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2.
Free Radic Biol Med ; 129: 364-371, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30312761

RESUMO

Generation of superoxide by xanthine oxidase can be stimulated under ischemic and aberrant calcium homeostasis. Because patients and mice with Duchenne muscular dystrophy (DMD) suffer from ischemia and excessive calcium influx, we tested the hypothesis that xanthine oxidase activity is elevated and contributes to disease pathology. Xanthine oxidase activity was measured by urinary isoxanthopterin in DMD patients at rest and in response to exercise. Urinary isoxanthopterin/creatinine was elevated compared to age-matched controls and Becker muscular dystrophy (BMD) patients. Concentrations were also increased after a six minute walk test in ambulatory patients. We also measured urinary isoxanthopterin in wildtype mice and a number of dystrophic mouse models; the DMD mouse model (mdx), mdx mice overexpressing a variety of transgenic miniaturized and chimeric skeletal muscle-specific dystrophins and utrophin and the ß-sarcoglycan deficient (Scgb-/-) mouse which represents type 2E human limb-girdle muscular dystrophy. Mdx and Scgb-/-mice had greater urinary isoxanthopterin/creatinine than wildtype mice while mdx mice expressing dystrophin or utrophin linking the extracellular matrix to the actin cytoskeleton were not different than wildtype. We also measured higher levels of urinary ortho-tyrosine in humans and mice deficient for dystrophin to confirm elevated oxidative stress. Surprisingly, mdx had lower xanthine oxidase protein levels and higher mRNA in gastrocnemius muscle compared to wildtype mice, however, the enzymatic activity of skeletal muscle xanthine oxidase was elevated above wildtype and a transgenic rescued mdx mouse (DysΔMTB-mdx). Downhill treadmill running also caused significant increases in mdx urinary isoxanthopterin that was prevented with the xanthine oxidase inhibitor allopurinol. Similarly, in vitro eccentric contraction-induced force drop of mdx muscle was attenuated by the allopurinol metabolite, oxypurinol. Together, our data suggests hyper-activity of xanthine oxidase in DMD, identifies xanthine oxidase activity as a contributing factor in eccentric contraction-induced force drop of dystrophin-deficient skeletal muscle and highlights the potential of isoxanthopterin as a noninvasive biomarker in DMD.

3.
Genet Med ; 2018 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-30245509

RESUMO

PURPOSE: TANGO2-related disorders were first described in 2016 and prior to this publication, only 15 individuals with TANGO2-related disorder were described in the literature. Primary features include metabolic crisis with rhabdomyolysis, encephalopathy, intellectual disability, seizures, and cardiac arrhythmias. We assess whether genotype and phenotype of TANGO2-related disorder has expanded since the initial discovery and determine the efficacy of exome sequencing (ES) as a diagnostic tool for detecting variants. METHODS: We present a series of 14 individuals from 11 unrelated families with complex medical and developmental histories, in whom ES or microarray identified compound heterozygous or homozygous variants in TANGO2. RESULTS: The initial presentation of patients with TANGO2-related disorders can be variable, including primarily neurological presentations. We expand the phenotype and genotype for TANGO2, highlighting the variability of the disorder. CONCLUSION: TANGO2-related disorders can have a more diverse clinical presentation than previously anticipated. We illustrate the utility of routine ES data reanalysis whereby discovery of novel disease genes can lead to a diagnosis in previously unsolved cases and the need for additional copy-number variation analysis when ES is performed.

