Fabry disease: Neurologic manifestations

INTRODUCTION — Fabry disease (also called angiokeratoma corporis diffusum, ceramide trihexosidosis, and Anderson-Fabry disease) is an X-linked glycolipid storage disease. It is caused by deficient activity of the lysosomal enzyme alpha-galactosidase A, which causes progressive accumulation of alpha-D-galactosyl moieties, such as globotriaosylceramide (the glycolipid substrate for alpha-galactosidase A), within multiple cell types and tissues of affected patients [1]. Numerous mutations have been found in the alpha-galactosidase A (GLA) gene on the long arm of the X chromosome (Xq22).

This topic will review the neurologic manifestations of Fabry disease and their treatment.

Other clinical aspects of Fabry disease are presented elsewhere. (See "Fabry disease: Clinical features and diagnosis" and "Fabry disease: Treatment and prognosis" and "Fabry disease: Cardiovascular disease".)

OVERVIEW — Clinical manifestations of Fabry disease usually become evident by 10 years of age in the severe classic form. Initial manifestations typically include neuropathic pain (acroparesthesia), hypohidrosis, poor exercise tolerance, gastrointestinal symptoms, and fever of unknown origin. The characteristic skin lesions known as angiokeratomas develop in the second decade of life, along with hearing loss. By the third decade of life, cardiovascular and renal disease become increasingly prominent [2,3].

Progressive accumulation of globotriaosylceramide within endothelial, perithelial, and smooth muscle cells of the vascular system, dorsal root ganglia, and cells of the autonomic nervous system, result in the neurologic manifestations of the disease [4,5]. These include a small-fiber peripheral neuropathy and an increased propensity for ischemic stroke in affected males and female heterozygotes. As seen in other manifestations of Fabry disease, these neurologic complications may be milder or absent in patients with nonclassical disease.

SMALL-FIBER PERIPHERAL NEUROPATHY — The length-dependent small-fiber peripheral neuropathy associated with Fabry disease may cause an almost constant discomfort of the hands and feet, with paroxysmal burning pains of the palms and soles [6,7]. Alternatively, it may cause recurrent painful episodes triggered by stress, fever, heat, fatigue, joint pain, or exercise [8]. The pain is sometimes misconstrued as "growth pain." Although pain tends to diminish with age secondary to progressive nerve fiber loss, it may be of sufficient severity to lead to suicide attempts.

The overall clinical characteristics are similar to those described in patients with idiopathic small fiber neuropathy (table 1). Patients have decreased cold and warm perception that first manifests in the feet associated with decreased epidermal nerve fiber density in the affected regions [9,10]. Electron microscopy of peripheral nerves reveals loss of unmyelinated and small myelinated nerve fibers and lamellar inclusions in the perineurium and the dorsal root ganglia likely consisting of glycosphingolipids [11,12]. Nerve conduction studies are consequently normal [9,10]. A study employing functional magnetic resonance neurography found that patients with Fabry disease had symmetrically enlarged dorsal root ganglia with decreased permeability of the blood-tissue interface, the latter consistent with dysfunctional perfusion [13].

Pain relief — The treatment of chronic neuropathic pain in patients with Fabry disease remains empiric [14]. Preventive pain therapy with gabapentin, pregabalin, carbamazepine, and amitriptyline appears to be beneficial [15].

One potential advantage of antiseizure medications is that compliance may be monitored and the risk of toxicity reduced by following serum levels. However, these levels do not have a direct correlation with neuropathic pain response.

Narcotic agents should be avoided if possible. Nonsteroidal anti-inflammatory agents should also be avoided, as these tend to be ineffective and may lead to renal toxicity.

As the management of chronic pain in Fabry disease may be challenging, pain scales such as the Brief Pain Inventory (BPI) and its short-form version (BPI-SF) are useful for monitoring treatment effectiveness. Instruments designed specifically for Fabry patients include the Würzburg Fabry Pain Questionnaire (FPQ) [16-18] and the Fabry-specific Pediatric Health and Pain Questionnaire (FPHPQ) [19].

Gabapentin and pregabalin — Gabapentin and pregabalin bind to the voltage-gated calcium channels at the alpha 2-delta subunit and inhibit neurotransmitter release. They have efficacy versus placebo in several neuropathic pain conditions. (See "Pharmacologic management of chronic non-cancer pain in adults", section on 'Antiseizure medications'.)

Advantages of gabapentin and pregabalin include low toxicity, a low incidence of drug interactions, and lack of liver metabolism.

In children less than 12 years old, the starting dose of gabapentin is 10 to 15 mg/kg per day divided into three doses. The dose may be slowly increased up to 50 mg/kg daily. For older children and adults, the initial dose is typically 300 mg three times per day (900 mg total per day). The maximum total dose may be in the range of 1800 to 2400 mg per day.

