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1.
Mol Genet Metab ; 142(1): 108453, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38522179

RESUMEN

Growing interest in therapeutic development for rare diseases necessitate a systematic approach to the collection and curation of natural history data that can be applied consistently across this group of heterogenous rare diseases. In this study, we discuss the challenges facing natural history studies for leukodystrophies and detail a novel standardized approach to creating a longitudinal natural history study using existing medical records. Prospective studies are uniquely challenging for rare diseases. Delays in diagnosis and overall rarity limit the timely collection of natural history data. When feasible, prospective studies are often cross-sectional rather than longitudinal and are unlikely to capture pre- or early- symptomatic disease trajectories, limiting their utility in characterizing the full natural history of the disease. Therapeutic development in leukodystrophies is subject to these same obstacles. The Global Leukodystrophy Initiative Clinical Trials Network (GLIA-CTN) comprises of a network of research institutions across the United States, supported by a multi-center biorepository protocol, to map the longitudinal clinical course of disease across leukodystrophies. As part of GLIA-CTN, we developed Standard Operating Procedures (SOPs) that delineated all study processes related to staff training, source documentation, and data sharing. Additionally, the SOP detailed the standardized approach to data extraction including diagnosis, clinical presentation, and medical events, such as age at gastrostomy tube placement. The key variables for extraction were selected through face validity, and common electronic case report forms (eCRF) across leukodystrophies were created to collect analyzable data. To enhance the depth of the data, clinical notes are extracted into "original" and "imputed" encounters, with imputed encounter referring to a historic event (e.g., loss of ambulation 3 months prior). Retrospective Functional Assessments were assigned by child neurologists, using a blinded dual-rater approach and score discrepancies were adjudicated by a third rater. Upon completion of extraction, data source verification is performed. Data missingness was evaluated using statistics. The proposed methodology will enable us to leverage existing medical records to address the persistent gap in natural history data within this unique disease group, allow for assessment of clinical trajectory both pre- and post-formal diagnosis, and promote recruitment of larger cohorts.


Asunto(s)
Enfermedades Raras , Humanos , Enfermedades Raras/diagnóstico , Enfermedades Raras/terapia , Enfermedades Raras/epidemiología , Estudios Longitudinales , Estados Unidos , Estudios Prospectivos
2.
Mol Genet Metab ; 142(4): 108521, 2024 Jun 29.
Artículo en Inglés | MEDLINE | ID: mdl-38964050

RESUMEN

OBJECTIVE: Metachromatic leukodystrophy (MLD) is a rare neurodegenerative disorder. Emerging therapies are most effective in the presymptomatic phase, and thus defining this window is critical. We hypothesize that early development delay may precede developmental plateau. With the advent of presymptomatic screening platforms and transformative therapies, it is essential to define the onset of neurologic disease. METHODS: The specific ages of gain and loss of developmental milestones were captured from the medical records of individuals affected by MLD. Milestone acquisition was characterized as: on target (obtained before the age limit of 90th percentile plus 2 standard deviations compared to a normative dataset), delayed (obtained after 90th percentile plus 2 standard deviations), or plateau (skills never gained). Regression was defined as the age at which skills were lost. LI-MLD was defined by age at onset before 2.5 years. RESULTS: Across an international cohort, 351 subjects were included (n = 194 LI-MLD subcohort). The median age at presentation of the LI-MLD cohort was 1.4 years (25th-75th %ile: 1.0-1.5). Within the LI-MLD cohort, 75/194 (39%) had developmental delay (or plateau) prior to MLD clinical presentation. Among the LI-MLD cohort with a minimum of 1.5 years of follow-up (n = 187), 73 (39.0%) subjects never attained independent ambulation. Within LI-MLD + delay subcohort, the median time between first missed milestone target to MLD decline was 0.60 years (maximum distance from delay to onset: 1.9 years). INTERPRETATION: Early developmental delay precedes regression in a subset of children affected by LI-MLD, defining the onset of neurologic dysfunction earlier than previously appreciated. The use of realworld data prior to diagnosis revealed an early deviation from typical development. Close monitoring for early developmental delay in presymptomatic individuals may help in earlier diagnosis with important consequences for treatment decisions.

