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1.
Hum Mutat ; 38(11): 1477-1484, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28726266

RESUMO

Biallelic GLDN mutations have recently been identified among infants with lethal congenital contracture syndrome 11 (LCCS11). GLDN encodes gliomedin, a protein required for the formation of the nodes of Ranvier and development of the human peripheral nervous system. We report six infants and children from four unrelated families with biallelic GLDN mutations, four of whom survived beyond the neonatal period into infancy, childhood, and late adolescence with intensive care and chronic respiratory and nutritional support. Our findings expand the genotypic and phenotypic spectrum of LCCS11 and demonstrate that the condition may not necessarily be lethal in the neonatal period.


Assuntos
Artrogripose/diagnóstico , Artrogripose/genética , Genes Letais , Proteínas de Membrana/genética , Mutação , Proteínas do Tecido Nervoso/genética , Fenótipo , Artrogripose/mortalidade , Biópsia , Análise Mutacional de DNA , Evolução Fatal , Estudos de Associação Genética , Humanos , Lactente , Recém-Nascido , Masculino , Linhagem , Raízes Nervosas Espinhais/ultraestrutura , Sequenciamento Completo do Exoma
2.
Brain ; 138(Pt 12): 3503-19, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26510951

RESUMO

Mitochondrial Complex IV [cytochrome c oxidase (COX)] deficiency is one of the most common respiratory chain defects in humans. The clinical phenotypes associated with COX deficiency include liver disease, cardiomyopathy and Leigh syndrome, a neurodegenerative disorder characterized by bilateral high signal lesions in the brainstem and basal ganglia. COX deficiency can result from mutations affecting many different mitochondrial proteins. The French-Canadian variant of COX-deficient Leigh syndrome is unique to the Saguenay-Lac-Saint-Jean region of Québec and is caused by a founder mutation in the LRPPRC gene. This encodes the leucine-rich pentatricopeptide repeat domain protein (LRPPRC), which is involved in post-transcriptional regulation of mitochondrial gene expression. Here, we present the clinical and molecular characterization of novel, recessive LRPPRC gene mutations, identified using whole exome and candidate gene sequencing. The 10 patients come from seven unrelated families of UK-Caucasian, UK-Pakistani, UK-Indian, Turkish and Iraqi origin. They resemble the French-Canadian Leigh syndrome patients in having intermittent severe lactic acidosis and early-onset neurodevelopmental problems with episodes of deterioration. In addition, many of our patients have had neonatal cardiomyopathy or congenital malformations, most commonly affecting the heart and the brain. All patients who were tested had isolated COX deficiency in skeletal muscle. Functional characterization of patients' fibroblasts and skeletal muscle homogenates showed decreased levels of mutant LRPPRC protein and impaired Complex IV enzyme activity, associated with abnormal COX assembly and reduced steady-state levels of numerous oxidative phosphorylation subunits. We also identified a Complex I assembly defect in skeletal muscle, indicating different roles for LRPPRC in post-transcriptional regulation of mitochondrial mRNAs between tissues. Patient fibroblasts showed decreased steady-state levels of mitochondrial mRNAs, although the length of poly(A) tails of mitochondrial transcripts were unaffected. Our study identifies LRPPRC as an important disease-causing gene in an early-onset, multisystem and neurological mitochondrial disease, which should be considered as a cause of COX deficiency even in patients originating outside of the French-Canadian population.


Assuntos
Deficiência de Citocromo-c Oxidase/genética , Doenças Mitocondriais/genética , Proteínas de Neoplasias/genética , Proteínas/genética , Canadá , Células Cultivadas , Pré-Escolar , Deficiência de Citocromo-c Oxidase/enzimologia , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Feminino , Fibroblastos/metabolismo , Humanos , Lactente , Recém-Nascido , Masculino , Doenças Mitocondriais/enzimologia , Doenças Mitocondriais/metabolismo , Proteínas Mitocondriais/metabolismo , Músculo Esquelético/metabolismo , Mutação , Linhagem , Proteínas/metabolismo , RNA Mensageiro/metabolismo , RNA Mitocondrial
3.
Front Neurol ; 5: 61, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24803913

RESUMO

Obstructive sleep apnea (OSA) patients have increased upper airway muscle activity, including such lingual muscles as the genioglossus (GG), geniohyoid (GH), and hyoglossus (HG). This adaptation partially protects their upper airway against obstructions. Rodents are used to study the central neural control of sleep and breathing but they do not naturally exhibit OSA. We investigated whether, in chronically instrumented, behaving rats, disconnecting the GH and HG muscles from the hyoid (H) apparatus would result in a compensatory increase of other upper airway muscle activity (electromyogram, EMG) and/or other signs of upper airway instability. We first determined that, in intact rats, lingual (GG and intrinsic) muscles maintained stable activity levels when quantified based on 2 h-long recordings conducted on days 6 through 22 after instrumentation. We then studied five rats in which the tendons connecting the GH and HG muscles to the H apparatus were experimentally severed. When quantified across all recording days, lingual EMG during slow-wave sleep (SWS) was modestly but significantly increased in rats with surgically altered upper airway [8.6 ± 0.7% (SE) vs. 6.1 ± 0.7% of the mean during wakefulness; p = 0.012]. Respiratory modulation of lingual EMG occurred mainly during SWS and was similarly infrequent in both groups, and the incidence of sighs and central apneas also was similar. Thus, a weakened action of selected lingual muscles did not produce sleep-disordered breathing but resulted in a relatively elevated activity in other lingual muscles during SWS. These results encourage more extensive surgical manipulations with the aim to obtain a rodent model with collapsible upper airway.

