Ida V.D. Schwartz

Threshold effect of urinary glycosaminoglycans and the walk test as indicators of disease progression in a survey of subjects with Mucopolysaccharidosis VI (Maroteaux-Lamy syndrome).

A cross‐sectional survey in individuals affected with the lysosomal storage disease Mucopolysaccharidosis VI (MPS VI) was conducted to establish demographics, urinary glycosaminoglycan (GAG) levels, and clinical progression of the disease. The survey evaluated 121 bona fide MPS VI‐affected individuals over the age of 4 years from 15 countries across the Americas, Europe, and Australasia representing greater than 10% of the estimated world prevalence of the disease. A medical history, complete physical exam, urinary GAG determination, and assessment of several clinical measures related to physical endurance, pulmonary function, joint range of motion, strength, and quality of life were completed for each participant. Although a wide variation in clinical presentation was observed, several general findings were obtained reflecting progression of the disease. Impaired physical endurance, as measured by the distance achieved in a 6‐min walk, could be demonstrated across all age groups of MPS VI‐affected individuals. High urinary GAG values (>200 μg/mg creatinine) were associated with an accelerated clinical course comprised of age‐adjusted short stature and low body weight, impaired endurance, compromised pulmonary function, and reduced joint range of motion. An unexpected result was the predominance of urinary GAG values <100 μg/mg creatinine for those participants over the age of 20 years. Pending the collection of longitudinal data, these results suggest that urinary GAG levels predict clinical morbidity, and longer‐term survival is associated with urinary GAG levels below a threshold of 100 μg/mg creatinine.

A clinical study of 77 patients with mucopolysaccharidosis type II

Aim: This study aims to assess the clinical features of 77 South American patients (73 Brazilian) with mucopolysaccharidosis type II (MPS II).

Identification and characterization of 13 new mutations in mucopolysaccharidosis type I patients.

In this study we have investigated a group of 29 Brazilian patients, who had been diagnosed with the lysosomal storage disorder, Mucopolysaccharidosis type I (MPS-I). MPS I is caused by a deficiency in the lysosomal hydrolase, alpha-L-iduronidase. Ninety percent of the MPS I patients in this study were genotyped and revealed 10 recurrent and thirteen novel IDUA gene mutations. Eight of these new mutations and three common mutations W402X, P533R, and R383H were individually expressed in CHO-K1 cells and analyzed for alpha-L-iduronidase protein and enzyme activity. A correlation was observed between the MPS I patient clinical phenotype and the associated mutant alpha-L-iduronidase protein/enzyme activity expressed in CHO-K1 cells. This was the first time that Brazilian MPS I patients had been thoroughly analyzed and highlighted the difficulties of mutation screening and clinical phenotype assessment in populations with high numbers of unique mutations.

Development and Testing of New Screening Method for Keratan Sulfate in Mucopolysaccharidosis IVA

Mucopolysaccharidosis IVA (MPS IVA), a progressive lysosomal storage disease, causes skeletal dysplasia through excessive storage of keratan sulfate (KS). We developed an ELISA-sandwich assay that used a MAb specific to KS. Forty-five blood and 59 urine specimens from MPS IVA patients (ages 1–65 y) were analyzed to determine whether KS concentration is a suitable marker for early diagnosis and longitudinal assessment of disease severity. Blood specimens were obtained from patients categorized as phenotypically severe (n = 36) and milder (n = 9). Urine specimens were also analyzed from patients categorized as severe (n = 56) and milder (n = 12), respectively. Blood KS levels (101–1525 ng/mL) in MPS IVA patients were two to eight times higher than those in age-matched controls (15–323 ng/mL). It was found that blood KS level varied with age and clinical severity. Blood KS levels in both MPS IVA and controls peaked between 5 and 10 y of age (mean, 776 versus 234 ng/mL, respectively). Blood levels in severe MPS IVA were 1.5 times higher than in the milder form. In contrast to blood, urine KS levels in both MPS IVA and controls peaked between 1 and 5 y (15.3 versus 0.26 mg/g creatinine), and thereafter declined with age. Urine KS level also varied with age and clinical severity, and the severe MPS IVA phenotype was associated with 6.7 times greater urine KS excretion than the milder one. These findings indicate that the new assay for blood or urine KS may be suitable for early diagnosis and longitudinal assessment of disease severity in MPS IVA.

