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Diagnosing Fabry Disease

Fabry disease diagnosis is challenging, as symptoms are diverse, varied, and can affect multiple organs1,2

While Fabry disease is considered “rare,” the disease manifestations are common. As a result of the multi-organ pathology often seen in patients with Fabry disease and the number of conditions that mimic many of the disease manifestations, diagnosis may be difficult.1,2

Use this tool to understand how Fabry disease may be diagnosed by specialty.

Symptoms

Does your patient present with any of the following symptoms?

  • Cardiomyopathy/LVH (without/mild hypertension)
  • Prominent papillary muscle
  • Cardiac arrhythmia (paroxysmal or permanent atrial fibrillation, bradycardia, malignant arrhythmia/ventricular tachycardia)
  • Myocardial infarction
  • Congestive heart failure
  • Intramyocardial fibrosis
  • Valvular disorder (mitral valve, aortic valve)
  • Dyspnea

Diagnostics

Consider the following tests & procedures:

  • ECG (changes with short P wave and short PR interval, increase in the QRS width and repolarization disturbances)
  • Stress ECG
  • Spiroergometry
  • Holter ECG (24 hours)
  • Echocardiography: LVH (end diastolic wall thickness >12 mm), prominent papillary muscle, myocardial replacement fibrosis
  • Blood: hs-troponin, NT-proBNP

Symptoms

Does your patient present with any of the following symptoms?

  • Cramp-style stomach pain (mostly after eating)
  • Diarrhea
  • Nausea
  • Vomiting
  • Constipation
  • Feeling of fullness/premature satiety
  • Bloating
  • Anorexia
  • Delayed gastric emptying

Diagnostics

Consider the following tests & procedures:

  • Medical history/physical examination
  • Ultrasound scan
  • Gastroscopy (EGD with biopsies)
  • Colonoscopy (with biopsies)
  • H2 breath test, if necessary
  • Video capsule endoscopy, if necessary

Symptoms

Does your patient present with any of the following symptoms?

  • Microalbuminuria/albuminuria
  • Podocyturia → Proteinuria (>300 mg/day)
  • GFR decrease (GFR >60 mL/min/1.73 m2)
  • Edemas in the hands and feet → Note relationship between leg edema and protein excretion
  • Parapelvic renal cysts
  • Progressive renal failure
  • Dialysis
  • Rare: renal tubular acidosis and nephrogenic diabetes insipidus

Diagnostics

Consider the following tests & procedures:

  • Renal function test: GFR from creatinine and urea clearance, serum creatinine (mg/dL), GFR (mL/min/1.73 m2) → Serum analysis, semi-quantitative protein or albumin using test strips, UPC, UAC → Spontaneous urine total protein, albumin, GFR from creatinine and urea clearance → 24-hour urine
  • Renal ultrasound (morphology, vascular lesions, cysts)
  • 24-hour blood pressure measurement
  • Renal biopsy if necessary (evaluation of GL-3 deposits, fibrosis, and sclerosis) → Discuss light microscopy using toluidine blue stain with pathology

Symptoms

Does your patient present with any of the following symptoms?

  • TIA, stroke, muscle weakness
  • Acroparesthesia → Burning pain in hands and feet
  • Small fiber neuropathy
  • Pain crises
  • Dyshidrosis (hypohidrosis, rarely hyperhidrosis)
  • Temperature intolerance
  • GI discomfort
  • Basilar ectasia/ectatic vessels (vertebrobasilar)
  • White matter lesions (WML)
  • Reduced lacrimation and salivation
  • Depression
  • Fatigue

Diagnostics

Consider the following tests & procedures:

  • Doppler/duplex ultrasound, particularly of the basilar artery
  • Cerebral MRI including MR angiography → WML, silent infarctions, spinal lesions, contrast medium enhancement
  • Electroneurography
  • “Bedside” thermal, vibration, and touch tests
  • QST (small fiber neuropathy where diabetes, alcohol abuse, etc. are excluded)
  • Skin biopsy if necessary
  • Assessment of pain/quality of life using scales such as BPI, WHO-5, MDI-10, SF-36
  • Questioning on sweating levels, temperature intolerance

Symptoms

Does your patient present with any of the following symptoms?

