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1.
Am J Med ; 131(2): 200.e1-200.e8, 2018 02.
Artículo en Inglés | MEDLINE | ID: mdl-28943383

RESUMEN

BACKGROUND: Fabry disease is an X-linked lysosomal storage disorder caused by the deficient activity of α-galactosidase A due to mutations in the GLA gene, which may be associated with increased left ventricular wall thickness and mimic the morphologic features of hypertrophic cardiomyopathy. Management strategies for these 2 diseases diverge, with Fabry disease-specific treatment utilizing recombinant α-galactosidase A enzyme replacement therapy. METHODS: We studied a prospectively assembled consecutive cohort of 585 patients (71% male) from 2 hypertrophic cardiomyopathy tertiary referral centers by screening for low α-galactosidase A activity in dried blood spots. Male patients with low α-galactosidase A activity levels and all females were tested for mutations in the GLA gene. RESULTS: In 585 patients previously diagnosed with hypertrophic cardiomyopathy, we identified 2 unrelated patients (0.34%), both with the GLA mutation encoding P.N215S, the most common mutation causing later-onset Fabry disease phenotype. These patients were both asymptomatic, a man aged 53 years and a woman aged 69 years, and demonstrated a mild cardiac phenotype with symmetric distribution of left ventricular hypertrophy. After family screening, a total of 27 new Fabry disease patients aged 2-81 years were identified in the 2 families, including 12 individuals who are now receiving enzyme replacement therapy. CONCLUSIONS: These observations support consideration for routine prospective screening for Fabry disease in all patients without a definitive etiology for left ventriclar hypertrophy. This strategy would likely result, through cascade family testing, in the earlier identification of new Fabry disease-affected males and female heterozygotes who may benefit from monitoring and/or enzyme replacement therapy.


Asunto(s)
Cardiomiopatía Hipertrófica/etiología , Enfermedad de Fabry/diagnóstico , Atención Terciaria de Salud , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Cardiomiopatía Hipertrófica/diagnóstico , Niño , Preescolar , Diagnóstico Diferencial , Terapia de Reemplazo Enzimático , Enfermedad de Fabry/complicaciones , Enfermedad de Fabry/tratamiento farmacológico , Enfermedad de Fabry/genética , Femenino , Pruebas Genéticas , Humanos , Masculino , Persona de Mediana Edad , Mutación , Linaje , Adulto Joven , alfa-Galactosidasa/sangre , alfa-Galactosidasa/genética , alfa-Galactosidasa/uso terapéutico
2.
J Proteome Res ; 16(10): 3787-3804, 2017 10 06.
Artículo en Inglés | MEDLINE | ID: mdl-28792770

RESUMEN

Clinical trials have been conducted for the neuronal ceroid lipofuscinoses (NCLs), a group of neurodegenerative lysosomal diseases that primarily affect children. Whereas clinical rating systems will evaluate long-term efficacy, biomarkers to measure short-term response to treatment would be extremely valuable. To identify candidate biomarkers, we analyzed autopsy brain and matching CSF samples from controls and three genetically distinct NCLs due to deficiencies in palmitoyl protein thioesterase 1 (CLN1 disease), tripeptidyl peptidase 1 (CLN2 disease), and CLN3 protein (CLN3 disease). Proteomic and biochemical methods were used to analyze lysosomal proteins, and, in general, we find that changes in protein expression compared with control were most similar between CLN2 disease and CLN3 disease. This is consistent with previous observations of biochemical similarities between these diseases. We also conducted unbiased proteomic analyses of CSF and brain using isobaric labeling/quantitative mass spectrometry. Significant alterations in protein expression were identified in each NCL, including reduced STXBP1 in CLN1 disease brain. Given the confounding variable of post-mortem changes, additional validation is required, but this study provides a useful starting set of candidate NCL biomarkers for further evaluation.


