Multidisciplinary management of Hunter syndrome.

Hunter syndrome is a rare, X-linked disorder caused by a deficiency of the lysosomal enzyme iduronate-2-sulfatase. In the absence of sufficient enzyme activity, glycosaminoglycans accumulate in the lysosomes of many tissues and organs and contribute to the multisystem, progressive pathologies seen in Hunter syndrome. The nervous, cardiovascular, respiratory, and musculoskeletal systems can be involved in individuals with Hunter syndrome. Although the management of some clinical problems associated with the disease may seem routine, the management is typically complex and requires the physician to be aware of the special issues surrounding the patient with Hunter syndrome, and a multidisciplinary approach should be taken. Subspecialties such as otorhinolaryngology, neurosurgery, orthopedics, cardiology, anesthesiology, pulmonology, and neurodevelopment will all have a role in management, as will specialty areas such as physiotherapy, audiology, and others. The important management topics are discussed in this review, and the use of enzyme-replacement therapy with recombinant human iduronate-2-sulfatase as a specific treatment for Hunter syndrome is presented.

Sweat rate and sweat electrolyte composition in international female soccer players during game specific training.

The purpose of this study was to determine the sweat rate and sweat electrolyte composition in female international level soccer players. Thirteen soccer players performed two 90 min soccer-specific training sessions (T1 and T2) on separate days. Hydration status was determined prior to each session and sweat loss, sweat rate and sweat composition (Na (+), K (+), Mg (++) and Ca (+)) were determined from patches worn during training. The mean sweat rate during T1 and T2 was 0.50+/-0.20 and 0.43+/-0.18 L.h (-1) respectively (P>0.05). The mean sweat electrolyte composition during T1 and T2 was: [Na (+)]: 43.9+/-15.0 and 46.2+/-7.9 mmol.L (-1); [K (+)]: 6.1+/-1.1 and 5.2+/-1.1 mmol.L (-1); [Mg (++)]: 0.1+/-0.0 and 0.1+/-0.0 mmol.L (-1); [Ca (+)]: 1.2+/-0.5 and 0.7+/-0.1 mmol.L (-1), respectively. When data from T1 and T2 were combined, there were no relationships between sweat rate and sweat concentration of any electrolyte. In conclusion, the sweat rate and sweat electrolyte losses in this cohort of international female soccer players, during soccer-specific training in cool conditions, were small. Electrolyte losses of this magnitude are unlikely to require special consideration in terms of optimising player hydration.

Regional anesthetic techniques are an alternative to general anesthesia for infants with Pompe's disease.

Pompe's disease or glycogen storage disease type II is a genetic disorder affecting skeletal and cardiac muscle. The infantile form is associated with gross hypertrophic cardiomegaly and death in the early years. General anesthesia is associated with potential major morbidity in these patients. We present our experience of regional anesthetic blocks used in five patients with the infantile form of glycogen storage disease type II with and without sedation for 11 surgical procedures during a clinical trial of replacement therapy for this condition. Both femoral nerve blockade and caudal epidural blockade were used with good result. The relative merits of the type of block are discussed in addition to the choice of sedation and risks of general anesthesia. The avoidance of general anesthesia in the newly presenting patient with Pompe's disease may reduce potential morbidity until enzyme replacement has been established.

Kinematic analysis of motor dysfunction in Niemann-Pick type C.

OBJECTIVE: To provide the first descriptive analysis of upper limb motor physiology in Niemann-Pick Type C disease (NP-C). METHODS: Fifteen patients with confirmed NP-C underwent motor physiology testing using accelerometry and surface EMG (sEMG). Tremor amplitude and frequency were quantified using accelerometry, and sEMG was examined for abnormal patterns consistent with various movement disorders. RESULTS: Forty-seven percent of patients had postural tremor in the upper limbs, generally bilateral, with frequencies ranging from 0.3 to 3 Hz, and an average amplitude of 1.20+/-0.98 mm. Eighty-seven percent of patients had bilateral action tremor with frequencies ranging from 2.0 to 3.7 Hz, and an average amplitude of 5.25+/-3.76 mm. sEMG revealed long but variable duration, variable amplitude muscle burst discharges during action in some patients, as well as short high frequency irregularly timed bursts in others. CONCLUSIONS: Accelerometric findings correlated with the clinical findings were most consistent with cerebellar outflow tremors. sEMG revealed a mix of dystonic, myoclonic and choreiform movements. SIGNIFICANCE: These quantitative methods may serve as ancillary measures of disease pathophysiology, markers of change over time, and methods to evaluate efficacy, and side effects, of new treatments as they are developed.

Biochemical monitoring after haemopoietic stem cell transplant for Hurler syndrome (MPSIH): implications for functional outcome after transplant in metabolic disease.

