Clearance of heparan sulfate in the brain prevents neurodegeneration and neurocognitive impairment in MPS II mice.

Mucopolysaccharidosis II (MPS II), a lysosomal storage disease caused by mutations in iduronate-2-sulfatase (IDS), is characterized by a wide variety of somatic and neurologic symptoms. The currently approved intravenous enzyme replacement therapy with recombinant IDS (idursulfase) is ineffective for CNS manifestations due to its inability to cross the blood-brain barrier (BBB). Here, we demonstrate that the clearance of heparan sulfate (HS) deposited in the brain by a BBB-penetrable antibody-enzyme fusion protein prevents neurodegeneration and neurocognitive dysfunctions in MPS II mice. The fusion protein pabinafusp alfa was chronically administered intravenously to MPS II mice. The drug reduced HS and attenuated histopathological changes in the brain, as well as in peripheral tissues. The loss of spatial learning abilities was completely suppressed by pabinafusp alfa, but not by idursulfase, indicating an association between HS deposition in the brain, neurodegeneration, and CNS manifestations in these mice. Furthermore, HS concentrations in the brain and reduction thereof by pabinafusp alpha correlated with those in the cerebrospinal fluid (CSF). Thus, repeated intravenous administration of pabinafusp alfa to MPS II mice decreased HS deposition in the brain, leading to prevention of neurodegeneration and maintenance of neurocognitive function, which may be predicted from HS concentrations in CSF.

Intrafamilial variability in the clinical manifestations of mucopolysaccharidosis type II: Data from the Hunter Outcome Survey (HOS).

Several cases of phenotypic variability among family members with mucopolysaccharidosis type II (MPS II) have been reported, but the data are limited. Data from patients enrolled in the Hunter Outcome Survey (HOS) were used to investigate intrafamilial variability in male siblings with MPS II. As of July 2015, data were available for 78 patients aged ≥5 years at last visit who had at least one affected sibling (39 sibling pairs). These patients were followed prospectively (i.e., they were alive at enrollment in HOS). The median age at the onset of signs and symptoms was the same for the elder and younger brothers (2.0 years); however, the younger brothers were typically diagnosed at a younger age than the elder brothers (median age, 2.5 and 5.1 years, respectively). Of the 39 pairs, eight pairs were classified as being discordant (the status of four or more signs and symptoms differed between the siblings); 21 pairs had one, two, or three signs and symptoms that differed between the siblings, and 10 pairs had none. Regression status of the majority of the developmental milestones studied was generally concordant among siblings. Functional classification, a measure of central nervous system involvement, was the same in 24/28 pairs, although four pairs were considered discordant as functional classification differed between the siblings. Overall, this analysis revealed similarity in the clinical manifestations of MPS II among siblings. This information should help to improve our understanding of the clinical presentation of the disease, including phenotype prediction in affected family members.

Cognitive and behaviour profiles of children with mucopolysaccharidosis Type II.

Mucopolysaccharidosis Type II (MPS II) or Hunter Syndrome is a rare X-linked condition, due to a defect in a lysosomal enzyme involved in the breakdown of glycosaminoglycans. It is a progressive condition with worsening over time; however, symptom severity and progression rates vary. Normal intellectual function has been reported in males with mild MPS II but few studies are available that provide comprehensive cognitive profiles. Enzyme replacement therapy (ERT) can stabilize physical symptoms and has become standard treatment. Whether ERT can influence cognition is currently unknown. Considering this, we conducted cognitive, fine motor, and behavioural assessments with three males (7;6-12;1 years) with mild MPS II before and after ERT. Generally, cognition, fine motor skills, and behaviour were in the normal range; however, specific deficits in attention and executive function were identified. Following ERT, some memory improvements were seen. Executive deficits remained, and processing speed declined over time.

Prevention of Neurocognitive Deficiency in Mucopolysaccharidosis Type II Mice by Central Nervous System-Directed, AAV9-Mediated Iduronate Sulfatase Gene Transfer.