3.
Am J Hum Genet ; 104(5): 925-935, 2019 05 02.
Artículo en Inglés | MEDLINE | ID: mdl-30982609

RESUMEN

Colony stimulating factor 1 receptor (CSF1R) plays key roles in regulating development and function of the monocyte/macrophage lineage, including microglia and osteoclasts. Mono-allelic mutations of CSF1R are known to cause hereditary diffuse leukoencephalopathy with spheroids (HDLS), an adult-onset progressive neurodegenerative disorder. Here, we report seven affected individuals from three unrelated families who had bi-allelic CSF1R mutations. In addition to early-onset HDLS-like neurological disorders, they had brain malformations and skeletal dysplasia compatible to dysosteosclerosis (DOS) or Pyle disease. We identified five CSF1R mutations that were homozygous or compound heterozygous in these affected individuals. Two of them were deep intronic mutations resulting in abnormal inclusion of intron sequences in the mRNA. Compared with Csf1r-null mice, the skeletal and neural phenotypes of the affected individuals appeared milder and variable, suggesting that at least one of the mutations in each affected individual is hypomorphic. Our results characterized a unique human skeletal phenotype caused by CSF1R deficiency and implied that bi-allelic CSF1R mutations cause a spectrum of neurological and skeletal disorders, probably depending on the residual CSF1R function.


Asunto(s)
Encéfalo/anomalías , Leucoencefalopatías/etiología , Mutación , Osteocondrodisplasias/etiología , Osteosclerosis/etiología , Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos/genética , Adolescente , Adulto , Alelos , Animales , Encéfalo/metabolismo , Encéfalo/patología , Preescolar , Femenino , Humanos , Leucoencefalopatías/patología , Masculino , Ratones , Ratones Noqueados , Osteocondrodisplasias/patología , Osteosclerosis/patología , Fenotipo , Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos/fisiología , Adulto Joven
4.
Neuropediatrics ; 53(2): 115-121, 2022 04.
Artículo en Inglés | MEDLINE | ID: mdl-35026854

RESUMEN

OBJECTIVE: Heterozygous NOTCH3 variants are known to cause cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), with patients typically presenting in adulthood. We describe three patients presenting at an early age with a vascular leukoencephalopathy. Genome sequencing revealed bi-allelic variants in the NOTCH3 gene. METHODS: Clinical records and available MRI and CT scans of three patients from two unrelated families were retrospectively reviewed. RESULTS: The patients presented at 9 to 14 months of age with developmental delay, seizures, or both. The disease course was characterized by cognitive impairment and variably recurrent strokes, migraine attacks, and seizures. MRI findings pointed at a small vessel disease, with extensive cerebral white matter abnormalities, atrophy, lacunes in the basal ganglia, microbleeds, and microcalcifications. The anterior temporal lobes were spared. Bi-allelic cysteine-sparing NOTCH3 variants in exons 1, 32, and 33 were found. INTERPRETATION: This study indicates that bi-allelic loss-of-function NOTCH3 variants may cause a vascular leukoencephalopathy, distinct from CADASIL.


Asunto(s)
CADASIL , Leucoencefalopatías , Receptor Notch3 , Adulto , Alelos , CADASIL/diagnóstico por imagen , CADASIL/genética , Humanos , Leucoencefalopatías/diagnóstico por imagen , Leucoencefalopatías/genética , Imagen por Resonancia Magnética , Mutación , Receptor Notch3/genética , Estudios Retrospectivos , Convulsiones
5.
Ann Neurol ; 88(2): 264-273, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32342562

RESUMEN

OBJECTIVE: Genome sequencing (GS) is promising for unsolved leukodystrophies, but its efficacy has not been prospectively studied. METHODS: A prospective time-delayed crossover design trial of GS to assess the efficacy of GS as a first-line diagnostic tool for genetic white matter disorders took place between December 1, 2015 and September 27, 2017. Patients were randomized to receive GS immediately with concurrent standard of care (SoC) testing, or to receive SoC testing for 4 months followed by GS. RESULTS: Thirty-four individuals were assessed at interim review. The genetic origin of 2 patient's leukoencephalopathy was resolved before randomization. Nine patients were stratified to the immediate intervention group and 23 patients to the delayed-GS arm. The efficacy of GS was significant relative to SoC in the immediate (5/9 [56%] vs 0/9 [0%]; Wild-Seber, p < 0.005) and delayed (control) arms (14/23 [61%] vs 5/23 [22%]; Wild-Seber, p < 0.005). The time to diagnosis was significantly shorter in the immediate-GS group (log-rank test, p = 0.04). The overall diagnostic efficacy of combined GS and SoC approaches was 26 of 34 (76.5%, 95% confidence interval = 58.8-89.3%) in <4 months, greater than historical norms of <50% over 5 years. Owing to loss of clinical equipoise, the trial design was altered to a single-arm observational study. INTERPRETATION: In this study, first-line GS provided earlier and greater diagnostic efficacy in white matter disorders. We provide an evidence-based diagnostic testing algorithm to enable appropriate clinical GS utilization in this population. ANN NEUROL 2020;88:264-273.