Asunto(s)
Encéfalo/metabolismo , Proteínas Munc18/genética , Lipofuscinosis Ceroideas Neuronales/genética , Proteómica , Aminopeptidasas/deficiencia , Aminopeptidasas/genética , Autopsia , Biomarcadores/líquido cefalorraquídeo , Biomarcadores/química , Biomarcadores/metabolismo , Encéfalo/patología , Líquido Cefalorraquídeo/química , Líquido Cefalorraquídeo/metabolismo , Dipeptidil-Peptidasas y Tripeptidil-Peptidasas/deficiencia , Dipeptidil-Peptidasas y Tripeptidil-Peptidasas/genética , Humanos , Glicoproteínas de Membrana/deficiencia , Glicoproteínas de Membrana/genética , Proteínas de la Membrana/deficiencia , Proteínas de la Membrana/genética , Chaperonas Moleculares/genética , Proteínas Munc18/deficiencia , Mutación , Lipofuscinosis Ceroideas Neuronales/líquido cefalorraquídeo , Lipofuscinosis Ceroideas Neuronales/metabolismo , Lipofuscinosis Ceroideas Neuronales/patología , Serina Proteasas/deficiencia , Serina Proteasas/genética , Tioléster Hidrolasas/deficiencia , Tioléster Hidrolasas/genética , Tripeptidil Peptidasa 1
3.
Neurology ; 87(6): 579-84, 2016 Aug 09.
Artículo en Inglés | MEDLINE | ID: mdl-27412140

RESUMEN

OBJECTIVE: To critically re-evaluate cases diagnosed as adult neuronal ceroid lipofuscinosis (ANCL) in order to aid clinicopathologic diagnosis as a route to further gene discovery. METHODS: Through establishment of an international consortium we pooled 47 unsolved cases regarded by referring centers as ANCL. Clinical and neuropathologic experts within the Consortium established diagnostic criteria for ANCL based on the literature to assess each case. A panel of 3 neuropathologists independently reviewed source pathologic data. Cases were given a final clinicopathologic classification of definite ANCL, probable ANCL, possible ANCL, or not ANCL. RESULTS: Of the 47 cases, only 16 fulfilled the Consortium's criteria of ANCL (5 definite, 2 probable, 9 possible). Definitive alternate diagnoses were made in 10, including Huntington disease, early-onset Alzheimer disease, Niemann-Pick disease, neuroserpinopathy, prion disease, and neurodegeneration with brain iron accumulation. Six cases had features suggesting an alternate diagnosis, but no specific condition was identified; in 15, the data were inadequate for classification. Misinterpretation of normal lipofuscin as abnormal storage material was the commonest cause of misdiagnosis. CONCLUSIONS: Diagnosis of ANCL remains challenging; expert pathologic analysis and recent molecular genetic advances revealed misdiagnoses in >1/3 of cases. We now have a refined group of cases that will facilitate identification of new causative genes.


Asunto(s)
Errores Diagnósticos , Lipofuscinosis Ceroideas Neuronales/clasificación , Lipofuscinosis Ceroideas Neuronales/diagnóstico , Adolescente , Adulto , Edad de Inicio , Humanos , Lipofuscina/metabolismo , Lipofuscinosis Ceroideas Neuronales/genética , Lipofuscinosis Ceroideas Neuronales/metabolismo , Neuronas/metabolismo , Neuronas/ultraestructura , Adulto Joven
4.
Neurologist ; 21(4): 61-5, 2016 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-27348141

RESUMEN

INTRODUCTION: Establishing a diagnosis of mitochondrial disease in adults remains a clinician's challenge. We report a case of syndrome reminiscent of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) in an adult patient who carries m.10158T>C mutation in complex I respiratory chain gene MT-ND3 (mitochondrially encoded NADH dehydrogenase 3). CASE REPORT: This 26-year-old man from Thailand presented with new-onset headaches, seizures, stroke-like episodes, and poor vision due to optic neuropathy and cortical blindness. Instead of expected mutations in the mitochondrial tRNA gene that are frequently associated with MELAS, the mutation in MT-ND3 with variable tissue heteroplasmy (blood 5.3%, muscle 89.5%) was demonstrated. The patient's clinical features, blood biomarkers, neuroimaging findings, muscle biopsy with histochemical and functional in vitro analysis, and genetic studies were analyzed and compared with all previously reported ND3 disease cases. CONCLUSIONS: ND3 disease due to m.10158T>C mutation was previously described only in patients with Leigh or Leigh-like syndrome. Our findings thus indicate that ND3 disease can manifest with atypical phenotype in adults. The diagnosis of mitochondrial disease caused by other than typical MELAS-associated mutations in adults with stroke-like episodes, headaches, and seizures should be considered. An analysis of tissue other than blood, which is more likely to harbor a tissue-specific mitochondrial DNA mutation at a measurable level, may be necessary for diagnosis.


