Mucolipidosis type II (ORPHA:576)
A rare, severe form of mucolipidosis characterized by growth retardation, skeletal abnormalities (dysostosis multiplex, craniosynostosis, contractures of the joints and osteopenia), facial dysmorphism, stiff skin, obstructive airway, cardiomegaly and severe global developmental delay.
Epidemiology
Mucolipidosis type II (MLII) and type III (MLIII) represent a continuum of clinical severity and reported data is either combined or reported separately; in all instances the data is over 10 years old. The combined birth prevalence is estimated between 1/ 37,000-455,000 worldwide, whereas the reported birth prevalence for MLII is estimated between 1/123,000-2,000,000 in Europe. A founder effect has been reported in Saguenay-Lac-St-Jean region of Quebec where birth prevalence is estimated at 1/6,000.
Clinical description
MLII patients present prenatally (hydrops fetalis), directly after birth or within the first months of live with dysmorphic features, cardiac involvement, respiratory symptoms, dysostosis multiplex, severe growth abnormalities, transient neonatal hyperparathyroidism inducing rickets-like bone disease (not always present), clubfeet, hypotonia and global developmental delay; all symptoms gradually worsen over time. Facial dysmorphism includes a flat face, shallow orbits with proptotic eyes (due to craniosynostosis), depressed nasal bridge, prominent mouth and gingival hypertrophy. Coarsening of facial features is progressive. Spinal cord compression develops over time. Postnatal growth (both length and weight) usually stops in the second 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. 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.
Etiology
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 (MP6) synthesis, the marker on the oligomannosyl type glycan side chains of lysosomal enzymes, which targets the enzymes to the lysosomes. Without the MP6 signal, the enzymes are missorted into the extracellular space, leading to accumulation of the enzymes in the tissues.
Diagnostic methods
Diagnosis is based on clinical/radiographic examination as well as detection of elevated plasma lysosomal enzyme or decreased lysosomal enzyme activity. Radiographs reveal increasing osteopenia and dysostosis multiplex (diaphyseal widening and shortening of tubular bones, anterior-inferior hook configuration of first and/or second 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.
Differential diagnosis
Differential diagnoses include Hurler syndrome, the infantile form of galactosialidosis, sialidosis type 2, infantile form of free sialic acid storage disease, and hypocalcemic rickets. Pacman dysplasia is in many instances the prenatal expression of MLII.
Antenatal diagnosis
Antenatal diagnosis is possible in chorionic villi by molecular testing.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.
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. Attention should be given to overfeeding, which should be avoided. 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.
Prognosis
The prognosis is poor with a fatal outcome (most commonly due to cardiorespiratory insufficiency) most often occurring in early childhood.

                            Last update: 
                            October 2021


                            - Expert reviewer(s): 
                            Dr E. [Esmee] OUSSOREN | MetabERN*


                                * European Reference Network