Mucopolysaccharidosis type II (MPS II; Hunter syndrome) is a rare X-linked recessive lysosomal disorder caused by defective iduronate-2-sulfatase (IDS), resulting in accumulation of heparan sulfate and dermatan sulfate glycosaminoglycans (GAGs). Enzyme replacement is the only Food and Drug Administration-approved therapy available for MPS II, but it is expensive and does not improve neurologic outcomes in MPS II patients. This study evaluated the effectiveness of adeno-associated virus (AAV) vector encoding human IDS delivered intracerebroventricularly in a murine model of MPS II. Supraphysiological levels of IDS were observed in the circulation (160-fold higher than wild type) for at least 28 weeks post injection and in most tested peripheral organs (up to 270-fold) at 10 months post injection. In contrast, only low levels of IDS were observed (7-40% of wild type) in all areas of the brain. Sustained IDS expression had a profound effect on normalization of GAG in all tested tissues and on prevention of hepatomegaly. Additionally, sustained IDS expression in the central nervous system (CNS) had a prominent effect in preventing neurocognitive deficit in MPS II mice treated at 2 months of age. This study demonstrates that CNS-directed, AAV9 mediated gene transfer is a potentially effective treatment for Hunter syndrome, as well as other monogenic disorders with neurologic involvement.

Genotype-phenotype relationship in mucopolysaccharidosis II: predictive power of IDS variants for the neuronopathic phenotype.

AIM: Mucopolysaccharidosis type II (MPS II) is caused by variants in the iduronate-2-sulphatase gene (IDS). Patients can be either neuronopathic with intellectual disability, or non-neuronopathic. Few studies have reported on the IDS genotype-phenotype relationship and on the molecular effects involved. We addressed this in a cohort study of Dutch patients with MPS II. METHOD: Intellectual performance was assessed for school performance, behaviour, and intelligence. Urinary glycosaminoglycans were quantified by mass spectrometry. IDS variants were analysed in expression studies for enzymatic activity and processing by immunoblotting. RESULTS: Six patients had a non-neuronopathic phenotype and 11 a neuronopathic phenotype, three of whom had epilepsy. Total deletion of IDS invariably resulted in the neuronopathic phenotype. Phenotypes of seven known IDS variants were consistent with the literature. Expression studies of nine variants were novel and showed impaired IDS enzymatic activity, aberrant intracellular processing, and elevated urinary excretion of heparan sulphate and dermatan sulphate irrespective of the MPS II phenotype. INTERPRETATION: We speculate that very low or cell-type-specific IDS residual activity is sufficient to prevent the neuronal phenotype of MPS II. Whereas the molecular effects of IDS variants do not distinguish between MPS II phenotypes, the IDS genotype is a strong predictor.

Cognitive, medical, and neuroimaging characteristics of attenuated mucopolysaccharidosis type II.

UNLABELLED: The phenotype of attenuated mucopolysaccharidosis type II (MPS II), also called Hunter syndrome, has not been previously studied in systematic manner. In contrast to the "severe" phenotype, the "attenuated" phenotype does not present with behavioral or cognitive impairment; however, the presence of mild behavior and cognitive impairment that might impact long-term functional outcomes is unknown. Previously, significant MRI abnormalities have been found in MPS II. Recent evidence suggests white matter abnormalities in many MPS disorders. METHODS: As the initial cross-sectional analysis of a longitudinal study, we studied the association of brain volumes and somatic disease burden with neuropsychological outcomes, including measures of intelligence, memory, and attention in 20 patients with attenuated MPS II with a mean age of 15.8. MRI volumes were compared to 55 normal controls. RESULTS: While IQ and memory were average, measures of attention were one standard deviation below the average range. Corpus callosum volumes were significantly different from age-matched controls, differing by 22%. Normal age-related volume increases in white matter were not seen in MPS II patients as they were in controls. Somatic disease burden and white matter and corpus callosum volumes were significantly associated with attention deficits. Neither age at evaluation nor age at starting treatment predicted attention outcomes. CONCLUSIONS: Despite average intelligence, attention is compromised in attenuated MPS II. Results confirm an important role of corpus callosum and cortical white matter abnormality in MPS II as well as the somatic disease burden in contributing to attention difficulties. Awareness by the patient and caregivers with appropriate management and symptomatic support will benefit the attenuated MPS II patient.

Health-Related Quality of Life in Patients with MPS II.

