Fabry Disease

Fabry disease (FD), also known as Anderson-Fabry disease, is an X-linked recessive lysosomal storage disorder and the 2nd most common of the lysosomal storage disorders (after Gaucher disease Gaucher disease Gaucher Disease (GD) is an autosomal recessive lysosomal storage disorder caused by a deficiency of glucocerebrosidase enzyme activity, resulting in accumulation of glucocerebroside in cells and certain organs. The disease is categorized into 3 types with variable clinical presentation. Gaucher Disease). Fabry disease is caused by a deficiency in the alpha-galactosidase enzyme (alpha-Gal A), resulting in the accumulation of the glycosphingolipid globotriaosylceramide (Gb3) in lysosomes. This accumulation leads to organ dysfunctions and clinical manifestations. Fabry disease is classified into classic (early-onset) and atypical (late-onset) FD. The clinical presentation and severity can vary but may include acroparesthesias, angiokeratomas, stroke, cardiovascular disease, and renal dysfunction. Diagnosis is made by measurement of alpha-Gal A enzyme activity or identification of an alpha-galactosidase A (GLA) gene mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations. There is no cure for FD. Management is supportive, including pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain control and slowing the progression of disease with enzyme replacement or chaperone therapies.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Table of Contents

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Overview

Etiology

  • X-linked recessive disorder
  • Mutation in GLA on chromosome Xq21.3-q22
  • Results in a deficiency of lysosomal alpha-Gal A

Classification

  • Classic type (early onset)
    • Less common
    • More severe
    • Onset: childhood to teenage years
  • Atypical type (late onset)
    • More common
    • Disease presentation based on particular organ system
    • Onset: age ≥ 30 years

Epidemiology

  • Prevalence:
    • Classic: 1 in 40,000 males
    • Atypical: 
      • 1 in 1,000–3,000 males
      • 1 in 6,000–40,000 females
  • Ethnicity:
    • More common in Caucasians
    • Rare in Asians
    • Also seen in African Americans
  • Men > women

Pathophysiology

  • Deficiency in alpha-Gal A → accumulation of Gb3 (also known as ceramide trihexoside) in the lysosomes of various cells and tissues
  • Gb3 derivatives are:
    • Cytotoxic
    • Proinflammatory
    • Profibrotic
  • Vascular endothelial accumulation leads to:
    • Vascular occlusion → ischemia and infarction
    • Narrowing and occlusion of cerebral vessels → cerebral infarcts
  • Accumulation in other tissues → organ dysfunction and clinical manifestations

Clinical Presentation

Time course

  • Age of onset: 
    • Classic: childhood to teenage years 
    • Atypical: 30 years or older
  • Progressive with advancing age
  • Life expectancy varies based on the severity of disease.
  • Death commonly occurs between the 4th and 5th decade of life due to cardiac, renal, or cerebrovascular complications.

Signs and symptoms

The clinical presentation and severity vary, and men have more severe symptoms than women do.

Musculocutaneous:

  • Limb pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain (acroparesthesia)
    • Major clinical symptom
    • Particularly affects hands and feet
    • Quality:
      • Numbness
      • Tingling
      • Burning
    • Precipitated by:
      • Stress
      • Extremes in temperature
      • Physical exertion
  • Angiokeratoma
    • Raised, red/purplish skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin lesions
    • Painless
    • Bathing trunk distribution 
      • Abdomen
      • Genital
      • Proximal lower extremities
  • Telangiectasias
Fabry disease_angiokeratoma

Angiokeratoma are often distributed on the buttocks, groin, umbilicus, and upper thighs. They are occasionally seen on the lips Lips The lips are the soft and movable most external parts of the oral cavity. The blood supply of the lips originates from the external carotid artery, and the innervation is through cranial nerves. Oral Cavity: Lips and Tongue and oral mucosa.

Image: “Angiokeratoma” by Alessandro P Burlina et al. License: CC BY 2.0

GI:

  • Abdominal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain
  • Nausea and vomiting
  • Constipation Constipation Constipation is common and may be due to a variety of causes. Constipation is generally defined as bowel movement frequency < 3 times per week. Patients who are constipated often strain to pass hard stools. The condition is classified as primary (also known as idiopathic or functional constipation) or secondary, and as acute or chronic. Constipation or diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea

Ocular:

  • Corneal verticillata
    • Corneal opacity
    • Diffuse haziness or “whorls” on slit lamp exam
  • “Fabry cataract” (anterior and posterior subcapsular cataracts)
  • Tortuosity and dilation of conjunctival and retinal vessels
Ocular changes in fabry disease

