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OBJECTIVES: Assess temporal changes, intercenter variability, and birthing person (BP) factors relating to interventions for extremely early deliveries. METHODS: Retrospective study of BPs and newborns delivered from 22-24 completed weeks at 13 US centers from 2011-2020. Rates of neonatology consultation, antenatal corticosteroids, cesarean delivery, live birth, attempted resuscitation (AR), and survival were assessed by epoch, center, and gestational age. RESULTS: 2028 BPs delivering 2327 newborns were included. Rates increased in epoch 2-at 22 weeks: neonatology consultation (37.6 vs 64.3%, P < .001), corticosteroids (11.4 vs 29.5%, P < .001), live birth (66.2 vs 78.6%, P < .001), AR (20.1 vs 36.9%, P < .001), overall survival (3.0 vs 8.9%, P = .005); and at 23 weeks: neonatology consultation (73.0 vs 80.5%, P = .02), corticosteroids (63.7 vs 83.7%, P < .001), cesarean delivery (28.0 vs 44.7%, P < .001), live birth (88.1 vs 95.1%, P < .001), AR (67.7 vs 85.2%, P < .001), survival (28.8 vs 41.6%, P < .001). Over time, intercenter variability increased at 22 weeks for corticosteroids (interquartile range 18.0 vs 42.0, P = .014) and decreased at 23 for neonatology consultation (interquartile range 23.0 vs 5.2, P = .045). In BP-level multivariate analysis, AR was associated with increasing gestational age and birth weight, Black BP race, previous premature delivery, and delivery center. CONCLUSIONS: Intervention rates for extremely early newborns increased and intercenter variability changed over time. In BP-level analysis, factors significantly associated with AR included Black BP race, previous premature delivery, and center.
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OBJECTIVE: Describe care surrounding the end of life (EOL) in the neonatal intensive care unit (NICU). STUDY DESIGN: Retrospective chart review of 208 infants who died in a level IV referral-only NICU over 5 years. RESULTS: A goals of care (GOC) conversation was documented before the day of death for 63% of infants. 73% died following withdrawal of life-sustaining treatment (WD); 13% died in a code. The median age at death was 17.5 days. 72% were held by a parent at EOL. 94% of families desired formal memory-making. We identified associations with mode of death and parental holding at death, including: WD was associated with palliative care consultation, early GOC conversations, and increased unit-specific length of stay. Holding was associated with chaplain visits, memory-making, and increased home-to-hospital distance. CONCLUSION: We present a detailed description of EOL care in an outborn NICU, including novel data on parental holding and memory-making.
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Unidades de Cuidado Intensivo Neonatal , Padres , Cuidado Terminal , Humanos , Recién Nacido , Estudios Retrospectivos , Femenino , Masculino , Padres/psicología , Privación de Tratamiento , Cuidados PaliativosRESUMEN
Genetic testing is increasingly used in clinical practice in the neonatal period, including in NICUs. This testing may have psychological consequences for parents. To best support families, neonatal clinicians should be aware of the various ways in which parents view and respond to genetic testing. In this review, we summarize research on the parental experience of having a newborn infant undergo genetic testing.
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Pruebas Genéticas , Unidades de Cuidado Intensivo Neonatal , Humanos , Recién Nacido , Padres/psicologíaRESUMEN
The aetiology of nodding syndrome remains unclear, and comprehensive genotyping and phenotyping data from patients remain sparse. Our objectives were to characterize the phenotype of patients with nodding syndrome, investigate potential contributors to disease aetiology, and evaluate response to immunotherapy. This cohort study investigated members of a single-family unit from Lamwo District, Uganda. The participants for this study were selected by the Ugandan Ministry of Health as representative for nodding syndrome and with a conducive family structure for genomic analyses. Of the eight family members who participated in the study at the National Institutes of Health (NIH) Clinical Center, three had nodding syndrome. The three affected patients were extensively evaluated with metagenomic sequencing for infectious pathogens, exome sequencing, spinal fluid immune analyses, neurometabolic and toxicology testing, continuous electroencephalography and neuroimaging. Five unaffected family members underwent a subset of testing for comparison. A distinctive interictal pattern of sleep-activated bursts of generalized and multifocal epileptiform discharges and slowing was observed in two patients. Brain imaging showed two patients had mild generalized cerebral atrophy, and both patients and unaffected family members had excessive metal deposition in the basal ganglia. Trace metal biochemical evaluation was normal. CSF was non-inflammatory and one patient had CSF-restricted oligoclonal bands. Onchocerca volvulus-specific antibodies were present in all patients and skin snips were negative for active onchocerciasis. Metagenomic sequencing of serum and CSF revealed hepatitis B virus in the serum of one patient. Vitamin B6 metabolites were borderline low in all family members and CSF pyridoxine metabolites were normal. Mitochondrial DNA testing was normal. Exome sequencing did not identify potentially causal candidate gene variants. Nodding syndrome is characterized by a distinctive pattern of sleep-activated epileptiform activity. The associated growth stunting may be due to hypothalamic dysfunction. Extensive testing years after disease onset did not clarify a causal aetiology. A trial of immunomodulation (plasmapheresis in two patients and intravenous immunoglobulin in one patient) was given without short-term effect, but longer-term follow-up was not possible to fully assess any benefit of this intervention.
