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1.
Mol Genet Metab ; 126(4): 470-474, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30792122

RESUMO

Alpha-mannosidosis is an ultra-rare progressive lysosomal storage disorder caused by deficiency of alpha-mannosidase. Timely diagnosis of the disease has the potential to influence patient outcomes as preventive therapies can be initiated at an early stage. However, no internationally-recognised algorithm is currently available for the diagnosis of the disease. With the aim of developing a diagnostic algorithm for alpha-mannosidosis an international panel of experts met to reach a consensus by applying the nominal group technique. Two proposals were developed for diagnostic algorithms of alpha-mannosidosis, one for patients ≤10 years of age and one for those >10 years of age. In younger patients, hearing impairment and/or speech delay are the cardinal symptoms that should prompt the clinician to look for additional symptoms that may provide further diagnostic clues. Older patients have different clinical presentations, and the presence of mental retardation and motor impairment progression and/or psychiatric manifestations should prompt the clinician to assess for other symptoms. In both younger and older patients, either additional metabolic monitoring or referral for testing is warranted upon suspicion of disease. Oligosaccharides in urine (historically performed) or serum were considered as an initial screening procedure, while enzymatic activity may also be considered as first choice in some centres. Molecular testing should be performed as a final confirmatory step. The developed algorithms can easily be applied in a variety of settings, and may help to favour early diagnosis of alpha mannosidosis and treatment.


Assuntos
Algoritmos , Internacionalidade , alfa-Manosidose/diagnóstico , Adolescente , Adulto , Fatores Etários , Criança , Pré-Escolar , Consenso , Progressão da Doença , Humanos , Pessoa de Meia-Idade , Adulto Jovem
2.
Mol Genet Metab ; 122(1-2): 107-112, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28457718

RESUMO

Mucopolysaccharidosis (MPS) VI is an autosomal recessive lysosomal storage disorder arising from deficient activity of N-acetylgalactosamine-4-sulfatase (arylsulfatase B) and subsequent intracellular accumulation of the glycosaminoglycans (GAGs) dermatan sulfate and chondroitin-4-sulfate. Manifestations are multi-systemic and include skeletal abnormalities such as dysostosis multiplex and short stature. Reference height-for-age growth charts for treatment-naïve MPS VI patients have been published for both the slowly and rapidly progressing populations. Categorization of disease progression for these charts was based on urinary GAG (uGAG) level; high (>200µg/mg creatinine) levels identified subjects as rapidly progressing. Height data for 141 patients who began galsulfase treatment by the age of 18years were collected and stratified by baseline uGAG level and age at ERT initiation in 3-year increments. The reference MPS VI growth charts were used to calculate change in Z-score from pre-treatment baseline to last follow-up. Among patients with high baseline uGAG levels, galsulfase ERT was associated with an increase in Z-score for those beginning treatment at 0-3, >3-6, >6-9, >9-12, and >12-15years of age (p<0.05). Increases in Z-score were not detected for patients who began treatment between 15 and 18years of age, nor for patients with low (≤200µg/mg creatinine) baseline uGAG levels, regardless of age at treatment initiation. The largest positive deviation from untreated reference populations was seen in the high uGAG excretion groups who began treatment by 6years of age, suggesting an age- and severity-dependent impact of galsulfase ERT on growth.


Assuntos
Estatura/efeitos dos fármacos , Terapia de Reposição de Enzimas , Mucopolissacaridose VI/tratamento farmacológico , N-Acetilgalactosamina-4-Sulfatase/uso terapêutico , Adolescente , Fatores Etários , Criança , Pré-Escolar , Terapia de Reposição de Enzimas/efeitos adversos , Terapia de Reposição de Enzimas/métodos , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Masculino , Mucopolissacaridose VI/fisiopatologia , N-Acetilgalactosamina-4-Sulfatase/administração & dosagem , N-Acetilgalactosamina-4-Sulfatase/efeitos adversos , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/uso terapêutico
3.
J Inherit Metab Dis ; 38(5): 957-67, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25526710

RESUMO

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.


