RESUMO
Action myoclonus renal failure (AMRF) syndrome is a rare form of progressive myoclonus epilepsy with renal dysfunction related to mutations in the SCARB2 gene. This gene is involved in lysosomal mannose-6-phosphate-independent trafficking of ß-glucocerebrosidase (GC), an enzyme deficient in Gaucher disease. We report a family with myoclonic epilepsy, ataxia and skeletal muscle atrophy but without cognitive impairment or overt renal disease. A novel SCARB2 mutation was indicated by a striking discrepancy between lymphocyte and fibroblast GC activity in the proband evaluated for possible Gaucher disease. Our findings expand the genetic and phenotypic diversity of AMRF and suggest that low GC activity may present an important biochemical clue to the diagnosis of AMRF.
Assuntos
Glucosilceramidase/metabolismo , Proteínas de Membrana Lisossomal/genética , Mutação/genética , Epilepsias Mioclônicas Progressivas/enzimologia , Epilepsias Mioclônicas Progressivas/genética , Receptores Depuradores/genética , Adolescente , Ativação Enzimática/fisiologia , Seguimentos , Humanos , Masculino , Epilepsias Mioclônicas Progressivas/diagnóstico , LinhagemRESUMO
In Israel, Krabbe disease is frequent in two Moslem Arab villages in the Jerusalem area. In this paper we present our experience of almost four decades with diagnosis of Krabbe disease, carrier screening and prenatal diagnosis. The screening program is well accepted by the community, and there is a clear trend towards premarital testing. The screening program and prenatal diagnosis have led to a decrease in the incidence of Krabbe disease from 1.6 per 1,000 live births to 0.82 per 1,000.
Assuntos
Testes Genéticos , Leucodistrofia de Células Globoides/genética , Pré-Escolar , Família , Inquéritos Epidemiológicos , Heterozigoto , Humanos , Aprendizagem , Diagnóstico Pré-NatalRESUMO
Niemann-Pick type C (NPC) disease is a lysosomal neurovisceral storage disease. The spectrum of the clinical presentation as well as the severity of the disease and the age of presentation may be highly variable. Fetal presentation is rarely described in the literature. Here, we report on seven new cases of fetal onset NPC of whom two were diagnosed in utero and five postnatally. The fetal clinical presentation, included, in utero splenomegaly (6/7), in utero hepatomegaly (5/7), in utero ascites (4/7), intra uterine growth retardation (IUGR) (2/7), and oligohydramnios (2/7). Placentomegaly was present in two of the three pregnancies examined. Congenital thrombocytopenia (4/4), congenital anemia (2/4), and petechial rash (2/5) were diagnosed immediately after birth. Three patients were born preterm. Pregnancy and postnatal outcome were remarkably poor with one case of intrauterine fetal death, one elective termination of pregnancy, and four patients who died within the first months of life from a rapidly fatal neonatal cholestatic disease. NPC1 gene mutation analysis identified all of the mutant alleles including three novel mutations. Splenomegaly, hepatomegaly, and ascites were the most consistent prenatal ultrasonographic findings of the NPC fetuses. We suggest that once identified these findings, should raise the suspicion of fetal NPC. Our study further expands the antenatal clinical spectrum of NPC and provides clues to its prenatal diagnosis.
