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1.
Mol Genet Metab ; 128(1-2): 68-74, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31104888

RESUMO

Sanfilippo syndrome or mucopolysaccharidosis type III (MPS III) is a childhood metabolic disorder marked by neuropathology arising due to impaired heparan sulphate (HS) catabolism. Consequently, partially degraded HS accumulates in the lysosomes of affected cells and is excreted in the urine. The measurement of HS in urine has long been considered a biomarker of Sanfilippo syndrome although it is largely non-specific. Using blood, urine and CSF collected from a cohort of Sanfilippo patients we investigated the utility of primary and secondary biomarkers to inform on disease activity. These included enzyme activity, specific oligosaccharides with non-reducing end residues reflective of the enzyme deficiency, and gangliosides. The diagnostic oligosaccharides - a HS disaccharide and tetrasaccharide - were elevated in the urine, plasma and CSF of all MPS IIIA and IIIB patients, respectively. There was no correlation between the concentrations in any of the matrices suggesting they reflect specific tissues and not overall disease burden. Enzyme activity did not inform on disease severity, with no measurable activity in CSF and activity approaching normal in MPS IIIA plasma. The concentration of gangliosides, GM2 and GM3, were significantly higher in the CSF of all MPS III subjects when compared to controls and correlated with the age of onset of first symptoms. Given that these gangliosides reflect delayed brain development they may be useful measures of disease burden, within the limitations of the clinical surrogates. Observation of these biochemical measurements in MPS III patients enrolled in clinical trials may determine whether they represent true pharmacodynamics biomarkers.


Assuntos
Biomarcadores/análise , Gangliosídeos/análise , Mucopolissacaridose III/diagnóstico , Oligossacarídeos/análise , Pré-Escolar , Gangliosídeos/sangue , Gangliosídeos/líquido cefalorraquidiano , Gangliosídeos/urina , Heparitina Sulfato/metabolismo , Humanos , Lactente , Mucopolissacaridose III/sangue , Mucopolissacaridose III/líquido cefalorraquidiano , Mucopolissacaridose III/urina , Oligossacarídeos/sangue , Oligossacarídeos/líquido cefalorraquidiano , Oligossacarídeos/urina
2.
Ital J Pediatr ; 45(1): 60, 2019 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-31088528

RESUMO

Filocamo et al. recently published a paper describing the presence of a pseudodeficiency allele, constituted by p.Ser141Ser and p.Arg737Gly polymorphisms at the NAGLU gene, which leads to a reduced level of the alpha-N-acetyl-D-glucosaminidase activity. Based on analysis performed in Brazilian patients, using a customized gene panel containing SGSH, NAGLU, HGSNAT and GNS we observed that p.Ser141Ser (rs659497) and p.Arg737Gly (rs86312) variants were present in homozygosis in all of our MPS IIIB patients and in the majority of MPS IIIA, IIIC and IIID patients, and there was no significant decrease of the alpha-N-acetyl-D-glucosaminidase enzyme activity in this group when compared with those without the "pseudodeficiency allele". Thus, we suggest that these two variants are not producing a pseudodeficiency allele.


Assuntos
Acetilglucosaminidase/genética , Mucopolissacaridose III/diagnóstico , Mucopolissacaridose III/genética , Polimorfismo Genético/genética , Brasil , Humanos
3.
Am J Med Genet A ; 176(9): 1799-1809, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30070758

RESUMO

Mucopolysaccharidosis type III (MPS III, Sanfilippo syndrome) has a variable age of onset and variable rate of progression. However, information regarding the natural history of this disorder in Asian populations is limited. A retrospective analysis was carried out for 28 patients with MPS III (types IIIA [n = 3], IIIB [n = 23], and IIIC [n = 2]; 15 males and 13 females; median age, 8.2 years; age range, 2.7-26.5 years) seen in six medical centers in Taiwan from January 1996 through October 2017. The median age at confirmed diagnosis was 4.6 years. The most common initial symptom was speech delay (75%), followed by hirsutism (64%) and hyperactivity (54%). Both z scores for height and weight were negatively correlated with age (r = -.693 and -0.718, respectively; p < .01). The most prevalent clinical manifestations were speech delay (100%) and intellectual disability (100%), followed by hirsutism (93%), hyperactivity (79%), coarse facial features (68%), sleep disorders (61%), and hepatosplenomegaly (61%). Ten patients (36%) had epilepsy, and the median age at the first seizure was 11 years. Thirteen patients (46%) experienced at least one surgical procedure. At the time of the present study, 7 of the 28 patients had passed away at the median age of 13.0 years. Molecular studies showed an allelic heterogeneity without clear genotype and phenotype correlations. MPS IIIB is the most frequent subtype among MPS III in the Taiwanese population. An understanding of the natural history of MPS III may allow early diagnosis and timely management of the disease facilitating better treatment outcomes.


