Galactokinase Deficiency

Etiology

Galactokinase deficiency results from a mutation in the GALK1gene (17q25.1), which codes for galactokinase enzyme. This disorder is inherited as an autosomal recessive trait. Researchers have identified more than 30 different mutations in patients with galactokinase deficiency. 

Epidemiology

The Prevalence of galactokinase deficiency ranges from 1 in 50,000 to 2,200,000. The Romani population has a high incidence of galactokinase deficiency, where the carrier frequency is 1 in 47[2]. In the United States, the incidence is approximately 1 in 100,000 newborns. 

Pathophysiology

Learning the Leloir pathway is important in understanding galactose metabolism defects.[3] Under the normal state, exogenous and endogenously produced galactose will be phosphorylated to galactose-1-phosphate (Gal-1-P) by enzyme galactokinase (GALK1). Galactose 1 phosphate reacts with UDP- glucose in the presence of galactose-1- phosphate uridyltransferase (GALT) to form glucose-1- phosphate and UDP-galactose. UDP-glucose can also be converted to UDP-galactose by UDP galactose-4'-epimerase (GALE) reaction.

Minor pathways exist, including conversion of galactose to galactonate by galactose dehydrogenase and the reduction of galactose to galactitol by aldose reductase. The minor pathways are generally not significant when the Leloir pathway is active. When the major pathways are blocked (GALK, GALT, and GALE), the minor pathways become significant. This blocking leads to the accumulation of galactitol in the lens, causing osmotic swelling of lens fibers, rupture of the cell membrane, and protein denaturation causing cataract. Cataract changes are reversible only if galactose is withdrawn from food before the rupture of the cell membrane.[4]

There are clinical reports of mental retardation in a few patients on long term follow up. The molecular and biochemical basis of mental retardation in galactokinase does not have a satisfactory explanation so far. Possible hypotheses include poor compliance with dietary restrictions. Accumulating galactitol with other toxic analytes could be a neurotoxin. Galactitol reduces the glutathione redox potential and causes cytotoxic effects. The possibility of mental retardation from GALK deficiency adds a compelling reason for strict dietary restriction.[5] The endogenous production of galactose is also considered an important etiological factor. 

Unlike classical galactosemia, gal-1-phosphate does not accumulate in galactokinase deficiency. Galactose-1-phosphate is the toxic metabolite in Type 1 galactosemia. Toxic effects may be due to its inhibitory effect on other enzymes such as phosphoglucomutase and depletion of high energy phosphates restricting the availability of ATP for uridyltriphosphate synthesis.[6]

History and Physical

Hereditary galactokinase deficiency is a rare metabolic disorder that usually produces no dramatic disease manifestations in the early weeks and months of life. Unexplained hyperbilirubinemia in the early neonatal period is a common presentation.[7] Bilateral cataract is the most common manifestation of the disease.[8] In cases that go unrecognized, cataract manifests as a failure to develop social smile or track objects visually.

Another frequently noted clinical feature is pseudotumor cerebri, which can be due to increased cerebrospinal fluid osmotic pressure from increased galactitol concentration.[9] Long term followup showed that these patients are at high risk of dyspraxia, mental retardation, motor delays, and hypergonadotropic hypogonadism.[10][1] Heterozygous carriers of galactokinase deficiency are at increased risk of presenile cataracts. Additional clinical features reported in the literature include microcephaly, failure to thrive, seizures, bilateral deafness, hypoglycemia, hypercholesterolemia, and hepatomegaly.[11] Ovarian failure is also common. However, it is unclear whether these clinical findings are due to galactokinase enzyme deficiency. 

Galactokinase deficiency has been reported in patients with congenital hyperinsulinemia. This information becomes significant because severe hyperglycemia goes undetected by bedside glucometer in patients with associated galactokinase deficiency due to the accumulation of galactose.[12]

Evaluation

Galactokinase should be a consideration in a newborn with cataracts or with abnormal newborn screens or galactosuria. The newborn screen includes the combination of fluorometric or bacterial inhibition assay for total galactose and Beutler fluorescent spot screening test. Since galactokinase deficiency is very rare and is part of the differential diagnosis of congenital galactosemia, it has been designated as a secondary target. Therefore, in order to screen for galactokinase deficiency, an additional test is required.

