AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Angiokeratoma corporis diffusum is an X-linked inherited disorder caused by a deficiency of the lysosomal enzyme alpha-galactosidase. This inborn error of metabolism results in unremitting deposition of neural glycosphingolipids in the lysosomes of the vascular endothelium; in fibroblasts; and in pericytes of the dermis, heart, kidneys, and autonomic nervous system. The Fabry disease (FD) gene is now known as the GLA gene.

Beta-mannosidosis, a lysosomal enzyme disorder (which also results in mental retardation, hearing loss, and renal failure); fucosidosis; sialidosis; galactosialidosis; aspartyl-glycosaminuria; GM1 gangliosidosis; and Kanzaki disease can also be causes of angiokeratoma corporis diffusum.¹ Additionally, several patients without detectable abnormalities have been reported.

Nucleoside sequencing of the entire alpha-galactosidase gene (GLA) has enabled theoretical treatment using recombinant technology.

Pathophysiology

A defect in the activity of alpha-galactosidase, a lysosomal enzyme, results in the insidious storage of 2 neutral glycosphingolipids: trihexosylceramide (galactosylgalactosylglucosylceramide) and digalactosylceramide (galabiosylceramide). These glycosphingolipids accumulate in many different types of cells. The most affected are the vascular endothelium and smooth muscle cells. Deposition of glycosphingolipids can be attributed to both endogenous production and diffusion of material from the circulation. As a result of the lack of this lysosomal enzyme that breaks down the glycolipid, persons with FD have 3-10 times the normal amount in their serum.

Larralde et al² have extensively explained the mechanism behind FD. The enzymatic defect in FD results in the accumulation of uncleaved glycosphingolipids in many human cell types. Particular types consist of endothelial cells, blood vessel cells, pericytes, vascular smooth muscle cells, renal epithelial cells, myocardial cells, skin structure cells, neuronal cells, and corneal cells.

Persons with FD who have type AB or B blood also accumulate blood group B glycosphingolipids (those with alpha-galactosyl–terminated residues) and can have more severe FD (related to greater body substrate mass) than patients with blood group A. This is because these blood groups have 2 additional terminal alpha-galactosyl moieties.

Specifically, deposits in lysosomes of endothelial, perithelial, and smooth muscle cells of blood vessels cause swelling into the hollow bore of the blood vessel. In so doing, the vessels are narrowed and reactively expand, which leads to ischemia and infarction. This occurs, to a greater or lesser extent, in all affected cells, underlying the protean manifestations of FD.

In 2004, Larralde et al² report that most families have "private" mutations (ie, mutations found only in that particular family). FD is transmitted in an X-linked recessive pattern. The gene is located at band Xq22. Similar to other entities with this inheritance pattern, hemizygous males are most severely affected. The female carrier of this disease has diminished levels of alpha-galactosidase, which is enough to cause some symptoms but also to be spared the full clinical manifestations. Deficient alpha-galactosidase A activity can be present in the plasma in persons who do not have the full manifestations of FD. The deficiency must be extensive for full effects to manifest.

Frequency

United States

Angiokeratoma corporis diffusum is rare; the estimated incidence is 1 case per 40,000 population. Others believe this prevalence is an overestimation. According to Larralde et al,² inheritance of the abnormal gene among whites (resulting in a hemizygous boy or a heterozygous girl) has been estimated to occur once in every 117,000 live births.

International

Most occurrences of angiokeratoma corporis diffusum are in whites; however, FD has been reported to occur in black persons, Latin Americans, Native Americans, Egyptians, and Asians.

Mortality/Morbidity

Renal failure secondary to uremia and hypertension is the major cause of death for men with FD aged 30-39 years, followed by congestive heart failure and cerebrovascular accidents. Heterozygous females develop angiokeratomas and cataracts and experience a milder clinical course. Some patients may have more serious involvement; however, lifespan is longer for women than for men diagnosed with this disease.

Hormonal function and fertility rates are normal in both male and female Anderson-Fabry patients compared with controls.

A variety of clinical findings occur in female carriers. The scope is vast and ranges from asymptomatic carriers to carriers with fully expressed FD. Asymptomatic corneal dystrophy occurs in approximately 70% of carriers. This is an indication of the carrier state. Approximately 30% of female carries have angiokeratomas, with less than 10% having paresthesias. A 2004 study by Larralde et al² of obligate female carriers found significant disease manifestations in 20 of 60 women. Another study performed on 20 carriers of FD showed that each woman had some symptom of FD, with a wide scope of manifestations. Larralde et al² concluded that FD might be designated a storage disease transmitted as an X-linked–dominant, not X-linked–recessive, disease.

Race

While FD is most common in whites, it has been reported in black persons, Latin Americans, Native Americans, Egyptians, and Asians.

Sex

Because FD is an X-linked recessive disease, only men are fully afflicted. Heterozygous women, in addition to transmitting the condition, may develop symptoms.