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Síndrome del Cabeceo , Oncocercosis , Estados Unidos , Humanos , Estudios de Cohortes , Inmunomodulación , GenómicaRESUMEN
OBJECTIVE: The authors aim to compare all code blue events, regardless of the need for chest compressions, in the neonatal intensive care unit (NICU) versus the pediatric intensive care unit (PICU). We hypothesize that code events in the two units differ, reflecting different disease processes. STUDY DESIGN: This is a retrospective analysis of 107 code events using the code narrator, which is an electronic medical record of real-time code documentation, from April 2018 to March 2019. Events were divided into two groups, NICU and PICU. Neonatal resuscitation program algorithm was used for NICU events and a pediatric advanced life-support algorithm was used for PICU events. Events and outcomes were compared using univariate analysis. The Mann-Whitney test and linear regressions were done to compare the total code duration, time from the start of code to airway insertion, and time from airway insertion to end of code event. RESULTS: In the PICU, there were almost four times more code blue events per month and more likely to involve patients with seizures and no chronic condition. NICU events more often involved ventilated patients and those under 2 months of age. The median code duration for NICU events was 2.5 times shorter than for PICU events (11.5 vs. 29 minutes), even when adjusted for patient characteristics. Survival to discharge was not different in the two groups. CONCLUSION: Our study suggests that NICU code events as compared with PICU code events are more likely to be driven by airway problems, involve patients <2 months of age, and resolve quickly once airway is taken care of. This supports the use of a ventilation-focused neonatal resuscitation program for patients in the NICU. KEY POINTS: · Code blue events are four times more common in PICU.. · NICU code events are 2.5 times shorter in duration compared with PICU events.. · NICU code events are more likely to be attributed to a problem with an airway..
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Reanimación Cardiopulmonar , Unidades de Cuidado Intensivo Pediátrico , Niño , Hospitales , Humanos , Recién Nacido , Unidades de Cuidado Intensivo Neonatal , Estudios Retrospectivos , Atención Terciaria de SaludRESUMEN
A woman with ichthyosis, contractures, and progressive neuropathy represents the first case of phosphoserine aminotransferase deficiency diagnosed and treated in an adult. She has novel compound heterozygous mutations in the gene PSAT1. Treatment with high dose oral L-serine completely resolved the ichthyosis. Consideration of this diagnosis is important because early treatment with L-serine repletion can halt progression of neurodegeneration and potentially improve neurological disabilities. As exome sequencing becomes more widely implemented in the diagnostic evaluation of progressive neurodegenerative phenotypes, adult neurologists and geneticists will increasingly encounter later onset manifestations of inborn errors of metabolism classically considered in infancy and early childhood.
