RESUMO
This corrects the article DOI: 10.1038/ejcn.2016.166.
RESUMO
BACKGROUND/OBJECTIVES: Phenylketonuria (PKU) is an autosomal recessive disease caused by deficient activity of phenylalanine hydroxylase. A low phenylalanine (Phe) diet is used to treat PKU. The diet is very restrictive, and dietary adherence tends to decrease as patients get older. Methods to improve dietary adherence and blood Phe control are continuously under investigation. SUBJECTS/METHODS: A new formula Phe-neutral amino acid (PheLNAA) has been tested in this study with the purpose of improving the compliance and lowering blood phenylalanine. The formula has been tested for nitrogen balance, and it is nutritionally complete. It is fortified with more nutritional additives that can be deficient in the PKU diet, such as B12, Biotin, DHA, Lutein and increased levels of large neutral amino acids to help lower blood Phe. The new formula has been tested on 12 patients with a loading test of 4 weeks. RESULTS: Fifty-eight percent of patients had a significant decline in blood Phe concentration from baseline throughout the study. The PheLNAA was well tolerated with excellent compliance and without illnesses during the study. CONCLUSIONS: In conclusion, the new formula is suitable for life-long treatment of PKU, and it offers the PKU clinic a new choice for treatment.
Assuntos
Aminoácidos Neutros/administração & dosagem , Alimentos Formulados , Alimentos Fortificados , Fenilalanina/sangue , Fenilcetonúrias/dietoterapia , Adolescente , Feminino , Humanos , Masculino , Cooperação do Paciente/psicologia , Fenilcetonúrias/sangue , Fenilcetonúrias/psicologia , Resultado do TratamentoRESUMO
Synpolydactyly is a relatively rare malformation. Recently, we came across a male infant with a familial synpolydactyly of the hands and feet. As most familial synpolydactyly syndromes have not been linked to any specific mutations, we felt further investigation was warranted. Using microarray and fluorescent in situ hybridization analysis, we identified a novel mutation of the SLC25A21 gene on chromosome 14.
RESUMO
Large neutral amino acids (LNAA) have been used on a limited number of patients with phenylketonuria (PKU) with the purpose of decreasing the influx of phenylalanine (Phe) to the brain. In an open-label study using LNAA, a surprising decline of blood Phe concentration was found in patients with PKU in metabolic treatment centres in Russia, the Ukraine, and the United States. To validate the data obtained from this trial, a short-term double-blind placebo control study was done using LNAA in patients with PKU, with the participation of three additional metabolic centres--Milan, Padua and Rio de Janeiro. The results of the short trial showed significant lowering of blood Phe concentration by an average of 39% from baseline. The data from the double-blind placebo control are encouraging, establishing proof of principle of the role of orally administered LNAA in lowering blood Phe concentrations in patients with PKU. Long-term studies will be needed to validate the acceptability, efficacy and safety of such treatment.
Assuntos
Aminoácidos Neutros/química , Aminoácidos Neutros/uso terapêutico , Fenilalanina/sangue , Fenilcetonúrias/sangue , Fenilcetonúrias/tratamento farmacológico , Adolescente , Adulto , Criança , Método Duplo-Cego , Feminino , Humanos , Masculino , Concentração Osmolar , Resultado do TratamentoRESUMO
Large neutral amino acids (LNAAs) have been used on a limited number of patients with phenylketonuria (PKU) with the purpose of decreasing the influx of phenylalanine (Phe) to the brain. In earlier studies on mice with PKU (ENU(2)/ENU(2)), LNAAs were given and a surprising decline in blood Phe concentrations was observed. The formula used in the mouse experiment (PreKUnil) lacked lysine. Therefore, a new formulation of LNAAs (NeoPhe) was developed, introducing changes in the concentration of some amino acids and adding lysine, so that such a mixture could be used in humans. The new formula was found to be effective in reducing blood Phe concentration in mice by about 50% of the elevated levels. Patients with PKU were given LNAAs and blood Phe concentrations were determined in an open-label study. Three centers--in Russia, the Ukraine and the USA--took part in the study. NeoPhe was given at 0.5 g/kg per day in three divided doses to eight subjects with PKU and at 1.0 g/kg per day to three patients, for one week. The NeoPhe resulted in decrease of elevated blood Phe by 50% in both groups. The preliminary data from this study are encouraging and a double blind placebo-controlled trial will be required to show long-term efficacy and tolerance of LNAAs in the treatment of PKU.
