ABSTRACT
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.
Subject(s)
Nodding Syndrome , Onchocerciasis , United States , Humans , Cohort Studies , Immunomodulation , GenomicsABSTRACT
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.
Subject(s)
Amino Acyl-tRNA Synthetases/genetics , Charcot-Marie-Tooth Disease/etiology , Developmental Disabilities/etiology , Hair Diseases/etiology , Microcephaly/etiology , Mutation , Nail Diseases/etiology , Adult , Amino Acid Sequence , Charcot-Marie-Tooth Disease/enzymology , Charcot-Marie-Tooth Disease/pathology , Developmental Disabilities/enzymology , Developmental Disabilities/pathology , Female , Genes, Recessive , Genetic Predisposition to Disease , Hair Diseases/enzymology , Hair Diseases/pathology , Humans , Male , Microcephaly/enzymology , Microcephaly/pathology , Nail Diseases/enzymology , Nail Diseases/pathology , Pedigree , Phenotype , Prognosis , Sequence Homology , Young AdultABSTRACT
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..
Subject(s)
Cardiopulmonary Resuscitation , Intensive Care Units, Pediatric , Child , Hospitals , Humans , Infant, Newborn , Intensive Care Units, Neonatal , Retrospective Studies , Tertiary HealthcareABSTRACT
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.
Subject(s)
Dopamine/biosynthesis , Gaucher Disease/diagnostic imaging , Neostriatum/diagnostic imaging , Parkinson Disease/diagnostic imaging , Adult , Aged , Case-Control Studies , Dihydroxyphenylalanine/analogs & derivatives , Female , Gaucher Disease/genetics , Gaucher Disease/metabolism , Genetic Predisposition to Disease , Glucosylceramidase/genetics , Heterozygote , Homozygote , Humans , Longitudinal Studies , Male , Middle Aged , Mutation , Neostriatum/metabolism , Parkinson Disease/genetics , Parkinson Disease/metabolism , Positron-Emission TomographyABSTRACT
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.
Subject(s)
Congenital Abnormalities/genetics , Ichthyosis/genetics , Serine/biosynthesis , Transaminases/genetics , Adult , Child, Preschool , Congenital Abnormalities/pathology , Female , Fetal Growth Retardation/genetics , Fetal Growth Retardation/metabolism , Fetal Growth Retardation/pathology , Humans , Ichthyosis/metabolism , Ichthyosis/pathology , Limb Deformities, Congenital/genetics , Limb Deformities, Congenital/pathology , Microcephaly/genetics , Microcephaly/pathology , Psychomotor Disorders/genetics , Psychomotor Disorders/pathology , Seizures/genetics , Seizures/pathology , Serine/deficiency , Serine/genetics , Sphingolipids/deficiency , Sphingolipids/genetics , Transaminases/deficiency , Exome SequencingABSTRACT
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.
Subject(s)
Electron Transport Complex I/genetics , Leigh Disease/genetics , Mitochondria/genetics , Mitochondrial Proteins/genetics , NADH Dehydrogenase/genetics , Adolescent , Adult , Alleles , Child , Female , Genetic Predisposition to Disease , Humans , Leigh Disease/pathology , Male , Mutation/genetics , Pedigree , RNA Splicing/genetics , Young AdultABSTRACT
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.
Subject(s)
Gaucher Disease/genetics , Glucosylceramidase/genetics , Parkinsonian Disorders/genetics , Adult , Female , Gaucher Disease/diagnosis , Humans , Longitudinal Studies , Male , Middle Aged , Mutation/genetics , Parkinsonian Disorders/diagnosis , Risk Factors , SiblingsABSTRACT
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.
Subject(s)
Kidney Diseases/genetics , Lung Diseases, Interstitial/genetics , Mutation, Missense/genetics , Adolescent , Adult , Female , Heterozygote , Humans , Infant , Longitudinal Studies , Lung/pathology , Male , Middle Aged , Pedigree , Phenotype , SyndromeABSTRACT
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.
Subject(s)
Coronary Disease/genetics , Hepatocyte Nuclear Factor 1-beta/genetics , Renal Tubular Transport, Inborn Errors/genetics , Smith-Magenis Syndrome/genetics , Chromosome Deletion , Chromosomes, Human, Pair 17/genetics , Coronary Disease/complications , Coronary Disease/diagnostic imaging , Humans , Male , Middle Aged , Renal Tubular Transport, Inborn Errors/complications , Renal Tubular Transport, Inborn Errors/diagnostic imaging , Smith-Magenis Syndrome/complications , Smith-Magenis Syndrome/diagnostic imagingABSTRACT
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.
