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Feb
14

A rare disease a day: Hurler Syndrome

Following on from past installments of “A rare disease a day” Hunter syndrome, Gaucher disease, Tay-Sachs, Morquio syndrome, Fabry disease, Sanfilippo syndrome, Krabbe Disease, Niemann-Pick Disease and Batten disease  it is now the turn of Hurler Syndrome.

Hurler syndrome (also known as MPS I, Hurler’s disease), results in the buildup of glycosaminoglycans due to a deficiency of alpha-L iduronidase (IDUA). Without this enzyme, heparan sulfate and dermatan sulfate accumulates. MPS I is divided into three subtypes. MPS I H or Hurler syndrome is the most severe of the MPS I subtypes. The other two types are MPS I S or Scheie syndrome and MPS I H-S or Hurler-Scheie syndrome. Hurler syndrome is autosomal recessive with an incidence of 1 per 100,000.

MPS I results in hepatosplenomegaly, dwarfism, unique facial features, progressive mental retardation, with death frequently by the age of 10 years. There may also be effects on language, hearing loss, an enlarged tongue,  the cornea become clouded, retinas  degenerate, carpal tunnel syndrome and restricted joint movement are common. Children may be large at birth, appearing normal but possibly with inguinal or umbilical hernias. Growth often ends around age 3, resulting in a short body trunk (maximum stature of less than 4 feet). MPSI also results in distinct facial features ( flat face, depressed nasal bridge, and bulging forehead). Ribs widen and are oar-shaped, while the liver, spleen and heart are often enlarged.  Children with Hurler syndrome often die before age 10.

There is no cure for MPS I. Treatment for MPS I consists of bone marrow transplantation (BMT) and umbilical cord blood transplantation (UCBT) which can lead to improvements in abnormal physical characteristics, (except for those affecting the skeleton and eyes), and halting of neurologic degeneration. But these are high risk procedures. In contrast enzyme replacement therapy (ERT) includes laronidase (Aldurazyme) from BioMarin Pharmaceutical which is commercialized by Genzyme. ERT reduces non-neurological symptoms and pain. A recent study in mice has suggested that if higher doses of the enzyme are used more will cross the BBB and possibly correct the neurological symptoms. Earlier use of ERT may also provide better outcomes  in the aorta and heart valves .

In 2001 it was shown that suppression of premature stop mutations by the aminoglycoside gentamycin may provide an effective treatment for Hurler syndrome patients with premature stop mutations in the IDUA gene. In 2013 it was shown that co-administration of the Nonsense-Mediated mRNA Decay (NMD) inhibitor 1, (NMDI-1) with the PTC suppression drug gentamicin enhanced alpha-L-iduronidase activity compared to gentamicin alone, leading to a greater reduction of GAG storage in mouse tissues, including the brain. Chloramphenicol is a peptidyl transferase inhibitor able to induce readthrough and has been proposed to enhance IDUA activity in fibroblasts from MPS I patients.

In addition, brain-targeted gene therapy with recombinant adeno-associated virus (rAAV5)-IDUA vectors in an MPS-I transgenic mouse model provides biochemical correction. Gene therapy with a long-terminal-repeat (LTR)-intact retroviral vector or a self-inactivating (SIN) vector has been tested on behavioral function in MPS I mice. The LTR vector achieved higher serum IDUA levels and better correction. Neonatal intracerebroventricular (ICV) infusion of AAV 8 vector transducing the human α-L-iduronidase gene in MPS I mice, prevented accumulation of GAG and GM3 ganglioside storage materials.  Gene therapyin immunosuppressed dogs, showed vector was efficiently delivered throughout the brain, induced α-N-acetyl-glucosaminidase production, cleared stored compounds and storage lesions.

Newborn screening could enable earlier treatment and intervention that could improve outcomes for MPS I patients.

 

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