Asunto(s)
Leucoencefalopatías/diagnóstico , Leucoencefalopatías/genética , Análisis de Secuencia de ADN/métodos , Niño , Preescolar , Estudios Cruzados , Femenino , Humanos , Lactante , Masculino , Estudios Prospectivos , Sustancia Blanca/patología
6.
Am J Med Genet A ; 182(8): 1906-1912, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32573057

RESUMEN

Leukodystrophies are a heterogeneous group of heritable disorders characterized by abnormal brain white matter signal on magnetic resonance imaging (MRI) and primary involvement of the cellular components of myelin. Previous estimates suggest the incidence of leukodystrophies as a whole to be 1 in 7,000 individuals, however the frequency of specific diagnoses relative to others has not been described. Next generation sequencing approaches offer the opportunity to redefine our understanding of the relative frequency of different leukodystrophies. We assessed the relative frequency of all 30 leukodystrophies (associated with 55 genes) in more than 49,000 exomes. We identified a relatively high frequency of disorders previously thought of as very rare, including Aicardi Goutières Syndrome, TUBB4A-related leukodystrophy, Peroxisomal biogenesis disorders, POLR3-related Leukodystrophy, Vanishing White Matter, and Pelizaeus-Merzbacher Disease. Despite the relative frequency of these conditions, carrier-screening laboratories regularly test only 20 of the 55 leukodystrophy-related genes, and do not test at all, or test only one or a few, genes for some of the higher frequency disorders. Relative frequency of leukodystrophies previously considered very rare suggests these disorders may benefit from expanded carrier screening.


Asunto(s)
Enfermedades Autoinmunes del Sistema Nervioso/genética , Enfermedades Desmielinizantes/genética , Malformaciones del Sistema Nervioso/genética , Enfermedad de Pelizaeus-Merzbacher/genética , ARN Polimerasa III/genética , Tubulina (Proteína)/genética , Enfermedades Autoinmunes del Sistema Nervioso/patología , Enfermedades Desmielinizantes/epidemiología , Enfermedades Desmielinizantes/patología , Exoma/genética , Femenino , Predisposición Genética a la Enfermedad , Heterocigoto , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Enfermedades por Almacenamiento Lisosomal/epidemiología , Enfermedades por Almacenamiento Lisosomal/genética , Imagen por Resonancia Magnética , Masculino , Vaina de Mielina/genética , Vaina de Mielina/metabolismo , Malformaciones del Sistema Nervioso/patología , Enfermedad de Pelizaeus-Merzbacher/epidemiología , Enfermedad de Pelizaeus-Merzbacher/patología , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/patología
7.
Am J Hum Genet ; 96(4): 675-81, 2015 Apr 02.
Artículo en Inglés | MEDLINE | ID: mdl-25817015

RESUMEN

Mutations in genes encoding aminoacyl-tRNA synthetases are known to cause leukodystrophies and genetic leukoencephalopathies-heritable disorders that result in white matter abnormalities in the central nervous system. Here we report three individuals (two siblings and an unrelated individual) with severe infantile epileptic encephalopathy, clubfoot, absent deep tendon reflexes, extrapyramidal symptoms, and persistently deficient myelination on MRI. Analysis by whole exome sequencing identified mutations in the nuclear-encoded alanyl-tRNA synthetase (AARS) in these two unrelated families: the two affected siblings are compound heterozygous for p.Lys81Thr and p.Arg751Gly AARS, and the single affected child is homozygous for p.Arg751Gly AARS. The two identified mutations were found to result in a significant reduction in function. Mutations in AARS were previously associated with an autosomal-dominant inherited form of axonal neuropathy, Charcot-Marie-Tooth disease type 2N (CMT2N). The autosomal-recessive AARS mutations identified in the individuals described here, however, cause a severe infantile epileptic encephalopathy with a central myelin defect and peripheral neuropathy, demonstrating that defects of alanyl-tRNA charging can result in a wide spectrum of disease manifestations.


