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1.
Am J Med Genet A ; 194(9): e63646, 2024 09.
Artículo en Inglés | MEDLINE | ID: mdl-38702915

RESUMEN

Molecular genetics enables more precise diagnoses of skeletal dysplasia and other skeletal disorders (SDs). We investigated the clinical utility of multigene panel testing for 5011 unrelated individuals with SD in the United States (December 2019-April 2022). Median (range) age was 8 (0-90) years, 70.5% had short stature and/or disproportionate growth, 27.4% had a positive molecular diagnosis (MDx), and 30 individuals received two MDx. Genes most commonly contributing to MDx were FGFR3 (16.9%), ALPL (13.0%), and COL1A1 (10.3%). Most of the 112 genes associated with ≥1 MDx were primarily involved in signal transduction (n = 35), metabolism (n = 23), or extracellular matrix organization (n = 17). There were implications associated with specific care/treatment options for 84.4% (1158/1372) of MDx-positive individuals; >50% were linked to conditions with targeted therapy approved or in clinical development, including osteogenesis imperfecta, achondroplasia, hypophosphatasia, and mucopolysaccharidosis. Forty individuals with initially inconclusive results became MDx-positive following family testing. Follow-up mucopolysaccharidosis enzyme activity testing was positive in 14 individuals (10 of these were not MDx-positive). Our findings showed that inclusion of metabolic genes associated with SD increased the clinical utility of a gene panel and confirmed that integrated use of comprehensive gene panel testing with orthogonal testing reduced the burden of inconclusive results.


Asunto(s)
Pruebas Genéticas , Humanos , Niño , Preescolar , Adolescente , Masculino , Femenino , Lactante , Adulto , Recién Nacido , Pruebas Genéticas/métodos , Persona de Mediana Edad , Adulto Joven , Anciano , Anciano de 80 o más Años , Enfermedades del Desarrollo Óseo/genética , Enfermedades del Desarrollo Óseo/diagnóstico , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos/genética , Osteogénesis Imperfecta/genética , Osteogénesis Imperfecta/diagnóstico , Osteogénesis Imperfecta/patología , Estudios de Cohortes
2.
Epilepsia ; 63(7): e68-e73, 2022 07.
Artículo en Inglés | MEDLINE | ID: mdl-35474188

RESUMEN

This study assessed the effectiveness of genetic testing in shortening the time to diagnosis of late infantile neuronal ceroid lipofuscinosis type 2 (CLN2) disease. Individuals who received epilepsy gene panel testing through Behind the Seizure® , a sponsored genetic testing program (Cohort A), were compared to children outside of the sponsored testing program during the same period (Cohort B). Two cohorts were analyzed: children aged ≥24 to ≤60 months with unprovoked seizure onset at ≥24 months between December 2016 and January 2020 (Cohort 1) and children aged 0 to ≤60 months at time of testing with unprovoked seizure onset at any age between February 2019 and January 2020 (Cohort 2). The diagnostic yield in Cohort 1A (n = 1814) was 8.4% (n = 153). The TPP1 diagnostic yield within Cohort 1A was 2.9-fold higher compared to Cohort 1B (1.0%, n = 18/1814 vs. .35%, n = 8/2303; p = .0157). The average time from first symptom to CLN2 disease diagnosis was significantly shorter than previously reported (9.8 vs. 22.7 months, p < .001). These findings indicate that facilitated access to early epilepsy gene panel testing helps to increase diagnostic yield for CLN2 disease and shortens the time to diagnosis, enabling earlier intervention.


