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1.
Neuropathology ; 2020 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-32219895

RESUMO

GM1 gangliosidosis is a storage disorder with autosomal recessive inheritance caused by deficiency of ß-galactosidase (GLB1), which is a lysosomal hydrolase, due to mutations in GLB1. We describe here an autopsy case of GM1 gangliosidosis in a female patient who survived for 38 years with a long period of artificial respiratory support (ARS). She was born after a normal pregnancy and delivery. Although development was normal until one year old, she was unable to walk at two years old and started having seizures by nine years old. At 21 years old, she became unable to communicate and was bed-ridden. At 36 years old, she suffered from pneumonia and required ARS. She died of pneumonia at 40 years old. Neuropathological examination revealed severe atrophy, predominantly found in the frontal lobes. Microscopically, severe gliosis and neuronal loss were observed in the cerebral cortex, putamen, cerebellum, the latter including Purkinje cell and granule cell layers. The hippocampus was relatively preserved. Severe neuronal swelling was observed in the limbic regions and stored a material in these neurons negative for periodic acid-Schiff (PAS). A PAS-positive granular storage material in neurons and macrophages was mainly observed in the brainstem and limbic regions. Exome analysis showed a known c.152T>C (p.I51T) variant that has been described in type III patients and a novel c.1348-2A>G variant in GLB1. Detailed analysis of reverse transcription-polymerase chain reaction products of GLB1 mRNA revealed that these variants were present in a compound heterozygous state. In our case, clinical features and neuropathological findings were most consistent with type II, although the entire course was longer than any previously reported cases. This may be explained by the residual enzyme activity in this patient whose severity lay between types II and III. Our finding of relative preservation of the limbic regions suggests that neuronal loss in GM1 gangliosidosis has regional selectivity.

2.
Chem Commun (Camb) ; 55(85): 12845-12848, 2019 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-31596280

RESUMO

Multivalent mannosides with inherent macrophage recognition abilities, built on ß-cyclodextrin, RAFT cyclopeptide or peptide dendrimer cores, trigger selective inhibition of lysosomal ß-glucocerebrosidase or α-mannosidase depending on valency and topology, offering new opportunities in multitargeted drug design.


Assuntos
Desenho de Fármacos , Manosídeos/química , Glucosilceramidase/antagonistas & inibidores , Lectinas/química , Macrófagos/metabolismo , Manosídeos/metabolismo , Peptídeos Cíclicos/química , alfa-Manosidase/antagonistas & inibidores , beta-Ciclodextrinas/química
3.
Yonago Acta Med ; 62(3): 244-252, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31582890

RESUMO

Background: During the investigation of causative variants of Mendelian disorders using next-generation sequencing, the enormous number of possible candidates makes the detection process complex, and the use of multidimensional methods is required. Although the utility of several variant prioritization tools has been reported, their effectiveness in Japanese patients remains largely unknown. Methods: We selected 5 free variant prioritization tools (PhenIX, hiPHIVE, Phen-Gen, eXtasy-order statistics, and eXtasy-combined max) and assessed their effectiveness in Japanese patient populations. To compare these tools, we conducted 2 studies: one based on simulated data of 100 diseases and another based on the exome data of 20 in-house patients with Mendelian disorders. To this end we selected 100 pathogenic variants from the "Database of Pathogenic Variants (DPV)" and created 100 variant call format (VCF) files that each had pathogenic variants based on reference human genome data from the 1000 Genomes Project. The later "in-house" study used exome data from 20 Japanese patients with Mendelian disorders. In both studies, we utilized 1-5 terms of "Human Phenotype Ontology" as clinical information. Results: In our analysis based on simulated disease data, the detection rate of the top 10 causative variants was 91% for hiPHIVE, and 88% for PhenIX, based on 100 sets of simulated disease VCF data. Also, both software packages detected 82% of the top 1 causative variants. When we used data from our in-house patients instead, we found that these two programs (PhenIX and hiPHIVE) produced higher detection rates than the other three systems in our study. The detection rate of the top 1 causative variant was 71.4% for PhenIX, 65.0% for hiPHIVE. Conclusion: The rates of detecting causative variants in two Exomizer software packages, hiPHIVE and PhenIX, were higher than for the other three software systems we analyzed, with respect to Japanese patients.

