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BACKGROUND: Biallelic ZBTB11 variants have previously been associated with an ultrarare subtype of autosomal recessive intellectual developmental disorder (MRT69). OBJECTIVE: The aim was to provide insights into the clinical and genetic characteristics of ZBTB11-related disorders (ZBTB11-RD), with a particular emphasis on progressive complex movement abnormalities. METHODS: Thirteen new and 16 previously reported affected individuals, ranging in age from 2 to 50 years, with biallelic ZBTB11 variants underwent clinical and genetic characterization. RESULTS: All patients exhibited a range of neurodevelopmental phenotypes with varying severity, encompassing ocular and neurological features. Eleven new patients presented with complex abnormal movements, including ataxia, dystonia, myoclonus, stereotypies, and tremor, and 7 new patients exhibited cataracts. Deep brain stimulation was successful in treating 1 patient with generalized progressive dystonia. Our analysis revealed 13 novel variants. CONCLUSIONS: This study provides additional insights into the clinical features and spectrum of ZBTB11-RD, highlighting the progressive nature of movement abnormalities in the background of neurodevelopmental phenotype. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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In the field of rare diseases, progress in molecular diagnostics led to the recognition that variants linked to autosomal-dominant neurodegenerative diseases of later onset can, in the context of biallelic inheritance, cause devastating neurodevelopmental disorders and infantile or childhood-onset neurodegeneration. TOR1A-associated arthrogryposis multiplex congenita 5 (AMC5) is a rare neurodevelopmental disorder arising from biallelic variants in TOR1A, a gene that in the heterozygous state is associated with torsion dystonia-1 (DYT1 or DYT-TOR1A), an early-onset dystonia with reduced penetrance. While 15 individuals with AMC5-TOR1A have been reported (less than 10 in detail), a systematic investigation of the full disease-associated spectrum has not been conducted. Here, we assess the clinical, radiological and molecular characteristics of 57 individuals from 40 families with biallelic variants in TOR1A. Median age at last follow-up was 3 years (0-24 years). Most individuals presented with severe congenital flexion contractures (95%) and variable developmental delay (79%). Motor symptoms were reported in 79% and included lower limb spasticity and pyramidal signs, as well as gait disturbances. Facial dysmorphism was an integral part of the phenotype, with key features being a broad/full nasal tip, narrowing of the forehead and full cheeks. Analysis of disease-associated manifestations delineated a phenotypic spectrum ranging from normal cognition and mild gait disturbance to congenital arthrogryposis, global developmental delay, intellectual disability, absent speech and inability to walk. In a subset, the presentation was consistent with foetal akinesia deformation sequence with severe intrauterine abnormalities. Survival was 71%, with higher mortality in males. Death occurred at a median age of 1.2 months (1 week-9 years), due to respiratory failure, cardiac arrest or sepsis. Analysis of brain MRI studies identified non-specific neuroimaging features, including a hypoplastic corpus callosum (72%), foci of signal abnormality in the subcortical and periventricular white matter (55%), diffuse white matter volume loss (45%), mega cisterna magna (36%) and arachnoid cysts (27%). The molecular spectrum included 22 distinct variants, defining a mutational hotspot in the C-terminal domain of the Torsin-1A protein. Genotype-phenotype analysis revealed an association of missense variants in the 3-helix bundle domain to an attenuated phenotype, while missense variants near the Walker A/B motif as well as biallelic truncating variants were linked to early death. In summary, this systematic cross-sectional analysis of a large cohort of individuals with biallelic TOR1A variants across a wide age-range delineates the clinical and genetic spectrum of TOR1A-related autosomal-recessive disease and highlights potential predictors for disease severity and survival.