Subject(s)
Action Potentials/physiology , Chediak-Higashi Syndrome/pathology , Neural Conduction/physiology , Peripheral Nervous System/physiopathology , Adolescent , Adult , Child , Child, Preschool , Electromyography , Female , Humans , Male , Young AdultABSTRACT
PURPOSE: Medical diagnosis and molecular or biochemical confirmation typically rely on the knowledge of the clinician. Although this is very difficult in extremely rare diseases, we hypothesized that the recording of patient phenotypes in Human Phenotype Ontology (HPO) terms and computationally ranking putative disease-associated sequence variants improves diagnosis, particularly for patients with atypical clinical profiles. METHODS: Using simulated exomes and the National Institutes of Health Undiagnosed Diseases Program (UDP) patient cohort and associated exome sequence, we tested our hypothesis using Exomiser. Exomiser ranks candidate variants based on patient phenotype similarity to (i) known disease-gene phenotypes, (ii) model organism phenotypes of candidate orthologs, and (iii) phenotypes of protein-protein association neighbors. RESULTS: Benchmarking showed Exomiser ranked the causal variant as the top hit in 97% of known disease-gene associations and ranked the correct seeded variant in up to 87% when detectable disease-gene associations were unavailable. Using UDP data, Exomiser ranked the causative variant(s) within the top 10 variants for 11 previously diagnosed variants and achieved a diagnosis for 4 of 23 cases undiagnosed by clinical evaluation. CONCLUSION: Structured phenotyping of patients and computational analysis are effective adjuncts for diagnosing patients with genetic disorders.Genet Med 18 6, 608-617.
Subject(s)
Exome Sequencing/methods , Exome/genetics , Rare Diseases/genetics , Rare Diseases/physiopathology , Animals , Computational Biology , Databases, Genetic , Disease Models, Animal , Genetic Association Studies , Genetic Variation , Humans , Mice , National Institutes of Health (U.S.) , Patients , Phenotype , Rare Diseases/diagnosis , Rare Diseases/epidemiology , United States , ZebrafishABSTRACT
Patients with generalized arterial calcification of infancy (GACI) develop vascular calcifications early in life. About half of them die within the first 6 months despite optimal medical care. A subset of those who survive eventually develop hypophosphatemic rickets. Since hypophosphatemia and hyperphosphaturia have been previously associated with increased survival in GACI patients, physicians often avoid phosphate repletion as treatment for rickets. As a consequence, GACI patients develop severe rachitic complications such as short stature and skeletal deformities. It appears that the recognition of hypophosphatemia later in life in some GACI patients is a consequence of having survived the first few months of life, and not the cause of their survival per se. Here, we report the long-term follow-up of a GACI patient who was phosphate-repleted for his rickets for more than 7 years without worsening of vascular calcification.
Subject(s)
Phosphoric Diester Hydrolases/genetics , Pyrophosphatases/genetics , Rickets, Hypophosphatemic/drug therapy , Vascular Calcification/drug therapy , Adolescent , Adult , Child , Follow-Up Studies , Humans , Male , Mutation , Phosphates/administration & dosage , Rickets, Hypophosphatemic/genetics , Rickets, Hypophosphatemic/physiopathology , Vascular Calcification/genetics , Vascular Calcification/physiopathologyABSTRACT
Gaucher disease, the inherited deficiency of the enzyme glucocerebrosidase, is the most common of the lysosomal storage disorders. Type 2 Gaucher disease, the most severe and progressive form, manifests either prenatally or in the first months of life, followed by death within the first years of life. The rarity of the many lysosomal storage disorders makes their diagnosis a challenge, especially in the newborn period when the focus is often on more prevalent illnesses. Thus, a heightened awareness of the presentation of these rare diseases is necessary to ensure their timely consideration. This review, designed to serve as a guide to physicians treating newborns and infants with Gaucher disease, discusses the presenting manifestations of Type 2 Gaucher disease, the diagnostic work-up, associated genotypes and suggestions for management. We also address the ethical concerns that may arise with this progressive and lethal disorder, since currently available treatments may prolong life, but do not impact the neurological manifestations of the disease.