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Anomalías Congénitas/genética , Ictiosis/genética , Serina/biosíntesis , Transaminasas/genética , Adulto , Preescolar , Anomalías Congénitas/patología , Femenino , Retardo del Crecimiento Fetal/genética , Retardo del Crecimiento Fetal/metabolismo , Retardo del Crecimiento Fetal/patología , Humanos , Ictiosis/metabolismo , Ictiosis/patología , Deformidades Congénitas de las Extremidades/genética , Deformidades Congénitas de las Extremidades/patología , Microcefalia/genética , Microcefalia/patología , Trastornos Psicomotores/genética , Trastornos Psicomotores/patología , Convulsiones/genética , Convulsiones/patología , Serina/deficiencia , Serina/genética , Esfingolípidos/deficiencia , Esfingolípidos/genética , Transaminasas/deficiencia , Secuenciación del ExomaRESUMEN
AIM: To describe the ophthalmologic findings on the largest cohort of patients with sialidosis type I due to deficiency of the lysosomal sialidase, neuraminidase 1 (NEU1) and to introduce a quantitative neuroretinal image analysis approach to the associated 'macular cherry-red spot'. METHODS: Seven patients with sialidosis type I (mutations in NEU1) and one with galactosialidosis (mutations in CTSA) were included. All patients underwent detailed ophthalmological examinations. The reflectivity of macular optical coherence tomography (OCT) was measured using greyscale analysis (Fiji) and compared with age-matched healthy volunteers. Four patients were evaluated over a time of 1.5+0.5 years. RESULTS: The mean age of the patients at their first visit was 27.5+9.8 years. All patients had a macular cherry-red spot, clear corneas and visually non-significant lenticular opacities. The mean visual acuity was LogMar 0.4 (20/50)+0.4 (20/20 to 20/125). Six patients had good visual function. Optic atrophy was present in two individuals with reduced acuity. A significant increase in macular reflectivity was present in all patients compared to age-matched controls (p<0.0001). CONCLUSION: Most of our patients (75%) have preserved visual acuity, even in adulthood. The presence of optic atrophy is associated with poor visual acuity. Increased macular reflectivity by OCT greyscale measurements is noted in all patients, although the underlying biological basis is unknown. These findings complement the current methods for examining and monitoring disease progression, especially in patients for whom visualisation of the cherry-red spot is not entirely clear. TRIAL REGISTRATION NUMBER: NCT00029965.
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Angiografía con Fluoresceína/métodos , Mácula Lútea/patología , Mucolipidosis/diagnóstico , Imagen Multimodal , Enfermedades de la Retina/diagnóstico , Tomografía de Coherencia Óptica/métodos , Agudeza Visual , Adolescente , Adulto , Niño , Femenino , Fondo de Ojo , Humanos , Masculino , Mucolipidosis/complicaciones , Enfermedades de la Retina/etiología , Adulto JovenRESUMEN
Leigh syndrome is a genetically heterogeneous disorder resulting from deficient oxidative energy biogenesis. The syndrome is characterized by subacute episodic decompensations, transiently elevated lactate, and necrotizing brain lesions most often in the striatum and brainstem. Acute decompensation is often triggered by viral infections. Sequalae from repeated episodes leads to progressive neurological deterioration and death. The severity of Leigh syndrome varies widely, from a rapid demise in childhood to rare adult presentations. Although the causes of Leigh syndrome include genes affecting a variety of different pathways, more than 75 of them are nuclear or mitochondrial encoded genes involved in the assembly and catalytic activity of mitochondrial respiratory complex I. Here we report the detailed clinical and molecular phenotype of two adults with mild presentations of NDUFS3 and NDUFAF6-related Leigh Syndrome. Mitochondrial assays revealed slightly reduced complex I activity in one proband and normal complex I activity in the other. The proband with NDUFS3-related Leigh syndrome was mildly affected and lived into adulthood with novel biallelic variants causing aberrant mRNA splicing (NM_004551.2:c.419G > A; p.Arg140Gln; NM_004551.2:c.381 + 6 T > C). The proband with NDUFAF6-related Leigh syndrome had biallelic variants that cause defects in mRNA splicing (NM_152416.3:c.371 T > C; p.Ile124Thr; NM_152416.3:c.420 + 2_420 + 3insTA). The mild phenotypes of these two individuals may be attributed to some residual production of normal NDUFS3 and NDUFAF6 proteins by NDUFS3 and NDUFAF6 mRNA isoforms alongside mutant transcripts. Taken together, these cases reported herein suggest that splice-regulatory variants to complex I proteins could result in milder phenotypes.