Common ocular changes in Fabry disease:
a: Cornea verticillata
b: Increased vessel tortuosity and aneurysms (arrows)
c: Increased tortuosity of superior temporalis artery and vein
d: Lens opacity

Image: “Typical ocular changes seen in Fabry disease” by Gisela Kalkum et al. License: CC BY 4.0

Renal:

  • Proteinuria
  • Hematuria
  • Renal failure

Neurologic:

  • Transient ischemic attacks
  • Ischemic stroke Ischemic Stroke An ischemic stroke (also known as cerebrovascular accident) is an acute neurologic injury that occurs as a result of brain ischemia; this condition may be due to cerebral blood vessel occlusion by thrombosis or embolism, or rarely due to systemic hypoperfusion. Ischemic Stroke

Cardiac:

  • Often extensive and progressive
  • Myocardial infarction Myocardial infarction MI is ischemia and death of an area of myocardial tissue due to insufficient blood flow and oxygenation, usually from thrombus formation on a ruptured atherosclerotic plaque in the epicardial arteries. Clinical presentation is most commonly with chest pain, but women and patients with diabetes may have atypical symptoms. Myocardial Infarction
  • Arrhythmias and conduction abnormalities
  • Left ventricular hypertrophy
  • Heart failure
  • Valvular abnormalities

Auricular:

  • Vertigo Vertigo Vertigo is defined as the perceived sensation of rotational motion while remaining still. A very common complaint in primary care and the ER, vertigo is more frequently experienced by women and its prevalence increases with age. Vertigo is classified into peripheral or central based on its etiology. Vertigo
  • Hearing loss Hearing loss Hearing loss, also known as hearing impairment, is any degree of impairment in the ability to apprehend sound as determined by audiometry to be below normal hearing thresholds. Clinical presentation may occur at birth or as a gradual loss of hearing with age, including a short-term or sudden loss at any point. Hearing Loss
  • Tinnitus

Other:

  • Fatigue
  • Fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever
  • Body aches
  • Pedal edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema
  • Exercise, heat or cold intolerance
  • Decreased sweating (hypohidrosis) or the absence of sweating (anhidrosis)

Diagnosis and Management

Diagnosis

Clinical suspicion in children or adolescents will lead to testing and diagnosis. However, a late diagnosis is not uncommon given the varied clinical presentation.

  • In males, diagnosis is made with alpha-Gal A enzyme assay.
    • < 3% of normal enzyme activity confirms the diagnosis.
    • Not accurate in females, where enzyme activity is normal
  • In females, genetic testing for the GLA mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations is used to make the diagnosis.
  • A tissue biopsy will show glycolipid deposits.
  • Prenatal genetic screening and newborn Newborn A neonate, or newborn, is defined as a child less than 28 days old. A thorough physical examination should be performed within the first 24 hours of life to identify abnormalities and improve outcomes by offering timely treatment. Physical Examination of the Newborn screening are also available.

Management

  • There is no cure for FD.  
  • Treatment is multidisciplinary and largely supportive, including:
    • Pain control
    • Medical management of cardiac, renal, and/or cerebrovascular complications
    • Slowing the build-up of fatty substances and progression of disease
      • Enzyme replacement therapy with recombinant alpha-Gal A
      • Chaperone therapy repairs the faulty enzyme.