Asunto(s)
Epilepsia , Lipofuscinosis Ceroideas Neuronales , Aminopeptidasas/genética , Niño , Dipeptidil-Peptidasas y Tripeptidil-Peptidasas/genética , Epilepsia/diagnóstico , Epilepsia/genética , Pruebas Genéticas , Humanos , Lipofuscinosis Ceroideas Neuronales/diagnóstico , Lipofuscinosis Ceroideas Neuronales/genética , Convulsiones/genética , Serina Proteasas/genética , Tripeptidil Peptidasa 1
3.
Hum Mutat ; 42(11): 1384-1398, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-34387910

RESUMEN

Mucopolysaccharidosis IVA (MPS IVA, Morquio A syndrome) is a rare autosomal recessive lysosomal storage disorder caused by mutations in the N-acetylgalactosamine-6-sulfatase (GALNS) gene. We collected, analyzed, and uniformly summarized all published GALNS gene variants, thus updating the previous mutation review (published in 2014). In addition, new variants were communicated by seven reference laboratories in Europe, the Middle East, Latin America, Asia, and the United States. All data were analyzed to determine common alleles, geographic distribution, level of homozygosity, and genotype-phenotype correlation. Moreover, variants were classified according to their pathogenicity as suggested by ACMG. Including those previously published, we assembled 446 unique variants, among which 68 were novel, from 1190 subjects (including newborn screening positive subjects). Variants' distribution was missense (65.0%), followed by nonsense (8.1%), splicing (7.2%), small frameshift deletions(del)/insertions(ins) (7.0%), intronic (4.0%), and large del/ins and complex rearrangements (3.8%). Half (50.4%) of the subjects were homozygous, 37.1% were compound heterozygous, and 10.7% had only one variant detected. The novel variants underwent in silico analysis to evaluate their pathogenicity. All variants were submitted to ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/) to make them publicly available. Mutation updates are essential for the correct molecular diagnoses, genetic counseling, prenatal and preimplantation diagnosis, and disease management.


Asunto(s)
Condroitinsulfatasas/genética , Mucopolisacaridosis IV/genética , Mutación , Estudios de Asociación Genética , Humanos
4.
Mol Genet Metab ; 119(1-2): 160-7, 2016 09.
Artículo en Inglés | MEDLINE | ID: mdl-27553878

RESUMEN

Neuronal ceroid lipofuscinoses (NCLs) are a heterogeneous group of lysosomal storage disorders. NCLs include the rare autosomal recessive neurodegenerative disorder neuronal ceroid lipofuscinosis type 2 (CLN2) disease, caused by mutations in the tripeptidyl peptidase 1 (TPP1)/CLN2 gene and the resulting TPP1 enzyme deficiency. CLN2 disease most commonly presents with seizures and/or ataxia in the late-infantile period (ages 2-4), often in combination with a history of language delay, followed by progressive childhood dementia, motor and visual deterioration, and early death. Atypical phenotypes are characterized by later onset and, in some instances, longer life expectancies. Early diagnosis is important to optimize clinical care and improve outcomes; however, currently, delays in diagnosis are common due to low disease awareness, nonspecific clinical presentation, and limited access to diagnostic testing in some regions. In May 2015, international experts met to recommend best laboratory practices for early diagnosis of CLN2 disease. When clinical signs suggest an NCL, TPP1 enzyme activity should be among the first tests performed (together with the palmitoyl-protein thioesterase enzyme activity assay to rule out CLN1 disease). However, reaching an initial suspicion of an NCL or CLN2 disease can be challenging; thus, use of an epilepsy gene panel for investigation of unexplained seizures in the late-infantile/childhood ages is encouraged. To confirm clinical suspicion of CLN2 disease, the recommended gold standard for laboratory diagnosis is demonstration of deficient TPP1 enzyme activity (in leukocytes, fibroblasts, or dried blood spots) and the identification of causative mutations in each allele of the TPP1/CLN2 gene. When it is not possible to perform both analyses, either demonstration of a) deficient TPP1 enzyme activity in leukocytes or fibroblasts, or b) detection of two pathogenic mutations in trans is diagnostic for CLN2 disease.