Hurler Syndrome is corrected by allogeneic BMT by the action of donor enzyme on recipient tissue. In this paper, we describe monitoring of 39 patients transplanted in two centres to determine donor chimerism, enzyme level and residual substrate - expressed as dermatan sulphate to chondroitin sulphate ratio. We show that in fully engrafted recipients, the enzyme level, expressed as mumol/g total protein/h, post-transplant is 24.2 from an unrelated donor and 10.2 from a heterozygote family donor (P<0.0001). There is a tight relationship between mean post-transplant enzyme level and residual substrate - Spearman's rank correlation coefficient (Rho) was -0.76 and -0.80 at 12 and 24 months, respectively (P<0.0001). We propose that these differences affect patient outcome. As unrelated donor transplant outcomes improve and especially given the higher levels of donor cell engraftment following cord transplants, our data might influence donor selection where only heterozygote-matched family members are available.

Attenuated type I mucopolysaccharidosis in the differential diagnosis of juvenile idiopathic arthritis: a series of 13 patients with Scheie syndrome.

OBJECTIVE: Mucopolysaccharidosis type I (MPS I) is a genetic lysosomal storage disorder caused by deficient activity of the enzyme alpha-L-iduronidase. Incomplete breakdown of glycosaminoglycans leads to progressive accumulation of these substances in many tissues throughout the body. Patients with the less severe form of MPS I (Scheie syndrome) usually present in the first decade of life with frequent articular involvement, and may survive into adulthood. Especially in these attenuated phenotypes, a definitive diagnosis may be delayed for years because clusters of early symptoms are difficult to recognize for physicians not familiar with the disease, and since the disease progresses slowly over decades. We would like to increase the awareness of this type of MPS I disease among rheumatologists and unravel diagnostic pitfalls. METHODS: We have reviewed medical histories of 13 patients (6 males and 7 females) with Scheie syndrome seen in 5 European centers. RESULTS: All patients had prominent musculoskeletal involvement at the onset of their disease in childhood. Diagnosis was delayed in almost all cases (range 4-54 years). CONCLUSION: We suggest that patients who present with progressive non-inflammatory joint involvement in the first decade of life, particularly with stiffness of the fingers and difficulty using the hands, should be screened for metabolic diseases, including MPS I. MPS I should be considered if patients with arthropathy lack the typical characteristics of inflammatory arthropathy.

The ocular features of the mucopolysaccharidoses.

AIMS: The mucopolysaccharidoses (MPS) are a heterogeneous group of rare disorders characterised by accumulation of glycosaminoglycans within multiple organ systems. This study aimed to determine the prevalence and severity of ocular complications in patients with MPS. METHODS: Clinical ophthalmic features and electrodiagnostic results of 50 patients with a diagnosis of MPS were retrospectively reviewed. RESULTS: A total of 79% of MPS IH patients had a visual acuity of less than 6/12 equivalent in their better eye, compared to 44% of MPS IH/S and 25% of MPS VI patients. In total, 16% of MPS IH and 25% of MPS IH/S had severe corneal opacification, compared to 38% of MPS VI patients. 16% of MPS IH patients had optic atrophy; 21% of MPS VI patients had mild disc swelling, 29% had markedly swollen discs, and 14% had optic atrophy. One patient with MPS IH, one with MPS IH/S and six with MPS VI had ocular hypertension. One MPS VI patient had glaucoma that required topical therapy. Nine patients with MPS IH had electrodiagnostic evidence of retinopathy, as did one MPS VI patient. CONCLUSIONS: Ocular complications causing significant reduction in vision are common in MPS. The majority of MPS I and MPS VI patients have corneal opacification, which can lead to difficulties in diagnosis and monitoring of glaucoma, optic disc changes, and retinopathy.

Heparan sulfate levels in mucopolysaccharidoses and mucolipidoses.

Glycosaminoglycans are accumulated in both mucopolysaccharidoses (MPS) and mucolipidoses (ML). MPS I, II, III and VII and ML II and ML III patients cannot properly degrade heparan sulphate (HS). In spite of the importance of HS storage in the metabolic pathway in these diseases, blood and urine HS levels have not been determined systematically using a simple and economical method. Using a new ELISA method using anti-HS antibodies, HS concentrations in blood and urine were determined in MPS and ML II and ML III patients. HS concentrations were determined in 156 plasma samples from MPS I (n = 23), MPS II (n = 26), MPS III (n = 24), MPS IV (n = 62), MPS VI (n = 5), MPS VII (n = 5), ML II (n = 8) and ML III (n = 3), and 205 urine samples from MPS I (n = 33), MPS II (n = 33), MPS III (n = 30), MPS IV (n = 82), MPS VI (n = 7), MPS VII (n = 9), ML II (n = 8) and ML III (n = 3). The ELISA method used monoclonal antibodies against HS. MPS I, II, III and VII and ML II and III patients had significant elevation in plasma HS, compared to the age-matched controls (p < 0.0001). Eighty-three out of 89 (93.3%) of individual values in the above MPS types and ML were above the mean +2SD of the controls. In urine samples, 75% of individual values in patients with those types were above the mean +2SD of the controls. In contrast to the previous understanding of the HS metabolic pathway, plasma HS levels in all five MPS VI and 15% of MPS IV patients were elevated above the mean +2SD of the controls. These findings suggest that HS concentration determined by ELISA, especially in plasma, could be a helpful marker for detection of the most severe MPS I, II, III, VI and VII and ML II, distinguishing them from normal populations.