Differential Diagnosis

  • Gaucher disease Gaucher disease Gaucher Disease (GD) is an autosomal recessive lysosomal storage disorder caused by a deficiency of glucocerebrosidase enzyme activity, resulting in accumulation of glucocerebroside in cells and certain organs. The disease is categorized into 3 types with variable clinical presentation. Gaucher Disease (GD): a lysosomal storage disorder caused by a deficiency of glucocerebrosidase enzyme activity, resulting in accumulation of glucocerebroside. Infantile GD presents within 6 months of life with progressive neurodegeneration, loss of motor skills, hypotonia, feeding difficulties, hepatosplenomegaly, and death before age 3. Diagnosis is made with measurement of acid beta-glucosidase activity and confirmed with genetic analysis. Management is supportive.
  • Tay-Sachs disease Tay-Sachs disease Tay-Sachs disease is an autosomal recessive lysosomal storage disorder caused by genetic mutations in the hexosaminidase A (HEXA) gene, leading to progressive neurodegeneration. Classic symptoms in infants include rapid degeneration of cognitive and neuromuscular abilities, progressive blindness, and a macular cherry-red spot on physical examination. Tay-Sachs Disease: an autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritancelysosomal storage disorder caused by genetic mutations in the hexosaminidase A (HEXA) gene, leading to progressive neurodegeneration. Classic symptoms in infants include rapid degeneration of cognitive and neuromuscular abilities, progressive blindness, and a macular cherry-red spot upon physical examination. Diagnosis is made with measurement of enzyme activity. Management is supportive.
  • Niemann-Pick disease Niemann-Pick disease Niemann-Pick disease (NPD) is a rare, inherited, lysosomal storage disorder. The disease is classified on the basis of the genetic mutation. Type A and type B result from mutations in the SMPD-1 gene, resulting in acid sphingomyelinase enzyme deficiency. Type C results from NPC1 or NPC2 gene mutations, which are needed for intracellular transport of lipids. Niemann-Pick Disease type A (NPD-A): a lysosomal storage disorder caused by an acid sphingomyelinase enzyme deficiency. The disease is characterized by progressive neurodegeneration starting within a few months of life and resulting in death by age 3. Clinical manifestations include macular cherry-red spot, difficulty feeding, loss of motor skills, hypotonia, and organomegaly. Diagnosis includes measurement of sphingomyelinase enzyme activity and genetic testing. Management is supportive. 
  • Sandhoff disease (SD): a lysosomal storage disorder caused by a deficiency in both HEXA and the hexosaminidase B (HEXB). Juvenile SD is characterized by progressive neurodegeneration starting at 6 months of age. Clinical manifestations include organomegaly, skeletal abnormalities, hyperacusis, macular cherry-red spot, blindness, and seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures. Diagnosis is made by measurement of HEXA and HEXB, as well as genetic analysis. Management is supportive.
  • Pompe disease (glycogen storage disease II): a lysosomal and glycogen storage disorder caused by acid alpha glucosidase (GAA) deficiency . There are 3 types with variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables onset and presentations. Clinical manifestations include failure to thrive Failure to Thrive Failure to thrive (FTT), or faltering growth, describes suboptimal weight gain and growth in children. The majority of cases are due to inadequate caloric intake; however, genetic, infectious, and oncological etiologies are also common. Failure to Thrive, feeding difficulty, hypotonia, progressive muscle weakness, hypertrophic cardiomyopathy Hypertrophic Cardiomyopathy Hypertrophic cardiomyopathy (HCM) is the most commonly inherited cardiomyopathy, which is characterized by an asymmetric increase in thickness (hypertrophy) of the left ventricular wall, diastolic dysfunction, and often left ventricular outflow tract obstruction. Hypertrophic Cardiomyopathy, and respiratory failure Respiratory failure Respiratory failure is a syndrome that develops when the respiratory system is unable to maintain oxygenation and/or ventilation. Respiratory failure may be acute or chronic and is classified as hypoxemic, hypercapnic, or a combination of the two. Respiratory Failure. Diagnosis is made with enzyme activity measurement and molecular gene analysis. Management includes supportive measures and enzyme replacement.

References

  1. Maur, M., Koop, J. B., Curhan, G. C., Gassock, R. J., Deputy Editor. Lam, A. Q. (2021). Fabry disease: Clinical features and diagnosis. UptoDate. Retrieved July 15, 2021 from https://www.uptodate.com/contents/fabry-disease-clinical-features-and-diagnosis
  2. Ahsan, N. Chief Editor Lutsep, H. L. Fabry Disease. (2018). Medscape. Retrieved July 15, 2021 from https://emedicine.medscape.com/article/1952086-overview
  3. Fabry Disease. (2020). Cleveland Clinic. Retrieved July 15, 2021 from https://my.clevelandclinic.org/health/diseases/16235-fabry-disease
  4. Fuller, M., Meikle, P. J., Hopwood, J. J. (2006). Chapter 2 Epidemiology of lysosomal storage diseases: an overview. In Fabry Disease: Perspectives from 5 Years of FOS. Oxford PharmaGenesis. https://pubmed.ncbi.nlm.nih.gov/21290683/
  5. Zar-Kessler, C., Karaa, A., Sims, K. B., Clarke, V., Kuo, B. (2016). Understanding the gastrointestinal manifestations of Fabry disease: promoting prompt diagnosis. Therap Adv Gastroenterol; 9(4):626-634. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4913334/
  6. Luxner, L. (2019). Fabry Disease More Common Than Previously Thought, Experts Say. Fabry Disease News. Retrieved July 27, 2021 from https://fabrydiseasenews.com/2019/03/20/fabry-disease-more-…
  7. Fabry Disease Audiology Symptoms. (2006). From National Fabry Disease Foundation. Retrieved July 29, 2021 from https://www.fabrydisease.org/index.php/component/content/article?id=127
  8. Fabry Disease. (2019). From National Organization for Rare Disorders. https://rarediseases.org/rare-diseases/fabry-disease/

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