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Complejo I de Transporte de Electrón/genética , Enfermedad de Leigh/genética , Mitocondrias/genética , Proteínas Mitocondriales/genética , NADH Deshidrogenasa/genética , Adolescente , Adulto , Alelos , Niño , Femenino , Predisposición Genética a la Enfermedad , Humanos , Enfermedad de Leigh/patología , Masculino , Mutación/genética , Linaje , Empalme del ARN/genética , Adulto JovenRESUMEN
Mutations in GBA1, the gene mutated in Gaucher disease, are a common genetic risk factor for Parkinson disease, although the penetrance is low. We performed [18 F]-fluorodopa positron emission tomography studies of 57 homozygous and heterozygous GBA1 mutation carriers (15 with parkinsonism) and 98 controls looking for early indications of dopamine loss using voxelwise analyses to identify group differences in striatal [18 F]-fluorodopa uptake (Ki ). Forty-eight subjects were followed longitudinally. Cross-sectional and longitudinal comparisons of Ki and Ki change found significant effects of Parkinson disease. However, at baseline and over time, striatal [18 F]-fluorodopa uptake in mutation carriers without parkinsonism did not significantly differ from controls. ANN NEUROL 2020;87:652-657.
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Dopamina/biosíntesis , Enfermedad de Gaucher/diagnóstico por imagen , Neostriado/diagnóstico por imagen , Enfermedad de Parkinson/diagnóstico por imagen , Adulto , Anciano , Estudios de Casos y Controles , Dihidroxifenilalanina/análogos & derivados , Femenino , Enfermedad de Gaucher/genética , Enfermedad de Gaucher/metabolismo , Predisposición Genética a la Enfermedad , Glucosilceramidasa/genética , Heterocigoto , Homocigoto , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Mutación , Neostriado/metabolismo , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/metabolismo , Tomografía de Emisión de PositronesRESUMEN
BACKGROUND: Although the association between mutations in GBA1 and parkinsonism is well established, most GBA1 mutation carriers never develop parkinsonism, implicating the contribution of other genetic, epigenetic, and/or environmental modifiers. OBJECTIVES: To identify factors predisposing to or offering protection from parkinsonism among siblings with Gaucher's disease) discordant for Parkinson disease (PD). METHODS: This prospective, longitudinal study included nine sib pairs with Gaucher disease, but discordant for PD. Assessments included neurological, neuropsychological, olfactory, motor, nonmotor evaluations, and transcranial sonography. Validated mood and nonmotor questionnaires assessed fatigue, olfactory dysfunction, sleepiness, sleep disturbances, anxiety, and/or depression. RESULTS: There was no relationship between Gaucher treatments, genotype, or splenectomy and PD. Male sex predominance, younger age, and milder Gaucher disease symptoms were observed among the patients with PD. Substantia nigral echogenicity, olfactory dysfunction, serum triglycerides levels, and 9-hole peg scores, but not caffeine, alcohol, or tobacco use, environmental exposures, uric acid, or glucose levels, differed significantly between groups. CONCLUSIONS: Longitudinal evaluation of discordant sib pairs may help identify PD risk factors. © 2019 International Parkinson and Movement Disorder Society.
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Enfermedad de Gaucher/genética , Glucosilceramidasa/genética , Trastornos Parkinsonianos/genética , Adulto , Femenino , Enfermedad de Gaucher/diagnóstico , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Mutación/genética , Trastornos Parkinsonianos/diagnóstico , Factores de Riesgo , HermanosRESUMEN
BACKGROUND: 17q12 deletion syndrome encompasses a broad constellation of clinical phenotypes, including renal magnesium wasting, maturity-onset diabetes of the young (MODY), renal cysts, genitourinary malformations, and neuropsychiatric illness. Manifestations outside of the renal, endocrine, and nervous systems have not been well described. CASE PRESENTATION: We report a 62-year-old male referred to the Undiagnosed Diseases Program (UDP) at the National Institutes of Health (NIH) who presented with persistent hypermagnesiuric hypomagnesemia and was found to have a 17q12 deletion. The patient exhibited several known manifestations of the syndrome, including severe hypomagnesemia, renal cysts, diabetes and cognitive deficits. Coronary CT revealed extensive coronary calcifications, with a coronary artery calcification score of 12,427. Vascular calcifications have not been previously reported in this condition. We describe several physiologic mechanisms and a review of literature to support the expansion of the 17q12 deletion syndrome to include vascular calcification. CONCLUSION: Extensive coronary and vascular calcifications may be an extension of the 17q12 deletion phenotype, particularly if hypomagnesemia and hyperparathyroidism are prevalent. In patients with 17q12 deletions involving HNF1B, hyperparathyroidism and hypomagnesemia may contribute to significant cardiovascular risk.