4.
Neurology ; 90(15): e1333-e1338, 2018 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-29540582

RESUMO

OBJECTIVES: To investigate motor function associations with age, sex, and D4Z4 repeats among participants with early-onset facioscapulohumeral muscular dystrophy (FSHD) type 1 as defined by weakness onset before 10 years of age. METHODS: We collected standardized motor assessments, including manual muscle testing (MMT), quantitative muscle testing, functional motor evaluations, and clinical severity scores (CSSs), at 12 Cooperative International Neuromuscular Research Group centers. To measure associations, we used linear regression models adjusted for sex, evaluation age, age at onset of weakness, and D4Z4 repeats. RESULTS: Among 52 participants (60% female, mean age 22.9 ± 14.7 years), weakness was most pronounced in the shoulder and abdominal musculature. Older enrollment age was associated with greater CSSs (p = 0.003). When adjusted for enrollment age, sex, and D4Z4 repeats, younger age at onset of facial weakness was associated with greater CSSs, slower velocities in timed function tests, and lower MMT scores (p < 0.05). CONCLUSION: Significant clinical variability was observed in early-onset FSHD. Earlier age at onset of facial weakness was associated with greater disease severity. Longitudinal assessments are needed to determine the rate of disease progression in this population.

5.
Child Neurol Open ; 5: 2329048X17751526, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29372173

RESUMO

A 12-year-old boy presented with acute flaccid weakness of the right upper extremity and was found to have acute flaccid myelitis with transverse myelitis involving the cervical cord (C1-T1). An interdisciplinary team-based approach was undertaken, including input from a generalist, an infectious diseases physician, and a pediatric neurologist. Consultation was sought from the Minnesota Department of Health to investigate for a potential etiology and source of the responsible infection. Evaluation for an infectious etiology demonstrated infection with human echovirus 11. The patient recovered with some disability. Echovirus 11 is among the more common etiologies of acute flaccid myelitis and should be considered in the differential diagnosis of this increasingly recognized pediatric infection.

6.
Hum Mol Genet ; 26(24): 4849-4860, 2017 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-29036646

RESUMO

We present eight patients with de novo, deleterious sequence variants in the PBX1 gene. PBX1 encodes a three amino acid loop extension (TALE) homeodomain transcription factor that forms multimeric complexes with TALE and HOX proteins to regulate target gene transcription during development. As previously reported, Pbx1 homozygous mutant mice (Pbx1-/-) develop malformations and hypoplasia or aplasia of multiple organs, including the craniofacial skeleton, ear, branchial arches, heart, lungs, diaphragm, gut, kidneys, and gonads. Clinical findings similar to those in Pbx mutant mice were observed in all patients with varying expressivity and severity, including external ear anomalies, abnormal branchial arch derivatives, heart malformations, diaphragmatic hernia, renal hypoplasia and ambiguous genitalia. All patients but one had developmental delays. Previously reported patients with congenital anomalies affecting the kidney and urinary tract exhibited deletions and loss of function variants in PBX1. The sequence variants in our cases included missense substitutions adjacent to the PBX1 homeodomain (p.Arg184Pro, p.Met224Lys, and p.Arg227Pro) or within the homeodomain (p.Arg234Pro, and p.Arg235Gln), whereas p.Ser262Glnfs*2, and p.Arg288* yielded truncated PBX1 proteins. Functional studies on five PBX1 sequence variants revealed perturbation of intrinsic, PBX-dependent transactivation ability and altered nuclear translocation, suggesting abnormal interactions between mutant PBX1 proteins and wild-type TALE or HOX cofactors. It is likely that the mutations directly affect the transcription of PBX1 target genes to impact embryonic development. We conclude that deleterious sequence variants in PBX1 cause intellectual disability and pleiotropic malformations resembling those in Pbx1 mutant mice, arguing for strong conservation of gene function between these two species.


Assuntos
Deficiência Intelectual/genética , Fator de Transcrição 1 de Leucemia de Células Pré-B/genética , Fator de Transcrição 1 de Leucemia de Células Pré-B/metabolismo , Adolescente , Adulto , Sequência de Aminoácidos , Animais , Criança , Pré-Escolar , Feminino , Pleiotropia Genética/genética , Proteínas de Homeodomínio/genética , Humanos , Lactente , Recém-Nascido , Masculino , Camundongos , Gravidez , Ligação Proteica , Proteínas Proto-Oncogênicas/genética , Fatores de Transcrição/genética
7.
Muscle Nerve ; 55(6): 875-883, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-27718512

