RESUMEN
Coenzyme Q10 (CoQ10) deficiency can manifest diversely, from isolated myopathy to multisystem involvement. Immune dysregulation has not been reported as a feature of the disease. We report a four-year old girl with failure to thrive, recurrent infections, developmental delay with hypotonia, and CoQ10 deficiency with impaired immune function, which improved after CoQ10 and immunoglobulin replacement therapy. Immune dysfunction in CoQ10 deficiency should be considered and treated appropriately.
Asunto(s)
Ataxia/inmunología , Ataxia/metabolismo , Inmunidad/fisiología , Enfermedades Mitocondriales/inmunología , Enfermedades Mitocondriales/metabolismo , Debilidad Muscular/inmunología , Debilidad Muscular/metabolismo , Ubiquinona/análogos & derivados , Ubiquinona/deficiencia , Ataxia/diagnóstico , Ataxia/tratamiento farmacológico , Preescolar , Terapia de Reemplazo Enzimático , Femenino , Humanos , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Subgrupos Linfocitarios/inmunología , Subgrupos Linfocitarios/metabolismo , Enfermedades Mitocondriales/diagnóstico , Enfermedades Mitocondriales/tratamiento farmacológico , Debilidad Muscular/diagnóstico , Debilidad Muscular/tratamiento farmacológico , Resultado del Tratamiento , Ubiquinona/inmunología , Ubiquinona/metabolismo , Ubiquinona/uso terapéuticoRESUMEN
Progressive skeletal disease accounts for some of the most debilitating complications of type 1 Gaucher disease. In this 48-month, prospective, non-randomized, open-label study of the effect of enzyme replacement therapy on bone response, 33 imiglucerase-naïve patients (median age 43 years with one or more skeletal manifestations such as osteopenia, history of bone crisis, or other documented bone pathology) received imiglucerase 60 U/kg/2 weeks. Substantial improvements were observed in bone pain (BP), bone crises (BC), and bone mineral density (BMD). Improvements in BP were observed at 3 months (p < 0.001 vs baseline) and continued progressively throughout the study, with 39% of patients reporting pain at 48 months vs 73% at baseline. Eleven of the 13 patients with a pre-treatment history of BC had no recurrences. Biochemical markers for bone formation increased; markers for bone resorption decreased. Steady improvement of spine and femoral neck BMD, measured using dual-energy X-ray absorptiometry was noted. Mean Z score for spine increased from -0.72 +/- 1.302 at baseline to near-normal levels (-0.09 +/- 1.503) by month 48 (p = 0.042) and for femoral neck from -0.59 +/- 1.352 to -0.17 +/- 1.206 (p = 0.035) at month 36. This increase was sustained at 48 months. With imiglucerase treatment, patients should anticipate resolution of BC, rapid improvement in BP, increases in BMD, and decreased skeletal complications.
Asunto(s)
Densidad Ósea , Enfermedad de Gaucher/tratamiento farmacológico , Glucosilceramidasa/uso terapéutico , Columna Vertebral/metabolismo , Enfermedades Óseas , Enfermedades Óseas Metabólicas , Estudios de Cohortes , Femenino , Humanos , Estudios Longitudinales , Masculino , Estudios ProspectivosRESUMEN
Von Hippel-Lindau is an autosomal dominant familial tumor syndrome with a risk of developing central nervous system and retinal hemangioblastomas, kidney cysts and clear cell carcinoma, cyst adenomas of other organs and pheochromocytoma. Despite continued elaboration of the neurobiologic role of the von Hippel-Lindau protein, the mainstay of management remains the definitive clinical diagnosis of von Hippel-Lindau syndrome (as distinct from sporadic cases of single von Hippel-Lindau-associated tumors), clinical monitoring and preemptive intervention by surgical or ablative therapy. Specific pharmacologic treatment awaits further biologic understanding of critical pathogenic components. Increasingly sensitive imaging and surgical techniques allow for optimum clinical management and intervention. This article will review von Hippel-Lindau molecular genetics, genotype-phenotype correlations and clinical classification, current understanding of the biology of the von Hippel-Lindau protein, its role in the pathophysiology of this disorder and the consequent implications for future therapeutic/interventional strategies. Central nervous system manifestations will be highlighted.
