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Gene test interpretation: GLA (Fabry disease gene)

Gene test interpretation: GLA (Fabry disease gene)
Literature review current through: Jan 2024.
This topic last updated: Aug 10, 2023.

INTRODUCTION — This monograph discusses implications of genetic test results for the GLA gene. GLA encodes alpha-galactosidase A (alpha-Gal A), the enzyme deficient in Fabry disease.

Indications for testing and care of the tested individual are discussed separately [1]. (See 'Resources' below.)

BACKGROUND

How to read the report — The table summarizes considerations for reviewing the report, including the importance of obtaining a hard copy, verifying the correct individual was tested, and reviewing which gene(s) and which variant(s) were analyzed (table 1).

Testing for clinical care should be performed in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory or other nationally certified laboratory. If not done initially and results will impact clinical decision-making (expected or unexpected positive results, negative results in an at-risk individual), testing should be repeated in a CLIA-certified laboratory.

DNA variants are designated with a "c"; variants in protein sequence are designated with a "p" (as in p.Ala143Thr [p.A143T]). (See 'Clinically important variants' below.)

The glossary summarizes terms that may be used in the report (table 2); a more extensive glossary is also available. (See "Genetics: Glossary of terms".)

GLA gene

Function — GLA encodes alpha-galactosidase A (alpha-Gal A), a lysosomal enzyme that breaks down glycolipids such as globoside.

When cells cannot break down globoside, the metabolic intermediate globotriaosylceramide (Gb3) and its derivative lyso-Gb3 accumulate, producing inclusions that impair cellular function. Other potentially affected cell types include vascular smooth muscle, pericytes, autonomic and dorsal root ganglia, kidney (glomerular, tubular, and interstitial), cardiac (including conduction fibers), and cornea (vascular and lymphatic endothelium). Unexplained factors may contribute to pathogenesis.

Clinically important variants — Over 1000 GLA variants have been described. Most kindreds have specific (private) mutations; de novo mutations are rare. The clinical significance of a variant can be checked using the Fabry gene database (fabry-database.org) "mutation search" feature [2].

Establishing genotype-phenotype correlations has been challenging, although some have been described. Variants that dramatically reduce or abolish alpha-Gal A activity usually cause the classic Fabry phenotype. Variants with some residual alpha-Gal A activity usually cause the later-onset (also called atypical) phenotype. Some variants prominently affect a single organ system. As an example, the p.Glu66Gln (pE66Q) variant appears to cause kidney-only manifestations. (See 'Clinical features' below and "Fabry disease: Clinical features and diagnosis", section on 'Genetics'.)

Routine genetic testing of GLA involves sequencing the coding region and intron-exon boundaries; this will detect nearly all disease variants. If a variant has not previously been described or is classified as a variant of uncertain significance (VUS), clinical evaluation including alpha-Gal A activity (and biopsy of an affected tissue or organ in some cases) becomes especially important. Rarely, additional genetic analysis may be indicated including deletion/duplication analysis and/or evaluation for deep intronic variants. A Fabry specialist should be involved. (See 'Diagnosis' below and 'Resources' below.)

One of the most common variants detected in newborn screening is p.Ala143Thr (p.A143T). This is generally considered a benign polymorphism; however, individuals with symptoms or positive biopsy findings may warrant additional evaluations [3]. The p.Asn313Tyr (p.D313Y) and p.Arg118Cys (pR118C) variants are also considered benign.

Inheritance — GLA is located on the X chromosome. Inheritance is X-linked with variable penetrance (likelihood of manifesting Fabry disease) and variable expressivity (specific constellation of clinical manifestations). (See "Inheritance patterns of monogenic disorders (Mendelian and non-Mendelian)", section on 'Penetrance and expressivity'.)

Males with a GLA variant are hemizygous and affected. They transmit the variant to all of their daughters, who are obligate heterozygous (algorithm 1). Father-to-son transmission does not occur.

Females with a GLA variant are heterozygotes (with rare exceptions). Their clinical course varies from asymptomatic to severely affected. A high proportion of females will have some symptoms of Fabry disease (69 percent in one study) and should not be discounted [4]. X-chromosome inactivation (lyonization) likely determines much of this phenotypic variation [5]. Mothers can transmit the disease-causing variant to sons or daughters (algorithm 1). There is an equal likelihood of transmitting the X chromosome with the GLA variant or the X chromosome without the GLA variant.

