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Mucolipidosis type II

Synonym(s) I-cell disease
N-acetylglucosamine 1-phosphotransferase deficiency
Prevalence <1 / 1 000 000
Inheritance Autosomal recessive
Age of onset Neonatal
  • E77.0
  • C0020725
  • C2931894
  • C538602
MedDRA -


Disease definition

Mucolipidosis II (MLII) is a slowly progressive lysosomal disorder characterized by growth retardation, skeletal abnormalities, facial dysmorphism, stiff skin, developmental delay and cardiomegaly.


The worldwide prevalence is unknown. Estimated live birth prevalence values have been reported in Portugal (1/123,500), Japan (1/252,500), the Netherlands (1/625,500) and Ireland (1/64,100). A founder effect has been reported the in Saguenay-Lac-St-Jean region of Quebec.

Clinical description

Infants present at birth with hypotonia, growth retardation and gradually worsening skeletal deformities, including ulnar deviation of hands with broadening and camptomelic fingers, kyphosis, hip dislocation, clubfeet and deformed long bones. A limited range of motion of shoulder joints is noted at birth. Neonatal transient hyperparathyroidism has been documented in severe cases of MLII. Flat face, shallow orbits with proptotic eyes, depressed nasal bridge, prominent mouth and gingival hypertrophy are apparent soon after birth. Coarsening of facial features is progressive. Skin is stiff and thickened, especially around the earlobes. Early motor milestones are delayed and cognitive functioning is below normal. Postnatal growth usually stops in the 2nd year of life and contractures develop in all joints. Most patients never walk. Cardiac involvement most commonly includes the thickening and insufficiency of the mitral or aortic valves. Voice is hoarse and breathing is noisy due to the progressive narrowing of airways, mucosal thickening and stiffening of all connective tissues which, along with cardiac involvement, leads to cardiorespiratory insufficiency.


MLII is due to mutations in the GNPTAB gene (12q23.3), encoding the alpha and beta subunits of the N-acetylglucosamine phosphotransferase complex. Mutations in this gene lead to a failure of mannose-6-phosphate synthesis, the marker on the oligomannosyl type glycan side chains of lysosomal enzymes, which targets the enzymes to the lysosomes of connective tissue cells. Failing lysosomal function (rather than a true storage of undigested products) represents the pathogenesis of ML II.

Diagnostic methods

Diagnosis is based on clinical/radiographical examination as well as plasma enzyme assays. Radiographs reveal increasing osteopenia and dysostosis multiplex (diaphyseal widening and shortening of tubular bones, anterior-inferior hook configuration of 1st and/or 2nd lumbar vertebra, and relatively long pubic and ischial bones). Lysosomal hydrolase levels in plasma and other body fluids are 5-20 times higher than normal. Molecular mutation screening of the GNPTAB gene confirms diagnosis. Assay of the enzyme defect, visualizing cytoplasmic inclusions and documenting increased urinary oligosaccharide levels are possible but not routinely available.

Differential diagnosis

Differential diagnoses include Hurler syndrome; GM1 gangliosidosis type 1; the infantile form of galactosialidosis; sialidosis type 2; free sialic acid storage disease, infantile form; hypocalcemic rickets; and ML III. Pacman dysplasia (see these terms) is in many instances the prenatal expression of ML II.

Antenatal diagnosis

Prenatal diagnosis is possible in families with a known disease-causing mutation.

Genetic counseling

MLII is inherited autosomal recessively and genetic counseling is possible.

Management and treatment

There is no cure for MLII and treatment is supportive. Interactive programs to stimulate cognitive development, as well as ''low-impact'' therapies (such as aqua therapy) and occupational and/or speech therapy may be beneficial. Gingivectomy may be considered in those with severe mouth pain and infections. Respiratory support and assisted ventilation may be necessary in some cases. Infants and toddlers should have regular follow-ups (every 3 months) to monitor cardiac and pulmonary functioning, and afterwards every year throughout early childhood.


The prognosis is poor with a fatal outcome (most commonly due to cardiorespiratory insufficiency) most often occurring in childhood.

Expert reviewer(s)

  • Dr Jules LEROY

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