Mucopolysaccharidosis type II (MPS II), also known as Hunter syndrome, is a chronic and progressive X-linked lysosomal disease that mainly affects males. The National MPS Society (2013) reports that MPS II affects 1 in 100,000 to 1 in 150,000 males worldwide. Two distinct forms of the disease are based on age of onset and clinical course: attenuated and severe. MPS II affects many organ systems including the nervous, cardiovascular, gastrointestinal and respiratory systems. Clinical manifestations can include progressive hearing loss, mental impairment, and enlarged liver and spleen. This study focuses on the health-related quality of life of individuals (HRQOL) with MPS II as measured by the parent and self-report versions of the Pediatric Quality of Life Inventory (PedsQL™). Both parents of patients with MPS II as well as patients themselves reported lower scores on all domains of the PedsQL™ (physical, emotional, social and school functioning) indicating that children with MPS II have an overall lower HRQOL when compared to a healthy sample. When compared with patients with other chronic illnesses (cancer, MSUD, galactosemia,), the MPS II sample had significantly lower scores on a number of PedsQL™ scales, suggesting an overall lower HRQOL. No significant relationships were found using scores from parent or self report PedsQL™ measures and length of time on ERT.

The Hunter Syndrome-Functional Outcomes for Clinical Understanding Scale (HS-FOCUS) Questionnaire: item reduction and further validation.

PURPOSE: The Hunter Syndrome-Functional Outcomes for Clinical Understanding Scale (HS-FOCUS) Questionnaire is a patient and parent-completed disease-specific instrument used in Hunter syndrome (mucopolysaccharidosis II), a rare paediatric progressive multi-systemic lysosomal storage disease. The objective of this study was to shorten the number of items of the Questionnaire to reduce response burden while maintaining its content validity. METHODS: Data collected in a clinical trial were used. An iterative process helped identifying redundant or low performing items based on content validity and psychometric properties. Validation on the retained items was assessed using patients and parent's responses in terms of reliability, validity and responsiveness. RESULTS: The HS-FOCUS was completed by 49 patients and 84 parents. Items were mainly removed owing to high floor effects, high inter-item correlations (>0.80) or inadequate content. The shortened patient and parent versions (18 and 21 items) each contained five function domains. Internal consistency and test-retest reliability were >0.70 for most domains, except Breathing and School/work. Concurrent validity was demonstrated by significant correlations (>0.30) with similar concepts of previously validated measures. Significant differences were found in all domain scores across levels of disability. CONCLUSIONS: The shortened HS-FOCUS is a reliable, valid and responsive measure, where burden in answering the Questionnaire was reduced without compromising its validity.

Long-term experience with enzyme replacement therapy (ERT) in MPS II patients with a severe phenotype: an international case series.

INTRODUCTION: No published clinical trial data are available to inform the use of enzyme replacement therapy (ERT) in patients with the severe (neuropathic) phenotype of mucopolysaccharidosis II (MPS II). Current guidelines recommend ERT administered intravenously be used on a trial basis in this population. AIMS/METHODS: A retrospective chart review was conducted at five international centers for this case series of 22 patients with neuropathic MPS II who received intravenous idursulfase 0.5 mg/kg weekly for at least 2 consecutive years. We collected data about urinary glycosaminoglycan levels, adverse events, and the following somatic signs/symptoms: skeletal disease, joint range of motion, liver/spleen size, respiratory infections, cardiac disease, diarrhea, skin/hair texture, and hospitalizations. RESULTS: The age at diagnosis was 2 months to 5 years, and the age at idursulfase initiation was between 18 months and 21 years. One of 22 patients experienced improvements in seven somatic signs/symptoms; 17/22 experienced improvements in five to six somatic signs/symptoms; and 4/22 experienced improvements in four somatic signs/symptoms. None experienced fewer than four improvements. No new safety concerns arose. Infusion-related reactions were experienced by 4/22 patients but were successfully managed using accepted strategies. CONCLUSIONS: Long-term treatment with idursulfase was associated with improvements in somatic manifestations in this case series of patients with neuropathic MPS II. The family and medical team should maintain open lines of communication to make treatment decisions that take into consideration the benefits and limitations of ERT in this population.

MPS II: adaptive behavior of patients and impact on the family system.

