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1.
J Child Neurol ; 37(12-14): 984-991, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36184928

RESUMO

Neuronal ceroid lipofuscinosis type 2 (CLN2) disease is a very rare neurodegenerative lysosomal storage disorder. Progression is rapid and irreversible, making early diagnosis crucial for timely treatment. A group of pediatric neurologists and neuroradiologists with expertise in CLN2 convened to discuss early electroencephalogram (EEG) and magnetic resonance imaging (MRI) findings in CLN2 diagnosis. Of 18 CLN2 cases, 16 (88.9%) had background slowing and 16 (88.9%) had epileptiform discharges on initial EEG. Seven of 17 (41.2%) patients who received intermittent low-frequency photic stimulation had a photoparoxysmal response. Initial MRIs showed subtle cerebellar (n = 14, 77.8%) or cerebral (n = 9, 50.0%) atrophy, white matter abnormalities (n = 11, 61.1%), and basal ganglia T2 hypointensity (n = 6, 33.3%), which became more apparent on follow-up MRI. The recognition of even subtle cerebellar atrophy and white matter signal changes in children aged 2-5 years who present with language delay, new-onset seizures, and an EEG with epileptiform discharges and background slowing should prompt investigation for CLN2. Because these early signs are not unique to CLN2, genetic testing is essential early in the diagnostic journey.


Assuntos
Lipofuscinoses Ceroides Neuronais , Criança , Humanos , Lipofuscinoses Ceroides Neuronais/diagnóstico , Eletroencefalografia , Imageamento por Ressonância Magnética , Gânglios da Base , Atrofia
2.
Neurology ; 2022 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-35835557

RESUMO

BACKGROUND AND OBJECTIVES: Spinal muscular atrophy (SMA) was added to the Recommended Uniform Screening Panel (RUSP) in July 2018, largely on the basis of the availability and efficacy of newly-approved disease modifying therapies. New York State (NYS) started universal newborn screening for SMA in October 2018. The authors report the findings from the first 3 years of screening. METHODS: Statewide neonatal screening was conducted using DNA extracted from dried blood spots using a real-time quantitative polymerase chain reaction (qPCR) assay. Retrospective follow-up data were collected from 9 referral centers across the state on 34 infants. RESULTS: In the first three years since statewide implementation, nearly 650,000 infants have been screened for SMA. 34 babies screened positive and were referred to a neuromuscular specialty care center. The incidence remains lower than previously predicted. The majority (94%), including all infants with 2-3 copies of SMN2, have received treatment. Among treated infants, the overwhelming majority (97%; 29/30) have received gene replacement. All infants in this cohort with 3 copies of SMN2 are clinically asymptomatic post-treatment based on early clinical follow-up data. Infants with 2 copies of SMN2 are more variable in their outcomes. Electrodiagnostic outcomes data from a subgroup of patients (n=11) for whom pre- and post-treatment data demonstrated either improvement or no change in CMAP amplitude at last clinical follow-up compared to pre-treatment baseline. Most infants were treated before 6 weeks of age (median = 34.5 DOL; range 11-180). Delays and barriers to treatment identified by treating clinicians followed two broad themes: medical and non-medical. Medical delays most commonly reported were presence of AAV9 antibodies and elevated troponin I levels. Non-medical barriers included delays in obtaining insurance as well as insurance policies regarding specific treatment modalities. DISCUSSION: The findings from the NYS cohort of newborn screen-identified infants are consistent with other reports of improved outcomes from early diagnosis and treatment. Additional biomarkers of motor neuron health including electromyography can potentially be helpful in detecting pre-clinical decline.