Asunto(s)
Complejo I de Transporte de Electrón/genética , Síndrome MELAS/diagnóstico , Síndrome MELAS/genética , Enfermedades del Nervio Óptico/diagnóstico , Enfermedades del Nervio Óptico/genética , Adulto , Humanos , Masculino , Mutación/genética
5.
Neurology ; 86(20): 1880-6, 2016 May 17.
Artículo en Inglés | MEDLINE | ID: mdl-27164662

RESUMEN

OBJECTIVE: Using a semiautomated volumetric MRI assessment method, we aimed to identify determinants of white matter hyperintensity (WMH) burden in patients with Fabry disease (FD). METHODS: Patients with confirmed FD and brain MRI available for this analysis were eligible for this protocol after written consent. Clinical characteristics were abstracted from medical records. T2 fluid-attenuated inversion recovery MRI were transferred in electronic format and analyzed for WMH volume (WMHV) using a validated, computer-assisted method. WMHV was normalized for head size (nWMHV) and natural log-transformed (lnWMHV) for univariate and multivariate linear regression analyses. Level of significance was set at p < 0.05 for all analyses. RESULTS: Of 223 patients with FD and WMHV analyzed, 132 (59%) were female. Mean age at MRI was 39.2 ± 14.9 (range 9.6-72.7) years, and 136 (61%) patients received enzyme replacement therapy prior to enrollment. Median nWMHV was 2.7 cm(3) (interquartile range 1.8-4.0). Age (ß 0.02, p = 0.008) and history of stroke (ß 1.13, p = 0.02) were independently associated with lnWMHV. However, WMH burden-as well as WMHV predictors-varied by decade of life in this cohort of patients with FD (p < 0.0001). CONCLUSIONS: In this largest-to-date cohort of patients with FD who had volumetric analysis of MRI, age and prior stroke independently predicted the burden of WMH. The 4th decade of life appears to be critical in progression of WMH burden, as novel predictors of WMHV emerged in patients aged 31-40 years. Future studies to elucidate the biology of WMH in FD and its role as potential MRI marker of disease progression are needed.


Asunto(s)
Encéfalo/diagnóstico por imagen , Enfermedad de Fabry/diagnóstico por imagen , Sustancia Blanca/diagnóstico por imagen , Adolescente , Adulto , Factores de Edad , Anciano , Niño , Terapia de Reemplazo Enzimático , Enfermedad de Fabry/tratamiento farmacológico , Enfermedad de Fabry/epidemiología , Femenino , Humanos , Interpretación de Imagen Asistida por Computador/métodos , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Reconocimiento de Normas Patrones Automatizadas/métodos , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Accidente Cerebrovascular/epidemiología , Adulto Joven
7.
J Biol Chem ; 290(16): 10309-24, 2015 Apr 17.
Artículo en Inglés | MEDLINE | ID: mdl-25750174

RESUMEN

Lysosomes are ubiquitous membrane-enclosed organelles filled with an acidic interior and are central to the autophagic, endocytic, or phagocytic pathway. In contrast to its classical function as the waste management machinery, lysosomes are now considered to be an integral part of various cellular signaling processes. The diverse functionality of this single organelle requires a very complex and coordinated regulation of its activity with transcription factor EB (TFEB), a master regulator of lysosomal biogenesis, at its core. However, mechanisms by which TFEB is regulated are poorly understood. This study demonstrates that gemfibrozil, an agonist of peroxisome proliferator-activated receptor (PPAR) α, alone and in conjunction with all-trans-retinoic acid is capable of enhancing TFEB in brain cells. We also observed that PPARα, but not PPARß and PPARγ, is involved in gemfibrozil-mediated up-regulation of TFEB. Reporter assay and chromatin immunoprecipitation studies confirmed the recruitment of retinoid X receptor α, PPARα, and PGC1α on the PPAR-binding site on the Tfeb promoter as well. Subsequently, the drug-mediated induction of TFEB caused an increase in lysosomal protein and the lysosomal abundance in cell. Collectively, this study reinforces the link between lysosomal biogenesis and lipid metabolism with TFEB at the crossroads. Furthermore, gemfibrozil may be of therapeutic value in the treatment of lysosomal storage disorders in which autophagy-lysosome pathway plays an important role.