Assuntos
5-Metiltetra-Hidrofolato-Homocisteína S-Metiltransferase/deficiência , Erros Inatos do Metabolismo dos Aminoácidos , Vitamina B 12/metabolismo , 5-Metiltetra-Hidrofolato-Homocisteína S-Metiltransferase/genética , 5-Metiltetra-Hidrofolato-Homocisteína S-Metiltransferase/metabolismo , Adolescente , Idade de Início , Erros Inatos do Metabolismo dos Aminoácidos/diagnóstico , Erros Inatos do Metabolismo dos Aminoácidos/genética , Erros Inatos do Metabolismo dos Aminoácidos/terapia , Células Cultivadas , Criança , Pré-Escolar , Progressão da Doença , Feminino , Ferredoxina-NADP Redutase/deficiência , Ferredoxina-NADP Redutase/genética , Ferredoxina-NADP Redutase/metabolismo , Humanos , Lactente , Recém-Nascido , Masculino , Metilação , Gravidez , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
4.
Clin Genet ; 86(3): 258-63, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23980562

RESUMO

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 61 years of age, died, whereas nine (age range 23-55) are alive. Eleven patients have undergone enzyme replacement therapy (ERT) for a period of 5-10 years. 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.


Assuntos
Doença de Fabry/genética , Doença de Fabry/patologia , Fenótipo , Adulto , Terapia de Reposição de Enzimas/estatística & dados numéricos , Doença de Fabry/tratamento farmacológico , Doença de Fabry/mortalidade , Hemizigoto , Humanos , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto/genética , Linhagem
5.
Neuropediatrics ; 45(2): 123-8, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24258525

RESUMO

Argininemia is a rare inherited disorder of the urea cycle because of a deficiency of the enzyme arginase I causing an increase of arginine and guanidino compounds in the blood, urine, and cerebrospinal fluid. The clinical picture is characterized by a mild cognitive dysfunction, progressive asymmetrical paraparesis, and seizures. Here, we describe two cases of argininemia where either epilepsia partialis continua (EPC) or nonconvulsive status epilepticus (NCSE) were the presenting manifestations of epilepsy. This is the first report of EPC in an urea cycle disorder. In both the cases, status epilepticus resolved with anticonvulsive drugs. EPC was successfully treated with levetiracetam, and NCSE with valproic acid. No side effects were observed. Because hyperammonemia and NCSE may have the same features of stupor, a neurophysiological approach might prove useful in differentiating these two conditions. Overall, our results strongly indicate that a correct NCSE diagnosis is mandatory to prevent further deterioration in these patients.


Assuntos
Epilepsia Parcial Contínua/diagnóstico , Epilepsia Generalizada/diagnóstico , Hiperargininemia/diagnóstico , Criança , Pré-Escolar , Epilepsia Parcial Contínua/complicações , Epilepsia Generalizada/complicações , Humanos , Hiperargininemia/complicações , Masculino
6.
Clin Genet ; 81(5): 485-90, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-21457233

RESUMO

The Fabry Outcome Survey (FOS) was established to extend the knowledge of the natural history of Fabry disease and to assess the effects of enzyme replacement therapy (ERT) with agalsidase alfa. As of March 2009, 64 boys and 34 girls with Fabry disease had enrolled in the FOS and been treated with agalsidase alfa for at least 6 months. The prevalence of symptoms tended to be reduced after 12 and 24 months of ERT in patients who experienced symptoms at baseline. In the entire population, non-significant decreases in the prevalence of gastrointestinal problems in boys and pain crises in girls were observed after 12-24 months. Kidney function and left ventricular mass indexed to height remained stable. Fifty-eight treatment-related adverse events were reported in 23 patients (21 boys and 2 girls), including 55 infusion reactions. Anti-agalsidase alfa IgG antibodies were found in two boys. No IgE antibodies were reported. This study represents the largest observational study of paediatric Fabry disease patients treated with ERT and indicates continued safety of long-term ERT in children. Continued long-term follow-up is recommended to determine early initiation of ERT, which could potentially slow or prevent the progression of serious morbidities of Fabry disease.


Assuntos
Terapia de Reposição de Enzimas , Doença de Fabry/tratamento farmacológico , alfa-Galactosidase/uso terapêutico , Adolescente , Criança , Pré-Escolar , Terapia de Reposição de Enzimas/efeitos adversos , Feminino , Humanos , Masculino , Fatores de Tempo , Resultado do Tratamento , alfa-Galactosidase/efeitos adversos
7.
Clin Genet ; 81(3): 224-33, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21517827

