GBA gene
Also known as: Glucocerebrosidase Deficiency, Glucosylceramidase Deficiency
OMIM#230800 https://omim.org/entry/230800
1. The Disease:
Gaucher disease (GD) is a lysosomal storage disorder encompassing three main forms (types 1, 2 and 3), a fetal form and a variant with cardiac involvement (Gaucher disease – ophthalmoplegia – cardiovascular calcification or Gaucher-like disease).
2. The Symptoms:
GD type 1 is characterized by the presence of clinical or radiographic evidence of bone disease (osteopenia, focal lytic or sclerotic lesions, and osteonecrosis), hepatosplenomegaly, anemia and thrombocytopenia, lung disease, and the absence of primary central nervous system disease.
GD types 2 and 3 are characterized by the presence of primary neurologic disease; in the past, they were distinguished by age of onset and rate of disease progression, but these distinctions are not absolute.
Disease with onset before age two years, limited psychomotor development, and a rapidly progressive course with death by age two to four years, is classified as GD type 2.
Individuals with GD type 3 may have onset before age two years, but often have a more slowly progressive course, with survival into the third or fourth decade.
Lack of early signs or symptoms does not exclude the diagnosis.
3. Actions to take in case of early diagnosis:
- Infants with a positive genetic test (having 2 mutations or 2 copies of a single mutations in the GBA gene) should have confirmatory test for Gaucher disease through the measurement of glucocerebrosidase (glucosylceramidase) enzyme activity in white blood cells or filter paper.
- Infants with a positive molecular and biochemical test should IMMEDIATELY be referred to a Clinical Geneticist who can evaluate the patient and determine whether she/he may be eligible for two possible treatments: 1) enzyme replacement therapy (ERT), and 2) substrate reduction therapy (SRT) for the ones who cannot receive ERT.
- As the clinical manifestations of GD I are multisystemic, a multidisciplinary approach is required to proactively recognize and manage complications. The multidisciplinary care team should include genetics, pediatrics, orthopedian surgeon, physical therapy and occupational therapy, but may also include specialities such as neurology, cardiology, as deemed appropriate based on individual patient needs. Routine assessment of the various affected organs and systems is necessary, and each specialist in the multidisciplinary team should oversee continuing evaluations once a clinical problem is identified.
- Hematopoietic stem cell transplantation (HSCT) has been largely superseded by enzyme replacement therapy or substrate reduction therapy (SRT).
- Enzyme replacement therapy (ERT) is the first choice of treatment: first line therapy. Currently, there are three recombinant glucocerebrosidase enzyme preparations available: imiglucerase (Cerezyme®); velalglucerase-alfa (VPRIV®); and taliglucerase-alfa (Elelyso®). Regular intravenous infusions of the recombinant enzymes have been demonstrated to be safe and effective in reversing those features resulting from hematologic and visceral (liver/spleen) involvement. Thrombocytopenia may persist in individuals with residual splenomegaly and/or the presence of splenic nodules.
- Substrate reduction therapy (SRT) aims to restore metabolic homeostasis by limiting the amount of substrate precursor synthesized (and eventually subject to catabolism) to a level that can be effectively cleared by the mutated enzyme with residual hydrolytic activity. Miglustat is the first oral agent for the treatment of individuals with mild to moderate Gaucher disease for which ERT is not a therapeutic option (e.g., because of constraints such as allergy, hypersensitivity, or poor venous access). Eliglustat, an alternative inhibitor of glucosylceramide synthetase, has been shown in clinical trials to be a safe and effective treatment for individuals with Gaucher disease type 1 who are not on any therapy as well as those previously treated with ERT. Reported side effects of eliglustat were generally mild. (2) The use of eliglustat requires cytochrome P450 2D6 genotyping and avoidance of drugs that may interact through this metabolic pathway.
- Genetic counseling is highly recommended for family planning and evaluation of at-risk family members such as siblings.
4. For more information
Biblio: https://www.ncbi.nlm.nih.gov/books/NBK1269/