Assuntos
Mucopolissacaridose III/diagnóstico , Mucopolissacaridose III/etiologia , Acetilglucosaminidase/genética , Acetilglucosaminidase/metabolismo , Adolescente , Adulto , Biomarcadores , Criança , Pré-Escolar , Análise Mutacional de DNA , Eletroencefalografia , Ativação Enzimática , Feminino , Estudos de Associação Genética , Humanos , Estimativa de Kaplan-Meier , Masculino , Mucopolissacaridose III/metabolismo , Mucopolissacaridose III/mortalidade , Imagem Multimodal/métodos , Mutação , Fenótipo , Estudos Retrospectivos , Avaliação de Sintomas , Taiwan , Adulto Jovem
4.
BMJ Case Rep ; 20182018 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-30049674

RESUMO

Mucopolysaccharidosis IIIB (MPS IIIB) is an autosomal recessive lysosomal storage disorder. In comparison to Hurler syndrome (MPS I) and Hunter syndrome (MPS II), characteristic facial and physical features tend to be milder and progression of neurological symptoms may initially be slower. Obvious neurological and behavioural symptoms may not appear until age 2-6 years, but once they begin, progression is relentless, leading to death by the early 20s. Although there is currently no known cure for MPS IIIB, enzyme replacement clinical trials are showing hope for delay in the progression of symptoms. Early diagnosis is therefore necessary before neurological symptoms have progressed. In our case, MPS IIIB was diagnosed at an early age because recurrent wheezing and otitis media in conjunction with hepatomegaly were recognised as more than trivial findings. A thorough examination and a definitive proactive decision to perform a liver biopsy resulted in early diagnosis of a rare disease.


Assuntos
Mucopolissacaridose III/diagnóstico , Pré-Escolar , Diagnóstico Tardio , Diagnóstico Diferencial , Hepatomegalia/etiologia , Humanos , Masculino , Mucopolissacaridose III/complicações , Mucopolissacaridose III/diagnóstico por imagem , Otite Média/etiologia , Sons Respiratórios/etiologia , Tomografia Computadorizada por Raios X
5.
J Pediatr ; 197: 198-206.e2, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29661560

RESUMO

OBJECTIVE: To evaluate the natural course of disease progression in patients with Sanfilippo syndrome type B (mucopolysaccharidosis type IIIB), identify potential end points for future therapy trials, and characterize biomarkers related to the disease. STUDY DESIGN: A prospective, multicenter study was conducted. Baseline, 6-month, and 12-month assessments included neurodevelopmental status (Bayley Scales of Infant Development, Third edition), adaptive status (Vineland Adaptive Behavior Scales, Second Edition), volumetric brain magnetic resonance imaging, cerebrospinal fluid heparan sulfate, and urine glycosaminoglycan (GAG) measurements. RESULTS: Nineteen patients aged 1.6-31.7 years were enrolled. Over 12 months, cognition, adaptive behavior, and cortical gray matter volume (GMV) declined in most patients. For patients diagnosed at <6 years, although there was no overall mean change over 12 months, there were 10%-48%, 3%-66%, and 1%-14% decreases in cognitive development quotient score, Vineland Adaptive Behavior Scales, Second Edition development quotient score, and cortical GMV in 8/12, 9/11, and 10/11 patients, respectively. Mean urine GAG and cerebrospinal fluid heparan sulfate levels were stable, but patients diagnosed at <6 years (n = 14) had higher levels than those ≥6 years at diagnosis (n = 4), which was likely associated with age as they also were generally younger. CONCLUSIONS: Cognition, adaptive behavior, and cortical GMV measures sensitively tracked deterioration in patients with mucopolysaccharidosis type IIIB aged ≤8.6 years. Biomarkers may have prognostic value, but their sensitivity to disease progression requires further investigation. These findings should help evaluate enzyme replacement and gene therapy agents for this rare, devastating, neurodegenerative disease. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01509768.