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Distonía , Trastornos Distónicos , Malformaciones del Sistema Nervioso , Masculino , Humanos , Estudios Transversales , Mutación/genética , Fenotipo , Distonía/genética , Trastornos Distónicos/genética , Chaperonas Moleculares/genéticaRESUMEN
Vacuolar-type H+-ATPase (V-ATPase) is a multimeric complex present in a variety of cellular membranes that acts as an ATP-dependent proton pump and plays a key role in pH homeostasis and intracellular signalling pathways. In humans, 22 autosomal genes encode for a redundant set of subunits allowing the composition of diverse V-ATPase complexes with specific properties and expression. Sixteen subunits have been linked to human disease. Here we describe 26 patients harbouring 20 distinct pathogenic de novo missense ATP6V1A variants, mainly clustering within the ATP synthase α/ß family-nucleotide-binding domain. At a mean age of 7 years (extremes: 6 weeks, youngest deceased patient to 22 years, oldest patient) clinical pictures included early lethal encephalopathies with rapidly progressive massive brain atrophy, severe developmental epileptic encephalopathies and static intellectual disability with epilepsy. The first clinical manifestation was early hypotonia, in 70%; 81% developed epilepsy, manifested as developmental epileptic encephalopathies in 58% of the cohort and with infantile spasms in 62%; 63% of developmental epileptic encephalopathies failed to achieve any developmental, communicative or motor skills. Less severe outcomes were observed in 23% of patients who, at a mean age of 10 years and 6 months, exhibited moderate intellectual disability, with independent walking and variable epilepsy. None of the patients developed communicative language. Microcephaly (38%) and amelogenesis imperfecta/enamel dysplasia (42%) were additional clinical features. Brain MRI demonstrated hypomyelination and generalized atrophy in 68%. Atrophy was progressive in all eight individuals undergoing repeated MRIs. Fibroblasts of two patients with developmental epileptic encephalopathies showed decreased LAMP1 expression, Lysotracker staining and increased organelle pH, consistent with lysosomal impairment and loss of V-ATPase function. Fibroblasts of two patients with milder disease, exhibited a different phenotype with increased Lysotracker staining, decreased organelle pH and no significant modification in LAMP1 expression. Quantification of substrates for lysosomal enzymes in cellular extracts from four patients revealed discrete accumulation. Transmission electron microscopy of fibroblasts of four patients with variable severity and of induced pluripotent stem cell-derived neurons from two patients with developmental epileptic encephalopathies showed electron-dense inclusions, lipid droplets, osmiophilic material and lamellated membrane structures resembling phospholipids. Quantitative assessment in induced pluripotent stem cell-derived neurons identified significantly smaller lysosomes. ATP6V1A-related encephalopathy represents a new paradigm among lysosomal disorders. It results from a dysfunctional endo-lysosomal membrane protein causing altered pH homeostasis. Its pathophysiology implies intracellular accumulation of substrates whose composition remains unclear, and a combination of developmental brain abnormalities and neurodegenerative changes established during prenatal and early postanal development, whose severity is variably determined by specific pathogenic variants.
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Encefalopatías , Epilepsia , Discapacidad Intelectual , Espasmos Infantiles , ATPasas de Translocación de Protón Vacuolares , Adenosina Trifosfato , Atrofia , Niño , Homeostasis , Humanos , Lactante , Lisosomas , FenotipoRESUMEN
PURPOSE: To assess the magnitude of benefit to early treatment initiation, enabled by newborn screening or prenatal diagnosis, in patients with cross-reactive immunological material (CRIM)-negative infantile Pompe disease (IPD), treated with enzyme replacement therapy (ERT) and prophylactic immune tolerance induction (ITI) with rituximab, methotrexate, and intravenous immunoglobulin (IVIG). METHODS: A total of 41 CRIM-negative IPD patients were evaluated. Among patients who were treated with ERT + ITI (n = 30), those who were invasive ventilator-free at baseline and had ≥6 months of follow-up were stratified based on age at treatment initiation: (1) early (≤4 weeks), (2) intermediate (>4 and ≤15 weeks), and (3) late (>15 weeks). A historical cohort of 11 CRIM-negative patients with IPD treated with ERT monotherapy served as an additional comparator group. RESULTS: Twenty patients were included; five, seven, and eight in early, intermediate, and late treatment groups, respectively. Genotypes were similar across the three groups. Early-treated patients showed significant improvements in left ventricular mass index, motor and pulmonary outcomes, as well as biomarkers creatine kinase and urinary glucose tetrasaccharide, compared with those treated later. CONCLUSION: Our preliminary data suggest that early treatment with ERT + ITI can transform the long-term CRIM-negative IPD phenotype, which represents the most severe end of the Pompe disease spectrum.