Age

In males, signs and symptoms begin in late childhood or adolescence. By age 20-29 years, most affected men experience the full brunt of the disease. Heterozygous women first note symptoms by age 20 years to early 30 years. Möhrenschlager et al⁴ report that the Anderson-Fabry disease register shows the median cumulative survival of hemizygous men with FD is 50 years, compared with 70 years for females. This means that men live approximately 20 years less than unaffected men and that women live 15 years less than unaffected women. Some men, however, even without enzyme replacement, live to their 70s.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

FD is variable in its clinical symptoms and, as a result, can be a challenge to define if it does not manifest in classic fashion or in a person whose family is not known to have FD. The classic presentation of FD is a male with initial manifestations occurring in childhood or adolescence. The initial findings are intermittent or chronic paresthesias and episodes of severe acral and/or GI distress (Fabry crisis), heat intolerance, hypohidrosis or anhidrosis, and generalized angiokeratomas.

If the diagnosis is missed, it will, in almost all cases, be made when a patient presents with (1) end-stage kidney failure or (2) cardiac or cerebrovascular pathology with early mortality. If the disease is milder (intermediate forms), it may not be diagnosed until late adulthood.

Some variants of FD only have renal and/or cardiac pathology and no angiokeratomas. A physician can establish that a patient has FD by searching for low activity of alpha-galactosyl A in plasma, leukocytes, cultured skin fibroblasts, or dried blood spots on filter paper.² Because of the Lyon effect, enzymatic detection of carriers can be misleading; thus, specific genetic analysis can be helpful in making the diagnosis.

In its typical form, FD starts in early childhood and manifests with constant acral paresthesia (acroparesthesia, ie, chronic burning, neuropathic tingling, or unmitigated acral discomfort). Intermittent Fabry crisis is the term for incapacitating sharp pain lasting minutes to days. This can occur in children, but it often stops occurring in adulthood. Crises can be triggered by any kind of stress, including disease, extremes in temperature, exercise, or emotional trauma. In addition to pain, a crisis can also manifest with fatigue, low-grade fever, and joint pain.²

The Fabry Registry⁵ published the baseline demographic and clinical characteristics of the first 1765 patients enrolled in the Fabry Registry. Of these patients, 54% are males (16% aged <20 y) and 46% are females (13% aged <20 y). The median ages at symptom onset and at diagnosis are 9 and 23 years, respectively, for males and 13 and 32 years, respectively, for females. Frequent presenting symptoms in males include neurological discomfort and pathology (62%), skin signs (31%), gastroenterological signs (19%), unspecified renal pathology (17%), and ophthalmological pathology (11%). Frequent presenting symptoms in females include neurological pain (41%), gastroenterological symptoms (13%), ophthalmological symptoms (12%), and skin eruptions (12%).

In men and women with FD reporting renal progression, the median age at occurrence was 38 years for both men and women. In men and women with FD reporting an onset of cerebrovascular and cardiovascular events, the median age at occurrence was 43 and 47 years, respectively, for females, and 38 and 41 years, respectively, for males.

• Recurrent fevers and vague pain in the hands and feet, resulting in periodically incapacitating pain in the fingers, toes, and occasionally the entire extremity, usually precede physical signs of FD. Typically, fever, heat, cold, and exertion trigger pain. Paroxysmal vertigo has occurred as an initial manifestation of FD, which may initially help to establish the diagnosis.
• In 2007, Moeller and Jensen⁶ noted that females with FD who present with pain and neurological symptoms are often not appropriately assessed and are misdiagnosed. This is likely because many physicians assume that FD's X-linked pattern of inheritance means it cannot occur in women.
• As stated, the second type of pain is a nagging, chronic, constant discomfort in the hands and feet, characterized by burning tingling paresthesias.
• Some patients with FD manifest with chronic exercise-induced pain, fasciculations, and cramps of the feet and legs. This can affect other members of their families.⁷
• Subsequently, angiokeratomas develop, which are the typical skin lesions for which the disease is named. Angiokeratomas usually manifest after puberty and increase in number with age; they can become generalized and involve the mucosa. Angiokeratomas occur as a result of lysosomal storage of Gb3 in cutaneous endothelial cells. This results in impairment of capillary wall integrity and the development of secondary ectasias.
• Atypical presentations can occur. In 2005, Choudhury et al⁸ reported an 11-year-old boy with FD who had a 6-year history of widespread petechia, rare papules with an overlying crust, and acral paresthesias of the hands and feet.
• Not every case of angiokeratoma corporis diffusum is due to FD. An idiopathic or cutaneous variant of angiokeratoma corporis diffusum has been described as a discrete clinical category of disease occurring only in the skin in persons with no metabolic disease or lysosomal defect.
• Ocular changes may be detected during the disease course. Although ocular involvement may be extensive (affecting the lens, cornea, conjunctiva, and retina), visual impairment is unusual. The fact that FD does not compromise ocular acuity is notable. It is sometimes a useful finding that helps diagnose FD. FD is commonly associated with a corneal opacity that can only be noted with slitlamp biomicroscopy. This corneal opacity shows a whorled pattern. Persons with FD sometimes manifest anterior capsular deposits in the lens or granular spokelike deposits on the posterior lens, termed Fabry cataract.²
• Patients may develop chronic edema of the feet before true renal or cardiac dysfunction.
• A history of heat intolerance secondary to hypohidrosis is often noted.
• With the relentless progression of the disease, cardiac infiltration can result in angina, myocardial infarction, mitral valve prolapse, congestive heart failure, hypertension, mitral insufficiency, and left ventricular hypertrophy. Other cardiac findings may include angina pectoris, aortic outflow abnormalities, arrhythmia, coronary artery disease, myocardial infarction, myocardial ischemia, ECG abnormalities, valvular lesions, varicose veins, and altered vasomotion.
• Similarly, glycolipid deposits in the CNS result in paresis, seizures, hemiplegia, labyrinthine disorders, aphasia, tremor, sensory disturbances, and loss of consciousness.
• Renal pathology is one of the hallmarks of FD and is the most frequent cause of death, usually when patients are aged 30-50 years.
• • Polyuria due to concentration defects can be among the first manifestations of kidney malfunction but, in many cases, does not prompt testing that leads to a diagnosis.² As persons with FD approach age 20 years, proteinuria increases as the patient ages.
  • Polarization microscopy of the sediment of urine demonstrates birefringent lipid globules (ie, renal tubular epithelial cells or cell fragments with lipid inclusions) with the characteristic Maltese cross configuration.
  • Birefringent inclusions in the urinary sediment (ie, fat-laden epithelial cells or mulberry cells) may be noted.
  • While protein, red blood cells, casts, desquamated urinary tract cells, and the characteristic Maltese crosses of lipid globules can be seen in childhood, the kidneys do not exhibit signs of deterioration until the patient is older. By middle age, azotemia and progressive proteinuria reflect deteriorating renal function. Uremia usually ensues and heralds end-stage renal disease.
• When the GI system is affected, a patient with FD has a history of intermittent nonbloody diarrhea and proctocolitis.
• Rheumatologically, patients may have arthritis of the distal interphalangeal joints with some loss of motion and limitation of movement of the temporomandibular joints.
• Angiokeratoma corporis diffusum is linked to beta-mannosidosis. Mental retardation, hearing loss, and renal failure are also linked to angiokeratoma corporis diffusum. In one case, the activity level of beta-mannosidase in the patient's plasma was 2% of the normal range, while the level in the patient's mother was 40%.¹
• Persons with FD have a high rate of subclinical hypothyroidism.
• Other nervous system findings of FD include headache, hearing loss, psychologic/psychiatric disease, tinnitus, tremors, vertigo, and aphasia.
• Depression is common in adults with FD and is an underdiagnosed problem.⁹
• Dominguez et al,¹⁰ in 2007, found that restless legs syndrome is common in FD patients and is associated with neuropathic pain.

