RESUMEN
BACKGROUND: A significant proportion of people with clozapine-treated schizophrenia develop 'checking' compulsions, a phenomenon yet to be understood. AIMS: To use habit formation models developed in cognitive neuroscience to investigate the dynamic interplay between psychosis, clozapine dose and obsessive-compulsive symptoms (OCS). METHOD: Using the anonymised electronic records of a cohort of clozapine-treated patients, including longitudinal assessments of OCS and psychosis, we performed longitudinal multi-level mediation and multi-level moderation analyses to explore associations of psychosis with obsessiveness and excessive checking. Classic bivariate correlation tests were used to assess clozapine load and checking compulsions. The influence of specific genetic variants was tested in a subsample. RESULTS: A total of 196 clozapine-treated individuals and 459 face-to-face assessments were included. We found significant OCS to be common (37.9%), with checking being the most prevalent symptom. In mediation models, psychosis severity mediated checking behaviour indirectly by inducing obsessions (r = 0.07, 95% CI 0.04-0.09; P < 0.001). No direct effect of psychosis on checking was identified (r = -0.28, 95% CI -0.09 to 0.03; P = 0.340). After psychosis remission (n = 65), checking compulsions correlated with both clozapine plasma levels (r = 0.35; P = 0.004) and dose (r = 0.38; P = 0.002). None of the glutamatergic and serotonergic genetic variants were found to moderate the effect of psychosis on obsession and compulsion (SLC6A4, SLC1A1 and HTR2C) survived the multiple comparisons correction. CONCLUSIONS: We elucidated different phases of the complex interplay of psychosis and compulsions, which may inform clinicians' therapeutic decisions.
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Antipsicóticos , Clozapina , Trastornos Psicóticos , Esquizofrenia Resistente al Tratamiento , Humanos , Clozapina/efectos adversos , Clozapina/uso terapéutico , Masculino , Femenino , Adulto , Antipsicóticos/efectos adversos , Estudios Longitudinales , Trastornos Psicóticos/tratamiento farmacológico , Esquizofrenia Resistente al Tratamiento/tratamiento farmacológico , Esquizofrenia Resistente al Tratamiento/genética , Persona de Mediana Edad , Conducta Compulsiva/inducido químicamente , Trastorno Obsesivo Compulsivo/tratamiento farmacológico , Trastorno Obsesivo Compulsivo/inducido químicamente , Esquizofrenia/tratamiento farmacológicoRESUMEN
BACKGROUND: Obsessive-compulsive symptoms (OCS) are commonly associated with clozapine treatment but are frequently overlooked by clinicians despite their potential impact on patients' quality of life. In this study, we explored whether OCS severity impacted subjective wellbeing and general functioning, independently of depressive and psychotic symptoms. METHODS: We used anonymised electronic healthcare records from a large cohort of patients who were treated with clozapine and assessed annually for OCS, wellbeing, general functioning, and psychopathology using standardised scales as part of routine clinical practice. We used statistical mixed linear model techniques to evaluate the longitudinal influence of OCS severity on wellbeing and general functioning. RESULTS: A total of 184 patients were included, with 527 face-to-face assessments and 64.7% evaluated three or more times. Different linear mixed models demonstrated that OCS in patients treated with clozapine were associated with significantly worse wellbeing scores, independently of depression and psychotic symptoms, but OCS did not impair general functioning. Obsessional thinking and hoarding behaviour, but not compulsions, were significantly associated with the impact on wellbeing, which may be attributable to the ego-syntonic nature of the compulsions. CONCLUSIONS: Given the frequent occurrence of OCS and their negative impact on wellbeing, we encourage clinicians to routinely assess and treat OCS in patients who are taking clozapine.