4.
Am J Hum Genet ; 108(9): 1692-1709, 2021 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-34375587

RESUMO

Kainate receptors (KARs) are glutamate-gated cation channels with diverse roles in the central nervous system. Bi-allelic loss of function of the KAR-encoding gene GRIK2 causes a nonsyndromic neurodevelopmental disorder (NDD) with intellectual disability and developmental delay as core features. The extent to which mono-allelic variants in GRIK2 also underlie NDDs is less understood because only a single individual has been reported previously. Here, we describe an additional eleven individuals with heterozygous de novo variants in GRIK2 causative for neurodevelopmental deficits that include intellectual disability. Five children harbored recurrent de novo variants (three encoding p.Thr660Lys and two p.Thr660Arg), and four children and one adult were homozygous for a previously reported variant (c.1969G>A [p.Ala657Thr]). Individuals with shared variants had some overlapping behavioral and neurological dysfunction, suggesting that the GRIK2 variants are likely pathogenic. Analogous mutations introduced into recombinant GluK2 KAR subunits at sites within the M3 transmembrane domain (encoding p.Ala657Thr, p.Thr660Lys, and p.Thr660Arg) and the M3-S2 linker domain (encoding p.Ile668Thr) had complex effects on functional properties and membrane localization of homomeric and heteromeric KARs. Both p.Thr660Lys and p.Thr660Arg mutant KARs exhibited markedly slowed gating kinetics, similar to p.Ala657Thr-containing receptors. Moreover, we observed emerging genotype-phenotype correlations, including the presence of severe epilepsy in individuals with the p.Thr660Lys variant and hypomyelination in individuals with either the p.Thr660Lys or p.Thr660Arg variant. Collectively, these results demonstrate that human GRIK2 variants predicted to alter channel function are causative for early childhood development disorders and further emphasize the importance of clarifying the role of KARs in early nervous system development.


Assuntos
Encéfalo/metabolismo , Deficiências do Desenvolvimento/genética , Epilepsia/genética , Deficiência Intelectual/genética , Mutação , Receptores de Ácido Caínico/genética , Adolescente , Adulto , Alelos , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Criança , Pré-Escolar , Deficiências do Desenvolvimento/diagnóstico por imagem , Deficiências do Desenvolvimento/metabolismo , Deficiências do Desenvolvimento/patologia , Epilepsia/diagnóstico por imagem , Epilepsia/metabolismo , Epilepsia/patologia , Potenciais Evocados/fisiologia , Regulação da Expressão Gênica no Desenvolvimento , Estudos de Associação Genética , Heterozigoto , Homozigoto , Humanos , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/metabolismo , Deficiência Intelectual/patologia , Ativação do Canal Iônico , Masculino , Modelos Moleculares , Neurônios/metabolismo , Neurônios/patologia , Conformação Proteica , Receptores de Ácido Caínico/química , Receptores de Ácido Caínico/metabolismo , Receptor de GluK2 Cainato
5.
Radiol Case Rep ; 16(8): 1951-1955, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34149981

RESUMO

Fibrocartilaginous embolic infarction of the spinal cord is a rare cause of acute back pain and motor weakness. Most symptoms start after minor trauma that is often considered harmless and forgotten, however these minor injuries can result in lethal consequences. It is quite rare to diagnose fibrocartilaginous embolism in a timely manner and start treatment to prevent poor outcomes. We present the case of a previously healthy eight-year-old female with sudden onset neck pain and progressive bilateral upper extremity weakness following an injury while playing with her younger sister. Magnetic resonance imaging of the cervical spinal cord without contrast revealed a posterior disc protrusion suggestive of post-traumatic spinal cord infarction due to fibrocartilaginous embolism. In young, otherwise healthy, patients with acute motor deficits, radiographic imaging can help identify rare presentations like fibrocartilaginous embolism in order to rapidly diagnose and efficiently treat such patients.

