Galactosemia is a group of diseases caused by congenital deficiency or reduced activity of enzymes involved in galactose metabolism, leading to accumulation of galactose and its metabolites. It results from impairment of any of the four enzymes in the Leloir pathway. It follows an autosomal recessive inheritance pattern.
The incidence in Japan is estimated at 1 in 900,000 to 1,000,000 people. It is a target disease of newborn mass screening, with a screening rate of 100% in both Japan and the United States, and about 39% in Europe 1). GALT deficiency is designated as an intractable disease.
It is classified into the following four types based on the deficient enzyme.
The prevalence of classic galactosemia (type I) varies greatly by region, reported as 1:40,000–60,000 in Europe, 1:50,000 in the United States, 1:100,000 in Japan, and 1:400,000 in Taiwan1). Type IV (GALM deficiency) is a relatively new form first described in 2019, with 42 cases reported to date and an estimated incidence of 1:228,4112).
QWhat types of galactosemia are there?
A
It is classified into four types based on the causative enzyme deficiency. Type I (GALT deficiency) is the most severe, presenting with multi-organ dysfunction from the neonatal period. Type II (GALK deficiency) has cataract as the only symptom. Type III (GALE deficiency) includes a severe central type and a mild peripheral type. Type IV (GALM deficiency) is the most recently identified type, with clinical features similar to GALK deficiency.
The presentation of symptoms varies greatly depending on the type.
Type I: Poor feeding, vomiting, poor weight gain, and jaundice appear within the first week of life. General condition rapidly deteriorates after starting breast milk or formula containing lactose.
Type II: No systemic symptoms; onset is insidious. Patients may first present with decreased vision.
Type III (central type): Similar to type I, hypotonia, poor feeding, vomiting, and weight loss occur.
Type IV: Often asymptomatic, detected by newborn screening.
Liver failure: Presents with jaundice, hepatomegaly, and coagulation abnormalities (INR 4.2). Reports of AST 135, ALT 244, and hyperammonemia (248 µg/dL) 4).
E. coli sepsis: High galactose levels promote E. coli growth.
Cataracts: Oil drop cataracts (bilateral) are observed 4).
Cytopenia: May present with transient pancytopenia: Hb 7 g/dL, neutrophils 870/mm³, platelets 65,000/mm³ 4).
Long-term complications: Speech delay, learning disabilities, motor impairment, ovarian failure, brain damage (85%), decreased bone density (26.5%) 1).
Type II (GALK Deficiency)
Cataract: This is the only symptom. No systemic symptoms are observed.
Insidious onset: Presents as infantile or juvenile cataract.
Reversibility: Cataract may resolve if treatment is started within 2–3 weeks after birth.
Type III (GALE deficiency) is divided into central and peripheral types. The central type presents with severe symptoms similar to type I and causes cataract. The peripheral type is mild, mainly affecting red blood cells and white blood cells, and is not associated with cataract.
Type IV (GALM deficiency) has a clinical picture similar to GALK deficiency. The risk of cataract is reported as 11.9% (5/42 cases)2). Transient cholestasis (2/43 cases) and mild transaminase elevation (10/43 cases) may occur2).
Known neurological complications in adulthood include ataxic gait, tremor, cognitive impairment, and sensorineural hearing loss. MRI shows diffuse white matter changes and moderate cerebellar atrophy3).
Cataract is a common ophthalmic complication in most types (except peripheral GALE deficiency and Duarte type).
Progression of opacity: Begins with oil droplet opacity of the lens nucleus, presents as lamellar cataract with equatorial opacity, and progresses to total cataract.
Oil drop cataract: A characteristic finding in type I, observed bilaterally4).
Reversibility: Cataract is considered reversible with lactose restriction from early infancy. However, cataract may still develop even with dietary restriction.
QWhat is the morphology of cataract due to galactosemia?
A
It begins with oil droplet opacity of the lens nucleus (oil drop cataract) and progresses to lamellar cataract with equatorial opacity. Further progression leads to total cataract. It is considered reversible with lactose restriction in early infancy, but may still develop even with dietary restriction. See the section on “Standard Treatment” for details.
All of these diseases follow an autosomal recessive inheritance pattern.
GALT gene: Located on chromosome 9p13, approximately 4.3 kb, consisting of 11 exons. It forms a homodimer of 379 amino acids and has a His-Pro-His motif at the active site1).
Mutation diversity: The Human Gene Mutation Database (HGMD) lists 319 GALT mutations (251 missense/nonsense, 27 splice site, 24 small deletions, 5 insertions, 8 large deletions)1).
Ethnic differences: Q188R accounts for about 70% of alleles in Europe, K285N for about 54% in Germany and Austria, and S135L for about 50% in African Americans1).
Consanguinity: Consanguineous marriage increases the risk of homozygosity and may lead to multiple rare diseases5).
In Japan, this disease is included in newborn mass screening. Blood galactose level, galactose-1-phosphate (Gal-1-P) level, and red blood cell GALT activity are measured. As soon as the diagnosis is made, lactose restriction is started immediately.
Red blood cell GALT activity: Normal value is 3.5 U/g Hb or higher. A decrease to 2.3 U/g Hb has been reported4). This is the gold standard for definitive diagnosis.