Physical

Physical findings involve the skin, heart, lungs, extremities, eyes, and neurologic system.

• Skin
• • The hallmark of the disease, angiokeratoma, is a lightly verrucous, deep-red to blue-black papule varying in size from punctate to 0.5 cm.
  • Early, small lesions may not be hyperkeratotic; however, as lesions age and enlarge, their surfaces become somewhat crusty. Discrete verrucous overgrowth can occur.
  • Great variation in lesion size is evident, making patients appear as if they are "peppered with buckshot."
  • The papules of FD are symmetric and do not blanch with pressure (diascopy negative).
  • Angiokeratomas can appear almost anywhere; however, typically they spare the face, scalp, and ears. Lesions tend to concentrate between the umbilicus and the knees, with a predilection for the scrotum, penis, lower back, thighs, hips, buttocks, and lips. Some authors have stated that the angiokeratomas occur in the "bathing trunk" area.
  • Patients with FD can have scant body hair.
  • Other skin findings include varicose veins, stasis-related edema, lymphedema of the arms and legs, and edematous upper eyelids.
• Cardiac
• • FD is associated with a high prevalence of cardiac morbidity. In 2007, Linhart et al¹¹ noted that while FD has well-described associations with microvascular disease, deficiency of GLA is associated with premature macrovascular events such as stroke and, likely, heart attack.
  • Sadick and Thomas¹² studied the heart pathology in 12 patients and reported that 5 had cardiovascular symptoms, 9 had left ventricular hypertrophy on ECG tracings, 1 had a short PR interval, 3 had epicardial coronary disease, 4 had a rat-tail appearance on left-sided ventriculogram images, and 6 were assessment by myocardial biopsy, which demonstrated extensive vacuolation of the myocytes on light microscopy and concentric, myelinoid lamellar cytoplasmic inclusion bodies on electron microscopy.
  • Alterations in parameters as reported by Sadick and Thomas¹² were (1) traditional parameters of diastolic function, including peak E velocity, peak A velocity, and deceleration time, were no different between FD patients and normal controls; (2) isovolumic relaxation time was significantly prolonged in FD patients; (3) pulmonary venous atrial reversal duration exceeded that of mitral A wave duration in patients with FD; and (4) septal E' velocity with Doppler tissue imaging was much lower in FD patients compared with normal controls.
  • Murmurs associated with mitral regurgitation and stenosis may be heard.
  • Left ventricular hypertrophy is apparent in patients with more advanced disease.
  • Signs of congestive heart failure and hypertension are noted.
• Pulmonary: Wheezing respirations and dyspnea frequently are noted.
• Extremities: Lymphedema and varicose veins are common.
• Auditory: Hearing loss can be a familial part of FD.¹³ Vestibular and auditory deficits in FD  patients are often responsive to enzyme replacement therapy.¹⁴
• Ocular
• • Ocular changes may be specific, and the diagnosis may be made on the basis of ophthalmologic examination findings.
  • Corneal changes vary from diffuse haziness to corneal opacities characterized by whorled streaks extending from a central point to the periphery of the cornea. This change is identical to chloroquine or amiodarone toxicity.
  • Posterior capsular cataracts with whitish spokelike deposits of granular material may be seen. This type of cataract may be the first sign of ocular involvement and is so characteristic that it has been dubbed the Fabry cataract.
  • Occasionally, aneurysmal dilatation of thin-walled venules is seen on the bulbar conjunctiva.
  • Mild-to-marked tortuosity and angulation of the retinal vessels occur. Conjunctival vascular tortuosity may be the most common eye finding associated with FD.
• Neurologic: Multifocal small vessel involvement may result in hemiplegia, hemianesthesia, balance disorders, and personality changes. Chiari type I malformation has been reported in some patients with FD and should be sought if apposite MRI screening is performed. The role of general screening for Chiari type I malformation is not clear. Chronic meningitis and thalamic involvement has been described in a woman with FD.¹⁵
• Skeletal: Osteopenia and osteoporosis have been linked to FD.¹⁶ Bilateral femoral head and distal tibial osteonecrosis have also been linked to FD. Osteopenia is common in FD patients.¹⁷
• Gastrointestinal: In 2008, Hoffmann et al¹⁸ found gastrointestinal symptoms common in 342 patients with FD, with symptoms similar to inflammatory bowl disease; these symptoms improved with enzyme replacement therapy.