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Enfermedad del Almacenamiento de Glucógeno Tipo II , Terapia de Reemplazo Enzimático , Femenino , Enfermedad del Almacenamiento de Glucógeno Tipo II/diagnóstico , Enfermedad del Almacenamiento de Glucógeno Tipo II/tratamiento farmacológico , Enfermedad del Almacenamiento de Glucógeno Tipo II/genética , Humanos , Tolerancia Inmunológica , Recién Nacido , Tamizaje Neonatal , Embarazo , Resultado del Tratamiento , alfa-Glucosidasas/genética , alfa-Glucosidasas/uso terapéuticoRESUMEN
SMARCA4 encodes a central ATPase subunit in the BRG1-/BRM-associated factors (BAF) or polybromo-associated BAF (PBAF) complex in humans, which is responsible in part for chromatin remodeling and transcriptional regulation. Variants in this and other genes encoding BAF/PBAF complexes have been implicated in Coffin-Siris Syndrome, a multiple congenital anomaly syndrome classically characterized by learning and developmental differences, coarse facial features, hypertrichosis, and underdevelopment of the fifth digits/nails of the hands and feet. Individuals with SMARCA4 variants have been previously reported and appear to display a variable phenotype. We describe here a cohort of 15 unrelated individuals with SMARCA4 variants from the Coffin-Siris syndrome/BAF pathway disorders registry who further display variability in severity and degrees of learning impairment and health issues. Within this cohort, we also report two individuals with novel nonsense variants who appear to have a phenotype of milder learning/behavioral differences and no organ-system involvement.
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Anomalías Múltiples/genética , ADN Helicasas/genética , Proteínas de Unión al ADN/genética , Cara/anomalías , Predisposición Genética a la Enfermedad , Deformidades Congénitas de la Mano/genética , Discapacidad Intelectual/genética , Micrognatismo/genética , Cuello/anomalías , Proteínas Nucleares/genética , Factores de Transcripción/genética , Anomalías Múltiples/epidemiología , Anomalías Múltiples/patología , Adolescente , Niño , Preescolar , Proteínas Cromosómicas no Histona/genética , Codón sin Sentido/genética , Cara/patología , Femenino , Estudios de Asociación Genética , Deformidades Congénitas de la Mano/epidemiología , Deformidades Congénitas de la Mano/patología , Humanos , Lactante , Discapacidad Intelectual/epidemiología , Discapacidad Intelectual/patología , Masculino , Micrognatismo/epidemiología , Micrognatismo/patología , Cuello/patología , FenotipoRESUMEN
SATB2-associated syndrome (SAS) is an autosomal dominant neurodevelopmental disorder caused by alterations in the SATB2 gene. Here we present a review of published pathogenic variants in the SATB2 gene to date and report 38 novel alterations found in 57 additional previously unreported individuals. Overall, we present a compilation of 120 unique variants identified in 155 unrelated families ranging from single nucleotide coding variants to genomic rearrangements distributed throughout the entire coding region of SATB2. Single nucleotide variants predicted to result in the occurrence of a premature stop codon were the most commonly seen (51/120 = 42.5%) followed by missense variants (31/120 = 25.8%). We review the rather limited functional characterization of pathogenic variants and discuss current understanding of the consequences of the different molecular alterations. We present an expansive phenotypic review along with novel genotype-phenotype correlations. Lastly, we discuss current knowledge of animal models and present future prospects. This review should help provide better guidance for the care of individuals diagnosed with SAS.
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Proteínas de Unión a la Región de Fijación a la Matriz/genética , Mutación , Trastornos del Neurodesarrollo/genética , Factores de Transcripción/genética , Adolescente , Animales , Niño , Preescolar , Codón de Terminación , Modelos Animales de Enfermedad , Femenino , Reordenamiento Génico , Estudios de Asociación Genética , Humanos , Masculino , Mutación Missense , Polimorfismo de Nucleótido SimpleRESUMEN
Mitochondrial DNA maintenance (mtDNA) defects have a wide range of causes, each with a set of phenotypes that overlap with many other neurological or muscular diseases. Clinicians face the challenge of narrowing down a long list of differential diagnosis when encountered with non-specific neuromuscular symptoms. Biallelic pathogenic variants in the Thymidine Kinase 2 (TK2) gene cause a myopathic form of mitochondrial DNA maintenance defect. Since the first description in 2001, there have been 71 patients reported with 42 unique pathogenic variants. Here we are reporting 11 new cases with 5 novel pathogenic variants. We describe and analyze a total of 82 cases with 47 unique TK2 pathogenic variants in effort to formulate a comprehensive molecular and clinical spectrum of TK2-related mtDNA maintenance disorders.