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Antipsicóticos , Clozapina , Trastorno Obsesivo Compulsivo , Esquizofrenia , Humanos , Clozapina/efectos adversos , Antipsicóticos/efectos adversos , Esquizofrenia/epidemiología , Estudios Longitudinales , Calidad de Vida , Trastorno Obsesivo Compulsivo/tratamiento farmacológico , Trastorno Obsesivo Compulsivo/epidemiología , Trastorno Obsesivo Compulsivo/diagnóstico , Escalas de Valoración Psiquiátrica , ComorbilidadRESUMEN
BACKGROUND: Betaine is an "alternate" methyl donor for homocysteine remethylation catalyzed by betaine homocysteine methyltransferase (BHMT), an enzyme mainly expressed in the liver and kidney. Betaine has been used for more than 30 years in pyridoxine non-responsive cystathionine beta-synthase (pnrCBS) and cobalamin C (cblC) deficiencies to lower the hyperhomocysteinemia, although little is known about the optimal therapeutic dosage and its pharmacokinetic in these patients. AIMS: We compared 2 betaine doses (100 mg/kg/day vs. 250 mg/kg/day) in children affected by pnrCBS or cblC deficiencies. We also measured the pharmacokinetics parameters after a single dose of betaine (100 or 250 mg/kg) in these patients. METHODS: We conducted a prospective, randomized, crossover clinical trial with blinded evaluation. The primary outcome was the equivalence of total plasma homocysteine (tHcy) concentrations upon one-month oral treatment with betaine at 100 versus 250 mg/kg/day. RESULTS: Eleven patients completed the study (5 pnrCBS and 6 cblC). tHcy concentrations were equivalent after a one-month treatment period for the two betaine dosages. Multivariate analysis showed a significant effect of betaine dose on methionine (Met) (p = 0.01) and S-adenosylmethionine (SAM) concentrations (p = 0.006). CONCLUSIONS: Our analysis shows that there is no overt benefit to increasing betaine dosage higher than 100 mg/kg/day to lower tHcy concentrations in pnrCBS and cblC deficiencies. However, increasing betaine up to 250 mg/kg/d could benefit cblC patients through the increase of methionine and SAM concentrations, as low Met and SAM concentrations are involved in the pathophysiology of this disease. In contrast, in pnrCBS deficiency, betaine doses higher than 100 mg/kg/day could be harmful to these patients with pre-existing hypermethioninemia. TRIAL REGISTRATION: Clinical Trials, NCT02404337. Registered 23 May 2015-prospectively registered, https://clinicaltrials.gov .
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Homocistinuria , Deficiencia de Vitamina B 12 , Humanos , Niño , Betaína/uso terapéutico , Estudios Prospectivos , Homocistinuria/tratamiento farmacológico , Cistationina betasintasa/uso terapéutico , Metionina , S-Adenosilmetionina/uso terapéutico , HomocisteínaRESUMEN
We present a patient who developed, after an early-onset, a stable course of spastic paraplegia and ataxia for 4 decades and eventually succumbed to two episodes of postinfectious lactic acidosis. Diagnostic workup including muscle biopsy and postmortem analysis, oxymetric analysis, spectrophotometric enzyme analysis, and MitoExome sequencing revealed a necrotizing leukoencephalomyelopathy due to the so far unreported biallelic variant of the NDUFV1 gene (p.(Pro122Leu)). This case extends our understanding of NDUFV1 variants with a 14-fold longer lifetime than so far reported cases, and will foster sensitivity toward respiratory chain disease also in adult patients with sudden deteriorating neurological deficits.
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Ataxia Cerebelosa , Paraplejía Espástica Hereditaria , Adulto , Ataxia , Ataxia Cerebelosa/genética , Complejo I de Transporte de Electrón/genética , Humanos , Paraplejía/genética , Paraplejía Espástica Hereditaria/genéticaRESUMEN
Rhabdomyolysis with myoglobinuria is a recognized complication of dystrophinopathies. It can be triggered by infections, exercise or volatile anesthetics. To our knowledge, it has never been reported in boys with Duchenne muscular dystrophy (DMD) after the administration of bisphosphonates. We report two patients with DMD who presented an apparent transient rhabdomyolysis with myoglobinuria after zoledronate administration. Possible mechanisms could involve hypophosphatemia, a known dose-dependent side effect of bisphosphonates, and/or direct myotoxicity of biphosphonates. Physicians and families should be aware of rhabdomyolysis with myoglobinuria as a potential uncommon side effect of bisphosphonates in DMD, in particular of zoledronate.