Asunto(s)
Astrocitos/metabolismo , Gemfibrozilo/farmacología , Neuronas/metabolismo , PPAR alfa/agonistas , Animales , Astrocitos/citología , Astrocitos/efectos de los fármacos , Autofagia/efectos de los fármacos , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/genética , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/metabolismo , Encéfalo/citología , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Regulación de la Expresión Génica , Humanos , Metabolismo de los Lípidos/efectos de los fármacos , Lisosomas/efectos de los fármacos , Lisosomas/metabolismo , Ratones , Neuronas/citología , Neuronas/efectos de los fármacos , PPAR alfa/genética , PPAR alfa/metabolismo , PPAR gamma/genética , PPAR gamma/metabolismo , PPAR-beta/genética , PPAR-beta/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma , Cultivo Primario de Células , Regiones Promotoras Genéticas , Unión Proteica , Receptor alfa X Retinoide/genética , Receptor alfa X Retinoide/metabolismo , Transducción de Señal , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Tretinoina/farmacología
8.
Genet Med ; 17(4): 253-261, 2015 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-25412400

RESUMEN

PURPOSE: Next-generation sequencing-based methods are being adopted broadly for genetic diagnostic testing, but the performance characteristics of these techniques with regard to test accuracy and reproducibility have not been fully defined. METHODS: We developed a targeted enrichment and next-generation sequencing approach for genetic diagnostic testing of patients with inherited eye disorders, including inherited retinal degenerations, optic atrophy, and glaucoma. In preparation for providing this genetic eye disease (GEDi) test on a CLIA-certified basis, we performed experiments to measure the sensitivity, specificity, and reproducibility, as well as the clinical sensitivity, of the test. RESULTS: The GEDi test is highly reproducible and accurate, with sensitivity and specificity of 97.9 and 100%, respectively, for single-nucleotide variant detection. The sensitivity for variant detection was notably better than the 88.3% achieved by whole-exome sequencing using the same metrics, because of better coverage of targeted genes in the GEDi test as compared with a commercially available exome capture set. Prospective testing of 192 patients with inherited retinal degenerations indicated that the clinical sensitivity of the GEDi test is high, with a diagnostic rate of 51%. CONCLUSION: Based on quantified performance metrics, the data suggest that selective targeted enrichment is preferable to whole-exome sequencing for genetic diagnostic testing.


Asunto(s)
Oftalmopatías/diagnóstico , Oftalmopatías/genética , Pruebas Genéticas , Secuenciación de Nucleótidos de Alto Rendimiento , Exoma/genética , Oftalmopatías/patología , Genotipo , Humanos , Polimorfismo de Nucleótido Simple , Estudios Prospectivos , Reproducibilidad de los Resultados , Sensibilidad y Especificidad
10.
J Immunol Res ; 2014: 164309, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-25309931

RESUMEN

Mitochondria are critical subcellular organelles that are required for several metabolic processes, including oxidative phosphorylation, as well as signaling and tissue-specific processes. Current understanding of the role of mitochondria in both the innate and adaptive immune systems is expanding. Concurrently, immunodeficiencies arising from perturbation of mitochondrial elements are increasingly recognized. Recent observations of immune dysfunction and increased incidence of infection in patients with primary mitochondrial disorders further support an important role for mitochondria in the proper function of the immune system. Here we review current findings.


Asunto(s)
Inmunidad Adaptativa/inmunología , Sistema Inmunológico/inmunología , Inmunidad Innata/inmunología , Mitocondrias/inmunología , Enfermedades Mitocondriales/inmunología , Predisposición Genética a la Enfermedad/genética , Humanos , Sistema Inmunológico/citología , Sistema Inmunológico/metabolismo , Mitocondrias/genética , Mitocondrias/metabolismo , Enfermedades Mitocondriales/genética , Enfermedades Mitocondriales/metabolismo , Modelos Inmunológicos , Mutación
12.
BMC Med Genet ; 15: 30, 2014 Mar 06.
Artículo en Inglés | MEDLINE | ID: mdl-24602372

RESUMEN

BACKGROUND: D-bifunctional protein deficiency, caused by recessive mutations in HSD17B4, is a severe, infantile-onset disorder of peroxisomal fatty acid oxidation. Few affected patients survive past two years of age. Compound heterozygous mutations in HSD17B4 have also been reported in two sisters diagnosed with Perrault syndrome (MIM # 233400), who presented in adolescence with ovarian dysgenesis, hearing loss, and ataxia. CASE PRESENTATION: An adult male presented with cerebellar ataxia, peripheral neuropathy, hearing loss, and azoospermia. The clinical presentation, in combination with biochemical findings in serum, urine, and muscle biopsy, suggested a mitochondrial disorder. Commercial genetic testing of 18 ataxia and mitochondrial disease genes was negative. Targeted exome sequencing followed by analysis of single nucleotide variants and small insertions/deletions failed to reveal a genetic basis of disease. Application of a computational algorithm to infer copy number variants (CNVs) from exome data revealed a heterozygous 12 kb deletion of exons 10-13 of HSD17B4 that was compounded with a rare missense variant (p.A196V) at a highly conserved residue. Retrospective review of patient records revealed mildly elevated ratios of pristanic:phytanic acid and arachidonic:docosahexaenoic acid, consistent with dysfunctional peroxisomal fatty acid oxidation. CONCLUSION: Our case expands the phenotypic spectrum of HSD17B4-deficiency, representing the first male case reported with infertility. Furthermore, it points to crosstalk between mitochondria and peroxisomes in HSD17B4-deficiency and Perrault syndrome.