Asunto(s)
Aminopeptidasas/sangre , Dipeptidil-Peptidasas y Tripeptidil-Peptidasas/sangre , Diagnóstico Precoz , Lipofuscinosis Ceroideas Neuronales/sangre , Serina Proteasas/sangre , Aminopeptidasas/genética , Encéfalo/fisiopatología , Preescolar , Demencia/complicaciones , Demencia/fisiopatología , Dipeptidil-Peptidasas y Tripeptidil-Peptidasas/genética , Pruebas con Sangre Seca , Terapia de Reemplazo Enzimático , Femenino , Humanos , Trastornos del Desarrollo del Lenguaje/complicaciones , Trastornos del Desarrollo del Lenguaje/fisiopatología , Leucocitos/enzimología , Masculino , Mutación , Lipofuscinosis Ceroideas Neuronales/complicaciones , Lipofuscinosis Ceroideas Neuronales/genética , Lipofuscinosis Ceroideas Neuronales/fisiopatología , Fenotipo , Serina Proteasas/genética , Tripeptidil Peptidasa 1
5.
PLoS One ; 16(9): e0255933, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34469436

RESUMEN

Epilepsy is one of the most common childhood-onset neurological conditions with a genetic etiology. Genetic diagnosis provides potential for etiologically-based management and treatment. Existing research has focused on early-onset (<24 months) epilepsies; data regarding later-onset epilepsies is limited. The goal of this study was to determine the diagnostic yield of a clinically available epilepsy panel in a selected pediatric epilepsy cohort with epilepsy onset between 24-60 months of life and evaluate whether this approach decreases the age of diagnosis of neuronal ceroid lipofuscinosis type 2 (CLN2). Next-generation sequencing (NGS)-based epilepsy panels, including genes associated with epileptic encephalopathies and inborn errors of metabolism (IEMs) that present with epilepsy, were used. Copy-number variant (CNV) detection from NGS data was included. Variant interpretation was performed per American College of Medical Genetics and Genomics (ACMG) guidelines. Results are reported from 211 consecutive patients with the following inclusion criteria: 24-60 months of age at the time of enrollment, first unprovoked seizure at/after 24 months, and at least one additional finding such as EEG/MRI abnormalities, speech delay, or motor symptoms. Median age was 42 months at testing and 30 months at first seizure onset; the mean delay from first seizure to comprehensive genetic testing was 10.3 months. A genetic diagnosis was established in 43 patients (20.4%). CNVs were reported in 25.6% diagnosed patients; 27.3% of CNVs identified were intragenic. Within the diagnosed cohort, 11 (25.6%) patients were diagnosed with an IEM. The predominant molecular diagnosis was CLN2 (14% of diagnosed patients). For these patients, diagnosis was achieved 12-24 months earlier than reported by natural history of the disease. This study supports comprehensive genetic testing for patients whose first seizure occurs ≥ 24 months of age. It also supports early application of testing in this age group, as the identified diagnoses can have significant impact on patient management and outcome.


Asunto(s)
Variaciones en el Número de Copia de ADN , Epilepsia/diagnóstico , Pruebas Genéticas/métodos , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Lipofuscinosis Ceroideas Neuronales/diagnóstico , Edad de Inicio , Preescolar , Estudios de Cohortes , Epilepsia/complicaciones , Epilepsia/genética , Femenino , Humanos , Lactante , Masculino , Lipofuscinosis Ceroideas Neuronales/complicaciones , Lipofuscinosis Ceroideas Neuronales/genética , Tripeptidil Peptidasa 1
6.
Behav Brain Res ; 186(2): 161-7, 2008 Jan 25.
Artículo en Inglés | MEDLINE | ID: mdl-17868931