Mucopolysaccharidoses in Brazil: what happens from birth to biochemical diagnosis?

Mucopolysaccharidoses (MPS) form a group of inherited metabolic disorders characterized by intralysosomal storage of glycosaminoglycans. This study aimed to investigate the path followed by Brazilian patients from birth to diagnosis. An interview was conducted with patients parents or guardians with subsequent review of patients medical records. One hundred thirteen patients with MPS were included (MPS I: 18, MPS II: 43, MPS IIIA: 2, MPS IIIB: 3, MPS IIIC: 1, MPS IVA: 15, MPS IVB: 1, MPS VI: 29, MPS VII: 1) from 97 families. Median age at the onset of signs/symptoms was 18 months (MPS I: 18, MPS II: 24, MPS IVA: 8, MPS VI: 8). Skeletal abnormalities (for MPS IVA and MPS VI), joint contractures (for MPS II), and typical facial features (for MPS I) were the most frequently reported first signs/symptoms. Several health professionals were involved in patients care as of the onset of symptoms until biochemical diagnosis was established. Median age at diagnosis was 76 months (MPS I: 75, MPS II: 95, MPS IVA: 75, MPS VI: 52). Considering the group as a whole, there was a 4.8‐year delay between the onset of signs/symptoms and the establishment of the diagnosis. Considering that specific therapies are available for some of these disorders and that early treatment is likely to change more favorably the natural history of the disease, efforts should be made to minimize this delay. We believe that this situation can be improved by measures that both increase awareness of health professionals about MPS and improve access to diagnostic tests.

Identification of a common mutation in mucopolysaccharidosis IVA: correlation among genotype, phenotype, and keratan sulfate

AbstractMucopolysaccharidosis IVA (MPS IVA) is a lysosomal storage disorder caused by the deficiency of N-acetylgalactosamine-6-sulfate sulfatase (GALNS). Mutation screening of the GALNS was performed by genomic PCR and direct sequence analyses in 20 MPS IVA patients from Latin America. In this study, 12 different gene mutations including nine unreported ones were identified in 16 severe and four attenuated patients and accounted for 90.0% of the unrelated mutant alleles. The gene alterations were missense mutations except one insertion. Six recurrent mutations, p.A75G, p.G116S, p.G139S, p.N164T, p.R380S, and p.R386C, accounted for 5.0, 10.0, 5.0, 7.5, 5.0, and 32.5% of the unrelated mutant alleles, respectively. The p.R386C mutation was identified in all Latin American populations studied. Eleven mutations correlated with a severe form, while one mutation, p.R380S, was associated with an attenuated form. MPS IVA patients had an elevation of urine and plasma keratan sulfate (KS) concentrations compared with those of the age-matched control. KS concentrations in severe patients were higher than those in attenuated patients. These data provide evidence for extensive allelic heterogeneity and presence of a common mutation in Latin American patients. Accumulation of mutations with clinical description and KS concentration will lead us to predict clinical severity of the patient more precisely.

Oxidative stress in patients with mucopolysaccharidosis type II before and during enzyme replacement therapy

Mucopolysaccharidosis type II (MPS II) is a lysosomal storage disorder caused by deficiency of the enzyme iduronate-2-sulfatase, responsible for the degradation of glycosaminoglycans dermatan and heparan sulfate. Once the generation of free radicals is involved in the pathogenesis of many diseases, including some inborn errors of metabolism, the aim of this study was to evaluate blood oxidative stress parameters in MPS II patients, before and during 6 months of enzyme replacement therapy. We found significantly increased levels of malondialdehyde and carbonyl groups in plasma as well as erythrocyte catalase activity in patients before treatment compared to the control group. Plasma sulfhydryl group content and total antioxidant status were significantly reduced before treatment, while superoxide dismutase enzyme was not altered at this time when compared to controls. During enzyme replacement therapy, there was a significant reduction in levels of malondialdehyde when compared to pretreatment. Sulfhydryl groups were significantly increased until three months of treatment in MPS II patients in comparison to pretreatment. There were no significant alterations in plasma total antioxidant status and carbonyl groups as well as in catalase and superoxide dismutase activities during treatment in relation to pretreatment. The results indicate that MPS II patients are subject to lipid and protein oxidative damage and present reduction in non-enzymatic antioxidants, suggesting a possible involvement of free radicals in the pathophysiology of this disease. Also, the results may suggest that enzyme replacement therapy seems to protect against lipid peroxidation and protein damage in these patients.