Assuntos
Aminoácidos Neutros/uso terapêutico , Fenilcetonúrias/tratamento farmacológico , Adolescente , Adulto , Animais , Encéfalo/metabolismo , Dieta , Método Duplo-Cego , Feminino , Humanos , Lisina/química , Masculino , Camundongos , Fenilalanina/sangue , PlacebosRESUMO
This study describes gene expression in the fetus hearts obtained from mouse model for phenylketonuria. These hearts have cardiovascular disease (CVD). Therefore genes involved in CVD were examined. Several genes associated with heart development and inflammation were found to be altered. In order to investigate whether the abnormal gene expression alters transcription and translation, the levels of troponin mRNA and protein were determined. One step real time RT-PCR showed a reduction in cardiac troponin I, troponin T2 and ryanodine receptor 2. Determination of troponin I and T protein levels showed reduced levels of these proteins. Our results suggest that altered gene expression affects protein production. These changes are likely involved in the cardiovascular defects seen in the mouse.
Assuntos
Coração Fetal/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Cardiopatias/metabolismo , Inflamação/patologia , Fenilcetonúria Materna/metabolismo , Animais , Cruzamentos Genéticos , Modelos Animais de Doenças , Feminino , Cardiopatias/patologia , Heterozigoto , Homozigoto , Camundongos , Fenilcetonúria Materna/genética , Gravidez , Análise Serial de Proteínas , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Canal de Liberação de Cálcio do Receptor de Rianodina/análise , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Troponina I/análise , Troponina I/genética , Troponina T/análise , Troponina T/genéticaRESUMO
Analysis of outcome data from 305 of the 414 offspring from the Maternal Phenylketonuria Collaborative Study (MPKUCS), plus 70 control offspring, revealed significant deficits in the IQ (intelligence quotient), as measured by the Wechsler Intelligence Scale for Children--Revised (WISC-R), when maternal metabolic control during pregnancy was delayed and/or inadequate. There were, however, 23 'outliers' (7.5% of the 305) in which the offspring's intellectual IQ was worse (n =10) or better (n =13) than expected. The aim of this study was to determine whether collection parameters were incomplete or whether these subjects were true biological variants influenced by other undetected factors or, perhaps, by modifier genes. Among the 10 offspring whose intellectual functioning was worse than expected, additional complications were uncovered that could explain the poor outcome. Four of the 13 offspring with higher than expected IQ had mothers with mild variants of PKU in which the insult to the fetus would not be expected to be as profound. For the other nine offspring whose intellectual performance was better than expected, there was no explanation, based on the parameters studied. We hypothesize that modifier genes will, at times, protect the fetus despite high maternal concentrations of phenylalanine. Not all offspring from the same (untreated) PKU mother may be similarly affected. Finding the source of these modifiers might effect the treatment of MPKU.
Assuntos
Fenilcetonúrias/psicologia , Adolescente , Adulto , Coleta de Dados , Feminino , Humanos , Deficiência Intelectual/genética , Deficiência Intelectual/psicologia , Fenilcetonúrias/genética , Fatores de Risco , Resultado do Tratamento , Escalas de WechslerRESUMO
Canavan disease (CD) is an autosomal recessive disorder caused by aspartoacylase deficiency leading to accumulation of N-acetylaspartic acid and spongy degeneration of the brain. The mouse model for CD showed low levels of glutamate and gamma-aminobutyric acid (GABA) in the brain. Whether the low levels of glutamate and GABA observed in the CD mouse brain lead to abnormal production of glutamate-GABA associated enzymes and resulting succinate production is not obvious. While glutamate dehydrogenase and alpha-ketoglutarate dehydrogenase complex activities are lower in the cerebellum and brain stem of the CD mouse, alanine aminotransferase and succinate semialdehyde dehydrogenase (SSADH) activities and succinate level are similar to the levels observed in the wild type. Deficiency of SSADH has been suggested to be associated with mental retardation and hypotonia, similar to the clinical features of CD. The normal SSADH activity in the CD mouse brain suggests that mental retardation and hypotonia seen in the CD mouse is not due to SSADH activity and if documented also in patients with CD.