RESUMO

Fabry disease: polymorphic haplotypes and a novel missense mutation in the GLA gene. Fabry disease (FD) is an X-linked lysosomal storage disorder with a heterogeneous spectrum of clinical manifestations that are caused by the deficiency of α-galactosidase A (α-Gal-A) activity. Although useful for diagnosis in males, enzyme activity is not a reliable biochemical marker in heterozygous females due to random X-chromosome inactivation, thus rendering DNA sequencing of the α-Gal-A gene, alpha-galactosidase gene (GLA), the most reliable test for the confirmation of diagnosis in females. The spectrum of GLA mutations is highly heterogeneous. Many polymorphic GLA variants have been described, but it is unclear if haplotypes formed by combinations of such variants correlate with FD, thus complicating molecular diagnosis in females with normal α-Gal-A activity. We tested 67 female probands with clinical manifestations that may be associated with FD and 110 control males with normal α-Gal-A activity. Five different combinations of GLA polymorphic variants were identified in 14 of the 67 females, whereas clearcut pathogenetic alterations, p.Met51Ile and p.Met290Leu, were identified in two cases. The latter has not been reported so far, and both mutant forms were found to be responsive to the pharmacological chaperone deoxygalactonojirimycin (DGJ; migalastat hydrochloride). Analysis of the male control population, as well as male relatives of a suspected FD female proband, permitted the identification of seven different GLA gene haplotypes in strong linkage disequilibrium. The identification of haplotypes in control males provides evidence against their involvement in the development of FD phenotypic manifestations.


Assuntos
Doença de Fabry/genética , Haplótipos , Mutação de Sentido Incorreto , alfa-Galactosidase/genética , Adulto , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo
8.
Br J Dermatol ; 166(4): 712-20, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22452439

RESUMO

Isolated angiokeratomas are common benign cutaneous lesions, generally deemed unworthy of further investigation. In contrast, diffuse angiokeratomas should alert the physician to a possible diagnosis of Fabry disease, a rare X-linked lysosomal storage disorder, characterized by α-galactosidase deficiency. Glycosphingolipids accumulate in cells throughout the body resulting in progressive multi-organ failure. Difficulties are encountered when trying to interpret the significance of angiokeratomas because they may also occur in other lysosomal storage disorders and rarely in an isolated manner in Fabry disease. We present an algorithm for the classification of angiokeratomas which might prove useful for the diagnosis and management of Fabry disease. Assessment of the clinical features and location of the lesions, personal and family history, skin biopsy, dermoscopy and electron microscopy imaging are sequential steps in the diagnostic process. Assessing the deficiency of α-galactosidase enzyme activity is essential to confirm the diagnosis in males, while mutation analysis is always needed in females. Potentially this algorithm can change the current approach to patients when Fabry disease is suspected, thus improving the diagnostic strategy and management of this disorder. It remains to be decided whether the use of an algorithm might reduce the number of genetic consultations. As evidence has shown the efficacy of enzyme replacement therapy in halting progression of the disease before the onset of irreversible organ damage, it is advisable to aim at an early diagnosis in order to achieve timely initiation of effective treatment with benefits for patients and appropriate use of medical resources.


Assuntos
Angioceratoma/etiologia , Técnicas de Apoio para a Decisão , Doença de Fabry/patologia , Pele/patologia , Algoritmos , Biópsia/métodos , Dermoscopia , Doença de Fabry/complicações , Feminino , Humanos , Doenças por Armazenamento dos Lisossomos do Sistema Nervoso/complicações , Doenças por Armazenamento dos Lisossomos do Sistema Nervoso/patologia , Masculino , Microscopia Eletrônica
9.
Biochim Biophys Acta ; 1802(2): 247-52, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19941952

RESUMO

Fabry Disease (FD) is an X-linked multisystemic lysosomal disorder caused by mutations of alpha-galactosidase (GLA) gene. Only a few of the 450 genetic lesions identified so far have been characterised by in vitro expression studies. Thus the significance of newly identified GLA nucleotide variants in FD patients which lead to alpha-galactosidase (GAL-A) amino acid substitutions or intronic changes can be uncertain. We identified three GLA mutations, c.155G>A (p.C52Y), c.548G>C (p.G183A), c.647A>G (p.Y216C) in as many individuals (two male; one female) and performed in vitro expression studies and Western blot analysis in order to clarify their functional effects. Reduced GAL-A activity and normal or partially reduced mutant proteins were present in all overexpressed mutant systems in which three-dimensional structural analysis showed that the active site was not directly involved. We hypothesize that the three new mutations affect the GAL-A protein, leading to conformational FD. When mutant proteins overexpressed in COS-1 cells and in patients' lymphocytes were tested in the presence of the 1-deoxygalactonojirimicin (DGJ) chaperone, the p.G183A and p.Y216C systems showed increased GAL-A enzyme activities and protein stabilisation while p.C52Y was not responsive. We underline that genetic, biochemical and functional studies are helpful in clarifying the consequences of the missense genetic lesions detected in FD. ERT is the elective therapy for Fabry patients, but it is not always possible to issue the enzyme's active form in all involved organs. Our study endorses the hypothesis that an active site-specific chemical chaperone, which could be administered orally, might be effective in treating GAL-A conformational defects.