4.
Hum Genome Var ; 6: 22, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31044084

RESUMO

Galactosialidosis is an autosomal recessive lysosomal storage disease caused by the combined deficiency of lysosomal ß-galactosidase and neuraminidase due to a defect in the protective protein/cathepsin A. Patients present with various clinical manifestations and are classified into three types according to the age of onset: the early infantile type, the late infantile type, and the juvenile/adult type. We report a Japanese female case of juvenile/adult type galactosialidosis. Clinically, she presented with short stature, coarse facies, angiokeratoma, remarkable action myoclonus, and cerebellar ataxia. The patient was diagnosed with galactosialidosis with confirmation of impaired ß-galactosidase and neuraminidase function in cultured skin fibroblasts. Sanger sequencing for CTSA identified a compound heterozygous mutation consisting of NM_00308.3(CTSA):c.746 + 3A>G and c.655-1G>A. Additional analysis of her mother's DNA sequence indicated that the former mutation originated from her mother, and therefore the latter was estimated to be from the father or was a de novo mutation. Both mutations are considered pathogenic owing to possible splicing abnormalities. One of them (c.655-1G>A) is novel because it has never been reported previously.

5.
Yonago Acta Med ; 62(1): 159-162, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30962759

RESUMO

We report the case of a 6-year-old male who developed recurrent erythema nodosum (EN) at the age of 3 years. The patient exhibited hypertelorism, low-set ears, micrognathia, moderate intellectual disability, thin long fingers, loose anagen hair, and prominent palmoplantar wrinkles. A heterozygous single nucleotide variant in the SHOC2 gene (c.4 A > G, p.S2G) was identified. Patients with a SHOC2 mutation exhibit a unique combination of ectodermal abnormalities including darkly pigmented skin and loose anagen hair. This report is the first to describe EN in a patient with SHOC2 mutation, and to examine the patient's hair using scanning electron microscopy. We hypothesize that the RAS/MAPK pathway is associated with the pathogenesis of cutaneous lesions in patients with SHOC2 mutations via autoinflammation and disturbance of epithelial stem cells.

6.
J Med Chem ; 62(12): 5832-5843, 2019 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-31017416

RESUMO

α-Mannosidosis (AM) results from deficient lysosomal α-mannosidase (LAMAN) activity and subsequent substrate accumulation in the lysosome, leading to severe pathology. Many of the AM-causative mutations compromise enzyme folding and could be rescued with purpose-designed pharmacological chaperones (PCs). We found that PCs combining a LAMAN glycone-binding motif based on the 5 N,6 O-oxomethylidenemannojirimycin (OMJ) glycomimetic core and different aglycones, in either mono- or multivalent displays, elicit binding modes involving glycone and nonglycone enzyme regions that reinforce the protein folding and stabilization potential. Multivalent derivatives exhibited potent enzyme inhibition that generally prevailed over the chaperone effect. On the contrary, monovalent OMJ derivatives with LAMAN aglycone binding area-fitting substituents proved effective as activity enhancers for several mutant LAMAN forms in AM patient fibroblasts and/or transfected MAN2 B1-KO cells. This translated into a significant improvement in endosomal/lysosomal function, reverting not only the primary LAMAN substrate accumulation but also the additional downstream consequences such as cholesterol accumulation.

7.
BMC Neurol ; 18(1): 117, 2018 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-30119649

RESUMO

BACKGROUND: Niemann-Pick disease type C (NPC) is a lysosomal storage disorder with severe prognosis. Disease-specific therapy is crucial to prevent disease progression; however, diagnosing NPC is quite difficult because of remarkably variable clinical presentations. The NPC Suspicion Index (NPC-SI) was developed to overcome this problem. Identifying preclinical cases is important for prevention and therapy. Here, we report three newly diagnosed NPC cases, one typical juvenile-onset case and the cases of two sisters with symptoms neurologically/psychiatrically indistinguishable from dystonia and schizophrenia, respectively. CASE PRESENTATION: In Case 1, a 25-year-old man presented with a 14-year history of intellectual disability, clumsiness, spastic ataxia, dysphagia, and frequent falls. Neurological examination revealed vertical supranuclear gaze palsy and involuntary movements. Ultrasonography revealed mild splenomegaly, and filipin staining of skin fibroblasts was positive with a variant staining pattern. NPC1 gene analysis showed compound heterozygous mutations, including c.1421C > T (p.P474L), a known causative mutation, and c.3722 T > C (p.L1241S), a new mutation. In Case 2, a 28-year-old woman, the proband, who had marked splenomegaly in her childhood, survived well, contrary to the expected severe prognosis of infantile NPC. She had minor neuropsychiatric symptoms including auditory hallucinations, nocturnal urination, and sleep paralysis. At the age of 28 years, she presented with a 1-year history of orofacial and oromandibular painful dystonia. The patient's 35-year-old sister (Case 3) was diagnosed with schizophrenia. In both cases, filipin staining of skin fibroblasts was positive with variant staining patterns, as well as elevated levels of urinary bile acids. NPC1 gene analysis showed compound heterozygous mutations including c.3011C > T (p.S1004 L), a known causative mutation, and c.160_161insG (p.D54GfsX4), a new mutation. Their mother, who was under therapy with modafinil for narcolepsy, shared the latter mutation. CONCLUSIONS: Marked clinical variability was observed in our three cases. NPC could masquerade as a pure neuropsychiatric disorder such as dystonia or schizophrenia. Abdominal ultrasonography, history evaluation, and neurological examination were quite important in the diagnostic process.


