RESUMEN
BACKGROUND: Knowledge about inflammatory bowel disease (IBD) in patients with Hermansky-Pudlak syndrome (HPS), a rare autosomal recessive disorder characterized by defective biogenesis of lysosome-related organelles, could provide insights into IBD in general. OBJECTIVE: To expand the understanding of IBD in patients with HPS. METHODS: Retrospective review of records from patients with HPS evaluated at the National Institutes of Health Clinical Center from 1995 to 2019 was conducted. Clinical features of IBD, genotyping results and histologic findings of colectomy specimens were analysed. RESULTS: IBD affected 37 (14.2%; 12 male, 25 female) of 261 patients with HPS. Median age of onset was 17 years; range was 1 to 52 years. The most common symptoms of HPS IBD were hematochezia, abdominal pain and loose stools. Fistulae or extra-intestinal manifestations developed in 30% or 22%, respectively. Genotyping showed that patients with biallelic variants in HPS1, HPS3, HPS4 or HPS6 were diagnosed with IBD. Six children had very early-onset IBD. Patients with HPS-3 had mild manifestations of IBD. Medical therapy and bowel resection were utilized to treat 73% and 35% of patients with HPS IBD, respectively; 7 of 13 patients receiving anti-tumor necrosis factor alpha therapy had prolonged clinical responses. Active cryptitis, chronic inflammatory changes, granulomas and ceroid lipofuscinosis were histopathologic findings in three colectomy specimens. CONCLUSIONS: IBD resembling Crohn's disease affects some patients with HPS; genetic heterogeneity is a feature of HPS IBD. HPS3 is a new gene associated with human IBD. Very early-onset IBD can develop in HPS.
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Síndrome de Hermanski-Pudlak/complicaciones , Enfermedades Inflamatorias del Intestino/complicaciones , Dolor Abdominal/etiología , Adolescente , Adulto , Edad de Inicio , Niño , Preescolar , Defecación , Femenino , Hemorragia Gastrointestinal/etiología , Genotipo , Humanos , Lactante , Enfermedades Inflamatorias del Intestino/genética , Enfermedades Inflamatorias del Intestino/patología , Enfermedades Inflamatorias del Intestino/terapia , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Adulto JovenRESUMEN
Undiagnosed rare diseases (URDs) account for a significant portion of the overall rare disease burden, depending upon the country. Hence, URDs represent an unmet medical need. A specific challenge posed by the ensemble of the URD patient cohort is the heterogeneity of its composition; the group, indeed, includes very rare, still unidentified conditions as well as clinical variants of recognized rare diseases. Exact disease recognition requires new approaches that cut across national and institutional boundaries, may need the implementation of methods new to diagnostics, and embrace clinical care and research. To address these issues, the Undiagnosed Diseases Network International (UDNI) was established in 2014, with the major aims of providing diagnoses to patients, implementing additional diagnostic tools, and fostering research on novel diseases, their mechanisms, and their pathways. The UDNI involves centres with internationally recognized expertise, and its scientific resources and know-how aim to fill the knowledge gaps that impede diagnosis, in particularly for ultra-rare diseases. Consequently, the UDNI fosters the translation of research into medical practice, aided by active patient involvement. The goals of the UDNI are to work collaboratively and at an international scale to: 1) provide diagnoses for individuals who have conditions that have eluded diagnosis by clinical experts; 2) gain insights into the etiology and pathogenesis of novel diseases; 3) contribute to standards of diagnosing unsolved patients; and 4) share the results of UDNI research in a timely manner and as broadly as possible.
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Salud Global , Servicios de Información/organización & administración , Cooperación Internacional , Enfermedades Raras/diagnóstico , Enfermedades no Diagnosticadas , Investigación Biomédica , Humanos , Enfermedades Raras/etiología , Factores de TiempoRESUMEN
One Sentence Summary: A Bayesian repeated measures model based on quantitative muscle strength data from a prospective Natural History Study was developed to determine disease progression and design clinical trials for GNE myopathy, a rare and slowly progressive muscle disease. GNE myopathy is a rare muscle disease characterized by slowly progressive weakness and atrophy of skeletal muscles. To address the significant challenges of defining the natural history and designing clinical trials for GNE myopathy, we developed a Bayesian latent variable repeated measures model to determine disease progression. The model is based on longitudinal quantitative muscle strength data collected as part of a prospective Natural History Study. The GNE Myopathy Progression Model provides an understanding of disease progression that would have otherwise required a natural history of unfeasible duration. "Disease age," the model-generated measure of disease progression, highly correlates with a variety of clinical, functional and patient-reported outcomes. With the incorporation of a treatment effect parameter to the GNE Disease Progression Model, we describe a novel GNE Myopathy Disease Modification Analysis that significantly increases power and reduces the number of subjects required to test the effectiveness of novel therapies when compared to more traditional analysis methods. The GNE Myopathy Disease Progression Model and Disease Modification Analysis can be applied to muscle diseases with prospectively collected muscle strength data, and a variety of rare and slowly progressive diseases.