Assuntos
Doença de Fabry/genética , Mutação , alfa-Galactosidase/genética , Animais , Células COS , Chlorocebus aethiops , Mapeamento Cromossômico , DNA/genética , DNA/isolamento & purificação , Primers do DNA , Terapia de Reposição de Enzimas/métodos , Doença de Fabry/tratamento farmacológico , Doença de Fabry/enzimologia , Feminino , Humanos , Masculino , Modelos Moleculares , Conformação Molecular , Mutagênese Sítio-Dirigida , Fenótipo , Conformação Proteica , Transfecção , Cromossomo X/genética , alfa-Galactosidase/química
10.
Neuropediatrics ; 42(3): 97-103, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21744316

RESUMO

BACKGROUND: We have reviewed the occurrence of epilepsy in our patients with argininosuccinic aciduria (ASA) (OMIM 207900) and the possible relationship of late epilepsy to symptomatic seizures in the neonatal period, hyperammonaemia and treatments. METHODS: We retrospectively analysed 11 ASA patients (8 neonatal onset and 3 late onset), 6 of whom had developed epilepsy. RESULTS: Epilepsy in our sample was frequent (55 %). It developed after a seizure-free period from the onset of the metabolic disease and seizures were responsive to treatment in all cases. Arginine plasma levels were kept in the same range for the 2 groups of patients with and without epilepsy. CONCLUSIONS: Although epilepsy is reported to be common among patients with ASA, very few long-term follow-up studies are available. The pathophysiological mechanism of epileptogenesis remains unclear. Neither hyperammonaemia nor acute symptomatic seizures at birth seem to be predictive of late epilepsy. Excessive arginine dosages as a cause of epilepsy could be reasonably excluded since our 3 late onset patients developed epilepsy before the diagnosis of ASA, at a time when they were likely to be arginine deficient. Arginine deficiency may not be excluded as cause of epilepsy, but further studies are needed to define its role.


Assuntos
Acidúria Argininossuccínica/complicações , Epilepsia/complicações , Adolescente , Arginina/sangue , Acidúria Argininossuccínica/sangue , Criança , Pré-Escolar , Epilepsia/sangue , Feminino , Seguimentos , Humanos , Lactente , Masculino , Estudos Retrospectivos , Adulto Jovem
11.
Acta Paediatr ; 100(4): 605-11, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21114524

RESUMO

AIM: To evaluate the safety and explore the efficacy of enzyme replacement therapy (ERT) for Fabry disease with agalsidase alfa in young children enrolled in the Fabry Outcome Survey (FOS). METHODS: This retrospective chart review identified eight children (mean age= 5.0±1.6 [mean ±SD]) in FOS who began treatment with agalsidase alfa (0.2 mg/kg, i.v., every other week) when <7 years old. Vital signs and adverse events were monitored throughout the study period. Glomerular filtration rate (GFR) was estimated, and left ventricular mass indexed to height(2.7) (LVMi) was assessed with echocardiography. Patients received 1.2-6.7 years of treatment (mean=4.2 years). RESULTS: Infusion reactions occurred in three patients and were of mild or moderate severity. IgG antibodies to agalsidase alfa were found in one patient who experienced two mild and one moderate infusion reactions. Mean GFR was within the normal range at baseline and remained normal. LVMi was above the 75th percentile of age-matched children in 5 of 6 patients evaluated at baseline. Only two patients exceeded this threshold at their last assessment. CONCLUSION: Long-term observation will be needed to determine whether early initiation of ERT will prevent major organ dysfunction in these patients.


Assuntos
Terapia de Reposição de Enzimas , Doença de Fabry/tratamento farmacológico , Doença de Fabry/enzimologia , alfa-Galactosidase/uso terapêutico , Criança , Pré-Escolar , Toxidermias/etiologia , Terapia de Reposição de Enzimas/efeitos adversos , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Humanos , Hipertrofia Ventricular Esquerda/induzido quimicamente , Imunoglobulina G/imunologia , Infusões Intravenosas/efeitos adversos , Isoenzimas/efeitos adversos , Isoenzimas/uso terapêutico , Masculino , Proteínas Recombinantes , Estudos Retrospectivos , Segurança , Resultado do Tratamento , alfa-Galactosidase/efeitos adversos
12.
Eur J Pediatr ; 168(9): 1069-74, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19066956