RESUMEN

Increased glutamatergic activity is believed to play a significant role in the development of levodopa-induced dyskinesias (LID). LID may therefore be attenuated by a reduction in glutamatergic function. This was tested pharmacologically in MPTP monkeys by increasing the formation of kynurenic acid (KYNA), a tryptophan metabolite that inhibits glutamate release and also blocks NMDA receptors directly. KYNA synthesis was stimulated by prolonged systemic administration of the kynurenine 3-hydroxylase inhibitor Ro 61-8048. Four MPTP cynomolgus monkeys received l-dopa (LD; 100mg) with benserazide (25 mg) for one month. Progressively, all these animals developed LID. Four other MPTP monkeys received Ro 61-8048 (50mg/kg) daily 3 h before administration of LD/benserazide for one month. The addition of Ro 61-8048 reduced the development of LID but did not affect the antiparkinsonian efficacy of LD. Moreover, Ro 61-8048 administration caused sustained increases in serum kynurenine and KYNA concentrations, which reverted to basal values 24 h after the last treatment. This effect of Ro 61-8048 was less pronounced in the CSF. These results demonstrate that long-lasting elevation of KYNA levels caused by prolonged inhibition of kynurenine 3-hydroxylase is associated with a significant reduction in LID but does not compromise the benefits of chronic LD therapy.


Asunto(s)
Antiparkinsonianos/efectos adversos , Discinesia Inducida por Medicamentos/enzimología , Discinesia Inducida por Medicamentos/etiología , Quinurenina 3-Monooxigenasa/metabolismo , Levodopa/efectos adversos , Animales , Conducta Animal/efectos de los fármacos , Modelos Animales de Enfermedad , Interacciones Farmacológicas , Discinesia Inducida por Medicamentos/prevención & control , Inhibidores Enzimáticos/uso terapéutico , Femenino , Ácido Quinurénico/sangre , Quinurenina/sangre , Quinurenina 3-Monooxigenasa/antagonistas & inhibidores , Macaca fascicularis , Actividad Motora/efectos de los fármacos , Trastornos Parkinsonianos/tratamiento farmacológico , Ácido Quinolínico/sangre , Ácido Quinolínico/líquido cefalorraquídeo , Sulfonamidas/uso terapéutico , Tiazoles/uso terapéutico , Factores de Tiempo
7.
Nat Neurosci ; 5(12): 1263-4, 2002 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-12436114

RESUMEN

Drug addiction has been linked to protracted functional changes in neural circuits involved in motivation that can lead to drug dependence, craving and relapse. Here we investigated the role of the phosphatidylinositol 3 kinase (PI3K) signal transduction pathway in long-lasting behavioral sensitization to cocaine in rats, an animal model of the long-lasting functional changes induced by repeated drug use. Our results show that PI3K is required for the expression, but not the induction, of behavioral sensitization to cocaine.


Asunto(s)
Encéfalo/efectos de los fármacos , Encéfalo/enzimología , Trastornos Relacionados con Cocaína/enzimología , Cocaína/farmacología , Plasticidad Neuronal/efectos de los fármacos , Neuronas/efectos de los fármacos , Neuronas/enzimología , Fosfatidilinositol 3-Quinasas/efectos de los fármacos , Animales , Conducta Animal/efectos de los fármacos , Conducta Animal/fisiología , Encéfalo/fisiopatología , Cromonas/farmacología , Trastornos Relacionados con Cocaína/fisiopatología , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/farmacología , Masculino , Morfolinas/farmacología , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Plasticidad Neuronal/fisiología , Fosfatidilinositol 3-Quinasas/metabolismo , Ratas , Ratas Wistar , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología
8.
Pharmacol Biochem Behav ; 81(4): 701-8, 2005 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-16005056