Asunto(s)
Anomalías Múltiples/genética , Alanina-ARNt Ligasa/genética , Epilepsia/genética , Modelos Moleculares , Vaina de Mielina/patología , Enfermedades del Sistema Nervioso Periférico/genética , Fenotipo , Anomalías Múltiples/patología , Alanina-ARNt Ligasa/química , Secuencia de Aminoácidos , Secuencia de Bases , Epilepsia/patología , Genes Recesivos/genética , Humanos , Lactante , Recién Nacido , Datos de Secuencia Molecular , Mutación/genética , Enfermedades del Sistema Nervioso Periférico/patología , Estudios Prospectivos , Análisis de Secuencia de ADN , Síndrome , Estados Unidos
9.
Am J Med Genet A ; 176(6): 1443-1448, 2018 06.
Artículo en Inglés | MEDLINE | ID: mdl-29696782

RESUMEN

Early-onset epileptic encephalopathies (EOEEs) are a genetically heterogeneous collection of severe epilepsies often associated with psychomotor regression. Mutations in SZT2, a known seizure threshold regulator gene, are a newly identified cause of EOEE. We present an individual with EOEE, macrocephaly, and developmental regression with compound heterozygous mutations in SZT2 as identified by whole exome sequencing. Serial imaging characterized the novel finding of progressive loss of central myelination. This case expands our clinical understanding of the SZT2-phenotype and emphasizes the role of this gene in the diagnostic investigation for EOEE and leukoencephalopathies.


Asunto(s)
Leucoencefalopatías/genética , Mutación , Proteínas del Tejido Nervioso/genética , Espasmos Infantiles/genética , Sistemas de Transporte de Aminoácidos Acídicos/deficiencia , Sistemas de Transporte de Aminoácidos Acídicos/genética , Antiportadores/deficiencia , Antiportadores/genética , Preescolar , Discapacidades del Desarrollo/genética , Femenino , Enfermedades Desmielinizantes del Sistema Nervioso Central Hereditarias/diagnóstico por imagen , Enfermedades Desmielinizantes del Sistema Nervioso Central Hereditarias/etiología , Enfermedades Desmielinizantes del Sistema Nervioso Central Hereditarias/genética , Heterocigoto , Humanos , Lactante , Leucoencefalopatías/diagnóstico por imagen , Leucoencefalopatías/etiología , Imagen por Resonancia Magnética , Megalencefalia/diagnóstico por imagen , Megalencefalia/genética , Enfermedades Mitocondriales/diagnóstico por imagen , Enfermedades Mitocondriales/etiología , Enfermedades Mitocondriales/genética , Trastornos Psicomotores/diagnóstico por imagen , Trastornos Psicomotores/etiología , Trastornos Psicomotores/genética , Espasmos Infantiles/diagnóstico por imagen , Espasmos Infantiles/etiología
10.
J Med Genet ; 54(5): 330-337, 2017 05.
Artículo en Inglés | MEDLINE | ID: mdl-27799409

RESUMEN

BACKGROUND: Acyl-CoA binding domain containing protein 5 (ACBD5) is a peroxisomal membrane protein with a cytosolic acyl-CoA binding domain. Because of its acyl-CoA binding domain, ACBD5 has been assumed to function as an intracellular carrier of acyl-CoA esters. In addition, a role for ACBD5 in pexophagy has been suggested. However, the precise role of ACBD5 in peroxisomal metabolism and/or functioning has not yet been established. Previously, a genetic ACBD5 deficiency was identified in three siblings with retinal dystrophy and white matter disease. We identified a pathogenic mutation in ACBD5 in another patient and studied the consequences of the ACBD5 defect in patient material and in ACBD5-deficient HeLa cells to uncover this role. METHODS: We studied a girl who presented with progressive leukodystrophy, syndromic cleft palate, ataxia and retinal dystrophy. We performed biochemical, cell biological and molecular studies in patient material and in ACBD5-deficient HeLa cells generated by CRISPR-Cas9 genome editing. RESULTS: We identified a homozygous deleterious indel mutation in ACBD5, leading to complete loss of ACBD5 protein in the patient. Our studies showed that ACBD5 deficiency leads to accumulation of very long-chain fatty acids (VLCFAs) due to impaired peroxisomal ß-oxidation. No effect on pexophagy was found. CONCLUSIONS: Our investigations strongly suggest that ACBD5 plays an important role in sequestering C26-CoA in the cytosol and thereby facilitates transport into the peroxisome and subsequent ß-oxidation. Accordingly, ACBD5 deficiency is a novel single peroxisomal enzyme deficiency caused by impaired VLCFA metabolism, leading to retinal dystrophy and white matter disease.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/deficiencia , Ácidos Grasos/metabolismo , Proteínas de la Membrana/deficiencia , Peroxisomas/metabolismo , Acilcoenzima A/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Autofagia , Preescolar , ADN Complementario/genética , Femenino , Fibroblastos/metabolismo , Prueba de Complementación Genética , Células HeLa , Humanos , Lactante , Imagen por Resonancia Magnética , Proteínas de la Membrana/metabolismo , Piel/patología
11.
Neurogenetics ; 18(4): 185-194, 2017 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-28842795