Causes

A defect in the activity of alpha-galactosidase, a lysosomal enzyme, results in the insidious storage of 2 neutral glycosphingolipids: trihexosylceramide (galactosylgalactosylglucosylceramide) and digalactosylceramide (galabiosylceramide). Angiokeratoma corporis diffusum is inherited in an X-linked recessive pattern.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Angiokeratoma of the scrotum (Fordyce angiokeratoma)
Adult-type beta-galactosidase deficiency
Aspartylglycosaminuria
Adult-onset variant of alpha-N-acetylgalactosaminidase deficiency
Beta-mannosidosis
Fucosidosis
Multiple sclerosis¹⁹
Sialidosis

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Urinalysis: Urine sediment contains cells with birefringent lipid globules termed Maltese crosses.
• Biochemistry: Levels in serum, leukocytes, tears, skin biopsy samples, and cell cultures demonstrate alpha-galactosidase deficiency. These tests are the most definitive means of diagnosis.
• Papaxanthos-Roche et al²⁰ noted that azoospermia can be a feature of FD.

Imaging Studies

• A variety of imaging studies can be used to evaluate FD. These include cardiac, body, and brain imaging tests.
• • Neurological: In a group of young FD patients with normal MRI findings, a significant increment of greater than 12% in apparent diffusion coefficient values in the corona radiata occurred compared with age-matched controls. The difference might demonstrate increased interstitial water in tissue after the Starling equilibrium under raised cerebral blood flow. This increase water content has been previously defined as a manifestation of FD. Thus, increased apparent diffusion coefficient values might occur before conventional MRI changes in persons with FD. Increased apparent diffusion coefficient values seem to be a sensitive marker of disease progression and the healing effect of enzymatic replacement therapy.²¹
  • Cardiac: Echocardiography can disclose left ventricular hypertrophy and systolic anterior motion of the mitral leaflets. Cardiac catheterization can show marked gradient loss in the left ventricular peak systolic outflow gradient, which indicates the presence of left ventricular outflow obstruction.

Procedures

• Total skin examination
• • The characteristic angiokeratoma of FD is found diffusely and is not limited to the scrotum as it is in Fordyce angiokeratoma.
  • Mibelli angiokeratoma is observed primarily on the dorsum of the hands and feet.
  • Angiokeratoma circumscriptum is a rare type of angiokeratoma with a unilateral distribution of discrete papules and nodules localized to a small area of the legs or trunk.
• Ophthalmologic examination: Slitlamp examination demonstrates characteristic corneal opacity. Also, look for the unique spokelike cataracts in the posterior capsule.

Histologic Findings

Histology shows numerous, dilated, thin-walled, endothelial-lined, blood-engorged capillaries in the papillary dermis, with an overlying hyperkeratotic epidermis. Careful inspection may reveal cytoplasmic vacuoles containing lipid in the endothelial cells, fibroblasts, and pericytes. However, in most patients, histologic findings essentially are identical to those of other angiokeratomas.

Endomyocardial biopsy findings of the heart can demonstrate sarcoplasmic vacuolization of cardiac muscle cells under light microscopy and lamellated zebra bodies in the cytoplasm under electron microscopy.

Electromicroscopy investigation can show stromal cells in hemizygous tissue and endothelial and smooth muscle cells in heterozygous tissue; cells contain membrane-bound inclusions with a lamellar structure (ie, inclusion bodies with a zebralike appearance).

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

As a multisystemic disease, angiokeratoma corporis diffusum requires treatment by a number of specialists. Treatment is intended to extend the lifespan of affected patients and make their lives more comfortable, especially in light of the often excruciating pain they experience.

Early detection of FD has made extending the lifespan and improving the quality of life possible for these patients. The administration of recombinant human alpha-galactosidase A replacement therapy can reverse and delay cardiac, renal, and neural damage to patients with FD.

Future treatments of FD that seem promising include (1) substrate deprivation based on the inhibition of an earlier step in the synthesis of the accumulating glycosphingolipid and (2) gene therapy.