RESUMEN

Mounting evidence suggests that chronic stress may have a detrimental effect on dopaminergic function and, in certain individuals, could contribute to the pathophysiology of central nervous system disorders like depression, schizophrenia, and Parkinson's disease. Therefore, the effects of chronic elevated brain levels of corticotropin-releasing factor (CRF), a crucial mediator of the behavioral stress response, on dopaminergic function were investigated. Rats treated intracerebroventricularly (i.c.v.) with 1 microg of CRF per day for 13 days displayed a decreased stereotyped response to D-amphetamine 1 day after chronic CRF and 1 month post-CRF. These rats also displayed an increased cataleptic response to eticlopride at 2 days post-CRF, consistent with decreased functional activity in the dopaminergic systems. CRF treatment induced a transient decrease of dopamine tissue levels in the prefrontal cortex at 1 day and 1 week post-CRF, an increase in the nucleus accumbens 1 week post-CRF and no change in the striatum. An increase of the dihydroxyphenylacetic acid/dopamine (DOPAC/DA) ratio, an indicator of dopamine turnover, also was seen in the prefrontal cortex and striatum in CRF-treated animals at 1 week post-CRF. The dopaminergic system is very sensitive to oxidative insults. Levels of malondialdehyde, a membrane lipid peroxidation marker, also were measured in the same brain areas. In the prefrontal cortex, we observed a decrease of malondialdehyde at 1 week after chronic CRF treatment. This result may indicate an activation of the antioxidant system in response to chronic stress. These results show that chronic hyperactivity of the CRF system leads to a transient dysfunction of the dopaminergic systems, possibly through oxidative mechanisms, and suggest that stress could be a cofactor in the pathogenesis and/or progression of disorders of the dopaminergic systems.


Asunto(s)
Hormona Liberadora de Corticotropina/farmacología , Receptores de Dopamina D2/fisiología , Ácido 3,4-Dihidroxifenilacético/metabolismo , Animales , Conducta Animal/efectos de los fármacos , Catalepsia/inducido químicamente , Catalepsia/patología , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Hormona Liberadora de Corticotropina/administración & dosificación , Dextroanfetamina/farmacología , Dopamina/metabolismo , Dopaminérgicos/farmacología , Antagonistas de Dopamina/farmacología , Antagonistas de los Receptores de Dopamina D2 , Inyecciones Intraventriculares , Masculino , Ratones , Actividad Motora/efectos de los fármacos , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/metabolismo , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Ratas , Ratas Wistar , Salicilamidas/farmacología , Conducta Estereotipada/efectos de los fármacos , Factores de Tiempo
9.
Brain Res ; 925(2): 133-40, 2002 Jan 25.
Artículo en Inglés | MEDLINE | ID: mdl-11792361

RESUMEN

Nitric oxide is a gaseous neurotransmitter that plays a significant role in various forms of synaptic plasticity and may play a role in the behavioral effects of psychostimulant drugs and in cocaine addiction. The course of drug addiction consists of different phases. Relapse into drug-seeking behavior following a period of abstinence is believed to represent one of the major factors leading to the perpetuation of the addictive cycle. In this respect, experimental extinction procedures provide a measure of the motivational properties of drugs as reflected by the persistence of drug-seeking behavior in the absence of the drug and by the reinstatement of responding by non-contingent drug administration. Pretreatment with the nitric oxide synthase inhibitor L-NG-nitroarginine methyl ester (L-NAME, 50 mg/kg IP twice daily for 4 days) impaired responding for cocaine self-administration when the drug was available and the increase of drug-seeking behavior upon abrupt cessation of cocaine availability observed in control rats was significantly reduced after treatment with L-NAME. In addition, the priming effect of a non-contingent injection of cocaine on extinguished cocaine self-administration was also diminished by the same treatment. The acquisition of cocaine self-administration, in contrast, was not affected by treatment with L-NAME. These observations lend further support to the hypothesis of the involvement of nitric oxide in cocaine addiction and extend previous findings to components of the cocaine addictive cycle associated with relapse.


