Mucopolysaccharidosis Type 1

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Retrieved

2021-01-23

Source

Orphanet

Trials

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Genes

IDUA, SLC26A1, RPS27, TTK, MPEG1, FUT1, ARSB, BMP4, CAT, CD34, CTSB, INSR, NBN, NME1, PTPRC, TP53

Drugs

6'-(R)-methyl-5-O-(5-amino-5,6-dideoxy-alpha-L-talofuranosyl)-paromamine sulfate, Adeno-associated viral vector serotype 2/6 encoding zinc-finger nucleases and the human alpha L-iduronidase gene, Allogeneic multi-virus specific T lymphocytes targeting BK virus, cytomegalovirus, human herpesvirus-6, Epstein Barr virus and adenovirus, Laronidase ( ALDURAZYME ), Recombinant adeno-associated viral vector serotype 9 containing human iduronidase gene, Recombinant human insulin receptor monoclonal antibody-fused-alpha-L-iduronidase, autologous CD34+ haematopoietic stem and progenitor cells genetically modified with the lentiviral vector IDUA LV, encoding for the alpha-L-iduronidase cDNA, haematopoietic stem cells and blood progenitors umbilical cord-derived expanded with (1R, 4R)-N1-(2-benzyl-7-(2-methyl-2H-tetrazol-5-yl)-9H-pyrimido[4,5-b]indol-4-yl)cyclohexane-1,4-diamine dihydrobromide dihydrate

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Mucopolysaccharidosis type 1 (MPS 1) is a rare lysosomal storage disease belonging to the group of mucopolysaccharidoses. There are three variants, differing widely in their severity, with Hurler syndrome being the most severe, Scheie syndrome the mildest and Hurler-Scheie syndrome giving an intermediate phenotype.

Epidemiology

Prevalence is estimated at 1/100,000, with Hurler syndrome accounting for 57% of cases, Hurler-Scheie syndrome accounting for 23% of cases and Scheie syndrome accounting for 20% of cases.

Clinical description

In the severe form (Hurler syndrome or MPS I-H; see this term) skeletal deformities and a delay in motor and intellectual development are the leading symptoms. Onset occurs 6-8 months after birth. Other manifestations include corneal clouding, organomegaly, heart disease, short stature, hernias, facial dysmorphism and hirsutism. Radiological examination of the skeleton reveals the characteristic pattern of dysostosis multiplex. Hydrocephaly can occur after the age of two. Patients with the adult-onset form (Scheie syndrome or MPS I-S; see this term) are of almost normal height and do not show intellectual deficiency. Typical symptoms are stiff joints, corneal opacities, carpal tunnel syndrome and mild skeletal changes. Aortic valve disease can be present. Compression of the cervical spinal cord, caused by glycosaminoglycan infiltration of the dura, may lead to spastic paresis if not corrected by neurosurgical intervention. Patients with the intermediate form (Hurler-Scheie syndrome or MPS I-H/S; see this term) have normal or almost normal intelligence, but exhibit various degrees of physical impairment.

Etiology

The different phenotypes are caused by allelic mutations in the alpha-L-iduronidase (IDUA) gene (localized to 4p16.3). The mutations result in complete deficiency of the enzyme in Hurler syndrome or partial function in Scheie syndrome, leading to lysosomal accumulation of dermatan sulfate (DS) and heparan sulfate (HS).

Diagnostic methods

Early diagnosis is difficult as the first clinical signs are not specific (hernias, respiratory infections, etc.) but it is very important to allow early treatment. Biological diagnosis relies on detection of increased urinary excretion of DS and HS and the demonstration of the enzymatic deficiency (in plasma, leucocytes, fibroblasts, trophoblastic cells or amniocytes).

Differential diagnosis

Mucopolysaccharidosis type VI (Maroteaux-Lamy syndrome; see this term) resembles mucopolysaccharidosis type I in many aspects, MPS VI patients, however, never have intellectual impairment. Mucopolysaccharidosis type II (see this term), an X-linked recessive disorder in which severe joint contractures are a characteristic symptom, also has many features in common with mucopolysaccharidosis type I.

Antenatal diagnosis

Antenatal diagnosis can be performed by enzyme assay or molecular genetics in families where the mutation has been identified.

Genetic counseling

Transmission is autosomal recessive. Genetic counseling is recommended.

Management and treatment

The genotype should be established at diagnosis in all patients as this may aid in determining the therapeutic approach. Symptomatic treatment should be proposed by a multidisciplinary team. Hematopoietic stem cell transplantation has been shown to be useful in some patients. Treatment with the enzyme substitute (laronidase) obtained EU marketing authorization as an orphan drug in 2003. All patients including those who have not received a transplant or whose graft has failed may benefit significantly from enzyme replacement therapy (ERT). Given as weekly infusions, it leads to improvement of lung function and joint mobility.

Prognosis

Early treatment slows progression of the disease. However, it is not effective against neurological lesions. Life expectancy is normal or only slightly affected in Scheie syndrome, but is reduced in Hurler syndrome, with death occurring before adolescence due to serious cardiovascular and respiratory complications.