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Teorema de Bayes , Progresión de la Enfermedad , Miopatías Distales/fisiopatología , Algoritmos , Humanos , Estudios ProspectivosRESUMEN
Patients with primary serine biosynthetic defects manifest with intellectual disability, microcephaly, ichthyosis, seizures and peripheral neuropathy. The underlying pathogenesis of peripheral neuropathy in these patients has not been elucidated, but could be related to a decrease in the availability of certain classical sphingolipids, or to an increase in atypical sphingolipids. Here, we show that patients with primary serine deficiency have a statistically significant elevation in specific atypical sphingolipids, namely deoxydihydroceramides of 18-22 carbons in acyl length. We also show that patients with aberrant plasma serine and alanine levels secondary to mitochondrial disorders also display peripheral neuropathy along with similar elevations of atypical sphingolipids. We hypothesize that the etiology of peripheral neuropathy in patients with primary mitochondrial disorders is related to this elevation of deoxysphingolipids, in turn caused by increased availability of alanine and decreased availability of serine. These findings could have important therapeutic implications for the management of these patients.
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Errores Innatos del Metabolismo de los Aminoácidos/fisiopatología , Enfermedades Mitocondriales/fisiopatología , Serina/deficiencia , Esfingolípidos/metabolismo , Adolescente , Adulto , Anciano , Estudios de Casos y Controles , Niño , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Adulto JovenRESUMEN
Mitochondrial aminoacyl-tRNA synthetases (mtARSs) are essential, ubiquitously expressed enzymes that covalently attach amino acids to their corresponding tRNA molecules during translation of mitochondrial genes. Deleterious variants in the mtARS genes cause a diverse array of phenotypes, many of which involve the nervous system. Moreover, distinct mutations in mtARSs often cause different clinical manifestations. Recently, the gene encoding mitochondrial tryptophanyl tRNA synthetase (WARS2) was reported to cause 2 different neurological phenotypes, a form of autosomal recessive intellectual disability and a syndrome of severe infantile-onset leukoencephalopathy. Here, we report the case of a 17-year-old boy with compound heterozygous mutations in WARS2 (p.Trp13Gly, p.Ser228Trp) who presented with infantile-onset, Levodopa-responsive Parkinsonism at the age of 2 years. Analysis of patient-derived dermal fibroblasts revealed decreased steady-state WARS2 protein and normal OXPHOS content. Muscle mitochondrial studies suggested mitochondrial proliferation without obvious respiratory chain deficiencies at the age of 9 years. This case expands the phenotypic spectrum of WARS2 deficiency and emphasizes the importance of mitochondrial protein synthesis in the pathogenesis of Parkinsonism.
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Alelos , Mutación , Trastornos Parkinsonianos/diagnóstico , Trastornos Parkinsonianos/genética , Triptófano-ARNt Ligasa/genética , Adolescente , Edad de Inicio , Biopsia , Análisis Mutacional de ADN , Fibroblastos/metabolismo , Estudios de Asociación Genética , Genotipo , Humanos , Levodopa/uso terapéutico , Imagen por Resonancia Magnética , Masculino , Trastornos Parkinsonianos/tratamiento farmacológico , Fenotipo , Polimorfismo de Nucleótido Simple , Medicina de PrecisiónRESUMEN
Mitochondrial encephalopathies are a heterogeneous group of disorders that, usually carry grave prognosis. Recently a homozygous mutation, Gly372Ser, in the TIMM50 gene, was reported in an abstract form, in three sibs who suffered from intractable epilepsy and developmental delay accompanied by 3-methylglutaconic aciduria. We now report on four patients from two unrelated families who presented with severe intellectual disability and seizure disorder, accompanied by slightly elevated lactate level, 3-methylglutaconic aciduria and variable deficiency of mitochondrial complex V. Using exome analysis we identified two homozygous missense mutations, Arg217Trp and Thr252Met, in the TIMM50 gene. The TIMM50 protein is a subunit of TIM23 complex, the mitochondrial import machinery. It serves as the major receptor in the intermembrane space, binding to proteins which cross the mitochondrial inner membrane on their way to the matrix. The mutations, which affected evolutionary conserved residues and segregated with the disease in the families, were neither present in large cohorts of control exome analyses nor in our ethnic specific exome cohort. Given the phenotypic similarity, we conclude that missense mutations in TIMM50 are likely manifesting by severe intellectual disability and epilepsy accompanied by 3-methylglutaconic aciduria and variable mitochondrial complex V deficiency. 3-methylglutaconic aciduria is emerging as an important biomarker for mitochondrial dysfunction, in particular for mitochondrial membrane defects.