Asunto(s)
Conducta Animal/efectos de los fármacos , Trastornos Relacionados con Cocaína/metabolismo , Cocaína/administración & dosificación , Extinción Psicológica/efectos de los fármacos , Óxido Nítrico/biosíntesis , Animales , Trastornos Relacionados con Cocaína/tratamiento farmacológico , Esquema de Medicación , Inhibidores Enzimáticos/uso terapéutico , Inyecciones Intravenosas , Masculino , NG-Nitroarginina Metil Éster/uso terapéutico , Óxido Nítrico/antagonistas & inhibidores , Óxido Nítrico Sintasa/antagonistas & inhibidores , Ratas , Ratas Wistar , Refuerzo en Psicología , Autoadministración
10.
Future Med Chem ; 2(5): 803-42, 2010 May.
Artículo en Inglés | MEDLINE | ID: mdl-21426204

RESUMEN

Neuropathic pain, a severe chronic pain condition characterized by a complex pathophysiology, is a largely unmet medical need. Ion channels, which underlie cell excitability, are heavily implicated in the biological mechanisms that generate and sustain neuropathic pain. This review highlights the biological evidence supporting the involvement of voltage-, proton- and ligand-gated ion channels in the neuropathic pain setting. Ion channel modulators at different research or development stages are reviewed and referenced. Ion channel modulation is one of the main avenues to achieve novel, improved neuropathic pain treatments. Voltage-gated sodium and calcium channel and glutamate receptor modulators are likely to produce new, improved agents in the future. Rationally targeting subtypes of known ion channels, tackling recently discovered ion channel targets or combining drugs with different mechanism of action will be primary sources of new drugs in the longer term.


Asunto(s)
Canales Iónicos/antagonistas & inhibidores , Canales Iónicos/metabolismo , Moduladores del Transporte de Membrana/química , Moduladores del Transporte de Membrana/uso terapéutico , Neuralgia/tratamiento farmacológico , Animales , Humanos
11.
Mov Disord ; 20(7): 792-802, 2005 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-15954116

RESUMEN

Homeostatic interactions between dopamine and glutamate are central to the normal physiology of the basal ganglia. This relationship is altered in Parkinsonism and in levodopa-induced dyskinesias (LID), resulting in an upregulation of corticostriatal glutamatergic function. Kynurenic acid (KYNA), a tryptophan metabolite with antagonist activity at ionotropic glutamate receptors and the capability to inhibit glutamate release presynaptically, might therefore be of therapeutic value in LID. To evaluate this hypothesis, we used a pharmacological tool, the kynurenine 3-hydroxylase inhibitor Ro 61-8048, which raises KYNA levels acutely. Ro 61-8048 was tested in MPTP cynomolgus monkeys with a stable parkinsonian syndrome and reproducible dyskinesias after each dose of levodopa. Serum and CSF concentrations of KYNA and its precursor kynurenine increased dose-dependently after Ro 61-8048 administration, alone or in combination with levodopa. Coadministration of Ro 61-8048 with levodopa produced a moderate but significant reduction in the severity of dyskinesias while maintaining the motor benefit. These results suggest that elevation of KYNA levels through inhibition of kynurenine 3-hydroxylase constitutes a promising novel approach for managing LID in Parkinson's disease.


Asunto(s)
Antiparkinsonianos/uso terapéutico , Discinesia Inducida por Medicamentos/tratamiento farmacológico , Levodopa/uso terapéutico , Oxigenasas de Función Mixta/metabolismo , Trastornos Parkinsonianos/tratamiento farmacológico , Análisis de Varianza , Animales , Conducta Animal/efectos de los fármacos , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Femenino , Ácido Quinurénico/metabolismo , Quinurenina 3-Monooxigenasa , Macaca fascicularis , Oxigenasas de Función Mixta/antagonistas & inhibidores , Oxigenasas de Función Mixta/sangre , Actividad Motora/efectos de los fármacos , Ácido Quinolínico/sangre , Ácido Quinolínico/líquido cefalorraquídeo , Sulfonamidas/sangre , Sulfonamidas/líquido cefalorraquídeo , Sulfonamidas/farmacología , Tiazoles/sangre , Tiazoles/líquido cefalorraquídeo , Tiazoles/farmacología , Factores de Tiempo
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