Mucopolysaccharidosis type II (MPS II), also known as Hunter syndrome, is a chronic and progressive X-linked lysosomal disease that mainly affects males. It occurs in 1 in every 65,000 to 1 in 132,000 births. There are two distinct forms of the disease based on age of onset and clinical course: mild and severe. MPS II affects many organ systems including the nervous, cardiovascular, gastrointestinal and respiratory systems. Complications can include vision problems, progressive hearing loss, thickened and elastic skin, mental impairment, and enlarged liver and spleen. We herein focus on the adaptive behavior of individuals with MPS II, and the impact of MPS II on the family system. Outcomes from the Vineland-II Adaptive Behavior Scales showed that the MPS II patient sample experienced significantly lower functioning in communication, daily living skills, socialization, and motor skills compared to normative data. Patients with severe MPS II were found to have significantly lower adaptive functioning in all domains, as compared to those with mild MPS II. Length of time on ERT had no significant relationship to adaptive functioning. Results from the Peds QL Family Impact Module indicated that families of patients with MPS II experienced a lower overall health-related quality of life and overall lower family functioning (including lower emotional and cognitive functioning) than those with chronic illnesses residing in an inpatient setting.

The impact of Hunter syndrome (mucopolysaccharidosis type II) on health-related quality of life.

BACKGROUND: Hunter syndrome (mucopolysaccharidosis type II (MPS II)) is a rare metabolic disease that can severely compromise health, well-being and life expectancy. Little evidence has been published on the impact of MPS II on health-related quality of life (HRQL). The objective of this study was to describe this impact using the Hunter Syndrome-Functional Outcomes for Clinical Understanding Scale (HS-FOCUS) questionnaire and a range of standard validated questionnaires previously used in paediatric populations. METHODS: Clinical and demographic characteristics collected in a clinical trial and responses to four HRQL questionnaires completed both by patients and parents prior to enzyme replacement treatment were used. The association between questionnaire scores and clinical function parameters were tested using Spearman rank-order correlations. Results were compared to scores in other paediatric populations with chronic conditions obtained through a targeted literature search of published studies. RESULTS: Overall, 96 male patients with MPS II and their parents were enrolled in the trial. All parents completed the questionnaires and 53 patients above 12 years old also completed the self-reported versions. Parents' and patients' responses were analysed separately and results were very similar. Dysfunction according to the HS-FOCUS and the CHAQ was most pronounced in the physical function domains. Very low scores were reported in the Self Esteem and Family Cohesion domains in the CHQ and HUI3 disutility values indicated a moderate impact. Scores reported by patients and their parents were consistently lower than scores in the other paediatric populations identified (except the parent-reported Behaviour score); and considerably lower than normative values. CONCLUSIONS: This study describes the impact on HRQL in patients with MPS II and provides a broader context by comparing it with that of other chronic paediatric diseases. Physical function and the ability to perform day-to-day activities were the most affected areas and a considerable impact on the psychological aspects of patients' HRQL was also found, with a higher level of impairment across most dimensions (particularly Pain and Self Esteem) than that of other paediatric populations. Such humanistic data provide increasingly important support for establishing priorities for health care spending, and as a component of health economic analysis.

The Hunter syndrome-functional outcomes for clinical understanding scale (HS-FOCUS) questionnaire: evaluation of measurement properties.

PURPOSE: This study was to conduct the psychometric validation of the patient and parent versions of the Hunter syndrome-functional outcomes for clinical understanding scale (HS-FOCUS). METHODS: Data collected in a 53-week placebo-controlled multinational trial were used to evaluate item performance and reliability, validity, and ability to detect change of the six HS-FOCUS function domains. RESULTS: HS-FOCUS was completed by 49 patients above 12 years old and 84 parents. Floor effects and high average inter-item correlations suggested that some items were less informative or redundant. For both patients and parents, the internal consistency and test-retest reliability met the >0.70 criteria for all domains except for the breathing, sleeping, and schooling/work in patients. Construct validity showed moderate to high correlations with CHAQ, CHQ, and HUI3 in activity-related concepts. Significant differences in domain scores were found in most domains among severity in disability measured by CHAQ DIS. Significant differences in HS-FOCUS change scores were found in patients whose CHAQ DIS score also changed. CONCLUSIONS: Psychometric validation of the HS-FOCUS demonstrates it is a reliable, valid, and responsive instrument that can be applied in clinical trials or disease registries. Findings on the individual item performance suggest some items could be removed without compromising its validity.

[Life experiences of mothers in parenting children with Hunter's syndrome].