RESUMEN

An X-linked condition characterized by the combination of hypomyelinating leukodystrophy and spondylometaphyseal dysplasia (H-SMD) has been observed in only four families, with linkage to Xq25-27, and recent genetic characterization in two families with a common AIFM1 mutation. In our study, 12 patients (6 families) with H-SMD were identified and underwent comprehensive assessment accompanied by whole-exome sequencing (WES). Pedigree analysis in all families was consistent with X-linked recessive inheritance. Presentation typically occurred between 12 and 36 months. In addition to the two disease-defining features of spondylometaphyseal dysplasia and hypomyelination on MRI, common clinical signs and symptoms included motor deterioration, spasticity, tremor, ataxia, dysarthria, cognitive defects, pulmonary hypertension, nystagmus, and vision loss due to retinopathy. The course of the disease was slowly progressive. All patients had maternally inherited or de novo mutations in or near exon 7 of AIFM1, within a region of 70 bp, including synonymous and intronic changes. AIFM1 mutations have previously been associated with neurologic presentations as varied as intellectual disability, hearing loss, neuropathy, and striatal necrosis, while AIFM1 mutations in this small region present with a distinct phenotype implicating bone. Analysis of cell lines derived from four patients identified significant reductions in AIFM1 mRNA and protein levels in osteoblasts. We hypothesize that AIFM1 functions in bone metabolism and myelination and is responsible for the unique phenotype in this condition.


Asunto(s)
Factor Inductor de la Apoptosis/genética , Genes Ligados a X/genética , Predisposición Genética a la Enfermedad , Mutación/genética , Humanos , Discapacidad Intelectual/genética , Masculino , Vaina de Mielina/genética , Vaina de Mielina/metabolismo , Osteocondrodisplasias/genética , Linaje , Fenotipo , Análisis de Secuencia de ADN
12.
Mol Genet Metab ; 122(1-2): 18-32, 2017 09.
Artículo en Inglés | MEDLINE | ID: mdl-28863857

RESUMEN

Leukodystrophies are a broad class of genetic disorders that result in disruption or destruction of central myelination. Although the mechanisms underlying these disorders are heterogeneous, there are many common symptoms that affect patients irrespective of the genetic diagnosis. The comfort and quality of life of these children is a primary goal that can complement efforts directed at curative therapies. Contained within this report is a systems-based approach to management of complications that result from leukodystrophies. We discuss the initial evaluation, identification of common medical issues, and management options to establish a comprehensive, standardized care approach. We will also address clinical topics relevant to select leukodystrophies, such as gallbladder pathology and adrenal insufficiency. The recommendations within this review rely on existing studies and consensus opinions and underscore the need for future research on evidence-based outcomes to better treat the manifestations of this unique set of genetic disorders.


Asunto(s)
Enfermedades Desmielinizantes/terapia , Enfermedades Desmielinizantes del Sistema Nervioso Central Hereditarias/terapia , Leucoencefalopatías/terapia , Enfermedades por Almacenamiento Lisosomal/prevención & control , Enfermedades por Almacenamiento Lisosomal/terapia , Insuficiencia Suprarrenal/terapia , Adulto , Niño , Enfermedades Desmielinizantes/congénito , Femenino , Vesícula Biliar/patología , Predisposición Genética a la Enfermedad , Humanos , Leucoencefalopatías/congénito , Masculino , Calidad de Vida
13.
Ann Neurol ; 79(6): 1031-1037, 2016 06.
Artículo en Inglés | MEDLINE | ID: mdl-27159321

RESUMEN

Here we report whole exome sequencing (WES) on a cohort of 71 patients with persistently unresolved white matter abnormalities with a suspected diagnosis of leukodystrophy or genetic leukoencephalopathy. WES analyses were performed on trio, or greater, family groups. Diagnostic pathogenic variants were identified in 35% (25 of 71) of patients. Potentially pathogenic variants were identified in clinically relevant genes in a further 7% (5 of 71) of cases, giving a total yield of clinical diagnoses in 42% of individuals. These findings provide evidence that WES can substantially decrease the number of unresolved white matter cases. Ann Neurol 2016;79:1031-1037.