RESUMO

INTRODUCTION: Dystrophinopathies are X-linked muscle degenerative disorders that result in progressive muscle weakness complicated by bone loss. This study's goal was to evaluate feasibility and tolerability of whole-body, low-intensity vibration (WBLIV) and its potential effects on muscle and bone in patients with Duchenne or Becker muscular dystrophy. METHODS: This 12-month pilot study included 5 patients (age 5.9-21.7 years) who used a low-intensity Marodyne LivMD plate vibrating at 30-90 Hz for 10 min/day for the first 6 months. Timed motor function tests, myometry, and peripheral quantitative computed tomography were performed at baseline and at 6 and 12 months. RESULTS: Motor function and lower extremity muscle strength remained either unchanged or improved during the intervention phase, followed by deterioration after WBLIV discontinuation. Indices of bone density and geometry remained stable in the tibia. CONCLUSIONS: WBLIV was well tolerated and appeared to have a stabilizing effect on lower extremity muscle function and bone measures. Muscle Nerve 55: 875-883, 2017.


Assuntos
Densidade Óssea/fisiologia , Força Muscular/fisiologia , Músculo Esquelético/fisiopatologia , Distrofias Musculares/complicações , Distrofias Musculares/patologia , Vibração , Adolescente , Adulto , Criança , Feminino , Seguimentos , Humanos , Masculino , Dinamômetro de Força Muscular , Músculo Esquelético/patologia , Distrofias Musculares/terapia , Projetos Piloto , Fatores de Tempo , Tomografia Computadorizada por Raios X , Caminhada , Adulto Jovem
8.
Pediatr Neurol ; 66: 108-111, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27867041

RESUMO

BACKGROUND: Genetic alterations are significant causes of epilepsy syndromes; especially early-onset epileptic encephalopathies and voltage-gated sodium channelopathies are among the best described. Mutations in the SCN2A subunit of voltage-gated sodium channels have been associated with benign familial neonatal-infantile seizures, generalized epilepsy febrile seizures plus, and an early-onset infantile epileptic encephalopathy. METHOD: We describe two infants with medically refractory seizures due to a de novo SCN2A mutation. RESULTS: The first child responded to intravenous lidocaine with significant reduction in seizure frequency and was successfully transitioned to enteral mexiletine. Mexiletine was subsequently used in a second infant with reduction in seizure frequency. CONCLUSION: Class 1b antiarrhythmic agents, lidocaine and mexiletine, may be useful in infants with medically refractory early infantile epileptic encephalopathy secondary to mutations in SCN2A.


Assuntos
Anticonvulsivantes/administração & dosagem , Epilepsia/tratamento farmacológico , Epilepsia/genética , Mexiletina/administração & dosagem , Canal de Sódio Disparado por Voltagem NAV1.2/genética , Bloqueadores do Canal de Sódio Disparado por Voltagem/administração & dosagem , Administração Oral , Antiarrítmicos/administração & dosagem , Epilepsia/fisiopatologia , Humanos , Lactente , Recém-Nascido , Mutação
9.
Pediatrics ; 137(5)2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-27244801

RESUMO

Newborn screening has dramatically reduced rates of untreated congenital hypothyroidism (CH). However, in low-income nations where newborn screening programs do not exist, untreated CH remains a significant health and societal challenge. The goal of this report is to alert health care providers about the potential of undiagnosed CH in unscreened immigrant children. We report 3 siblings of Somali descent with CH who started treatment with levothyroxine at age 0.5 years, 7.7 years, and 14.8 years and were followed for 8 years. This case series demonstrates a spectrum of severity, response to treatment, and neurocognitive and growth outcomes depending on the age at treatment initiation. Patient 1, now 22 years old, went undiagnosed for 14.8 years. On diagnosis, his height was -7.5 SDs with a very delayed bone age of -13.5 SDs. His longstanding CH was associated with empty sella syndrome, static encephalopathy, and severe musculoskeletal deformities. Even after treatment, his height (-5.2 SDs) and cognitive deficits remained the most severe of the 3 siblings. Patient 2, diagnosed at 7.7 years, had moderate CH manifestations and thus a relatively intermediate outcome after treatment. Patient 3, who had the earliest diagnosis at 0.5 years, displayed the best response, but continues to have residual global developmental delay. In conclusion, untreated CH remains an important diagnostic consideration among immigrant children.


