Genetics of Fabry Disease Clinical Presentation

Fabry disease should be considered in patients with the isolated features detailed below or in those who show signs of multisystemic involvement in a pattern consistent with renal, cardiac, and cerebrovascular involvement. A detailed and complete medical and family history and thorough physical examination are necessary.

A detailed medical and family history should be obtained, with emphasis on the following:

• Presence, location, and density of skin rash (angiokeratoma)
• Characteristics, frequency, and intensity of pain (acroparesthesia)
• Bowel habits, abdominal cramping, vomiting, nausea, and food intolerance
• History of abnormal sweating
• Heat, cold, and exercise intolerance and easy fatigability
• Family history of kidney failure, heart disease, stroke, or other signs or symptoms of Fabry disease in X-linked pattern of segregation

Patients with classic Fabry disease typically have α -Gal A activity of less than 1% and often demonstrate the full spectrum of symptoms. The 2 categories of classic disease manifestation are as follows:

Early manifestations

Early manifestations generally begin in childhood or adolescence and include the characteristic corneal and lenticular opacities, skin lesions (angiokeratoma), pain in the extremities (acroparesthesia), and decreased ability to sweat (hypohidrosis). In addition, patients may have chronic abdominal pain and diarrhea. Some patients may experience spontaneous relief of these early symptoms during adulthood (eg, symptomatic improvement of acroparesthesias).

The earliest reported symptom of Fabry disease is often intermittent or chronic acroparesthesias. These pain episodes are described as burning, tingling, and numbness and are thought to be related to the involvement of the vascular supply and small fibers of the peripheral nervous system. Pain, especially in the hands and feet, may occur daily and may vary in severity. These episodes may occur in both sexes and may begin as early as age 2 years. Pain may be triggered by a body temperature increase due to exercise, fever, emotional stress, or environmental temperature changes. Extreme pain attacks, referred to as Fabry pain crises, usually affect male patients and are described as severe episodes that last several hours to days. These episodes may be accompanied by low-grade fever, body pains, and fatigue.

GI manifestations of Fabry disease are common and are believed to be caused by the deposition of GL-3 in the small vessels and the autonomic ganglia of the intestine. GI symptoms often begin in adolescence and may worsen with age. Common manifestations include episodes of postprandial abdominal pain and bloating, followed by multiple bowel movements, diarrhea, nausea, vomiting, and early satiety. Symptoms are generally more frequent and appear earlier in life in males compared with female carriers.

Dermal manifestations of Fabry disease include cutaneous vascular lesions (angiokeratomas) and abnormal sweating (anhidrosis or, more commonly, hypohidrosis). Weakening of the capillary wall and vascular ectasia within the epidermis and dermis causes angiokeratomas. They usually manifest at age 5-13 years and initially appear as small, slightly raised, purplish-red, nonblanching angiectases. The number and size of these lesions progressively increase with age. Anhidrosis or hypohidrosis is also frequently reported and is thought to be secondary to lipid accumulation in the eccrine cells of the sweat glands and dysfunction of the autonomic nervous system.

Corneal manifestations are reported in more than 70-90% of patients. The best-known ocular symptom is a pattern of whitish spiral streaks in the corneal epithelium known as cornea verticillata.

Some patients may have recurrent fevers with no obvious source. Pain usually accompanies the fevers, and an elevated erythrocyte sedimentation rate may be present.

Disease symptoms and implications may affect the patient's school performance, level of activity, and mental health.

Late and serious clinical manifestations of Fabry disease

During the late stage of the disease, the progressive deterioration of renal, cardiac, and nervous system function ultimately results in significant morbidity and mortality.

Kidney involvement is a prominent feature and is the main cause of premature death in classic Fabry disease. It develops as a result of the progressive accumulation of GL-3 in the renal endothelium and other kidney cell types. Microalbuminuria, proteinuria, and isosthenuria may be apparent in adolescence and early adulthood. Progressive kidney disease is marked by the progression of proteinuria, an increase in serum creatinine levels, and the reduction of the glomerular filtration rate (GFR) during the third decade of life. Long-term hemodialysis is often required, and renal transplantation is usually successful.

Fabry-related cardiovascular disease is a key cause of premature death. Early signs of cardiac involvement include interventricular septal and left ventricular hypertrophy (LVH) associated with valvular regurgitation.

Clinical signs of congestive heart failure may accompany the progressive concentric LVH and diastolic dysfunction observed in advanced stages of the disease. Mitral valve prolapse and thickening may also be observed.

Common initial electrocardiographic abnormalities include sinus bradycardia, nonspecific ST-segment changes, T-wave inversion, and shortened PR interval.

