Handbook of Genetic Counseling/Fabry Disease

Fabry Disease

Introduction and Contracting

• Counselor1 will do introductions and get the consent form
• I'll explain that I'm going to obtain medical and family history

Medical History

• DOB
• What is your ethnicity or country where your ancestors are from?
• Blood type
• When did you notice your first symptoms What age?
• How were you diagnosed? (enzyme activity or gene testing?)
• When were you diagnosed?
• Review current meds to make sure nothing has changed
• "I am going to go through a number of symptoms and want you to let me know if you currently have any of them, have experienced them in the past, or if you have ever been diagnosed with any of the symptoms I list"
  • high cholesterol (do you know how high, when was it diagnosed)
  • anemia or low blood count (when, did you receive treatment for it)
  • muscle pain (myalgia) (describe when, where, how often, intensity, or contributory factors)
  • joint pain (arthralgia) (describe when, where, how often, intensity, anything that contributes)
  • other pain (except acroparesthesia)
  • insufficient sweating or inability to sweat (refer to last page -- when do you notice this, have you ever had any serious problems as a result (overheating))
  • Any Fabry skin markings (angiokeratomas - little purple marks) (Where?)
  • sensitivity to loud noises? (describe how sensitive, how often is this a problem)
  • any dizziness? (describe when, what seems to cause it, how often, is it when you get up from sitting, is room spinning)
  • any abnormalities in the cornea of eyes (corneal swirls don't affect vision or deposits which can cause cloudiness)
  • any headaches (when, how often, require medication, migraine-like)
  • any difficulty breathing (when, how often, anything that seems to bring it on)
  • high blood pressure (what is it usually)
  • low blood pressure (what is it usually)
  • enlarged heart which is called left ventricular hypertrophy or right ventricular hypertrophy (when discovered, what you were told about it)
  • heart ever skip a beat or been told you have conduction abnormalities of heart
  • any swelling in extremities
  • heart murmur
  • slow heart beat
  • any chest pain (any medication for it (nitroglycerin))
  • abdominal pain (refer to last page -- when, how often, severity, anything that precedes it i.e.) eating)
  • diarrhea (when, how often, severity, anything that you think contributes)
  • protein or blood in urine (when first noted, currently)
  • pain in hands and feet - describe
  • depression or felt down (how long, when diagnosed, thoughts of suicide)
  • loss of strength (WHAT DO THEY MEAN?)

Other Diagnoses/Problems

• infectious diseases such as tuberculosis
• allergies (describe - medication, food, seasonal)
• nutritional problems, endocrine or hormone problems (hyperthyroidism, hypothyroidism), metabolic diseases
• bleeding disorders
• arthritis or muscle weakness
• any skin problems such as dry skin (eczema)
• hearing problems or vision problems (corrective lenses)
• breast abnormalities
• respiratory problems such as asthma
• other heart problems not mentioned (heart attack or stroke)
• any GI problems such as colitis or Crone's disease or liver problems
• any GU problems such as difficulty urinating or any kidney problems
• neurological diseases (MS, Parkinson's) or neurological symptoms not mentioned already
• any psychiatric problems such as schizophrenia

Pedigree

(Quick family history and will focus on anyone that may have any Fabry symptoms)

• 3 generations
• you are currently married
• do you have any children from this or past relationships
• list full brothers and sisters from youngest to oldest
• any half brothers or sisters
• do any of them have any Fabry symptoms
• any of them have children?
• Get info on the children
• Are parents still living?
• Mother have brothers or sisters? Any fabry symptoms? Get info on the aunt's children
• Get maternal grandparents if need another generation
• Father have any brothers or sisters get info but don't need paternal cousins
• Paternal grandparents if needed

Inheritance

• Review genes and chromosomes briefly
• Talk about X and Y chromosomes
• Gene for Fabry disease is on X chromosome so it is an X linked disease
• The gene gives the cells instructions on how to make an enzyme (alpha-galactosidase A) that breaks down certain fatty substances
• An alteration in this gene changes the instructions
• Since men only have one copy of the X chromosome they only have one copy of the instructions for the protein
• if that copy is altered they won't make any of the protein
• Women that inherit an altered copy of the gene will often have symptoms as well, but sometimes they are not as severe because they still have one working gene and can make some of the enzyme
• Men that have the altered gene causing Fabry will pass it on to all their girls because the girls but they give their y chromosome to their boys so they won't be affected
• Women that have the altered gene causing Fabry have a 50% chance of passing it on to each of their girls and their boys (like tossing a coin to see which X chromosome they get)

Psychosocial

• Will it be difficult if you end up flying out every two weeks?
• How do the symptoms affect your life?
• Probably difficult dealing with pain
• Do others know you have Fabry disease do they seem to understand what it is?
• How do you explain it to others?
• Are you involved with any support groups?
• Would you like to be?
• Patients with Fabry often experience clinical depression, denial of clinical symptoms, feeling of isolation and loneliness