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Adenosina Trifosfatasas/deficiencia , Epilepsia/genética , Proteínas de la Membrana/deficiencia , Proteínas de Transporte de Membrana/genética , Errores Innatos del Metabolismo/genética , Encefalomiopatías Mitocondriales/genética , Adenosina Trifosfatasas/genética , Proteínas Portadoras/genética , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Proteínas de la Membrana/genética , Proteínas del Complejo de Importación de Proteínas Precursoras Mitocondriales , ATPasas de Translocación de Protón Mitocondriales , Mutación , Polimorfismo de Nucleótido Simple , EmbarazoRESUMEN
5-Oxoprolinuria (pyroglutamic aciduria) resulting from glutathione synthetase (GSS) deficiency is an inherited autosomal recessive disorder characterized, in its severe form, by massive urinary excretion of 5-oxoproline, metabolic acidosis, haemolytic anaemia and central nervous system damage. The metabolic defect results in low GSH levels presumably with feedback over-stimulation of gamma-glutamylcysteine synthesis and its subsequent conversion to 5-oxoproline. In this study, we cloned and characterized the human GSS gene and examined three families with four cases of well-documented 5-oxoprolinuria. We identified seven mutations at the GSS locus on six alleles: one splice site mutation, two deletions and four missense mutations. Bacterial expression and yeast complementation assays of the cDNAs encoded by these alleles demonstrated their functional defects. We also characterized a fifth case, an homozygous missense mutation in the gene in an individual affected by a milder-form of the GSS deficiency, which is apparently restricted to erythrocytes and only associated with haemolytic anaemia. Our data provide the first molecular genetic analysis of 5-oxoprolinuria and demonstrate that GSS deficiency with oxoprolinuria and GSS deficiency without 5-oxoprolinuria are caused by mutations in the same gene.
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Errores Innatos del Metabolismo de los Aminoácidos/genética , Glutatión Sintasa/genética , Mutación , Ácido Pirrolidona Carboxílico/metabolismo , Errores Innatos del Metabolismo de los Aminoácidos/complicaciones , Anemia/complicaciones , Anemia/genética , Sitios de Unión , Eritrocitos/patología , Escherichia coli/genética , Escherichia coli/metabolismo , Femenino , Prueba de Complementación Genética , Glutatión Sintasa/metabolismo , Heterocigoto , Humanos , Masculino , Datos de Secuencia Molecular , Linaje , Reacción en Cadena de la Polimerasa , Empalme del ARN , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Schizosaccharomyces/genética , Schizosaccharomyces/metabolismo , Análisis de Secuencia de ADNRESUMEN
We have found mutations in the Menkes disease gene (MNK) which impair, but do not abolish, correct mRNA splicing in patients with less severe clinical phenotypes. In one family, four males aged 2-36 years with a distinctive Menkes variant have a mutation at the +3 position of a splice donor site near the 3' end of the Menkes coding sequence that is associated with exon skipping and a stable mutant transcript. In an unrelated 15-year-old male with typical occipital horn syndrome, a point mutation at the -2 exonic position of a splice donor site in the middle of the gene causes exon-skipping and activation of a cryptic splice acceptor site. In both mutations, maintenance of some normal splicing is demonstrable by RT-PCR, cDNA sequencing and ribonuclease protection.