Assuntos
Ascite/genética , Proteínas de Transporte/genética , Hepatomegalia/genética , Doenças por Armazenamento dos Lisossomos/genética , Glicoproteínas de Membrana/genética , Doença de Niemann-Pick Tipo C/genética , Esplenomegalia/genética , Ascite/diagnóstico por imagem , Análise Mutacional de DNA , Feminino , Morte Fetal , Feto , Hepatomegalia/diagnóstico por imagem , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Doenças por Armazenamento dos Lisossomos/diagnóstico por imagem , Proteína C1 de Niemann-Pick , Doença de Niemann-Pick Tipo C/diagnóstico , Gravidez , Diagnóstico Pré-Natal , Esplenomegalia/diagnóstico por imagem , Ultrassonografia Pré-NatalRESUMO
Mucolipidosis type IV (MLIV) is a neurodegenerative channelopathy that is caused by the deficiency of TRPML1 activity, a nonselective cation channel. TRPML1 is a lysosomal membrane protein, and thus, MLIV is a lysosomal storage disorder. The basic, specific function of TRPML1 has not been yet clarified. A recent report (Soyombo AA, Tjon-Kon-Sang S, Rbaibi Y, Bashllari E, Bisceglia J, Muallem S, Kiselyov K: J Biol Chem 281:7294-7301, 2006) indicated that TRPML1 functions as an outwardly proton channel whose function is the prevention of overacidification of these organelles. Thus, in MLIV the lysosomal pH is lower than normal. Furthermore, attempts by these investigators to increase slightly the lysososmal pH with either Nigericin or Chloroquine suggested corrective effect of the abnormal storage in MLIV cells. We investigated this approach using these agents with cultured fibroblasts from severely affected and milder patients. Our data indicated that there was no reduction in the total number of storage vesicles by either agent, although Nigericin resulted in a change in the nature of the storage materials, reducing the presence of lamellated substances (lipids) so that the storage vesicles contained predominantly granulated substances. On the other hand, transfection with the normal MCOLN1 cDNA (the gene coding for TRPML1) resulted in the removal of almost all the storage materials.
Assuntos
Concentração de Íons de Hidrogênio , Lisossomos/metabolismo , Mucolipidoses/fisiopatologia , Antimaláricos/farmacologia , Células Cultivadas , Cloroquina/farmacologia , Fibroblastos/citologia , Fibroblastos/fisiologia , Humanos , Ionóforos/farmacologia , Lisossomos/efeitos dos fármacos , Nigericina/farmacologia , Canais de Cátion TRPM/genética , Canais de Cátion TRPM/metabolismo , Canais de Potencial de Receptor TransitórioRESUMO
We report the first known case in Israel of a patient with an early childhood onset of ceroid-lipofuscinosis who is homozygous to a mutation of the CLN8 gene. This patient further expands the clinical varieties of CLN8, initially reported in Finland and Turkey and recently in Italy. The ultrastructural pathology of a skin biopsy specimen revealed abundant typical fingerprint profiles, but rare granular osmiophilic bodies and curvilinear structures. Sequencing of exon 3 of the CLN8 gene revealed a novel C>G missense mutation at a conserved amino acid glutamine 256 to glutamic acid. Our findings further raise the possibility of the existence of a Mediterranean CLN8 variant.
Assuntos
Proteínas de Membrana/genética , Mutação de Sentido Incorreto , Lipofuscinoses Ceroides Neuronais/genética , Pré-Escolar , Células Epiteliais/patologia , Células Epiteliais/ultraestrutura , Homozigoto , Humanos , Israel , Masculino , Região do Mediterrâneo , Microscopia Eletrônica , Lipofuscinoses Ceroides Neuronais/patologia , FenótipoRESUMO
BACKGROUND: Human beta-mannosidosis, a rare disorder of oligosaccharide catabolism, results from a deficiency of beta-mannosidase activity. So far, mutational analysis has been performed in only seven families and revealed 11 mutations in the MANBA gene which encodes the enzyme beta-mannosidase. OBJECTIVES: We report here a 36-year-old Arab female with beta-mannosidosis who presented with mental retardation and multiple angiokeratomas. We describe in this patient a novel null mutation and review the previously reported MANBA gene mutations and their clinical correlations. METHODS: Histopathology, ultrastructural analysis, and enzyme assays were performed. Sequencing of cDNA and genomic DNA analysis was conducted in a search for a mutation in the MANBA gene. RESULTS: Histopathology of a skin biopsy specimen from the patient showed the characteristic findings of angiokeratoma. Electron microscopy showed cytoplasmic vacuolation. Enzymatic activity of beta-mannosidase in the patient's serum, leukocytes, and fibroblasts was less than 1% of control values. Sequencing of the MANBA cDNA revealed a G-->A transition in exon 6 at nucleotide position c.693, resulting in the formation of a stop codon (W231X). LIMITATIONS: Only one family was studied. CONCLUSIONS: A new case of human beta-mannosidosis is presented and the first MANBA gene mutation from Arab ancestry is reported. Reviewing the reported MANBA gene mutations does not reveal a clear genotype-phenotype correlation. The importance of angiokeratoma corporis diffusum as the clue to the diagnosis of beta-mannosidosis and other lysosomal storage diseases is emphasized.