GALT enzyme analysis is performed if there is clinical suspicion for galactosemia, positive newborn screen for galactosemia, or investigation of a possible carrier state.[13] If the GALT level is less than 24.5 nmol/h/mg of hemoglobin, it could indicate either classical glactosemia or Duarte-variant galactosemia, and GALT gene analysis is automatically performed. If the GALT levels are more than 24.5 nmol/h/mg of hemoglobin and if the total galactose is elevated on the newborn screen, a provider should check the erythrocytes GAL1P (galactose -1-phosphate) levels. If that is normal, galactokinase enzyme assay should be done. The majority of the programs use semiquantitative methods to measure GALT activity.

Approximately 30 percent of programs measure total galactose (galactose plus Gal-1-P) either as a primary screening method or combined with GALT testing. Therefore, a negative newborn screen for galactosemia must be interpreted based on the nature of the test. If dietary monitoring is required, GAL1P/Gal-1-Phos erythrocytes levels are typically measured. Recent studies developed to measure early morning urine galactitol relative to galactose intake can be useful for measuring dietary compliance in galactokinase deficiency patients.[14]

Urine and serum levels of galactose and galactitol also become elevated in galactokinase deficiency patients. Galactose concentration in the blood is decreased or normalized completely with dietary restriction of galactose.[15]

Patients with suspected pseudotumor cerebri in GALK deficiency should have a detailed ophthalmological examination followed by neuroimaging. Following neuroimaging, a lumbar puncture is critical to measure the CSF opening pressure.

Molecular testing for galactokinase deficiency includes full gene sequencing followed by a targeted gene deletion/duplication analysis rather than targeted mutation testing.

Clinicians need to offer genetic counseling to the families of newborns affected with any type of galactosemia irrespective of the severity. Since it is an autosomal recessive condition, both parents must be affected, and the recurrence rate is at least 25 percent. Identifying specific mutations in the affected infant and the carrier screening options should be discussed with the families. Prenatal testing by amniocentesis or chorionic villus sampling or preimplantation genetic testing can be offered to those who are at risk of having a child with galactosemia. 

Treatment / Management

The early start of dietary galactose restriction with calcium supplements is essential; this results in a significant reduction in metabolite levels.[16] Minor sources of galactose, including legumes, green vegetables, and milk products, can probably be disregarded since the assumption is that a small amount of galactose is probably metabolized and excreted before galactitol forms. Treatment started within two to three weeks of age will reverse the cataract changes in the lens. If the cataract is too dense or mature, it requires surgical removal. Once switched to soy-based formula, infants usually develop normally, but recent studies show increasing incidence of developmental complications. 

Long term follow-up involves measurements of the galactose and its metabolites, especially the measurement of galactitol in the RBC. Routine ophthalmologic examination by slit lamp is necessary. In patients with developmental delays or mental retardation, neurodevelopmental testing is important. Blood sugar checks should be performed regularly due to the incidence of hypoglycemia. 

Differential Diagnosis

Classic galactosemia: Classic galactosemia is an autosomal recessive disorder caused by the deficiency of GALT. It usually arouses clinician suspicion in infants with an abnormal newborn screen, hypergalactosemia, or galactosuria. Almost all the patients manifest in the neonatal period if not diagnosed at birth. Classic galactosemia results in life-threatening complications, including feeding problems, failure to thrive, hepatocellular damage, E. coli sepsis, and bleeding. If dietary restrictions start within ten days of life, complications of liver failure, sepsis, and neonatal death are preventable.  

Duarte galactosemia (DG): It is an autosomal recessive condition resulting from partial impairment of galactose-1-phosphate uridyltransferase (GALT).[17] DG is similar to lethal classic galactosemia but with milder symptoms. Hypergalactosemia is not marked as in the classical variety, and many cases are missed in the newborn screen. Severe neonatal complications are preventable if the treatment starts within ten days of life. 

Epimerase deficiency galactosemia: Epimerase deficiency should be considered in an infant with failure to thrive, liver disease, and elevated erythrocyte galactose-1-phosphate concentration with normal GALT enzyme activity. Detection of reduced GALE enzyme activity is diagnostic.[18]

Prognosis

Prognosis is excellent if the patients continue to have galactose free diet. Adequate treatment prevents the formation of cataracts or at least partially resolves them if treatment commences before the cataract maturation. 

Complications

Cataract formation and pseudotumor cerebri are the two common complications in galactokinase patients. Despite strict dietary restrictions, there are reports of developmental delay, dyspraxia, and hypogonadotropic hypogonadism in a few patients.