Assuntos
Aldeído Oxirredutases/deficiência , Doença de Canavan/enzimologia , Deficiência Intelectual/enzimologia , Hipotonia Muscular/enzimologia , Aldeído Oxirredutases/genética , Animais , Doença de Canavan/genética , Deficiência Intelectual/genética , Camundongos , Camundongos Knockout , Hipotonia Muscular/genética , Succinato-Semialdeído DesidrogenaseRESUMO
A 16-year-old adolescent with mild hyperphenylalaninaemia was given a high-protein 'body building' supplement twice daily, causing headaches, decreased school performance and mild depression. All symptoms disappeared after cessation of the supplement. The phenylalanine hydroxylase mutation H170D/IVS1nt5G>T was found to be responsive to tetrahydrobiopterin with significant decrease in blood phenylalanine concentration and increase in tyrosine blood content. A brain phenylalanine level of 0.5 mmol/L was initially documented, which decreased to the normal carrier range of 0.2 mmol/L within one month of discontinuance of the protein supplement. At present, the patient is on a normal diet without phenylalanine restriction.
Assuntos
Aminoácidos/administração & dosagem , Aminoácidos/efeitos adversos , Biopterinas/análogos & derivados , Depressão/etiologia , Suplementos Nutricionais , Cefaleia/etiologia , Fenilcetonúrias/complicações , Adolescente , Biopterinas/administração & dosagem , Depressão/induzido quimicamente , Relação Dose-Resposta a Droga , Cefaleia/induzido quimicamente , Humanos , Masculino , Mutação , Fenilalanina/sangue , Fenilalanina Hidroxilase/genética , Fenilcetonúrias/genética , SomatotiposRESUMO
Malonyl CoA decarboxylase (MCD) is an enzyme involved in the metabolism of fatty acids synthesis. Based on reports of MCD deficiency, this enzyme is particular important in muscle and brain metabolism. Mutations in the MCD gene result in a deficiency of MCD activity, that lead to psychomotor retardation, cardiomyopathy and neonatal death. To date however, only a few patients have been reported with defects in MCD. We report here studies of a patient with MCD deficiency, who presented with hypotonia, cardiomyopathy and psychomotor retardation. DNA sequencing of MCD revealed a homozygous intronic mutation, specifically a -5 C to T transition near the acceptor site for exon 3. RT-PCR amplification of exons 2 and 3 revealed that although mRNA from a normal control sample yielded one major DNA band, the mutant mRNA sample resulted in two distinct DNA fragments. Sequencing of the patient's two RT-PCR products revealed that the larger molecular weight fragments contained exons 2 and 3 as well as the intervening intronic sequence. The smaller size band from the patient contained the properly spliced exons, similar to the normal control. Western blotting analysis of the expressed protein showed only a faint band in the patient sample in contrast to a robust band in the control. In addition, the enzyme activity of the mutant protein was lower than that of the control protein. The data indicate that homozygous mutation in intron 2 disrupt normal splicing of the gene, leading to lower expression of the MCD protein and MCD deficiency.
Assuntos
Encefalopatias Metabólicas Congênitas/enzimologia , Encefalopatias Metabólicas Congênitas/genética , Encéfalo/enzimologia , Carboxiliases/deficiência , Carboxiliases/genética , Genes/genética , Íntrons/genética , Mutação/fisiologia , Sítios de Splice de RNA/genética , Sequência de Bases , Encéfalo/anormalidades , Encéfalo/fisiopatologia , Análise Mutacional de DNA , DNA Complementar/análise , DNA Complementar/genética , Ácidos Graxos/genética , Ácidos Graxos/metabolismo , Homozigoto , Humanos , Malonil Coenzima A/genética , Malonil Coenzima A/metabolismo , RNA Mensageiro/análise , RNA Mensageiro/genéticaAssuntos
Deficiência de Ácido Fólico/diagnóstico , Deficiência de Ácido Fólico/genética , Ácido Fólico/metabolismo , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/etnologia , Polimorfismo Genético , Alelos , População Negra , Genótipo , Heterozigoto , Homozigoto , Humanos , Mutação , População BrancaRESUMO
The frequency and types of congenital heart disease in offspring from pregnancies in women with hyperphenylalaninemia were examined in the international prospective Maternal Phenylketonuria Collaborative Study. Relationships of congenital heart disease in offspring to the basal blood phenylalanine level in the mother, metabolic control through diet during pregnancy, and phenylalanine hydroxylase mutations in mother and offspring were determined. The 416 offspring from 412 maternal phenylketonuria pregnancies that produced live births and 100 offspring from the 99 control pregnancies were included in this examination. Thirty-four of the 235 offspring (14%; 95% CI, 10.2 to 19.6%) from pregnancies in phenylketonuric women with a basal phenylalanine level > or = 900 microM (15 mg/dL) [normal blood phenylalanine < 120 microM (2 mg/dL)] and not in metabolic control [phenylalanine level < or = 600 microM (10 mg/dL)] by the eighth gestational week had congenital heart disease compared with one control offspring (1%) with congenital heart disease. One offspring among the 50 (2%) from mothers with non-phenylketonuria mild hyperphenylalaninemia also had congenital heart disease. Coarctation of the aorta and hypoplastic left heart syndrome were overrepresented compared with expected percentages among those with congenital heart disease in the general population. A basal maternal phenylalanine level > 1800 microM (30 mg/dL) significantly increased the risk for bearing a child with congenital heart disease (p = 0.003). Phenylalanine hydroxylase mutations in the mothers and offspring did not have an independent relationship to congenital heart disease but were related through the basal maternal phenylalanine levels. The data in this study indicate that a basal maternal phenylalanine level of 900 microM may be a threshold for congenital heart disease, that women with the most severe degree of phenylketonuria are at highest risk for bearing such a child, and that prevention of the congenital heart disease requires initiation of the low phenylalanine diet before conception or early in pregnancy with metabolic control no later than the eighth gestational week.