PURPOSE: The purpose of this study was to explore the experiences of Korean mothers in parenting children with Hunter's syndrome, an X linked recessive genetically inherited disease usually affecting boys. METHODS: Data were collected from 14 mothers having children with Hunter's syndrome, through two focus group interviews and individual in-depth interviews. Qualitative data from the field notes and transcribed notes were analyzed using the grounded theory methodology developed by Strauss & Corbin (1998). RESULTS: The core category about the process of rearing children with Hunter's syndrome was identified as "navigating in the maze". The process of rearing children with Hunter's syndrome passed through three phases; 'entering an unknown region', 'struggling to escape from the unknown region', 'settling down in the unknown region'. CONCLUSION: In this study "navigating in the maze", as the core category deeply showed joys and sorrows of mothers in the process of rearing their children with Hunter's syndrome. In this rearing process they gradually adjusted themselves to their given condition. Also they gained initiatively coping strategies to care for, and protect their children. Therefore health care providers can establish supportive programs in the clinical field to empower these mothers by reflecting their proactive coping strategies.

Avaliação do desempenho motor em crianças com mucopolissacaridose II / Motor development evaluation in children with mucopolysacharidosis II

A mucopolissacaridose (MPS) é uma doença multissistêmica decorrente da incapacidade do organismo em realizar um processo metabólico específico da degradação lisossômica dos glicosaminoglicanos (GAGs). O acúmulo progressivo de GAG em vários órgãos e tecidos resulta em desordens funcional e estrutural no indivíduo acometido pelas MPS. A MPS do tipo II trata-se de uma doença metabólica hereditária, ligada ao cromossomo X, cujo principal comprometimento é o atraso no desenvolvimento neuropsicomotor. O objetivo do estudo foi avaliar o desenvolvimento motor de crianças com MPS II. Foi realizado um estudo de caso com duascrianças, atendidas na APAE de Maceió (AL). Para a coleta de dados utilizou-se a Escala de Desenvolvimento Motor, e a análise de dados foi realizada por meio da comparação entre a idade cronológica de cada criança. Os resultados apontaram que as crianças apresentam perfil motor classificado em ?Muito Inferior?, corroborando com os achados na literatura e destacando a necessidade de intervenção precoce através da redução de danos e manutenção das habilidades remanescentes. O presente estudo também observou a característica progressiva dessa doença genética ainda pouco estudada. Dessa forma, destaca-se a importância de estudos sobre o desempenho motor, visando conhecer ao desenvolvimento de crianças com MPS II em diferentes etapas evolutivas, para fundamentar a prática clínica auxiliando na redução dos déficits funcionais, contribuindo, consequentemente, no desenvolvimento cognitivo, afetivo e social.(AU)

Mucopolysaccharidosis (MPS) is a multisystem disease caused by the body?s inability to perform a metabolic process specific to lysosomal degradation of glycosaminoglycans (GAGs). The progressive accumulationof GAG in various organs and tissues results in functional and structural disorders in individuals affected by MPS. MPS type II is an inherited metabolic disease, linked to the X chromosome, whose main impairment isthe delay in neuropsychomotor development. The purpose of this study was to evaluate the motor development of children affected by MPS II. A case study was carried out with two children, attending the ?APAE Maceio? institution. The Scale of Motor Development was used for data collection and data analysis was performed by comparing the chronological age of each child. Results showed that the children present motor profile classified as ?Very Low?, confirming the findings in the literature, highlighting the need for early intervention through harmreduction and maintenance of the remaining skills. This study also observed that the progressive characteristic of this genetic disease is still poorly studied. Therefore, the importance of studies on motor performance should be highlighted in order to determine the development of children affected by MPS II at different evolutionary stages to support the clinical practice in helping to reduce functional deficits, thus contributing to the cognitive, affective and social developments.(AU)

Avaliação do desempenho motor em crianças com mucopolissacaridose II / Motor development evaluation in children with mucopolysacharidosis II

