OMIM ID:
Fabry Disease
Alternate Names
Defective Genes
Clinical Characteristics
Ocular Features
Fabry disease is a lysosomal enzyme (alpha-galactosidase A) deficiency resulting in the accumulation of globotriaosylceramide (Gb3) and related glycosphingolipids throughout the body. The signature ocular manifestation is the whorl-like corneal pattern of lipid (glycosphingolipid) deposits which are present in both hemizygous males and heterozygous females. These are sometimes referred to as cornea verticillata or Fleischer vortex dystrophy with a pattern similar to that seen in some patients using atabrine or amiodarone. A general ‘haze’ throughout the cornea is even more common. Lens opacities may also be distinctive and generally are one of two types: spoke-like opacities beneath the posterior capsule among males, and wedge-shaped anterior subcapsular deposits, again primarily in males. The corneal and lens opacities seldom cause significant vision problems.
Involvement of the ocular vessels is present in almost all patients. A notable increase in tortuosity of conjunctival vessels is present in 97% of hemizygous males and 78% of heterozygous females. Increased retinal vessel tortuosity is less common but arteriolar involvement significantly increases the risk of central retinal artery occlusions. An 11 yo Turkish female heterozygote with a cilioretinal artery occlusion and anterior ischemic optic neuropathy in one eye has been reported.
Systemic Features
The relatively common occurrence and the protean nature of Fabry disease has lead to its designation by some as the Great Imposter, replacing syphilis to which this term was previously applied. Compounding the diagnostic difficulties in some individuals is the absence of the complete classical phenotype due to the presence of DNA variants that may modify the expression of some the clinical features.
Most signs present in the first or second decade of life with generally earlier onset in males. The presence of proteinuria before the age of 20 years in the absence of other primary kidney disease should always raise the possibility of Fabry disease. However, the diagnosis is often not made until the third decade in males and the fourth decade in females. Glycosphingolipid inclusion deposits in endothelial cells are responsible for the systemic signs and symptoms including renal and heart disease which are the most common causes of premature death. Small vessel involvement resulting in cerebrovascular disease and painful peripheral neuropathy can be debilitating. The risk of ischemic strokes is increased. Cardiac manifestations include hypertrophic cardiomyopathy (60%), mainly involving the left ventricle, and dysfunction of the mitral and aortic valves (10 to 25%). Dysfunction of renal glomeruli may progress to renal failure by the third to fifth decade in males. The angiokeratomas and angiomas (most pronounced in a swimming trunk pattern) are secondary to vascular involvement of cutaneous vessels but are non-specific since they also occur in other lysosomal diseases. The life expectancy of females is reduced by about 5 years and for males about 16 years compared with the general US population.
Involvment of the autonomic system manifests as intermittent fever, hypohidrosis, and poor temperature control. Some patients have periodic crises of severe pain in the extremities as well as intermittent epigastric pain. Hearing loss and episodic tinnitus are common complaints.
Genetics
Inheritance
This is an X-linked disorder and generally assumed to be recessive although some have suggested dominance since most heterozygous females have significant manifestations that can be life-threatening. The mutations in the responsible gene (GLA), located at Xq22, involve a variety of deletions, rearrangements and single base pair changes. Defects in the GLA gene lead to dysfunction of the enzyme alpha-galactosidase A resulting in lysosomal deposition of glycosphingolipids throughout the body, especially in vascular endothelial cells.
The milder disease and increase in the range of clinical manifestations among females is likely a reflection of variable patterns of X-inactivation.
Increased tortuosity of retinal arterioles is also seen in fucidosis (230000), Williams syndrome (194050), and in a condition known as retinal arteriolar tortuosity (611773, 180000).
Pedigree
X-linked dominant, father affected
X-linked inheritance patterns result when disease-causing mutations are located on the X chromosome. Males have one X chromosome while females have two. A mutation on the male's X chromosome frequently is lethal or renders him unable to reproduce. However, in rare cases when males have children, they can expect that all of then will inherit the condition.
X-linked inheritance patterns result when disease-causing mutations are located on the X chromosome. Males have one X chromosome while females have two. A mutation on the male's X chromosome frequently is lethal or at least renders them unable to reproduce. However, in rare cases when males have children, they can expect that all of then will inherit the condition.
X-linked dominant, mother affected
X-linked inheritance patterns result from mutations located on the X chromosome. Females have two X chromosomes of which only one carries a mutation in X-linked dominant disorders. This usually results in expression of the disease and women with a single mutation have the disorder caused by the mutation. Half of their offspring, male and female, will inherit the mutation. Men, with only one X chromosome, will always have the condition if they inherit the one with the mutation. Men would transmit it to all of their offspring. Without a modifying normal gene on a second X chromosome, X-linked dominant conditions are frequently lethal in such males. The result is a vertical transmission pattern, usually from female to female.
X-linked inheritance patterns result from mutations located on the X chromosome. Females have two X chromosomes of which only one carries a mutation in X-linked dominant disorders. This usually results in expression of the disease and women with a single mutation have the disorder caused by the mutation. Half of their offspring, male and female, will inherit the mutation. Men, with only one X chromosome, will always have the condition if they inherit the one with the mutation. Men would transmit it to all of their offspring. Without a modifying normal gene on a second X chromosome, X-linked dominant conditions are frequently lethal in such males. The result is a vertical transmission pattern, usually from female to female.