4.
PLoS One ; 9(1): e86545, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24466145

RESUMO

Sleep-wake behavior is regulated by a circadian rhythm, homeostatically and by additional mechanisms that determine the timing of slow-wave sleep and rapid eye movement sleep (REMS) episodes. The posterior hypothalamus coordinates the neural and humoral signals with the rest-activity cycle. It contains wake-active neurons, and is a site where stimulation of inhibitory GABAA receptors promotes sleep, whereas their antagonism enhances wakefulness. We explored whether GABAergic mechanisms present in the posterior hypothalamus contribute to the homeostatic and other aspects of sleep-wake regulation. Using micropunches of tissue extracted from either the perifornical (PF) or dorsomedial (DM) regions of the posterior hypothalamus of rats, we determined that mRNA levels for selected subunits of GABAA receptors (ß1, ß3 and ε) were higher at the end of the active period or following sleep deprivation, when the need for sleep is high, than after several hours of sleep, when sleep need is partially fulfilled. Such a pattern was present in the PF region only, and was consistent with changes in ß1 subunit and GABA synthesizing enzyme (GAD) protein levels. In contrast, in the DM region, the levels of GABAA receptor subunit mRNAs and proteins (α1, α2, ß1) and GAD varied with circadian time, but were not responsive to sleep deprivation. Separate experiments with sleep-wake monitoring and local perfusion of the PF region with the GABAA receptor antagonist bicuculline revealed that the antagonist had a weaker sleep-reducing effect when sleep need was enhanced by sleep deprivation and that the increased amount of REMS characteristic of the late sleep period was dependent on endogenous GABAergic inhibition. These results support the concept that a varying magnitude of GABAergic inhibition exerted within the PF region contributes to the homeostatic regulation of sleep and shapes its temporal pattern, whereas GABAergic mechanisms in the DM region contribute to circadian regulation.


Assuntos
Hipotálamo/fisiologia , Receptores de GABA-A/metabolismo , Sono/fisiologia , Animais , Bicuculina/farmacologia , Ritmo Circadiano/efeitos dos fármacos , Ritmo Circadiano/fisiologia , Antagonistas de Receptores de GABA-A/metabolismo , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Masculino , RNA Mensageiro/genética , Ratos , Ratos Sprague-Dawley , Sono/efeitos dos fármacos , Privação do Sono/metabolismo , Privação do Sono/fisiopatologia , Vigília/efeitos dos fármacos , Vigília/fisiologia
5.
J Chem Neuroanat ; 52: 87-94, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23932955

RESUMO

Perinatal alcohol exposure (AE) has multiple detrimental effects on cognitive and various behavioral outcomes, but little is known about its impact on the autonomic functions. In a rat model of fetal alcohol spectrum disorders (FASD), we investigated neurochemical and neuroanatomical alterations in two brainstem nuclei, the hypoglossal nucleus (XIIn) and the dorsal nucleus of the vagus nerve (Xdn). One group of male Sprague-Dawley rats (n=6) received 2.625 g/kg ethanol intragastrically twice daily on postnatal days (PD) 4-9, a period equivalent to the third trimester of human pregnancy, and another group (n=6) was sham-intubated. On PD 18-19, the rats were perfused and medullary sections were immunohistochemically processed for choline acetyltransferase (ChAT) or two aminergic receptors that mediate excitatory drive to motoneurons, α1-adrenergic (α1-R) and serotonin 2A (5-HT(2A)-R), and c-Fos. Based on ChAT labeling, AE rats had reduced numbers of motoneurons in the ventral XIIn (XIIn-v; 35.4±1.3 motoneurons per side and section vs. 40.0±1.2, p=0.022), but not in the dorsal XIIn or Xdn. Consistent with ChAT data, both the numbers of α1-R-labeled motoneurons in the XIIn-v and the area of the XIIn-v measured using 5-HT(2A)-R staining were significantly smaller in AE rats (19.7±1.5 vs. 25.0±1.4, p=0.031 and 0.063 mm² ±0.002 vs. 0.074±0.002, p=0.002, respectively). Concurrently, both 5-HT(2A)-R and c-Fos staining tended to be higher in AE rats, suggesting an increased activation. Thus, postnatal AE causes motoneuronal loss in the XIIn-v. This may compromise upper airway control and contribute to increased risk of upper airway obstructions and sudden infant death in FASD victims.


