Fabry's disease

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ghazal Sanadgol, M.D.[2]

Fabry’s disease (also known as alpha-galactosidase A deficiency, ceramide trihexosidase deficiency, angiokeratoma corporis diffusum, Anderson Fabry disease) is an X-linked recessive inherited lysosomal storage disorder.

Fabry’s disease is a rare inherited genetic condition that leads to the α-galactosidase A enzyme deficiency in individuals. Fabry’s disease (or Anderson – Fabry disease) was first described separately by two physicians at the end of the 19th century. The feature and pathophysiology of the disease have been revealed through the years by various scientists.

Fabry’s disease can be classified based on its different phenotypes or complications. Its different phenotypes are: classic and late-onset. The different complications involves: cardiac, renal, and neuropathic forms.

Genes involved in the pathogenesis of Fabry’s disease include the GLA gene, which codes the important enzyme of alpha-galactosidase. The absence or lack of this enzyme causes Gb3 accumulation in different organs. The main pathological finding is detection of these inclusion in different cells with electron microscopies.

Fabry’s disease is caused by a mutation in the GLA gene.

Fabry’s disease is often misdiagnosed due to its rarity and wide range of non-specific clinical manifestations. Fabry’s disease be differentiated from various kind of condition based on the symptoms and organ involvement.

Fabry’s disease is a rare condition with a prevalence of approximately 6:100,000 to 0.8:100,000 in men. This disease mostly affects men and has no rational disparities.

There are no established risk factors for Fabry’s disease.

According to National society of Genetic Counselors, screening for Fabry’s disease in patient family member is recommended. The early prenatal and newborn screening can be done by α-Gal A enzyme and GLA mutation analyses. Based on American Heart Failure society the Fabry’s disease screening should be done in males with unexplained cardiac hypertrophy.

If Fabry’s disease leaves untreated it can lead to end-stage renal disease (ESRD), cardiomyopathy, and stroke which are the main causes of death in these patients. Enzyme replacement therapy (ERT) treatment has an important role in their life expectancy and disease complications.

A positive history of angiokeratomas, peripheral neuropathies, gradually decreased sweating, and gastrointestinal manifestations in childhood are suggestive of classic Fabry’s disease. In the late-onset form of the disease neuropathic pain and gastrointestinal manifestation is not common and they may have organ-specific symptoms.

The presence of angiokeratomas on physical examination is highly suggestive of Fabry’s disease. other physical examinations can be varied due to organ involvement.

A reduced concentration of serum Alpha-galactosidase A level or its activity is diagnostic of Fabry’s disease. Other laboratory findings can vary due to organ involvement.

However the ECG patterns are not specific for Fabry’s , it may be helpful in the diagnosis of Fabry’s disease cardiac complications.

CT scan can show different non-specific aspects of the brain, lung, and kidney involvement in Fabry’s disease.

MRI can play an important role in the diagnosis of the brain and cardiac complications of Fabry’s disease. there are also some non-specific findings in renal involvement.

Echocardiography and renal ultrasound can reveal the diagnostic pattern of Fabry’s disease in these particular organs.

There are no other imaging findings associated with Fabry’s disease.

There are no other diagnostic studies associated with Fabry’s disease.

The mainstay of therapy for Fabry’s disease is enzyme replacement by Agalsidases. Other treatment is increasing the enzyme activity by Migalastat. There are also some general treatments for Fabry’s disease complications.

Kidney transplantation can be a surgical option in certain Fabry’s disease patients.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Ghazal Sanadgol, M.D.[2]

Fabry’s disease is a rare inherited genetic condition that leads to the α-galactosidase A enzyme deficiency in individuals. Fabry disease (or Anderson – Fabry disease) was first described separately by two physicians at the end of the 19th century. The feature and pathophysiology of the disease have been revealed through the years by various scientists.