RESUMO

BACKGROUND: Neutropenia and/or neutrophil dysfunction are part of glycogen storage disease type 1b (GSD1b) phenotype. Recent studies indicated that activation of apoptosis and increased reactive oxygen species are implicated in the pathogenesis of neutropenia in GSD1b. METHODS: We studied seven GSD1b patients over a 2-year-period to evaluate the efficacy of vitamin E, a known antioxidant, in preventing or improving the clinical manifestations associated with neutropenia and neutrophil dysfunction. Frequency and severity of infections, neutrophil counts and function, ileocolonoscopy and intestinal histology, were monitored. During the first year, patients did not assume vitamin E; during the second year of the study, vitamin E supplementation was added to their therapeutic regimens. RESULTS: During vitamin E supplementation, the mean values of neutrophil counts were significantly higher (p < 0.05) and neutrophil counts lower than 500/mm(3) were found less frequently (p < 0.05); the frequency and severity of infections, mouth ulcers and perianal lesions, was reduced (p < 0.05); ileocolonoscopy and histology showed a mild improvement. Vitamin E supplementation did not result in changes in neutrophil function. CONCLUSIONS: These results suggest that vitamin E supplementation might be beneficial in GSD1b patients and may alleviate disease manifestations associated with neutropenia.


Assuntos
Infecções Bacterianas/epidemiologia , Infecções Bacterianas/prevenção & controle , Doença de Depósito de Glicogênio Tipo I/tratamento farmacológico , Neutropenia/tratamento farmacológico , Vitamina E/uso terapêutico , Adolescente , Adulto , Antiporters/genética , Criança , Pré-Escolar , Análise Mutacional de DNA , Feminino , Doença de Depósito de Glicogênio Tipo I/genética , Humanos , Masculino , Proteínas de Transporte de Monossacarídeos/genética , Mutação Puntual/genética , Estudos Prospectivos , Resultado do Tratamento , Adulto Jovem
13.
Ital J Pediatr ; 45(1): 93, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31370860

RESUMO

BACKGROUND: The treatment with recombinant human growth hormone in patients affected by Mucopolysaccharidoses (MPS) is considered whenever a concurrent diagnosis of growth hormone deficiency is demonstrated. The short- and long-term effects of recombinant human growth hormone in this selected cohort is still debated, given the natural progression of disease-related skeletal malformations and the paucity of treated patients reported in literature. The presented case series provides detailed information about the response to recombinant growth hormone in MPS patients diagnosed with growth hormone deficiency. CASES PRESENTATION: The growth patterns of 4 MPS female patients (current age: 11.7-14.3 years) treated with recombinant human growth hormone due to growth hormone deficiency have been retrospectively analyzed. Two patients, diagnosed with MPS IH, had undergone haematopoietic stem cell transplantation at an early age; the remaining two patients were affected by MPS IV and VI and were treated with enzyme replacement therapy. 4/4 patients presented with a progressive growth deceleration before the diagnosis of growth hormone deficiency was confirmed. This trend was initially reverted by a remarkable increase in height velocity after the start of recombinant growth hormone. We recorded an average increase in height velocity z-score of + 4.23 ± 2.9 and + 4.55 ± 0.96 respectively after 6 and 12 months of treatment. After the first 12-24 months, growth showed a deceleration in all the patients. While in a girl with MPS IH recombinant human growth hormone was discontinued due to a lack in clinical efficacy, 3/4 patients grew at a stable pace, tracking the height centile achieved after the cited initial increase in height velocity. Furthermore, mineral bone density assessed via bone densitometry, showed a remarkable increase in the two patients who were tested before and after starting treatment. CONCLUSIONS: Recombinant human growth hormone appears to have effectively reverted the growth deceleration experienced by MPS patients diagnosed with growth hormone deficiency, at least during the first 12-24 months of treatment.