FABRY DISEASE

Epidemiology — The prevalence of classic Fabry disease in the general male population is stated as 1:40,000, but this is likely an underestimate [6]. Many individuals remain undiagnosed, especially males with late-onset manifestations and females. (See "Fabry disease: Clinical features and diagnosis", section on 'Epidemiology'.)

The likelihood of identifying a Fabry disease variant from newborn screening is 1:3200; however, the p.Alal143Thr variant is often included in these estimates, and this is considered a benign polymorphism [6]. (See 'GLA gene' above.)

While Fabry disease is rare overall, the prevalence is much higher in individuals with certain types of organ dysfunction. Among males with chronic kidney disease (CKD) requiring dialysis, the prevalence is as high as 1 in 500 [6]. Prevalence may be even higher in males with unexplained stroke at a young age or hypertrophic cardiomyopathy. The prevalence in females with these conditions is also likely to be increased.

Clinical features — The spectrum and onset of clinical manifestations (table 3) depend on the amount of functional alpha-Gal A in affected tissues; this cannot be predicted by the specific GLA variant or even the findings in first-degree relatives. Each variant is different, and every individual has different modifying factors. (See "Fabry disease: Clinical features and diagnosis".)

Classic Fabry disease – Classic disease is defined based on findings in males. A typical presentation is a five-year-old male with burning pain in the hands and feet, with especially severe pain coinciding with fever ("pain crisis"). Gastrointestinal symptoms (diarrhea and/or constipation) may start at approximately 10 to 11 years, along with proteinuria and CKD. Cerebral white matter lesions may be seen by late adolescence, with stroke and memory loss occurring in the fourth or fifth decade. Cardiac manifestations including PR interval shortening and left ventricular hypertrophy also occur during the third to fifth decades. Angiokeratomas are common, especially under the umbilicus (picture 1). Corneal whorls require slit lamp examination for detection.

Later-onset disease – Later-onset disease may occur with less severe GLA variants in males or with classic disease variants in females. Pain may be less prominent, with milder CKD or heart disease.

Diagnosis — Fabry disease may be suspected in a male or female with any of the following:

A pathogenic variant in GLA.

A first-degree relative with Fabry disease, unexplained early death, left ventricular hypertrophy, or early stroke.

A suggestive personal history, including CKD of unknown origin, unexplained left ventricular hypertrophy, or early stroke. (See 'Clinical features' above.)

Histologic evidence of zebra bodies and/or whorls in a biopsy specimen. Zebra bodies are not pathognomonic for Fabry disease; they can also be seen with drug-induced phospholipidosis, which is discussed separately. (See "Fabry disease: Kidney manifestations", section on 'Pathology'.)

The initial evaluation consists of:

Males – Measurement of alpha-Gal A activity from peripheral blood leukocytes. Undetectable activity (<3 percent) is sufficient to diagnose classic Fabry disease. Males with suspected Fabry disease and higher enzyme levels (3 to 35 percent) can be evaluated with genetic testing and/or biopsy with histopathology of an involved tissue. If genetic testing is done first, establishing a baseline alpha-galactosidase enzyme activity level is recommended.

Females – Genetic testing is typically used. Low alpha-Gal A enzyme activity may be helpful, but normal alpha-Gal A activity does not exclude Fabry disease since females are heterozygous and X-inactivation is variable.

All individuals – Regardless of sex, genetic testing should be performed to identify the specific variant, which facilitates counseling and testing in first-degree relatives and therapeutic decision-making. (See 'Management' below and 'Considerations for relatives' below.)

If the diagnosis is uncertain (absent, mild, or nonspecific symptoms; variant of uncertain significance [VUS]), enzyme activity and/or biopsy with histopathology may be helpful to confirm or exclude disease and guide therapeutic decision-making. Histopathology can show classic Gb3 inclusions even prior to symptom development (picture 2).

If genetic testing does not reveal a GLA variant, a gene panel to evaluate other genes or more extensive evaluation of the GLA gene (targeted deletion/duplication analysis and evaluation for deep intronic variants) may be indicated. A Fabry disease specialist and/or genetics expert can determine the best individualized approach. Manifestations of Fabry disease can be subtle, and gene panel testing may be reasonable for any individual with a first-degree relative with kidney disease [7].

Management — Management by a Fabry disease expert is ideal to determine indications for disease-modifying therapy, choice of therapy, appropriate administration (dosing, premedication if needed), and monitoring. If direct care by a Fabry expert is not possible, consultation or comanagement can provide essential guidance.

There are two main disease-modifying therapeutic approaches [6].