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Adenosina Trifosfatasas/genética , Proteínas Portadoras/genética , Proteínas de Transporte de Catión , Síndrome de Ehlers-Danlos/genética , Síndrome del Pelo Ensortijado/genética , Hueso Occipital/anomalías , Mutación Puntual , Empalme del ARN , Proteínas Recombinantes de Fusión , Adenosina Trifosfatasas/química , Adolescente , Animales , Secuencia de Bases , Células Cultivadas , Ceruloplasmina/análisis , Cobre/sangre , ATPasas Transportadoras de Cobre , Análisis Mutacional de ADN , Dihidroxifenilalanina/sangre , Dihidroxifenilalanina/líquido cefalorraquídeo , Síndrome de Ehlers-Danlos/sangre , Síndrome de Ehlers-Danlos/líquido cefalorraquídeo , Síndrome de Ehlers-Danlos/clasificación , Exones , Femenino , Fibroblastos/metabolismo , Humanos , Masculino , Síndrome del Pelo Ensortijado/sangre , Síndrome del Pelo Ensortijado/líquido cefalorraquídeo , Metoxihidroxifenilglicol/análogos & derivados , Metoxihidroxifenilglicol/sangre , Metoxihidroxifenilglicol/líquido cefalorraquídeo , Ratones , Ratones Mutantes Neurológicos , Datos de Secuencia Molecular , Linaje , Fenotipo , Reacción en Cadena de la Polimerasa , Homología de Secuencia de Aminoácido , Especificidad de la Especie , Regiones Terminadoras GenéticasRESUMEN
Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disorder characterized by oculocutaneous albinism and a storage pool deficiency due to an absence of platelet dense bodies. Lysosomal ceroid lipofuscinosis, pulmonary fibrosis and granulomatous colitis are occasional manifestations of the disease. HPS occurs with a frequency of one in 1800 in north-west Puerto Rico due to a founder effect. Several non-Puerto Rican patients also have mutations in HPS1, which produces a protein of unknown function. Another gene, ADTB3A, causes HPS in the pearl mouse and in two brothers with HPS-2 (refs. 11,12). ADTB3A encodes a coat protein involved in vesicle formation, implicating HPS as a disorder of membrane trafficking. We sought to identify other HPS-causing genes. Using homozygosity mapping on pooled DNA of 6 families from central Puerto Rico, we localized a new HPS susceptibility gene to a 1.6-cM interval on chromosome 3q24. The gene, HPS3, has 17 exons, and a putative 113.7-kD product expected to reveal how new vesicles form in specialized cells. The homozygous, disease-causing mutation is a large deletion and represents the second example of a founder mutation causing HPS on the small island of Puerto Rico. We also present an allele-specific assay for diagnosing individuals heterozygous or homozygous for this mutation.
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Proteínas Portadoras/genética , Cromosomas Humanos Par 3/genética , Síndrome de Hermanski-Pudlak/genética , Alelos , Secuencia de Aminoácidos , Northern Blotting , Análisis Mutacional de ADN , Femenino , Efecto Fundador , Tamización de Portadores Genéticos , Predisposición Genética a la Enfermedad , Genotipo , Síndrome de Hermanski-Pudlak/epidemiología , Homocigoto , Humanos , Péptidos y Proteínas de Señalización Intracelular , Masculino , Datos de Secuencia Molecular , Mutación , Especificidad de Órganos , Linaje , Fenotipo , Mapeo Físico de Cromosoma , Puerto Rico/epidemiología , Eliminación de SecuenciaRESUMEN
CD154 is an immunostimulatory ligand for CD40 that markedly influences alloimmunity. Its presence in platelets suggests that its release and subsequent immune effects are driven by trauma and thus could be relevant following organ transplantation. However, the release of platelet derived CD154 and its consequences have not been investigated in a clinical transplant setting. To better characterize the relationship between platelet activation and CD154 release, we investigated CD154 release by platelets obtained from normal individuals, and patients with two genetic defects that influence platelet granule development. Using these unique patient populations and immune-electron microscopy, we confirmed that CD154 was an alpha granule and not a cell surface protein, and thereafter optimized the methods for its in vivo measurement in humans. We then investigated plasma CD154 levels in kidney and liver transplant recipients and found no evidence that CD154 levels fluctuated systemically as a result of kidney or liver transplant procedures. Paradoxically, we found that kidney transplant patients had significantly lower systemic CD154 levels during episodes of rejection. These data suggest that the immune effects of CD154 are likely mediated through local and not systemic mechanisms, and discourage the use of CD154 as a peripheral biomarker in organ transplantation.