Asunto(s)
Neoplasias Encefálicas/genética , Proteínas Supresoras de Tumor , Ubiquitina-Proteína Ligasas , Enfermedad de von Hippel-Lindau/genética , Neoplasias Encefálicas/clasificación , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/cirugía , Transformación Celular Neoplásica/genética , Aberraciones Cromosómicas , Genes Dominantes/genética , Genotipo , Humanos , Ligasas/genética , Fenotipo , Pronóstico , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau , Enfermedad de von Hippel-Lindau/clasificación , Enfermedad de von Hippel-Lindau/diagnóstico , Enfermedad de von Hippel-Lindau/cirugíaRESUMEN
The effect of enzyme replacement therapy on health-related quality of life in 25 adults with type 1 Gaucher disease was investigated over a 2-year period. Quality of life was assessed using the SF-36 Health Survey (SF-36). Psychological functioning was assessed using the Symptom Checklist--90R. The results indicated significant improvement in 7 of 8 SF scale scores beginning at 18 months of therapy (P < 0.05 to 0.001). The SF scale showing improvement first was Vitality (energy level and fatigue) at 6 months of therapy (P < 0.01). The SF-36 scales showing the largest improvements were Role-Physical and Social Functioning (P < 0.001). Compared to the general US adult population, the study population's health profile was significantly lower prior to starting therapy but by 24 months of therapy there were no differences between the two. No differences were found in psychological functioning compared to a US adult normative group at the start of therapy. However, within the study population there was significant improvement in mood and global functioning and fewer psychological symptoms reported at 24 months of therapy. The findings indicate that enzyme replacement therapy for type 1 Gaucher disease has a positive impact on health-related quality of life from the patient's perspective.
Asunto(s)
Enfermedad de Gaucher/tratamiento farmacológico , Glucosilceramidasa/uso terapéutico , Calidad de Vida , Adulto , Anciano , Femenino , Enfermedad de Gaucher/rehabilitación , Humanos , Modelos Lineales , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Método Simple Ciego , Estadísticas no Paramétricas , Resultado del TratamientoRESUMEN
Brunner et al. [1993: Am J Hum Genet 52: 1032-1039; 1993: Science 262:578-580] described males with an MAO-A deficiency state resulting from a premature stop codon in the coding region of the MAOA gene. This deficiency state was associated with abnormal levels of amines and amine metabolites in urine and plasma of affected males, as well as low normal intelligence and apparent difficulty in impulse control, including inappropriate sexual behavior. In the present study, disruption of the MAOA gene was evaluated in males with mental retardation with and without a history of sexually deviant behavior, as well as normal controls, healthy males, and patients with other diseases (Parkinson disease, Lesch-Nyhan syndrome). When available, plasma samples were evaluated first for levels of 3-methoxy, 4-hydroxyphenolglycol (MHPG), a metabolite of norepinephrine which serves as the most sensitive index of MAO-A activity in humans. Blood DNA from individuals with abnormally low MHPG, and from other individuals for whom metabolite levels were not available, were screened for nucleotide variations in the coding region of the MAOA gene by single-strand conformational polymorphism (SSCP) analysis across all 15 exons and splice junctions, and by sequencing, when indicated by either altered metabolites or SSCP shifts. No evidence for mutations disrupting the MAOA gene was found in 398 samples from the target populations, including institutionalized mentally retarded males (N = 352) and males participating in a sexual disorders clinic (N = 46), as well as control groups (N = 75). These studies indicate that MAOA deficiency states are not common in humans.
Asunto(s)
Pruebas Genéticas , Monoaminooxidasa/genética , Adulto , Cromatografía Líquida de Alta Presión , Humanos , Discapacidad Intelectual/genética , Masculino , Metoxihidroxifenilglicol/sangre , Persona de Mediana Edad , Trastornos Parafílicos/genética , Reacción en Cadena de la Polimerasa , Polimorfismo Conformacional Retorcido-Simple , Análisis de Secuencia de ADNRESUMEN
Early-onset, generalized primary torsion dystonia (PTD) is an autosomal dominantly inherited disorder, characterized by involuntary movements and abnormal postures. The majority of cases are caused by a 3-bp deletion in the DYT1 gene on chromosome 9q34 that allows for specific genetic testing. We developed a simple, reliable, and cost-effective, PCR-based screening method for this mutation. Testing results from a cohort of 550 cases, including patients with different forms of dystonia and unclassified movement disorders, revealed that 72.2% of the patients with typical early-onset generalized PTD carried the GAG deletion in the DYT1 gene. Among 300 cases with late-onset focal/segmental dystonia, only 3 patients tested positive for the GAG deletion whereas 12.8% of the patients with an unclassified movement disorder were GAG positive. Our results confirm a genotype/phenotype correlation in early-onset PTD and show that application of strict clinical criteria leads to accurate prediction of carrier status in more than two-thirds of patients with this type of dystonia. Currently, we suggest that testing be recommended in individuals with age of onset of dystonia below 30 years and/or a positive family history of early-onset PTD. Testing is not recommended in patients with onset of symptoms after 30 years or in asymptomatic individuals under the age of 18.