Assuntos
Biomarcadores/metabolismo , Mucopolissacaridose III/diagnóstico , Transtornos do Neurodesenvolvimento/etiologia , Adolescente , Adulto , Encéfalo/diagnóstico por imagem , Líquido Cefalorraquidiano/metabolismo , Criança , Pré-Escolar , Progressão da Doença , Feminino , Glicosaminoglicanos/urina , Heparitina Sulfato/metabolismo , Humanos , Lactente , Estudos Longitudinais , Imagem por Ressonância Magnética , Masculino , Mucopolissacaridose III/complicações , Transtornos do Neurodesenvolvimento/epidemiologia , Estudos Prospectivos , Adulto Jovem
6.
Orphanet J Rare Dis ; 13(1): 2, 2018 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-29310675

RESUMO

BACKGROUND: Rare diseases are often un- or misdiagnosed for extended periods, resulting in a long diagnostic delay that may significantly add to the burden of the disease. An early diagnosis is particularly essential if a disease-modifying treatment is available. The purpose of this study was to assess the extent of the diagnostic delay in the two ultra-rare diseases, i.e., mucopolysaccharidosis I (MPS I) and III (MPS III), both of which are lysosomal storage disorders with different phenotypic severities (MPS 1 is characterized by the severe Hurler and the more attenuated non-Hurler phenotypes, MPS III is characterized by the severe rapidly progressing (RP) phenotype and more attenuated slowly progressing (SP) phenotype). We investigated whether the diagnostic delay changed over the previous decades. RESULTS: The diagnostic delay, which is defined as the time between the first visit to a medical doctor for disease-related symptoms and the final diagnosis, was assessed using telephone interviews with patients diagnosed between 1988 and 2017 and/or their parents or legal guardian(s). In addition, the medical charts were reviewed. For MPS I (n = 29), the median diagnostic delay was 8 months (range 1-24 months) for Hurler patients and 28 months (range 2-147 months) for non-Hurler patients. For MPS III (n = 46), the median diagnostic delay was 33 months (range 1-365 months). No difference was observed between the RP and SP phenotypic groups. Comparing the diagnostic delay over time using 5-year time intervals, no reduction in the diagnostic delay was observed for MPS I or MPS III. CONCLUSIONS: In the Netherlands, the time to diagnosis for patients with MPS I and MPS III has not changed between 1988 and 2017, and an extensive delay still exists between the first visit to a medical doctor for disease-related symptoms and the final diagnosis. The numerous campaigns launched to increase awareness, leading to earlier diagnosis of these rare disorders, particularly of MPS I, have failed to achieve their goal. Robust selected screening protocols embedded in national guidelines and newborn screening for disorders that meet the criteria for population screening may be the only effective approaches for reducing the diagnostic delay.


Assuntos
Diagnóstico Tardio , Mucopolissacaridose III/diagnóstico , Mucopolissacaridose I/diagnóstico , Pré-Escolar , Diagnóstico Precoce , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Triagem Neonatal , Doenças Raras , Fatores de Tempo
7.
Sci Rep ; 7(1): 16406, 2017 11 27.
Artigo em Inglês | MEDLINE | ID: mdl-29180785

RESUMO

HSD17B1 is a steroid metabolising enzyme. We have previously generated knockout mice that had the entire coding region of Hsd17b1 replaced with lacZ-neo cassette (Hsd17b1-LacZ/Neo mice). This resulted in a 90% reduction of HSD17B1 activity, associated with severe subfertility in the knockout females. The present study indicates that Hsd17b1-LacZ/Neo male mice have a metabolic phenotype, including reduced adipose mass, increased lean mass and lipid accumulation in the liver. During the characterisation of this metabolic phenotype, it became evident that the expression of the Naglu gene, located closely upstream of Hsd17b1, was severely reduced in all tissues analysed. Similar results were obtained from Hsd17b1-LacZ mice after removing the neo cassette from the locus or by crossing the Hsd17b1-LacZ/Neo mice with transgenic mice constitutively expressing human HSD17B1. The deficiency of Naglu caused the accumulation of glycosaminoglycans in all studied mouse models lacking the Hsd17b1 gene. The metabolic phenotypes of the Hsd17b1 knockout mouse models were recapitulated in Naglu knockout mice. Based on the data we propose that the Hsd17b1 gene includes a regulatory element controlling Naglu expression and the metabolic phenotype in mice lacking the Hsd17b1 genomic region is caused by the reduced expression of Naglu rather than the lack of Hsd17b1.


Assuntos
17-Hidroxiesteroide Desidrogenases/genética , Alelos , Deleção de Genes , Estudos de Associação Genética , Doenças por Armazenamento dos Lisossomos/genética , Fenótipo , Animais , Modelos Animais de Doenças , Expressão Gênica , Loci Gênicos , Glicosaminoglicanos/metabolismo , Doenças por Armazenamento dos Lisossomos/diagnóstico , Doenças por Armazenamento dos Lisossomos/metabolismo , Lisossomos/metabolismo , Masculino , Camundongos , Mucopolissacaridose III/diagnóstico , Mucopolissacaridose III/genética , Mucopolissacaridose III/metabolismo
8.
Ann Neurol ; 82(5): 686-696, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29023963