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Plaquetas/inmunología , Ligando de CD40/metabolismo , Ligando de CD40/ultraestructura , Trasplante de Riñón/inmunología , Trasplante de Hígado/inmunología , Biomarcadores/metabolismo , Plaquetas/fisiología , Ligando de CD40/inmunología , Estudios de Casos y Controles , Adhesión Celular/inmunología , Femenino , Rechazo de Injerto/inmunología , Supervivencia de Injerto/inmunología , Humanos , Trasplante de Riñón/efectos adversos , Trasplante de Hígado/efectos adversos , Masculino , Activación Plaquetaria/inmunología , Valores de Referencia , Sensibilidad y Especificidad , Trasplante Homólogo/inmunologíaRESUMEN
Cystinosis is an autosomal recessive lysosomal storage disease caused by mutations in CTNS. The most prevalent CTNS mutation is a homozygous 57-kb deletion that also includes an adjacent gene named SHPK (CARKL), encoding sedoheptulokinase. Patients with this deletion have elevated urinary concentrations of sedoheptulose. Using derivatisation with pentafluorobenzyl hydroxylamine and liquid chromatography-tandem mass spectrometry (LC-MS/MS), we developed a new sensitive method for the quantification of sedoheptulose in dried blood spots. This method can be utilized as a quick screening test to detect cystinosis patients homozygous for the 57-kb deletion in CTNS; which is the most common mutation of cystinosis. Sedoheptulose concentrations in the deleted patients were 6 to 23 times above the upper limit for controls. The assessment of sedoheptulose in a bloodspot from a known cystinosis patient homozygous for the 57-kb deletion retrieved from the Dutch neonatal screening program showed that sedoheptulose was already elevated in the neonatal period. There was no overlap in sedoheptulose levels between cystinosis patients homozygous for the 57-kb deletion and cystinosis patients not homozygous for this deletion. Our presented method can be used prior to mutation analysis to detect cystinosis patients homozygous for the 57-kb deletion. We feel that the presented method enables fast (pre)-symptomatic detection of cystinosis patients homozygous for the 57-kb deletion, allowing early treatment.
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Cistinosis/diagnóstico , Cistinosis/enzimología , Eliminación de Gen , Heptosas/sangre , Tamizaje Neonatal/métodos , Sistemas de Transporte de Aminoácidos Neutros/genética , Cistinosis/sangre , Cistinosis/genética , Humanos , Recién Nacido , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Espectrometría de Masas en Tándem , Factores de Transcripción/genéticaRESUMEN
Hermansky-Pudlak syndrome (HPS) is a disorder of oculocutaneous albinism (OCA) and platelet storage pool deficiency. Eight different disease-causing genes have been identified, whose gene products are thought to be involved in the biogenesis of lysosome-related organelles. HPS type 1 (HPS-1) is the most common HPS subtype in Puerto Rico, with a frequency of 1:1800 in the northwest of the island due to a founder mutation, i.e. a 16-bp duplication in exon 15 of the HPS1 gene (c.1472_1487dup16; p.H497QfsX90). We identified three Puerto Rican HPS-1 patients who carried compound heterozygous HPS1 mutations. One patient was heterozygous for c.937G>A, causing a missense mutation (p.G313S) at the 3 splice junction of exon 10. This mutation resulted in activation of a cryptic intronic splice site causing an aberrantly spliced HPS1 mRNA that included 144-bp of intronic sequence, producing 11 novel amino acids followed by a stop codon. The other two patients were heterozygous for the previously reported c.972delC in HPS1, resulting in a frameshift and a premature stop codon (p.M325WfsX6). These findings indicate that, among Puerto Ricans, other HPS1 mutations apart from the 16-bp duplication should be considered in the analysis of this population.
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Anomalías Múltiples/genética , Síndrome de Hermanski-Pudlak/genética , Proteínas de la Membrana/genética , Adulto , Empalme Alternativo , Secuencia de Bases , Análisis Mutacional de ADN , Femenino , Síndrome de Hermanski-Pudlak/diagnóstico , Humanos , Masculino , Datos de Secuencia Molecular , Mutación Missense , Puerto Rico , Adulto JovenRESUMEN
Attention-Deficit/Hyperactivity Disorder (ADHD) has a very high heritability (0.8), suggesting that about 80% of phenotypic variance is due to genetic factors. We used the integration of statistical and functional approaches to discover a novel gene that contributes to ADHD. For our statistical approach, we started with a linkage study based on large multigenerational families in a population isolate, followed by fine mapping of targeted regions using a family-based design. Family- and population-based association studies in five samples from disparate regions of the world were used for replication. Brain imaging studies were performed to evaluate gene function. The linkage study discovered a genome region harbored in the Latrophilin 3 gene (LPHN3). In the world-wide samples (total n=6360, with 2627 ADHD cases and 2531 controls) statistical association of LPHN3 and ADHD was confirmed. Functional studies revealed that LPHN3 variants are expressed in key brain regions related to attention and activity, affect metabolism in neural circuits implicated in ADHD, and are associated with response to stimulant medication. Linkage and replicated association of ADHD with a novel non-candidate gene (LPHN3) provide new insights into the genetics, neurobiology, and treatment of ADHD.