Asunto(s)
Anomalías Múltiples/diagnóstico , Ataxia/diagnóstico , Pérdida Auditiva Sensorineural/diagnóstico , Enfermedades Mitocondriales/diagnóstico , Proteína-2 Multifuncional Peroxisomal/deficiencia , Anomalías Múltiples/enzimología , Anomalías Múltiples/genética , Adulto , Ataxia/enzimología , Ataxia/genética , Azoospermia/diagnóstico , Azoospermia/enzimología , Azoospermia/genética , Secuencia de Bases , Variaciones en el Número de Copia de ADN , Dosificación de Gen , Pérdida Auditiva Sensorineural/enzimología , Pérdida Auditiva Sensorineural/genética , Heterocigoto , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Enfermedades Mitocondriales/enzimología , Enfermedades Mitocondriales/genética , Técnicas de Diagnóstico Molecular , Datos de Secuencia Molecular , Proteína-2 Multifuncional Peroxisomal/genética , Fenotipo , Análisis de Secuencia de ADN , Eliminación de Secuencia
13.
Hum Mol Genet ; 23(8): 2005-22, 2014 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-24271013

RESUMEN

Neuronal ceroid lipofuscinosis (NCL) comprises ∼13 genetically distinct lysosomal disorders primarily affecting the central nervous system. Here we report successful reprograming of patient fibroblasts into induced pluripotent stem cells (iPSCs) for the two most common NCL subtypes: classic late-infantile NCL, caused by TPP1(CLN2) mutation, and juvenile NCL, caused by CLN3 mutation. CLN2/TPP1- and CLN3-iPSCs displayed overlapping but distinct biochemical and morphological abnormalities within the endosomal-lysosomal system. In neuronal derivatives, further abnormalities were observed in mitochondria, Golgi and endoplasmic reticulum. While lysosomal storage was undetectable in iPSCs, progressive disease subtype-specific storage material was evident upon neural differentiation and was rescued by reintroducing the non-mutated NCL proteins. In proof-of-concept studies, we further documented differential effects of potential small molecule TPP1 activity inducers. Fenofibrate and gemfibrozil, previously reported to induce TPP1 activity in control cells, failed to increase TPP1 activity in patient iPSC-derived neural progenitor cells. Conversely, nonsense suppression by PTC124 resulted in both an increase of TPP1 activity and attenuation of neuropathology in patient iPSC-derived neural progenitor cells. This study therefore documents the high value of this powerful new set of tools for improved drug screening and for investigating early mechanisms driving NCL pathogenesis.


Asunto(s)
Aminopeptidasas/genética , Dipeptidil-Peptidasas y Tripeptidil-Peptidasas/genética , Células Madre Pluripotentes Inducidas/metabolismo , Glicoproteínas de Membrana/genética , Modelos Neurológicos , Chaperonas Moleculares/genética , Mutación/genética , Lipofuscinosis Ceroideas Neuronales/genética , Serina Proteasas/genética , Aminopeptidasas/metabolismo , Western Blotting , Estudios de Casos y Controles , Proliferación Celular , Células Cultivadas , Dipeptidil-Peptidasas y Tripeptidil-Peptidasas/metabolismo , Electrofisiología , Retículo Endoplásmico/efectos de los fármacos , Retículo Endoplásmico/metabolismo , Fenofibrato/farmacología , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Fibroblastos/patología , Gemfibrozilo/farmacología , Aparato de Golgi/efectos de los fármacos , Aparato de Golgi/metabolismo , Humanos , Técnicas para Inmunoenzimas , Células Madre Pluripotentes Inducidas/efectos de los fármacos , Células Madre Pluripotentes Inducidas/patología , Lisosomas/efectos de los fármacos , Lisosomas/metabolismo , Glicoproteínas de Membrana/metabolismo , Chaperonas Moleculares/metabolismo , Lipofuscinosis Ceroideas Neuronales/metabolismo , Lipofuscinosis Ceroideas Neuronales/patología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/patología , Serina Proteasas/metabolismo , Tripeptidil Peptidasa 1
14.
Curr Neurol Neurosci Rep ; 13(8): 366, 2013 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-23775425