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Conservadores de la Densidad Ósea/efectos adversos , Conservadores de la Densidad Ósea/uso terapéutico , Distrofia Muscular de Duchenne/tratamiento farmacológico , Mioglobinuria/etiología , Ácido Zoledrónico/efectos adversos , Ácido Zoledrónico/uso terapéutico , Adolescente , Humanos , Masculino , Distrofia Muscular de Duchenne/complicacionesRESUMEN
BACKGROUND: Hyperammonaemia is a key sign of decompensation in organic acidurias (OAs) and can contribute to severe neurological complications, thus requiring rapid treatment. METHODS: A post-hoc analysis of two retrospective studies analysed the efficacy of carglumic acid ± ammonia (NH3) scavengers compared with scavengers alone for reducing plasma NH3 levels in patients with OAs and hyperammonaemia (plasma NH3 > 60 µmol/L) during decompensation episodes. NH3 was analysed in 12-h periods at 0-48 h and 24-h periods at 48-120 h. Treatment-emergent adverse events (TEAEs) were recorded. RESULTS: Of 98 episodes, 38 were treated with carglumic acid (34 patients), 33 with NH3 scavengers (22 patients) and 27 with carglumic acid combined with NH3 scavengers (27 patients). Overall, 45% (carglumic acid group), 46% (NH3 scavengers group) and 74% (combination group) of episodes occurred in neonates. Median episode duration was 6 days for the carglumic acid and combination groups, and 9 days for the NH3 scavenger group. Median baseline NH3 level was: 199 µmol/L, carglumic acid; 122 µmol/L, NH3 scavengers; and 271 µmol/L, combination; 13, 30 and 11% of episodes required extracorporeal detoxification (ED), respectively. Data were censored at ED initiation. While baseline NH3 levels were higher in the combination and carglumic acid groups, mean reduction in NH3 levels to 72 h in both groups was greater than the NH3 scavengers' group; reductions were greatest in the combination group. Mean change in plasma NH3 vs baseline in the carglumic acid, NH3 scavengers and combination groups, respectively, was - 13, + 12% and - 27% at 0-12 h (p < 0.05 NH3 scavengers vs combination); - 47, - 22% and - 52% at 12-24 h (not significant); - 44, - 5% and - 61% at 24-48 h; and - 66, - 16% and - 76% at 48-72 h (p < 0.05 carglumic acid/combination groups vs NH3 scavengers for both timepoints). The number of TEAEs was similar between groups and mainly related to the disease/condition. CONCLUSIONS: Carglumic acid is a well-tolerated and efficacious treatment for OA decompensation episodes. When given alone or combined with NH3 scavengers, the reduction in NH3 was greater than with NH3 scavengers alone in the first 72 h.