RESUMO

OBJECTIVE: Mucopolysaccharidosis IIIA or Sanfilippo disease type A is a progressive neurodegenerative disorder presenting in early childhood, caused by an inherited deficiency of the lysosomal hydrolase sulfamidase. New missense mutations, for which genotype-phenotype correlations are currently unknown, are frequently reported, hampering early prediction of phenotypic severity and efficacy assessment of new disease-modifying treatments. We aimed to design a method to determine phenotypic severity early in the disease course. METHODS: Fifty-three patients were included for whom skin fibroblasts and data on disease course and mutation analysis were available. Patients were phenotypically characterized on clinical data as rapidly progressing or slowly progressing. Sulfamidase activity was measured in fibroblasts cultured at 37 °C and at 30 °C. RESULTS: Sulfamidase activity in fibroblasts from patients homozygous or compound heterozygous for a combination of known severe mutations remained below the limit of quantification under both culture conditions. In contrast, sulfamidase activity in fibroblasts from patients homozygous or compound heterozygous for a known mild mutation increased above the limit of quantification when cultured at 30 °C. With division on the basis of the patients' phenotype, fibroblasts from slowly progressing patients could be separated from rapidly progressing patients by increase in sulfamidase activity when cultured at 30 °C (p < 0.001, sensitivity = 96%, specificity = 93%). INTERPRETATION: Phenotypic severity strongly correlates with the potential to increase sulfamidase activity in fibroblasts cultured at 30 °C, allowing reliable distinction between patients with rapidly progressing or slowly progressing phenotypes. This method may provide an essential tool for assessment of treatment effects and for health care and life planning decisions. Ann Neurol 2017;82:686-696.


Assuntos
Fibroblastos/metabolismo , Hidrolases/metabolismo , Mucopolissacaridose III/diagnóstico , Mucopolissacaridose III/enzimologia , Adolescente , Adulto , Técnicas de Cultura de Células , Células Cultivadas , Criança , Pré-Escolar , Progressão da Doença , Feminino , Humanos , Limite de Detecção , Masculino , Fenótipo , Valor Preditivo dos Testes , Temperatura , Adulto Jovem
9.
J Autism Dev Disord ; 47(11): 3620-3633, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28856504

RESUMO

The prevalence of autism spectrum disorder (ASD) in many genetic disorders is well documented but not as yet in Mucopolysaccharidosis type III (MPS III). MPS III is a recessively inherited metabolic disorder and evidence suggests that symptoms of ASD present in MPS III. This systematic review examined the extant literature on the symptoms of ASD in MPS III and quality assessed a total of 16 studies. Results indicated that difficulties within speech, language and communication consistent with ASD were present in MPS III, whilst repetitive and restricted behaviours and interests were less widely reported. The presence of ASD-like symptoms can result in late diagnosis or misdiagnosis of MPS III and prevent opportunities for genetic counselling and the provision of treatments.


Assuntos
Transtorno do Espectro Autista/epidemiologia , Mucopolissacaridose III/epidemiologia , Adolescente , Adulto , Transtorno do Espectro Autista/diagnóstico , Criança , Erros de Diagnóstico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mucopolissacaridose III/diagnóstico
10.
Metab Brain Dis ; 32(5): 1403-1415, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28382573

RESUMO

The monogenic defects in specific lysosomal enzymes in mucopolysaccharidosis (MPS) III lead to lysosomal storage of glycosaminoglycans and complex CNS and somatic pathology, for which the detailed mechanisms remain unclear. In this study, serum samples from patients with MPS IIIA (age 2-9 yr) and MPS IIIB (2-13 yr) and healthy controls (age 2-9 yr) were assayed by global metabolomics profiling of 658 metabolites using mass spectrometry. Significant alterations were detected in 423 metabolites in all MPS III patients, of which 366 (86.5%) decreased and 57 (13.5%) increased. Similar profiles were observed when analyzing data from MPS IIIA and MPS IIIB samples separately, with only limited age variations in 36 metabolites. The observed metabolic disturbances in MPS III patients involve virtually all major pathways of amino acid (101/150), peptide (17/21), carbohydrate (19/23), lipid (221/325), nucleotide (15/25), energy (8/9), vitamins and co-factors (8/21), and xenobiotics (34/84) metabolism. Notably, detected serum metabolite decreases involved all key amino acids, all major neurotransmitter pathways, and broad neuroprotective compounds. The elevated metabolites are predominantly lipid derivatives, and also include cysteine metabolites and a fibrinogen peptide fragment, consistent with the status of oxidative stress and inflammation in MPS III. This study demonstrates that the lysosomal glycosaminoglycans storage triggers profound metabolic disturbances in patients with MPS III disorders, leading to severe functional depression of virtually all metabolic pathways, which emerge early during the disease progression. Serum global metabolomics profiling may provide an important and minimally invasive tool for better understanding the disease mechanisms and identification of potential biomarkers for MPS III.


