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Rigoldi M.,Rare Metabolic Diseases Unit | Concolino D.,University of Catanzaro | Morrone A.,University of Florence | Morrone A.,Paediatric Neurology Unit and Laboratories | And 7 more authors.
Clinical Genetics | Year: 2014

We analysed the clinical history of 16 hemizygous males affected by Anderson-Fabry Disease, from four families, to verify their intrafamilial phenotypic variability. Seven male patients, ranging from 26 to 61years of age, died, whereas nine (age range 23-55) are alive. Eleven patients have undergone enzyme replacement therapy (ERT) for a period of 5-10years. We have found a wide range of intrafamilial phenotypic variability in these families, both in terms of target-organs and severity of the disease. Overall, our findings confirm previous data from the literature showing a high degree of intrafamilial phenotypic variability in patients carrying the same mutation. Furthermore, our results underscore the difficulty in giving accurate prognostic information to patients during genetic counselling, both in terms of rate of disease progression and involvement of different organs, when such prognosis is solely based on the patient's family history. © 2013 John Wiley & Sons A/S.

De Filippi P.,University of Pavia | Saeidi K.,University of Pavia | Ravaglia S.,Irccs Neurological Institute C Mondino | Dardis A.,University of Santa Maria in Ecuador | And 18 more authors.
Orphanet Journal of Rare Diseases | Year: 2014

Background: Pompe's disease is a progressive myopathy caused by mutations in the lysosomal enzyme acid alphaglucosidase gene (GAA). A wide clinical variability occurs also in patients sharing the same GAA mutations, even within the same family.Methods. For a large series of GSDII patients we collected some clinical data as age of onset of the disease, presence or absence of muscular pain, Walton score, 6-Minute Walking Test, Vital Capacity, and Creatine Kinase. DNA was extracted and tested for GAA mutations and some genetic polymorphisms able to influence muscle properties (ACE, ACTN3, AGT and PPAR genes). We compared the polymorphisms analyzed in groups of patients with Pompe disease clustered for their homogeneous genotype.Results: We have been able to identify four subgroups of patients completely homogeneous for their genotype, and two groups homogeneous as far as the second mutation is defined "very severe" or "potentially less severe". When disease free life was studied we observed a high significant difference between groups. The DD genotype in the ACE gene and the XX genotype in the ACTN3 gene were significantly associated to an earlier age of onset of the disease. The ACE DD genotype was also associated to the presence of muscle pain.Conclusions: We demonstrate that ACE and ACTN3 polymorphisms are genetic factors able to modulate the clinical phenotype of patients affected with Pompe disease. © 2014 De Filippi et al.; licensee BioMed Central Ltd.

Manara R.,University of Padua | Priante E.,University of Padua | Priante E.,University of Florence | Grimaldi M.,Neuroradiology Section | And 4 more authors.
American Journal of Neuroradiology | Year: 2012

BACKGROUND AND PURPOSE: Hunter syndrome (MPS type II) is a rare X-linked recessive disease caused by lysosomal enzyme iduronate-2-sulfatase deficiency, characterized by frequent and variable brain and skull involvement. Our objective was determine the frequency of closed cephaloceles in a large cohort of subjects affected with Hunter syndrome and to investigate possible correlations with clinical and neuroradiologic findings. MATERIALS AND METHODS: Brain MR imaging of 33 patients (32 males and 1 female, age range 2.5-30.8 years, mean age 10.4 years) affected with Hunter syndrome were retrospectively evaluated. Eleven (age range 3.6-30.8 years; mean age 15.1) presented with an "attenuated" phenotype, while 22 (age range 2.5-19.1 years; mean age 8.2) had a "severe" phenotype. RESULTS: A closed cephalocele was detected in 9/33 patients (27%) at the level of anterior and middle fossa in 6 and 3 cases, respectively; 6/9 subjects were affected with the attenuated phenotype and 1/9 suffered from epilepsy. Closed cephaloceles did not show a significant association with other brain and spine MR imaging features of Hunter disease, such as enlargement of perivascular spaces, cisterna magna, pituitary sella, ventricles and subarachnoid spaces, craniosynostosis, dens hypoplasia, white matter abnormalities, spinal stenosis due to periodontoid cap, platyspondylia, or intervertebral disk anomalies. CONCLUSIONS: Closed cephaloceles are frequent in Hunter syndrome and should be considered a neuroradiologic feature of this disease.