6.
Genet Med ; 22(8): 1296-1302, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32418989

RESUMO

PURPOSE: Spinal muscular atrophy (SMA) was added to the Recommended Uniform Screening Panel (RUSP) in July 2018, following FDA approval of the first effective SMA treatment, and demonstration of feasibility of high-throughput newborn screening using a primary molecular assay. SMA newborn screening was implemented in New York State (NYS) on 1 October 2018. METHODS: Screening was conducted using DNA extracted from dried blood spots with a multiplex real-time quantitative polymerase chain reaction (qPCR) assay targeting the recurrent SMN1 exon 7 gene deletion. RESULTS: During the first year, 225,093 infants were tested. Eight screened positive, were referred for follow-up, and confirmed to be homozygous for the deletion. Infants with two or three copies of the SMN2 gene, predicting more severe, earlier-onset SMA, were treated with antisense oligonucleotide and/or gene therapy. One infant with ≥4 copies SMN2 also received gene therapy. CONCLUSION: Newborn screening permits presymptomatic SMA diagnosis, when treatment initiation is most beneficial. At 1 in 28,137 (95% confidence interval [CI]: 1 in 14,259 to 55,525), the NYS SMA incidence is 2.6- to 4.7-fold lower than expected. The low SMA incidence is likely attributable to imprecise and biased estimates, coupled with increased awareness, access to and uptake of carrier screening, genetic counseling, cascade testing, prenatal diagnosis, and advanced reproductive technologies.


Assuntos
Atrofia Muscular Espinal , Triagem Neonatal , Feminino , Homozigoto , Humanos , Incidência , Lactente , Recém-Nascido , Atrofia Muscular Espinal/diagnóstico , Atrofia Muscular Espinal/epidemiologia , Atrofia Muscular Espinal/genética , New York , Gravidez , Proteína 1 de Sobrevivência do Neurônio Motor/genética
7.
Genet Med ; 22(6): 1108-1118, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32089546

RESUMO

PURPOSE: Newborn screening (NBS) for Krabbe disease (KD) is performed by measurement of galactocerebrosidase (GALC) activity as the primary test. This revealed that GALC activity has poor specificity for KD. Psychosine (PSY) was proposed as a disease marker useful to reduce the false positive rate for NBS and for disease monitoring. We report a highly sensitive PSY assay that allows identification of KD patients with minimal PSY elevations. METHODS: PSY was extracted from dried blood spots or erythrocytes with methanol containing d5-PSY as internal standard, and measured by liquid chromatography-tandem mass spectrometry. RESULTS: Analysis of PSY in samples from controls (N = 209), GALC pseudodeficiency carriers (N = 55), GALC pathogenic variant carriers (N = 27), patients with infantile KD (N = 26), and patients with late-onset KD (N = 11) allowed for the development of an effective laboratory screening and diagnostic algorithm. Additional longitudinal measurements were used to track therapeutic efficacy of hematopoietic stem cell transplantion (HSCT). CONCLUSION: This study supports PSY quantitation as a critical component of NBS for KD. It helps to differentiate infantile from later onset KD variants, as well as from GALC variant and pseudodeficiency carriers. Additionally, this study provides further data that PSY measurement can be useful to monitor KD progression before and after treatment.


Assuntos
Leucodistrofia de Células Globoides , Psicosina , Teste em Amostras de Sangue Seco , Galactosilceramidase/genética , Humanos , Recém-Nascido , Leucodistrofia de Células Globoides/diagnóstico , Leucodistrofia de Células Globoides/genética , Triagem Neonatal
8.
Clin Case Rep ; 7(11): 2087-2091, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31788257

RESUMO

Myelin basic protein (MBP) contributes to peripheral and central nervous system myelin. Developmental myelinopathies exist on a clinical spectrum, but MBP is not included on leukodystrophy or CMT gene panels. This ring chromosome 18 case presents serial MRI and EMG/NCS, shedding light on the early clinical course of the disorder.