Assuntos
Hipotireoidismo Congênito/diagnóstico , Hipotireoidismo Congênito/tratamento farmacológico , Emigrantes e Imigrantes , Tiroxina/uso terapêutico , Adolescente , Encefalopatias/etiologia , Criança , Transtornos Cognitivos/etiologia , Hipotireoidismo Congênito/complicações , Diagnóstico Tardio , Síndrome da Sela Vazia/etiologia , Seguimentos , Transtornos do Crescimento/etiologia , Humanos , Lactente , Deformidades Congênitas das Extremidades Inferiores/etiologia , Masculino , Linhagem , Somália
10.
Am J Hum Genet ; 98(5): 1001-1010, 2016 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-27108799

RESUMO

Whole-exome sequencing of 13 individuals with developmental delay commonly accompanied by abnormal muscle tone and seizures identified de novo missense mutations enriched within a sub-region of GNB1, a gene encoding the guanine nucleotide-binding protein subunit beta-1, Gß. These 13 individuals were identified among a base of 5,855 individuals recruited for various undiagnosed genetic disorders. The probability of observing 13 or more de novo mutations by chance among 5,855 individuals is very low (p = 7.1 × 10(-21)), implicating GNB1 as a genome-wide-significant disease-associated gene. The majority of these 13 mutations affect known Gß binding sites, which suggests that a likely disease mechanism is through the disruption of the protein interface required for Gα-Gßγ interaction (resulting in a constitutively active Gßγ) or through the disruption of residues relevant for interaction between Gßγ and certain downstream effectors (resulting in reduced interaction with the effectors). Strikingly, 8 of the 13 individuals recruited here for a neurodevelopmental disorder have a germline de novo GNB1 mutation that overlaps a set of five recurrent somatic tumor mutations for which recent functional studies demonstrated a gain-of-function effect due to constitutive activation of G protein downstream signaling cascades for some of the affected residues.


Assuntos
Deficiências do Desenvolvimento/etiologia , Subunidades beta da Proteína de Ligação ao GTP/genética , Mutação em Linhagem Germinativa/genética , Deficiência Intelectual/etiologia , Hipotonia Muscular/etiologia , Convulsões/etiologia , Adolescente , Adulto , Criança , Pré-Escolar , Deficiências do Desenvolvimento/patologia , Exoma/genética , Feminino , Subunidades beta da Proteína de Ligação ao GTP/química , Humanos , Lactente , Deficiência Intelectual/patologia , Masculino , Hipotonia Muscular/patologia , Fenótipo , Conformação Proteica , Convulsões/patologia , Transdução de Sinais , Adulto Jovem
11.
Muscle Nerve ; 54(4): 681-9, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-26930423

RESUMO

INTRODUCTION: Outcomes sensitive to change over time in non-ambulatory boys/men with Duchenne muscular dystrophy (DMD) are not well-established. METHODS: Subjects (n = 91; 16.8 ± 4.5 years old) were assessed at baseline and 6-month intervals for 2 years. We analyzed all subjects using an intent-to-treat model and a subset of stronger subjects with Brooke Scale score ≤4, using repeated measures. RESULTS: Eight patients (12-33 years old) died during the study. Sixty-six completed 12-month follow-up, and 51 completed 24-month follow-up. Those taking corticosteroids performed better at baseline, but rates of decline were similar. Forced vital capacity percent predicted (FVC% predicted) declined significantly only after 2 years. However, Brooke and Egen Klassifikation (EK) Scale scores, elbow flexion, and grip strength declined significantly over both 1 and 2 years. CONCLUSION: Brooke and EK Scale scores, elbow flexion, and grip strength were outcomes most responsive to change. FVC% predicted was responsive to change over 2 years. Corticosteroids benefited non-ambulatory DMD subjects but did not affect decline rates of measures tested here. Muscle Nerve 54: 681-689, 2016.