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Trastorno por Déficit de Atención con Hiperactividad/tratamiento farmacológico , Trastorno por Déficit de Atención con Hiperactividad/genética , Estimulantes del Sistema Nervioso Central/uso terapéutico , Predisposición Genética a la Enfermedad , Receptores Acoplados a Proteínas G/genética , Receptores de Péptidos/genética , Adolescente , Adulto , Encéfalo/metabolismo , Supervivencia Celular/genética , Niño , Preescolar , Mapeo Cromosómico , Femenino , Ligamiento Genético , Genotipo , Humanos , Espectroscopía de Resonancia Magnética/métodos , Masculino , Polimorfismo Genético , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Péptidos/metabolismoRESUMEN
OBJECTIVE: To identify genetic causes of COACH syndrome BACKGROUND: COACH syndrome is a rare autosomal recessive disorder characterised by Cerebellar vermis hypoplasia, Oligophrenia (developmental delay/mental retardation), Ataxia, Coloboma, and Hepatic fibrosis. The vermis hypoplasia falls in a spectrum of mid-hindbrain malformation called the molar tooth sign (MTS), making COACH a Joubert syndrome related disorder (JSRD). METHODS: In a cohort of 251 families with JSRD, 26 subjects in 23 families met criteria for COACH syndrome, defined as JSRD plus clinically apparent liver disease. Diagnostic criteria for JSRD were clinical findings (intellectual impairment, hypotonia, ataxia) plus supportive brain imaging findings (MTS or cerebellar vermis hypoplasia). MKS3/TMEM67 was sequenced in all subjects for whom DNA was available. In COACH subjects without MKS3 mutations, CC2D2A, RPGRIP1L and CEP290 were also sequenced. RESULTS: 19/23 families (83%) with COACH syndrome carried MKS3 mutations, compared to 2/209 (1%) with JSRD but no liver disease. Two other families with COACH carried CC2D2A mutations, one family carried RPGRIP1L mutations, and one lacked mutations in MKS3, CC2D2A, RPGRIP1L and CEP290. Liver biopsies from three subjects, each with mutations in one of the three genes, revealed changes within the congenital hepatic fibrosis/ductal plate malformation spectrum. In JSRD with and without liver disease, MKS3 mutations account for 21/232 families (9%). CONCLUSIONS: Mutations in MKS3 are responsible for the majority of COACH syndrome, with minor contributions from CC2D2A and RPGRIP1L; therefore, MKS3 should be the first gene tested in patients with JSRD plus liver disease and/or coloboma, followed by CC2D2A and RPGRIP1L.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Ataxia/genética , Cerebelo/anomalías , Coloboma/genética , Discapacidad Intelectual/genética , Cirrosis Hepática/genética , Proteínas de la Membrana/genética , Proteínas/genética , Adolescente , Proteínas del Citoesqueleto , Femenino , Humanos , Lactante , Cirrosis Hepática/patología , Masculino , Mutación , Síndrome , Adulto JovenRESUMEN
BACKGROUND: In the last decade, Hermansky-Pudlak syndrome (HPS) has arisen as an instructive disorder for cell biologists to study the biogenesis of lysosome related organelles (LROs). Of the eight human HPS subtypes, only subtypes 1 through 5 are well described. AIM: To characterise extensively the HPS-6 subtype, caused by defects in HPS6, a subunit of the biogenesis of lysosome related organelles complex-2 (BLOC-2). METHODS: Mutation analysis for the HPS6 gene was performed on DNA from our group of unclassified HPS patients. The clinical phenotype of patients with HPS6 mutations was then carefully ascertained, and their cultured dermal melanocytes were employed for cellular immunofluorescence studies. RESULTS: Molecular studies showed a variety of mutations in the single exon HPS6 gene, including frame shift, missense, and nonsense mutations as well as a approximately 20 kb deletion spanning the entire HPS6 genomic region. Cellular studies revealed that the melanogenic proteins tyrosinase and tyrosinase related protein 1 failed to be efficiently delivered to the melanosomes of HPS-6 patients, explaining their hypopigmentation. Clinical studies indicated that HPS-6 patients exhibit oculocutaneous albinism and a bleeding diathesis. Importantly, granulomatous colitis and pulmonary fibrosis, debilitating features present in HPS subtypes 1 and 4, were not detected in our HPS-6 patients. CONCLUSION: The HPS-6 subtype resembles other BLOC-2 defective subtypes (that is, HPS-3 and HPS-5) in its molecular, cellular and clinical findings. These findings are not only important for providing a prognosis to newly diagnosed HPS-6 patients, but also for further elucidation of HPS function in the biogenesis of LROs.