Sleep abnormalities in untreated patients with mucopolysaccharidosis type VI.

Mucopolysaccharidosis type VI (MPS VI) is a lysosomal storage disease that affects an enzyme responsible for the degradation of glycosaminoglycans (GAGs). Partially degraded GAGs accumulate in several tissues, such as the upper airways (UA), which leads to the development of obstructive sleep apnea (OSA). Our objective was to determine the prevalence of OSA in a group of untreated patients with MPS VI and the association of OSA with clinical and echocardiographic findings. Patients aged 4 years or older with a biochemical diagnosis of MPS VI were included. Data about clinical history, physical examination, Doppler echocardiogram, and overnight polysomnography (PSG) were collected. Our results showed that of the 28 participants, 14 were boys; mean age was 98.5 months, and mean age at MPS VI diagnosis was 48.4 months. Snoring, witnessed apnea, pectus carinatum, and macroglossia were the main clinical findings. PSG results showed that 23:27 patients (85.1%) had OSA which was mild in 4, moderate in 5, and severe in 14 patients. Echocardiograms showed evidence of pulmonary hypertension (PH) in 14 patients. Lower (P = 0.037) and nadir SpO2 (P = 0.007) were positively associated with PH. Clinical signs suggestive of respiratory abnormalities during sleep were not significantly correlated with the results of PSG. We conclude that the prevalence of OSA in patients with MPS VI was high, and the level of desaturation was positively correlated with PH. Symptoms during sleep were not associated with PSG findings, which suggests that this population should undergo routine PSG as earlier as possible. This study provides baseline data to estimate the potential impact of specific treatments in the sleep abnormalities presented by patients with MPS VI.

Prospective study of 11 Brazilian patients with mucopolysaccharidosis II

OBJECTIVE To assess the progression of mucopolysaccharidosis II in 11 Brazilian patients over a 12-month period. METHODS Eleven Brazilian patients with mucopolysaccharidosis II were prospectively studied at the Division of Medical Genetics of Hospital de Clínicas de Porto Alegre. The initial assessment and the assessment at 12 months included: anamnesis, physical examination, abdominal nuclear magnetic resonance, echocardiogram, 6-minute walk test, audiometry, serum biochemical tests and urinary glycosaminoglycan concentration. RESULTS The major findings after comparing the assessments were: 1) two patients had growth retardation; 2) two patients showed negative weight change; 3) one patient went from obese to overweight; 4) three patients revealed left ventricle hypertrophy; of these, two increased the number of cardiac valve lesions; 5) there was no statistically significant difference between the mean distances obtained on the 6-minute walk test; 6) there was splenic enlargement; 7) there was an increase in gamma-glutamyltransferase levels; 8) the urinary concentration of glycosaminoglycans remained unchanged. CONCLUSIONS In general, echocardiographic findings were the only variable with deterioration and possible immediate clinical consequences. Although a 12-month period is too short to detect changes in most variables related to mucopolysaccharidosis II, its progressive nature should be taken into account when evaluating the efficiency of treatment protocols.

Mucopolysaccharidosis type VI (Maroteaux-Lamy syndrome): assessment of joint mobility and grip and pinch strength.

OBJECTIVE To describe the profile of joint mobility and grip and pinch strength of MPS VI patients and to correlate this with urinary excretion of glycosaminoglycans (GAGs), ARSB activity, and the distance covered in a 6-minute walking test (6MWT). METHODS This was an observational study of 28 patients with MPS VI, who had not undergone specific treatment. All patients were assessed for amplitude of joint mobility (shoulder, elbow, and knee), grip and pinch strength and urinary GAG excretion and also performed the 6MWT. RESULTS Shoulder flexion exhibited the greatest limitation, with no correlation with age, followed by knee extension and elbow flexion, both of which were correlated inversely with age. Hand grip strength was compromised in all patients, and pinch strength exhibited a positive correlation with age. CONCLUSIONS The fact that restricted shoulder flexion was not correlated with age suggests that this finding is present early on in MPS VI and that it constitutes an important clinical sign that should arouse diagnostic suspicion of this disease. The amplitude of knee extension and elbow flexion, in turn, are possible markers of disease progression since they have a negative correlation with age. Further studies are needed to confirm these hypotheses.