Assuntos
Árabes/genética , Códon sem Sentido , Doença de Fabry/etiologia , beta-Manosidase/genética , beta-Manosidose/complicações , beta-Manosidose/genética , Adenina , Adulto , Sequência de Bases , Códon de Terminação , Citoplasma/ultraestrutura , Éxons , Doença de Fabry/patologia , Feminino , Guanina , Humanos , Microscopia Eletrônica , Dados de Sequência Molecular , Pele/patologia , Vacúolos/ultraestruturaRESUMO
Wolman disease is a rapidly fatal lysosomal storage disease caused by the complete absence of lysosomal acid lipase activity. We report the cure of an infant with Wolman disease following transplantation of unrelated HLA-mismatched umbilical cord blood-derived stem cells. Umbilical cord blood was chosen as the stem-cell source because of its immediate availability and reduced tendency to cause graft-versus-host disease. The transplantation resulted in restoration of normal acid lipase levels before the onset of permanent end-organ damage. Four years after transplantation, the patient is thriving and has normal levels of acid lipase in peripheral blood cells. To our knowledge, this is the first report of a successful unrelated cord blood transplant in a patient with Wolman disease. Umbilical cord stem cells transplantation can restore acid lipase levels in Wolman disease, and if performed early, can cure the disease.
Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical , Doença de Wolman/terapia , Encéfalo/anatomia & histologia , Desenvolvimento Infantil , Pré-Escolar , Feminino , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Lactente , Imageamento por Ressonância Magnética , Transplante HomólogoRESUMO
Prevention programs for the detection of heterozygotes of relatively prevalent autosomal recessive diseases in various ethnic groups are available in recent years in Israel. Several lysosomal storage disorders (LSD) are included in this program. The goal of the program is the ascertainment of high risk couples before the birth of affected offspring. This is performed by a population screening program that addresses the specific needs and requirements of various population groups in Israel. The programs are supervised and designed by medical/clinical geneticists and are accompanied by genetic counseling prior to and after testing. Three types of population screening programs are in operation. The first type is offered to the general population and is directed to premarital and married couples. High risk families mostly opt for prenatal diagnosis. The second type is performed for diseases with a frequency of about 1:1000. This occurrence is common in Israel only in various Arab communities due to the high rate of consanguinity. The third type is a premarital screening performed by the Orthodox Jewish community and is operated by a nonprofit organization--"Dor Yeshorim". Two heterozygotes for a particular disease are advised not to proceed with the marriage and thus avoid the dilemma of prenatal diagnosis. Founder mutations of the relevant genes for each ethnic group are tested and the testing is tailored for each individual according to his/her ethnic background. Genetic counseling presents family planning options to high risk couples. These programs have resulted in a significant reduction in the birth of affected patients of the tested LSD a well as other recessive diseases in recent years.
Assuntos
Triagem de Portadores Genéticos/métodos , Testes Genéticos/métodos , Doenças por Armazenamento dos Lisossomos/prevenção & controle , Humanos , Israel , Doenças por Armazenamento dos Lisossomos/genéticaRESUMO
Mucolipidosis II (ML II) and Mucolipidosis type III (ML III) are autosomal recessive disorders of lysosomal hydrolases trafficking due to the deficiency of the multimeric enzyme, UDP-N-acetylglucosamine-1-phosphotransferase. The alpha/beta subunits encoded by the GNPTA gene is the catalytic subunit of the enzyme while the gamma recognition subunit is encoded by the GNPTAG gene. We report the molecular analysis of GNPTA in 21 families with ML II and 3 families with ML III. The ML II mutant genotypes included three splice-site mutations [IVS1-2A>G; IVS17+1G>A; IVS18+1G>A] in seven Palestinian, Israeli Arab-Muslims, and Turkish patients; a two base pair deletion [c.3503_4delTC] [corrected] in 11 patients from Israel, Turkey, and Ireland; two nonsense mutations [c.2533C>T (Q845X); c.3613C>T (R1205X)], in a Turkish and an Arab-Muslim patient from the Nablus area, respectively, and an insertion mutation [c.2916insT] in a patient from Nablus. The ML III mutant genotypes included a splice-site mutation [IVS17+6T>G] in two patients from Irish/Scottish origin who were compound heterozygous for a nonsense mutation [c.3565C>T (R1189X)] and the deletion mutation [c.3503_4delTC] [corrected] respectively. The third ML III patient from France was compound heterozygous for a missense mutation [c.1196C>T] and the same deletion [c.3503_4delTC] [corrected] found homozygous in 11 ML II patients. The 21 ML II patients were homozygous while the three ML III patients were compound heterozygous for mutations in GNPTA. The results of this study confirm that ML II or ML III phenotype is not due to the localization of the mutations, but rather to the severity of the mutations, ML II and ML III might be allelic, and ML III is genetically heterogeneous. We suggest that the diseases due to mutations in GNPTA represent a clinical continuum between ML III and ML II, and the classification of these diseases should be based on the age of onset, clinical symptoms, and severity.