Assuntos
Etanol/toxicidade , Nervo Hipoglosso/efeitos dos fármacos , Nervo Hipoglosso/patologia , Neurônios Motores/efeitos dos fármacos , Neurônios Motores/patologia , Fatores Etários , Animais , Animais Recém-Nascidos , Etanol/administração & dosagem , Feminino , Masculino , Gravidez , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley
6.
Respir Physiol Neurobiol ; 188(3): 308-17, 2013 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-23732510

RESUMO

In obstructive sleep apnea (OSA) patients, inspiratory activation (IA) of lingual muscles protects the upper airway from collapse. We aimed to determine when rats' lingual muscles exhibit IA. In 5 Sprague-Dawley and 3 Wistar rats, we monitored cortical EEG and lingual, diaphragmatic and nuchal electromyograms (EMGs), and identified segments of records when lingual EMG exhibited IA. Individual segments lasted 2.4-269 s (median: 14.5 s), most (89%) occurred during slow-wave sleep (SWS), and they collectively occupied 0.3-6.1% of the total recording time. IA usually started to increase with a delay after SWS onset and ended with an arousal, or declined prior to rapid eye movement sleep. IA of lingual EMG was not accompanied by increased diaphragmatic activity or respiratory rate changes, but occurred when cortical EEG power was particularly low in a low beta-1 frequency range (12.5-16.4 Hz). A deep SWS-related activation of upper airway muscles may be an endogenous phenomenon designed to protect the upper airway against collapse.


Assuntos
Músculo Esquelético/fisiologia , Mecânica Respiratória/fisiologia , Sono/fisiologia , Língua/fisiologia , Vigília/fisiologia , Animais , Interpretação Estatística de Dados , Eletroencefalografia , Eletromiografia , Masculino , Ratos , Apneia Obstrutiva do Sono/fisiopatologia
7.
PLoS One ; 8(4): e62410, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23630631

RESUMO

Rapid eye movement sleep (REMS) is generated in the brainstem by a distributed network of neurochemically distinct neurons. In the pons, the main subtypes are cholinergic and glutamatergic REMS-on cells and aminergic REMS-off cells. Pontine REMS-on cells send axons to the ventrolateral medulla (VLM), but little is known about REMS-related activity of VLM cells. In urethane-anesthetized rats, dorsomedial pontine injections of carbachol trigger REMS-like episodes that include cortical and hippocampal activation and suppression of motoneuronal activity; the episodes last 4-8 min and can be elicited repeatedly. We used this model to determine whether VLM catecholaminergic cells are silenced during REMS, as is typical of most aminergic neurons studied to date, and to investigate other REMS-related cells in this region. In 18 anesthetized, paralyzed and artificially ventilated rats, we obtained extracellular recordings from VLM cells when REMS-like episodes were elicited by pontine carbachol injections (10 mM, 10 nl). One major group were the cells that were activated during the episodes (n = 10). Their baseline firing rate of 3.7±2.1 (SD) Hz increased to 9.7±2.1 Hz. Most were found in the adrenergic C1 region and at sites located less than 50 µm from dopamine ß-hydroxylase-positive (DBH(+)) neurons. Another major group were the silenced or suppressed cells (n = 35). Most were localized in the lateral reticular nucleus (LRN) and distantly from any DBH(+) cells. Their baseline firing rates were 6.8±4.4 Hz and 15.8±7.1 Hz, respectively, with the activity of the latter reduced to 7.4±3.8 Hz. We conclude that, in contrast to the pontine noradrenergic cells that are silenced during REMS, medullary adrenergic C1 neurons, many of which drive the sympathetic output, are activated. Our data also show that afferent input transmitted to the cerebellum through the LRN is attenuated during REMS. This may distort the spatial representation of body position during REMS.


Assuntos
Neurônios Adrenérgicos/fisiologia , Bulbo/citologia , Sono REM , Potenciais de Ação , Animais , Pressão Sanguínea , Carbacol/farmacologia , Agonistas Colinérgicos/farmacologia , Dopamina beta-Hidroxilase/metabolismo , Masculino , Bulbo/fisiologia , Ratos , Ratos Sprague-Dawley , Análise de Célula Única
8.
Respir Physiol Neurobiol ; 188(3): 301-7, 2013 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-23665050

RESUMO

Serotonin (5-HT), norepinephrine and orexins (ORX) are the three best established mediators of wake-related activation of hypoglossal (XII) motoneurons that innervate the muscles of the tongue. Since the tongue's use is temporarily closely aligned with the rest-activity cycle, we tested whether expression of mRNA for relevant 5-HT, norepinephrine and ORX receptors varies in the XII nucleus with the rest-activity cycle. Adult rats (n=7-9/group) were decapitated at 8-9 am (near rest period onset) or at 6-7 pm (near active period onset). Tissue micropunches were extracted from medullary slices containing the XII motor and sensory external cuneate (ECN) nuclei. 5-HT2A, α1-adrenergic and ORX type 2 receptor mRNAs were quantified using RT-PCR. Only 5-HT2A receptor mRNA levels differed between the two time points and were higher at the active period onset; no differences were detected in the ECN. Consistent with the mRNA results, 5-HT2A protein levels were also higher in the XII nucleus at the active period onset than at rest onset. Thus, the endogenous serotonergic excitatory drive to XII motoneurons may be enhanced through circadian- or activity-dependent mechanisms that increase the availability of 5-HT2A receptors prior to the active period. Conversely, reduced levels of 5-HT2A receptors during the rest-sleep period may exacerbate the propensity for sleep-disordered breathing in subjects with anatomically compromised upper airway.