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Enfermedad Coronaria/genética , Factor Nuclear 1-beta del Hepatocito/genética , Defectos Congénitos del Transporte Tubular Renal/genética , Síndrome de Smith-Magenis/genética , Deleción Cromosómica , Cromosomas Humanos Par 17/genética , Enfermedad Coronaria/complicaciones , Enfermedad Coronaria/diagnóstico por imagen , Humanos , Masculino , Persona de Mediana Edad , Defectos Congénitos del Transporte Tubular Renal/complicaciones , Defectos Congénitos del Transporte Tubular Renal/diagnóstico por imagen , Síndrome de Smith-Magenis/complicaciones , Síndrome de Smith-Magenis/diagnóstico por imagenRESUMEN
Aminoacyl-tRNA synthetases (ARSs) are essential enzymes responsible for charging tRNA molecules with cognate amino acids. Consistent with the essential function and ubiquitous expression of ARSs, mutations in 32 of the 37 ARS-encoding loci cause severe, early-onset recessive phenotypes. Previous genetic and functional data suggest a loss-of-function mechanism; however, our understanding of the allelic and locus heterogeneity of ARS-related disease is incomplete. Cysteinyl-tRNA synthetase (CARS) encodes the enzyme that charges tRNACys with cysteine in the cytoplasm. To date, CARS variants have not been implicated in any human disease phenotype. Here, we report on four subjects from three families with complex syndromes that include microcephaly, developmental delay, and brittle hair and nails. Each affected person carries bi-allelic CARS variants: one individual is compound heterozygous for c.1138C>T (p.Gln380∗) and c.1022G>A (p.Arg341His), two related individuals are compound heterozygous for c.1076C>T (p.Ser359Leu) and c.1199T>A (p.Leu400Gln), and one individual is homozygous for c.2061dup (p.Ser688Glnfs∗2). Measurement of protein abundance, yeast complementation assays, and assessments of tRNA charging indicate that each CARS variant causes a loss-of-function effect. Compared to subjects with previously reported ARS-related diseases, individuals with bi-allelic CARS variants are unique in presenting with a brittle-hair-and-nail phenotype, which most likely reflects the high cysteine content in human keratins. In sum, our efforts implicate CARS variants in human inherited disease, expand the locus and clinical heterogeneity of ARS-related clinical phenotypes, and further support impaired tRNA charging as the primary mechanism of recessive ARS-related disease.
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Aminoacil-ARNt Sintetasas/genética , Enfermedad de Charcot-Marie-Tooth/etiología , Discapacidades del Desarrollo/etiología , Enfermedades del Cabello/etiología , Microcefalia/etiología , Mutación , Enfermedades de la Uña/etiología , Adulto , Secuencia de Aminoácidos , Enfermedad de Charcot-Marie-Tooth/enzimología , Enfermedad de Charcot-Marie-Tooth/patología , Discapacidades del Desarrollo/enzimología , Discapacidades del Desarrollo/patología , Femenino , Genes Recesivos , Predisposición Genética a la Enfermedad , Enfermedades del Cabello/enzimología , Enfermedades del Cabello/patología , Humanos , Masculino , Microcefalia/enzimología , Microcefalia/patología , Enfermedades de la Uña/enzimología , Enfermedades de la Uña/patología , Linaje , Fenotipo , Pronóstico , Homología de Secuencia , Adulto JovenRESUMEN
BACKGROUND: Copa syndrome is a rare autosomal dominant disorder with abnormal intracellular vesicle trafficking. The objective of this work is to expand the knowledge about this disorder by delineating phenotypic features of an unreported COPA family. METHODS AND RESULTS: A heterozygous missense variant (c.698 G>A, p.Arg233His) in COPA was identified in four members of a three-generation kindred with lung, autoimmune and malignant disease of unknown aetiology. Ages of onset were 56, 26, 16 and 1 year, with earlier age of onset in successive generations. Presenting symptoms were cough and dyspnoea. Findings included small lung cysts, follicular bronchiolitis, interstitial lung disease, neuroendocrine cell hyperplasia, rheumatoid arthritis, avascular necrosis and select abnormal autoimmune serologies. Neither alveolar haemorrhage nor glomerular disease were present. Features not previously associated with Copa syndrome included neuromyelitis optica, pulmonary carcinoid tumour, clear cell renal carcinoma, renal cysts, hepatic cysts, nephrolithiasis, pyelonephritis and meningitis. Longitudinal evaluations demonstrated slow progression of lung disease and extrapulmonary cysts. CONCLUSIONS: Worsening severity with successive generations may be observed in Copa syndrome. Extrapulmonary cysts, malignancies, autoimmune neurological disorders and infections are clinical features that may be associated with Copa syndrome. Further studies are indicated to fully define the phenotypic spectrum of this disorder.