Genetic analysis: Identification of mutations allows determination of type and prognosis1)2).
WES (whole exome sequencing): Cases of classic galactosemia first diagnosed at age 34 have been reported, and it is also useful for late diagnosis in adulthood3).
Transferrin isoelectric focusing (TfIEF): Detects abnormal patterns of sialotransferrin. Useful for differential diagnosis and assessment of dietary compliance3)4).
It is important to differentiate from diseases that present with similar liver dysfunction in the neonatal period. Differential diagnoses include congenital hepatitis, tyrosinemia type I, citrullinemia type II, and Fanconi-Bickel syndrome 4).
QCan it be missed in newborn screening?
A
In Japan and the United States, the screening rate is 100%, but in Europe it is only about 39% 1). Additionally, after transfusion, red blood cell GALT activity may show false normal values, which can lead to missed detection 5). Cases diagnosed for the first time in adulthood due to neurological symptoms have also been reported 3).
Galactose (lactose) restriction is the basis of treatment.
After NBS diagnosis: Immediately start lactose restriction. Use lactose- and galactose-free formula.
Strategy based on GALT activity: If red blood cell GALT activity is less than 10%, lifelong lactose restriction is necessary. Duarte type does not require treatment 1).
GALM deficiency: Asymptomatic cases can be monitored 2).
Long-term management requires the following regular assessments.
Measurement of blood galactose, Gal-1-P, and erythrocyte galactitol levels
Regular eye examinations to assess cataract formation
Monitoring of systemic complications (neurodevelopment, ovarian function, bone density, etc.)
QCan cataracts develop even with dietary restrictions?
A
Cataracts are considered reversible with early lactose restriction in infancy, but they may still develop even under dietary restrictions. The mechanism is not fully understood. Long-term follow-up is especially important in type II.
6. Pathophysiology and Detailed Mechanism of Onset
Galactose is metabolized through the Leloir pathway. Four enzymes in this pathway act sequentially.
GALM (galactose mutarotase): Converts β-D-galactose to α-D-galactose.
GALK (galactokinase): Phosphorylates α-D-galactose to galactose-1-phosphate.
GALT (galactose-1-phosphate uridylyltransferase): Catalyzes the exchange between galactose-1-phosphate and UDP-glucose, producing glucose-1-phosphate and UDP-galactose.
GALE (UDP-galactose-4-epimerase): Catalyzes the interconversion of UDP-glucose and UDP-galactose.
If any of these enzymes is deficient, metabolites upstream of the mutation accumulate and are shunted to alternative pathways.
The ophthalmologically important alternative pathway is the aldose reductase pathway. Accumulated galactose is converted to galactitol by aldose reductase. Galactitol is osmotically active and tends to accumulate in lens fiber cells due to high aldose reductase concentration in the anterior lens. This accumulation causes lens swelling, cell lysis, and cataract formation.
Misfolding of GALT protein: Structural abnormalities in mutant GALT protein contribute to reduced enzyme activity1).
Abnormal glycosylation: Accumulation of Gal-1-P decreases UDP-galactose, impairing glycosylation of glycoproteins and glycolipids. This is detected as elevated sialotransferrin3)4).
Bone marrow failure: Normal hematopoiesis requires glycosylation, and its impairment causes transient cytopenia4).
Effects on brain tissue: Brain tissue is particularly sensitive to accumulation of metabolites, leading to long-term neurological complications3).
Lucas et al. (2021) reported a case of classic galactosemia diagnosed for the first time at age 34 by whole-exome sequencing3). The patient was a compound heterozygote (Q188R + K285N) presenting with ataxic gait, tremor, cognitive impairment, and sensorineural hearing loss. MRI showed diffuse white matter changes and moderate cerebellar atrophy. After starting a low-galactose diet, sialotransferrin decreased by 75%.
7. Latest Research and Future Perspectives (Research-stage Reports)
In animal models, gene replacement therapy using AAV9 vectors in the neonatal period has been successful, raising expectations for clinical application 1). mRNA therapy is also being studied as a promising option.
Lucas et al. (2021) reported that sialotransferrin and N-glycan profiles are useful as surrogate markers of disease activity 3). Since sialotransferrin decreased by 75% after starting a low-galactose diet, it is considered applicable for monitoring treatment effects.
Wang YC, Lan LC, Yang X, et al. A case report of classic galactosemia with a GALT gene variant and a literature review. BMC Pediatr. 2024;24:352.
Sánchez-Pintos P, Camba-Garea MJ, Martin López-Pardo B, et al. Clinical and biochemical evolution after partial dietary liberalization of two cases of galactosemia due to galactose mutarotase deficiency. BMC Pediatr. 2024;24:620.
Lucas-Del-Pozo S, Moreno-Martinez D, Camprodon-Gomez M, et al. Galactosemia diagnosis by whole exome sequencing later in life. Mov Disord Clin Pract. 2021;8(S1):S37-S39.
Gianniki M, Nikaina I, Avgerinou G, et al. Transient cytopenias as a rare presentation of classic galactosemia. Cureus. 2022;14(3):e23101.
Dogulu N, Kose E, Tuna Kirsaglioglu C, et al. Co-occurring atypical galactosemia and Wilson disease. Mol Syndromol. 2022;13:454-458.
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