• Dermatology: Carbon dioxide laser treatment can improve cosmetic appearance by removing angiokeratomas from the skin. Variable pulse width 532-nm Nd:YAG laser therapy, 578-nm copper vapor laser therapy, and flashlamp-pumped dye laser therapy can also be used to treat angiokeratomas. Hyperhidrosis can be treated with topical and systemic antiperspirant agents. Hypohidrosis or anhidrosis can be treated with moisturizers and topical applications of artificial lacrimal fluid and saliva.
• Nephrology: Renal insufficiency, the most common cause of mortality, can be treated with hemodialysis or kidney transplantation. Renal transplantation may benefit patients because it supplies a source of the missing enzyme alpha-galactosidase A.
• Neurology: Two antiseizure medications, diphenylhydantoin and carbamazepine, are the most helpful in alleviating the debilitating pain of neurologic involvement.
• Pulmonology: Obstructive lung disease is a problem late in the disease process. Discourage patients from smoking.
• Gene therapy: In recent years, nucleoside sequencing of the entire alpha-galactosidase A gene has enabled theoretical treatment using recombinant technology.
• Replacement therapy: Occasionally, infusions of plasma or partially purified enzyme from healthy donors have produced promising results.

Surgical Care

Kidney transplantation often is beneficial. Kidney transplantation improves survival. In addition to restoring renal reserve, the transplanted kidney produces a portion of the lacking enzyme alpha-galactosidase.

Consultations

• Nephrologist: Kidney failure is responsible for most fatalities associated with angiokeratoma corporis diffusum. A nephrologist can determine when renal dialysis and transplantation are indicated.
• Neurologist: Patients describe the pain associated with nerve involvement of FD as excruciating. In addition, a number of CNS problems are associated with this condition.
• Cardiologist: In addition to congestive heart failure and hypertension resulting from renal impairment, frequent primary dysfunction of the heart occurs.
• Pulmonologist: As the lung vasculature becomes increasingly affected, obstructive pulmonary disease often develops.
• Geneticist: Genetic counseling is helpful in this genetically transmitted disease.

Diet

A low-salt, high-protein diet may be used to help stave off renal problems, peripheral edema, and congestive heart failure.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

The goals of pharmacotherapy are to reduce morbidity and prevent complications.

Early intervention with enzyme replacement therapy (ERT) with intravenous infusions of recombinant human alpha-galactosidase A consistently and clearly decreases Gb3 levels in the blood plasma and clears vascular endothelial cellular lysosomal inclusions. While effects on other tissue are no so obvious, ERT, when initiated early, seems to prevent cellular damage and disease complications.²²

Lidove et al²³ noted that  2 formulations of the enzyme alpha-galactosidase A are used in Europe: agalsidase alpha (produced in a human cell line) and agalsidase beta (produced in Chinese hamster ovary cells). Lidove et al,²³ based on a review of 11 trials, reported that these preparations both appear to have clinical efficacy but that further assessments are needed. The trials have not been optimal in design and would benefit from a prospective design and a specific investigation into the effects of ERT in women and on the use of ERT early in the course of FD to halt organ damage before it starts. Additionally, Kim et al²⁴ noted that the pulmonary manifestations of FD respond positively to ERT.

Drug Category: Anticonvulsants

Antiseizure medications are the most helpful in alleviating the debilitating pain of neurologic involvement.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Inpatient care depends on the involved organ system.

Further Outpatient Care

• Many patients with FD require renal dialysis.
• FD is an important risk factor for stroke; thus, this should be accounted for when providing outpatient care.
• Edema (eg, lymphedema) can be treated with compression stockings.
• Dry corneas can be treated with artificial tears.

Deterrence/Prevention

• Screening for FD using analysis of spots of whole blood fails to identify one third of female carriers.²⁵
• With regard to urinary testing, the Fabry hemizygotes have higher concentrations of the substrate for the deficient enzyme, ceramide trihexoside, lactosylceramide, and ceramide in combination with decreased concentrations of glucosylceramide and sphingomyelin. Ratios of these analytes enhanced distinction between the control and Fabry groups. The Fabry heterozygotes had levels between the Fabry hemizygotes and the control group.²⁶

Complications

• Renal: Azotemia and progressive proteinuria can lead to frank uremia.
• Neurologic: Pain from FD can be debilitating. Other neurologic problems include paresis, seizures, hemiplegia, labyrinthine disorders, aphasia, tremor, sensory disturbances, and loss of consciousness.
• Cardiac
• • Fatal cardiac complications can result from cardiac hypertrophy, ventricular tachycardias, and dilated cardiomyopathy.
  • A number of other cardiac complications may occur, including mitral regurgitation, mitral stenosis, left ventricular hypertrophy, congestive heart failure, and hypertension.
  • Arrhythmias occur commonly in older patients with FD. Pacemaker implantation is often required, especially because of the possibility of sudden cardiac death associated with FD.
• Other: Wheezing and dyspnea occur as small vessels in the lungs are affected. Fairly marked lymphedema and varicose veins result from the disease's effect on small blood vessels of the legs.

Prognosis

• Few afflicted men live to be older than 50 years. A male cardiac variant exists in which patients have enough alpha-galactosidase to stave off the renal, neurologic, and skin changes typical of FD. Patients develop cardiac manifestations, especially cardiomyopathy.
• Heterozygous women have a longer lifespan with the disease because if they develop renal and cardiac symptoms, they do so later in life.