Keratan sulphate levels in mucopolysaccharidoses and mucolipidoses.

The mucopolysaccharidoses (MPS) is characterized by accumulation of glycosaminoglycans (GAGs), and mucolipidosis (ML) by accumulation of GAGs and sphingolipids. Each type of MPS accumulates specific GAGs. The lysosomal enzymes N-acetylgalactosamine-6-sulphate sulphatase and beta-galactosidase involve the stepwise degradation of keratan sulphate (KS). Deficiency of these enzymes results in elevation of KS levels in the body fluids and in tissues, leading to MPS IV disease. In this study, we evaluated blood and urine KS levels in types of MPS and ML other than MPS IV. Eighty-five plasma samples came from MPS I (n = 18), MPS II (n = 28), MPS III (n = 20), MPS VI (n = 3), MPS VII (n = 5) and ML (n = 11) patients while 127 urine samples came from MPS I (n = 34), MPS II (n = 34), MPS III (n = 32), MPS VI (n = 7), MPS VII (n = 9) and ML (n = 11) patients. KS levels were determined using the ELISA method. Plasma KS levels varied with age in both control and patient populations. In all age groups, the mean values of plasma KS in MPS and ML patients were significantly higher than those in the age-matched controls. Plasma KS values in four newborn patients were above the mean + 2SD of the age-matched controls (mean, 41 ng/ml). Overall, 85.9% of individual values in non-type IV MPS and ML patients were above the mean + 2SD of the age-matched controls. For urine KS levels, 24.4% of individual values in patients were above the mean + 2SD of the age-matched controls. In conclusion, KS in blood is elevated in each type of non-type IV MPS examined, in contrast to the conventional understanding. This finding suggests that measurement of KS level provides a new diagnostic biomarker in a wide variety of mucopolysaccharidoses and mucolipidoses in addition to MPS IV.

Otorhinolaryngological manifestations of the mucopolysaccharidoses.

The mucopolysaccharidoses (MPS) are a family of related inherited metabolic disorders where, due to specific lysosomal enzyme deficiencies, partially degraded glycosaminoglycans (GAGs) accumulate in the body's cells. Due to the ubiquitous nature of GAGs in the body this deposition can occur in many tissue types and may interfere with cellular function. Although these conditions are rare, there is a propensity for the disease process to cause problems with the function of the ears, noses and throats of affected patients. In this review, we present an overview of the clinical manifestations of MPS in general and highlight the problems specifically presenting in the field of otorhinolaryngology.

Craniovertebral abnormalities in Type VI mucopolysaccharidosis (Maroteaux-Lamy syndrome).

INTRODUCTION: The craniovertebral abnormalities found in patients with Type VI mucopolysaccharidosis (Maroteaux-Lamy syndrome) are described, and the indications for and outcomes of surgery in this group are assessed. METHODS: The clinical histories and radiological findings in all patients with Type VI mucopolysaccharidosis treated at Royal Manchester Children's Hospital during the past 10 years were reviewed. RESULTS: The typical findings in patients with this disease are of canal stenosis at the level of the foramen magnum and upper cervical spine with or without cord compression. The stenosis is secondary to thickening of the posterior longitudinal ligament. Atlantoaxial instability is rare. Of nine patients under regular clinical review, four underwent decompressive surgery for cervical cord compression. Three of the four showed improvement in their neurological symptoms and signs postoperatively. Of the children reviewed, six had radiological evidence of cord compression, although only those with neurological signs or symptoms were treated surgically. DISCUSSION: Despite the often formidable anesthetic challenge, surgery is indicated in those patients who present with progressive neurological deficit due to cervical myelopathy. Surgery can be undertaken safely if the associated medical problems in these children are recognized and managed appropriately.

Increased risk of vitamin B12 deficiency in patients with phenylketonuria on an unrestricted or relaxed diet.

OBJECTIVE: To investigate whether dietary relaxation or cessation in patients with phenylketonuria (PKU) predisposes to vitamin B12 deficiency. STUDY DESIGN: Patients with PKU aged 11 to 38 years underwent a neurologic examination and dietetic assessment and were divided according to their diet into 1 of 3 groups: Strict - those on a strict low phenylalanine (phe) diet with amino acid, mineral, and vitamin supplements; Relaxed - those on a total protein intake of approximately 1 g/kg/d with 50% of this from natural protein and 50% from amino acid, mineral, and vitamin supplements; Unrestricted - those on no formal protein restriction and not taking amino acid supplements. Assays of blood samples were taken for vitamin B12 and folate levels by standard assays. Results were analyzed with Student t test. RESULTS: Vitamin B12 levels were significantly lower in the PKU groups on relaxed or unrestricted diets compared with the normal population (P <.0001 [unrestricted] and.0034 [relaxed]). Folate levels were significantly elevated in all PKU groups (<.0001). CONCLUSION: Patients with PKU who are no longer under strict dietary control may be at risk from vitamin B12 deficiency. We recommend that all patients should remain under medical and dietetic supervision and in particular have their vitamin B12 status monitored.