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Enfermedades Renales/genética , Enfermedades Pulmonares Intersticiales/genética , Mutación Missense/genética , Adolescente , Adulto , Femenino , Heterocigoto , Humanos , Lactante , Estudios Longitudinales , Pulmón/patología , Masculino , Persona de Mediana Edad , Linaje , Fenotipo , SíndromeRESUMEN
OBJECTIVE: To describe the features of 2 unrelated adults with xeroderma pigmentosum complementation group F (XP-F) ascertained in a neurology care setting. METHODS: We report the clinical, imaging, molecular, and nucleotide excision repair (NER) capacity of 2 middle-aged women with progressive neurodegeneration ultimately diagnosed with XP-F. RESULTS: Both patients presented with adult-onset progressive neurologic deterioration involving chorea, ataxia, hearing loss, cognitive deficits, profound brain atrophy, and a history of skin photosensitivity, skin freckling, and/or skin neoplasms. We identified compound heterozygous pathogenic mutations in ERCC4 and confirmed deficient NER capacity in skin fibroblasts from both patients. CONCLUSIONS: These cases illustrate the role of NER dysfunction in neurodegeneration and how adult-onset neurodegeneration could be the major symptom bringing XP-F patients to clinical attention. XP-F should be considered by neurologists in the differential diagnosis of patients with adult-onset progressive neurodegeneration accompanied by global brain atrophy and a history of heightened sun sensitivity, excessive freckling, and skin malignancies.
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Traditionally, the use of genomic information for personalized medical decisions relies on prior discovery and validation of genotype-phenotype associations. This approach constrains care for patients presenting with undescribed problems. The National Institutes of Health (NIH) Undiagnosed Diseases Program (UDP) hypothesized that defining disease as maladaptation to an ecological niche allows delineation of a logical framework to diagnose and evaluate such patients. Herein, we present the philosophical bases, methodologies, and processes implemented by the NIH UDP. The NIH UDP incorporated use of the Human Phenotype Ontology, developed a genomic alignment strategy cognizant of parental genotypes, pursued agnostic biochemical analyses, implemented functional validation, and established virtual villages of global experts. This systematic approach provided a foundation for the diagnostic or non-diagnostic answers provided to patients and serves as a paradigm for scalable translational research.
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OBJECTIVE: To delineate the developmental and progressive neurodegenerative features in 9 young adults with the atypical form of Chediak-Higashi disease (CHD) enrolled in a natural history study. METHODS: Patients with atypical clinical features, but diagnostically confirmed CHD by standard evaluation of blood smears and molecular genotyping, underwent complete neurologic evaluation, MRI of the brain, electrophysiologic examination, and neuropsychological testing. Fibroblasts were collected to investigate the cellular phenotype and correlation with the clinical presentation. RESULTS: In 9 mildly affected patients with CHD, we documented learning and behavioral difficulties along with developmental structural abnormalities of the cerebellum and posterior fossa, which are apparent early in childhood. A range of progressive neurologic problems emerge in early adulthood, including cerebellar deficits, polyneuropathies, spasticity, cognitive decline, and parkinsonism. CONCLUSIONS: Patients with undiagnosed atypical CHD manifesting some of these wide-ranging yet nonspecific neurologic complaints may reside in general and specialty neurology clinics. The absence of the typical bleeding or infectious diathesis in mildly affected patients with CHD renders them difficult to diagnose. Identification of these individuals is important not only for close surveillance of potential CHD-related systemic complications but also for a full understanding of the natural history of CHD and the potential role of the disease-causing protein, LYST, to the pathophysiology of other neurodevelopmental and neurodegenerative disorders.