Assuntos
Ritmo Circadiano/fisiologia , Nervo Hipoglosso/fisiologia , Neurônios Motores/fisiologia , Receptores de Neurotransmissores/fisiologia , Vigília/fisiologia , Animais , Nervo Hipoglosso/citologia , Masculino , Bulbo/metabolismo , Norepinefrina/metabolismo , Receptores de Orexina/efeitos dos fármacos , Receptores de Orexina/fisiologia , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Ratos , Ratos Sprague-Dawley , Receptor 5-HT2A de Serotonina/fisiologia , Receptores Adrenérgicos alfa 1/efeitos dos fármacos , Receptores Adrenérgicos alfa 1/fisiologia , Descanso/fisiologia , Sono/fisiologia , Síndromes da Apneia do Sono/fisiopatologia
9.
Am J Physiol Regul Integr Comp Physiol ; 304(7): R514-22, 2013 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-23364524

RESUMO

Persons affected by obstructive sleep apnea (OSA) have increased arterial blood pressure and elevated activity in upper airway muscles. Many cardiorespiratory features of OSA have been reproduced in rodents subjected to chronic-intermittent hypoxia (CIH). We previously reported that, following exposure to CIH, rats have increased noradrenergic terminal density in brain stem sensory and motor nuclei and upregulated expression of the excitatory α(1)-adrenergic receptors in the hypoglossal motor nucleus. This suggested that CIH may enhance central catecholaminergic transmission. We now quantified c-Fos expression in different groups of pontomedullary catecholaminergic neurons as an indirect way of assessing their baseline activity in rats subjected to CIH or sham treatment (7 AM-5 PM daily for 35 days). One day after the last CIH exposure, the rats were gently kept awake for 2.5 h and then were anesthetized and perfused, and their pontomedullary brain sections were subjected to dopamine ß-hydroxylase (DBH) and c-Fos immunohistochemistry. DBH-positive cells were counted in the A1/C1, A2/C2, A5, subcoeruleus (sub-C) and A7 groups of catecholaminergic neurons, and the percentages of those expressing c-Fos were determined. We found that fewer DBH cells expressed c-Fos in CIH- than in sham-treated rats in the medulla (significant in the A1 group). In the pons (rostral A5, sub-C, and A7), c-Fos expression did not differ between the CIH- and sham-treated animals. We suggest that, when measured 20 h after the last CIH exposure, catecholaminergic transmission is enhanced through terminal sprouting and receptor upregulation rather than through increased baseline activity in pontomedullary catecholaminergic neurons.


Assuntos
Catecolaminas/metabolismo , Regulação da Expressão Gênica/fisiologia , Hipóxia/metabolismo , Neurônios/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Animais , Catecolaminas/genética , Masculino , Bulbo/efeitos dos fármacos , Bulbo/fisiologia , Oxigênio/metabolismo , Proteínas Proto-Oncogênicas c-fos/genética , Ratos , Ratos Sprague-Dawley
10.
J Appl Physiol (1985) ; 114(1): 119-30, 2013 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-23104701

RESUMO

The perifornical (PF) region of the posterior hypothalamus promotes wakefulness and facilitates motor activity. In anesthetized rats, local disinhibition of PF neurons by GABA(A) receptor antagonists activates orexin (OX) neurons and elicits a systemic response, including increases of hypoglossal nerve activity (XIIa), respiratory rate, heart rate, and blood pressure. The increase of XIIa is mediated to hypoglossal (XII) motoneurons by pathways that do not require noradrenergic or serotonergic projections. We hypothesized that the pathway might include OX-dependent activation locally within the PF region or direct projections of OX neurons to the XII nucleus. Adult, male Sprague-Dawley rats were urethane anesthetized, vagotomized, paralyzed, and ventilated. Gabazine (GABA(A) receptor antagonist, 0.18 mM, 20 nl) was injected into the PF region, and ~2 h later, a second gabazine injection was performed preceded by injection of a dual OX1/2 receptor antagonist (almorexant; 90 mM) either into the XII nucleus (40-60 nl at 2-3 rostrocaudal levels; n = 6 rats), or into the PF region (40-60 nl; n = 6 rats). XIIa, respiratory rate, heart rate, and arterial blood pressure were analyzed for 70 min after each gabazine injection. The excitatory effects of PF gabazine on XIIa, respiratory, and heart rates were significantly reduced by up to 44-82% when gabazine injections were preceded by PF almorexant injections, but not when almorexant was injected into the XII nucleus. These data suggest that a significant portion of XII motoneuronal and cardiorespiratory activation evoked by disinhibition of PF neurons is mediated by local OX-dependent mechanisms within the posterior hypothalamus.