RESUMEN

Neuronal ceroid lipofuscinosis (NCL), first clinically described in 1826 and pathologically defined in the 1960s, refers to a group of disorders mostly diagnosed in the childhood years that involve the accumulation of lysosomal storage material with characteristic ultrastructure and prominent neurodegenerative features including vision loss, seizures, motor and cognitive function deterioration, and often times, psychiatric disturbances. All NCL disorders evidence early morbidity and treatment options are limited to symptomatic and palliative care. While distinct genetic forms of NCL have long been recognized, recent genetic advances are considerably widening the NCL genotypic and phenotypic spectrum, highlighting significant overlap with other neurodegenerative diseases. This review will discuss these recent advances and the expanded potential for increased awareness and new research that will ultimately lead to effective treatments for NCL and related disorders.


Asunto(s)
Lipofuscinosis Ceroideas Neuronales/diagnóstico , Lipofuscinosis Ceroideas Neuronales/genética , Genotipo , Humanos , Fenotipo
15.
Neurology ; 80(19): 1762-70, 2013 May 07.
Artículo en Inglés | MEDLINE | ID: mdl-23596069

RESUMEN

OBJECTIVE: To evaluate the utility of targeted exome sequencing for the molecular diagnosis of mitochondrial disorders, which exhibit marked phenotypic and genetic heterogeneity. METHODS: We considered a diverse set of 102 patients with suspected mitochondrial disorders based on clinical, biochemical, and/or molecular findings, and whose disease ranged from mild to severe, with varying age at onset. We sequenced the mitochondrial genome (mtDNA) and the exons of 1,598 nuclear-encoded genes implicated in mitochondrial biology, mitochondrial disease, or monogenic disorders with phenotypic overlap. We prioritized variants likely to underlie disease and established molecular diagnoses in accordance with current clinical genetic guidelines. RESULTS: Targeted exome sequencing yielded molecular diagnoses in established disease loci in 22% of cases, including 17 of 18 (94%) with prior molecular diagnoses and 5 of 84 (6%) without. The 5 new diagnoses implicated 2 genes associated with canonical mitochondrial disorders (NDUFV1, POLG2), and 3 genes known to underlie other neurologic disorders (DPYD, KARS, WFS1), underscoring the phenotypic and biochemical overlap with other inborn errors. We prioritized variants in an additional 26 patients, including recessive, X-linked, and mtDNA variants that were enriched 2-fold over background and await further support of pathogenicity. In one case, we modeled patient mutations in yeast to provide evidence that recessive mutations in ATP5A1 can underlie combined respiratory chain deficiency. CONCLUSION: The results demonstrate that targeted exome sequencing is an effective alternative to the sequential testing of mtDNA and individual nuclear genes as part of the investigation of mitochondrial disease. Our study underscores the ongoing challenge of variant interpretation in the clinical setting.


Asunto(s)
ADN Mitocondrial/genética , Exoma/genética , Marcación de Gen/métodos , Enfermedades Mitocondriales/diagnóstico , Enfermedades Mitocondriales/genética , Análisis de Secuencia de ADN/métodos , Adolescente , Adulto , Secuencia de Aminoácidos , Niño , Preescolar , Femenino , Predisposición Genética a la Enfermedad , Humanos , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Linaje , Adulto Joven
16.
Hum Mol Genet ; 22(7): 1417-23, 2013 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-23297359

RESUMEN

Kufs disease, an adult-onset neuronal ceroid lipofuscinosis, is challenging to diagnose and genetically heterogeneous. Mutations in CLN6 were recently identified in recessive Kufs disease presenting as progressive myoclonus epilepsy (Type A), whereas the molecular basis of cases presenting with dementia and motor features (Type B) is unknown. We performed genome-wide linkage mapping of two families with recessive Type B Kufs disease and identified a single region on chromosome 11 to which both families showed linkage. Exome sequencing of five samples from the two families identified homozygous and compound heterozygous missense mutations in CTSF within this linkage region. We subsequently sequenced CTSF in 22 unrelated individuals with suspected recessive Kufs disease, and identified an additional patient with compound heterozygous mutations. CTSF encodes cathepsin F, a lysosomal cysteine protease, dysfunction of which is a highly plausible candidate mechanism for a storage disorder like ceroid lipofuscinosis. In silico modeling suggested the missense mutations would alter protein structure and function. Moreover, re-examination of a previously published mouse knockout of Ctsf shows that it recapitulates the light and electron-microscopic pathological features of Kufs disease. Although CTSF mutations account for a minority of cases of type B Kufs, CTSF screening should be considered in cases with early-onset dementia and may avoid the need for invasive biopsies.