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ADN Mitocondrial/genética , Mitocondrias/genética , Enfermedades Mitocondriales/genética , Enfermedades Mitocondriales/patología , Enfermedades Musculares/genética , Enfermedades Musculares/patología , Mutación , Timidina Quinasa/genética , Adolescente , Adulto , Anciano , Niño , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Pronóstico , Adulto JovenRESUMEN
Previous reports have identified SLC6A1 variants in patients with generalized epilepsies, such as myoclonic-atonic epilepsy and childhood absence epilepsy. However, to date, none of the identified SLC6A1 variants has been functionally tested for an effect on GAT-1 transporter activity. The purpose of this study was to determine the incidence of SLC6A1 variants in 460 unselected epilepsy patients and to evaluate the impact of the identified variants on γ-aminobutyric acid (GABA)transport. Targeted resequencing was used to screen 460 unselected epilepsy patients for variants in SLC6A1. Five missense variants, one in-frame deletion, one nonsense variant, and one intronic splice-site variant were identified, representing a 1.7% diagnostic yield. Using a [3 H]-GABA transport assay, the seven identified exonic variants were found to reduce GABA transport activity. A minigene splicing assay revealed that the splice-site variant disrupted canonical splicing of exon 9 in the mRNA transcript, leading to premature protein truncation. These findings demonstrate that SLC6A1 is an important contributor to childhood epilepsy and that reduced GAT-1 function is a common consequence of epilepsy-causing SLC6A1 variants.
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Epilepsia/genética , Epilepsia/metabolismo , Proteínas Transportadoras de GABA en la Membrana Plasmática/metabolismo , Regulación de la Expresión Génica/genética , Mutación/genética , Estudios de Cohortes , Análisis Mutacional de ADN , Femenino , Proteínas Transportadoras de GABA en la Membrana Plasmática/genética , Predisposición Genética a la Enfermedad/genética , Células HEK293 , Células HeLa , Humanos , Masculino , ARN Mensajero/metabolismo , Transfección , Tritio/farmacocinética , Ácido gamma-Aminobutírico/metabolismoRESUMEN
SYNJ1 encodes a polyphosphoinositide phosphatase, synaptojanin 1, which contains two consecutive phosphatase domains and plays a prominent role in synaptic vesicle dynamics. Autosomal recessive inherited variants in SYNJ1 have previously been associated with two different neurological diseases: a recurrent homozygous missense variant (p.Arg258Gln) that abolishes Sac1 phosphatase activity was identified in three independent families with early onset parkinsonism, whereas a homozygous nonsense variant (p.Arg136*) causing a severe decrease of mRNA transcript was found in a single patient with intractable epilepsy and tau pathology. We performed whole exome or genome sequencing in three independent sib pairs with early onset refractory seizures and progressive neurological decline, and identified novel segregating recessive SYNJ1 defects. A homozygous missense variant resulting in an amino acid substitution (p.Tyr888Cys) was found to impair, but not abolish, the dual phosphatase activity of SYNJ1, whereas three premature stop variants (homozygote p.Trp843* and compound heterozygote p.Gln647Argfs*6/p.Ser1122Thrfs*3) almost completely abolished mRNA transcript production. A genetic follow-up screening in a large cohort of 543 patients with a wide phenotypical range of epilepsies and intellectual disability revealed no additional pathogenic variants, showing that SYNJ1 deficiency is rare and probably linked to a specific phenotype. While variants leading to early onset parkinsonism selectively abolish Sac1 function, our results provide evidence that a critical reduction of the dual phosphatase activity of SYNJ1 underlies a severe disorder with neonatal refractory epilepsy and a neurodegenerative disease course. These findings further expand the clinical spectrum of synaptic dysregulation in patients with severe epilepsy, and emphasize the importance of this biological pathway in seizure pathophysiology.