• Fabry disease (or Anderson – Fabry disease) was first described separately by two physicians, Johannes Fabry in Germany and William Anderson in England, at the end of the 19th century.
  • In 1898, Fabry named it “angiokeratoma corporis diffusum” following his 13-years-old patient’s symptoms of red-purple skin lesion and subsequent albuminuria.
  • In the same year, Anderson reported a 39-years-old patient with angiokeratomas, proteinuria, finger deformities, varicose veins, and lymphedema. ^[1]
• In 1909, the neurological symptoms of the disease were described by Steiner and Voerner.
• In 1925, the cardiac and ophthalmic complications and the possible hereditary feature of the disease were reported by Weicksel.
• In 1947, systemic vascular involvement was demonstrated by Pompen et al. during Fabry’s patients’ autopsy.^[2]
• In 1953, the disease was recognized as a storage disease by Horbostel and Scriba.^[3]
• In 1963, Sweeley and Klionsky identified the aggregation of certain types of glycolipids in various cells of patients with Fabry’s disease.^[4]
• In 1965, the nature of Fabry’s disease was identified as the X-linked genetic disease by Opitz et al. for the first time.^[5]
• In 1970, the specific α-galactosidase A enzyme deficiency was recognized as a cause of the disease.^[6]
• In 2001, specific enzyme replacement therapy for Fabry’s disease, namely Fabrazyme, was commercially introduced in Europe and in 2003 in the USA.^[7]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Ghazal Sanadgol, M.D.[2]

Fabry’s disease can be classified based on its different phenotypes or complications. Its different phenotypes are: classic and late-onset. The different complications involve: cardiac, renal, and neuropathic forms.

Heterozygous females can be categorized in both groups based on the severity of the disease, from severe classic ones to less severe atypical and even no symptoms.^[4]

• Cardiac variant
• Renal variant
• Neuropathic form
  • Infantile form
  • Juvenile form

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Ghazal Sanadgol, M.D.[2]

Genes involved in the pathogenesis of Fabry’s disease include the GLA gene, which codes the important enzyme of alpha-galactosidase. The absence or lack of this enzyme causes Gb3 accumulation in different organs. The main pathological finding is detection of these inclusion in different cells with electron microscopies.

• GLA gene codes information for the alpha-galactosidase enzyme.
• The normal function of the alpha-galactosidase enzyme is to breakdown globotriaosylceramide (also abbreviated as Gb3, GL-3, or ceramide trihexoside) into glucocerebroside in lysosomes.
• Gb3 is produced in the catabolism pathway of Globoside, an essential glycosphingolipid in the cell membrane (RBCs and Kidney), that is mainly metabolized in the lysosome of the spleen, liver , and bone marrow.^[1]

• Fabry disease is caused by a deficiency of alpha-galactosidase.
• Mutations to the GLA gene encoding α-GAL may result in a complete loss of function of the enzyme.
• Alpha-galactosidase is a lysosomal protein responsible for breaking down globotriaosylceramide(Gb3) a fatty substance stored in various types of cardiac and renal cells.^[2]
• Improper catabolism causes globotriaosylceramide (Gb3) to accumulate in cells lining blood vessels in the skin, kidney, heart, and nervous system. As a result, signs, and symptoms of Fabry diseasseven begin to manifest.^[3]
• Accumulation of globotriaosylceramide (Gb3) in different tissues leads to cellular death, compromised energy metabolism, small vessel injury, potassium-calcium channel dysfunction in the endothelial cells, oxidative stress,impaired autophagosome maturation, tissue ischemia, irreversible cardiac and renal tissue fibrosis.^[4]

• Fabry’s disease follows an X-linked inheritance pattern.
• Since it is inherited in an X-linked pattern, males are homozygous and pass the disease to all daughters but no sons.
• Females are heterozygous with 50% chance of passing the mutated gene to both daughters and sons.^[5]
• Skewed nonrandom X chromosome inactivation may cause paradoxical nature of the disease that is seen in females,; they have a varied presentation from being asymptomatic to having very severe symptoms and having a presentation similar to that seen in males with the classical type.^[6]
• Gene function: GLA gene encodes information for alpha-Gal-A.
• Gene location: GLA has its locus located on the Longarm of chromosome X in position Xq22. It has seven exons distributed over 1290 base pairs of coding part. ^[7][8]
• Demonstrates extensive allelic heterogeneity but no genetic locus heterogeneity.^[9]
• 585 mutations have so far been recorded for Fabry’s disease.^[10]
• Mutations demonstrated include Missense, Non-sense point mutations,splicing mutations, small deletion/Insertion, and large deletions.^[11]

• The most important characteristics of Fabry’s disease on gross pathology are:
  • Kidney
    • Kidney enlargement
    • Renal cysts of cortical and parapelvic
    • Decreased cortical thickness^[12]
  • Heart
    • Four chamber cardiomegaly( frequently LVH with interventricular septum hypertrophy)^[13]
  • Eye
    • Conjunctiva
      • Ampullary and saccular aneurysms of small venules
      • Thrombosis^[14]
    • Retina
      • Segmental dilatation and tortuosity of venules and arteries
      • Whorl-like corneal dystrophic pattern^[15]
  • Nervous system
    • Central nervous system
      • White matter lesion ^[16]

On microscopic histopathological analysis, tissue deposition of glycosphingolipids crystalline is a characteristic finding of Fabry’s disease.