Assuntos
Pressão Arterial/fisiologia , Nervo Hipoglosso/fisiologia , Hipotálamo Posterior/fisiologia , Receptores Acoplados a Proteínas-G/antagonistas & inibidores , Receptores de Neuropeptídeos/antagonistas & inibidores , Animais , Pressão Arterial/efeitos dos fármacos , Antagonistas GABAérgicos/farmacologia , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Nervo Hipoglosso/efeitos dos fármacos , Nervo Hipoglosso/metabolismo , Hipotálamo Posterior/efeitos dos fármacos , Hipotálamo Posterior/metabolismo , Masculino , Neurônios Motores/efeitos dos fármacos , Neurônios Motores/metabolismo , Neurônios Motores/fisiologia , Norepinefrina/farmacologia , Receptores de Orexina , Piridazinas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores Acoplados a Proteínas-G/metabolismo , Receptores de GABA/metabolismo , Receptores de Neuropeptídeos/metabolismo , Taxa Respiratória/efeitos dos fármacos , Taxa Respiratória/fisiologia
11.
J Appl Physiol (1985) ; 112(2): 305-12, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22016369

RESUMO

In obstructive sleep apnea patients, elevated activity of the lingual muscles during wakefulness protects the upper airway against occlusions. A possibly related form of respiratory neuroplasticity is present in rats exposed to acute and chronic intermittent hypoxia (CIH). Since rats exposed to CIH have increased density of noradrenergic terminals and increased α(1)-adrenoceptor immunoreactivity in the hypoglossal (XII) nucleus, we investigated whether these anatomic indexes of increased noradrenergic innervation translate to increased sensitivity of XII motoneurons to noradrenergic activation. Adult male Sprague-Dawley rats were subjected to CIH for 35 days, with O(2) level varying between 24% and 7% with 180-s period for 10 h/day. They were then anesthetized, vagotomized, paralyzed, and artificially ventilated. The dorsal medulla was exposed, and phenylephrine (2 mM, 10 nl) and then the α(1)-adrenoceptor antagonist prazosin (0.2 mM, 3 × 40 nl) were microinjected into the XII nucleus while XII nerve activity (XIIa) was recorded. The area under integrated XIIa was measured before and at different times after microinjections. The excitatory effect of phenylephrine on XII motoneurons was similar in sham- and CIH-treated rats. In contrast, spontaneous XIIa was more profoundly reduced following prazosin injections in CIH- than sham-treated rats [to 21 ± 7% (SE) vs. 40 ± 8% of baseline, P < 0.05] without significant changes in central respiratory rate, arterial blood pressure, or heart rate. Thus, consistent with increased neuroanatomic measures of noradrenergic innervation of XII motoneurons following exposure to CIH, prazosin injections revealed a stronger endogenous noradrenergic excitatory drive to XII motoneurons in CIH- than sham-treated anesthetized rats.


Assuntos
Neurônios Adrenérgicos/metabolismo , Nervo Hipoglosso/fisiologia , Hipóxia/fisiopatologia , Neurônios Motores/fisiologia , Receptores Adrenérgicos/metabolismo , Apneia Obstrutiva do Sono , Antagonistas de Receptores Adrenérgicos alfa 1/farmacologia , Animais , Modelos Animais de Doenças , Nervo Hipoglosso/citologia , Nervo Hipoglosso/efeitos dos fármacos , Hipóxia/tratamento farmacológico , Masculino , Neurônios Motores/efeitos dos fármacos , Neurônios Motores/patologia , Norepinefrina/metabolismo , Prazosina/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores Adrenérgicos/efeitos dos fármacos
12.
Am J Med Genet A ; 155A(8): 2003-7, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21739600

RESUMO

Alterations of the Fragile Mental Retardation 2 gene (FMR2, synonym AFF2) can result in non-specific, mild to borderline X-linked intellectual disability (XLID), and behavioral problems. The well-known molecular pathomechanism of this condition, also referred to as FRAXE, is a (CCG)(n) trinucleotide repeat expansion which leads to silencing of the FMR2 gene. However, deletions within the FMR2 gene may also be causative of the disorder. Here, we report on two brothers diagnosed with FRAXE in whom a small deletion in the FMR2 gene was detected by whole genome array comparative genomic hybridization (CGH). The deletion was also present in their clinically healthy mother and maternal uncle who was similarly affected, but not in a healthy older brother of the two patients. Our observation demonstrates that FMR2 gene deletions may contribute to the FRAXE phenotype. Therefore, we suggest that screening for FMR2 gene deletions using array CGH should be considered in patients with non-specific XLID and absent trinucleotide expansion.


Assuntos
Transtorno Autístico/genética , Cromossomos Humanos X/genética , Síndrome do Cromossomo X Frágil/genética , Deleção de Genes , Proteínas Nucleares/genética , Criança , Hibridização Genômica Comparativa , Síndrome do Cromossomo X Frágil/diagnóstico , Estudos de Associação Genética , Humanos , Masculino
13.
Hum Mutat ; 32(6): E2211-25, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21618344

RESUMO

Hereditary sensory and autonomic neuropathy type I (HSAN-I) is an axonal peripheral neuropathy leading to progressive distal sensory loss and severe ulcerations. Mutations in SPTLC1 and SPTLC2, encoding the two subunits of serine palmitoyltransferase (SPT), the enzyme catalyzing the first and rate-limiting step in the de novo synthesis of sphingolipids, have been reported to cause HSAN-I. Here, we demonstrate that the SPTLC1 mutations p.S331F and p.A352V result in a reduction of SPT activity in vitro and are associated with increased levels of the deoxysphingoid bases 1-deoxy-sphinganine and 1-deoxymethyl-sphinganine in patients' plasma samples. Stably expressing p.S331F-SPTLC1 HEK293T cell lines likewise show accumulation of deoxysphingoid bases, but this accumulation is not observed in HEK293T cells overexpressing p.A352V-SPTLC1. These results confirm that the increased formation of deoxysphingoid bases is a key feature for HSAN-I as it is associated with all pathogenic SPTLC1 and SPTLC2 mutations reported so far, but also warrant for caution in the interpretation of in vitro data.