Assuntos
Doenças Metabólicas/metabolismo , Metabolômica/métodos , Mucopolissacaridose III/metabolismo , Envelhecimento/metabolismo , Aminoácidos/sangue , Biomarcadores , Criança , Pré-Escolar , Feminino , Glicosaminoglicanos/metabolismo , Humanos , Metabolismo dos Lipídeos/genética , Lisossomos/metabolismo , Masculino , Espectrometria de Massas , Doenças Metabólicas/diagnóstico , Redes e Vias Metabólicas/genética , Mucopolissacaridose III/diagnóstico , Neurotransmissores/metabolismo , Estresse Oxidativo
11.
World J Pediatr ; 13(4): 374-380, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28101780

RESUMO

BACKGROUND: Mucopolysaccharidoses type III (MPS III) are a group of autosomal recessive lysosomal storage diseases, caused by mutations in genes that code for enzymes involved in the lysosomal degradation of heparan sulphate: heparan sulfate sulfamidase (SGSH), α-Nacetylglucosaminidase (NAGLU), heparan sulfate acetyl-CoA: α-glucosaminide N-acetyltransferase (HGSNAT), and N-acetylglucosamine-6-sulfatase (GNS). METHODS: In this study, we have performed the molecular analysis of the SGSH, NAGLU and HGSNAT genes in 10 patients from 6 different MPS III Tunisian families. RESULTS: In the SGSH gene, two mutations were identified: one novel (p.D477N) and one already described (p.Q365X). In the NAGLU gene, two novel mutations were discovered (p.L550P and p.E153X). For the novel missense mutations found in these two genes we performed an in silico structural analysis and the results were consistent with the clinical course of the patients harboring those mutations. Finally, in HGSNAT gene, we found the splicesite mutation c.234+1G>A that had already been reported as relatively frequent in MPS IIIC patients from countries surrounding the basin of the Mediterranean sea. Its presence in two Tunisian MPS IIIC families points to the hypothesis of its peri Mediterranean origin. With the exception of the c.234+1G>A mutation, that was identified in two unrelated MPS IIIC families, the other identified mutations were family-specific and were always found in homozygosity in the patients studied, thus reflecting the existence of consanguinity in MPS III Tunisian families. CONCLUSIONS: Three novel mutations are reported here, further contributing to the knowledge of the molecular basis of these diseases. The results of this study will allow carrier detection in affected families and prenatal molecular diagnosis, leading to an improvement in genetic counseling.


Assuntos
Análise Mutacional de DNA , Predisposição Genética para Doença/epidemiologia , Mucopolissacaridose III/diagnóstico , Mucopolissacaridose III/genética , Mutação de Sentido Incorreto , Acetilglucosaminidase/genética , Feminino , Humanos , Hidrolases/genética , Recém-Nascido , Masculino , Linhagem , Medição de Risco , Amostragem , Tunísia
12.
Eur J Hum Genet ; 25(2): 253-256, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27827379

RESUMO

Klüver-Bucy syndrome (KBS) comprises a set of neurobehavioral symptoms with psychic blindness, hypersexuality, disinhibition, hyperorality, and hypermetamorphosis that were originally observed after bilateral lobectomy in Rhesus monkeys. We investigated two siblings with KBS from a consanguineous family by whole-exome sequencing and autozygosity mapping. We detected a homozygous variant in the heparan-α-glucosaminidase-N-acetyltransferase gene (HGSNAT; c.518G>A, p.(G173D), NCBI ClinVar RCV000239404.1), which segregated with the phenotype. Disease-causing variants in this gene are known to be associated with autosomal recessive Mucopolysaccharidosis type IIIC (MPSIIIC, Sanfilippo C). This lysosomal storage disease is due to deficiency of the acetyl-CoA:α-glucosaminidase-N-acetyltransferase, which was shown to be reduced in patient fibroblasts. Our report extends the phenotype associated with MPSIIIC. Besides MPSIIIA and MPSIIIB, due to variants in SGSH and NAGLU, this is the third subtype of Sanfilippo disease to be associated with KBS. MPSIII should be included in the differential diagnosis of young patients with KBS.