Asunto(s)
Proteínas Portadoras/genética , Distonía/genética , Pruebas Genéticas/métodos , Chaperonas Moleculares , Adulto , Edad de Inicio , Anciano , Niño , Preescolar , Distonía/etnología , Ética Médica , Femenino , Pruebas Genéticas/psicología , Heterocigoto , Humanos , Lactante , Judíos , Masculino , Linaje , Reacción en Cadena de la Polimerasa/métodos , Diagnóstico Prenatal , Eliminación de Secuencia , Repeticiones de Trinucleótidos/genéticaRESUMEN
OBJECTIVES: To show that Norrie disease can occur in a girl and to describe her ophthalmologic and genetic features. METHODS: Amplification of DNA polymerase chain reaction and sequencing of asymmetric polymerase chain reaction for exon 3 were performed on the blood specimen obtained from a girl born with bilateral retinal detachments. PATIENT: A female child with bilateral retinal detachment who had 2 uncles in whom Norrie disease had already been diagnosed. RESULTS: The child had a mutation in the third exon (T776-->A; Ile 123-->Asn) identical to the mutation found in her uncles. CONCLUSIONS: Norrie disease can occur in girls. The most likely explanation is nonrandom or unfavorable X inactivation, although timing of development of the peripheral retina and its blood supply could render it vulnerable to effects of the mutant allele at a critical developmental phase.
Asunto(s)
Ceguera/genética , Discapacidades del Desarrollo/genética , Heterocigoto , Mutación , Enfermedades del Sistema Nervioso/genética , Desprendimiento de Retina/genética , Enfermedades de la Retina/genética , Exones , Femenino , Humanos , Lactante , Desprendimiento de Retina/patología , Enfermedades de la Retina/patología , Cromosoma XRESUMEN
A large Costa Rican kindred has been identified with 15 males affected with congenital blindness, progressive bearing loss, and venous insufficiency. Due to ophthalmological and audio-otological findings, including bilateral retinal dysplasia and detachment, progressive bilateral sensorineural hearing loss, and an X-linked pattern of inheritance, a tentative diagnosis of Norrie disease was considered. However, venous insufficiency is a clinical finding not reportedly associated with Norrie disease. Genetic linkage analysis using microsatellite repeat markers demonstrated linkage to Xp11.23-11.4 (z = 2.723 at theta = 0.0). A candidate gene approach using the Norrie disease gene (NDP), which maps to Xp11.3, revealed a point mutation in the third exon resulting in substitution of phenylalanine for leucine at position 61. The precise function of the gene product, norrin, has yet to be elucidated; however, it has been postulated to be involved in the regulation of neural cell differentiation and proliferation, although hypotheses have been considered for its role in vascular development in the eye. The finding of a mutation in NDP in association with peripheral vascular disease may provide valuable insight into the potential role of this gene in cellular processes.
Asunto(s)
Ceguera/genética , Sordera/genética , Discapacidad Intelectual/genética , Enfermedades Vasculares Periféricas/genética , Costa Rica , Ligamiento Genético , Humanos , Cariotipificación , Masculino , Fenotipo , Cromosoma XRESUMEN
BACKGROUND: The Norrie disease (ND) gene (Xp11.3) (McKusick 310600) consists of one untranslated exon and two exons partially translated as the Norrie disease protein (Norrin). Norrin has sequence homology and computer-predicted tertiary structure of a growth factor containing a cystine knot motif, which affects endothelial cell migration and proliferation. Norrie disease (congenital retinal detachment), X-linked primary retinal dysplasia (congenital retinal fold), and X-linked exudative vitreoretinopathy (congenital macular ectopia) are allelic disorders. METHODS: Blood was drawn for genetic studies from members of two families to test for ND gene mutations. Sixteen unaffected family members were examined ophthalmologically. If any retinal abnormality were identified, fundus photography and fluorescein angiography was performed. RESULTS: Family A had ND (R109stp), and family B had X-linked exudative vitreoretinopathy (R121L). The retinas of 11 offspring of carrier females were examined: three of seven carrier females, three of three otherwise healthy females, and one of one otherwise healthy male had peripheral inner retinal vascular abnormalities. The retinas of five offspring of affected males were examined: none of three carrier females and none of two otherwise healthy males had this peripheral retinal finding. CONCLUSIONS: Peripheral inner retinal vascular abnormalities similar to regressed retinopathy of prematurity were identified in seven offspring of carriers of ND gene mutations in two families. These ophthalmologic findings, especially in four genetically healthy offspring, strongly support the hypothesis that abnormal Norrin may have an adverse transplacental (environmental) effect on normal inner retinal vasculogenesis.