9.
Contemp Clin Trials Commun ; 11: 113-119, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30094386

RESUMO

BACKGROUND/AIMS: Recruitment and retention of research participants are challenging and critical components of successful clinical trials and natural history studies. Infants with spinal muscular atrophy (SMA) have been a particularly challenging population to study due to their fragile and complex medical issues, poor prognosis and, until 2016, a lack of effective therapies. Recruitment of healthy infants into clinical trials and natural history studies is also challenging and sometimes assumed to not be feasible. METHODS: In 2011, our group initiated a two-year, longitudinal natural history study of infants with SMA and healthy infant controls to provide data to assist in the analysis and interpretation of planned clinical trials in infants with SMA. The recruitment goal was to enroll 27 infants less than 6 months of age with SMA and 27 age-matched healthy infants within the two-year enrollment period. A detailed recruitment and retention plan was developed for this purpose. In addition, a survey was administered to participant families to understand the determinants of participation in the study. RESULTS: All healthy infants were recruited within the study's first year and 26 SMA infants were recruited within the two-year recruitment period. Thirty-eight participant families responded to the recruitment determinants survey. Nearly half of respondents (18/38, 48%) reported that they first heard of the study from their physician or neurologist. The most common reason to decide to enroll their infant (22/38, 58%) and to remain in the study (28/38, 74%) was their understanding of the importance of the study. Thematic recruitment tools such as a study brochure, video on social media, and presentations at advocacy meetings were reported to positively influence the decision to enroll. CONCLUSIONS: A proactive, thematic and inclusive recruitment and retention plan that effectively communicates the rationale of a clinical study and partners with patients, advocacy groups and the local communities can effectively recruit participants in vulnerable populations. Recommendations for the proactive integration of recruitment and retention plans into clinical trial protocol development are provided.

10.
Muscle Nerve ; 57(2): 193-199, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28833236

RESUMO

INTRODUCTION: The aim of this study was to determine the safety and therapeutic potential of L-carnitine and valproic acid (VPA) in infants with spinal muscular atrophy (SMA). METHODS: Our investigation was an open-label phase 2 multicenter trial of L-carnitine and VPA in infants with SMA type I with retrospective comparison to an untreated, matched cohort. Primary outcomes were: safety and adverse events; secondary outcomes were survival, time to death/>16 hours/day of ventilator support; motor outcomes; and maximum ulnar compound motor action potential amplitude. RESULTS: A total of 245 AEs were observed in 35 of the 37 treated subjects (95%). Respiratory events accounted for 49% of all adverse events, resulting in 14 deaths. Survival was not significantly different between treated and untreated cohorts. DISCUSSION: This trial provides evidence that, in infants with SMA type I, L-carnitine/VPA is ineffective at altering survival. The substantial proportion of infants reaching end-points within 6 months of enrollment underscores the urgent need for pre-symptomatic treatment in SMA type I. Muscle Nerve 57: 193-199, 2018.


Assuntos
Carnitina/uso terapêutico , GABAérgicos/uso terapêutico , Atrofias Musculares Espinais da Infância/tratamento farmacológico , Ácido Valproico/uso terapêutico , Complexo Vitamínico B/uso terapêutico , Potenciais de Ação/efeitos dos fármacos , Carnitina/efeitos adversos , Estudos de Coortes , Quimioterapia Combinada , Feminino , GABAérgicos/efeitos adversos , Humanos , Lactente , Masculino , Resultados Negativos , Respiração Artificial , Estudos Retrospectivos , Atrofias Musculares Espinais da Infância/fisiopatologia , Análise de Sobrevida , Resultado do Tratamento , Ácido Valproico/efeitos adversos , Complexo Vitamínico B/efeitos adversos
11.
Ann Neurol ; 82(6): 883-891, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29149772

RESUMO

OBJECTIVE: Infantile-onset spinal muscular atrophy (SMA) is the most common genetic cause of infant mortality, typically resulting in death preceding age 2. Clinical trials in this population require an understanding of disease progression and identification of meaningful biomarkers to hasten therapeutic development and predict outcomes. METHODS: A longitudinal, multicenter, prospective natural history study enrolled 26 SMA infants and 27 control infants aged <6 months. Recruitment occurred at 14 centers over 21 months within the NINDS-sponsored NeuroNEXT (National Network for Excellence in Neuroscience Clinical Trials) Network. Infant motor function scales (Test of Infant Motor Performance Screening Items [TIMPSI], The Children's Hospital of Philadelphia Infant Test for Neuromuscular Disorders, and Alberta Infant Motor Score) and putative physiological and molecular biomarkers were assessed preceding age 6 months and at 6, 9, 12, 18, and 24 months with progression, correlations between motor function and biomarkers, and hazard ratios analyzed. RESULTS: Motor function scores (MFS) and compound muscle action potential (CMAP) decreased rapidly in SMA infants, whereas MFS in all healthy infants rapidly increased. Correlations were identified between TIMPSI and CMAP in SMA infants. TIMPSI at first study visit was associated with risk of combined endpoint of death or permanent invasive ventilation in SMA infants. Post-hoc analysis of survival to combined endpoint in SMA infants with 2 copies of SMN2 indicated a median age of 8 months at death (95% confidence interval, 6, 17). INTERPRETATION: These data of SMA and control outcome measures delineates meaningful change in clinical trials in infantile-onset SMA. The power and utility of NeuroNEXT to provide "real-world," prospective natural history data sets to accelerate public and private drug development programs for rare disease is demonstrated. Ann Neurol 2017;82:883-891.


