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Mucopolysaccharidosis type 2
A lysosomal storage disease with multisystemic involvement leading to a massive accumulation of glycosaminoglycans and a wide variety of symptoms including distinctive coarse facial features, short stature, cardio-respiratory involvement and skeletal abnormalities. It manifests as a continuum varying from a severe form with neurodegeneration to an attenuated form without neuronal involvement.
ORPHA:580Classification level: Disorder
Mucopolysaccharidosis type 2 (MPS2) prevalence at birth in Europe is 1/166,000. It is an X-linked recessive disorder; very rare cases of female presentation have been reported.
MPS2 patients appear healthy at birth, with initial symptoms appearing between 18 months and 4 years of age. Macrocephaly develops during infancy and infants initially grow at normal or above average rates. Initial manifestations include: frequent respiratory tract infections (in particular otitis media); umbilical and inguinal hernia; intractable diarrhea; hepatosplenomegaly; and skin lesions resembling an orange peel (on the shoulder, back and thighs). A distinctive facies with thickening of lips and nostrils as well as an enlarged and protruding tongue forms slowly and may become evident between 2-4 years of age, later in attenuated cases. Progression varies from a severe form (MPS2, severe form) with early psychomotor regression to an attenuated form (MPS2, attenuated form) which manifests without cognitive involvement.
MPS2 results from iduronate-2-sulfatase (I2S) deficiency, which leads lysosomal accumulation of two specific mucopolysaccharides, dermatan sulfate (DS) and heparan sulfate (HS). The causative gene, IDS, is located on Xq28, approximately 320 mutations have been reported to cause MPS2.
Diagnosis is based on clinical signs followed by the detection of increased levels of DS and HS in the urine and confirmed by the demonstration of the enzyme deficiency in the serum, leukocytes or fibroblasts, or in dried blood spot samples. Enzymatic activity of another sulfatase should also be assessed. Genetic testing requires searching for exonic or whole-gene deletions, for point mutations in IDS and its promoter region, and for recombination with the nearby pseudogene IDS2.
Differential diagnoses include mucopolysaccharidosis type 1, 6, 7; sialidosis type 2; mucolipidosis type 2 and 3; and multiple sulfatase deficiency.
Prenatal diagnosis by measuring IDS activity or by mutation analysis in chorionic villi or amniocytes is only performed for male fetuses.
Women at risk of being a carrier should undergo genetic testing as MPS2 is X-linked recessive. Female carriers transmit the disorder to 50% of their sons; only 12 cases of affected girls have been described due to skewed X-inactivation.
Management and treatment
All patients should be considered for weekly intravenous enzyme replacement therapy (ERT) which has been shown to alleviate somatic symptoms. Cranial shunting should be performed to relieve cases of hydrocephalus. Hernia repair, tonsillectomy and adenoidectomy (to liberate the upper respiratory tract) and in some cases positive pressure ventilation or tracheostomy may be required. Cardiac valve or hip replacement and carpal tunnel release may be necessary over time. Extensive palliative care is required, patients must be regularly evaluated by echocardiogram, respiratory function, full radiologic examination to identify dysostosis multiplex, cranial and cervical MRI with or without lumbar puncture to assess cerebrospinal fluid pressure, hearing tests, eye exams and nerve conduction velocity tests.
Prognosis is highly variable. In the severe form (60-80% of cases) life expectancy is markedly reduced, death generally occurring before the age of 25 often as a result of cardio-respiratory complications. In the attenuated form, patients may survive into adulthood, sometimes even beyond the age of 60, and intellectual deficits are most often absent in these cases.