Assuntos
Cardiopatias Congênitas/etiologia , Fenilcetonúrias/complicações , Feminino , Cardiopatias Congênitas/diagnóstico por imagem , Cardiopatias Congênitas/epidemiologia , Humanos , Incidência , Fenilalanina Hidroxilase/genética , Fenilcetonúrias/genética , Gravidez , Estudos Prospectivos , Ultrassonografia Pré-Natal , Estados Unidos/epidemiologiaRESUMO
Childhood ataxia with diffuse central nervous system hypomyelination syndrome (CACH) is a recently described leukodystrophy of unknown etiology. To characterize the neuropathological features and gain insight as to the pathogenesis of this disorder, we studied cerebral tissue from six patients with the CACH syndrome. Evaluation of toluidine blue-stained, semithin sections of white matter from CACH patients disclosed unusual cells with "foamy" cytoplasm, small round nuclei and fine chromatin. Electron microscopy (EM) revealed cells in the white matter with abundant cytoplasm containing many mitochondria and loosely clustered, membranous structures, but lacking the lysosomal structures seen in macrophages. Further analysis of tissue sections with antibodies and special stains demonstrated that the abnormal cells with abundant cytoplasm labeled with oligodendroglial markers, but did not react with macrophage or astrocytic markers. Double immunolabeling with macrophage and oligodendroglial markers clearly distinguished macrophages from the "foamy" oligodendroglial cells (FODCs). Proteolipid protein (PLP) mRNA in situ hybridization demonstrated PLP mRNA transcripts in a high proportion of oligodendrocytes in CACH patients compared to control patients, and PLP mRNA transcript signal in cells, morphologically consistent with FODCs. Normal and pathological brain control tissues did not contain FODCs. These neuropathological findings will be useful pathological identifiers of CACH, and may provide clues to the pathogenesis of this disorder.
Assuntos
Ataxia/complicações , Ataxia/patologia , Encéfalo/patologia , Células Espumosas/patologia , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/complicações , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/patologia , Oligodendroglia/patologia , Ataxia/metabolismo , Biomarcadores , Biópsia , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Criança , Pré-Escolar , Feminino , Células Espumosas/metabolismo , Células Espumosas/ultraestrutura , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/metabolismo , Humanos , Lactente , Masculino , Oligodendroglia/metabolismo , Oligodendroglia/ultraestrutura , Fenótipo , RNA Mensageiro/metabolismoRESUMO
UNLABELLED: The Maternal Phenylketonuria Study began in 1984 and during the intervening years, 572 pregnancies in hyperphenylalaninemic women and 99 controls and their outcomes have been evaluated. Among hyperphenylalaninemic women who delivered a live infant, only 15.9% were treated and in metabolic control preconceptually, however, another 18.4% were in control by 10 weeks. Compared to the results reported by Lenke and Levy in 1980, there is a marked improvement in outcome with treatment. Microcephaly was unusual in preconceptually treated pregnancies with well controlled phenylalanine restricted diets. Even in pregnancies that established control after conception but before the 8th week, congenital heart disease did not occur in the offspring, however, it did occur in 12% of pregnancies not achieving control until after 10 weeks of pregnancy. CONCLUSION: The recommended level of blood phenylalanine during pregnancy is 120-360 mumol/l. Best results were obtained by close cooperation between the attending obstetrician and a metabolic team experienced in the care of persons with phenylketonuria.