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INTRODUCTION: Chediak-Higashi disease (CHD) is a rare autosomal recessive disorder with hematologic, infectious, pigmentary, and neurologic manifestations. Classic CHD (C-CHD) presents in early childhood with severe infectious or hematologic complications unless treated with bone marrow transplantation. Atypical CHD (A-CHD) has less severe hematologic and infectious manifestations. Both C-CHD and A-CHD develop neurological problems. METHODS: Eighteen patients with CHD (9 A-CHD and 9 C-CHD) underwent electrodiagnostic studies as part of a natural history study (NCT 00005917). Longitudinal studies were available for 10 patients. RESULTS: All A-CHD patients had either sensory neuropathy, sensorimotor neuropathy, and/or diffuse neurogenic findings. In C-CHD, 3 adults had sensorimotor neuropathies with diffuse neurogenic findings, and 1 adult had a sensory neuropathy. The 5 children with C-CHD had normal electrodiagnostic findings. CONCLUSIONS: CHD can result in sensory or sensorimotor neuropathies and/or a diffuse motor neuronopathy. It may take 2-3 decades for the neuropathic findings to develop, because children appear to be spared. Muscle Nerve 55: 359-365, 2017.
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Potenciales de Acción/fisiología , Síndrome de Chediak-Higashi/patología , Conducción Nerviosa/fisiología , Sistema Nervioso Periférico/fisiopatología , Adolescente , Adulto , Niño , Preescolar , Electromiografía , Femenino , Humanos , Masculino , Adulto JovenRESUMEN
OBJECTIVE: The goal of this study was to characterize the parkinsonian phenotype in patients with Gaucher disease (GD) who developed parkinsonism in order to evaluate clinical course and prognosis. METHODS: This is a retrospective observational study conducted at the Clinical Center of the NIH, Bethesda, MD, over a period of 10 years. The study included 19 patients with GD and parkinsonism. The severity of Gaucher and parkinsonian symptoms was determined from clinical data including physical, neurologic, pathologic, and neurocognitive evaluations, family histories, imaging studies, olfactory testing, and validated questionnaires. RESULTS: We found an earlier age at onset of parkinsonism and evidence of mild cognitive dysfunction in our cohort. Although the clinical course in some patients was similar to that of idiopathic Parkinson disease with a favorable levodopa response, others exhibited features characteristic of dementia with Lewy bodies. When we examined the patients as a group, we did not observe a uniformly aggressive form of parkinsonism after the initial onset of symptoms, contrary to other published reports. CONCLUSIONS: Appreciable clinical variation was seen in this cohort with GD and parkinsonism. Although some patients had early onset and prominent cognitive changes, others had a later, slower course, indicating that GBA1 mutations may not be a reliable prognostic indicator in Parkinson disease in clinical settings.
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OBJECTIVE: To delineate the developmental and progressive neurodegenerative features in 9 young adults with the atypical form of Chediak-Higashi disease (CHD) enrolled in a natural history study. METHODS: Patients with atypical clinical features, but diagnostically confirmed CHD by standard evaluation of blood smears and molecular genotyping, underwent complete neurologic evaluation, MRI of the brain, electrophysiologic examination, and neuropsychological testing. Fibroblasts were collected to investigate the cellular phenotype and correlation with the clinical presentation. RESULTS: In 9 mildly affected patients with CHD, we documented learning and behavioral difficulties along with developmental structural abnormalities of the cerebellum and posterior fossa, which are apparent early in childhood. A range of progressive neurologic problems emerge in early adulthood, including cerebellar deficits, polyneuropathies, spasticity, cognitive decline, and parkinsonism. CONCLUSIONS: Patients with undiagnosed atypical CHD manifesting some of these wide-ranging yet nonspecific neurologic complaints may reside in general and specialty neurology clinics. The absence of the typical bleeding or infectious diathesis in mildly affected patients with CHD renders them difficult to diagnose. Identification of these individuals is important not only for close surveillance of potential CHD-related systemic complications but also for a full understanding of the natural history of CHD and the potential role of the disease-causing protein, LYST, to the pathophysiology of other neurodevelopmental and neurodegenerative disorders.