Panel testing recommended at Breda Genetics for this condition:

Pan251 Galactosemia (GALE, GALK1, GALM, GALT)


Galactosemia includes a group of rare metabolic disorders due to the body’s inability to metabolize galactose, a carbohydrate contained in milk and its derivatives, which consequently accumulates in the blood. It is a congenital genetic defect, transmitted in an autosomal recessive pathway, which can be responsible for a very serious phenotype that can culminate in death, if not treated. Children with galactosemia can present symptoms from birth, in particular among the most frequent we find hepatic and renal insufficiency, lethargy and growth failure, cataracts, coagulation defects and intellectual disability. There are several forms of galactosemia, which are distinguished by severity and phenotypic presentation. Diagnosis is suggested on the basis of the clinical picture and by metabolic testing and confirmed with DNA sequencing. Often, it is identified through neonatal metabolic screening. There is no definitive cure for this disease, but the elimination of galactose from the diet prevents acute toxicity and can prevent the progression of some symptoms.

Detailed clinical description

Nowadays, 4 different forms of galactosemia have been described, each of which affects an enzyme involved in a different step of galactose metabolism.

Type I galactosemia (also known as classic galactosemia) is the most common and generally more severe form of this condition. It is characterized by the neonatal onset of symptoms such as poor growth, liver dysfunction that can cause jaundice and hepatosplenomegaly, hypoglycemia, hypotonia, sepsis and cataracts. Almost all females with this form of galactosemia develop premature ovarian failure during adolescence. Long-term complications, which can occur especially in the case of a late diagnosis, include intellectual disability, verbal dyspraxia and impaired motor functions.

In type I galactosemia clear genotype-phenotype correlations exist; indeed it is possible to distinguish the classical form, the clinical variant and the biochemical variant. The difference between these forms is closely linked to the residual activity of the enzyme: in the classic form the residual enzymatic activity is less than 1%, in the clinical variant there is a residual activity between 1% and 10%, in the biochemical variant the GALT enzyme maintains a residual activity greater than 15% (on average 25%). Generally, the greater the residual activity, the milder the associated phenotype will be. One of the biochemical forms is Duarte galactosemia, in which patients are generally healthy but have increased blood levels of galactose and biochemical abnormalities.

Type II galactosemia (known as galactokinase deficiency) clinically manifests as early onset cataracts and increased levels of galactose in the blood, in the absence of the other typical signs.

Type III galactosemia (known as epimerase deficiency galactosemia) can be divided into generalized, intermediate or peripheral. The generalized form has a similar presentation to classical galactosemia, with hypotonia, hepatic dysfunction, poor growth, and long-term effects such as developmental delay, deafness, and skeletal abnormalities. In the peripheral form, there is a deficit of enzymatic activity only in circulating red blood cells and white blood cells and for this reason, it is usually the mildest clinical manifestation. In fact, newborns are usually asymptomatic and the diagnosis is made only following a biochemical test that highlights the presence of galactosemia.

Type IV galactosemia has only recently been discovered and has a similar clinical presentation to type II galactosemia, with bilateral infantile cataracts and absence of gastrointestinal, hepatic and neurodevelopmental problems.

In most cases, galactosemia is identified through neonatal screening for certain metabolic diseases. The suspicion is placed on the basis of the clinical picture and from a biochemical point of view, one of the most used tests for diagnosis is the Beulter test. However, this test is not indicative in some types of galactosemia such as type II. This is why the diagnosis is always confirmed on a molecular basis by looking for the underlying genetic defect.


Classic galactosemia (type I) is the most frequent form and has a prevalence of approximately 1:16,000 to 1:50,000 live births. However, the prevalence is very variable, especially on the basis of ethnic origin (for example in Irish Traveler population it is about 1:480). Type II galactosemia is much rarer, with a prevalence comprised between 1:50,000 and 1:2,200,000; type III galactosemia has a prevalence of approximately 1:70,000 in American children of European descent. The prevalence of IV galactosemia is unknown, due to the recent discovery and the low number of reported cases.

