Galactosemia Type I (Classic and Variant Galactosemia) via the GALT Gene, 5.5 kb Common Deletion

Galactosemia is a defect in the metabolism of galactose resulting in elevated levels of galactose and derivatives such as galactose-1-phosphate and galactitol. Severity of this disorder is quite variable, though it is generally categorized into three groups based on patient phenotype (Berry 2014). The first is the most severe “classic” form with onset in early infancy, and is characterized by feeding difficulties, vomiting, diarrhea, jaundice, cataracts, hypotonia, hepatomegaly and sepsis. If the amount of lactose in the diet is not reduced in the first days of life, these symptoms progress to death. Even in surviving patients, ovarian failure and lifelong speech and cognitive disabilities are expected (Berry 2014; Fridovich-Keil and Walter 2014). The second phenotypic category is termed "clinical variant" galactosemia, which also presents early in infancy and is more common in African Americans and native Africans in South Africa (Crushell et al. 2009; Berry 2014; Fridovich-Keil and Walter 2014). These patients tend to present with feeding difficulties, which may include failure to thrive, and hepatocellular damage, such as cirrhosis and bleeding. In these patients, if a lactose-restricted diet is implemented within the first days of life, the severe neonatal complications are typically prevented and the patients do not appear to be at risk for long-term complications (Berry 2014). The third phenotypic category is termed "biochemical variant galactosemia", the most common form of which is "Duarte variant galactosemia". Biochemical variant galactosemia is currently not thought to result in clinical disease in most patients (Berry 2014; Fridovich-Keil et al. 2014).

Today in wealthy nations, nearly all cases of classic galactosemia are detected through routine neonatal screening. However, it may be more difficult to detect patients with clinical and biochemical variant galactosemias because the galactose level in such patients is not as high as in classic galactosemia patients, and results of breath testing may be normal (Berry 2014). In situations where the activity of the GALT enzyme is always tested or the patient is fed enough lactose, clinical and biochemical variant galactosemias should be detectable (Berry 2014; Fridovich-Keil et al. 2014).

Galactosemia is an autosomal recessive disorder. Pathogenic variants in the GALT gene are the primary genetic cause of galactosemia. Relatively small numbers of cases are caused by pathogenic variants in the GALK1 (galactokinase) and GALE (UDPgalactose-4’-epimerase) genes. GALT encodes the enzyme galactose-1-phosphate uridyltransferase. Over 300 causative GALT variants have been reported to date (Human Gene Mutation Database; ARUP GALT Database at http://arup.utah.edu/database/GALT/GALT_display.php). Roughly 70% of these variants are missense, although frameshift, nonsense, splicing, small insertions and deletion variants and gross deletions have all been reported. A complex ~5.5 kb deletion has been described. This particular deletion results in the loss of the GALT promoter and coding region, although a portion of exon 8 and intron 8 are retained (Barbouth et al. 2006; Coffee et al. 2006; Boutron et al. 2012). This deletion is thought to be more common in individuals of Ashkenazi Jewish descent (Coffee et al. 2006).

Although limited data is available on the prevalence of this deletion, Coffee et al. (2006) observed the deletion on 5 out of 52 alleles from galactosemic individuals with no or only one previously identified causative GALT sequence variant. These individuals were pulled from a group of 331 patients diagnosed biochemically with galactosemia, suggesting an overall frequency of the deletion of ~1% (5 out of 662 alleles). However, Coffee et al. (2006) note that they had previously detected this deletion in three unrelated Ashkenazi Jewish individuals, suggesting a possible founder effect and higher prevalence of the deletion in this population. In addition, both of the families in which this deletion was identified by Boutron et al. (2012) were of Ashkenazi Jewish descent, providing additional support for a founder effect.

This test involves amplification of patient DNA with several sets of specific PCR primers that flank the common GALT 5.5 kb complex deletion. In a patient with the deletion, two separate primer sets amplify across the deletion resulting in 1,234 bp and 1,689 bp products. Other control primers are used to detect the normal allele. Sanger sequencing of the deletion products will also be done to confirm breakpoint positions. This test permits the identification of patients with normal genotypes, patients who are homozygous for the deletion, and heterozygous carriers. This test is designed to detect only the common 5.5 kb deletion. Other deletions in the GALT gene may not be detectable via this method, but may be detectable via GALT-specific array CGH (Test #600). PreventionGenetics also offers a sequencing test for the GALT gene (Test #7665).