A mucopolissacaridose (MPS) é uma doença multissistêmica decorrente da incapacidade do organismo em realizar um processo metabólico específico da degradação lisossômica dos glicosaminoglicanos (GAGs). O acúmulo progressivo de GAG em vários órgãos e tecidos resulta em desordens funcional e estrutural no indivíduo acometido pelas MPS. A MPS do tipo II trata-se de uma doença metabólica hereditária, ligada ao cromossomo X, cujo principal comprometimento é o atraso no desenvolvimento neuropsicomotor. O objetivo do estudo foi avaliar o desenvolvimento motor de crianças com MPS II. Foi realizado um estudo de caso com duas crianças, atendidas na APAE de Maceió (AL). Para a coleta de dados utilizou-se a Escala de Desenvolvimento Motor, e a análise de dados foi realizada por meio da comparação entre a idade cronológica de cada criança. Os resultados apontaram que as crianças apresentam perfil motor classificado em ?Muito Inferior?, corroborando com os achados na literatura e destacando a necessidade de intervenção precoce através da redução de danos e manutenção das habilidades remanescentes. O presente estudo também observou a característica progressiva dessa doença genética ainda pouco estudada. Dessa forma, destaca-se a importância de estudos sobre o desempenho motor, visando conhecer ao desenvolvimento de crianças com MPS II em diferentes etapas evolutivas, para fundamentar a prática clínica auxiliando na redução dos déficits funcionais, contribuindo, consequentemente, no desenvolvimento cognitivo, afetivo e social.

Mucopolysaccharidosis (MPS) is a multisystem disease caused by the body?s inability to perform a metabolic process specific to lysosomal degradation of glycosaminoglycans (GAGs). The progressive accumulationof GAG in various organs and tissues results in functional and structural disorders in individuals affected by MPS. MPS type II is an inherited metabolic disease, linked to the X chromosome, whose main impairment isthe delay in neuropsychomotor development. The purpose of this study was to evaluate the motor development of children affected by MPS II. A case study was carried out with two children, attending the ?APAE Maceio? institution. The Scale of Motor Development was used for data collection and data analysis was performed by comparing the chronological age of each child. Results showed that the children present motor profile classified as ?Very Low?, confirming the findings in the literature, highlighting the need for early intervention through harmreduction and maintenance of the remaining skills. This study also observed that the progressive characteristic of this genetic disease is still poorly studied. Therefore, the importance of studies on motor performance should be highlighted in order to determine the development of children affected by MPS II at different evolutionary stages to support the clinical practice in helping to reduce functional deficits, thus contributing to the cognitive, affective and social developments.

Hunter disease before and during enzyme replacement therapy.

Mucopolysaccharidosis type II (Hunter disease) is a lysosomal storage disease attributable to X-linked deficiency of the enzyme α-L-iduronate-sulfatase. Because of this deficiency, glycosaminoglycanes accumulate in various tissues and body fluids. We describe three patients representing the broad spectrum of Hunter disease and their response to enzyme replacement therapy. Patient 1 did not manifest central nervous system involvement, patient 2 manifested moderate neurologic disease, and patient 3 had already manifested a severe neurologic course during early infancy. In all patients, improvements in visceral organ size, physical capacity, and gastrointestinal functioning were reported. Moreover, all three patients demonstrated a gain in height, improved functioning of the upper limb, and a reduced need for antibiotics to treat upper airway infections. The response to enzyme replacement therapy occurred independent of type of genetic mutation (missense or frame shift), and we observed only mild infusion-related reactions. We conclude that all patients with mucopolysaccharidosis type II (those with and without clinical central nervous system involvement) may benefit from enzyme replacement therapy.

Hunter syndrome (Muccopolysaccharridosis Type II) in Macedonia and Bulgaria.

BACKGROUND: Mucopolysaccharidosis II (MPS II) is caused by a deficiency of iduronate-2-sulfatase (IDS; EC 3.1.6.13). METHODS AND RESULTS: We describe 11 boys from Bulgaria and Macedonia detected in the period from 1998 to 2008. The mean age at diagnosis was 4.77+/-1.29 years. All children were severely retarded: IQ ranged from 34-80, and they all had coarse faces and hepatomegaly. In addition, splenomegaly was found in 81.81% patients, dysostosis in 45.45%, kyphosis in 27.27%, deafness in 18.08%, growth below the third percentile in 45.45%, growth below the parental target height in all patients, stiff joints in 56.56% and hypertrophic myocardiopathy in 18.18% children. Two patients died at the age of 11 and 35 years. Plasma iduronate-2-sulfatase was low in all probands and normal in parents and relatives. Two new mutations were discovered: p.K236N (c.708G>C) in a child with a moderately severe phenotype, and p.Q80K (c.238C>A) which resulted in a severe phenotype and early death at the age of 11 years. Heterozygote carriers of the pathogenic allele were 29 female relatives. The calculated incidence rate for MPS II in Macedonia (censuses 1994 and 2002, children under 14 years: 483,923 and 426,280) and Bulgaria (censuses 1992 and 2006, children under 14 years: 1 126, 598 and 1,077,020) are 0.36 and 0.46 respectively, while the calculated prevalence rate are 3.6 and 4.6 per 1,000,000 boys (aged 0-14 years). Correlating phenotype and genotype remains a complex endeavour. CONCLUSIONS: We report calculated incidence and prevalence rates in two South Eastern European countries, and 2 novel genetic alterations correlated with their phenotypes.