Asunto(s)
Ceguera/genética , Proteínas del Ojo/genética , Genes , Pérdida Auditiva Sensorineural/genética , Heterocigoto , Discapacidad Intelectual/genética , Intercambio Materno-Fetal/genética , Mutación Puntual , Enfermedades de la Retina/genética , Adulto , Secuencia de Aminoácidos , Ceguera/congénito , Preescolar , Femenino , Angiografía con Fluoresceína , Fondo de Ojo , Ligamiento Genético/genética , Humanos , Masculino , Datos de Secuencia Molecular , Linaje , Embarazo , Estructura Secundaria de Proteína , Estructura Terciaria de Proteína , Enfermedades de la Retina/patología , Vasos Retinianos/anomalías , Vasos Retinianos/patología , Cromosoma X/genéticaAsunto(s)
Hialuronoglucosaminidasa/deficiencia , Errores Innatos del Metabolismo/patología , Adolescente , Tobillo/patología , Femenino , Dedos/patología , Trastornos del Crecimiento/etiología , Histiocitos , Humanos , Ácido Hialurónico/metabolismo , Errores Innatos del Metabolismo/complicaciones , Errores Innatos del Metabolismo/fisiopatología , Microscopía Electrónica , Huesos Pélvicos/patologíaRESUMEN
We report our experience to date in mutation identification in the Norrie disease (ND) gene. We carried out mutational analysis in 26 kindreds in an attempt to identify regions presumed critical to protein function and potentially correlated with generation of the disease phenotype. All coding exons, as well as noncoding regions of exons 1 and 2, 636 nucleotides in the noncoding region of exon 3, and 197 nucleotides of 5' flanking sequence, were analyzed for single-strand conformation polymorphisms (SSCP) by polymerase chain reaction (PCR) amplification of genomic DNA. DNA fragments that showed altered SSCP band mobilities were sequenced to locate the specific mutations. In addition to three previously described submicroscopic deletions encompassing the entire ND gene, we have now identified 6 intragenic deletions, 8 missense (seven point mutations, one 9-bp deletion), 6 nonsense (three point mutations, three single bp deletions/frameshift) and one 10-bp insertion, creating an expanded repeat in the 5' noncoding region of exon 1. Thus, mutations have been identified in a total of 24 of 26 (92%) of the kindreds we have studied to date. With the exception of two different mutations, each found in two apparently unrelated kindreds, these mutations are unique and expand the genotype database. Localization of the majority of point mutations at or near cysteine residues, potentially critical in protein tertiary structure, supports a previous protein model for norrin as member of a cystine knot growth factor family (Meitinger et al., 1993). Genotype-phenotype correlations were not evident with the limited clinical data available, except in the cases of larger submicroscopic deletions associated with a more severe neurologic syndrome.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Ceguera/genética , Proteínas del Ojo/genética , Proteínas del Tejido Nervioso/genética , Adolescente , Adulto , Secuencia de Bases , Niño , Preescolar , Mapeo Cromosómico , Análisis Mutacional de ADN , Humanos , Lactante , Persona de Mediana Edad , Modelos Genéticos , Datos de Secuencia Molecular , Mutación , Linaje , Reacción en Cadena de la Polimerasa , Polimorfismo Conformacional Retorcido-Simple , Secuencias Repetitivas de Ácidos NucleicosRESUMEN
Positional cloning experiments have resulted recently in the isolation of a candidate gene for Norrie disease (pseudoglioma; NDP), a severe X-linked neurodevelopmental disorder. Here we report the isolation and analysis of human genomic DNA clones encompassing the NDP gene. The gene spans 28 kb and consists of 3 exons, the first of which is entirely contained within the 5' untranslated region. Detailed analysis of genomic deletions in Norrie patients shows that they are heterogeneous, both in size and in position. By PCR analysis, we found that expression of the NDP gene was not confined to the eye or to the brain. An extensive DNA and protein sequence comparison between the human NDP gene and related genes from the database revealed homology with cysteine-rich protein-binding domains of immediate--early genes implicated in the regulation of cell proliferation. We propose that NDP is a molecule related in function to these genes and may be involved in a pathway that regulates neural cell differentiation and proliferation.