Assuntos
Acetiltransferases/genética , Síndrome de Kluver-Bucy/genética , Mucopolissacaridose III/genética , Criança , Exoma , Feminino , Genes Recessivos , Homozigoto , Humanos , Síndrome de Kluver-Bucy/complicações , Síndrome de Kluver-Bucy/diagnóstico , Masculino , Mucopolissacaridose III/complicações , Mucopolissacaridose III/diagnóstico , Fenótipo , Irmãos
14.
Invest Ophthalmol Vis Sci ; 57(3): 1120-31, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26975023

RESUMO

PURPOSE: Retinal degeneration is a common feature of several lysosomal storage disorders, including the mucopolysaccharidoses, a group of metabolic disorders that is characterized by widespread accumulation of glycosaminoglycans due to lysosomal enzyme dysfunction. We used a new mouse model of mucopolysaccharidosis IIIE to study the effect of Arylsulfatase G (ARSG) deficiency on retina integrity. METHODS: The retina of Arsg knockout mice aged 1 to 24 months was studied by immunohistochemistry and Western blot analysis. Electron microscopic analyses were performed on retinas from 15- and 22-month-old animals. Photoreceptor and microglia cell numbers and retina thickness were determined to quantitatively characterize retinal degeneration in ARSG-deficient mice. RESULTS: Arsg knockout mice showed a progressive degeneration of photoreceptor cells starting between 1 and 6 months of age, resulting in the loss of more than 50% of photoreceptor cells in 24-month-old mice. Photoreceptor loss was accompanied by reactive astrogliosis, reactive microgliosis that was evident in the outer but not inner retina, and elevated expression levels of some lysosomal proteins. Electron microscopic analyses of retinas revealed no evidence for the presence of storage vacuoles. Of note, expression of ARSG protein in wild-type mice was detectable only in the RPE which, however, appeared morphologically unaffected in knockout mice at the electron microscopic level. CONCLUSIONS: To our knowledge, this is the first study demonstrating that ARSG deficiency results in progressive photoreceptor degeneration and dysregulation of various lysosomal proteins.


Assuntos
Arilsulfatases/deficiência , Modelos Animais de Doenças , Mucopolissacaridose III/enzimologia , Células Fotorreceptoras/enzimologia , Degeneração Retiniana/enzimologia , Animais , Arilsulfatases/metabolismo , Western Blotting , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microglia/patologia , Mucopolissacaridose III/diagnóstico , Células Fotorreceptoras/patologia , Proteínas/metabolismo , Degeneração Retiniana/diagnóstico , beta-N-Acetil-Hexosaminidases/metabolismo
15.
J Pediatr ; 170: 278-87.e1-4, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26787381

RESUMO

OBJECTIVES: To characterize the clinical course of mucopolysaccharidosis type IIIA (MPS IIIA), and identify potential endpoints for future treatment trials. STUDY DESIGN: Children with a confirmed diagnosis of MPS IIIA, functioning above a developmental age of 1 year, were followed for up to 2 years. Cognitive status and brain atrophy were assessed by standardized tests and volumetric magnetic resonance imaging, respectively. Liver and spleen volumes and cerebrospinal fluid and urine biomarker levels were measured. RESULTS: Twenty-five children, from 1.1 to 18.4 years old, were enrolled, and 24 followed for at least 12 months. 19 exhibited a rapidly progressing (RP) form of MPS IIIA, and 5, a more slowly progressing form. Children with RP plateaued in development by 30 months, followed by rapid regression after 40-50 months. In patients with RP, cognitive developmental quotients showed consistent steep declines associated with progressive cortical gray matter atrophy. Children with slowly progressing had a similar but more prolonged course. Liver and spleen volumes were approximately double normal size, and cerebrospinal fluid and urine heparin sulfate levels were elevated and relatively constant over time. CONCLUSION: Developmental quotient and cortical gray matter volume are sensitive markers of disease progression in MPS IIIA, and may have utility as clinical endpoints in treatment trials. For optimal outcomes, treatment may need to be instituted in children before the onset of steep cognitive decline and brain atrophy. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01047306.


Assuntos
Mucopolissacaridose III/diagnóstico , Adolescente , Atrofia , Biomarcadores/líquido cefalorraquidiano , Biomarcadores/urina , Criança , Desenvolvimento Infantil , Pré-Escolar , Cognição , Progressão da Doença , Feminino , Seguimentos , Substância Cinzenta/patologia , Humanos , Lactente , Fígado/patologia , Imagem por Ressonância Magnética , Masculino , Mucopolissacaridose III/líquido cefalorraquidiano , Mucopolissacaridose III/psicologia , Mucopolissacaridose III/urina , Tamanho do Órgão , Estudos Prospectivos , Índice de Gravidade de Doença , Baço/patologia
16.
Ophthalmic Genet ; 37(2): 217-27, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26331342