Patient Education

• Genetic counseling is urged. Both affected men and heterozygous women can transmit the gene. Sons of affected men are free of the gene, but daughters can pass the gene to future generations. In the offspring of heterozygous women, 50% of male children may have the disease and 50% of female children may become carriers.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to make the correct diagnosis because early symptoms may result in a misdiagnosis of rheumatic fever, neurosis, erythromelalgia, or collagen-vascular disease

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

1. Suzuki N, Konohana I, Fukushige T, Kanzaki T. Beta-mannosidosis with angiokeratoma corporis diffusum. J Dermatol. Nov 2004;31(11):931-5. [Medline].
2. Larralde M, Boggio P, Amartino H, Chamoles N. Fabry disease: a study of 6 hemizygous men and 5 heterozygous women with emphasis on dermatologic manifestations. Arch Dermatol. Dec 2004;140(12):1440-6. [Medline].
3. Molho-Pessach V, Bargal R, Abramowitz Y, Doviner V, Ingber A, Raas-Rothschild A, et al. Angiokeratoma corporis diffusum in human beta-mannosidosis: Report of a new case and a novel mutation. J Am Acad Dermatol. Sep 2007;57(3):407-12. [Medline].
4. Möhrenschlager M, Henkel V, Ring J. Fabry disease: more than angiokeratomas. Arch Dermatol. Dec 2004;140(12):1526-8. [Medline].
5. Eng CM, Fletcher J, Wilcox WR, Waldek S, Scott CR, Sillence DO, et al. Fabry disease: baseline medical characteristics of a cohort of 1765 males and females in the Fabry Registry. J Inherit Metab Dis. Apr 2007;30(2):184-92. [Medline].
6. Møller AT, Jensen TS. Neurological manifestations in Fabry's disease. Nat Clin Pract Neurol. Feb 2007;3(2):95-106. [Medline].
7. Nance CS, Klein CJ, Banikazemi M, Dikman SH, Phelps RG, McArthur JC, et al. Later-onset Fabry disease: an adult variant presenting with the cramp-fasciculation syndrome. Arch Neurol. Mar 2006;63(3):453-7. [Medline].
8. Choudhury S, Meehan S, Shin HT. Fabry disease: an atypical presentation. Pediatr Dermatol. Jul-Aug 2005;22(4):334-7. [Medline].
9. Cole AL, Lee PJ, Hughes DA, Deegan PB, Waldek S, Lachmann RH. Depression in adults with Fabry disease: a common and under-diagnosed problem. J Inherit Metab Dis. Nov 2007;30(6):943-51. [Medline].
10. Dominguez RO, Michref A, Tanus E, Amartino H. Restless legs syndrome in Fabry disease: clinical feature associated to neuropathic pain is overlooked. Rev Neurol. Oct 16-31 2007;45(8):474-8. [Medline].
11. Linhart A, Kampmann C, Zamorano JL, Sunder-Plassmann G, Beck M, Mehta A, et al. Cardiac manifestations of Anderson-Fabry disease: results from the international Fabry outcome survey. Trends Cardiovasc Med. May 2007;17(4):129-33. [Medline].
12. Sadick N, Thomas L. Cardiovascular manifestations in Fabry disease: a clinical and echocardiographic study. Heart Lung Circ. Jun 2007;16(3):200-6. [Medline].
13. Sergi B, Conti G. Hearing loss in a family affected by Fabry disease. J Inherit Metab Dis. Jun 2007;30(3):370-4. [Medline].
14. Palla A, Hegemann S, Widmer U, Straumann D. Vestibular and auditory deficits in Fabry disease and their response to enzyme replacement therapy. J Neurol. Oct 2007;254(10):1433-42. [Medline].
15. Lidove O, Chauveheid MP, Benoist L, Alexandra JF, Klein I, Papo T. Chronic meningitis and thalamic involvement in a woman: Fabry disease expanding phenotype. J Neurol Neurosurg Psychiatry. Sep 2007;78(9):1007. [Medline].
16. Germain DP, Benistan K, Boutouyrie P, Mutschler C. Osteopenia and osteoporosis: previously unrecognized manifestations of Fabry disease. Clin Genet. Jul 2005;68(1):93-5. [Medline].
17. Mersebach H, Johansson JO, Rasmussen AK, Bengtsson BA, Rosenberg K, Hasholt L, et al. Osteopenia: a common aspect of Fabry disease. Predictors of bone mineral density. Genet Med. Dec 2007;9(12):812-8. [Medline].
18. Hoffmann B, Schwarz M, Mehta A, Keshav S; Fabry Outcome Survey European Investigators. Gastrointestinal symptoms in 342 patients with Fabry disease: prevalence and response to enzyme replacement therapy. Clin Gastroenterol Hepatol. Dec 2007;5(12):1447-53. [Medline].
19. Callegaro D, Kaimen-Maciel DR. Fabry's disease as a differential diagnosis of MS. Int MS J. Jan 2006;13(1):27-30. [Medline].