Asunto(s)
Catepsina F/genética , Mutación Missense , Lipofuscinosis Ceroideas Neuronales/genética , Adulto , Animales , Células del Asta Anterior/patología , Estudios de Casos y Controles , Catepsina F/metabolismo , Mapeo Cromosómico , Consanguinidad , Análisis Mutacional de ADN , Exoma , Femenino , Estudios de Asociación Genética , Humanos , Escala de Lod , Ratones , Ratones Noqueados , Persona de Mediana Edad , Modelos Moleculares , Lipofuscinosis Ceroideas Neuronales/enzimología , Lipofuscinosis Ceroideas Neuronales/patología , Linaje , Estructura Secundaria de Proteína , Estructura Terciaria de Proteína , Análisis de Secuencia de ARN
17.
Angiogenesis ; 16(2): 387-404, 2013 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-23143660

RESUMEN

Altered RNA processing is an underlying mechanism of amyotrophic lateral sclerosis (ALS). Missense mutations in a number of genes involved in RNA function and metabolisms are associated with ALS. Among these genes is angiogenin (ANG), the fifth member of the vertebrate-specific, secreted ribonuclease superfamily. ANG is an angiogenic ribonuclease, and both its angiogenic and ribonucleolytic activities are important for motor neuron health. Ribonuclease 4 (RNASE4), the fourth member of this superfamily, shares the same promoters with ANG and is co-expressed with ANG. However, the biological role of RNASE4 is unknown. To determine whether RNASE4 is involved in ALS pathogenesis, we sequenced the coding region of RNASE4 in ALS and control subjects and characterized the angiogenic, neurogenic, and neuroprotective activities of RNASE4 protein. We identified an allelic association of SNP rs3748338 with ALS and demonstrated that RNASE4 protein is able to induce angiogenesis in in vitro, ex vivo, and in vivo assays. RNASE4 also induces neural differentiation of P19 mouse embryonal carcinoma cells and mouse embryonic stem cells. Moreover, RNASE4 not only stimulates the formation of neurofilaments from mouse embryonic cortical neurons, but also protects hypothermia-induced degeneration. Importantly, systemic treatment with RNASE4 protein slowed weight loss and enhanced neuromuscular function of SOD1 (G93A) mice.


Asunto(s)
Neovascularización Fisiológica , Neurogénesis , Ribonucleasas/metabolismo , Animales , Secuencia de Bases , Línea Celular , Cartilla de ADN , Humanos , Hibridación in Situ , Ratones , Reacción en Cadena de la Polimerasa , Polimorfismo Genético , Ribonucleasas/genética
18.
Mol Genet Metab ; 107(3): 456-61, 2012 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-23031366

RESUMEN

OBJECTIVE: Late-onset Pompe disease is a progressive, debilitating, and often fatal neuromuscular disorder resulting from the deficiency of a lysosomal enzyme, acid α-glucosidase. This extension study was conducted to determine the durability of the efficacy and safety of alglucosidase alfa observed over a period of 78 weeks in the Late-Onset Treatment Study (LOTS). METHODS: Patients who completed the LOTS study were eligible for this open-label extension study and received alglucosidase alfa 20mg/kg biweekly for an additional 26 weeks. The primary efficacy assessments were the distance walked during a 6-minute walk test and the percentage of predicted forced vital capacity in the upright position. Data are reported as change from patient's original LOTS baseline for each measure. RESULTS: The benefit of alglucosidase alfa treatment observed in LOTS at Week 78 was, in general, maintained at Week 104. The mean increase in distance walked measured 28.2 ± 66.5m from LOTS baseline to Week 78 and 21.3 ± 78.0m from LOTS baseline to Week 104. The mean change from baseline in percentage of predicted forced vital capacity was 1.3% ± 5.7% from LOTS baseline to Week 78 and 0.8% ± 6.7% from LOTS baseline to Week 104. Treatment-related adverse events were mainly infusion-associated reactions observed in 35% of patients. No deaths or anaphylactic reactions were observed during the extension study. CONCLUSIONS: The LOTS Extension study showed that patients treated with alglucosidase alfa for up to 104 weeks maintained the improved walking distance and stabilization in pulmonary function observed in the first 78 weeks of alglucosidase alfa therapy.