Assuntos
Mucolipidoses/genética , Mutação , Transferases (Outros Grupos de Fosfato Substituídos)/genética , Pré-Escolar , Consanguinidade , Éxons , Família , Feminino , Heterozigoto , Homozigoto , Humanos , Lactente , Masculino , Sítios de Splice de RNA , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
It is well established that the conversion of PrP(C) to PrP(Sc) is the key event in prion disease biology. In addition, several lines of evidence suggest that glycosaminoglycans (GAGs) and in particular heparan sulfate (HS) may play a role in the PrP(C) to PrP(Sc) conversion process. It has been proposed that PrP(Sc) accumulation in prion diseases may induce aberrant activation of lysosomal activity, which has been shown to result in neurodegeneration in a number of diseases, especially lysosomal storage disorders. Among such diseases, only the ones resulting from defects in GAGs degradation are accompanied by secretion of large amounts of GAG metabolites in urine. In this work, we show that GAGs are secreted in the urine of prion-infected animals and humans, and surprisingly, also in the urine of mice ablated for the PrP gene. We hypothesize that both the presence of PrP(Sc) or the absence of PrP(C) may alter the metabolism of GAGs.
Assuntos
Encéfalo/metabolismo , Glicosaminoglicanos/urina , Proteínas PrPC/metabolismo , Proteínas PrPSc/metabolismo , Doenças Priônicas/urina , Animais , Encéfalo/patologia , Encéfalo/fisiopatologia , Síndrome de Creutzfeldt-Jakob/genética , Síndrome de Creutzfeldt-Jakob/fisiopatologia , Síndrome de Creutzfeldt-Jakob/urina , Cricetinae , Modelos Animais de Doenças , Ativação Enzimática/genética , Hexosaminidases/metabolismo , Humanos , Lisossomos/metabolismo , Masculino , Camundongos , Camundongos Knockout , Neurônios/metabolismo , Proteínas PrPC/genética , Doenças Priônicas/genética , Doenças Priônicas/fisiopatologia , Scrapie/genética , Scrapie/fisiopatologia , Scrapie/urina , Ovinos , Regulação para Cima/genéticaRESUMO
Correlation between genotype and phenotype in Gaucher disease is limited. It is known that the most common mutation N370S is protective of neurological involvement, but for the V394L mutation, described as the fifth most common among Ashkenazi Jews, little data are available. This study reports all known patients from a large referral clinic and from the international registry with Gaucher disease who are documented to have the N370S/V394L genotype. Of 476 patients in the Gaucher Clinic, 7 patients (2.0%) had the N370S/V394L genotype; of 2,836 patients in the registry, there were 14 patients (0.8%) with this genotype. There was an overlap of 3 patients, making a total of 18 patients, reflecting the rarity of this genotype among the studied cohorts. Most of these patients had mild disease; only 8 patients required specific enzyme therapy, none was splenectomized. Only 3 patients had skeletal involvement, but other baseline parameters were very diverse. Although genotype-phenotype correlation in this case may be difficult, because the V394L mutation when seen in a compound heterozygote with a null allele results in neuronopathic disease, one cannot conclude that this mutation is protective of neuronopathic disease and hence this is important for counseling of at-risk populations.