Assuntos
Proteínas de Transporte/genética , Glicoproteínas de Membrana/genética , Doença de Niemann-Pick Tipo C , Esquizofrenia , Adulto , Variação Biológica da População , Feminino , Humanos , Masculino , Doença de Niemann-Pick Tipo C/complicações , Doença de Niemann-Pick Tipo C/genética , Esquizofrenia/complicações , Esquizofrenia/genética
8.
Medicine (Baltimore) ; 97(27): e11361, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29979419

RESUMO

RATIONALE: Gaucher disease (GD) is an autosomal recessive disorder that leads to multiorgan complications caused by ß-glucocerebrosidase deficiency due to mutations in the ß-glucocerebrosidase-encoding gene (GBA). GD morbidity in Japan is quite rare and clinical phenotype and gene mutation patterns of patients with GD in Japan and Western countries differ considerably. Of Japanese patients with GD, 57% develop types 2 or 3 GD with neurologic manifestations and younger onset, whereas only 6% of patients with GD develop those manifestations in Western countries. Thus, it is relatively difficult to find and diagnose GD in Japan. PATIENT CONCERNS: A 69-year-old Japanese female with mild anemia and thrombocytopenia but without neurologic symptoms was initially referred for gastric cancer. Preoperative F-deoxyglucose positron emission tomography/computed tomography (FDG PET/CT) showed accumulation in the bone marrow and paraabdominal lymph nodes. Following bone marrow aspiration found, abnormal foamy macrophages in the bone marrow and electron microscopy revealed that the macrophages were filled with tubular-form structures. Adding to these signs suggestive of a lysosomal disease, serum ß-glucocerebrosidase activity test found decreased. Sequencing of the patient's GBA gene revealed a RecNciI recombinant mutation and the novel mutation K157R (c.587A>G). DIAGNOSES: On the basis of these findings and clinical manifestations, the final diagnosis of type 1 GD was made. INTERVENTIONS: Enzyme replacement therapy (ERT) with velaglucerase α was started after the diagnosis of type 1 GD. OUTCOMES: The patient's ß-glucocerebrosidase activity as well as hemoglobin and platelet levels were restored by ERT without any side effects. Bone marrow aspirations 10 months after the start of the treatment with velaglucerase α showed reduction of Gaucher cells in bone marrow to 2% from 4% of total cellularity. LESSONS: This is the first report of F-FDG PET/CT application providing a clue for GD diagnosis. A novel mutation in GBA is described, which implies a potential pool of patients with GD with this mutation in Japan.


Assuntos
Doença de Gaucher/genética , Glucosilceramidase/genética , Neoplasias Gástricas/genética , Idoso , Grupo com Ancestrais do Continente Asiático , Medula Óssea/patologia , Terapia de Reposição de Enzimas/métodos , Feminino , Doença de Gaucher/complicações , Doença de Gaucher/diagnóstico , Humanos , Japão , Mutação , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Estômago/patologia , Neoplasias Gástricas/complicações
10.
Molecules ; 23(4)2018 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-29673163

RESUMO

A series of sp²-iminosugar glycomimetics differing in the reducing or nonreducing character, the configurational pattern (d-gluco or l-ido), the architecture of the glycone skeleton, and the nature of the nonglycone substituent has been synthesized and assayed for their inhibition properties towards commercial glycosidases. On the basis of their affinity and selectivity towards GH1 ß-glucosidases, reducing and nonreducing bicyclic derivatives having a hydroxylation profile of structural complementarity with d-glucose and incorporating an N'-octyl-isourea or -isothiourea segment were selected for further evaluation of their inhibitory/chaperoning potential against human glucocerebrosidase (GCase). The 1-deoxynojirimycin (DNJ)-related nonreducing conjugates behaved as stronger GCase inhibitors than the reducing counterparts and exhibited potent chaperoning capabilities in Gaucher fibroblasts hosting the neuronopathic G188S/G183W mutation, the isothiourea derivative being indeed one of the most efficient chaperone candidates reported up to date (70% activity enhancement at 20 pM). At their optimal concentration, the four selected compounds promoted mutant GCase activity enhancements over 3-fold; yet, the inhibitor/chaperoning balance became unfavorable at much lower concentration for nonreducing as compared to reducing derivatives.