Assuntos
Fenilcetonúria Materna , Adulto , Anormalidades Congênitas/etiologia , Feminino , Genótipo , Humanos , Fenilalanina/administração & dosagem , Fenilalanina/sangue , Fenilcetonúria Materna/sangue , Fenilcetonúria Materna/complicações , Fenilcetonúria Materna/dietoterapia , Fenilcetonúria Materna/genética , Gravidez , Resultado da Gravidez , PesquisaRESUMO
We describe an uncommon association of deletion 22q11 in a patient with Klinefelter syndrome. Even though congenital heart defects (CHD) are not associated with Klinefelter syndrome, further investigation of this patient with patent ductus arteriosus showed a microdeletion of chromosome 22q11.2. While this finding may be coincidental, it is important to further evaluate patients when the clinical features are suggestive of a secondary abnormality.
Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 22/genética , Permeabilidade do Canal Arterial/genética , Síndrome de Klinefelter/genética , Adulto , Bandeamento Cromossômico , Permeabilidade do Canal Arterial/patologia , Humanos , Hibridização In Situ , Cariotipagem , Síndrome de Klinefelter/complicações , MasculinoRESUMO
Maternal phenylketonuria (PKU) syndrome results in multiple congenital anomalies in the offspring, usually consisting of microcephaly, intrauterine growth retardation, dysmorphology, and congenital heart disease. Pregnancies treated preconceptionally with a phenylalanine-restricted diet and control of maternal blood phenylalanine levels within the recommended range result in normal offspring. However, in this 15-year study, several significant factors resulted in microcephaly in 27% of the offspring, and 7% exhibited serious congenital heart disease. These results occurred chiefly in women with mean IQ scores of 83 associated with low socioeconomic status and decreased educational achievement. Another important factor associated with suboptimal control of blood phenylalanine levels during pregnancy was the fact that most pregnancies were not carefully planned and occurred in women off dietary treatment with phenylalanine-restricted products. These results indicate that greater effort must be developed to assist women with PKU in remaining on diet during their reproductive years. It appears that continued adherence to the diet, resulting in normal maternal intelligence, is an important contribution to improved fetal development.
Assuntos
Fenilcetonúrias/complicações , Complicações na Gravidez/dietoterapia , Feminino , Cardiopatias Congênitas/etiologia , Humanos , Recém-Nascido , Inteligência , Fenilalanina/sangue , Fenilcetonúrias/dietoterapia , Fenilcetonúrias/psicologia , Gravidez , Complicações na Gravidez/psicologia , Resultado da GravidezRESUMO
With the ultimate goal of developing safe and effective in vivo gene therapy for the treatment of Canavan disease and other neurological disorders, we developed a non-viral lipid-entrapped, polycation-condensed delivery system (LPD) for central nervous system gene transfer, in conjunction with adeno-associated virus (AAV)-based plasmids containing recombinant aspartoacylase (ASPA). The gene delivery system was tested in healthy rodents and primates, before proceeding to preliminary studies in 2 children with Canavan disease. Toxicity and expression testing was first carried out in human 293 cells, which demonstrated effective transduction of cells and high levels of functional ASPA activity. We performed in vivo toxicity and expression testing of LPD/pAAVaspa and LPD/pAAVlac in rodents, which demonstrated widespread gene expression for more than 10 months after intraventricular delivery, and local expression in deep brain nuclei and white matter tracts for more than 6 months after intraparenchymal injections, with no significant adverse effects. We also performed intraventricular delivery of LPD/pAAVaspa to 2 cynomologous monkeys, with 2 additional monkeys receiving LPD and saline controls. None of the monkeys demonstrated significant adverse effects, and at 1 month the 2 LPD/pAAVaspa monkeys were positive for human ASPA transcript by reverse transcriptase polymerase chain reaction of brain tissue punches. Finally, we performed the first in vivo gene transfer study for a human neurodegenerative disease in 2 children with Canavan disease to assess the in vivo toxicity and efficacy of ASPA gene delivery. Our results suggest that LPD/pAAVaspa is well tolerated in human subjects and is associated with biochemical, radiological, and clinical changes.
