GLA Sequencing for Fabry Disease
Background:
Fabry disease (OMIM 301500) is a lysosomal storage disorder caused by deficiency of the enzyme, alpha-galactosidase A (GLA). GLA is responsible for breaking down fatty substances in the body called globotriaosylceramides (GL-3). Deficiency of GLA results in the gradual accumulation of GL-3 in the walls of the blood vessels and tissues such as the heart, kidneys, and brain, which causes progressive damage and potentially life-threatening problems. Due to X-linked recessive inheritance, males are more often affected with Fabry disease than females. However, females who are carriers for the disorder may have physical findings ranging from asymptomatic to severe and may depend in part on the randomness of X-inactivation and occasionally skewed X-inactivation. Affected males with classic Fabry disease typically have less than 1% GLA enzyme activity. Over 300 GLA mutations have been described and tend to be specific to a family.
Fabry disease has a spectrum of physical manifestations ranging from the severe classic form to renal variants associated with end stage renal disease, but without characteristic skin lesions and pain crises to milder cardiac variants. However, the most common presentation is the classical form that presents in childhood or adolescence. Individuals with classic Fabry disease may first present with painful crises, including acroparesthesia or "Fabry crises", due to accumulation of GL-3 in the nervous system. The pain can be brought on by changes in the weather, exposure to hot temperatures, stress and fatigue. Acroparesthesia is often used to describe burning, tingling, pain and constant discomfort in the hands and feet. It can occur on an intermittent or daily basis. "Fabry crises" are more intense, excruciating, burning pains felt not only in the hands and feet but also other areas of the body. These episodes can be debilitating and can last from minutes to several days. Accumulation of GL-3 in the nervous system and sweat glands may also result in decreased or absent sweating (hypohidrosis or anhidrosis) which can cause frequent fevers and overheating with exercise. Another frequent feature of classic Fabry disease is the appearance of cutaneous vascular lesions called angiokeratomas around the bellybutton, elbows and knees. In addition, a characteristic eye finding known as corneal whorling is often seen in affected males and carrier females. Corneal whorling does not affect vision and can be detected by an ophthalmologist with the use of a slit lamp.
As mentioned above, accumulation of GL-3 often occurs in the kidneys, heart and brain resulting in life-threatening complications. Renal findings include a reduction in kidney function causing proteinuria (protein in the urine) and eventually end stage renal disease (ESRD), which occurs in approximately 10% of patients. Premature morbidity and mortality in patients with Fabry disease commonly is a result of ESRD. Treatment for ESRD consists of hemodialysis or renal transplantation. Patients who survive treatment for ESRD will ultimately develop cerebrovascular and cardiovascular complications. Pathology of brain microvasculature can lead to stroke, thrombosis, hemorrhage and seizures. Cardiac findings can include conduction abnormalities, myocardial ischemia, valvular dysfunction, left ventricular hypertrophy and congestive heart failure. Additional clinical features in males with classic Fabry disease include auditory, gastrointestinal, pulmonary and psychological dysfunction.
Certain GLA mutations can result in milder, later onset forms of Fabry disease primarily affecting the renal and/or cardiovascular systems. Males with residual GLA activity (greater than 1%, typically 5-15%) may not present with classic Fabry disease but with only a cardiac phenotype characterized by hypertrophy of the left ventricle and interventricular septum, mitral valve insufficiency and/or conduction abnormalities consistent with cardiomyopathy in the sixth to eighth decade of life. These men are usually diagnosed as having "late-onset" hypertrophic cardiomyopathy (HCM). Thus GLA screening of males with later onset HCM should be considered in those who are not found to have a sarcomere gene mutation. Sachdev et al. 2002 reported that up to 14% of males with HCM diagnosed before the age of 40 years were found to have a GLA mutation. Men with the cardiac variant of Fabry disease may also have renal anomalies resulting in proteinuria but not in ESRD. In addition, men with the renal variant of Fabry, which results in ESRD, may have moderate to severe left ventricular hypertrophy.
In addition to confirming the diagnosis of Fabry disease in patients with clinically evident disease, genetic testing allows for early identification and diagnosis of individuals at greatest risk prior to the expression of typical clinical manifestations. If a mutation is identified in such a preclinical individual, regular and serial outpatient follow up is indicated. Referral to a specialist with specific expertise in the management of Fabry disease or to several specialists to create an individualized program is highly recommended for patients with established disease as well as their family members. In addition, enzyme replacement therapy for Fabry disease is clinically available and early treatment may reduce the occurrence and severity of major cardiac, renal and cerebral sequelae. If clinically unaffected members of a family with an identified mutation for Fabry are found not to carry that mutation (genotype negative), they can be definitively diagnosed as unaffected with Fabry and reassured that neither they nor their offspring will be at higher risk compared to the general population to develop these disorders. The need for serial follow up becomes unnecessary.