Assuntos
Hormônio do Crescimento Humano/uso terapêutico , Mucopolissacaridoses/tratamento farmacológico , Adolescente , Densidade Óssea/efeitos dos fármacos , Criança , Terapia de Reposição de Enzimas , Feminino , Transplante de Células-Tronco Hematopoéticas , Hormônio do Crescimento Humano/deficiência , Humanos , Estudos Retrospectivos
14.
Clin Genet ; 74(3): 260-6, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18445046

RESUMO

Anderson-Fabry disease (AFD) is a rare X-linked disorder caused by lysosomal storage of several glycosphingolipids, affecting virtually all organs and systems. Enzyme replacement therapy (ERT) for AFD has been available since 2001. Due to the highly variable nature of clinical manifestations in patients with AFD, it is very difficult to assess disease progression and the effects of therapy. We used the Mainz Severity Score Index (MSSI) as a measure of disease severity to study the effects of ERT in a population of 30 patients treated with agalsidase alfa for a median of 2.9 years (range, 1.0-6.2 years). Our data show that the MSSI captures the correlation between disease severity and both gender and age (1 - males performing worse than females at baseline and 2 - severity of diseases progresses with age in both sex). Furthermore, after at least 1 year of ERT, total MSSI scores were significantly lower than those at baseline (p < 0.001), suggesting a marked clinical improvement under ERT. In conclusion, the MSSI is a sensitive and useful tool for monitoring disease progression and assessing the effects of ERT in a population of patients from different treatment centres.


Assuntos
Doença de Fabry/tratamento farmacológico , alfa-Galactosidase/uso terapêutico , Adolescente , Adulto , Criança , Pré-Escolar , Gerenciamento Clínico , Doença de Fabry/patologia , Feminino , Humanos , Isoenzimas/uso terapêutico , Itália , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes , Índice de Gravidade de Doença , Fatores Sexuais , Resultado do Tratamento
15.
J Neurol Neurosurg Psychiatry ; 79(11): 1249-54, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18535022

RESUMO

BACKGROUND: Anderson-Fabry disease (AFD) is an X-linked lysosomal storage disorder caused by deficiency of alpha-galactosidase A. Central nervous system (CNS) manifestations consist mainly of cerebrovascular events. Brain MRI results are often abnormal. PURPOSE: The aim of the study was to describe CNS involvement in a group of Italian patients with AFD. METHODS: Clinical and brain MRI data of 43 patients with AFD (25 men, 41.94+/-10.83 years old and 18 women, 52.48+/-17.50 years old) were analysed retrospectively. 17 male patients and 7 female patients were under treatment with enzyme replacement therapy (ERT). RESULTS: All 43 patients had signs or symptoms of AFD. 16 men (64%) and 13 women (72%) demonstrated CNS involvement, although with varying severity. Overall, 6 men and 5 women had suffered from cerebrovascular accidents with an age at onset of 33.64+/-13.65 years and 53.68+/-11.71 years, respectively. Brain MR images were abnormal in 16/25 men and in 13/16 women. During CNS monitoring, some patients receiving ERT (5/17 men and 2/6 women) demonstrated neurological deterioration, especially those who had presented with cerebrovascular disease already before starting ERT. CONCLUSIONS: The study demonstrated a high frequency of CNS involvement in homozygous and heterozygous AFD patients, often characterised by early age at onset and abnormal brain MRIs. At present, ERT is widely used; however, potential beneficent effects may be disguised by the progression of irreversible pathology in short-term follow-up. Therefore, primary and secondary prophylaxes of cerebrovascular disease are extremely important.


Assuntos
Encéfalo/patologia , Doença de Fabry/patologia , Imageamento por Ressonância Magnética , Adulto , Idade de Início , Sistema Nervoso Central/patologia , Sistema Nervoso Central/fisiopatologia , Progressão da Doença , Doença de Fabry/epidemiologia , Doença de Fabry/fisiopatologia , Feminino , Humanos , Ataque Isquêmico Transitório/epidemiologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de Doença
16.
J Inherit Metab Dis ; 31(1): 55-66, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17957493

RESUMO

Methylmalonic acidaemia (MMA) is a genetic disorder caused by defects in methylmalonyl-CoA mutase or in any of the different proteins involved in the synthesis of adenosylcobalamin. The aim of this work was to examine the biochemical and clinical phenotype of 32 MMA patients according to their genotype, and to study the mutant mRNA stability by real-time PCR analysis. Using cellular and biochemical methods, we classified our patient cohort as having the MMA forms mut (n = 19), cblA (n = 9) and cblB (n = 4). All the mut (0) and some of the cblB patients had the most severe clinical and biochemical manifestations, displaying non-inducible propionate incorporation in the presence of hydroxocobalamin (OHCbl) in vitro and high plasma odd-numbered long-chain fatty acid (OLCFA) concentrations under dietary therapy. In contrast, mut (-) and cblA patients exhibited a milder phenotype with propionate incorporation enhanced by OHCbl and normal OLCFA levels under dietary therapy. No missense mutations identified in the MUT gene, including mut (0) and mut (-) changes, affected mRNA stability. A new sequence variation (c.562G>C) in the MMAA gene was identified. Most of the cblA patients carried premature termination codons (PTC) in both alleles. Interestingly, the transcripts containing the PTC mutations were insensitive to nonsense-mediated decay (NMD).