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Amoníaco/sangre , Glutamatos/uso terapéutico , Hiperamonemia/sangre , Hiperamonemia/tratamiento farmacológico , Adolescente , Adulto , Niño , Preescolar , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND AND OBJECTIVES: Patients affected with methylmalonic acidemia (MMA) and propionic acidemia (PA) exhibit diverse long-term complications and poor outcome. Liver disease is not a reported complication. The aim of this study was to characterize and extensively evaluate long-term liver involvement in MMA and PA patients. PATIENTS AND METHODS: We first describe four patients who had severe liver involvement during the course of their disease. Histology showed fibrosis and/or cirrhosis in 3 patients. Such liver involvement led us to retrospectively collect liver (clinical, laboratory and ultrasound) data of MMA (Nâ¯=â¯12) or PA patients (Nâ¯=â¯16) from 2003 to 2016. RESULTS: Alpha-fetoprotein (αFP) levels were increased in 8/16 and 3/12 PA and MMA patients, respectively, and tended to increase with age. Moderate and recurrent increase of GGT was observed in 4/16 PA patients and 4/12 MMA patients. Abnormal liver ultrasound with either hepatomegaly and/or hyperechoic liver was observed in 7/9 PA patients and 3/9 MMA patients. CONCLUSIONS: These data demonstrate that approximately half of the patients affected by MMA or PA had signs of liver abnormalities. The increase of αFP with age suggests progressive toxicity, which might be due to the metabolites accumulated in PA and MMA. These metabolites (e.g., methylmalonic acid and propionic acid derivatives) have previously been reported to have mitochondrial toxicity; this toxicity is confirmed by the results of histological and biochemical mitochondrial analyses of the liver in two of our MMA patients. In contrast to the moderate clinical, laboratory or ultrasound expression, severe pathological expression was found for three of the 4 patients who underwent liver biopsy, ranging from fibrosis to cirrhosis. These results emphasize the need for detailed liver function evaluation in organic aciduria patients, including liver biopsy when liver disease is suspected. TAKE HOME MESSAGE: MMA and PA patients exhibit long-term liver abnormalities.
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Errores Innatos del Metabolismo de los Aminoácidos/complicaciones , Hepatopatías/etiología , Hepatopatías/patología , Acidemia Propiónica/complicaciones , Adolescente , Adulto , Niño , Preescolar , Femenino , Estudios de Seguimiento , Humanos , Masculino , Pronóstico , Estudios Retrospectivos , Adulto JovenRESUMEN
OBJECTIVES: Early lung cancer (LC) diagnosis is key to improve prognosis. We explored here the diagnostic performance of a trained dog to discriminate exhaled gas samples obtained from patients with and patients without LC and healthy controls. METHODS: After appropriate training, we exposed the dog (a 3-year-old cross-breed between a Labrador Retriever and a Pitbull) to 390 samples of exhaled gas collected from 113 individuals (85 patients with LC and 28 controls, which included 11 patients without LC and 17 healthy individuals) for a total of 785 times. RESULTS: The trained dog recognized LC in exhaled gas with a sensitivity of 0.95, a specificity of 0.98, a positive predictive value of 0.95 and a negative predictive value of 0.98. The area under the curve of the receiver-operating characteristics curve was 0.971. CONCLUSIONS: This study shows that a well-trained dog can detect the presence of LC in exhaled gas samples with an extremely high accuracy.
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Pruebas Respiratorias/métodos , Detección Precoz del Cáncer , Espiración/fisiología , Neoplasias Pulmonares/diagnóstico , Adulto , Anciano , Anciano de 80 o más Años , Animales , Perros , Femenino , Humanos , Neoplasias Pulmonares/metabolismo , Masculino , Persona de Mediana Edad , Proyectos Piloto , Curva ROCRESUMEN
This phase 2 portion of a phase 1/2 study examined the efficacy and safety of LY2603618, a selective checkpoint kinase 1 inhibitor, combined with pemetrexed and cisplatin (LY+Pem+Cis) in patients with advanced nonsquamous non-small cell lung cancer (NSCLC). This multicenter, randomized, controlled, open-label study (NCT01139775) enrolled patients with stage IV nonsquamous NSCLC and an Eastern Cooperative Oncology Group performance status ≤1. Patients were randomized (2:1) to LY+Pem+Cis or pemetrexed and cisplatin (Pem+Cis). Induction therapy comprised four 21-day cycles of 500 mg/m2 pemetrexed and 75mg/m2 cisplatin on Day 1 (both arms) and 275mg LY2603618 on Day 2 (LY+Pem+Cis arm). Maintenance therapy comprised 500mg/m2 pemetrexed on Day 1 (both arms) and 275mg LY2603618 on Day 2 (LY+Pem+Cis arm) until disease progression. The primary endpoint was progression-free survival (PFS). Enrollment was permanently halted before target enrollment was met due to a greater number of thromboembolic events in the LY+Pem+Cis arm. Sixty-two patients were enrolled (LY+Pem+Cis, n=39; Pem+Cis, n=23). Bayesian and frequentist analysis demonstrated superior PFS in the LY+Pem+Cis arm vs the Pem+Cis arm (median [90% confidence interval]: LY+Pem+Cis, 4.7 months [4.