Synonyms
(OMIM 301500):
- ANGIOKERATOMA, DIFFUSE
- ANDERSON-FABRY DISEASE
- HEREDITARY DYSTOPIC LIPIDOSIS
- ALPHA-GALACTOSIDASE A DEFICIENCY
- GLA DEFICIENCY
- CERAMIDE TRIHEXOSIDASE DEFICIENCY
| Gene |
Protein |
OMIM# |
Locus |
| GLA |
ALPHA-GALACTOSIDASE A |
301500 |
Xq22 |
Other diseases caused by mutations in GLA: None reported.
Epidemiology:
- Incidence: approximately one in 50,000 males (range of one in 80,000 to one in 117,000)
- No racial predilection
- Males more frequently affected than females due to X-linked recessive inheritance
- Milder forms of Fabry that present later in life, such as the cardiac and renal variants, are believed to be underdiagnosed.
- Screening of males with left ventricular hypertrophy or hypertrophic cardiomyopathy found 3-4% to have reduced GLA enzyme activity.
- Screening of males with cryptogenic stroke found 5% had reduced GLA activity and up to 1% of males receiving hemodialysis had reduced levels.
Inheritance Pattern: X-linked recessive
- Children of a carrier female with an identified pathogenic GLA mutation have a 50% (or 1 in 2) chance of inheriting the same mutation. Male children that inherit this mutation will be affected and females who inherit the mutation will be carriers.
- Daughters of an affected male with an identified GLA mutation have 100% chance of inheriting the same mutation. Sons of an affected male with a GLA mutation have no risk of inheriting the mutation.
- Skewed X inactivation may alter the severity of symptoms in females with a pathogenic mutation.
- De novo mutations are rare but have been reported.
- If parents are not mutation carriers, the risk to have a second affected child is low (<3-4%) but above the population risk because of the possibility of germline mosaicism.
Test Indications:
- Patients with clinical features of Fabry disease, both male and female.
- Carrier testing for females with affected male relatives.
- Patients with left ventricular hypertrophy or cardiomyopathy who otherwise do not have a classic Fabry disease phenotype.
- Parents, siblings, and possibly children of a patient known to carry a mutation in GLA.
- Prenatal testing when a parent is diagnosed with Fabry disease and has an identified GLA mutation.
Test Outcomes:
- The detection of a pathogenic mutation in one copy of GLA is considered a positive test result.
- A negative test result should be interpreted with caution. Sequencing does not detect large deletions spanning several exons, or mutations in non-coding regions that could affect expression of the GLA gene.
Turn-Around-Times: 3 weeks
Methodology: Bi-directional sequence analysis of all 7 exons and splice sites in GLA, as well detection of the intron 4 cardiac variant (639+919G>A, aka IVS4+919G>A; Ishii et al. 2002). This gene sequencing test does not detect large deletions spanning several exons, or mutations in non-coding regions that could affect expression of the GLA gene.
Analytical and Clinical Sensitivity This assay is greater than 99.9% accurate in detecting mutations in the sequence analyzed. According to published data, GLA mutations have been detected in virtually 100% of patients with a clinical diagnosis of Fabry disease.
Cost and CPT Codes:
GLA Gene Sequencing
- Cost: $700
- CPT codes: 83891(1), 83894(1), 83898(8), 83904(8), 83909(1), 83912(1)
Testing for known familial mutation
- Cost: $250
- CPT codes: 83891(1), 83894(1), 83898(1), 83904(1), 83909(1), 83912(1)
References:
GeneTests Fabry Disease Review for Fabry Disease: www.GeneTests.com
Genzyme Genetics: Fabry Community Website: http://www.fabrycommunity.com/global/fc_p_hp_homepage.asp
Dobrovolny R, Dvorakova L, Ledvinova J, Magage S, et al (2005) Relationship between X-inactivation and clinical involvement in Fabry heterozygotes. Eleven novel mutations in the α-galactosidase A gene in the Czech and Slovak population. J. Mol. Med., 83: 647-54.
Germain DP, Shabber J, Cotigny S and Desnick RJ (2002) Fabry disease: twenty novel alpha-galactosidase A mutations and genotype-phenotype correlations in classical and variant phenotypes. Mol. Med. 8: 306-12.
Ishii S, Nakao S, Minamikawa-Tachino R, Desnick RJ and Fan J-Q (2002) Alternative Splicing in the α -Galactosidase A Gene: Increased Exon Inclusion Results in the Fabry Cardiac Phenotype. Am. J. Hum. Genet., 70: 994-1002.
Sachdev B, Takenaka T, Teraguchi H, Tei C, Lee P, McKenna WJ, Elliott PM (2002) Prevalence of Anderson-Fabry disease in male patients with late onset hypertrophic cardiomyopathy. Circulation 105:1407-11.
Schafer E, Baron K, Widmer U, Deegan P, et al (2005) Thirty-Four Novel Mutations of the GLA Gene in 121 Patients with Fabry Disease. Human Mutation, Mutations in Brief, 798: online
If you have any questions, please call the Laboratory for Molecular Medicine at 617-768-8500 or email us at LMM@partners.org
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