Enzyme replacement therapy – Provides the deficient alpha-Gal A enzyme (as agalsidase alfa or beta). A pegylated form of alpha-Gal A with a longer half-life is also available. Enzyme replacement slows progression of kidney disease and other disease manifestations. Intravenous administration is required, which may necessitate an implanted venous access device. Infusion reactions frequently occur and may need to be treated with premedications such as histamine receptor blockers and glucocorticoids if needed. Inhibitory anti-drug antibodies may develop and may interfere with efficacy [8]. (See "Fabry disease: Treatment and prognosis", section on 'Enzyme replacement therapy' and "Fabry disease: Treatment and prognosis", section on 'Infusion reactions'.)

Chaperone therapy – An oral small molecule (migalastat) assists in alpha-Gal A folding, stabilization, and trafficking to lysosomes, improving functional enzyme abundance. Migalastat structure is similar to the terminal galactose of the alpha-Gal A substrate Gb3 (see 'GLA gene' above). Oral administration eliminates the venous access requirement, infusion reactions, and anti-drug antibodies. However, only certain GLA variants are amenable to chaperone therapy. Amenability can be checked on a website or the prescribing information [9,10]. Individuals taking migalastat require monitoring of enzyme activity, biomarkers such as lyso-Gb3, and other markers of disease progression. (See "Fabry disease: Treatment and prognosis", section on 'Chaperone therapy (migalastat)'.)

Females with Fabry disease can become pregnant and may breastfeed while receiving enzyme replacement.

Supportive care is directed at specific manifestations and may include therapy for hypertension or CKD (including an angiotensin-converting enzyme [ACE] inhibitor and/or serum-glucose co-transporter 2 [SGLT2] inhibitor for proteinuric kidney disease, as well as dialysis or transplantation if needed), antianginal or heart failure therapy, implantable cardiac pacemaker or cardioverter-defibrillator, stroke prophylaxis, analgesic or antimotility agents (typically avoiding nonsteroidal antiinflammatory drugs), psychosocial support, and informational resources and counseling [3]. (See "Fabry disease: Treatment and prognosis".)

Monitoring involves regular assessments for complications and disease status [3]:

Pain – Neuropathic pain and gastrointestinal symptoms.

Kidney function – Serial glomerular filtration rate using the CKD-EPI calculator (calculator 1), plus spot urine protein-to-creatinine ratio every three to six months (or at least yearly).

Cardiac disease – Electrocardiogram (with Holter monitor if any abnormalities), echocardiogram at least every three years, and cardiac magnetic resonance imaging (MRI) for suspected cardiac hypertrophy or fibrosis.

Drug efficacy – For individuals receiving disease-modifying therapy, enzyme activity and adverse effects.

Investigational approaches for individuals wishing to participate in clinical trials include gene therapy and substrate reduction therapy. [6]. Involvement of a Fabry disease expert can help facilitate decision-making and trial access.

CONSIDERATIONS FOR RELATIVES

First-degree relatives — First-degree relatives should be counseled about the inheritance pattern and the benefits of testing. The implications for the child depend on the sex of the parent, as illustrated in the algorithm (algorithm 1). The age of testing can often be deferred until symptoms or clinical findings occur (late childhood to early adulthood) to allow informed consent and discussion of other implications.

Reproductive counseling — The risk of Fabry disease in offspring and alternative reproductive technologies can be addressed through reproductive counseling. It may be worth informing patients that disease-modifying therapies are an active area of investigation and that additional therapies may be available by the time the child reaches adulthood.

RESOURCES

UpToDate Fabry disease topics

Diagnosis – (See "Fabry disease: Clinical features and diagnosis".)

Management – (See "Fabry disease: Treatment and prognosis".)

Specific manifestations – (See "Fabry disease: Neurologic manifestations" and "Fabry disease: Cardiovascular disease" and "Fabry disease: Kidney manifestations".)

Background – (See "Inborn errors of metabolism: Classification" and "Inborn errors of metabolism: Identifying the specific disorder" and "Overview of hereditary neuropathies" and "Definition and classification of the cardiomyopathies".)

Fabry gene database (Sakuraba)fabry-database.org

Amenability to migalastatgalafoldamenabilitytable.us

Genetics experts

Clinical geneticists – American College of Medical Genetics and Genomics (ACMG).

Genetic counselors – National Society of Genetic Counselors (NSGC).

Genetic testing laboratories may provide access to a genetic counselor.

Fabry disease organizations (some include lists of clinical experts)

National Fabry Disease Foundation – fabrydisease.org

Fabry Support and Information Group – fabry.org

Fabry International Network – fabrynetwork.org

Canadian Fabry Association – fabrycanada.com

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