Asunto(s)
Análisis Mutacional de ADN , Exoma/genética , Leucoencefalopatías/diagnóstico , Leucoencefalopatías/genética , Sustancia Blanca/patología , Adolescente , Adulto , Niño , Preescolar , Femenino , Humanos , Leucoencefalopatías/patología , Masculino , Mutación , Adulto Joven
14.
Genet Med ; 17(9): 753-6, 2015 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-25521335

RESUMEN

PURPOSE: This study examines the analytic validity of a software tool designed to provide individuals with risk assessments for colorectal cancer based on personal health and family history information. The software is compatible with the US Surgeon General's My Family Health Portrait (MFHP). METHODS: An algorithm for risk assessment was created using accepted colorectal risk assessment guidelines and programmed into a software tool (MFHP). Risk assessments derived from 150 pedigrees using the MFHP tool were compared with "gold standard" risk assessments developed by three expert cancer genetic counselors. RESULTS: Genetic counselor risk assessments showed substantial, but not perfect, agreement. MFHP risk assessments for colorectal cancer yielded a sensitivity for colorectal cancer risk of 81% (95% confidence interval: 54-96%) and specificity of 90% (95% confidence interval: 83-94%), as compared with genetic counselor pedigree review. The positive predictive value for risk for MFHP was 48% (95% confidence interval: 29-68%), whereas the negative predictive value was 98% (95% confidence interval: 93-99%). Agreement between MFHP and genetic counselor pedigree review was moderate (κ = 0.54). CONCLUSION: The analytic validity of the MFHP colorectal cancer risk assessment software is similar to those of other types of screening tools used in primary care. Future investigations should explore the clinical validity and utility of the software in diverse population groups.Genet Med 17 9, 753-756.


Asunto(s)
Neoplasias Colorrectales/genética , Anamnesis/métodos , Medición de Riesgo/métodos , Adulto , Anciano , Anciano de 80 o más Años , Algoritmos , Neoplasias Colorrectales/diagnóstico , Salud de la Familia , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino , Anamnesis/normas , Persona de Mediana Edad , Linaje , Medición de Riesgo/normas , Programas Informáticos , Estados Unidos
15.
Mol Genet Metab ; 114(4): 516-26, 2015 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-25577286

RESUMEN

Leukodystrophies are inherited disorders whose primary pathophysiology consists of abnormal deposition or progressive disruption of brain myelin. Leukodystrophy patients manifest many of the same symptoms and medical complications despite the wide spectrum of genetic origins. Although no definitive cures exist, all of these conditions are treatable. This report provides the first expert consensus on the recognition and treatment of medical and psychosocial complications associated with leukodystrophies. We include a discussion of serious and potentially preventable medical complications and propose several preventive care strategies. We also outline the need for future research to prioritize clinical needs and subsequently develop, validate, and optimize specific care strategies.


Asunto(s)
Enfermedades Desmielinizantes , Leucoencefalopatías , Enfermedades Desmielinizantes/diagnóstico , Enfermedades Desmielinizantes/terapia , Manejo de la Enfermedad , Humanos , Leucoencefalopatías/diagnóstico , Leucoencefalopatías/terapia , Vaina de Mielina/fisiología
16.
Mol Genet Metab ; 114(4): 501-515, 2015 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-25655951

RESUMEN

Leukodystrophies (LD) and genetic leukoencephalopathies (gLE) are disorders that result in white matter abnormalities in the central nervous system (CNS). Magnetic resonance (MR) imaging (MRI) has dramatically improved and systematized the diagnosis of LDs and gLEs, and in combination with specific clinical features, such as Addison's disease in Adrenoleukodystrophy or hypodontia in Pol-III related or 4H leukodystrophy, can often resolve a case with a minimum of testing. The diagnostic odyssey for the majority LD and gLE patients, however, remains extensive--many patients will wait nearly a decade for a definitive diagnosis and at least half will remain unresolved. The combination of MRI, careful clinical evaluation and next generation genetic sequencing holds promise for both expediting the diagnostic process and dramatically reducing the number of unresolved cases. Here we present a workflow detailing the Global Leukodystrophy Initiative (GLIA) consensus recommendations for an approach to clinical diagnosis, including salient clinical features suggesting a specific diagnosis, neuroimaging features and molecular genetic testing. We also discuss recommendations on the use of broad-spectrum next-generation sequencing in instances of ambiguous MRI or clinical findings. We conclude with a proposal for systematic trials of genome-wide agnostic testing as a first line diagnostic in LDs and gLEs given the increasing number of genes associated with these disorders.