One advantage of pregabalin is twice daily dosing compared with three-time daily dosing for gabapentin. Pregabalin is usually started at a dose of 75 mg twice daily; the dose may be increased by the same amount after four to seven days to a typical total daily dose of 300 mg or to a maximum total daily dose of 600 mg as necessary and tolerated [20].

Both gabapentin and pregabalin can produce dose-dependent dizziness and sedation that can be reduced by starting with lower doses and titrating slowly.

The nearly complete renal clearance for gabapentin and pregabalin is potentially concerning in patients with Fabry disease, who are at risk for kidney disease. Therefore, renal function should be assessed before beginning gabapentin treatment and the dose should be adjusted accordingly, as renal function affects serum levels and half-life.

Carbamazepine and phenytoin — Several other antiseizure medications have been used for the treatment of neuropathic pain. Of the older drugs, carbamazepine and phenytoin have been used most often [21,22]. Carbamazepine and phenytoin appear to be effective but cause induction of the P450 system in the liver, which can be a concern in patients on multiple drugs that are metabolized by the liver, such as oral contraceptives.

Carbamazepine treatment may be considered when drug interactions are not a concern, especially in young male patients. For adults and children age ≥6 years, the initial carbamazepine dose is 200 mg per day in two divided doses. This is the same dose typically used for neuropathic pain in adults and epilepsy in children. The dose may be titrated at weekly intervals to a maximum of 1000 mg per day in children or 1200 mg per day in adults and adolescents age ≥16 years. Patients taking carbamazepine should undergo monitoring for the potential occurrence of cytopenia and liver toxicity.

Phenytoin is not commonly used for chronic treatment in children because of concerns about adverse cosmetic effects that include hirsutism, gingival hyperplasia, and coarse facial features. In addition, chronic phenytoin treatment has been associated with the potential for cerebellar atrophy and peripheral neuropathy.

Antidepressants — Amitriptyline, at doses well below those used in the treatment of depression, has been shown to be effective in the treatment of chronic neuropathic pain [23]. At the lower doses used for neuropathic pain, serious side effects are uncommon. Nonetheless, an electrocardiogram should be obtained before and after beginning treatment since amitriptyline can cause adverse changes in cardiac conduction.

The recommended starting dose of amitriptyline in children is 0.1 mg/kg at night. This can be slowly increased over two to four weeks up to 0.5 to 2 mg/kg nightly.

Limited evidence exists regarding the efficacy of serotonin norepinephrine reuptake inhibitors (SNRIs), such as duloxetine and venlafaxine, in the management of pain associated with Fabry disease. However, considering their use in treating neuropathic pain, these medications have also been considered as therapeutic options [24] (see "Pharmacologic management of chronic non-cancer pain in adults", section on 'Serotonin-norepinephrine reuptake inhibitors'). Caution is required when using venlafaxine due to necessary dose adjustments for kidney impairment and its potential to prolong the QT interval on electrocardiography (ECG). Venlafaxine is not approved for pediatric patients.

CEREBROVASCULAR COMPLICATIONS — Cerebral involvement in Fabry disease is due mainly to vasculopathy and a dilative arteriopathy in affected males and female carriers and may result in transient ischemic attack and ischemic stroke. There is evidence of a resting cerebrovascular hyperperfusion in males with Fabry disease, which may cause increased shear stress and vessel wall damage over time [25]. Cerebral manifestations may be classified either as large vessel or, more commonly, as small vessel disease. Cardiac embolism may also occur [26]. The manifestations of stroke in Fabry disease are no different from ischemic stroke due to other common etiologies, and any stroke-related clinical deficit might occur. White matter abnormalities, seen best on fluid-attenuated inversion recovery (FLAIR) MRI images, are asymptomatic or related to subtle neuropsychological deficits [26-31]. Cerebrovascular complications are rare in children, but increase through adult life.

In data from 2446 patients in the observational Fabry Registry, the following results were reported [32]:

●Stroke affected 138 patients (6 percent), including 86 of 1243 males (7 percent) and 52 of 1203 females (4 percent). Most strokes were ischemic (87 percent).

●Median age at first stroke for males and females was 39 and 45.7 years, respectively.

●The proportion of patients with a first stroke prior to the diagnosis of Fabry disease in males and females was 50 and 38 percent, respectively. The proportion who experienced a stroke prior to renal or cardiac events for males and females was 71 and 77 percent.

From these data, the risk of stroke in male subjects 35 to 45 years of age with the classic form of Fabry disease is approximately 12-fold higher compared with the general population of similar age. In addition, stroke often occurs before the renal or cardiac manifestations of Fabry disease.