Assuntos
Inibidores Enzimáticos/uso terapêutico , Doença de Gaucher/tratamento farmacológico , Doença de Gaucher/enzimologia , Glucosilceramidase/antagonistas & inibidores , Glucosilceramidase/genética , Imino Açúcares/uso terapêutico , Chaperonas Moleculares/uso terapêutico , 1-Desoxinojirimicina/uso terapêutico , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Doença de Gaucher/genética , Glucosamina/análogos & derivados , Glucosamina/uso terapêutico , Humanos , Mutação
11.
Brain Dev ; 40(1): 36-41, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28774669

RESUMO

PURPOSE: To clarify the relationship between macrocephaly and neurodevelopmental disorders, as well as identify the prevalence of PTEN mutations in autism spectrum disorders with macrocephaly in Japan. SUBJECTS AND METHODS: Diagnostic and other medical information of children with macrocephaly younger than 4years (n=93) were collected for analysis. PTEN gene mutation analysis was conducted in another set of 16 macrocephalic individuals aged 3-22years. RESULTS: Sixteen macrocephalic children were associated with neurodevelopmental disorders, including autism spectrum disorders (ASDs) (n=6), autistic traits (n=5), intellectual disability (n=5), attention deficit hyperactivity disorder (n=1), developmental coordination disorders (n=1), and language disorder (n=1). Male gender was significantly linked to these disorders, whereas a family history and degree of macrocephaly were not significantly linked to the diagnosis. A novel mutation in the PTEN gene was identified in a 16-year-old girl with autism, mental retardation, language delay, extreme macrocephaly (+4.7SD) with a prominent forehead, and digital minor anomalies. CONCLUSION: Children with macrocephaly, particularly males, are at a higher risk of neurodevelopmental disorders, rather than progressive etiologies, such as hydrocephalus and neurodegenerative disorders. The data provide a basis for routine health checks for young children in Japan, including the follow-up management and possible screening of PTEN mutations in children with ASDs and macrocephaly.


Assuntos
Transtorno do Espectro Autista/genética , Megalencefalia/genética , PTEN Fosfo-Hidrolase/genética , Transtorno do Espectro Autista/fisiopatologia , Transtorno Autístico/genética , Pré-Escolar , Anormalidades Craniofaciais , Estudos Transversais , Deficiências do Desenvolvimento/genética , Feminino , Humanos , Lactente , Deficiência Intelectual/genética , Japão , Transtornos do Desenvolvimento da Linguagem/genética , Masculino , Transtornos das Habilidades Motoras , Transtornos do Neurodesenvolvimento/epidemiologia , Transtornos do Neurodesenvolvimento/genética , PTEN Fosfo-Hidrolase/metabolismo , Prevalência
12.
J Endocr Soc ; 1(12): 1408-1416, 2017 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-29264464

RESUMO

Context: Hypoglycemia is the most common metabolic problem among small-for-gestational-age (SGA) neonates. However, the pathological mechanism and insulin/ insulin-like growth factor (IGF) signaling axis in neonates remain unknown. Objective: To determine the insulin/IGF axis in neonates, we analyzed the messenger RNA (mRNA) expression of insulin/IGF signaling in fetal umbilical cord blood. Setting: The Perinatal Medical Center of Tottori University Hospital. Participants: Fifty-two [42 appropriate-for-gestational-age (AGA) and 10 SGA] neonates. Interventions: Immediately collected cord blood was placed into a PAXgene Blood RNA Tube. Total RNA from the blood was purified using reagents provided in the PAXgene Blood RNA Kit within 4 days, and reverse transcription polymerase chain reaction (PCR) was performed. Main Outcome Measure: Quantitative real-time PCR analysis was applied to evaluate the mRNA expression of insulin receptor (INSR), IGF-I receptor (IGF1R), insulin receptor substrate 1 (IRS1), IRS2, and glucose transporters (SLC2A2 and SLC2A4). ß-Actin was used as a control gene. Results: Serum glucose and IGF-I levels in SGA neonates were significantly lower. The cord serum insulin levels were similar between AGA and SGA neonates. The IRS2 mRNA expression was significantly higher in SGA than in AGA neonates (P < 0.05). The IRS2 mRNA expression was significantly higher in hypoglycemic SGA neonates than in normoglycemic SGA neonates. Conclusions: We determined that intrauterine growth restriction induces increased IRS2 mRNA expression in cord blood, without hyperinsulinemia. The increased expression of IRS2 mRNA might be associated with abnormal glucose metabolism in SGA neonates. Our findings might lead to the elucidation of abnormal glucose metabolism in SGA neonates.