Asunto(s)
Enfermedades Desmielinizantes/diagnóstico , Enfermedades Desmielinizantes del Sistema Nervioso Central Hereditarias/diagnóstico , Enfermedades por Almacenamiento Lisosomal/diagnóstico , Adrenoleucodistrofia/diagnóstico , Anodoncia/diagnóstico , Humanos , Imagen por Resonancia Magnética
17.
Mol Genet Metab ; 114(4): 527-36, 2015 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-25684057

RESUMEN

Leukodystrophies are a heterogeneous, often progressive group of disorders manifesting a wide range of symptoms and complications. Most of these disorders have historically had no etiologic or disease specific therapeutic approaches. Recently, a greater understanding of the pathologic mechanisms associated with leukodystrophies has allowed clinicians and researchers to prioritize treatment strategies and advance research in therapies for specific disorders, some of which are on the verge of pilot or Phase I/II clinical trials. This shifts the care of leukodystrophy patients from the management of the complex array of symptoms and sequelae alone to targeted therapeutics. The unmet needs of leukodystrophy patients still remain an overwhelming burden. While the overwhelming consensus is that these disorders collectively are symptomatically treatable, leukodystrophy patients are in need of advanced therapies and if possible, a cure.


Asunto(s)
Enfermedades Desmielinizantes/terapia , Enfermedades Desmielinizantes del Sistema Nervioso Central Hereditarias/terapia , Leucodistrofia Metacromática/terapia , Leucoencefalopatías/terapia , Encefalopatías/prevención & control , Encefalopatías/terapia , Enfermedades Desmielinizantes/prevención & control , Enfermedades Desmielinizantes del Sistema Nervioso Central Hereditarias/prevención & control , Humanos , Leucodistrofia Metacromática/prevención & control , Leucoencefalopatías/prevención & control
18.
Am J Med Genet A ; 167A(2): 296-312, 2015 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-25604658

RESUMEN

Aicardi-Goutières syndrome is an inflammatory disease occurring due to mutations in any of TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR or IFIH1. We report on 374 patients from 299 families with mutations in these seven genes. Most patients conformed to one of two fairly stereotyped clinical profiles; either exhibiting an in utero disease-onset (74 patients; 22.8% of all patients where data were available), or a post-natal presentation, usually within the first year of life (223 patients; 68.6%), characterized by a sub-acute encephalopathy and a loss of previously acquired skills. Other clinically distinct phenotypes were also observed; particularly, bilateral striatal necrosis (13 patients; 3.6%) and non-syndromic spastic paraparesis (12 patients; 3.4%). We recorded 69 deaths (19.3% of patients with follow-up data). Of 285 patients for whom data were available, 210 (73.7%) were profoundly disabled, with no useful motor, speech and intellectual function. Chilblains, glaucoma, hypothyroidism, cardiomyopathy, intracerebral vasculitis, peripheral neuropathy, bowel inflammation and systemic lupus erythematosus were seen frequently enough to be confirmed as real associations with the Aicardi-Goutieres syndrome phenotype. We observed a robust relationship between mutations in all seven genes with increased type I interferon activity in cerebrospinal fluid and serum, and the increased expression of interferon-stimulated gene transcripts in peripheral blood. We recorded a positive correlation between the level of cerebrospinal fluid interferon activity assayed within one year of disease presentation and the degree of subsequent disability. Interferon-stimulated gene transcripts remained high in most patients, indicating an ongoing disease process. On the basis of substantial morbidity and mortality, our data highlight the urgent need to define coherent treatment strategies for the phenotypes associated with mutations in the Aicardi-Goutières syndrome-related genes. Our findings also make it clear that a window of therapeutic opportunity exists relevant to the majority of affected patients and indicate that the assessment of type I interferon activity might serve as a useful biomarker in future clinical trials.