Subject(s)
Gaucher Disease/diagnosis , Gaucher Disease/therapy , Glucosylceramidase/deficiency , Disease Management , Genotype , Glucosylceramidase/genetics , Humans , Infant , Infant, NewbornABSTRACT
BACKGROUND: Arterial calcifications are associated with increased cardiovascular risk, but the genetic basis of this association is unclear. METHODS: We performed clinical, radiographic, and genetic studies in three families with symptomatic arterial calcifications. Single-nucleotide-polymorphism analysis, targeted gene sequencing, quantitative polymerase-chain-reaction assays, Western blotting, enzyme measurements, transduction rescue experiments, and in vitro calcification assays were performed. RESULTS: We identified nine persons with calcifications of the lower-extremity arteries and hand and foot joint capsules: all five siblings in one family, three siblings in another, and one patient in a third family. Serum calcium, phosphate, and vitamin D levels were normal. Affected members of Family 1 shared a single 22.4-Mb region of homozygosity on chromosome 6 and had a homozygous nonsense mutation (c.662CâA, p.S221X) in NT5E, encoding CD73, which converts AMP to adenosine. Affected members of Family 2 had a homozygous missense mutation (c.1073GâA, p.C358Y) in NT5E. The proband of Family 3 was a compound heterozygote for c.662CâA and c.1609dupA (p.V537fsX7). All mutations found in the three families result in nonfunctional CD73. Cultured fibroblasts from affected members of Family 1 showed markedly reduced expression of NT5E messenger RNA, CD73 protein, and enzyme activity, as well as increased alkaline phosphatase levels and accumulated calcium phosphate crystals. Genetic rescue experiments normalized the CD73 and alkaline phosphatase activity in patients' cells, and adenosine treatment reduced the levels of alkaline phosphatase and calcification. CONCLUSIONS: We identified mutations in NT5E in members of three families with symptomatic arterial and joint calcifications. This gene encodes CD73, which converts AMP to adenosine, supporting a role for this metabolic pathway in inhibiting ectopic tissue calcification. (Funded by the National Human Genome Research Institute and the National Heart, Lung, and Blood Institute of the National Institutes of Health.).
Subject(s)
5'-Nucleotidase/genetics , Atherosclerosis/genetics , Calcinosis/genetics , Joint Diseases/genetics , Mutation , 5'-Nucleotidase/metabolism , Arteries/pathology , Chromosomes, Human, Pair 6 , Codon, Nonsense , DNA Mutational Analysis , Female , Fibroblasts/metabolism , Genotype , Humans , Intermittent Claudication/genetics , Lower Extremity/blood supply , Lower Extremity/diagnostic imaging , Mutation, Missense , Polymorphism, Single Nucleotide , RNA, Messenger/metabolism , RadiographyABSTRACT
PURPOSE: Using exome sequence data from 159 families participating in the National Institutes of Health Undiagnosed Diseases Program, we evaluated the number and inheritance mode of reportable incidental sequence variants. METHODS: Following the American College of Medical Genetics and Genomics recommendations for reporting of incidental findings from next-generation sequencing, we extracted variants in 56 genes from the exome sequence data of 543 subjects and determined the reportable incidental findings for each participant. We also defined variant status as inherited or de novo for those with available parental sequence data. RESULTS: We identified 14 independent reportable variants in 159 (8.8%) families. For nine families with parental sequence data in our cohort, a parent transmitted the variant to one or more children (nine minor children and four adult children). The remaining five variants occurred in adults for whom parental sequences were unavailable. CONCLUSION: Our results are consistent with the expectation that a small percentage of exomes will result in identification of an incidental finding under the American College of Medical Genetics and Genomics recommendations. Additionally, our analysis of family sequence data highlights that genome and exome sequencing of families has unavoidable implications for immediate family members and therefore requires appropriate counseling for the family.
Subject(s)
Exome/genetics , Genetic Predisposition to Disease/genetics , Genetic Variation , Sequence Analysis, DNA/methods , Adolescent , Adult , Child , Cohort Studies , Family Health , Female , Genetic Counseling , Genetic Diseases, Inborn/diagnosis , Genetic Diseases, Inborn/genetics , Genome, Human/genetics , Humans , Incidental Findings , Male , Metabolism, Inborn Errors/diagnosis , Metabolism, Inborn Errors/genetics , Middle Aged , National Institutes of Health (U.S.) , United States , Young AdultABSTRACT
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.
Subject(s)
Genetic Testing , Intensive Care Units, Neonatal , Humans , Infant, Newborn , Parents/psychologyABSTRACT
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.