Asunto(s)
Encéfalo/anomalías , Deleción Cromosómica , Proteínas del Ojo/genética , Genes , Proteínas Inmediatas-Precoces , Péptidos y Proteínas de Señalización Intercelular , Proteínas del Tejido Nervioso/genética , Enfermedades del Sistema Nervioso/genética , Retina/anomalías , Cromosoma X/ultraestructura , Secuencia de Aminoácidos , Animales , Atrofia , Secuencia de Bases , Encéfalo/embriología , Encéfalo/metabolismo , Encéfalo/patología , Preescolar , Proteína 61 Rica en Cisteína , Sordera/genética , Proteínas del Ojo/biosíntesis , Expresión Génica , Sustancias de Crecimiento/genética , Humanos , Masculino , Ratones/genética , Datos de Secuencia Molecular , Mucinas/genética , Proteínas del Tejido Nervioso/biosíntesis , Especificidad de Órganos , Proteínas/genética , Retina/embriología , Retina/metabolismo , Alineación de Secuencia , Homología de Secuencia , Porcinos/genética , Síndrome , Factor de von Willebrand/genéticaRESUMEN
It has been shown from pulsed-field gel electrophoresis (PFGE) that the monoamine oxidase genes A and B (MAOA & MAOB) and DXS7 loci are physically very close. We have therefore extended studies on their relationship through the characterisation of a 650 kb YAC isolated using L1.28 (recognising the DXS7 locus) as a probe. Restriction mapping of the YAC indicates that it contains both MAOA and MAOB genes in addition to the DXS7 locus. The map derived from the YL1.28-YAC is compatible both with the map from an independently derived YAC carrying MAOA and B genes and with the long range genomic map for the region. A series of subclones prepared from a 'phage library (lambda DASH II) of the YAC have been characterised and have been employed to determine the end point of the deletion of a Norrie disease (NDP) patient who has been shown to lack both DXS7 and MAO coding sequences. The pattern of retention of subclones in the deletion patient place the end point of the deletion within 30-130 kb of the proximal end of the YAC. By combining the data with established recombination analysis, we provide evidence that all or part of the NDP lies in the interval of approximately 250kb within the YAC.
Asunto(s)
Ceguera/genética , Ceguera/enzimología , Deleción Cromosómica , Mapeo Cromosómico , Cromosomas Fúngicos , ADN/genética , Sondas de ADN , Sordera/enzimología , Sordera/genética , Biblioteca de Genes , Marcadores Genéticos , Genoma Humano , Humanos , Discapacidad Intelectual/enzimología , Discapacidad Intelectual/genética , Monoaminooxidasa/genética , Cromosoma XRESUMEN
Previous analysis has refined the location of the gene for Norrie disease, a severe, X-linked, recessive neurodevelopmental disorder, to a yeast artificial chromosome subfragment of 160 kilobases (kb). This fragment was used to screen cDNA libraries from human fetal and adult retina. As a result, we have identified an evolutionarily conserved cDNA, which is expressed in fetal and adult brain and encodes a predicted protein of 133 amino acids. The cDNA detects genomic sequences which span a maximum of 50 kb, and which are partly deleted in several typical Norrie disease patients. An EcoRI polymorphism with a calculated heterozygosity value of 43% was observed. The locus identified is a strong candidate for the Norrie disease gene.