Assuntos
Limitação da Mobilidade , Distrofia Muscular de Duchenne/diagnóstico , Distrofia Muscular de Duchenne/fisiopatologia , Participação do Paciente/métodos , Adolescente , Corticosteroides/uso terapêutico , Adulto , Criança , Seguimentos , Força da Mão/fisiologia , Humanos , Masculino , Distrofia Muscular de Duchenne/tratamento farmacológico , Amplitude de Movimento Articular/fisiologia , Capacidade Vital/fisiologia , Adulto Jovem
12.
Muscle Nerve ; 51(4): 522-32, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25056178

RESUMO

INTRODUCTION: Therapeutic trials in Duchenne muscular dystrophy (DMD) often exclude non-ambulatory individuals. Here we establish optimal and reliable assessments in a multicenter trial. METHODS: Non-ambulatory boys/men with DMD (N = 91; 16.7 ± 4.5 years of age) were assessed by trained clinical evaluators. Feasibility (percentage completing task) and reliability [intraclass correlation coefficients (ICCs) between morning and afternoon tests] were measured. RESULTS: Forced vital capacity (FVC), assessed in all subjects, showed a mean of 47.8 ± 22% predicted (ICC 0.98). Brooke Upper Extremity Functional Rating (Brooke) and Egen Klassifikation (EK) scales in 100% of subjects showed ICCs ranging from 0.93 to 0.99. Manual muscle testing, range of motion, 9-hole peg test, and Jebsen-Taylor Hand Function Test (JHFT) demonstrated varied feasibility (99% to 70%), with ICCs ranging from 0.99 to 0.64. We found beneficial effects of different forms of corticosteroids for the Brooke scale, percent predicted FVC, and hand and finger strength. CONCLUSIONS: Reliable assessment of non-ambulatory boys/men with DMD is possible. Clinical trials will have to consider corticosteroid use.


Assuntos
Corticosteroides/uso terapêutico , Mãos/fisiopatologia , Distrofia Muscular de Duchenne/diagnóstico , Distrofia Muscular de Duchenne/tratamento farmacológico , Adolescente , Adulto , Criança , Avaliação da Deficiência , Mãos/inervação , Humanos , Masculino , Distrofia Muscular de Duchenne/fisiopatologia , Reprodutibilidade dos Testes , Resultado do Tratamento , Adulto Jovem
13.
Pediatr Neurol ; 50(6): 557-63, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24842254

RESUMO

BACKGROUND: The pathogenesis of Duchenne muscular dystrophy starts before birth. Despite this, clinical trials exclude young boys because traditional outcome measures rely on cooperation. We recently used the Bayley-III Scales of Infant and Toddler Development to study 24 infants and boys with Duchenne muscular dystrophy. Clinical evaluators at six centers were trained and certified to perform the Bayley-III. Here, we report 6- and 12-month follow-up of two subsets of these boys. PATIENTS: Nineteen boys (1.9 ± 0.8 years) were assessed at baseline and 6 months. Twelve boys (1.5 ± 0.8 years) were assessed at baseline, 6, and 12 months. RESULTS: Gross motor scores were lower at baseline compared with published controls (6.2 ± 1.7; normal 10 ± 3; P < 0.0001) and revealed a further declining trend to 5.7 ± 1.7 (P = 0.20) at 6 months. Repeated measures analysis of the 12 boys monitored for 12 months revealed that gross motor scores, again low at baseline (6.6 ± 1.7; P < 0.0001), declined at 6 months (5.9 ± 1.8) and further at 12 months (5.3 ± 2.0) (P = 0.11). Cognitive and language scores were lower at baseline compared with normal children (range, P = 0.002-<0.0001) and did not change significantly at 6 or 12 months (range, P = 0.89-0.09). Fine motor skills, also low at baseline, improved >1 year (P = 0.05). CONCLUSION: Development can reliably be measured in infants and young boys with Duchenne muscular dystrophy across time using the Bayley-III. Power calculations using these data reveal that motor development may be used as an outcome measure.