In an earlier literature review, the average age of onset for cerebrovascular symptoms of Fabry disease was 34 years for hemizygotes (n = 43) and 40 years for heterozygotes (n = 10) [29]. The most frequent cerebrovascular manifestations in hemizygotes were hemiparesis, vertigo, dizziness, diplopia, dysarthria, nystagmus, nausea, vomiting, head pain, hemiataxia, and ataxia of gait. Heterozygotes were prone to memory loss, dizziness, ataxia, hemiparesis, loss of consciousness, and hemisensory symptoms. The most common angiographic and pathologic features were elongation, ectasia, and tortuosity involving the vertebral and basilar arteries.

The cerebrovascular disease burden, in particular the white matter lesion load, increases with age. In a longitudinal study of 149 patients with Fabry disease, with a mean follow-up of seven years, factors associated with MRI progression of white matter lesions and cerebral infarctions were age and male sex [33]. In another MRI study, lesions were present in no male patient under age 26 compared with all patients over age 54 [34]. Of the patients with white matter lesions, neurologic symptoms were present in 37.5 percent.

White matter lesions also appear over time in female carriers. The Fabry Outcome Survey found that cerebrovascular events occurred in a high proportion of female and male patients (27 versus 12 percent) [35,36]. The mean age of cerebrovascular event onset was below 30 years in men and below 45 years in women. In a subsequent case series of patients with symptomatic Fabry disease, the frequency of marked white matter lesions was similar among male and female patients (4 of 13 versus 5 of 14 [31 versus 36 percent]) [37].

The high burden of white matter lesions and cerebrovascular events in women with Fabry disease (an X-linked disorder) may be explained by the lack of cross-correction from enzyme-replete to enzyme-deficient cells in females [38]. The risk of stroke is, in part, related to the ratio of mutated to normal cells in the vascular system resulting from random X-inactivation occurring in early development [39].

STROKE PREVENTION — Standard ischemic stroke prevention measures are considered effective in secondary (and possibly primary) prevention for patients with Fabry disease, although this conclusion is based solely upon clinical experience and expert opinion [5,40,41].

These measures include the use of antiplatelet agents. For primary prevention of ischemic stroke in adult males with the classic form of Fabry disease and a family history of stroke, and for secondary prevention of ischemic stroke in adults or children with Fabry disease, we suggest antiplatelet therapy with aspirin or clopidogrel. Antihypertensive agents and statins are often used. These treatments are discussed in detail separately. (See "Long-term antithrombotic therapy for the secondary prevention of ischemic stroke" and "Overview of secondary prevention of ischemic stroke".)

FABRY-SPECIFIC THERAPY — Available Fabry-specific treatments include enzyme replacement therapy (agalsidase alfa and agalsidase beta) and pharmacologic chaperone therapy (migalastat). The effect of these interventions for the various manifestations of Fabry disease, including neuropathic pain symptoms and risk of ischemic stroke, is reviewed elsewhere. (See "Fabry disease: Treatment and prognosis".)

REGISTRY — A Fabry disease registry has been established to better understand the disease. Information is available online at https://www.registrynxt.com/. Participation in the registry is voluntary.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Fabry disease".)

SUMMARY AND RECOMMENDATIONS

●Painful neuropathy – Peripheral neuropathy associated with Fabry disease causes an almost constant discomfort with paroxysmal burning pains of the hands and feet. (See 'Small-fiber peripheral neuropathy' above.)

●Pain relief – Prophylactic therapy for neuropathic pain with gabapentin, pregabalin, carbamazepine, or amitriptyline may provide relief. (See 'Pain relief' above.)

●Cerebrovascular complications – Cerebral involvement in Fabry disease is due mainly to vasculopathy and a dilative arteriopathy in affected males and female carriers and may result in transient ischemic attack, stroke, aneurysms, acute blindness, and accumulation of symptomatic and asymptomatic white matter lesions. Cerebrovascular complications are rare in children, but increase through adult life. (See 'Cerebrovascular complications' above.)

●Stroke prevention – For primary prevention of ischemic stroke in adult males with the classic form of Fabry disease and a family history of stroke, and for secondary prevention of ischemic stroke in adults or children with Fabry disease, we suggest antiplatelet therapy with aspirin or clopidogrel (Grade 2C). Antihypertensive agents and statins may be used as appropriate. (See 'Stroke prevention' above.)

●Fabry-specific therapy – Enzyme replacement therapy (agalsidase alfa and agalsidase beta) and pharmacologic chaperone therapy (migalastat), are discussed elsewhere. (See "Fabry disease: Treatment and prognosis".)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Robert Cruse, DO, and Raphael Schiffman, MD, MHSc, FAAN, who contributed to an earlier version of this topic review.