Síndrome de Hunter (mucopolisacaridosis tipo II). Claves para su reconocimiento y diagnóstico / Hunter syndrome (type II mucopolysaccharidosis). Keys for its recognition and diagnosis

Las mucopolisacaridosis (MPS) son un grupo de trastornos metabólicos hereditarios incluidos en las enfermedades lisosomales o de depósito. Son de causa genética, debidas al defecto en algunas enzimas intralisosomales necesarias para el procesamiento de los glicosaminoglicanos (GAG). El defecto en la degradación de estas macromoléculas provoca su acúmulo en las células de diferentes órganos, causando lesiones irreversibles y progresivas si no se tratan. La mucopolisacaridosis II (MPS II) o síndrome de Hunter (EH) está producida por las ausencia o disminución de la enzima iduronato-2-sulfasa (I2S), con el consiguiente bloqueo en la degradación de los glucosaminoglucanos dermatán-sulfato y heparánsulfato en los lisosomas citoplasmáticos, que se acumulan en los distintos tejidos provocando una afectación multisistémica progresiva e incapacitante. Es importante que tanto los pediatras, como otros especialistas que tratan niños, sepan reconocer aquellos síntomas o signos de alarma, para derivar a estos pacientes a unidades especializadas y realizar un diagnóstico precoz y certero que intente frenar su deterioro físico y neurológico. En los últimos años, los tratamientos específicos de la enfermedad, tanto la terapia de reemplazo enzimático como el trasplante de células madre, han ayudado a abordar la deficiencia enzimática subyacente en pacientes con MPS II. Sin embargo, la naturaleza multisistémica de este trastorno y la irreversibilidad de algunas manifestaciones hacen que la mayoría de los pacientes requieran un apoyo constante de muchos especialistas.(AU)

Mucopolysaccharidosis (MPS) is a group of metabolic hereditary disorders included in the lysosomal diseases. They are genetic diseases caused by the defects in intralysosomal enzymes necessary for the processing of Glycosaminoglycans. (GAG). The defect in the degradation of these macromolecules causes accumulation in the cells of different organs with irreversible and progressive lesions when we don´t treat them. The mucopolysaccharidosis II (MPS II) or Hunter’s Syndrome (EH) is caused by the absence or decrease of the enzyme iduronute-2-sulfatase (I2S), with the consequent blockage in the degradation of glycosaminoglycans, dermatan-sulfate and heparan sulfate, in cytoplasmic lysosomes, which accumulate in different tissues causing disabling progressive and multisystemic affectation. Pediatricians and other specialists, who treat children, must know to recognize those symptoms or signs of alarm and they must refer these patients to specialized units, and make early and accurate diagnoses to stop their physical and neurological deterioration. In the last years, specific treatments for the disease, enzyme replacement therapy, and stem cell transplantation have helped address the underlying enzyme deficiency in patients with MPS II. However, the multisystemic nature of this disorder and the irreversibility of some manifestations mean that most patients require constant support from many specialties.(AU)

Differences in MPS I and MPS II Disease Manifestations.

Mucopolysaccharidosis (MPS) type I and II are two closely related lysosomal storage diseases associated with disrupted glycosaminoglycan catabolism. In MPS II, the first step of degradation of heparan sulfate (HS) and dermatan sulfate (DS) is blocked by a deficiency in the lysosomal enzyme iduronate 2-sulfatase (IDS), while, in MPS I, blockage of the second step is caused by a deficiency in iduronidase (IDUA). The subsequent accumulation of HS and DS causes lysosomal hypertrophy and an increase in the number of lysosomes in cells, and impacts cellular functions, like cell adhesion, endocytosis, intracellular trafficking of different molecules, intracellular ionic balance, and inflammation. Characteristic phenotypical manifestations of both MPS I and II include skeletal disease, reflected in short stature, inguinal and umbilical hernias, hydrocephalus, hearing loss, coarse facial features, protruded abdomen with hepatosplenomegaly, and neurological involvement with varying functional concerns. However, a few manifestations are disease-specific, including corneal clouding in MPS I, epidermal manifestations in MPS II, and differences in the severity and nature of behavioral concerns. These phenotypic differences appear to be related to different ratios between DS and HS, and their sulfation levels. MPS I is characterized by higher DS/HS levels and lower sulfation levels, while HS levels dominate over DS levels in MPS II and sulfation levels are higher. The high presence of DS in the cornea and its involvement in the arrangement of collagen fibrils potentially causes corneal clouding to be prevalent in MPS I, but not in MPS II. The differences in neurological involvement may be due to the increased HS levels in MPS II, because of the involvement of HS in neuronal development. Current treatment options for patients with MPS II are often restricted to enzyme replacement therapy (ERT). While ERT has beneficial effects on respiratory and cardiopulmonary function and extends the lifespan of the patients, it does not significantly affect CNS manifestations, probably because the enzyme cannot pass the blood-brain barrier at sufficient levels. Many experimental therapies, therefore, aim at delivery of IDS to the CNS in an attempt to prevent neurocognitive decline in the patients.

Insights into Hunter syndrome from the structure of iduronate-2-sulfatase.