Assuntos
Atrofias Musculares Espinais da Infância/sangue , Atrofias Musculares Espinais da Infância/diagnóstico , Biomarcadores/sangue , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Lactente , Estudos Longitudinais , Masculino , Estudos Prospectivos , Atrofias Musculares Espinais da Infância/genética , Proteína 1 de Sobrevivência do Neurônio Motor/sangue , Proteína 1 de Sobrevivência do Neurônio Motor/genética , Proteína 2 de Sobrevivência do Neurônio Motor/sangue , Proteína 2 de Sobrevivência do Neurônio Motor/genética
12.
Ann Clin Transl Neurol ; 3(2): 132-45, 2016 02.
Artigo em Inglês | MEDLINE | ID: mdl-26900585

RESUMO

OBJECTIVE: This study prospectively assessed putative promising biomarkers for use in assessing infants with spinal muscular atrophy (SMA). METHODS: This prospective, multi-center natural history study targeted the enrollment of SMA infants and healthy control infants less than 6 months of age. Recruitment occurred at 14 centers within the NINDS National Network for Excellence in Neuroscience Clinical Trials (NeuroNEXT) Network. Infant motor function scales and putative electrophysiological, protein and molecular biomarkers were assessed at baseline and subsequent visits. RESULTS: Enrollment began November, 2012 and ended September, 2014 with 26 SMA infants and 27 healthy infants enrolled. Baseline demographic characteristics of the SMA and control infant cohorts aligned well. Motor function as assessed by the Test for Infant Motor Performance Items (TIMPSI) and the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) revealed significant differences between the SMA and control infants at baseline. Ulnar compound muscle action potential amplitude (CMAP) in SMA infants (1.4 ± 2.2 mV) was significantly reduced compared to controls (5.5 ± 2.0 mV). Electrical impedance myography (EIM) high-frequency reactance slope (Ohms/MHz) was significantly higher in SMA infants than controls SMA infants had lower survival motor neuron (SMN) mRNA levels in blood than controls, and several serum protein analytes were altered between cohorts. INTERPRETATION: By the time infants were recruited and presented for the baseline visit, SMA infants had reduced motor function compared to controls. Ulnar CMAP, EIM, blood SMN mRNA levels, and serum protein analytes were able to distinguish between cohorts at the enrollment visit.

13.
Muscle Nerve ; 42(5): 703-8, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20737553

RESUMO

Reliable outcome measures that reflect the underlying disease process and correlate with motor function in children with SMA are needed for clinical trials. Maximum ulnar compound muscle action potential (CMAP) data were collected at two visits over a 4-6-week period in children with SMA types II and III, 2-17 years of age, at four academic centers. Primary functional outcome measures included the Modified Hammersmith Functional Motor Scale (MHFMS) and MHFMS-Extend. CMAP negative peak amplitude and area showed excellent discrimination between the ambulatory and non-ambulatory SMA cohorts (ROC = 0.88). CMAP had excellent test-retest reliability (ICC = 0.96-0.97, n = 64) and moderate to strong correlation with the MHFMS and MHFMS-Extend (r = 0.61-0.73, n = 68, P < 0.001). Maximum ulnar CMAP amplitude and area is a feasible, valid, and reliable outcome measure for use in pediatric multicenter clinical trials in SMA. CMAP correlates well with motor function and has potential value as a relevant surrogate for disease status.