14.
Epileptic Disord ; 19(3): 339-344, 2017 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-28721930

RESUMO

SYNGAP1 gene mutation has been associated with epilepsy which is often drug resistant, with seizure types including eyelid myoclonia. However, detailed descriptions, including ictal video-EEG, have not been reported. We report the case of a 4-year-old boy who developed recurrent epileptic eyelid twitching at 1 year and 5 months of age. Seizures gradually increased in frequency to more than 50 times per day and manifested with upward eye deviation, motion arrest, loss of consciousness, and eyelid twitching lasting for five seconds. Ictal EEG showed rhythmic, generalized slow or spike-and-wave complex activity with posterior predominance. Moderate psychomotor developmental delay and unsteady gait were also noted. Neuroimaging results were normal. Seizures were refractory to carbamazepine and levetiracetam but were reduced in frequency by ethosuximide and lamotrigine administration. Genetic analysis identified a c.3583-6 G>A mutation in the SYNGAP1 gene. SYNGAP1 gene analysis should be considered for intellectually disabled patients with early-onset drug resistant eyelid twitching and photosensitivity. Further clinical research on SYNGAP1 function may be necessary to treat epilepsy of this aetiology. [Published with video sequence on www.epilepticdisorders.com].


Assuntos
Blefarospasmo/diagnóstico , Encéfalo/fisiopatologia , Epilepsia Resistente a Medicamentos/diagnóstico , Mutação , Proteínas Ativadoras de ras GTPase/genética , Blefarospasmo/genética , Blefarospasmo/fisiopatologia , Pré-Escolar , Epilepsia Resistente a Medicamentos/genética , Epilepsia Resistente a Medicamentos/fisiopatologia , Eletroencefalografia , Humanos , Masculino
15.
Brain Dev ; 39(10): 886-890, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28587793

RESUMO

Niemann-Pick disease type C (NPC) is a rare, progressive autosomal recessive disease. It is caused by mutations in either the NPC1 or NPC2 genes, resulting in defective regulation of intracellular lipid trafficking. Miglustat, which reversibly inhibits glucosylceramide synthase, reportedly has beneficial effects on the progressive neurological symptoms of NPC and was approved in Japan in 2012. Some reports suggested that miglustat therapy delayed the onset or progression of NPC when treatment was initiated before the onset of neurological manifestation or at an early stage. We report here a patient with the early-infantile form of NPC who started on miglustat at 4months of ages. To our knowledge, this patient is the youngest reported patient with NPC in which miglustat therapy was initiated. Our patient, who had hypotonia and developmental delay before treatment, remained stable and showed no new neurological symptoms. In addition, pulmonary involvement was improved during miglustat therapy. Our case and previous reports underscore the importance of early initiation of miglustat therapy for NPC.


Assuntos
1-Desoxinojirimicina/análogos & derivados , Doença de Niemann-Pick Tipo C/terapia , 1-Desoxinojirimicina/farmacologia , Sequência de Bases , Proteínas de Transporte/genética , Pré-Escolar , Deficiências do Desenvolvimento , Progressão da Doença , Glucosiltransferases/antagonistas & inibidores , Humanos , Japão , Masculino , Glicoproteínas de Membrana/genética , Mutação
16.
Neuropathology ; 37(5): 426-430, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28387450