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Síndrome de Hermanski-Pudlak/genética , Síndrome de Hermanski-Pudlak/patología , Péptidos y Proteínas de Señalización Intracelular/genética , Adolescente , Adulto , Secuencia de Aminoácidos , Secuencia de Bases , Northern Blotting , ADN/química , ADN/genética , Femenino , Variación Genética , Humanos , Inmunohistoquímica , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Masculino , Melanosomas/genética , Melanosomas/patología , Persona de Mediana Edad , Datos de Secuencia Molecular , Reacción en Cadena de la Polimerasa , Polimorfismo de Nucleótido Simple , Adulto JovenRESUMEN
OBJECTIVES: Cystinosis is a rare autosomal recessive lysosomal storage disorder with developmental and mineralization anomalies as part of its clinical presentation. The objective of this study was to provide the first systematic assessment of the craniofacial and dental characteristics associated with cystinosis. STUDY DESIGN: Oral and radiographic evaluations were performed on 73 patients with cystinosis. Analyses of cephalometry (n = 20), taurodontism (n = 47), caries (n = 47), enamel defects (n = 48), soft tissue anomalies (n = 48), and dental age (n = 41) were performed on the cystinosis group, and compared with age- and sex-comparable controls or standards. RESULTS: Cystinosis patients manifested relative mandibular deficiency, an increased facial height, and a reduced airway space. Taurodontism and enamel defects were significantly more prevalent in cystinosis patients compared with controls (P < 0.0001 and P = 0.027, respectively). Children (aged <15 years) with cystinosis also demonstrated a significant delay, of almost 9 months, of their dental development (P < 0.001). CONCLUSION: Novel craniofacial and dental features are associated with cystinosis. Craniofacial deficiencies may influence the swallowing and respiratory complications seen in cystinosis. Renal pathology and associated mineral imbalance may explain the dental root and enamel anomalies found in cystinosis patients; the developmental delays in cystinosis include delayed dental formation.
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Anomalías Craneofaciales/diagnóstico , Cistinosis/complicaciones , Anomalías Dentarias/diagnóstico , Adolescente , Adulto , Determinación de la Edad por los Dientes , Anodoncia/diagnóstico , Anodoncia/etiología , Estudios de Casos y Controles , Cefalometría , Niño , Preescolar , Anomalías Craneofaciales/etiología , Índice CPO , Caries Dental/diagnóstico , Caries Dental/etiología , Esmalte Dental/anomalías , Cavidad Pulpar/anomalías , Femenino , Glositis Migratoria Benigna/diagnóstico , Glositis Migratoria Benigna/etiología , Humanos , Masculino , Mandíbula/anomalías , Odontogénesis/fisiología , Anomalías Dentarias/etiología , Raíz del Diente/anomalías , Dimensión Vertical , Adulto JovenRESUMEN
Normal fibroblasts exposed to N-acetylmannosamine yielded lysosome-rich granular fractions loaded with free (unbound) sialic acid, whose velocity of egress increased with increasing initial loading. Fibroblast granular fractions of patients with Salla disease exhibited negligible egress of sialic acid, whether endogenous or derived from N-acetylmannosamine exposure. Salla disease represents the first disorder demonstrated to be caused by defective transport of a monosaccharide out of cellular lysosomes.
