduced enzyme activity results in the toxic accumulation of glycosphingolipids, particularly globortriaosylceramide (Gb3 or GL3), in blood vessels, renal epithelia, myocardium, peripheral nervous system, cornea and skin. Neuropathic pain is the most common manifestation of Fabry disease and can be extremely debilitating. This often develops during childhood and presents with episodes of burning and sharp pain in the hands and feet, especially during exercise and it is worse with increased heat or fever. It is thought to be due to ischaemic injury and metabolic failure, leading to the disruption of neuronal membranes and small fibre neuropathy, caused by a reduced density of myelinated Aδ and unmyelinated C-fibres and alterations in the function of ion channels, mediated by Gb3 and lyso Gb3. It is important to confirm small fibre neuropathy before any Fabry disease treatment modality is considered. There is a clinical need for novel techniques for assessing small fibre function to improve detection of small fibre neuropathy and expand the role of available therapies. The current Fabry disease guidelines are in favour of pharmacological management as the first-line treatment for pain associated with Fabry disease. Refractory cases would benefit from a rehabilitation approach with interdisciplinary input, including medical, physiotherapy and psychological disciplines and including a Pain Management Programme.

Characterizing mechanism-based pain phenotypes in patients with chronic pancreatitis: a cross-sectional analysis of the PROspective Evaluation of Chronic Pancreatitis for EpidEmiologic and Translational StuDies

“…This is consistent with somatic peripheral neuropathies that commonly feature spontaneous or evoked attacks or flare-ups of severe pain. 20,23,30 Using our classification system, approximately one-quarter of patients did not have a strong neuropathic or nociceptive pain component. There are multiple potential explanations for this, including that they suffer from another type of pain.…”

“…This is consistent with somatic peripheral neuropathies that commonly feature spontaneous or evoked attacks or flare-ups of severe pain. 20 , 23 , 30 …”

The potential consequences of bidirectional promoter methylation on GLA and HNRNPH2 expression in Fabry disease phenotypes in a family of patients carrying a GLA deletion variant

“…The majority of patients with FD may experience chronic or episodic pain, known as FD crises or acroparaesthesiae (12,(28)(29)(30). The development of pain in FD is hypothesized to be primarily neuropathic; the suggested cause is serum and tissue accumulation of Gb3 and its influence on the peripheral nervous system, which may lead to cell swelling (31)(32)(33)(34). Furthermore, a question has been raised on whether the HNRNPH2 and the BDP methylation may play a role in diagnosing and treating chronic pain in FD patients and other related FD clinical symptoms.…”

Cardiovascular magnetic resonance native T1 mapping in Anderson-Fabry disease: a systematic review and meta-analysis

“…Anderson-Fabry disease (AFD) is a rare multisystem X-linked lysosomal storage disorder caused by α-galactosidase A enzyme deficiency, resulting in progressive intracellular accumulation of glycosphingolipids in endothelial and smooth muscle cells [ 1 , 2 ]. Clinical features of classic AFD phenotype consist in skin disorders, corneal alterations, cerebrovascular complications, kidney failure, and cardiovascular disease, which represents a major cause of morbidity and mortality [ 3 , 4 ]. Long-term cardiac involvement in AFD results in left ventricular (LV) hypertrophy (LVH) and myocardial fibrosis, inducing several complications, mainly arrhythmias, valvular dysfunction, and coronary artery disease [ 5 ].…”