  • Acroparesthesia → Burning pain in hands and feet
  • Small fiber neuropathy
  • Pain crisis triggered by exercise, stress, temperature change/fever
  • Temperature intolerance
  • Dyshidrosis (hypohidrosis, rarely hyperhidrosis)
  • Gastrointestinal discomfort
  • Fibromyalgia
  • Cluster headache/migraine
  • Joint pain

Diagnostics

Consider the following tests & procedures:

  • Medical history/physical examination
  • Assessment of pain/quality of life using scales such as the BPI, WHO-5, MDI-10, SF-36 health survey
  • Electroneurography
  • “Bedside” tests such as thermal, vibration, and touch tests; QST
  • Skin biopsy if necessary
  • Questioning on sweating levels, temperature intolerance
  • MRI

Symptoms

Does your patient present with any of the following symptoms?

  • Acroparesthesia → Burning pain in hands and feet
  • Gastrointestinal discomfort
  • Small fiber neuropathy
  • Pain crisis triggered by exercise, stress, temperature change/fever
  • Heat intolerance
  • Dyshidrosis (hypohidrosis, rarely hyperhidrosis)
  • Cornea verticillata
  • Chronic pain in the extremities
  • Tortuous vessels along the rim of the eye
  • Angiokeratomas
  • Proteinuria (>300 mg/day)
  • Renal cysts
  • Elevated cystatin C levels
  • Tinnitus/hearing loss
  • Lethargy/tiredness

Diagnostics

Consider the following tests & procedures:

  • Medical history/family tree/clinical examination
  • Pediatric questionnaire on pain and quality of life
  • Questioning on sweating levels, temperature intolerance
  • ECG/24-hour ECG
  • Renal function test: albuminuria/creatinine/creatinine clearance/GFR/protein → Serum analysis/spontaneous urine/24-hour urine
  • Slit lamp examination/retroillumination/retinal examination and photography
  • Audiogram
  • Cerebral MRI

Symptoms

Does your patient present with any of the following symptoms?

  • Acroparesthesia → Burning pain in hands and feet
  • Small fiber neuropathy
  • Pain crisis triggered by exercise, stress, temperature change/fever
  • Joint pain
  • Elevated erythrocyte sedimentation rate

Diagnostics

Consider the following tests & procedures:

  • Medical history/physical examination
  • Assessment of pain/quality of life using scales such as BPI, WHO-5, MDI-10, SF-36 health survey
  • Electroneurography
  • “Bedside” tests such as thermal, vibration, and touch tests; QST
  • Skin biopsy if necessary
  • Questioning on sweating levels, temperature intolerance
  • Rheumatological laboratory diagnostics
  • Lack of response to therapy for rheumatic diseases

Fabry Disease Diagnostic Checklist

To download this diagnostic tool, please select a specialty:

It Could Be Fabry Disease

Confirm It Is Fabry Disease

It Could Be Fabry Disease

Does your patient’s medical or family history exhibit any of the following?

Patient medical history:

  • Any signs of kidney failure such as uremia or hypocalcemia?
  • Any of the symptoms listed above categorized by specialty?

Family medical history:

  • Any signs of kidney failure such as uremia or hypocalcemia in relatives?
  • Any unexplained incidents of death in the family?

Confirm It Is Fabry Disease

These tests can be used to confirm a Fabry disease diagnosis or aid in the diagnostic process:

  • GLA gene sequencing
  • Levels of alpha-galactosidase A (alpha-Gal A) activity
  • Levels of plasma lyso-Gb3

AND/OR

Molecular genetic/cytogenetic Fabry diagnosis from:

  • EDTA blood test
  • Serum
  • Buccal swab
Learn about the effects of Fabry disease.

See how Fabry disease can affect the various organ systems.

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BPI, Brief Pain Inventory; ECG, electrocardiogram; EDTA, ethylenediaminetetraacetic acid; EGD, endogastroduodenoscopy;
GFR, glomerular filtration rate; GI, gastrointestinal; GL-3, globotriaosylceramide; HS, high sensitivity; LVH, left ventricular hypertrophy;
lyso-Gb3, globotriaosylsphingosine; MDI-10, 10-item Major Depression Inventory; MR, magnetic resonance; MRI, magnetic resonance imaging;
NT-proBNP, N-terminal pro-brain natriuretic peptide; QST, quantitative sensory testing; SF-36, Short-Form-36; TIA, transient
ischemic attack; UAC, urine albumin to creatinine ratio; UPC, urine protein to creatinine ratio; WHO-5, World Health Organization-5.

References:

  1. Germain DP. Fabry disease. Orphanet J Rare Dis. 2010;5:30.
  2. Hoffmann B, Mayatepek E. Fabry disease-often seen, rarely diagnosed. Dtsch Arztebl Int. 2009;106(26):440-447.