Huemer M.,University of Zurich | Burer C.,University of Zurich | Jesina P.,Charles University | Kozich V.,Charles University | And 24 more authors.
Journal of Inherited Metabolic Disease | Year: 2015

Background: The cobalamin E (cblE) (MTRR, methionine synthase reductase) and cobalamin G (cblG) (MTR, methionine synthase) defects are rare inborn errors of cobalamin metabolism leading to impairment of the remethylation of homocysteine to methionine. Methods: Information on clinical and laboratory data at initial full assessment and during the course of the disease, treatment, outcome and quality of life was obtained in a survey-based, retrospective study from physicians caring for patients with the CblE or CblG defect. In addition, data on enzyme studies in cultured skin fibroblasts and mutations in the MTRR and MTR gene were analysed. Results: In 11 cblE and 13 cblG patients, failure to thrive, feeding problems, delayed milestones, muscular hypotonia, cognitive impairment and macrocytic anaemia were the most frequent symptoms. Delay in diagnosis depended on age at first symptom and clinical pattern at presentation and correlated significantly with impaired communication abilities at follow-up. Eighteen/22 patients presented with brain atrophy or white matter disease. Biochemical response to treatment with variable combinations of betaine, cobalamin, folate was significant. The overall course was considered improving (n = 8) or stable (n = 15) in 96 % of patients, however the average number of CNS symptoms per patient increased significantly over time and 16 of 23 patients were classified as developmentally delayed or severely handicapped. In vitro enzyme analysis data showed no correlation with outcome. Predominantly private mutations were detected and no genotype– phenotype correlations evident. Conclusions: The majority of patients with the cblE and cblG defect show limited clinical response to treatment and have neurocognitive impairment. © 2014, SSIEM.

Angelini C.,University of Padua | Semplicini C.,University of Padua | Ravaglia S.,University of Pavia | Ravaglia S.,Clinical Institute Beato Matteo | And 20 more authors.
Journal of Neurology | Year: 2012

The objective of this study was to describe a large Italian cohort of patients with late-onset glycogen storage disease type 2 (GSDII) at various stages of disease progression and to evaluate the clinical effectiveness of alglucosidase alpha enzyme replacement therapy (ERT). Previous studies showed in late-onset patients ERT efficacy against placebo and variable response in uncontrolled studies. Seventy-four juvenile or adult GSDII patients were treated with ERT in a multicenter open label, non-randomized study, from 12 months up to 54 months. Recombinant human alpha glucosidase (rh-GAA) was injected by intravenous route at 20 mg/kg every second week. Patients were divided into three groups according to ERT duration: Group A received treatment for 12-23 months (n = 16), Group B for 24-35 months (n = 14), and Group C for more than 36 months (n = 44). Clinical assessment included a 6-min walk test (6MWT), forced vital capacity (FVC), the Walton and Gardner-Medwin score, the number of hours of ventilation, body mass index, echocardiography and blood creatine kinase (CK). Included in our cohort were 33 males and 41 females (M:F = 0.8:1), with a mean age at first symptoms of 28.3 years (range 2-55 years) and a mean age of 43 years at study entry (range 7-72 years). Seven wheelchair bound patients, as well as 27 patients requiring ventilation support, were included. After treatment we could observe an increase in distance walked on the 6MWT in the large majority of patients (48/58; 83%), with an overall mean increase of 63 m (from 320 ± 161 to 383 ± 178 m). After treatment in the majority of patients FVC was improved or unchanged (45/69; 65%). In ventilated patients we observed an improvement in average number of hours off the ventilator (from 15.6 to 12.1 h). Six patients stopped mechanical ventilation and two others started it. The effect of therapy was not related to ERT duration. Nine of 64 patients (13%) that underwent to echocardiography showed a variable degree of cardiac hypertrophy (left ventriculum or septum), and a positive effect was observed after 36 months of ERT in one adult case. Discontinuation of treatment occurred in four patients: one drop-off case, one patient died for a sepsis after 34 months of treatment and two patients stopped ERT for worsening of general clinical condition. Mild adverse effects were observed in four cases (5%). This study represents the largest cohort of late-onset GSDII patients treated with ERT, and confirm a positive effect of treatment. These results, obtained in a large case series on therapy, indicate a favourable effect of ERT therapy, even in more advanced stage of the disease. © Springer-Verlag 2011.

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