Assuntos
Neuropatias Hereditárias Sensoriais e Autônomas/genética , Mutação , Serina C-Palmitoiltransferase/genética , Expressão Gênica , Células HEK293 , Neuropatias Hereditárias Sensoriais e Autônomas/sangue , Neuropatias Hereditárias Sensoriais e Autônomas/patologia , Humanos , Lipídeos , Conformação Proteica , Serina C-Palmitoiltransferase/química , Esfingosina/análogos & derivados , Esfingosina/sangue
14.
Behav Brain Res ; 221(1): 324-8, 2011 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-21420437

RESUMO

Consequences of prenatal alcohol exposure (AE) include motor hyperactivity, disrupted sleep and cognitive deficits. Hypothalamic orexin (ORX)-synthesizing neurons are important for the maintenance of vigilance and regulation of motor activity but their hyperactivity may contribute to anxiety disorders. Using a rat model, we tested whether ORX plays a role in behavioral consequences of prenatal AE. Male rat pups received 2.625 g/kg of alcohol (AE group) intragastrically twice daily on postnatal days (PD)4-9, a developmental period equivalent to the third trimester of human pregnancy. Control pups were sham-intubated (S group). On PD12-14, they received daily injections of either the ORX-1 receptor antagonist, SB-334867 (SB; 20mg/kg, i.p.) or vehicle (V) during the lights-off period. On PD16, they were subjected to the homing response (HR) test. On PD17, their motor activity was monitored in a novel environment. The percentage of tests in which HR acquisition was not achieved and the number of trials needed to reach the shortest HR latency were higher, whereas the percentage of successful trials was lower, in AE-V than in S-V rats (p = 0.0009-0.03). In contrast, these measures were not significantly different between AE-SB and either S-SB or S-V rats. Motor activity in AE-V rats was significantly higher than in S-V (p = 0.003), S-SB (p = 0.007) or AE-SB (p = 0.02) rats, with no difference between S-SB and AE-SB group. Our findings suggest that excessive activity of ORX neurons contributes to motor hyperactivity and impaired HR acquisition following perinatal AE and that these symptoms may be alleviated by systemic antagonism of ORX-1 receptors.


Assuntos
Benzoxazóis/farmacologia , Benzoxazóis/uso terapêutico , Etanol/farmacologia , Comportamento de Retorno ao Território Vital/efeitos dos fármacos , Hipercinese/tratamento farmacológico , Receptores Acoplados a Proteínas-G/antagonistas & inibidores , Receptores de Neuropeptídeos/antagonistas & inibidores , Ureia/análogos & derivados , Animais , Animais Recém-Nascidos , Modelos Animais de Doenças , Interações de Medicamentos , Etanol/antagonistas & inibidores , Hipercinese/induzido quimicamente , Masculino , Receptores de Orexina , Ratos , Ratos Sprague-Dawley , Ureia/farmacologia , Ureia/uso terapêutico
15.
Exp Physiol ; 96(5): 548-55, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21335420

RESUMO

Hypoglossal nerve activity (HNA) controls the position and movements of the tongue. In persons with compromised upper airway anatomy, sleep-related hypotonia of the tongue and other pharyngeal muscles causes increased upper airway resistance, or total upper airway obstructions, thus disrupting both sleep and breathing. Hypoglossal nerve activity reaches its nadir, and obstructive episodes are longest and most severe, during rapid eye movement stage of sleep (REMS). Microinjections of a cholinergic agonist, carbachol, into the pons have been used in vivo to investigate the mechanisms of respiratory control during REMS. Here, we recorded inspiratory-modulated phrenic nerve activity and HNA and microinjected carbachol (25-50 nl, 10 mm) into the pons in an in situ perfused working heart-brainstem rat preparation (WHBP), an ex vivo model previously validated for studies of the chemical and reflex control of breathing. Carbachol microinjections were made into 40 sites in 33 juvenile rat preparations and, at 24 sites, they triggered depression of HNA with increased respiratory rate and little change of phrenic nerve activity, a pattern akin to that during natural REMS in vivo. The REMS-like episodes started 151 ± 73 s (SD) following microinjections, lasted 20.3 ± 4.5 min, were elicited most effectively from the dorsal part of the rostral nucleus pontis oralis, and were prevented by perfusion of the preparation with atropine. The WHBP offers a novel model with which to investigate cellular and neurochemical mechanisms of REMS-related upper airway hypotonia in situ without anaesthesia and with full control over the cellular environment.