20. Papaxanthos-Roche A, Deminiere C, Bauduer F, Hocke C, Mayer G, Lacombe D. Azoospermia as a new feature of Fabry disease. Fertil Steril. Jan 26 2007;[Medline].
21. Politei JM, Capizzano AA. Magnetic resonance image findings in 5 young patients with Fabry disease. Neurologist. Mar 2006;12(2):103-5. [Medline].
22. Clarke JT. Narrative review: Fabry disease. Ann Intern Med. Mar 20 2007;146(6):425-33. [Medline].
23. Lidove O, Joly D, Barbey F, Bekri S, Alexandra JF, Peigne V, et al. Clinical results of enzyme replacement therapy in Fabry disease: a comprehensive review of literature. Int J Clin Pract. Feb 2007;61(2):293-302. [Medline].
24. Kim W, Pyeritz RE, Bernhardt BA, Casey M, Litt HI. Pulmonary manifestations of Fabry disease and positive response to enzyme replacement therapy. Am J Med Genet A. Feb 15 2007;143(4):377-81. [Medline].
25. Linthorst GE, Vedder AC, Aerts JM, Hollak CE. Screening for Fabry disease using whole blood spots fails to identify one-third of female carriers. Clin Chim Acta. Mar 2005;353(1-2):201-3. [Medline].
26. Fuller M, Sharp PC, Rozaklis T, Whitfield PD, Blacklock D, Hopwood JJ, et al. Urinary lipid profiling for the identification of fabry hemizygotes and heterozygotes. Clin Chem. Apr 2005;51(4):688-94. [Medline].
27. Amann-Vesti BR, Gitzelmann G, Widmer U, Bosshard NU, Steinmann B, Koppensteiner R. Severe lymphatic microangiopathy in Fabry disease. Lymphat Res Biol. 2003;1(3):185-9. [Medline].
28. Becker AE, Schoorl R, Balk AG, van der Heide RM. Cardiac manifestations of Fabry's disease. Report of a case with mitral insufficiency and electrocardiographic evidence of myocardial infarction. Am J Cardiol. Nov 1975;36(6):829-35. [Medline].
29. Bishop DF, Calhoun DH, Bernstein HS, Hantzopoulos P, Quinn M, Desnick RJ. Human alpha-galactosidase A: nucleotide sequence of a cDNA clone encoding the mature enzyme. Proc Natl Acad Sci U S A. Jul 1986;83(13):4859-63. [Medline].
30. Brady RO, Tallman JF, Johnson WG, Gal AE, Leahy WR, Quirk JM, et al. Replacement therapy for inherited enzyme deficiency. Use of purified ceramidetrihexosidase in Fabry's disease. N Engl J Med. Jul 5 1973;289(1):9-14. [Medline].
31. Brown LK, Miller A, Bhuptani A, Sloane MF, Zimmerman MI, Schilero G, et al. Pulmonary involvement in Fabry disease. Am J Respir Crit Care Med. Mar 1997;155(3):1004-10. [Medline].
32. Clarke JT, Iwanochko RM. Enzyme replacement therapy of Fabry disease. Mol Neurobiol. Aug 2005;32(1):43-50. [Medline].
33. Crutchfield KE, Patronas NJ, Dambrosia JM, Frei KP, Banerjee TK, Barton NW, et al. Quantitative analysis of cerebral vasculopathy in patients with Fabry disease. Neurology. Jun 1998;50(6):1746-9. [Medline].
34. Desnick RJ, Eng C. Fabry disease: alpha-galactosidase A deficiency in Fabry's disease. In: Freedberg IM et al. Fitzpatrick's Dermatology in General Medicine. 1998. 5^th ed. McGraw-Hill; 1998:2741-84.
35. Desnick RJ, Simmons RL, Allen KY, Woods JE, Anderson CF, Najarian JS, et al. Correction of enzymatic deficiencies by renal transplantation: Fabry's disease. Surgery. Aug 1972;72(2):203-11. [Medline].
36. Dvorak AM, Cable WJ, Osage JE, Kolodny EH. Diagnostic electron microscopy. II. Fabry's disease: use of biopsies from uninvolved skin. Acute and chronic changes involving the microvasculature and small unmyelinated nerves. Pathol Annu. 1981;16 Pt 1:139-58. [Medline].
37. Frost P, Tamala Y, Spaeth GL. Fabry's disease--glycolipid lipidosis. Histochemical and electron microscopic studies of two cases. Am J Med. Apr 1966;40(4):618-27. [Medline].
38. Grunnet ML, Spilsbury PR. The central nervous system in Fabry's disease. An ultrastructural study. Arch Neurol. Apr 1973;28(4):231-4. [Medline].
39. Hashimoto K, Lieberman P, Lamkin N Jr. Angiokeratoma corporis diffusum (Fabry disease). A lysosomal disease. Arch Dermatol. Oct 1976;112(10):1416-23. [Medline].
40. Kanitakis J, Allombert C, Doebelin B, Deroo-Berger MC, Grande S, Blanc S, et al. Fucosidosis with angiokeratoma. Immunohistochemical & electronmicroscopic study of a new case and literature review. J Cutan Pathol. Aug 2005;32(7):506-11. [Medline].
41. Kleinert J, Dehout F, Schwarting A, de Lorenzo AG, Ricci R, Kampmann C, et al. Anemia is a new complication in Fabry disease: data from the Fabry Outcome Survey. Kidney Int. May 2005;67(5):1955-60. [Medline].