• Glycosphingolipid inclusions morphology: coarsely lamellated appearance, maybe round with onion-skin likes structure (Myelin figures), or dense unstructured layer (Zebra bodies), some can be dark electrodense and amorphous especially in endothelial and mesangial cells.^[17]
• Electron Microscopy: The most accurate method for detection of glycosphingolipids depositions. preserved whole glycosphingolipids during the preparation process.^[18]
• Light microscopy is not as specific in confirming FD as electron microscopy and thus is only done when electron microscopy is unavailable.

• Immunofluorescence Microscopy: Negative, not react to IgG, IgM, IgA, C3, C1q antibodies.
• Immunohistochemistry: Murine anti-Gb3 antibody id used.^[24]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Ghazal Sanadgol, M.D.[2]

Fabry’s disease is caused by a mutation in the GLA gene.

• Fabry’s disease is a genetically X – linked inherited disorder due to a mutation in the GLA gene which is responsible for coding lysosomal enzyme alpha galactosidase A.

• The deficiency of the enzyme leads to a build up of Gb3 (Globotriaosylhexidase) in the lysosomes.
• These accumulations in various tissues leads to classic manifestations of fabry’s disease that include skin, cardiac, renal, and neurological involvement.^[1]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Ghazal Sanadgol, M.D.[2]

Fabry’s disease is often misdiagnosed due to its rarity and wide range of non-specific clinical manifestations. Fabry’s disease be differentiated from various kind of condition based on the symptoms and organ involvement.

• Angiokeratoma: Fucosidosis^[1],Sialidosis (Juvenile form)^[2], Acral pseudolymphomatous angiokeratoma of childhood^[3]
• Hypohidrosis/Anhidrosis :Horner syndrome, Topiramate usage, Acetylcholine intoxication, Ectodermal dysplasia
• Hyperhidrosis: Primary hyperhidrosis^[4]
• Lymphedema: Chronic Venus insufficiency, Rheumatic disorders

• Pain (neuropathic): rheumatic disorders, fibromyalgia, headache (Cluster), migraine, diabetic neuropathy, recurrent fever syndromes, porphyria, uremic neuropathy , Guillain-Barre‘ syndrome, hereditary neuropathy

• Abdominal pain, diarrhea, constipation: Gastritis, duodenal ulcer, celiac disease, gastrointestinal hemorrhage, Crohn’s disease, ulcerative colitis, diverticulitis, functional dyspepsia, irritable bowel syndrome, familial Mediterranean fever

• Cornea verticillate :Therapy with amiodarone, flecainide, tamoxifen; fucosidosis
• Tortuositas vasorum: Diabetes mellitus, arterial hypertension, nephrotic syndrome, neurofibromatosis type 1, fibromuscular dysplasia, Rendu-Osler-Weber disease, Velocardiofacial syndrome
• Uveitis: Rheumatic disorders, tubulointerstitial nephritis and uveitis syndrome (TINU), Bechet’s disease, sarcoidosis, Crohn’s disease
• Conjunctival aneurysms: Kawasaki syndrome, Diabetes mellitus

• Acute/chronic hearing loss: apoplexy, multiple sclerosis, leopard syndrome
• tinnitus: otosclerosis, borreliosis, sudden deafness, Meniere’s disease, acoustic neurinoma
• Dizziness: benign paroxysmal positional vertigo, Meniere’s disease, vestibular neuritis, cerebellar/brain stem infarction

• Angina pectoris, myocardial infarction: Atherosclerosis
• Palpitations: atrial fibrillation, Wolf-Parkinson-White syndrome, hyperthyroidism, drug induced palpitations
• Cardiomyopathy: Mitochondriopathies, Long QT syndrome, myocarditis, Pompe disease, Niemann-Pick disease, hemochromatosis, Duchenne/Becker muscular dystrophy, neurofibromatosis type 1, systemic lupus erythematosus, rheumatoid arthritis, dermatomyositis
• Valvular disorders: Endocarditis, rheumatic disorders, mucopolysaccharidoses
• Impaired variability of cardiac frequency :Arterial hypertension, mitral valve prolapse, diabetes mellitus, Sjogren syndrome, MELAS syndrome, obstructive sleep apnea