Assuntos
Carbacol/farmacologia , Neurônios Motores/efeitos dos fármacos , Ponte/efeitos dos fármacos , Taxa Respiratória/efeitos dos fármacos , Sono REM/efeitos dos fármacos , Sono REM/fisiologia , Animais , Atropina/farmacologia , Agonistas Colinérgicos/farmacologia , Diafragma/efeitos dos fármacos , Nervo Hipoglosso/efeitos dos fármacos , Nervo Hipoglosso/fisiologia , Microinjeções/métodos , Neurônios Motores/fisiologia , Hipotonia Muscular/fisiopatologia , Músculos Faríngeos/efeitos dos fármacos , Nervo Frênico/efeitos dos fármacos , Nervo Frênico/fisiologia , Ponte/fisiologia , Ratos , Taxa Respiratória/fisiologia
16.
Mitochondrion ; 11(3): 413-20, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21167962

RESUMO

Surf1 gene mutations were detected as a main cause for Leigh syndrome (LS), also known as infantile subacute necrotizing encephalomyelopathy. This syndrome which is commonly associated with systemic cytochrome c oxidase (COX) deficiency manifests in early childhood and has an invariable poor prognosis. Progressive disturbances of the respiratory function, for which both the metabolic condition and necrotizing brainstem lesions contribute, belong to the major symptoms of LS. A constitutive knockout (KO) mouse for Surf1 enables invasive investigations of distinct aspects of LS. In the present study the respiratory function was analyzed applying an arterially perfused brainstem preparation. Compared to wild type (WT) preparations Surf1 KO preparations had a higher baseline respiratory frequency and abnormal responses to hypoxia and hypercapnia that involved both respiratory frequency and motor nerve discharge pattern. These data suggest that COX deficiency impairs peripheral and/or central chemoreceptor function.


Assuntos
Hipercapnia/fisiopatologia , Hipóxia/fisiopatologia , Doença de Leigh/diagnóstico , Doença de Leigh/fisiopatologia , Proteínas de Membrana/deficiência , Proteínas de Membrana/metabolismo , Proteínas Mitocondriais/deficiência , Proteínas Mitocondriais/metabolismo , Animais , Células Quimiorreceptoras/fisiologia , Humanos , Doença de Leigh/genética , Masculino , Proteínas de Membrana/genética , Camundongos , Camundongos Knockout , Proteínas Mitocondriais/genética , Modelos Animais , Taxa Respiratória
17.
Lancet Neurol ; 9(11): 1053-9, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20801085

RESUMO

BACKGROUND: Duchenne muscular dystrophy is a rare X-linked progressive disease characterised by loss of ambulation at about age 10 years, with death in early adulthood due to respiratory and cardiac insufficiency. Steroids are effective at slowing the progression of muscle weakness; however, their use is limited by side-effects, prompting the search for alternatives. We assessed the effect of ciclosporin A as monotherapy and in combination with intermittent prednisone for the treatment of ambulant patients with this disorder. METHODS: Our study was a parallel-group, placebo-controlled, double-blind, multicentre trial at trial sites of the German muscular dystrophy network, MD-NET, over 36 months. Ambulant patients with Duchenne muscular dystrophy who were aged 5 years or older were randomly assigned to receive either ciclosporin A (3·5-4·0 mg/kg per day) or matching placebo. Allocation was done centrally with computer-generated random numbers. Patients and investigators were masked to the allocated treatment. After 3 months of treatment, both groups were also given intermittent prednisone for a further 12 months (0·75 mg/kg, alternating 10 days on with 10 days off). All patients who received at least one dose of study drug or placebo were included in the primary analysis. The primary outcome measure was manual muscle strength measured on the Medical Research Council (MRC) scale. This trial is registered with the German clinical trial register DRKS, number DRKS00000445. FINDINGS: 77 patients were randomly assigned to the ciclosporin A group and 76 to the placebo group; 73 patients on ciclosporin A and 73 on placebo received at least one dose and were available for efficacy analyses. 3 months of treatment with ciclosporin A alone did not show any significant improvement in primary outcome measures (mean change in the proportion of a possible total MRC score [%MRC] was -2·6 [SD 6·0] for patients on ciclosporin A and -0·8 [4·9] for patients on placebo; adjusted group difference estimate -0·88, 97·5% CI -2·6 to 0·9; p=0·26). The combination of ciclosporin A with intermittent steroids was not better than intermittent steroids alone over 12 months (mean change in %MRC was 0·7 [7·1] for patients on ciclosporin A and -0·3 [7·9] for patients on placebo; adjusted group difference estimate -0·85, -3·6 to 1·9; p=0·48). Numbers of adverse events (75 in patients on ciclosporin A and 74 on placebo) and serious adverse events (four with ciclosporin A and four with placebo) did not differ significantly between groups. INTERPRETATION: Ciclosporin A alone or in combination with intermittent prednisone does not improve muscle strength or functional abilities in ambulant boys with Duchenne muscular dystrophy, but is safe and well tolerated. FUNDING: German Federal Ministry of Education and Research, Action Benni and co eV, Novartis Pharma AG, and Deutsche Gesellschaft für Muskelkranke eV.