42. Ko YH, Kim HJ, Roh YS, Park CK, Kwon CK, Park MH. Atypical Fabry's disease. An oligosymptomatic variant. Arch Pathol Lab Med. Jan 1996;120(1):86-9. [Medline].
43. Lao LM, Kumakiri M, Mima H, Kuwahara H, Ishida H, Ishiguro K, et al. The ultrastructural characteristics of eccrine sweat glands in a Fabry disease patient with hypohidrosis. J Dermatol Sci. Nov 1998;18(2):109-17. [Medline].
44. Linthorst GE, Hollak CE, Donker-Koopman WE, Strijland A, Aerts JM. Enzyme therapy for Fabry disease: neutralizing antibodies toward agalsidase alpha and beta. Kidney Int. Oct 2004;66(4):1589-95. [Medline].
45. Lockman LA, Hunninghake DB, Krivit W, Desnick RJ. Relief of pain of Fabry's disease by diphenylhydantoin. Neurology. Aug 1973;23(8):871-5. [Medline].
46. Low M, Nicholls K, Tubridy N, Hand P, Velakoulis D, Kiers L, et al. Neurology of Fabry disease. Intern Med J. Jul 2007;37(7):436-47. [Medline].
47. Matsuzawa F, Aikawa S, Doi H, Okumiya T, Sakuraba H. Fabry disease: correlation between structural changes in alpha-galactosidase, and clinical and biochemical phenotypes. Hum Genet. Aug 2005;117(4):317-28. [Medline].
48. McNary WF, Lowenstein LM. A morphological study of the renal lesion in angiokeratoma corporis diffusum universale (Fabry's disease). J Urol. Jun 1965;93:641-8. [Medline].
49. Menkes DL, O''Neil TJ, Saenz KK. Fabry''s disease presenting as syncope, angiokeratomas, and spoke-like cataracts in a young man: discussion of the differential diagnosis. Mil Med. Nov 1997;162(11):773-6. [Medline].
50. Mitsias P, Levine SR. Cerebrovascular complications of Fabry's disease. Ann Neurol. Jul 1996;40(1):8-17. [Medline].
51. Morgan SH, Rudge P, Smith SJ, Bronstein AM, Kendall BE, Holly E, et al. The neurological complications of Anderson-Fabry disease (alpha-galactosidase A deficiency)--investigation of symptomatic and presymptomatic patients. Q J Med. May 1990;75(277):491-507. [Medline].
52. Ries M, Gupta S, Moore DF, Sachdev V, Quirk JM, Murray GJ, et al. Pediatric Fabry disease. Pediatrics. Mar 2005;115(3):e344-55. [Medline].
53. Rosenthal D, Lien YH, Lager D, Lai LW, Shang S, Leung N, et al. A novel alpha-galactosidase a mutant (M42L) identified in a renal variant of Fabry disease. Am J Kidney Dis. Nov 2004;44(5):e85-9. [Medline].
54. Sagebiel RW, Parker F. Cutaneous lesions of Fabry's disease: glycolipid lipidosis; light and electron microscopic findings. J Invest Dermatol. Mar 1968;50(3):208-13. [Medline].
55. Schaefer E, Mehta A, Gal A. Genotype and phenotype in Fabry disease: analysis of the Fabry Outcome Survey. Acta Paediatr Suppl. Mar 2005;94(447):87-92; discussion 79. [Medline].
56. Scott LJ, Griffin JW, Luciano C, Barton NW, Banerjee T, Crawford T, et al. Quantitative analysis of epidermal innervation in Fabry disease. Neurology. Apr 12 1999;52(6):1249-54. [Medline].
57. Shabbeer J, Yasuda M, Benson SD, Desnick RJ. Fabry disease: identification of 50 novel alpha-galactosidase A mutations causing the classic phenotype and three-dimensional structural analysis of 29 missense mutations. Hum Genomics. Mar 2006;2(5):297-309. [Medline].
58. Sheth KJ, Werlin SL, Freeman ME, Hodach AE. Gastrointestinal structure and function in Fabry's disease. Am J Gastroenterol. Sep 1981;76(3):246-51. [Medline].
59. Spaeth GL, Frost P. Fabry's disease. Its ocular manifestations. Arch Ophthalmol. Dec 1965;74(6):760-9. [Medline].
60. Utsumi K, Yamamoto N, Kase R, Takata T, Okumiya T, Saito H, et al. High incidence of thrombosis in Fabry's disease. Intern Med. May 1997;36(5):327-9. [Medline].
61. Wallace RD, Cooper WJ. Angiokeratoma corporis diffusum universale (Fabry). Am J Med. Oct 1965;39(4):656-61. [Medline].
62. Wang AM, Desnick RJ. Structural organization and complete sequence of the human alpha-N-acetylgalactosaminidase gene: homology with the alpha-galactosidase A gene provides evidence for evolution from a common ancestral gene. Genomics. May 1991;10(1):133-42. [Medline].
63. Wu KH, Tzung TY, Ro LS, Hsiao KJ. A novel mutation (c. 1072_1074delGAG) in the alpha-galactosidase gene of a Taiwanese family with Fabry disease. Acta Derm Venereol. 2004;84(4):310-1. [Medline].

Article Last Updated: Mar 13, 2008