-7.1]; Pem+Cis, 1.5 months [1.3-2.9]; P=0.022). Seven patients in the LY+Pem+Cis arm (vs 0 in the Pem+Cis arm) experienced serious thromboembolic events: pulmonary embolism (n=5), ischemic stroke (n=1), and cerebrovascular accident (n=1). Although the primary endpoint was met, the combination of LY2603618+Pem+Cis will not be further developed for treating advanced nonsquamous NSCLC due to the potential increased risk of thromboembolic events with this combination. ClinicalTrials.gov Identifier: NCT01139775.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1)/antagonistas & inhibidores , Cisplatino/administración & dosificación , Progresión de la Enfermedad , Femenino , Humanos , Quimioterapia de Inducción , Estimación de Kaplan-Meier , Neoplasias Pulmonares/mortalidad , Quimioterapia de Mantención , Masculino , Pemetrexed/administración & dosificación , Compuestos de Fenilurea/administración & dosificación , Pirazinas/administración & dosificación , Resultado del TratamientoRESUMEN
PURPOSE: To describe the retinal structure of a group of patients affected by methylmalonic aciduria with homocystinuria cblC type, caused by mutations in the MMACHC gene, using spectral domain optical coherence tomography (SD-OCT). METHODS: Young patients (n = 11, age 0-74 months) with cblC disease, detected by newborn screening or clinically diagnosed within 40 days of life, underwent molecular analysis and complete ophthalmic examination, including fundus photography and SD-OCT. In one case, we also performed fluorescein angiography (FA) and standard electroretinography (ERG). RESULTS: Molecular analysis of the MMACHC gene fully confirmed cblC disease in nine of 11 patients. Two patients harboured only a single heterozygous pathogenic MMACHC mutation and large unbalanced rearrangements were excluded by array-CGH analysis in both. All patients except two showed a bilateral maculopathy. In general, retinal changes were first observed before one year of age and progressed to a well-established maculopathy. Measurable visual acuities ranged from normal vision, in keeping with age, to bilateral, severe impairment of central vision. Nystagmus was present in six patients. Spectral domain optical coherence tomography (SD-OCT) showed macular thinning with severe alterations in outer, and partial sparing of inner, retinal layers. CONCLUSION: Patients affected by cblC disease may frequently show an early onset maculopathy with variable ophthalmoscopic appearance. Spectral domain optical coherence tomography (SD-OCT) broadens the knowledge of subtle retinal alterations during the disease's progression and helps to shed light on the pathological mechanism of maculopathy development.
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ADN/genética , Homocistinuria/complicaciones , Mácula Lútea/patología , Ácido Metilmalónico/orina , Mutación , Proteínas Proto-Oncogénicas c-cbl/genética , Enfermedades de la Retina/genética , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Niño , Preescolar , Análisis Mutacional de ADN , Electrorretinografía , Femenino , Homocistinuria/genética , Homocistinuria/metabolismo , Humanos , Lactante , Recién Nacido , Masculino , Oftalmoscopía , Oxidorreductasas , Reacción en Cadena de la Polimerasa , Proteínas Proto-Oncogénicas c-cbl/metabolismo , Enfermedades de la Retina/diagnóstico , Enfermedades de la Retina/etiología , Tomografía de Coherencia ÓpticaRESUMEN
The objective is to evaluate Grifols' DG-PT L Rec liquid reagent for prothrombin time (PT) determination in comparison to the laboratory's reference reagent (Siemens' Thromborel S). For linearity, the average master curve for PT and five nominal prothrombin concentrations was obtained from five calibration curves. Within-assay precision (repeatability) was calculated after measuring 20 successive tests of normal and pathological controls. For correlation, 581 routine clinical citrated plasma samples were assessed with both reagents. The BCS XP hemostasis analyzer was used. Linearity of the DG-PT L Rec was good (Pâ<â0.001). The coefficient of variation met the desirable imprecision of less than 2% (normal controls: 1.7%; pathological controls: 0.9%). Correlation between DG-PT L Rec and Thromborel S was high (râ=â0.9795; PT in %). In subgroups of anticoagulated, low fibrinogen, lipemic, jaundice, and hemolyzed samples the correlation was more than 0.95. Performance of DG-PT L Rec was high and comparable to the reference reagent.
