The GALC gene is associated with autosomal recessive Krabbe disease (MedGen UID: 44131).
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GALC: Analysis includes the large (30 kb) deletion for Krabbe Disease.
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Pathogenic variants in the GALC gene are the only known cause of Krabbe disease (PMID:10833326).
The GALC gene encodes the galactosylceramidase enzyme (also known as galactocerbrosidase) which removes galactose from galactocerebrosides, a major lipid components of neuronal myelin sheath, in the process of lipid degredation (PMID: 9125199).
Deleterious mutations in GALC (OMIM: 606890) are associated with Krabbe disease (OMIM: 245200). Krabbe disease is a rare, neurodegenerative lysosomal storage disorder whose main feature is leukodystrophy. The disorder is caused by the deficiency of the enzyme galactocerebrosidase (GALC).
There are several forms of Krabbe disease:
Affected individuals are diagnosed through a neurologic examination, imaging studies, and laboratory tests. MRI shows white matter changes in the majority but not all of EIKD patients (PMID: 21824559). Electroencephalogram results may initially be normal, but become abnormal with slowing, disorganization, and asymmetry. Electromyogram and nerve conduction study results are usually abnormal with low velocities, but may be normal in some affected adults. Most patients have elevated cerebrospinal fluid protein levels (PMID: 22520351).
Laboratory tests measure GALC enzyme activity in either blood or skin fibroblasts, and confirmation is provided by molecular studies. All EIKD patients have very low GALC activity with 0-5% of normal levels. Newborns with EIKD have been identified with the advent of newborn screening for Krabbe disease in New York state in 2006, and more are being diagnosed with a moderate to high risk for disease due to the identification of polymorphisms that lower the GALC activity to 8-20% of normal (pseuodeficiency; PMID: 27638583). The clinical implications of many of the identified polymorphisms are unknown at this time and may not result in a clinical phenotype. Most of the high-risk infants have not developed disease and remain asymptomatic (PMID: 27638597). These babies need to be followed long term to monitor for later-onset symptoms of Krabbe disease. Several other states have added Krabbe disease to their newborn screening panel, but it is not currently a recommended test on the Routine Uniform Newborn Screening Panel (PMID: 26795590). Biomarkers such as psychosine are being studied to characterize the Krabbe phenotype and address this difficult and controversial issue in hopes of ameliorating the psychological implications for patients, families, and physicians (PMID: 24388568, 28579020).
Other leukodystrophies, such as metachromatic leukodsytrophy (MLD) and X-linked adrenoleukodystrophy (XALD), may resemble Krabbe disease. Storage disorders with a neurodegenerative phenotype, such as GM1 gangliosidosis, including Morquio B, can present with neurologic involvement but have additional features including hepatomegaly and coarse facies. GM2 gangliosidoses also present with loss of motor skills, but additional features, such as the cherry red spot in Tay-Sachs, differentiates these disorders from Krabbe disease. Canavan disease can also present in childhood with developmental delay and severe hypotonia. Saposin A deficiency presents in infancy with abnormal myelination, but is caused by pathogenic variants in the PSAP gene. Pelizaeus-Merzbacher disease (PMD; PLP-1) is an X-linked disorder with neurologic manifestations due to leukoencephalopathy. Alexander disease is an autosomal dominant white matter disease that may also resemble Krabbe and is associated with the GFAP gene (PMID: 20301416).
The GALC gene is responsible for the production of GALC enzyme, which uses water molecules in the lysosomes to break down fats called galactolipids. This enzyme deficiency causes the galactolipids galactosylceramide and psychosine to accumulate in the lysosomes. The accumulation of galactosyloceramide and psychosine leads to demyelination in the central and peripheral nervous systems (PMID: 24252386).
There are more than 150 GALC mutations, with the most common being the 30-kb deletion found in patients with EIKD in either a homozygous state or as a heterozygous deletion with another disease-associated pathogenic allele (PMID: 24388568). Newborn screening identifies babies with very low GALC activity, and molecular studies identify known pathogenic variants consistent with EIKD (PMID: 26795590).
Presymptomatic newborns with low GALC activity and one pathogenic variant or one pathogenic variant and polymorphism(s) need to be followed for signs and symptoms of disease. One pathogenic variant and a mild mutation in trans in healthy individuals and asymptomatic newborns identified through newborn screening are thought to be associated with delayed onset of disease. It is believed that appropriate surveillance in the later-onset forms of the disorder will allow time to institute treatment (PMID: 24388568).
GALC shows autosomal recessive inheritance. Parents of an affected child are obligate carriers. Measurement of GALC activity can vary widely in carriers because of polymorphisms. Healthy carriers with low GALC activity and polymorphisms do not have clinical disease (PMID: 20301416). Offspring of adults with Krabbe disease are obligate carriers of a pathogenic variant in GALC.
Impetus for newborn screening for Krabbe disease came from the observation that affected infants identified due to a family history and transplanted with cord blood at younger ages than symptomatic infants survived longer and gained or maintained motor skills (PMID: 15901860).
At this time, the only disease-modifying treatment is hematopoietic stem cell transplantation (HSCT), which is thought to be most effective if performed in pre-symptomatic infants under 40 days of age. One study of transplanted EIKD patients showed that survivors functioned at a higher level than untreated infants or symptomatic infants who underwent HSCT (PMID: 28855403). Some later-onset patients have had HSCT with reported improvement of symptoms and slowed progression of disease (PMID: 27638597).
Clinical management interventions and recommendations include (PMID: 27638597):
Saudubray J-M, et al., eds. Inborn metabolic diseases diagnosis and treatment. 6th ed. Berlin, Germany: Springer; 2016.
Review date: October 2017
Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).
Our sequence analysis covers clinically important regions of each gene, including coding exons and 10 to 20 base pairs of adjacent intronic sequence on either side of the coding exons in the transcript listed below. In addition, the analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any limitations in the analysis of these genes will be listed on the report. Contact client services with any questions.
Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.
|Gene||Transcript reference||Sequencing analysis||Deletion/Duplication analysis|
*GALC: Analysis includes the large (30 kb) deletion for Krabbe Disease.