Conduction system involvement may be observed as early as the second decade of life, and, as it progresses, the risk of lethal arrhythmias and sudden death increases.

Permanent cardiac pacing is needed in approximately 10-20% of patients.

Damage to the coronary vascular bed may lead to angina pectoris, variant angina, and myocardial infarction.

Predominant involvement of small, penetrating vessels has been reported. This involvement does not necessarily follow the typical patterns observed in atherosclerosis.

CNS involvement may be observed on brain MRI as white matter changes. This involvement may be noted as early as the second or third decade of life, typically occurring earlier in males than in females. The primary ischemic-hypoxic damage in CNS results from prothrombotic and occlusive abnormalities, in addition to large-vessel ectasias. Patients may present with transient ischemic attacks, vascular thromboses, seizures, or hemorrhagic or ischemic stroke.

Paroxysmal attacks of severe rotational vertigo occur in many patients. Although these episodes are usually brief, some prolonged severe attacks require cessation of activities for several days. Megadolichobasilar compression of the vestibulocochlear nerve has been suggested as a likely cause for these episodes.

Sensorineural hearing loss has been frequently documented in patients with Fabry disease and most likely reflects vascular pathology of the inner ear.

Peripheral neuropathy in Fabry disease predominantly involves small nerve fibers. The progressive loss of temperature and pain sensation should be assessed during the physical examination.

Lymphedema of the legs is a poorly described and a less common manifestation. Often asymmetric, the symptom may start as a transient seasonal event with a tendency to become more severe and extensive over time. This manifestation presumably reflects the progressive GL-3 deposition in the lymphatic vessels and lymph nodes, compromising the lymphatic circulation.

Obstructive and constrictive lung diseases have both been documented in a subgroup of patients, often presenting as wheezing, dyspnea, or bronchitis.

Priapism has been associated with Fabry disease.

Mild anemia is probably due to decreased RBC survival.

Poor heat and exercise tolerance is commonly observed in patients. It may start at the early stages of the disease and is reported by both males and females. This poor tolerance is typically attributed to hypohidrosis and acroparesthesias and may become more pronounced in the presence of pulmonary disease or cardiomyopathy in later stages of the disease. Patients may report lack of energy and fatigue.

In atypical cases, individuals with residual enzyme activity demonstrate symptoms later in life, and the symptoms are usually limited to one or a few organs. For example, individuals with atypical cardiac variants usually do not have any signs or symptoms in childhood and present mainly with cardiac disease later in adulthood. In various surveys, approximately 3-12% of patients with unexplained LVH have been diagnosed with the cardiac variant of Fabry disease.

Clinical manifestations in female carriers vary greatly because of random X-chromosome inactivation. Although carriers commonly remain asymptomatic throughout life, many demonstrate clinical symptoms as variable and severe as those of affected males. Affected females may experience early manifestations of the disease, such as acroparesthesia and GI discomfort. Their symptoms may also be as severe and progressive as those seen in males (ie, they may develop renal failure). Females who are asymptomatic at the time of initial assessment should be closely and regularly monitored for any evidence of disease manifestation.

Skin symptoms

Angiokeratoma, small punctate reddish-to-bluish angiectases, may be either flat or slightly raised and may blanch with pressure. These are commonly observed as dense clusters of lesions on the umbilicus, flanks, thighs, penis, and scrotum.

Lesions in the oral mucosa and conjunctiva are observed in some patients.

Hypohidrosis and anhidrosis may be observed.

Visual symptoms

Vision is not usually impaired.

A slit-lamp examination reveals cornea verticillata, which manifests as whirl-like white-to–golden-brown opacities that extend from the center to the periphery of the cornea. Cornea verticillata is often prominent in female carriers and may play an important role in the early recognition of Fabry disease. Therefore, in females with either a positive family history or symptoms suggestive of Fabry disease, a slit-lamp examination can be very helpful.

Other possible ocular findings include lens, retinal and conjunctival changes.

Neurological symptoms

Peripheral neuropathy, specifically loss of temperature and pain sensation, has been reported.

Hearing deficit may be observed.

Lymphedema symptoms

Asymmetric involvement of the lower extremities with pitting edema has been reported in the absence of significant renal or cardiac disease.

Other symptoms

Characteristic facial appearance, such as coarse facial features, have been described by some authors.

The gene that encodes α -Gal A has been isolated and sequenced, and more than 245 different mutations (missense, nonsense, splice, deletion, and insertion errors) have been reported.

Attempts to correlate genotype with clinical presentation have been confounded by the fact that very few recurrent mutations have been reported.

The typical interfamilial variability of the disease phenotype may be due to other modifying factors, which may be genetically or environmentally derived.