General Info on Fabry

• one of over 40 genetically inherited lysosomal storage disorders
• caused by a change in a gene located on the x chromosome
• incidence - affects 1 in every 40,000 males
• heterozygous females may range from asymptomatic to as severely affected as males (rare)
• this gene instructs the body about how to make enzyme called alpha-galactosidase A (alpha-GAL)
• when gene is altered alpha-GAL is absent or not present in sufficient amounts
• alpha-GAL breaks down certain fatty substances normally present in body
• without it fatty materials (primarily globotriaosylceramide, or GL-3) accumulate in the body (mainly in the walls of blood vessels)
• vessels become narrowed, leading to decreased blood flow and decreased nourishment of the tissues normally supplied by these vessels
• process occurs in blood vessels throughout the body, particularly affecting vessels in the skin, kidneys, heart, brain and nervous system.
• accumulation over time causes progressive symptoms
• organ systems can stop functioning properly
• if diagnosed early then symptom management may be more effective and may lead to an improved quality of life
• Lifespan - usually live until fourth or fifth decade of life (usually from renal failure, cardiac, or cerebrovascular disease)

Symptoms

• wide range of symptoms progressive nature of the disease means that symptoms will frequently change or intensify
• not everyone with Fabry disease experiences all the symptoms and not everyone experiences the symptoms to the same degree
• Pain
  • common symptom
  • two types
  • constant acroparesthesia-- affects the hands and feet, primarily-described as burning, tingling pain and constant discomfort
  • episodic paresthesia ("Fabry crises") --intense, excruciating burning pain felt initially in the hands and feet, which often radiate to other parts of the body can be debilitating, and last from minutes to several days (affects approximately 10% of heterozygous females)
  • pain is ultimately the result of the build-up of GL-3
  • pain can be brought on by changes in weather, exposure to hot temperatures, stress, exercise, or fatigue
  • pain can be difficult to treat but usually responds to medications such as Tegretol (carbamazepine), Dilatin or Neurotin. Metoclopramide, Lipisorb (a nutritional supplement)
• Cerebrovascular
  • Premature Stroke
• ave age adulthood
• Eye
  • Corneal whorling (a starburst pattern on the cornea) ~70% of heterozygous females
  • do not affect vision
  • detectable through slit-lamp ophthalmoscopy
  • seen in childhood
  • vascular lesions of the conjunctiva and retina, and lens opacities
• Cardiovascular
  • Mitral valve prolapse
  • Cardiac arrhythmia
  • Coronary occlusion
  • Myocardial failure
  • Cardiac enlargement
  • Other signs of cardiac impairment
  • ave age adulthood
• Neurological
  • Intolerance to heat and cold
  • Inability to withstand exercise or change in temperatures
  • Pain already described
  • ave age childhood
• Dermatological
  • Inability to perspire adequately to cool the body (hypohidrosis or anhidrosis)
• ave age childhood
  • Angiokeratoma -- clusters of dark red skin lesions that do not blanch with pressure, primarily found in the area below the waist and above the knees (affects approximately 30% of heterozygous females)
  • can be removed with laser cosmetic
  • ave age adolescence
• Gastrointestinal
  • Abdominal cramping
  • Nausea
  • Diarrhea
  • Pain after a meal
  • Other signs of gastrointestinal distress
  • ave age adolescence
  • Pancrelipase may be beneficial in treating gastrointestinal hyperactivity
• Renal
  • Proteinuria
  • Progressive renal insufficiency
• ave age adulthood

Diagnosis

• Physical exam - angiokeratoma or corneal dystrophy
• Family history - X-linked recessive
• Enzyme assay - deficient alpha-GAL in plasma or leukocytes: http://www.genzymegenetics.com/Our-Services/Reproductive-Testing/fabry-enzyme-test.aspx
• Molecular - > 150 mutations identified
• Prenatal diagnosis available by DNA analysis if the mutation in the family is recognized. chorionic villus sampling (at 12 weeks) and amniocentesis (at 16 weeks), by demonstration of deficient alpha-GAL activity and XY karyotype, or linkage analysis

Treatment

(mostly symptomatic)

• Anti-convulsives
• ACE inhibitors
• Dialysis
• Renal transplant
• Enzyme replacement therapy
  • 2 phase 3 / 4 clinical trials from Genzyme and TKT
  • Problems - antibody response to new enzyme

Surveillance

• 24 hour urine: creatinine clearance (a measure of kidney function)
• EKG/ECHO/Cardiac MRI
• Brain MRI
• Pain assessment

Differential Diagnosis

• symptoms are similar to the following
  • rheumatoid arthritis
  • juvenile arthritis
  • rheumatic fever
  • erythromelalgia
  • lupus
  • "growing pains"
  • petechiae
  • Raynaud's syndrome
  • multiple sclerosis

References

• The Metabolic and Molecular Bases of Inherited Disease (eighth edition). Chapter 150 by Desnick, Loannou, & Eng. pp. 3733-3769.
• http://www.fabrycommunity.com/
• http://www.fabry.org/

Notes

The information in this outline was last updated in 2002.