PEDBASE.org - The Pediatric Database - Detailed information of FABRY DISEASE

FABRY DISEASE

DEFINITION:

A lysosomal storage disorder characterized by the accumulation of lipid (glycosphingolipid) in peripheral tissues resulting in the triad of acroparesthesia, angiokeratomas, and corneal opacities.

EPIDEMIOLOGY:

incidence: over 300 cases reported
age of onset:
- late childhood -> adolescence
risk factors:
- familial - x-linked recessive with complete penetrance but variable phenotype
  - chrom.#: Xq22
  - gene: alpha-galactosidase A
- M only

PATHOGENESIS:

1. Background

alpha-galactosidase A catalyzes the conversion of trihexosylceramide to dihexosylceramide
the alpha-galactosidase gene has been cloned
disease originally described by Fabry in 1898

2. Genetic Defect

genetic defect -> deficiency of alpha-galactosidase A activity -> accumulation of three glycosphingolipids in peripheral tissues:
- trihexosylceramide - in the endothelium of blood vessels and is the major cause of pathology
- digalactosylceramide - accumulate in the heart & kidneys
- blood group B-1 - increase the progression of the disglycolipid ease in those with type B blood group

CLINICAL FEATURES:

1. Neurological Manifestations

1. Peripheral Nervous System

1. Acroparesthesia

burning pain crises of the extremities
onset in childhood
may be the initial manifestation of the disease
crises
- periodic and excruciating
- may become more frequent and severe with age then lessen in the 2nd or 3rd decades
- precipitated by heat, cold, exercise, humidity, fever, and/or fatigue
- last from several hours to days
- usually associated with a low-grade fever and elevated ESR
- burning or tingling sensation beginning in the fingers and toes and spreading proximally

2. Central Nervous System

cerebral vascular disease with ischemia and infarction in cortical and brainstem areas -> strokes, seizures, person-ality changes, and hemiplegia
no mental retardation

2. Cutaneous Manifestations

1. Angiokeratomas

small dark purple-blue telangiectasia
may appear in childhood but usually not noted until after
10 years of age
most dense between the umbilicus and knees with propensity for umbilicus and buttocks
progressive increase in the size and number with age
do not blanch with pressure

2. Others

hypohidrosis
lymphedema of the legs

3. Ocular Manifestations

1. Cornea

linear/whorling opacities originating from a central vortex
also have lenticular opacities

2. Lens

cataracts

3. Retina

dilated and tortuous retinal vessels with aneurysmal dila-tation
papilledema +/- hypertensive changes

4. Respiratory Manifestations

chronic airflow obstruction
dyspnea

5. Cardiac Manifestations

conduction defects
hypertension
ischemic heart attacks
mitral valve insufficiency
thromboses

6. Gastrointestinal Manifestations

abdominal and/or flank pain
diarrhea
hepatomegaly
nausea and vomiting

7. Renal Manifestations

proteinuria eventually leading to end stage renal failure (ESRF) between the 2nd and 4th decades

8. Musculoskeletal Manifestations

permanent deformity of the distal interphalangeal joint of the fingers
avascular necrosis of the head of the femur or talus with limp, knee pain, and/or hip pain

9. Endocrine Manifestations

short stature
delayed puberty

INVESTIGATIONS:

1. Diagnosis

deficiency of alpha-galactosidase activity in WBC's or cultured skin fibroblasts
mild corneal opacities in 80% of obligate heterozygotes
prenatal
- deficiency of alpha-galactosidase activity in cultured chorionic villi or amniocytes

2. Serum

elevated trihexosylceramide
mild microcytic hypochromic anemia
abnormal renal function (ESRF)

3. Urine

elevated trihexosylceramide - WBC's and casts
lipid inclusions with characteristic - isosthenuria birefringent "Maltese crosses"
proteinuria +/- hematuria

4. EKG

left ventricular hypertrophy - T-wave inversion
ST segmental changes - short PR interval

5. Pathology

1. Biopsy

lipid accumulation in:
- kidneys - epithelial & endothelial cells of glomeruli and tubules
- airways - airway epithelium

MANAGEMENT:

1. Supportive

no treatment available for disease
multidisciplinary approach
- Paediatrics, Neurology, Dermatology, Ophthalmology, Cardio-logy, Nephrology, Endocrinology
- painful crises treated with low dose diphenylhydantoin or carbamazepine
- renal transplant for ESRF

2. Prognosis

mean age of survival is 42 years
death from ESRF or vascular disease of the heart or CNS

Pediatric Database - FABRY DISEASE

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