Psychological status of patients with mucopolysaccharidosis type II and their parents.

BACKGROUND: The aim of the present study was to delineate the psychological status of 10 patients with the attenuated phenotype of mucopolysaccharidosis type II (MPS-II) and their parents (six fathers and five mothers) for the improvement of clinical management. METHODS: Intellectual ability was evaluated using the Wechsler Intelligence Scale. Activities of daily living (ADL) was assessed using the Functional Independence Measure. The personality and psychiatric aspects were analyzed using the Yatabe-Guilford Personality test (Y-G test) and the Tree-Drawing Test. Mental health was assessed using the General Health Questionnaire 60 (GHQ-60) and State-Trait Anxiety Inventory (STAI). RESULTS: Intellectual background, measured with full-scale, verbal and performance IQ, were 72.8, 76.1 and 79.3, respectively. Nine of 10 patients were not judged as having neurosis and a psychotic tendency with the Y-G test. In the tree-drawing test, many patients drew a tree without ground, suggesting that they have difficulties in making relationships with surrounding people and the community. The child patient with a psychosis pattern on the Y-G test, drew a bizarre tree, suggesting psychological problems. GHQ-60 and STAI survey indicated that the patients and their parents had higher levels of anxiety. A significant negative correlation between GHQ-60 score and ADL (R = -0.77) was identified, suggesting that the psychological status may worsen as ADL decreases. CONCLUSIONS: Patients with MPS-II and their parents had higher risks for mental problems. Understanding psychological status is essential when providing genetic counseling or therapeutic intervention.

The management of children with Hunter syndrome - a case study.

Hunter syndrome (mucopolysaccharidosis type II) is a rare lysosomal storage disease caused by a deficiency of the lysosomal enzyme iduronate-2-sulphatase and the subsequent progressive cellular accumulation of glycosaminoglycans. Children with this debilitating disease can now be offered enzyme replacement therapy (ERT) with idursulfase to manage the signs and symptoms of the disease and to improve quality of life. As therapy involves a weekly infusion of enzyme, travel to the few designated specialist centres that provide treatment can be highly disruptive for both patients and carers. Providing ERT outside the hospital setting therefore offers a convenient alternative that can be delivered effectively with specialist nursing support. The authors report their experience of providing ERT to a patient with Hunter syndrome in a school. Through careful planning and the development of close working relationships between nurses, schools, local hospitals and patients' families, the authors found that managing patients outside the hospital setting can greatly benefit their quality of life.

Bone marrow transplantation in children with Hunter syndrome: outcome after 7 to 17 years.

OBJECTIVE: To evaluate the effect of bone marrow transplantation in children with Hunter syndrome. STUDY DESIGN: Eight boys received a bone marrow graft between the ages of 3 and 16 years from 1990 to 2000. In 6 cases, the donor was a sibling with identical HLA status, in 1 case an unrelated donor with HLA-compatible, and in 1 case a mismatched unrelated donor. A complete multidisciplinary evaluation was performed yearly. RESULTS: Successful engraftment was achieved in all patients, with the proportion of donor cells reaching > or =95% 1 month after transplantation in all patients. Patients have been followed from between 7 and 17 years and all are still alive, except for 1 boy who died at the age of 10 from unrelated causes. Cardiovascular abnormalities stabilized in all patients, hepatosplenomegaly resolved, and joint stiffness improved, Perceptual hearing defects remained stable, and transmission hearing defects improved. Only 1 child required subsequent surgery to correct kyphosis. Neuropsychological outcome was variable and appeared to be related to the severity of the syndrome. CONCLUSIONS: Bone marrow transplantation is effective on the no neuropsychological symptoms of Hunter disease.