Molecular genetics

Galactosemia is always inherited in an autosomal recessive manner. Molecularly, type I galactosemia is due to loss-of-function mutations in the GALT gene; type II galactosemia is due to mutations in the GALK1 gene; type III galactosemia is due to loss-of-function mutations in the GALE gene and finally type IV galactosemia is due to mutations in the GALM gene. Even large deletions/duplications can often be identified. For example, among the frequent variants identified in the GALT gene in the Ashkenazi Jewish population, there is a complex deletion of 5.2 Kb (Δ5.2Kb).

One of the most frequent variants of the GALT gene in the population of European origin is the missense mutation c.563A>G (p.Gln188Arg), which if present in homozygosity causes classic galactosemia. Other frequent mutations associated with the classic galactosemia phenotype are p.Lys285Asn and p.Leu195Pro. Among African Americans, those homozygous for the variant c.404C>T (p.Ser135Leu) have a better prognosis and usually manifest the clinical variant of galactosemia. Patients with the Duarte variant have a classical pathogenic mutation associated with the D2 allele in heterozygosity (in trans) or in homozygosity (in cis and in trans). The D2 allele consists of 5 variants in cis, of which the one that seems to influence most the enzymatic function is a deletion of 4bp in the 5 ‘UTR of the GALT gene (c.-119_-116delGTCA). The other variants are c.940A>G (p.Asn314Asp), c.378-27G>C, c.508-24G>A and c.507+62G>A.

Differential diagnosis

Differential diagnosis primarily includes all causes of neonatal hepatitis, such as infections, biliary atresia and metabolic liver disorders. These include hereditary fructose intolerance (due to mutations in the ALDOB gene), progressive intrahepatic cholestasis (due to mutations in the ATP8B1, ABCB11, ABCB4, TJP2 and NR1H4 genes), Alagille syndrome (caused by mutations in the JAG1 genes and NOTCH2), type I tyrosinemia (FAH gene), citrine deficiency (due to mutations in the SLC25A13 gene) and type C Neimann-Pick disease (NPC1 and NPC2 genes).

Other genetic disorders that fall within the differential diagnosis of galactosemia include hemochromatosis (HFE gene), Fanconi Bickel syndrome (mutations in SLC2A2) and congenital disorder of glycosylation type It, due to mutations in the PGM1 gene, which can cause a slight increase in galactose-1P in red blood cells.

Even lactose intolerance can give a neonatal phenotype partially similar to that of classical galactosemia.

Genetic testing strategy

Although most cases of galactosemia are identified by neonatal screening, this test may not be reliable in some forms of galactosemia. For this reason, it is recommended to proceed with the analysis of a Next Generation Sequencing panel that includes all the genes associated with this disorder. Breda Genetics offers the analysis of genes for galactosemia through multi-gene panels based on exome (EXOME 60MB) or whole genome (FULL GENOME) sequencing. Furthermore, in the event of a negative result, it is possible to proceed with the analysis of large deletions/duplications on the genes of interest starting from the sequencing data (algorithmic CNV), or through specific methods such as MLPA and qPCR.

Panel testing recommended at Breda Genetics for this condition:

Pan251 Galactosemia (GALE, GALK1, GALM, GALT)


Delnoy B, Coelho AI, Rubio-Gozalbo ME. Current and Future Treatments for Classic Galactosemia. J Pers Med. 2021 Jan 28;11(2):75. doi: 10.3390/jpm11020075. PMID: 33525536

Banford S, McCorvie TJ, Pey AL, Timson DJ. Galactosemia: Towards Pharmacological Chaperones. J Pers Med. 2021 Feb 7;11(2):106. doi: 10.3390/jpm11020106. PMID: 33562227

OMIM Phenotypic series Galactosemia – PS230400

Banford S, Timson DJ. The structural and molecular biology of type IV galactosemia. Biochimie. 2021 Apr;183:13-17. doi: 10.1016/j.biochi.2020.11.001. Epub 2020 Nov 9. PMID: 33181226

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