Galactosemia

name: Galactosemia
creation_date: '2026-02-06T03:39:54Z'
updated_date: '2026-02-17T21:53:14Z'
category: Genetic
synonyms:
- Galactose intolerance
description: >
  Galactosemia is an inborn error of galactose metabolism caused by deficiency
  of one of three enzymes in the Leloir pathway: galactose-1-phosphate
  uridyltransferase (GALT, classic galactosemia), galactokinase (GALK), or
  UDP-galactose-4-epimerase (GALE). Classic galactosemia (GALT deficiency) is
  the most severe form, presenting in neonates with feeding difficulties,
  failure to thrive, hepatomegaly, jaundice, and increased susceptibility to
  E. coli sepsis. Early dietary restriction of galactose prevents acute
  toxicity but long-term complications including cognitive impairment,
  speech disorders, and premature ovarian insufficiency may still occur.
disease_term:
  preferred_term: galactosemia
  term:
    id: MONDO:0018116
    label: galactosemia
parents:
- Inborn error of carbohydrate metabolism
- Newborn screening disorder
has_subtypes:
- name: Classic Galactosemia (GALT deficiency)
  subtype_term:
    preferred_term: classic galactosemia
    term:
      id: MONDO:0009258
      label: classic galactosemia
  description: >
    Most common and severe form caused by GALT deficiency. Presents in
    neonates with life-threatening illness if untreated.
- name: Galactokinase Deficiency
  description: >
    Milder form caused by GALK1 deficiency. Primary manifestation is
    cataracts without the systemic toxicity of classic galactosemia.
- name: Epimerase Deficiency
  description: >
    Caused by GALE deficiency. Phenotype ranges from benign peripheral
    form to severe generalized form resembling classic galactosemia.
pathophysiology:
- name: Galactose-1-phosphate accumulation
  description: >
    In classic galactosemia, GALT deficiency prevents conversion of
    galactose-1-phosphate (Gal-1-P) to UDP-galactose. Accumulated Gal-1-P
    is directly toxic to liver, brain, kidneys, and ovaries through
    multiple mechanisms including inhibition of phosphoglucomutase and
    depletion of inorganic phosphate.
- name: UDP-galactose deficiency
  description: >
    Reduced UDP-galactose impairs galactosylation of glycoproteins and
    glycolipids. Abnormal glycosylation affects brain development,
    folliculogenesis, and multiple cellular processes. This deficiency
    persists despite dietary treatment, contributing to long-term
    complications.
- name: Galactitol toxicity
  description: >
    Galactose is reduced to galactitol by aldose reductase. Galactitol
    accumulates in the lens causing osmotic stress and cataracts. In
    galactokinase deficiency, this is the primary pathogenic mechanism.
phenotypes:
- name: Neonatal jaundice
  frequency: FREQUENT
  description: >
    Conjugated hyperbilirubinemia appearing in the first week of life
    due to hepatocellular dysfunction.
- name: Hepatomegaly
  frequency: FREQUENT
  description: >
    Enlarged liver from hepatocellular damage and fatty infiltration.
- name: Failure to thrive
  frequency: FREQUENT
  description: >
    Poor weight gain and growth failure in affected neonates.
- name: Cataracts
  frequency: FREQUENT
  description: >
    Oil-droplet cataracts from galactitol accumulation in the lens.
    May be present at birth or develop in first weeks of life.
- name: E. coli sepsis
  frequency: OCCASIONAL
  description: >
    Increased susceptibility to gram-negative sepsis, particularly
    E. coli, in the neonatal period. Mechanism involves impaired
    neutrophil function and complement activation.
- name: Intellectual disability
  frequency: OCCASIONAL
  description: >
    Cognitive impairment may occur despite early dietary treatment,
    likely due to endogenous galactose production and UDP-galactose
    deficiency affecting brain development.
- name: Speech disorders
  frequency: FREQUENT
  description: >
    Verbal dyspraxia and speech delays are common long-term complications
    even with early treatment.
- name: Premature ovarian insufficiency
  frequency: FREQUENT
  description: >
    Over 80% of females with classic galactosemia develop hypergonadotropic
    hypogonadism with primary or secondary amenorrhea.
- name: Tremor
  frequency: OCCASIONAL
  description: >
    Movement disorders including tremor and ataxia may develop as
    long-term neurological complications.
genetic:
- name: GALT variants (Classic galactosemia)
  inheritance:
  - name: Autosomal recessive
  features: >
    Classic galactosemia is caused by biallelic pathogenic variants in
    GALT (9p13.3). The most common variants include Q188R (most common
    in European populations), K285N, S135L, and L195P. The Duarte variant
    (N314D) causes partial enzyme deficiency.
- name: GALK1 variants (Galactokinase deficiency)
  inheritance:
  - name: Autosomal recessive
  features: >
    Caused by biallelic pathogenic variants in GALK1 (17q25.1).
- name: GALE variants (Epimerase deficiency)
  inheritance:
  - name: Autosomal recessive
  features: >
    Caused by biallelic pathogenic variants in GALE (1p36.11).
treatments:
- name: Galactose-restricted diet
  description: >
    Lifelong dietary restriction of galactose is the cornerstone of
    treatment. Lactose-containing foods (milk, dairy) are eliminated
    and replaced with soy-based or elemental formulas in infancy.
- name: Calcium and vitamin D supplementation
  description: >
    Supplementation is necessary due to dairy restriction to prevent
    osteoporosis.
- name: Hormone replacement therapy
  description: >
    Estrogen and progesterone replacement for females with premature
    ovarian insufficiency.
- name: Speech therapy
  description: >
    Early intervention for speech and language delays.
references:
- reference: DOI:10.1002/jcp.20820
  title: 'Galactosemia: The good, the bad, and the unknown'
  findings: []
- reference: DOI:10.1002/jimd.12202
  title: 'Pathophysiology and targets for treatment in hereditary galactosemia: A
    systematic review of animal and cellular models'
  findings: []
- reference: DOI:10.1007/s10545-016-9993-2
  title: Assessment of ataxia phenotype in a new mouse model of galactose‐1
    phosphate uridylyltransferase (GALT) deficiency
  findings: []
- reference: DOI:10.3389/fgene.2024.1355962
  title: Brain function in classic galactosemia, a galactosemia network (GalNet)
    members review
  findings: []
- reference: DOI:10.3389/fpls.2020.00167
  title: Phosphoglucomutase Is Not the Target for Galactose Toxicity in Plants
  findings: []
- reference: PMID:1150052
  title: Reversibility of extensive liver damage in galactosemia.
  findings: []
- reference: PMID:1561928
  title: Association of Escherichia coli sepsis and galactosemia in neonates.
  findings: []
- reference: PMID:1706789
  title: 'Long-term prognosis in galactosaemia: results of a survey of 350 cases.'
  findings: []
- reference: PMID:31774565
  title: Galactose 1-phosphate accumulates to high levels in galactose-treated
    cells due to low GALT activity and absence of product inhibition of GALK.
  findings: []
- reference: PMID:331112
  title: Sepsis due to Escherichia coli in neonates with galactosemia.
  findings: []
- reference: PMID:39704415
  title: Misprocessing of α -Galactosidase A, Endoplasmic Reticulum Stress, and
    the Unfolded Protein Response.
  findings: []
- reference: PMID:41083920
  title: 'Myo-Inositol Deficiency, Structural Brain Changes, and Cerebral Perfusion
    Alterations in Classic Galactosemia: Preliminary Insights From a Multiparametric
    MRI Study.'
  findings: []