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Epilepsia Refractaria/genética , Proteínas del Tejido Nervioso/genética , Enfermedades Neurodegenerativas/genética , Monoéster Fosfórico Hidrolasas/genética , Edad de Inicio , Niño , Preescolar , Estudios de Cohortes , Consanguinidad , Exoma , Femenino , Humanos , Masculino , Linaje , FenotipoRESUMEN
Noonan syndrome is a common genetic disorder that causes multiple congenital abnormalities and a large number of potential health conditions. Most affected individuals have characteristic facial features that evolve with age; a broad, webbed neck; increased bleeding tendency; and a high incidence of congenital heart disease, failure to thrive, short stature, feeding difficulties, sternal deformity, renal malformation, pubertal delay, cryptorchidism, developmental or behavioral problems, vision problems, hearing loss, and lymphedema. Familial recurrence is consistent with an autosomal dominant mode of inheritance, but most cases are due to de novo mutations. Diagnosis can be made on the basis of clinical features, but may be missed in mildly affected patients. Molecular genetic testing can confirm diagnosis in 70% of cases and has important implications for genetic counseling and management. Most patients with Noonan syndrome are intellectually normal as adults, but some may require multidisciplinary evaluation and regular follow-up care. Age-based Noonan syndrome-specific growth charts and treatment guidelines are available.
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Síndrome de Noonan/diagnóstico , Síndrome de Noonan/terapia , Adolescente , Adulto , Distribución por Edad , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Síndrome de Noonan/epidemiología , Síndrome de Noonan/genética , Adulto JovenRESUMEN
BACKGROUND: A recurrent de novo variant (c.892C>T) in NACC1 causes a neurodevelopmental disorder with epilepsy, cataracts, feeding difficulties, and delayed brain myelination (NECFM). An unusual and consistently reported feature is episodic extreme irritability and inconsolability. We now characterize these episodes, their impact on the family, and ascertain treatments that may be effective. Parents of 14 affected individuals provided narratives describing the irritability episodes, including triggers, behavioral and physiological changes, and treatments. Simultaneously, parents of 15 children completed the Non-communicating Children's Pain Checklist-Revised (NCCPC-R), a measure to assess pain in non-verbal children. RESULTS: The episodes of extreme irritability include a prodromal, peak, and resolving phase, with normal periods in between. The children were rated to have extreme pain-related behaviors on the NCCPC-R scale, although it is unknown whether the physiologic changes described by parents are caused by pain. Attempted treatments included various classes of medications, with psychotropic and sedative medications being most effective (7/15). Nearly all families (13/14) describe how the episodes have a profound impact on their lives. CONCLUSIONS: NECFM caused by the recurrent variant c.892C>T is associated with a universal feature of incapacitating episodic irritability of unclear etiology. Further understanding of the pathophysiology can lead to more effective therapeutic strategies.
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Encéfalo , Catarata , Niño , Humanos , Hipnóticos y Sedantes , Dolor/genética , Padres , Enfermedades Raras , Proteínas de Neoplasias , Proteínas RepresorasRESUMEN
Autophagy regulates the degradation of damaged organelles and protein aggregates, and is critical for neuronal development, homeostasis, and maintenance, yet few neurodevelopmental disorders have been associated with pathogenic variants in genes encoding autophagy-related proteins. We report three individuals from two unrelated families with a neurodevelopmental disorder characterized by speech and motor impairment, and similar facial characteristics. Rare, conserved, bi-allelic variants were identified in ATG4D, encoding one of four ATG4 cysteine proteases important for autophagosome biogenesis, a hallmark of autophagy. Autophagosome biogenesis and induction of autophagy were intact in cells from affected individuals. However, studies evaluating the predominant substrate of ATG4D, GABARAPL1, demonstrated that three of the four ATG4D patient variants functionally impair ATG4D activity. GABARAPL1 is cleaved or "primed" by ATG4D and an in vitro GABARAPL1 priming assay revealed decreased priming activity for three of the four ATG4D variants. Furthermore, a rescue experiment performed in an ATG4 tetra knockout cell line, in which all four ATG4 isoforms were knocked out by gene editing, showed decreased GABARAPL1 priming activity for the two ATG4D missense variants located in the cysteine protease domain required for priming, suggesting that these variants impair the function of ATG4D. The clinical, bioinformatic, and functional data suggest that bi-allelic loss-of-function variants in ATG4D contribute to the pathogenesis of this syndromic neurodevelopmental disorder.