Assuntos
Doença de Gaucher/genética , Heterogeneidade Genética , Adolescente , Adulto , Criança , Pré-Escolar , Doença de Gaucher/diagnóstico , Doença de Gaucher/fisiopatologia , Genótipo , Humanos , Lactente , Pessoa de Meia-Idade , FenótipoRESUMO
A six-month-old infant girl presenting with progressive encephalopathy and abnormal myelination in the cerebral white matter was originally diagnosed as suffering from Krabbe disease. The diagnosis was based on a deficiency of galactocerebrosidase activity found in leukocytes isolated from whole blood. When cultured skin fibroblasts did not show a similar enzyme deficiency and sulphatide (stearoyl-1-14C) uptake indicated an abnormal storage of galactosylceramide, a deficiency of an activator was implied. A three base pair deletion was found in the saposin A coding sequence of the prosaposin gene leading to the deletion of a conserved valine at amino acid number 11 of the saposin A protein. This deletion in saposin A is proposed as the cause for the abnormal galactosylceramide metabolism in this infant. This is the first report of a saposin A mutation in humans leading to pathological consequences.
Assuntos
Leucodistrofia de Células Globoides/genética , Mutação , Saposinas/genética , Amniocentese , Sequência de Bases , Primers do DNA , Feminino , Galactosilceramidase/metabolismo , Humanos , Lactente , Leucodistrofia de Células Globoides/enzimologia , Leucodistrofia de Células Globoides/patologia , Imageamento por Ressonância Magnética , Reação em Cadeia da Polimerase , GravidezRESUMO
Hyperargininemia is a progressive neurometabolic disorder caused by deficiency of hepatic cytosolic arginase I, resulting from mutations in the ARG1 gene. We diagnosed arginase deficiency in a three-year-old male child of first-cousin Palestinian Arab parents. Prenatal diagnosis of an unaffected fetus was achieved in the second trimester of a subsequent pregnancy by cordocentesis and analysis of arginase activity in fetal erythrocytes. ARG1 mutation analysis in the proband revealed homozygosity for a deletion of 10,753 bp extending from the first intron to beyond the poly (A) site of the gene. This is the first gross deletion in the ARG1 gene to be identified and the first mutation to be described in an arginase-deficient patient of this ethnic origin. The identification of the ARG1 deletion in this family enabled first-trimester prenatal diagnosis in a subsequent pregnancy by multiplex PCR analysis performed on chorionic villous DNA.
Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/diagnóstico , Predisposição Genética para Doença , Hiperargininemia , Diagnóstico Pré-Natal , Adulto , Erros Inatos do Metabolismo dos Aminoácidos/sangue , Erros Inatos do Metabolismo dos Aminoácidos/genética , Arginase/análise , Pré-Escolar , Diagnóstico Diferencial , Eritrócitos/enzimologia , Feminino , Humanos , Lactente , Masculino , Mutação , Linhagem , Reação em Cadeia da Polimerase , Gravidez , Segundo Trimestre da GravidezRESUMO
Gaucher disease is the most common sphingolipid storage disease but genotype only broadly predicts phenotype. The 1604G-->A (1604A;R496H) mutation has been described as having a low incidence among Ashkenazi Jews. The purpose of this study was to ascertain phenotypic expression and prevalence of this mutation among patients with Gaucher disease and among healthy Ashkenazi Jews. Patients in two Gaucher clinics (in the United States and Israel) and from an international Gaucher registry were assessed for frequency and phenotype expression; 200 healthy Ashkenazi Jews were screened as well. Molecular analysis was performed by standard methods. In the Gaucher clinic with mostly Jewish patients, the gene frequency was 1.68% compared with 0.38% in the international registry with mostly non-Jewish patients. Among Ashkenazi Jewish controls, no alleles with 1604A were identified. There was a marked overrepresentation of severe alleles in patients carrying the 1604A mutation, suggesting that many patients who are compound heterozygotes for 1604A are not diagnosed as having Gaucher disease because their disease is presumably so mild as to evade detection. In view of its rarity and mild expression, the inclusion of the 1604A mutation in the standard kit for screening for Gaucher disease is unnecessary.