Assuntos
Ciclosporina/uso terapêutico , Distrofia Muscular de Duchenne/tratamento farmacológico , Criança , Método Duplo-Cego , Humanos , Masculino , Distrofia Muscular de Duchenne/fisiopatologia , Literatura de Revisão como Assunto , Resultado do Tratamento
18.
J Neurosci ; 30(5): 1810-21, 2010 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-20130190

RESUMO

Tauopathy comprises hyperphosphorylation of the microtubule-associated protein tau, causing intracellular aggregation and accumulation as neurofibrillary tangles and neuropil treads. Some primary tauopathies are linked to mutations in the MAPT gene coding for protein tau, but most are sporadic with unknown causes. Also, in Alzheimer's disease, the most frequent secondary tauopathy, neither the cause nor the pathological mechanisms and repercussions are understood. Transgenic mice expressing mutant Tau-P301L suffer cognitive and motor defects and die prematurely from unknown causes. Here, in situ electrophysiology in symptomatic Tau-P301L mice (7-8 months of age) revealed reduced postinspiratory discharges of laryngeal motor outputs that control laryngeal constrictor muscles. Under high chemical drive (hypercapnia), postinspiratory discharge was nearly abolished, whereas laryngeal inspiratory discharge was increased disproportionally. The latter may suggest a shift of postinspiratory laryngeal constrictor activity into inspiration. In vivo double-chamber plethysmography of Tau-P301L mice showed significantly reduced respiratory airflow but significantly increased chest movements during baseline breathing, but particularly in hypercapnia, confirming a significant increase in inspiratory resistive load. Histological analysis demonstrated hyperphosphorylated tau in brainstem nuclei, directly or indirectly involved in upper airway motor control (i.e., the Kölliker-Fuse, periaqueductal gray, and intermediate reticular nuclei). In contrast, young Tau-P301L mice did not show breathing disorders or brainstem tauopathy. Consequently, in aging Tau-P301L mice, progressive upper airway dysfunction is linked to progressive tauopathy in identified neural circuits. Because patients with tauopathy suffer from upper airway dysfunction, the Tau-P301L mice can serve as an experimental model to study disease-specific synaptic dysfunction in well defined functional neural circuits.


Assuntos
Tronco Encefálico/metabolismo , Mesencéfalo/metabolismo , Transtornos Respiratórios/genética , Transtornos Respiratórios/patologia , Tauopatias/complicações , Tauopatias/patologia , Proteínas tau/genética , Envelhecimento/genética , Envelhecimento/metabolismo , Animais , Tronco Encefálico/patologia , Modelos Animais de Doenças , Mesencéfalo/patologia , Camundongos , Camundongos Transgênicos , Mutação , Fosforilação , Pletismografia , Ventilação Pulmonar , Transtornos Respiratórios/fisiopatologia , Proteínas tau/metabolismo
19.
Respir Physiol Neurobiol ; 164(1-2): 72-9, 2008 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-18620081

RESUMO

The shape of the three-phase respiratory motor pattern (inspiration, postinspiration, late expiration) is controlled by a central pattern generator (CPG) located in the ponto-medullary brainstem. Synaptic interactions between and within specific sub-compartments of the CPG are subject of intensive research. This review addresses the neural control of postinspiratory activity as the essential determinant of inspiratory/expiratory phase duration. The generation of the postinspiratory phase depends on synaptic interaction between neurones of the nucleus tractus solitarii (NTS), which relay afferent inputs from pulmonary stretch receptors, and the pontine Kölliker-Fuse nucleus (KF) as integral parts of the CPG. Both regions undergo significant changes during the first three postnatal weeks in rodents. Developmental changes in glutamatergic synaptic functions and its modulation by brain-derived neurotrophic factor may have implications in synaptic plasticity within the NTS/KF axis. We propose that dependent on these developmental changes, the CPG becomes permissive for short- and long-term plasticity associated with environmental, metabolic and behavioural adaptation of the breathing pattern.


Assuntos
Adaptação Fisiológica/fisiologia , Plasticidade Neuronal/fisiologia , Neurônios/fisiologia , Dinâmica não Linear , Centro Respiratório/citologia , Centro Respiratório/crescimento & desenvolvimento , Animais , Animais Recém-Nascidos , Vias Neurais/fisiologia , Respiração
20.
Respir Physiol Neurobiol ; 161(1): 10-5, 2008 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-18155647

RESUMO

Apneas are common and prognostically relevant disorders of the central control of breathing, but pharmacological interventions are dissatisfying. The respiratory phenotype of C57BL/6J mice is characterized by the occurrence of spontaneous central apneas with laryngeal closure. In the present study we investigated the impact of the 5-HT(1A) receptor agonist 8-OH-DPAT on apneas in C57BL/6J mice, because of the important role of serotonin in the regulation of breathing and previous reports showing that serotonergic drugs can affect central apneas. Whole-body plethysmography in awake, unrestrained mice revealed that intraperitoneal application of 8-OH-DPAT (10microgkg(-1)) decreased the occurrence of spontaneous apneas from 1.91+/-0.25 to 1.05+/-0.05 apneas min(-1). The efficacy of 5-HT(1A) receptor activation was further verified in the in situ working heart-brainstem preparation. Here the apneas occurred at a frequency of 1.33+/-0.19min(-1). Intra-arterial perfusion with 1-2microM 8-OH-DPAT completely abolished spontaneous apneas. These results suggest that 5-HT(1A) receptor activation may be a potential treatment option for central apneas.


Assuntos
8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Agonistas do Receptor de Serotonina/farmacologia , Apneia do Sono Tipo Central/tratamento farmacológico , Animais , Camundongos , Camundongos Endogâmicos C57BL , Pletismografia Total
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