RESUMO

PURPOSE: To report longitudinal phenotypic findings in a patient with Sanfilippo syndrome type IIIA, harboring SGSH mutations, one of which is novel. METHODS: Heparan-N-sulfatidase enzyme function testing in skin fibroblasts and white blood cells and SGSH gene sequencing were obtained. Clinical office examinations, examinations under anesthesia, electroretinogram, spectral domain optical coherence tomography (SD-OCT), and fundus photography were performed over a 5-year period. RESULTS: Fundus examination revealed a progressive breadcrumb-like pigmentary retinopathy with perifoveal pigmentary involvement. SD-OCT showed loss of normal neuroretinal lamination and cystic macular changes responsive to treatment with carbonic anhydrase inhibitors. Electroretinography exhibited complex characteristics indicative of a generalized retinal rod > cone dysfunction with significant ON > OFF postreceptoral response compromise. Sequencing revealed compound heterozygous mutations in the SGSH gene, the novel c.88G > C (p.A30P) change and a second, previously reported one (c.734G > A, p.R245H). CONCLUSIONS: We have identified ocular features of a patient with Sanfilippo syndrome type IIIA harboring a novel SGHS mutation that were not previously known to occur in this disease - namely, a progressive retinopathy with distinctive features, cystic macular changes responsive to carbonic anhydrase inhibitors, and complex electroretinographic abnormalities consistent with postreceptoral dysfunction. SD-OCT imaging revealed retinal lamination changes consistent with previously reported histologic studies. Both the SD-OCT and the electroretinogram changes appear attributable to intraretinal deposition of heparan sulfate.


Assuntos
Hidrolases/genética , Mucopolissacaridose III/genética , Mutação , Retinite Pigmentosa/genética , Adulto , Eletrorretinografia , Fibroblastos/enzimologia , Humanos , Masculino , Mucopolissacaridose III/diagnóstico , Mucopolissacaridose III/enzimologia , Retinite Pigmentosa/diagnóstico , Retinite Pigmentosa/enzimologia , Pele/citologia , Sulfatases/metabolismo , Tomografia de Coerência Óptica
17.
Vestn Ross Akad Med Nauk ; (4): 419-27, 2015.
Artigo em Russo | MEDLINE | ID: mdl-26710524

RESUMO

Sanfilippo syndrome (mucopolysaccharidosis type III) is a lysosomal disorder caused by a defect in the catabolism of heparan sulfate. Mucopolysaccharidosis type III is the most common type of all mucopolysaccharidoses. The pathogenic basis of the disease consists of the storage of undegraded substrate in the central nervous system. Progressive cognitive decline resulting in dementia and behavioural abnormalities are the main clinical characteristics of Sanfilippo syndrome. Mucopolysaccharidosis type III may be misdiagnosed as otherforms of developmental delay, attention deficit/hyperactivity disorder and autistic spectrum disorders because of lack of somatic symptoms, presence of mild and atypical forms of the disease. Patients with Sanfilippo syndrome may have comparatively low urinary glycosaminoglycans levels resulting in false negative urinary assay. Definitive diagnosis is made by enzyme assay on leucocytes and cultured fibroblasts. There is currently no effective treatment of mucopolysaccharidosis type III, though ongoing researches of gene, substrate reduction and intrathecal enzyme replacement therapies expect getting curative method to alter devasting damage of central nervous system in near future.


Assuntos
Predisposição Genética para Doença , Mucopolissacaridose III , Fibroblastos/patologia , Saúde Global , Humanos , Morbidade/tendências , Mucopolissacaridose III/diagnóstico , Mucopolissacaridose III/epidemiologia , Mucopolissacaridose III/genética
18.
Pediatr Int ; 57(3): 331-8, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25851924

RESUMO

Mucopolysaccharidosis type III (MPS III, Sanfilippo syndrome) is a lysosomal storage disorder, caused by a deficiency in one of the four enzymes involved in the catabolism of glycosaminoglycan heparan sulfate. It is characterized by progressive cognitive decline and severe hyperactivity, with relatively mild somatic features. This review focuses on clinical features, diagnosis, treatment, and follow-up of MPS III, and provides information about supplementary tests and differential diagnosis. Given that few reviews of MPS III have been published, several studies were compiled to establish diagnostic recommendations. Quantitative urinary glycosaminoglycan analysis is strongly recommended, and measurement of disaccharides, heparin cofactor II-thrombin complex and gangliosides is also used. Enzyme activity of the different enzymes in blood serum, leukocytes or fibroblasts, and mutational analysis for SGSH, NAGLU, HGSNAT or GNS genes are required to confirm diagnosis and differentiate four subtypes of MPS III. Although there is no global consensus for treatment, enzyme replacement therapy and gene therapy can provide appropriate results. In this regard, recent publications on treatment and follow-up are discussed.