Asunto(s)
Terapia de Reemplazo Enzimático , Enfermedad del Almacenamiento de Glucógeno Tipo II/tratamiento farmacológico , Enfermedad del Almacenamiento de Glucógeno Tipo II/patología , alfa-Glucosidasas/uso terapéutico , Adolescente , Adulto , Edad de Inicio , Anciano , Estudios Transversales , Método Doble Ciego , Femenino , Enfermedad del Almacenamiento de Glucógeno Tipo II/diagnóstico , Enfermedad del Almacenamiento de Glucógeno Tipo II/enzimología , Estado de Salud , Humanos , Recién Nacido , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Actividad Motora/efectos de los fármacos , Tamizaje Neonatal , Placebos , Encuestas y Cuestionarios , alfa-Glucosidasas/metabolismo , alfa-Glucosidasas/farmacología
19.
Am J Hum Genet ; 91(1): 202-8, 2012 Jul 13.
Artículo en Inglés | MEDLINE | ID: mdl-22748208

RESUMEN

Neuronal ceroid lipofuscinosis (NCL) is a genetically heterogeneous group of lysosomal diseases that collectively compose the most common Mendelian form of childhood-onset neurodegeneration. It is estimated that ∼8% of individuals diagnosed with NCL by conservative clinical and histopathologic criteria have been ruled out for mutations in the nine known NCL-associated genes, suggesting that additional genes remain unidentified. To further understand the genetic underpinnings of the NCLs, we performed whole-exome sequencing on DNA samples from a Mexican family affected by a molecularly undefined form of NCL characterized by infantile-onset progressive myoclonic epilepsy (PME), vision loss, cognitive and motor regression, premature death, and prominent NCL-type storage material. Using a recessive model to filter the identified variants, we found a single homozygous variant, c.550C>T in KCTD7, that causes a p.Arg184Cys missense change in potassium channel tetramerization domain-containing protein 7 (KCTD7) in the affected individuals. The mutation was predicted to be deleterious and was absent in over 6,000 controls. The identified variant altered the localization pattern of KCTD7 and abrogated interaction with cullin-3, a ubiquitin-ligase component and known KCTD7 interactor. Intriguingly, murine cerebellar cells derived from a juvenile NCL model (CLN3) showed enrichment of endogenous KCTD7. Whereas KCTD7 mutations have previously been linked to PME without lysosomal storage, this study clearly demonstrates that KCTD7 mutations also cause a rare, infantile-onset NCL subtype designated as CLN14.


Asunto(s)
Mutación , Lipofuscinosis Ceroideas Neuronales/genética , Canales de Potasio/genética , Animales , Preescolar , Femenino , Células HEK293 , Humanos , Lactante , Masculino , Ratones , Ratones Endogámicos C57BL , Linaje , Complejo de la Endopetidasa Proteasomal/genética , Ubiquitina/genética
20.
Am J Med Genet A ; 158A(8): 1909-17, 2012 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-22786811

RESUMEN

Norrie disease (ND) is an X-linked recessive disorder characterized by congenital blindness, progressive sensorineural hearing loss and cognitive impairment. The ocular phenotype has been well described, while the extraocular manifestations of the disorder are not well understood. We present the data from the Norrie Disease Registry, which consists of 56 patients with detailed clinical histories and genotype data. This study represents the largest, detailed investigation into the phenotypic spectrum of ND to date and more importantly expands knowledge of the extraocular clinical manifestations. We identify several novel aspects of the syndrome that will improve the management of these patients. In particular, we expand our understanding of the neurologic manifestations in ND and identify a chronic seizure disorder in approximately 10% of all patients. In addition, details of the hearing phenotype are described including the median age of onset (12 years of age) and how genotype affects onset. Moreover, we find vascular disease to be a significant component of ND; and vascular health should be, in the future, a component of patient clinical care. In summary, the results expand our understanding of the phenotypic variability and genotypic heterogeneity in ND patients.


Asunto(s)
Ceguera/congénito , Enfermedades del Sistema Nervioso/patología , Espasmos Infantiles/patología , Ceguera/genética , Ceguera/patología , Enfermedades Genéticas Ligadas al Cromosoma X , Genotipo , Humanos , Masculino , Enfermedades del Sistema Nervioso/genética , Pruebas Neuropsicológicas , Fenotipo , Degeneración Retiniana , Espasmos Infantiles/genética , Encuestas y Cuestionarios
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