Asunto(s)
Fibroblastos/metabolismo , Lisosomas/metabolismo , Errores Innatos del Metabolismo/metabolismo , Ácidos Siálicos/metabolismo , Fraccionamiento Celular , Fibroblastos/efectos de los fármacos , Hexosaminas/farmacología , Humanos , Lisosomas/efectos de los fármacos , Ácido N-Acetilneuramínico , Ácidos Siálicos/análisis , Fracciones Subcelulares/análisisRESUMEN
The activity of a cystine transport system in lysosomes prepared from the leukocytes of patients with cystinosis was found to be deficient. In normal subjects, this system was resistant to N-ethylmaleimide and demonstrated saturation kinetics. Lysosomes from individuals heterozygous for cystinosis demonstrated a reduced maximum velocity for cystine egress from lysosomes. The rate of cystine escape from normal lysosomes was enhanced by adenosine triphosphate. The availability of normal and mutant lysosomes provides a means of investigating mechanisms of amino acid transport across lysosomal membranes.
Asunto(s)
Cistina/metabolismo , Cistinosis/metabolismo , Leucocitos/metabolismo , Transporte Biológico/efectos de los fármacos , Proteínas Portadoras/metabolismo , Cisteína/metabolismo , Etilmaleimida/farmacología , Humanos , Cinética , Lisosomas/metabolismoRESUMEN
Canavan disease (CD) is a fatal dysmyelinating genetic disorder associated with aspartoacylase deficiency, resulting in decreased brain acetate levels and reduced myelin lipid synthesis in the developing brain. Here we tested tolerability of a potent acetate precursor, glyceryl triacetate (GTA), at low doses in two infants diagnosed with CD, aged 8 and 13 months. Much higher doses of GTA were evaluated for toxicity in the tremor rat model of CD. GTA was given orally to the infants for up to 4.5 and 6 months, starting at 25 mg/kg twice daily, doubling the dose weekly until a maximum of 250 mg/kg reached. Wild-type and tremor rat pups were given GTA orally twice daily, initially at a dose of 4.2 g/kg from postnatal days 7 through 14, and at 5.8 g/kg from day 15 through 23, and thereafter in food (7.5%) and water (5%). At the end of the trial (approximately 90 to 120 days) sera and tissues from rats were analysed for changes in blood chemistry and histopathology. GTA treatment caused no detectable toxicity and the patients showed no deterioration in clinical status. In the high-dose animal studies, no significant differences in the mean blood chemistry values occurred between treated and untreated groups, and no lesions indicating toxicity were detectable in any of the tissues examined. Lack of GTA toxicity in two CD patients in low-dose trials, as well as in high-dose animal studies, suggests that higher, effective dose studies in human CD patients are warranted.
Asunto(s)
Enfermedad de Canavan/tratamiento farmacológico , Ratas , Temblor/tratamiento farmacológico , Triacetina/administración & dosificación , Triacetina/efectos adversos , Acetatos/administración & dosificación , Acetatos/efectos adversos , Acetatos/química , Administración Oral , Animales , Animales Recién Nacidos , Suplementos Dietéticos , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Femenino , Humanos , Lactante , Masculino , Ratas Endogámicas WKY , Temblor/patología , Triglicéridos/químicaRESUMEN
OBJECTIVE: Hutchinson-Gilford progeria syndrome (HGPS) is a rare early-onset accelerated senescence syndrome. In HGPS, a recently identified de novo dominant mutation of the lamin A gene (LMNA) produces abnormal lamin A, resulting in compromised nuclear membrane integrity. Clinical features include sclerotic skin, cardiovascular and bone abnormalities, and marked growth retardation. Craniofacial features include 'bird-like' facies, alopecia, craniofacial disproportion, and dental crowding. Our prospective study describes dental, oral soft tissue, and craniofacial bone features in HGPS. METHODS: Fifteen patients with confirmed p.G608G LMNA mutation (1-17 years, seven males, eight females) received comprehensive oral evaluations. Anomalies of oral soft tissue, gnathic bones, and dentition were identified. RESULTS: Radiographic findings included hypodontia (n = 7), dysmorphic teeth (n = 5), steep mandibular angles (n = 11), and thin basal bone (n = 11). Soft tissue findings included ogival palatal arch (n = 8), median sagittal palatal fissure (n = 7), and ankyloglossia (n = 7). Calculated dental ages (9 months to 11 years 2 months) were significantly lower than chronological ages (1 year 6 months to 17 years 8 months) (P = 0.002). Eleven children manifested a shorter mandibular body, anterior/posterior cranial base and ramus, but a larger gonial angle, compared to age/gender/race norms. CONCLUSION: Novel oral-craniofacial phenotypes and quantification of previously reported features are presented. Our findings expand the HGPS phenotype and provide additional insight into the complex pathogenesis of HGPS.