Assuntos
Alquil e Aril Transferases/genética , Erros Inatos do Metabolismo dos Aminoácidos/genética , Teste de Complementação Genética , Proteínas de Membrana Transportadoras/genética , Ácido Metilmalônico/sangue , Metilmalonil-CoA Mutase/genética , Proteínas Mitocondriais/genética , Biomarcadores/análise , Linhagem Celular , Estudos de Coortes , Genótipo , Humanos , Lactente , Recém-Nascido , Metilmalonil-CoA Mutase/classificação , Proteínas de Transporte da Membrana Mitocondrial , Mutação/fisiologia , Vitamina B 12/genética
17.
Clin Chim Acta ; 397(1-2): 72-6, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18710657

RESUMO

BACKGROUND: Quantification studies of mutated mRNAs have not been carried out on Morquio A patients. Such studies are very important for the determination of stability of premature termination codons (PTC) bearing transcripts in order to assess the appropriateness of introducing the newly developed therapeutic strategies such as "stop codon read-through therapy". METHODS: This paper focuses on the study of the GALNS gene and mRNAs in two severe forms of Morquio A patients' fibroblasts with development of a new and rapid real-time RT-PCR for detection and quantification of absolute mRNA copy number. RESULTS: We identified two new mutations c.385A>T (p.K129X) and c.899-1G>C) in Pt1 and a known splicing defect c.120+1G>A in Pt2. Using RT-PCR and real-time RT-PCR in Pt2 we detected low levels of mRNAs, suggesting its instability; in Pt1, we detected three aberrant mRNAs introducing premature stop codons, suggesting that both the c.385A>T and c.899-1G>C mutations produce mRNAs capable of escaping the nonsense-mediated decay (NMD) pathway. CONCLUSIONS: The development of a real-time RT-PCR assay allows to absolutely quantify the GALNS mRNAs carrying mutations that lead to PTCs bearing transcripts, which escape the NMD process and are potentially suitable for the new therapeutic approach.


Assuntos
Condroitina Sulfatases/genética , Fibroblastos/enzimologia , Mucopolissacaridose IV/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Alelos , Criança , Códon sem Sentido/genética , Éxons/genética , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , Mutação , RNA Mensageiro/análise , RNA Mensageiro/genética
18.
Orphanet J Rare Dis ; 12(1): 98, 2017 05 23.
Artigo em Inglês | MEDLINE | ID: mdl-28535791

RESUMO

BACKGROUND: This post hoc subanalysis examined outcomes in adult patients with Morquio A (mucopolysaccharidosis IVA) who received enzyme replacement therapy (ERT) with elosulfase alfa over a 120-weeks period. Patients ≥18 years of age evaluated in an open-label, long-term extension study of elosulfase alfa (modified per protocol [MPP], n = 32; intent-to-treat [ITT], n = 37; MOR-005; NCT01415427) were compared with the ≥18-year-old untreated population with 2-years follow-up from a Morquio A natural history study (n = 10; MorCAP; NCT00787995). The MOR-005 MPP population excluded patients who underwent orthopedic surgical procedures or were noncompliant with study protocol (defined as missing ≥20% of ERT infusions). No MorCAP patients underwent orthopedic surgical procedures during the relevant time period. Endurance was assessed by the 6-min walk test (6MWT) and 3-min stair climb test (3MSCT). Activities of daily living (ADLs) were assessed by the MPS Health Assessment Questionnaire (MPS HAQ). RESULTS: Least squares (LS) mean (SE) 6MWT distances increased by 34.9 (11.7) m (MPP) and 30.5 (10.8) m (ITT) by week 120; LS mean (SE) change in 3MSCT at week 120 was 6.7 (1.8) stairs/min (MPP) and 5.9 (1.7) stairs/min (ITT). MorCAP patients showed no improvement in 6MWT distance or 3MSCT over a similar period of time. Pulmonary function measures remained unchanged in both MOR-005 and MorCAP adults. All MPS HAQ domain scores improved in MOR-005 adults, whereas MorCAP adults had unchanged caregiver assistance and mobility outcomes and worsened self-care outcomes. CONCLUSIONS: Long-term ERT in adult patients with Morquio A was associated with increased endurance and improvement in performance of ADLs. TRIAL REGISTRATION: Trial Registration NCT01415427 . Name of registry: Long-Term Efficacy and Safety Extension Study of BMN 110 in Patients With Mucopolysaccharidosis IVA (Morquio A Syndrome). Registered 8 August 2011, retrospectively registered.