Assuntos
Diagnóstico por Imagem , Gerenciamento Clínico , Glicosaminoglicanos/metabolismo , Mucopolissacaridose III , Saúde Global , Humanos , Morbidade , Mucopolissacaridose III/diagnóstico , Mucopolissacaridose III/epidemiologia , Mucopolissacaridose III/terapia
19.
Mol Genet Metab ; 114(4): 594-8, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25770355

RESUMO

The Sanfilippo Behavior Rating Scale (SBRS), a 68 item questionnaire, has been developed to assess the behavioral phenotype of children with Sanfilippo syndrome and its progression over time. Fifteen scales rate orality, movement/activity, attention/self-control, emotional function including anger and fear, and social interaction. Items within scales intercorrelate; measures of internal consistency are adequate. Twelve scales are grouped into 4 abnormality clusters: Movement, Lack of fear, Social/emotional and Executive Dysfunction. A Loess age-trajectory analysis showed that Lack of Fear, Social/Emotional and Executive Dysfunction increased steadily with age; Orality and Mood/Anger/Aggression leveled off. Movement peaked around 6years, then declined as children's excessive/purposeless actions stopped. Compared with standard scales, SBRS Movement was appropriately associated with the Vineland Motor scale; SBRS Lack of Fear had significant associations with the Autism Diagnostic Observation Schedule (ADOS), indicating a symptom overlap between Sanfilippo syndrome and autism. This suggests that reduced fearfulness may be the most salient/sensitive SBRS marker of disease progression. Volumetric MRI showed that increased Lack of Fear was significantly associated with reduced amygdala volume, consistent with our hypothesis that the behavior seen in Sanfilippo syndrome is a variant of Klüver-Bucy syndrome. Hippocampal volume loss had twice the effect on Social-Emotional Dysfunction as amygdala loss, consistent with a hippocampal role in attachment and social emotions. In conclusion, the SBRS assesses the Sanfilippo behavioral phenotype; it can measure behavior change that accompanies disease progression and/or results from treatment.


Assuntos
Escala de Avaliação Comportamental , Comportamento , Mucopolissacaridose III/psicologia , Adolescente , Tonsila do Cerebelo/patologia , Transtorno Autístico/diagnóstico , Transtorno Autístico/psicologia , Criança , Pré-Escolar , Medo , Feminino , Humanos , Lactente , Masculino , Mucopolissacaridose III/diagnóstico , Mucopolissacaridose III/patologia , Neuroimagem , Fenótipo , Comportamento Social , Inquéritos e Questionários
20.
Mol Genet Metab ; 114(2): 123-8, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25458519

RESUMO

Mucopolysaccharidoses (MPS) are complex storage disorders that result in the accumulation of glycosaminoglycans (GAGs) in urine, blood, brain and other tissues. Symptomatic patients are typically screened for MPS by analysis of GAG in urine. Current screening methods used in clinical laboratories are based on colorimetric assays that lack the sensitivity and specificity to reliably detect mild GAG elevations that occur in some patients with MPS. We have developed a straightforward, reliable method to quantify chondroitin sulfate (CS), dermatan sulfate (DS) and heparan sulfate (HS) in urine by stable isotope dilution tandem mass spectrometry. The GAGs were methanolyzed to uronic acid-N-acetylhexosamine or iduronic acid-N-glucosamine dimers and mixed with stable isotope labeled internal standards derived from deuteriomethanolysis of GAG standards. Specific dimers derived from HS, DS and CS were separated by ultra-performance liquid chromatography and analyzed by electrospray ionization tandem mass spectrometry using selected reaction monitoring for each targeted GAG product and its corresponding internal standard. The method was robust with a mean inaccuracy from 1 to 15%, imprecision below 11%, and a lower limit of quantification of 0.4mg/L for CS, DS and HS. We demonstrate that the method has the required sensitivity and specificity to discriminate patients with MPS III, MPS IVA and MPS VI from those with MPS I or MPS II and can detect mildly elevated GAG species relative to age-specific reference intervals. This assay may also be used for the monitoring of patients following therapeutic intervention. Patients with MPS IVB are, however, not detectable by this method.


Assuntos
Sulfatos de Condroitina/urina , Cromatografia Líquida/métodos , Dermatan Sulfato/urina , Heparitina Sulfato/urina , Mucopolissacaridoses/diagnóstico , Espectrometria de Massas em Tandem/métodos , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Glicosaminoglicanos/urina , Humanos , Lactente , Pessoa de Meia-Idade , Mucopolissacaridose II/diagnóstico , Mucopolissacaridose III/diagnóstico , Mucopolissacaridose IV , Mucopolissacaridose VI/diagnóstico , Técnica de Diluição de Radioisótopos , Valores de Referência , Espectrometria de Massas por Ionização por Electrospray , Adulto Jovem
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