Asunto(s)
Ceguera/genética , Cromosoma X , Secuencia de Aminoácidos , Secuencia de Bases , Ceguera/congénito , Mapeo Cromosómico , Cromosomas Fúngicos , ADN/genética , Análisis Mutacional de ADN , Biblioteca de Genes , Ligamiento Genético , Humanos , Masculino , Datos de Secuencia Molecular , Eliminación de SecuenciaRESUMEN
Norrie disease is a human X-linked recessive disorder of unknown etiology characterized by congenital blindness, sensory neural deafness and mental retardation. This disease gene was previously linked to the DXS7 (L1.28) locus and the MAO genes in band Xp11.3. We report here fine physical mapping of the obligate region containing the Norrie disease gene (NDP) defined by a recombination and by the smallest submicroscopic chromosomal deletion associated with Norrie disease identified to date. Analysis, using in addition two overlapping YAC clones from this region, allowed orientation of the MAOA and MAOB genes in a 5'-3'-3'-5' configuration. A recombination event between a (GT)n polymorphism in intron 2 of the MAOB gene and the NDP locus, in a family previously reported to have a recombination between DXS7 and NDP, delineates a flanking marker telomeric to this disease gene. An anonymous DNA probe, dc12, present in one of the YACs and in a patient with a submicroscopic deletion which includes MAOA and MAOB but not L1.28, serves as a flanking marker centromeric to the disease gene. An Alu-PCR fragment from the right arm of the MAO YAC (YMAO.AluR) is not deleted in this patient and also delineates the centromeric extent of the obligate disease region. The apparent order of these loci is telomere ... DXS7-MAOA-MAOB-NDP-dc12-YMAO.AluR ... centromere. Together these data define the obligate region containing the NDP gene to a chromosomal segment less than 150 kb.
Asunto(s)
Ceguera/genética , Sordera/genética , Discapacidad Intelectual/genética , Cromosoma X , Secuencia de Bases , Ceguera/congénito , Preescolar , Deleción Cromosómica , Mapeo Cromosómico , Cromosomas Fúngicos , ADN , Sordera/congénito , Femenino , Genoma Humano , Biblioteca Genómica , Humanos , Masculino , Datos de Secuencia Molecular , Linaje , Recombinación Genética , SíndromeRESUMEN
Norrie disease is a rare X-linked recessive disorder characterized by blindness from infancy. The gene for Norrie disease has been localized to Xp11.3. More recently, the genes for monoamine oxidase (MAOA, MAOB) have been mapped to the same region. This study evaluates the clinical, biochemical, and neuropsychiatric data in an affected male and 2 obligate heterozygote females from a single family with a submicroscopic deletion involving Norrie disease and MAO genes. The propositus was a profoundly retarded, blind male; he also had neurologic abnormalities including myoclonus and stereotopy-habit disorder. Both obligate carrier females had a normal IQ. The propositus' mother met diagnostic criteria for "chronic hypomania and schizotypal features." The propositus' MAO activity was undetectable and the female heterozygotes had reduced levels comparable to patients receiving MAO inhibiting antidepressants. MAO substrate and metabolite abnormalities were found in the propositus' plasma and CSF. This study indicates that subtle biochemical and possibly neuropsychiatric abnormalities may be detected in some heterozygotes with the microdeletion in Xp11.3 due to loss of the gene product for the MAO genes; this deletion can also explain some of the complex phenotype of this contiguous gene syndrome in the propositus.
Asunto(s)
Ceguera/genética , Deleción Cromosómica , Monoaminooxidasa/genética , Cromosoma X , Adolescente , Ceguera/metabolismo , Ceguera/psicología , Femenino , Heterocigoto , Humanos , Discapacidad Intelectual/genética , Masculino , Monoaminooxidasa/deficiencia , Mioclonía/genética , Fenotipo , Conducta Estereotipada , SíndromeRESUMEN
Norrie disease is an X-linked recessive disorder characterized by congenital blindness and, in many cases, mental retardation. Some Norrie disease cases have been shown to be associated with a submicroscopic deletion in chromosomal region Xp11.3. Cerebrospinal fluid (CSF) was collected from four male patients with an X-chromosomal deletion associated with Norrie disease. CSF proteins were resolved using two-dimensional gel electrophoresis and then analyzed by computer using the Elsie V program. Our analysis revealed a protein that appears to be altered in patients with Norrie disease deletion.