Assuntos
Condroitina Sulfatases/administração & dosagem , Internacionalidade , Mucopolissacaridose IV/diagnóstico , Mucopolissacaridose IV/tratamento farmacológico , Adulto , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Estudos Longitudinais , Masculino , Mucopolissacaridose IV/fisiopatologia , Autocuidado/tendências , Resultado do Tratamento , Adulto Jovem
19.
Mol Genet Metab Rep ; 12: 85-91, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28702361

RESUMO

Fabry disease (FD) [OMIM 301500] is an X-linked lysosomal storage disorder caused by a deficiency of the lysosomal enzyme alpha-galactosidase A, resulting in progressive multisystem accumulation of globotriaosylceramide (Gb3). Although the introduction of Enzyme Replacement Therapy (ERT) resulted in a variety of clinical benefits, life-long intravenous (IV) treatment with ERT with an every other week schedule, may interfere with daily life activities and impact on QoL. We report here a multicentric, observational, longitudinal data analysis on a large cohort of 85 Italian FD patients (45 males, 40 females) from 11 out of 20 Italian regions, who received a cumulative number of 4269 home infusions of agalsidase alfa. For the whole cohort, the average duration of home therapy was 1 year and 11 months (range 3 months-4 years and 6 months), and during this period, compliance to treatment (number of infusions performed vs scheduled) reached 100%. The EQ-5 VAS scale was administered to patients to evaluate the self-reported QoL, 58% of patients showing an increase of EQ-5 VAS score at follow up compared to baseline (home treatment start) or remaining stable. A mild increase of average disease severity, measured through Mainz Severity Score Index (MSSI), was found during hospital treatment (p < 0,007), while it remained stable between the first home therapy infusion and last follow up. Interestingly, 4 out of 7 (57%) patients, showing an improvement in FD-related clinical status after starting home therapy, had previously a sub-optimal compliance to treatment during the period of hospital treatment management. Only 4 adverse non serious reactions (0,093%) were reported totally in 2 patients during home treatment. We conclude that home infusions in eligible patients with FD are safe, contribute to improve treatment compliance and therapeutic clinical outcomes, and may have a positive impact on self-perceived QoL.

20.
J Neurol ; 262(1): 154-64, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25355454

RESUMO

PMM2-CDG (PMM2 gene mutations) is the most common congenital disorder of N-glycosylation. We conducted a nationwide survey to characterize the frequency, clinical features, glycosylation and genetic correlates in Italian patients with PMM2-CDG. Clinical information was obtained through a questionnaire filled in by the referral physicians including demographics, neurological and systemic features, neuroimaging data and genotype. Glycosylation analyses of serum transferrin were complemented by MALDI-Mass Spectrometry (MALDI-MS). Between 1996 and 2012, data on 37 Italian patients with PMM2-CDG were collected. All the patients with a severe phenotype were unable to walk unaided, 84 % had severe intellectual disability and 81 % microcephaly. Conversely, among 17 mildly affected patients 82 % had independent ambulation, 64 % had borderline to mild intellectual disability and 35 % microcephaly. Epilepsy and stroke-like events did not occur among patients with the mild phenotype. The rate and extent of systemic involvement were more pronounced in severely affected patients. The L32R misfolding mutation of the PMM2 gene occurred in 70 % of the patients with the mild phenotype and was associated with a less severe underglycosylation of serum Tf at MALDI-MS analyses. Despite their different disease severity, all patients had progressive (olivo)ponto-cerebellar atrophy that was the hallmark clinical feature for the diagnosis. A mild neurological phenotype of PMM2-CDG marked by preserved ambulatory ability and autonomy and associated with L32R mutation is particularly frequent in Italy. PMM2-CDG should be considered in patients with even mild developmental disability and/or unexplained progressive cerebellar atrophy.


Assuntos
Defeitos Congênitos da Glicosilação/genética , Defeitos Congênitos da Glicosilação/fisiopatologia , Atrofias Olivopontocerebelares/patologia , Fosfotransferases (Fosfomutases)/genética , Índice de Gravidade de Doença , Adolescente , Adulto , Criança , Pré-Escolar , Defeitos Congênitos da Glicosilação/complicações , Progressão da Doença , Feminino , Humanos , Itália , Masculino , Atrofias Olivopontocerebelares/etiologia , Fenótipo , Transferrina/análise , Adulto Jovem
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