Hurler Syndrome

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Retrieved

2021-01-23

Source

Orphanet

Trials

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Genes

IDUA, IDS, ARSB, MAN2B1, HGSNAT, GNE, TTK, VPS33A, SGSH, RPS27, CTSA, GNPTAB, AGA, GNPTG, NEU1, SLC26A1, NAGLU, RINT1, KRAS, GUSB, GNS, MPEG1, FUCA1, FGFR1, SUMF1, GLB1, AFP, PHEX, NSUN2, TBX1

IDUA, IDS, ARSB, MAN2B1, HGSNAT, GNE, TTK, VPS33A, SGSH, RPS27, CTSA, GNPTAB, AGA, GNPTG, NEU1, SLC26A1, NAGLU, RINT1, KRAS, GUSB, GNS, MPEG1, FUCA1, FGFR1, SUMF1, GLB1, AFP, PHEX, NSUN2, TBX1, PHKG2, NME1, NBN, FUT1, CAT, ORI6

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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Hurler syndrome is the most severe form of mucopolysaccharidosis type 1 (MPS1; see this term), a rare lysosomal storage disease, characterized by skeletal abnormalities, cognitive impairment, heart disease, respiratory problems, enlarged liver and spleen, characteristic facies and reduced life expectancy.

Epidemiology

The prevalence of the Hurler subtype of MPS1 is estimated at 1/200,000 in Europe.

Clinical description

Patients present within the first year of life with musculoskeletal alterations including short stature, dysostosis multiplex, thoracic-lumbar kyphosis, progressive coarsening of the facial features (including large head with bulging frontal bones, depressed nasal bridge with broad nasal tip and anteverted nostrils, full cheeks and enlarged lips), cardiomyopathy and valvular abnormalities, neurosensorial hearing loss, enlarged tonsils and adenoids, and nasal secretion. Developmental delay is usually observed between 12 and 24 months of life and is primarily in the realm of speech with progressive cognitive and sensorial deterioration. Hydrocephaly can occur after the age of two. Diffuse corneal compromise leading to corneal opacity becomes detectable from three years of age onwards. Other manifestations include organomegaly, hernias and hirsutism.

Etiology

Hurler syndrome is caused by mutations in the IDUAgene (4p16.3) leading to a complete deficiency in the alpha-L-iduronidase enzyme and lysosomal accumulation of dermatan sulfate and heparan sulfate.

Diagnostic methods

Early diagnosis is difficult as the first clinical manifestations are not specific. Diagnosis is based on detection of increased urinary excretion of heparan and dermatan sulfate and confirmed by demonstration of enzymatic deficiency in leukocytes or fibroblasts. Genetic testing is available.

Differential diagnosis

Differential diagnoses include the milder form of mucopolysaccharidosis type 1, the Hurler-Scheie syndrome (see this term), although this form is associated with only slight cognitive impairment. Differential diagnoses also include mucopolysaccharidosis type 6 and type 2 and mucolipidosis type 2 (see these terms).

Antenatal diagnosis

Antenatal diagnosis is possible by measurement of enzymatic activity in cultivated chorionic villus or amniocytes and by genetic testing if the disease-causing mutation is known.

Genetic counseling

Transmission is autosomal recessive. Genetic counseling and testing should be offered to couples with a positive family history.

Management and treatment

Management is multidisciplinary. Hematopoietic stem cell transplantation (HSCT) is the treatment of choice for patients with Hurler syndrome under 2.5 years of age (and in selected patients over this age limit) as it can prolong survival, preserve neurocognition, and ameliorate some somatic features. HSCT should be performed early in the disease course, before developmental deterioration begins. Enzyme replacement therapy (ERT) with laronidase is recommended for all Hurler patients and is a lifelong therapy which alleviates non neurological symptoms. The early use of ERT has been shown to delay or even prevent the development of some of the clinical features of this condition. Additional management of Hurler syndrome is largely supportive, and includes surgical interventions (e.g. adenotonsillectomy, hernia repair, ventriculoperitoneal shunt, cardiac valve replacement, carpal tunnel release, spinal decompression); physical, occupational, and speech therapies; respiratory support (e.g., continuous positive pressure ventilation with oxygen supplementation); hearing aids; and medications for pain and gastrointestinal disturbances.

Prognosis

Patients often succumb to the condition in the first decade from respiratory and cardiac complications but ERT and HSCT can improve life expectancy. The timing of diagnosis, and therefore of treatment initiation, is an important factor for the success of both HSCT and laronidase.