Subject(s)
Intensive Care Units, Neonatal , Parents , Terminal Care , Humans , Infant, Newborn , Retrospective Studies , Female , Male , Parents/psychology , Withholding Treatment , Palliative CareABSTRACT
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.
ABSTRACT
Mutations in GBA, the gene encoding glucocerebrosidase, the enzyme deficient in Gaucher disease, are common risk factors for Parkinson disease, as patients with Parkinson disease are over five times more likely to carry GBA mutations than healthy controls. Patients with GBA mutations generally have an earlier onset of Parkinson disease and more cognitive impairment than those without GBA mutations. We investigated whether GBA mutations alter the neurobiology of Parkinson disease, studying brain dopamine synthesis and resting regional cerebral blood flow in 107 subjects (38 women, 69 men). We measured dopamine synthesis with (18)F-fluorodopa positron emission tomography, and resting regional cerebral blood flow with H(2)(15)O positron emission tomography in the wakeful, resting state in four study groups: (i) patients with Parkinson disease and Gaucher disease (n = 7, average age = 56.6 ± 9.2 years); (ii) patients with Parkinson disease without GBA mutations (n = 11, 62.1 ± 7.1 years); (iii) patients with Gaucher disease without parkinsonism, but with a family history of Parkinson disease (n = 14, 52.6 ± 12.4 years); and (iv) healthy GBA-mutation carriers with a family history of Parkinson disease (n = 7, 50.1 ± 18 years). We compared each study group with a matched control group. Data were analysed with region of interest and voxel-based methods. Disease duration and Parkinson disease functional and staging scores were similar in the two groups with parkinsonism, as was striatal dopamine synthesis: both had greatest loss in the caudal striatum (putamen Ki loss: 44 and 42%, respectively), with less reduction in the caudate (20 and 18% loss). However, the group with both Parkinson and Gaucher diseases showed decreased resting regional cerebral blood flow in the lateral parieto-occipital association cortex and precuneus bilaterally. Furthermore, two subjects with Gaucher disease without parkinsonian manifestations showed diminished striatal dopamine. In conclusion, the pattern of dopamine loss in patients with both Parkinson and Gaucher disease was similar to sporadic Parkinson disease, indicating comparable damage in midbrain neurons. However, H(2)(15)O positron emission tomography studies indicated that these subjects have decreased resting activity in a pattern characteristic of diffuse Lewy body disease. These findings provide insight into the pathophysiology of GBA-associated parkinsonism.
Subject(s)
Cerebrovascular Circulation/physiology , Dopamine/biosynthesis , Glucosylceramidase/metabolism , Parkinsonian Disorders/diagnostic imaging , Parkinsonian Disorders/enzymology , Positron-Emission Tomography , Adolescent , Adult , Aged , Female , Glucosylceramidase/genetics , Humans , Male , Middle Aged , Mutation/physiology , Parkinsonian Disorders/genetics , Positron-Emission Tomography/methods , Young AdultABSTRACT
PURPOSE: This report describes the National Institutes of Health Undiagnosed Diseases Program, details the Program's application of genomic technology to establish diagnoses, and details the Program's success rate during its first 2 years. METHODS: Each accepted study participant was extensively phenotyped. A subset of participants and selected family members (29 patients and 78 unaffected family members) was subjected to an integrated set of genomic analyses including high-density single-nucleotide polymorphism arrays and whole exome or genome analysis. RESULTS: Of 1,191 medical records reviewed, 326 patients were accepted and 160 were admitted directly to the National Institutes of Health Clinical Center on the Undiagnosed Diseases Program service. Of those, 47% were children, 55% were females, and 53% had neurologic disorders. Diagnoses were reached on 39 participants (24%) on clinical, biochemical, pathologic, or molecular grounds; 21 diagnoses involved rare or ultra-rare diseases. Three disorders were diagnosed based on single-nucleotide polymorphism array analysis and three others using whole exome sequencing and filtering of variants. Two new disorders were discovered. Analysis of the single-nucleotide polymorphism array study cohort revealed that large stretches of homozygosity were more common in affected participants relative to controls. CONCLUSION: The National Institutes of Health Undiagnosed Diseases Program addresses an unmet need, i.e., the diagnosis of patients with complex, multisystem disorders. It may serve as a model for the clinical application of emerging genomic technologies and is providing insights into the characteristics of diseases that remain undiagnosed after extensive clinical workup.