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BACKGROUND: Genomics enables individualized diagnosis and treatment, but large challenges remain to functionally interpret rare variants. To date, only one causative variant has been described for KCNK9 imprinting syndrome (KIS). The genotypic and phenotypic spectrum of KIS has yet to be described and the precise mechanism of disease fully understood. METHODS: This study discovers mechanisms underlying KCNK9 imprinting syndrome (KIS) by describing 15 novel KCNK9 alterations from 47 KIS-affected individuals. We use clinical genetics and computer-assisted facial phenotyping to describe the phenotypic spectrum of KIS. We then interrogate the functional effects of the variants in the encoded TASK3 channel using sequence-based analysis, 3D molecular mechanic and dynamic protein modeling, and in vitro electrophysiological and functional methodologies. RESULTS: We describe the broader genetic and phenotypic variability for KIS in a cohort of individuals identifying an additional mutational hotspot at p.Arg131 and demonstrating the common features of this neurodevelopmental disorder to include motor and speech delay, intellectual disability, early feeding difficulties, muscular hypotonia, behavioral abnormalities, and dysmorphic features. The computational protein modeling and in vitro electrophysiological studies discover variability of the impact of KCNK9 variants on TASK3 channel function identifying variants causing gain and others causing loss of conductance. The most consistent functional impact of KCNK9 genetic variants, however, was altered channel regulation. CONCLUSIONS: This study extends our understanding of KIS mechanisms demonstrating its complex etiology including gain and loss of channel function and consistent loss of channel regulation. These data are rapidly applicable to diagnostic strategies, as KIS is not identifiable from clinical features alone and thus should be molecularly diagnosed. Furthermore, our data suggests unique therapeutic strategies may be needed to address the specific functional consequences of KCNK9 variation on channel function and regulation.
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Discapacidad Intelectual , Canales de Potasio de Dominio Poro en Tándem , Genotipo , Humanos , Discapacidad Intelectual/genética , Hipotonía Muscular , Mutación , Fenotipo , Canales de Potasio de Dominio Poro en Tándem/genética , Canales de Potasio de Dominio Poro en Tándem/metabolismoRESUMEN
Adams-Oliver syndrome (AOS) is a congenital condition characterized by aplasia cutis congenita of the scalp and transverse limb defects. Other clinical features reported in association with AOS include cardiac malformations, cutis marmorata telangiectatica congenita, prenatal complications, and ophthalmic abnormalities. Reported ophthalmic manifestations range from Peters anomaly-like findings and cataract formation to incomplete or abnormal retinal vasculature, optic nerve hypoplasia, and rod dystrophy. We report the novel case of a 3-month-old boy with AOS type 2 who was found to have bilateral progressive macular ischemia.
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Displasia Ectodérmica , Deformidades Congénitas de las Extremidades , Degeneración Macular , Dermatosis del Cuero Cabelludo/congénito , Femenino , Humanos , Lactante , Masculino , Embarazo , Cuero CabelludoAsunto(s)
Antiparkinsonianos/uso terapéutico , Síndrome de Chediak-Higashi/tratamiento farmacológico , Levodopa/uso terapéutico , Enfermedad de Parkinson/tratamiento farmacológico , Síndrome de Chediak-Higashi/diagnóstico , Síndrome de Chediak-Higashi/genética , Electromiografía , Humanos , Hiperpigmentación/genética , Imagen por Resonancia Magnética , Masculino , Trastornos del Movimiento/tratamiento farmacológico , Trastornos del Movimiento/etiología , Mutación Missense , Examen Neurológico , Enfermedad de Parkinson/diagnóstico , Piel/patología , Adulto JovenRESUMEN
We investigated an outbreak of Coxsackie B4 arthritis in a neonatal unit involving 20 neonates and 12 staff members, over an eight-month period. Laboratory investigations, serology tests, indicate that the outbreak was caused by Coxsackie B4 virus. Contamination of one of the overhead water reservoirs, supplying the nursery, was responsible. After the water tanks were cleaned out, no new cases were reported over five years.