Assuntos
Potenciais de Ação/fisiologia , Músculo Esquelético/fisiopatologia , Atrofias Musculares Espinais da Infância/fisiopatologia , Adolescente , Carnitina/uso terapêutico , Criança , Pré-Escolar , Eletromiografia , Feminino , GABAérgicos/uso terapêutico , Humanos , Masculino , Movimento/fisiologia , Curva ROC , Reprodutibilidade dos Testes , Atrofias Musculares Espinais da Infância/tratamento farmacológico , Resultado do Tratamento , Nervo Ulnar/fisiopatologia , Ácido Valproico/uso terapêutico
14.
Brain Dev ; 31(8): 638-40, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19004586

RESUMO

Congenital enlargement of the cerebral ventricles is now commonly recognized in utero due to the availability of high resolution prenatal ultrasonography. It is important to distinguish between congenital hydrocephalus and ventricular enlargement due to malformations, infections or other destructive processes because these disorders can have markedly different prognoses. We report an infant diagnosed with Aicardi syndrome in the newborn period based on brain MRI and ophthalmological findings after she was referred for evaluation of hydrocephalus seen on fetal ultrasound. Aicardi syndrome most commonly comes to medical attention because of seizures later in infancy.


Assuntos
Ventrículos Cerebrais/anormalidades , Encefalite/congênito , Doenças Fetais/diagnóstico por imagem , Hidrocefalia/diagnóstico por imagem , Síndrome Acrocalosal/diagnóstico por imagem , Diagnóstico Diferencial , Eletroencefalografia , Encefalite/diagnóstico por imagem , Feminino , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Gravidez , Espasmos Infantis/diagnóstico , Síndrome , Ultrassonografia Pré-Natal
16.
Nat Clin Pract Neurol ; 2(10): 566-72; quiz 573, 2006 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-16990830

RESUMO

BACKGROUND: A 39-year-old man presented with a history of several months of progressive personality changes, social withdrawal, bradykinesia, mutism, dysphagia, worsening gait, and difficulty with daily living activities. Examination revealed an atypical parkinsonian appearance with incomplete supranuclear ophthalmoplegia and an unusual oculomotor disorder characterized by both low-amplitude, intermittent opsoclonus, and slow, nystagmoid intrusions. INVESTIGATIONS: Routine laboratory testing, autoimmune and infectious serologies, brain MRI, lumbar puncture, electroencephalogram, whole-body CT scan, paraneoplastic serologies, small bowel biopsy, 18F-fluorodeoxyglucose positron emission tomography CT scan, brain biopsy, and testicular ultrasound. DIAGNOSIS: Anti-Ma2 paraneoplastic encephalitis in association with metastatic testicular cancer; initially misdiagnosed as CNS Whipple's disease. MANAGEMENT: Corticosteroids, intravenous immunoglobulins, orchiectomy, muscle relaxants, mycophenolate mofetil, plasmapheresis, and bleomycin, etoposide and platinum chemotherapy.


Assuntos
Antígenos de Neoplasias/metabolismo , Erros de Diagnóstico , Encefalite/diagnóstico , Proteínas do Tecido Nervoso/metabolismo , Síndromes Paraneoplásicas/diagnóstico , Doença de Whipple/diagnóstico , Adulto , Antígenos de Neoplasias/imunologia , Encéfalo/patologia , Lesões Encefálicas/complicações , Diagnóstico Diferencial , Encefalite/fisiopatologia , Evolução Fatal , Feminino , Fluordesoxiglucose F18 , Humanos , Imunossupressores/uso terapêutico , Imageamento por Ressonância Magnética , Masculino , Proteínas do Tecido Nervoso/imunologia , Síndromes Paraneoplásicas/tratamento farmacológico , Síndromes Paraneoplásicas/fisiopatologia , Tomografia por Emissão de Pósitrons , Convulsões/etiologia , Neoplasias Testiculares
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