• Proteinuria/progressive renal failure: Diabetes mellitus, arterial hypertension, glomerulonephritis, systemic lupus erythematosus, hemolytic-uremic syndrome, gout, amyloidosis, diabetes mellitus, Henoch-Schonlein purpura

• TIA, apoplexy, white matter lesions: Atherosclerosis, multiple sclerosis, mitochondriopathies, CADASIL^[5]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Ghazal Sanadgol, M.D.[2]

Fabry’s disease is a rare condition with a prevalence of approximately 6:100,000 to 0.8:100,000 in men. This disease mostly affects men and has no rational disparities.

• In 2021, the prevalence of Fabry’s disease was estimated to be approximately 6:100,000 to 0.8:100,000 in men.
• The prevalence of classic phenotype is estimated approximately 4.5:100,000 to 2.5:100,000 in men.
• The prevalence of atypical phenotype is about 100:100,000 to 33:100,000 in men and 16:100,000 to 2.5:100,000 in females.^[1]

• Incidence of Fabry’s disease is commonly underestimated.^[1]

• Men are more commonly affected with Fabry’s disease than females. The male to female ratio is approximately 2 to 1.^[1]

• The prevalence of Fabry’s disease does not vary by race.^[1]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Ghazal Sanadgol, M.D.[2]

There are no established risk factors for Fabry’s disease.

There are no established risk factors for Fabry’s disease.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Ghazal Sanadgol, M.D.[2]

According to National Society of Genetic Counselors, screening for Fabry’s disease in the patient’s family members is recommended. The early prenatal and newborn screening can be done by α-Gal A enzyme and GLA mutation analyses. Based on the American Heart Failure Society, Fabry’s disease screening should be done in males with unexplained cardiac hypertrophy.

• There is insufficient evidence to recommend routine newborn screening for Fabry’s disease in the general population.

• According to the National Society of Genetic Counselors, screening for Fabry’s disease for family members of the affected individual is recommended by: 
  • Measuring alpha-galactosidase activity in men
  • Sequencing the GLA gene in females
  • Prenatal and preimplantation testing
    • Early prenatal diagnosis:
      • 10 weeks: α-Gal A enzyme and GLA mutation analyses by chorionic villus sampling
      • 15 weeks: α-Gal A enzyme activity by amniocentesis^[1]
  • Newborn screening
    • In males: α-Gal A activity and GLA gene sequencing in blood spots^[2][3]
• According to the 2009 Heart Failure Society of America, screening for Fabry’s disease is recommended for all men with sporadic or non-autosomal transmission of unexplained cardiac hypertrophy.^[4]
• There is insufficient evidence to recommend routine screening for Fabry’s disease in the dialysis population.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Ghazal Sanadgol, M.D.[2]

If Fabry’s disease leaves untreated it can lead to end-stage renal disease (ESRD), cardiomyopathy, and stroke which are the main causes of death in these patients. Enzyme replacement therapy (ERT) treatment has an important role in their life expectancy and disease complications.

• The symptoms of classic Fabry’s disease usually develop in childhood or adolescents , and start with symptoms such as neuropathic pains, angiokeratomas, dyshidrosis, GI symptoms, and etc.
• Without treatment, lifespan of homozygote men will dramatically reduced to fifth decade and the main causes of deaths are renal failure, heart disease or stroke.^[1]

• The symptoms of late-onset Fabry’s disease in females and atypical variants are accrue in higher ages and are less severe.
• With out treatment, life span of heterozygote females will be at seventh decade and the main causes of death are cardiac dysfunction, cancer and stroke. Empty citation (help)Empty citation (help)^[2]

• Common complications that can develop as a result of Fabry’s disease are:
  • Heart problems including cardiomyopathy, Arrhythmia, Heart failure
  • Renal failure (ESRD)
  • Peripheral neuropathy
  • Strokes (such as TIA)
• Complications that can develop as a result of the treatment of Fabry’s disease with enzyme replacement therapy are:
  • Infusion reactions: rigors, fever, etc.
  • Seroconversion: presents of anti-bodies may lower the efficacy of ERT.^[3]

• The prognosis of Fabry’s disease improves with treatment. Without treatment, Fabry’s disease will result in reduced life expectancy.^[4]