Asunto(s)
Adenosina Desaminasa/genética , Enfermedades Autoinmunes del Sistema Nervioso/diagnóstico , Enfermedades Autoinmunes del Sistema Nervioso/genética , ARN Helicasas DEAD-box/genética , Exodesoxirribonucleasas/genética , Proteínas de Unión al GTP Monoméricas/genética , Mutación , Malformaciones del Sistema Nervioso/diagnóstico , Malformaciones del Sistema Nervioso/genética , Fenotipo , Fosfoproteínas/genética , Ribonucleasa H/genética , Estudios de Asociación Genética , Genotipo , Humanos , Helicasa Inducida por Interferón IFIH1 , Interferones/sangre , Interferones/líquido cefalorraquídeo , Pterinas/líquido cefalorraquídeo , Proteína 1 que Contiene Dominios SAM y HD
19.
J Genet Couns ; 23(5): 734-41, 2014 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-24777551

RESUMEN

Uniparental disomy is a genetic cause of disease that may result in the inheritance of an autosomal recessive condition. A child with developmental delay and hypotonia was seen and found to have severely abnormal myelination. Lysosomal enzyme testing identified an isolated deficiency of beta-galactosidase. Subsequently, homozygous missense mutations in the galactosidase, beta 1 (GLB1) gene on chromosome 3 were found. Parental testing confirmed inheritance of two copies of the same mutated maternal GLB1 gene, and no paternal copy. SNP analysis was also done to confirm paternity. The patient was ultimately diagnosed with autosomal recessive GM1 gangliosidosis caused by maternal uniparental isodisomy. We provide a review of this patient and others in which uniparental disomy (UPD) of a non-imprinted chromosome unexpectedly caused an autosomal recessive condition. This is the first case of GM1 gangliosidosis reported in the literature to have been caused by UPD. It is important for genetic counselors and other health care providers to be aware of the possibility of autosomal recessive disease caused by UPD. UPD as a cause of autosomal recessive disease drastically changes the recurrence risk for families, and discussions surrounding UPD can be complex. Working with families to understand UPD when it occurs requires a secure and trusting counselor-family relationship.


Asunto(s)
Gangliosidosis GM1/genética , Disomía Uniparental , Femenino , Humanos , Lactante , Polimorfismo de Nucleótido Simple
20.
Pediatr Neurol ; 121: 11-19, 2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-34111619

RESUMEN

BACKGROUND: A recurrent homozygous missense variant, c.160G>C;p.(Val54Leu) in HIKESHI, was found to cause a hypomyelinating leukodystrophy with high frequency in the Ashkenazi Jewish population. We provide extended phenotypic classification of this disorder based on clinical history of a further seven affected individuals, assess carrier frequency in the Ashkenazi Jewish population, and provide a neuropathological study. METHODS: Clinical information, neuroimaging, and biosamples were collected. Brain autopsy was performed for one case. RESULTS: Individuals with HIKESHI-related disease share common clinical features: early axial hypotonia evolving to dystonia or with progressive spasticity, hyperreflexia and clonus, feeding difficulties with poor growth, and nystagmus. Severe morbidity or death during febrile illness occurred in five of the nine affected individuals. Magnetic resonance images of seven patients were analyzed and demonstrated diffuse hypomyelination and thin corpus callosum. Genotyping data of more than 125,000 Ashkenazi Jewish individuals revealed a carrier frequency of 1 in 216. Gross pathology examination in one case revealed abnormal white matter. Microscopically, there was a near-total absence of myelin with a relative preservation of axons. The cerebral white matter showed several reactive astrocytes and microglia. CONCLUSIONS: We provide pathologic evidence for a primary disorder of the myelin in HIKESHI-related leukodystrophy. These findings are consistent with the hypomyelination seen in brain magnetic resonance imaging and with the clinical features of early-onset spastic/dystonic quadriplegia and nystagmus. The high carrier rate of the recurrent variant seen in the Ashkenazi Jewish population requires increased attention to screening and diagnosis of this condition, particularly in this population.


Asunto(s)
Proteínas Portadoras/genética , Enfermedades Desmielinizantes del Sistema Nervioso Central Hereditarias/patología , Enfermedades Desmielinizantes del Sistema Nervioso Central Hereditarias/fisiopatología , Niño , Cuerpo Calloso/diagnóstico por imagen , Cuerpo Calloso/patología , Humanos , Judíos/genética , Imagen por Resonancia Magnética , Secuenciación Completa del Genoma
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