Asunto(s)
Ceguera/líquido cefalorraquídeo , Proteínas del Líquido Cefalorraquídeo/aislamiento & purificación , Deleción Cromosómica , Cromosoma X , Ceguera/congénito , Ceguera/genética , Proteínas del Líquido Cefalorraquídeo/genética , Electroforesis en Gel Bidimensional , Humanos , Discapacidad Intelectual/líquido cefalorraquídeo , Discapacidad Intelectual/genética , Masculino , Monoaminooxidasa/deficienciaRESUMEN
Two individuals with an X-chromosomal deletion were recently found to lack the genes encoding monoamine oxidase type A (MAO-A) and MAO-B. This abnormality was associated with almost total (90%) reductions in the oxidatively deaminated urinary metabolites of the MAO-A substrate, norepinephrine, and with marked (100-fold) increases in an MAO-B substrate, phenylethylamine, confirming systemic functional consequences of the genetic enzyme deficiency. However, urinary concentrations of the deaminated metabolites of dopamine and serotonin (5-HT) were essentially normal. To investigate other deaminating systems besides MAO-A and MAO-B that might produce these metabolites of dopamine and 5-HT, we examined plasma amine oxidase (AO) activity in these two patients and two additional patients with the same X-chromosomal deletion. Normal plasma AO activity was found in all four Norrie disease-deletion patients, in four patients with classic Norrie disease without a chromosomal deletion, and in family members of patients from both groups. Marked plasma amine metabolite abnormalities and essentially absent platelet MAO-B activity were found in all four Norrie disease-deletion patients, but in none of the other subjects in the two comparison groups. These results indicate that plasma AO is encoded by gene(s) independent of those for MAO-A and MAO-B, and raise the possibility that plasma AO, and perhaps the closely related tissue AO, benzylamine oxidase, as well as other atypical AOs or MAOs encoded independently from MAO-A and MAO-B may contribute to the oxidative deamination of dopamine and 5-HT in humans.
Asunto(s)
Amina Oxidasa (conteniendo Cobre) , Ceguera/genética , Dopamina/metabolismo , Monoaminooxidasa/deficiencia , Oxidorreductasas actuantes sobre Donantes de Grupo CH-NH/sangre , Retina/anomalías , Serotonina/metabolismo , Aberraciones Cromosómicas Sexuales/enzimología , Adolescente , Adulto , Ceguera/enzimología , Deleción Cromosómica , Femenino , Humanos , Masculino , Monoaminooxidasa/genética , Norepinefrina/metabolismo , Fenetilaminas/metabolismo , Cromosoma XRESUMEN
Urinary and plasma amines and amine metabolites were quantified in two individuals with Norrie disease resulting from a deletion in chromosomal region Xp11.3, recently reported to be associated with absence of the gene encoding monoamine oxidase (MAO)-A and nondetectable MAO-A activity in fibroblasts and MAO-B activity in platelets. Marked (four-to 100-fold) elevations in levels of urinary phenylethylamine, o-tyramine, and m-tyramine (which are preferential substrates for MAO-B) and marked reductions (90%) in levels of 3-methoxy-4-hydroxyphenylglycol (a deaminated metabolite of norepinephrine, a preferential substrate for MAO-A) in urine and plasma confirmed the presence of a systemic, functionally significant reduction in the activities of both MAO isozymes. The magnitude of these changes, which are equivalent to those found in subjects taking MAO-inhibiting antidepressants, suggests that early initiation of dietary and drug restrictions may be clinically important in these and other patients with X-chromosomal mutations involving MAO. These findings further support the proposition that the MAOA and MAOB genes are located in close proximity on the X chromosome. Negligible changes in the metabolites of dopamine and serotonin raise the possibility that other metabolic pathways are of importance for their production, that dietary or intestinal bacterial sources contribute substantially to the presence of these amine metabolites in urine, or both.
Asunto(s)
Aminas Biogénicas/metabolismo , Deleción Cromosómica , Genes , Enfermedades Genéticas Congénitas/metabolismo , Monoaminooxidasa/genética , Cromosoma X , Adolescente , Aminas Biogénicas/orina , Plaquetas/metabolismo , Niño , Dopamina/metabolismo , Enfermedades Genéticas Congénitas/enzimología , Enfermedades Genéticas Congénitas/genética , Humanos , Masculino , Valores de Referencia , Serotonina/sangreRESUMEN
Norrie disease (ND), atrophia bulborum hereditaria, is caused by a gene defect on the proximal short arm of the X-chromosome. As shown by us and others, microdeletions spanning the DXS7 locus are not uncommon in this disorder, and there is recent evidence that, at least in some of the Norrie deletion patients, the monoamine oxidase (MAO) A and B genes are deleted as well. Molecular hybridization experiments with 19 cloned DNA fragments have enabled us to construct a preliminary long-range restriction map around DXS77, DXS7, MAO-A and MAO-B, and to localize the distal end point of an ND deletion between DXS77 and DXS7.