Galactokinase Deficiency

Article initiated by:

Fabliha A. Mukit, M.D.

All authors and contributors:

Hays Torgerson Cape, Shiva N. Bohn, S. Grace Prakalapakorn, MD, MPH, Fabliha A. Mukit, M.D.

Assigned editor:

Angeline Nguyen

Review:

Assigned status Update Pending

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Illustration of bilateral pediatric cataracts by Fabliha A. Mukit, MD using an iPad and the Procreate app.

Disease Entity

Disease

Galactokinase deficiency (Type II Galactosemia) is caused by an inborn error of metabolism that affects the body’s ability to metabolize galactose. Newborn screening is important because newborns are exposed to high concentrations of galactose in breast milk and other dairy containing formulas.   Galactokinase deficiency is inherited in an autosomal recessive trait pattern and results in the mutation of the galactokinase enzyme.  Dietary modifications can help to limit the progression of the disease which makes newborn screening particularly important.

Initially, newborns are usually screened for galactosemia and if positive then additional tests are run to test for galactokinase deficiency.  Unlike the other forms of galactosemia, glucokinase deficiency is rarer and more insidious since the first presenting symptom is typically the formation of nuclear cataracts without any provoking intolerance symptoms. A holistic understanding of galactokinase deficiency can help ophthalmologist recognize and treat patients with this condition.  

Epidemiology

Galactokinase deficiency, caused by a deficiency in galactokinase (GALK1), is the mildest form of galactosemia.  The prevalence of type II galactosemia ranges from 1 in 50,00 to 2,200,000. (Ramani) In the United States the incidence of type II galactosemia is 1 in 100,000 neonates.

Etiology

Galactokinase deficiency, also known as type II galactosemia, results from a mutation in the galactokinase enzyme.  The galactokinase enzyme is encoded by the GALK1 gene found on the chromosome 17q25.1.  The galactokinase gene contains 8 exons and 7 introns as well as regions that encode the glucokinase signature sequence and two ATP binding sites.  More than 20 mutations have been mapped out by researchers at various positions throughout the galactokinase gene sequence.

Pathophysiology

An understanding of the Leloir pathway of galactose metabolism is necessary to understand why a galactokinase deficiency can cause several associated complications. There are 3 major cytosolic enzymes in this pathway that are associated with developing a form of hypergalactosemia. These enzymes are: 1) galactokinase (GALK), 2) galactose-1-phosphate uridyltransferase (GALT) and 3) UDP-galactose 4’-epimerase (GALE).

Under normal conditions, galactose is produced endogenously or exogenously and is phosphorylated to galactose-1-phosphate by galactokinase (GALK1).  Galactose-1-phosphate uridyltransferase (GALT) then catalyzes the next reaction which is the conversion of galactose-1-phosphate and UDP-glucose to form glucose-1-phosphate and UDP-galactose.  Galactose-4’-epimerase (GALE) can then convert UDP-glucose to UDP-galactose [Figure 1].

Minor pathways of galactose metabolism exist and are generally not significant if the Leloir pathway is active. Minor pathways include the conversion of galactose to galactonate by galactose dehydrogenase and the reduction of galactose to galactitol by aldose reductase.  

When the Leloir pathway gets blocked the minor pathways become significant.  In patients that have a mutation in the galactokinase enzyme, galactose is readily available to be converted to galactitol by aldose reductase.  Galactitol is osmotically active and can accumulate in the lens fiber cells. Accumulation of galactitol in the lens causes swelling, cell lysis and eventually cataracts. In patients with suspected galactokinase deficiency, infantile cataracts can be avoided through eliminating galactose from their diet.  

Leloir Pathway illustration by Fabliha A. Mukit, MD using an iPad and the Procreate app.

Diagnosis

Physical Exam

Galactosemia type II can be difficult to recognize in the early stages of life due to the lack of dramatic symptomatic manifestations that present. The most common ophthalmic manifestation of the disease is the development of bilateral nuclear sclerosis cataracts which can sometimes go unrecognized. In cases of bilateral cataracts that go unrecognized, the symptoms manifest as a nystagmus, failure to develop social smile, or diminished ability to track objects. It has also been seen that heterozygous carriers of galactokinase deficiency are at increased risk of pre-senile cataracts (development of lens opacification earlier than 40 years of age).

Outside of ophthalmic symptoms, there are other systemic manifestations of the disease. Hyperbilirubinemia is one of the more common symptoms which presents in the neonatal period. Another clinical feature that has been frequently noted is pseudotumor cerebri. Pseudotumor cerebri (also known as Idiopathic Intracranial Hypertension) can be due to increased cerebrospinal fluid from osmotic pressure caused by the increased galactitol concentration.  Long term follow-up showed that these patients are at risk of dyspraxia, mental retardation, motor delays, and hypergonadotropic hypogonadism.

Differential Diagnosis

• Type I Galactosemia (Classic Galactosemia) – AR, severe form, complete deficiency of galactose-1-phosphate-uridyltransferase
• Duarte Galactosemia – AR, partial impairment of galactose-1-phosphate-uridyltransferase (GALT)
• Epimerase Deficiency Galactosemia – elevated erythrocyte galactose-1-phosphate, normal concentrations of GAL enzyme activity

Classic galactosemia (Type I), an autosomal recessive disorder resulting from GALT (galactose-1-phosphate-uridyltransferase) deficiency, is the more severe form of Galactosemia. Newborn screening tests are designed to detect classical galactosemia. If the initial screening is positive, then secondary diagnostic tests for hypergalactosemia and galactosuria are ordered.

Newborns with GALT deficiency can suffer from severe comorbidities such as feeding problems, failure to thrive, hepatocellular damage, E. coli sepsis, and bleeding. If the patient is diagnosed early and begins dietary restrictions within ten days of life, complications of liver failure, sepsis, and neonatal death are preventable.

Duarte galactosemia is an autosomal recessive condition resulting from partial impairment of galactose-1-phosphate uridyltransferase (GALT). It is a less severe form than classic galactosemia and presents with milder symptoms. An important factor masking the diagnosis is the lack of hypergalactosemia found in patients with the disease. The condition can still be prevented if treated in a timely manner, however, it can be difficult to diagnose.

Epimerase deficiency galactosemia should be considered as a diagnosis in patients with failure to thrive, liver disease, and elevated erythrocyte galactose-1-phosphate concentrations with normal GAL enzyme activity. Diagnosis is achieved when there is a detection of reduced GALE enzyme activity.

Complications

Nuclear sclerosis cataract formation due to the accumulation of galactitol seems to be the only consistent abnormality in patients suffering from galactokinase deficiency. Unusual cases of pseudotumor cerebri, recurrent seizures, mental retardation and complement factor deficiency have been described in patients with galactokinase mutations.  However, while other abnormalities have been reported, it is unclear if they are the result of galactokinase deficiency.

Management

General treatment

Early dietary modifications are essential to the patient having more favorable outcomes.  When treatment is started within two to three weeks of age, reversal of cataract formation can occur. It is recommended that patients have strict galactose restriction with calcium supplementation to reduce metabolite levels. Soy based formula is recommended for infants with identified galactokinase deficiencies.  

Follow - Up

Long-term follow-ups with the patients primary care provider are necessary to monitor their measurements of galactose, its derivative metabolites, and measurements of galactitol in red blood cells. Routine ophthalmologic evaluation by slit lamp examination are also necessary to monitor for cataract formation.  If a patient develops a cataract that is dense and mature, surgical interventions will be required with or without intraocular lens implant.