globotriaosylceramide and Eye-Diseases

Fabry disease (FD) is an X-linked lysosomal storage disorder caused by accumulation of Gb-3 (globotriaosylceramide) in cellular lysosomes of tissues throughout the body. With advancing age, lysosomal Gb-3 accumulates in blood vessel walls, nerve cells, smooth muscle, and vital organs. Premature death commonly results from renal failure, heart attack, and stroke when the diagnosis is delayed or overlooked. One of the earliest and most distinctive physical features of FD is a whorl-like keratopathy. This finding is easily identifiable during a routine eye examination with a slit lamp, making eye care practitioners uniquely postured to identify patients and families with this incurable genetic disorder. Much of the pain, suffering, and adverse impact of FD can be avoided if an alert eye care expert sees the patient at an early age, identifies the condition, and makes the appropriate referral. The importance of obtaining a thorough medical history, ancestral health history, and review of systems to correlate ocular and systemic manifestations is emphasized. This report reviews the multisystem involvement of FD and describes the clinical characteristics and expected chronological appearance of ophthalmic and systemic manifestations. The discoveries of late-onset variants, increased prevalence, and modified inheritance pattern of FD are discussed. The profound therapeutic effects of recombinant enzyme replacement therapy (ERT) on multiple organ systems are detailed and demonstrated in a Fabry proband. Improved quality and quantity of life after initiation of ERT underscore the importance of early recognition and correlation of FD symptoms and clinical signs. Treatment strategies and the effectiveness of new adjunctive chaperone therapy are addressed.

Topics: DNA; Eye Diseases; Fabry Disease; Genetic Predisposition to Disease; Global Health; Humans; Lysosomes; Mutation; Prevalence; Trihexosylceramides

Fabry disease (FD, OMIM 301500) is an X-linked inherited disorder of metabolism due to mutations in the gene encoding alpha-galactosidase A, a lysosomal enzyme. The enzymatic defect leads to the accumulation of neutral glycosphingolipids throughout the body, particularly within endothelial cells. Resulting narrowing and tortuosity of small blood vessels lead to tissue ischaemia and infarction. Inability to prevent the progression of glycosphingolipid deposition causes significant morbidity (acroparesthesia, angiokeratoma, autonomic dysfunction, cardiomyopathy and deafness), and mortality from early onset strokes, heart attack and renal failure in adulthood. Demonstration of alpha-galactosidase A deficiency in leukocytes or plasma is the definitive method for the diagnosis of affected hemizygous males. Most heterozygotes present with a cardiac, renal or neurological symptomatology, although to a lesser extent than what is observed in hemizygotes. Due to random X-chromosomal inactivation, enzymatic detection of carriers is often inconclusive. Molecular testing of possible carriers is therefore mandatory for accurate genetic counselling. The GLA gene has been cloned and more than 200 mutations have been identified. Medical management is symptomatic and consists of partial pain relief with analgesic drugs (gabapentin, carbamazepine), whereas renal transplantation or dialysis is available for patients experiencing end-stage renal failure. However, the ability to produce high doses of alpha-galactosidase A in vitro has opened the way to clinical studies and enzyme replacement therapy has recently been validated as a therapeutic agent for FD patients in clinical trials. Long term safety and efficacy of replacement therapy are currently being investigated.

Topics: alpha-Galactosidase; Amino Acid Substitution; Cardiovascular Diseases; Disease Progression; Eye Diseases; Fabry Disease; Female; Genetic Carrier Screening; Genetic Counseling; Genotype; Humans; Infant; Kidney Failure, Chronic; Kidney Transplantation; Male; Mutation; Pregnancy; Prenatal Diagnosis; Trihexosylceramides; X Chromosome