Hunter syndrome is a rare but devastating childhood disease caused by mutations in the IDS gene encoding iduronate-2-sulfatase, a crucial enzyme in the lysosomal degradation pathway of dermatan sulfate and heparan sulfate. These complex glycosaminoglycans have important roles in cell adhesion, growth, proliferation and repair, and their degradation and recycling in the lysosome is essential for cellular maintenance. A variety of disease-causing mutations have been identified throughout the IDS gene. However, understanding the molecular basis of the disease has been impaired by the lack of structural data. Here, we present the crystal structure of human IDS with a covalently bound sulfate ion in the active site. This structure provides essential insight into multiple mechanisms by which pathogenic mutations interfere with enzyme function, and a compelling explanation for severe Hunter syndrome phenotypes. Understanding the structural consequences of disease-associated mutations will facilitate the identification of patients that may benefit from specific tailored therapies.

Genotype-phenotype correlation in 44 Czech, Slovak, Croatian and Serbian patients with mucopolysaccharidosis type II.

Mucopolysaccharidosis type II (Hunter syndrome, MPS II, OMIM 309900) is an X-linked lysosomal storage disorder caused by deficiency of iduronate-2-sulfatase (IDS). We analyzed clinical and laboratory data from 44 Slavic patients with this disease. In total, 21 Czech, 7 Slovak, 9 Croatian and 7 Serbian patients (43 M/1 F) were included in the study (median age 11.0 years, range 1.2-43 years). Birth prevalence ranged from 1:69,223 (Serbia) to 1:192,626 (Czech Rep.). In the majority of patients (71%), the disease manifested in infancy. Cognitive functions were normal in 10 patients. Four, six and 24 patients had mild, moderate, and severe developmental delay, respectively, typically subsequent to developmental regression (59%). Residual enzyme activity showed no predictive value, and estimation of glycosaminoglycans (GAGs) had only limited importance for prognosis. Mutation analysis performed in 36 families led to the identification of 12 novel mutations, eight of which were small deletions/insertions. Large deletions/rearrangements and all but one small deletion/insertion led to a severe phenotype. This genotype-phenotype correlation was also identified in six cases with recurrent missense mutations. Based on patient genotype, the severity of the disease may be predicted with high probability in approximately half of MPS II patients.

Neurological findings in Hunter disease: pathology and possible therapeutic effects reviewed.

Hunter disease (mucopolysaccharidosis type II, MPS II) is an X-linked lysosomal storage disease caused by deficiency of iduronate-2-sulfatase. Accumulation of chondroitin sulfate B and heparan sulfate in various tissues is the biochemical consequence of MPS II. Children with Hunter disease are normal at birth, and symptoms occur between 2 and 10 years of age. Typical symptoms include coarse facies with enlarged tongue and prominent forehead as well as a short, stocky built stature with short neck. The cardiovascular, respiratory and gastrointestinal systems may be affected, and oral, dermatological and psychiatric as well as neurological complications are described. Life expectancy is markedly reduced and may be limited to 12 years for severely affected patients. The most common causes of death are airway obstruction and cardiac failure. The most severe symptoms may result from neurological symptoms or complications including hydrocephalus, spinal cord compression, cervical myelopathy, optic nerve compression, and hearing impairment. Patients may also develop carpal tunnel syndrome, sleep apnoea, seizures or mental retardation. This review describes characteristic neurological manifestations in MPS II and its underlying pathophysiology. In addition, an appraisal is given whether or not enzyme replacement therapy may be able to improve in particular the neurological symptoms of Hunter disease.

Molecular investigations of a novel iduronate-2-sulfatase mutant in a Chinese patient.

BACKGROUND: Molecular investigations of iduronate-2-sulfatase (IDS) mutants for the X-linked lysosomal storage disease mucopolysaccharidosis type II (MPS II, Hunter disease), commonly depends on transient expression studies to verify a single nucleotide change to be pathogenic. In 2 severely affected patients, IDS missense mutations, c.1016T>C (novel) and c.1016T>G (known) were identified predicting the substitution of an ambivalent cyclic proline and a hydrophilic arginine respectively for the hydrophobic leucine at residue 339. We hypothesized that residue Leu339 may be functionally critical. METHODS: We performed a study for the 2 mutations by in-situ mutagenesis, in vitro expression, and functional analysis. RESULTS: Transient expression revealed that both the missense variants had stable mRNA but their residual enzyme activities remained <2.5% of normal level. The effect of the missense mutations on protein expression was detected by Western blot analysis. Both the missense mutations synthesized the precursor form but had reduced mature form of IDS. CONCLUSION: The novel mutation p.L339P is a disease-causing mutation affecting maturation of the protein.

Pituitary function studies in a case of mild Hunter's syndrome (MPS IIB).

Pituitary function studies were performed in a patient with mild Hunter's syndrome (mucopolysaccharidosis type IIB, MPS IIB) in order to exclude growth hormone deficiency as a possible contributing cause of his short stature. The results indicated that anterior pituitary function and, in particular, growth hormone secretion was normal. The most likely explanation for the short stature is an osseous growth plate disturbance with infiltration of the epiphyses by mucopolysaccharides.