Assuntos
Amidoidrolases/genética , Amidoidrolases/metabolismo , Doença de Canavan/terapia , Terapia Genética , Animais , Animais Recém-Nascidos , Encéfalo/patologia , Encéfalo/fisiopatologia , Doença de Canavan/enzimologia , Doença de Canavan/genética , Células Cultivadas , Sistema Nervoso Central/enzimologia , Sistema Nervoso Central/fisiopatologia , Pré-Escolar , Humanos , Lactente , Macaca fascicularis , Imageamento por Ressonância Magnética , Masculino , Projetos Piloto , Ratos , Ratos Endogâmicos F344 , Resultado do Tratamento , beta-Galactosidase/genética , beta-Galactosidase/metabolismoRESUMO
BACKGROUND: Canavan disease (CD) is an autosomal recessive leukodystrophy characterized by deficiency of aspartoacylase (ASPA) and increased levels of N-acetylaspartic acid (NAA) in brain and body fluids, severe mental retardation and early death. Gene therapy has been attempted in a number of children with CD. The lack of an animal model has been a limiting factor in developing vectors for the treatment of CD. This paper reports the successful creation of a knock-out mouse for Canavan disease that can be used for gene transfer. METHODS: Genomic library lambda knock-out shuttle (lambdaKOS) was screened and a specific pKOS/Aspa clone was isolated and used to create a plasmid with 10 base pair (bp) deletion of exon four of the murine aspa. Following linearization, the plasmid was electroporated to ES cells. Correctly targeted ES clones were identified following positive and negative selection and confirmed by Southern analysis. Chimeras were generated by injection of ES cells to blastocysts. Germ line transmission was achieved by the birth of heterozygous mice as confirmed by Southern analysis. RESULTS: Heterozygous mice born following these experiments have no overt phenotype. The homozygous mice display neurological impairment, macrocephaly, generalized white matter disease, deficient ASPA activity and high levels of NAA in urine. Magnetic resonance imaging (MRI) and spectroscopy (MRS) of the brain of the homozygous mice show white matter changes characteristic of Canavan disease and elevated NAA levels. CONCLUSION: The newly created ASPA deficient mouse establishes an important animal model of Canavan disease. This model should be useful for developing gene transfer vectors to treat Canavan disease. Vectors for the central nervous system (CNS) and modulation of NAA levels in the brain should further add to the understanding of the pathophysiology of Canavan disease. Data generated from this animal model will be useful for developing strategies for gene therapy in other neurodegenerative diseases.
Assuntos
Doença de Canavan/genética , Sistema Nervoso Central/metabolismo , Modelos Animais de Doenças , Técnicas de Transferência de Genes , Amidoidrolases/genética , Animais , Encéfalo/anormalidades , Encéfalo/patologia , Doença de Canavan/terapia , Clonagem Molecular , Terapia Genética , Imageamento por Ressonância Magnética , Camundongos , Camundongos Knockout , FenótipoRESUMO
Canavan disease is a severe progressive leukodystrophy characterized by swelling and spongy degeneration of the white matter of the brain. It is an autosomal recessive disease found more frequently among Ashkenazi Jews. The clinical features are those of severe mental retardation with inability to gain developmental milestones. Hypotonia, head lag and macrocephaly are characteristic of Canavan disease and become apparent after 5-6 months of age. Massive excretion in the urine of N-acetylaspartic acid is the biochemical marker for Canavan disease, which is caused by deficiency of the enzyme aspartoacylase. This discovery allowed for accurate diagnosis of Canavan disease, while prior to that, a brain biopsy was needed. The gene for aspartoacylase has been cloned and two mutations predominate among Ashkenazi Jewish individuals with Canavan disease and account for more than 98% of the Ashkenazi Jewish patients. The mutations among other ethnic groups are more diverse. The carrier frequency for the two common mutations among Ashkenazi Jews was found to be surprisingly high, 1:37. Screening for carriers is now common practice for this population. A knock-out mouse for Canavan disease is being genetically engineered in our laboratory. The mouse model will allow for development of strategies for gene therapy.
Assuntos
Doença de Canavan , Amidoidrolases/genética , Animais , Doença de Canavan/diagnóstico , Doença de Canavan/genética , Doença de Canavan/fisiopatologia , Doença de Canavan/prevenção & controle , Modelos Animais de Doenças , Humanos , Judeus , CamundongosRESUMO
Canavan disease is a severe, progressive autosomal recessive neurodegenerative leukodystrophy. Canavan disease occurs more frequently among Ashkenazi Jewish individuals with two predominant mutations in the aspartoacylase (ASPA) gene. The disease is less frequent in non-Jewish individuals and the mutations randomly reside on the ASPA gene, with one mutation seen more frequently among patients of European extraction. In the present study we report a novel homozygous donor splice site mutation of intron 4 in a child with first-cousin parents of Turkish extraction.