RESUMO

Niemann-Pick disease type C (NPC) is a cholesterol storage disease caused by defective cellular cholesterol transportation. The onset and progression of NPC are variable, and autopsy findings have mainly been reported for the adult and juvenile forms of this disease. Here we report the clinical and pathological findings from a 9-year-old female patient with the late infantile form of NPC due to NPC1 gene mutation. She had notable splenomegaly at 4 months of age. She lost the ability to speak at 18 months of age. She learned to walk, but often fell and could no longer walk after 30 months. At 3 years of age, she was diagnosed with NPC. Sequence analysis of the NPC1 gene revealed compound heterozygous mutation of T2108C (F703S) and C2348G (S813X) (both novel). Thereafter, the patient suffered repeated respiratory infections and died of respiratory failure at 9 years of age. Pathological findings included cerebral atrophy (particularly of white matter), severe demyelination, and the loss of neurons from the cerebrum and from the nuclei of the brain stem. Remnant neuronal cells and microglia in the cerebrum, cerebellum, and brain stem had become swollen and foamy. Neurons of the hippocampal CA1 and Purkinje cells were relatively spared, and senile plaques and axonal spheroids were not present. Foamy cells were also observed in other organs, especially the spleen and bone marrow. The F703S mutation in this patient was localized in a sterol-sensing domain (SSD). Severe neurological phenotypes have been previously reported in patients with missense mutations in an SSD. It is considered that the combination of a nonsense mutation and missense mutation in an SSD was responsible for the severe neurological phenotype of our present patient. While pathological findings of adult/juvenile forms of NPC have included swollen neurons and glia, neuronal cell loss, and NFTs, demyelination may be a predominant finding in the infantile form of NPC.


Assuntos
Encéfalo/patologia , Doenças Desmielinizantes/patologia , Doença de Niemann-Pick Tipo C/patologia , Criança , Feminino , Humanos
18.
Hum Genome Var ; 4: 16047, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28144448

RESUMO

Pulmonary alveolar microlithiasis (PAM) is a rare autosomal recessive disease caused by mutations in SLC34A2 and characterized by intra-alveolar accumulation of microliths. We diagnosed a case of PAM in a 27-year-old Japanese female and identified a novel mutation in SLC34A2 (c.1390 G>C [G464R] in exon 12).

19.
J Med Chem ; 60(5): 1829-1842, 2017 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-28171725

RESUMO

Amphiphilic glycomimetics encompassing a rigid, undistortable nortropane skeleton based on 1,6-anhydro-l-idonojirimycin and a polyfluorinated antenna, when formulated as the corresponding inclusion complexes with ß-cyclodextrin (ßCD), have been shown to behave as pharmacological chaperones (PCs) that efficiently rescue lysosomal ß-glucocerebrosidase mutants associated with the neuronopathic variants of Gaucher disease (GD), including the highly refractory L444P/L444P and L444P/P415R single nucleotide polymorphs, in patient fibroblasts. The body of work here presented includes the design criteria for the PC prototype, the synthesis of a series of candidates, the characterization of the PC:ßCD complexes, the determination of the selectivity profiles toward a panel of commercial and human lysosomal glycosidases, the evaluation of the chaperoning activity in type 1 (non-neuronopathic), type 2 (acute neuronopathic), and type 3 (adult neuronopathic) GD fibroblasts, the confirmation of the rescuing mechanism by immunolabeling, and the analysis of the PC:GCase binding mode by docking experiments.


Assuntos
Flúor/química , Doença de Gaucher/enzimologia , Glucosilceramidase/metabolismo , Chaperonas Moleculares/metabolismo , beta-Ciclodextrinas/química , Células Cultivadas , Humanos , Simulação de Acoplamento Molecular
20.
No To Hattatsu ; 49(3): 203-6, 2017 05.
Artigo em Japonês | MEDLINE | ID: mdl-30113798

RESUMO

We describe the case of a 15-year-old male with early juvenile type GM2 gangliosidosis. He first manifested with progressive clumsiness in his extremities at the age of 1.5 years, followed by motor regression. Intellectual disability became evident as late as age 6 years. This discrepancy along with rapid motor deterioration after varicella infection, lack of startle response or macrocephaly, and paucity of myoclonus were thought to be characteristic of juvenile GM2 gangliosidosis. In contrast to the cerebellar atrophy as the initial finding in usual juvenile GM2 gangliosidosis, magnetic resonance imaging revealed initially cerebral, and subsequently cerebellar, progressive atrophy. Autistic behavioral problems, including phonophobia, during intellectual regression in this patient was also unusual in juvenile GM2 gangliosidosis. Thus, recognition of these features would prompt proper diagnosis and insights into the pathomechanisms of GM2 gangliosidosis.


Assuntos
Gangliosidoses GM2/diagnóstico por imagem , Adolescente , Idade de Início , Encéfalo/diagnóstico por imagem , Gangliosidoses GM2/fisiopatologia , Humanos , Imagem por Ressonância Magnética , Masculino , Índice de Gravidade de Doença
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