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Artritis Infecciosa/epidemiología , Infecciones por Coxsackievirus/epidemiología , Brotes de Enfermedades , Enterovirus Humano B/aislamiento & purificación , Enfermedades del Prematuro/epidemiología , Salas Cuna en Hospital , Adulto , Artritis Infecciosa/virología , Infecciones por Coxsackievirus/virología , Humanos , Recién Nacido de Bajo Peso , Recién Nacido , Recien Nacido Prematuro , Enfermedades del Prematuro/virología , Personal de HospitalRESUMEN
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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BACKGROUND: The hard edges of adult finger clip probes of the pulse oximetry oxygen saturation (POOS) monitor can cause skin damage if used for prolonged periods in a neonate. Covering the skin under the probe with Micropore surgical tape or a gauze piece might prevent such injury. The study was done to see if the protective covering would affect the accuracy of the readings. METHODS: POOS was studied in 50 full-term neonates in the first week of life. After obtaining consent from their parents the neonates had POOS readings taken directly (standard technique) and through the protective covering. Bland-Altman plots were used to compare the new method with the standard technique. A test of repeatability for each method was also performed. RESULTS: The Bland-Altman plots suggest that there is no significant loss of accuracy when readings are taken through the protective covering. The mean difference was 0.06 (SD of 1.39) and 0.04 (SD 1.3) with Micropore and gauze respectively compared to the standard method. The mean difference was 0.22 (SD 0.23) on testing repeatability with the standard method. CONCLUSION: Interposing Micropore or gauze does not significantly affect the accuracy of the POOS reading. The difference between the standard method and the new method was less than the difference seen on testing repeatability of the standard method.
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Vendajes , Recién Nacido/sangre , Oximetría/instrumentación , Oxígeno/sangre , Diseño de Equipo , Pie , Humanos , Presión Parcial , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Piel/lesionesRESUMEN
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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Cerebelo/patología , Síndrome de Chediak-Higashi , Discapacidades para el Aprendizaje , Enfermedades Neurodegenerativas , Adolescente , Adulto , Síndrome de Chediak-Higashi/complicaciones , Síndrome de Chediak-Higashi/diagnóstico , Síndrome de Chediak-Higashi/genética , Fosa Craneal Posterior/patología , Electromiografía , Femenino , Estudios de Seguimiento , Humanos , Discapacidades para el Aprendizaje/etiología , Discapacidades para el Aprendizaje/patología , Discapacidades para el Aprendizaje/fisiopatología , Imagen por Resonancia Magnética , Masculino , Enfermedades Neurodegenerativas/etiología , Enfermedades Neurodegenerativas/patología , Enfermedades Neurodegenerativas/fisiopatología , Índice de Severidad de la Enfermedad , Adulto JovenRESUMEN
OBJECTIVE: To determine the phenotypic spectrum caused by mutations in GRIN1 encoding the NMDA receptor subunit GluN1 and to investigate their underlying functional pathophysiology. METHODS: We collected molecular and clinical data from several diagnostic and research cohorts. Functional consequences of GRIN1 mutations were investigated in Xenopus laevis oocytes. RESULTS: We identified heterozygous de novo GRIN1 mutations in 14 individuals and reviewed the phenotypes of all 9 previously reported patients. These 23 individuals presented with a distinct phenotype of profound developmental delay, severe intellectual disability with absent speech, muscular hypotonia, hyperkinetic movement disorder, oculogyric crises, cortical blindness, generalized cerebral atrophy, and epilepsy. Mutations cluster within transmembrane segments and result in loss of channel function of varying severity with a dominant-negative effect. In addition, we describe 2 homozygous GRIN1 mutations (1 missense, 1 truncation), each segregating with severe neurodevelopmental phenotypes in consanguineous families. CONCLUSIONS: De novo GRIN1 mutations are associated with severe intellectual disability with cortical visual impairment as well as oculomotor and movement disorders being discriminating phenotypic features. Loss of NMDA receptor function appears to be the underlying disease mechanism. The identification of both heterozygous and homozygous mutations blurs the borders of dominant and recessive inheritance of GRIN1-associated disorders.