Assuntos
Desenvolvimento Infantil , Distrofia Muscular de Duchenne/diagnóstico , Pré-Escolar , Cognição , Seguimentos , Humanos , Lactente , Linguagem , Testes de Linguagem , Estudos Longitudinais , Masculino , Atividade Motora , Destreza Motora , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/fisiopatologia , Distrofia Muscular de Duchenne/psicologia
14.
Neuromuscul Disord ; 23(7): 529-39, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23726376

RESUMO

Therapeutic trials in Duchenne Muscular Dystrophy (DMD) exclude young boys because traditional outcome measures rely on cooperation. The Bayley III Scales of Infant and Toddler Development (Bayley III) have been validated in developing children and those with developmental disorders but have not been studied in DMD. Expanded Hammersmith Functional Motor Scale (HFMSE) and North Star Ambulatory Assessment (NSAA) may also be useful in this young DMD population. Clinical evaluators from the MDA-DMD Clinical Research Network were trained in these assessment tools. Infants and boys with DMD (n = 24; 1.9 ± 0.7 years) were assessed. The mean Bayley III motor composite score was low (82.8 ± 8; p ≤ .0001) (normal = 100 ± 15). Mean gross motor and fine motor function scaled scores were low (both p ≤ .0001). The mean cognitive comprehensive (p=.0002), receptive language (p ≤ .0001), and expressive language (p = .0001) were also low compared to normal children. Age was negatively associated with Bayley III gross motor (r = -0.44; p = .02) but not with fine motor, cognitive, or language scores. HFMSE (n=23) showed a mean score of 31 ± 13. NSAA (n = 18 boys; 2.2 ± 0.4 years) showed a mean score of 12 ± 5. Outcome assessments of young boys with DMD are feasible and in this multicenter study were best demonstrated using the Bayley III.


Assuntos
Cognição/fisiologia , Atividade Motora/fisiologia , Distrofia Muscular de Duchenne/terapia , Avaliação de Resultados (Cuidados de Saúde) , Fatores Etários , Criança , Desenvolvimento Infantil/fisiologia , Pré-Escolar , Ensaios Clínicos como Assunto , Deficiências do Desenvolvimento/complicações , Deficiências do Desenvolvimento/fisiopatologia , Deficiências do Desenvolvimento/terapia , Humanos , Lactente , Masculino , Distrofia Muscular de Duchenne/complicações , Distrofia Muscular de Duchenne/fisiopatologia , Avaliação de Resultados (Cuidados de Saúde)/métodos
15.
J Neuroimmunol ; 123(1-2): 123-34, 2002 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-11880157

RESUMO

Nasal administration of synthetic CD4(+) epitopes of the acetylcholine receptor (AChR) prevents experimental myasthenia gravis (EMG) in C57Bl/6 mice, but not in IL4-deficient C57Bl/6 (IL4(-/-)) mice. Here we verify that nasal tolerance requires IL4, by showing that CD4(+) cells from C57Bl/6 mice treated nasally with a pool of AChR CD4(+) epitopes protected IL4(-/-) mice from EMG and caused a reduced production of anti-AChR antibody. CD4(+) cells from C57Bl/6 mice treated with unrelated peptides or sham-treated did not induce protection. CD4(+) cells from C57Bl/6 mice treated with just one AChR peptide protected IL4(-/-) mice from EMG without affecting antibody synthesis.


Assuntos
Transferência Adotiva , Linfócitos T CD4-Positivos/imunologia , Epitopos de Linfócito T , Miastenia Gravis Autoimune Experimental/prevenção & controle , Receptores Colinérgicos/imunologia , Administração Intranasal , Animais , Anticorpos/sangue , Feminino , Imunização , Imunoglobulina G/classificação , Imunofenotipagem , Interferon gama/biossíntese , Interleucina-4/biossíntese , Camundongos , Receptores Colinérgicos/análise
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