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Pruebas de Coagulación Sanguínea/métodos , Tiempo de Protrombina/métodos , Tromboplastina/uso terapéutico , Hemostasis , Humanos , Estudios Prospectivos , Tromboplastina/farmacologíaRESUMEN
Primary 5-oxoprolinuria (pyroglutamic aciduria) is caused by a genetic defect in the γ-glutamyl cycle, affecting either glutathione synthetase or 5-oxoprolinase. While several dozens of patients with glutathione synthetase deficiency have been reported, with hemolytic anemia representing the clinical key feature, 5-oxoprolinase deficiency due to OPLAH mutations is less frequent and so far has not attracted much attention. This has prompted us to investigate the clinical phenotype as well as the underlying genotype in patients from 14 families of various ethnic backgrounds who underwent diagnostic mutation analysis following the detection of 5-oxoprolinuria. In all patients with 5-oxoprolinuria studied, bi-allelic mutations in OPLAH were indicated. An autosomal recessive mode of inheritance for 5-oxoprolinase deficiency is further supported by the identification of a single mutation in all 9/14 parent sample sets investigated (except for the father of one patient whose result suggests homozygosity), and the absence of 5-oxoprolinuria in all tested heterozygotes. It is remarkable, that all 20 mutations identified were novel and private to the respective families. Clinical features were highly variable and in several sib pairs, did not segregate with 5-oxoprolinuria. Although a pathogenic role of 5-oxoprolinase deficiency remains possible, this is not supported by our findings. Additional patient ascertainment and long-term follow-up is needed to establish the benign nature of this inborn error of metabolism. It is important that all symptomatic patients with persistently elevated levels of 5-oxoproline and no obvious explanation are investigated for the genetic etiology.
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Errores Innatos del Metabolismo de los Aminoácidos/genética , Glutatión Sintasa/deficiencia , Piroglutamato Hidrolasa/deficiencia , Piroglutamato Hidrolasa/genética , Ácido Pirrolidona Carboxílico/metabolismo , Adolescente , Alelos , Errores Innatos del Metabolismo de los Aminoácidos/enzimología , Errores Innatos del Metabolismo de los Aminoácidos/fisiopatología , Niño , Preescolar , Femenino , Glutatión/metabolismo , Glutatión Sintasa/genética , Heterocigoto , Homocigoto , Humanos , Lactante , Masculino , MutaciónRESUMEN
Alterations in reward processes may underlie motivational and anhedonic symptoms in depression and schizophrenia. However it remains unclear whether these alterations are disorder-specific or shared, and whether they clearly relate to symptom generation or not. We studied brain responses to unexpected rewards during a simulated slot-machine game in 24 patients with depression, 21 patients with schizophrenia, and 21 healthy controls using functional magnetic resonance imaging. We investigated relationships between brain activation, task-related motivation, and questionnaire rated anhedonia. There was reduced activation in the orbitofrontal cortex, ventral striatum, inferior temporal gyrus, and occipital cortex in both depression and schizophrenia in comparison with healthy participants during receipt of unexpected reward. In the medial prefrontal cortex both patient groups showed reduced activation, with activation significantly more abnormal in schizophrenia than depression. Anterior cingulate and medial frontal cortical activation predicted task-related motivation, which in turn predicted anhedonia severity in schizophrenia. Our findings provide evidence for overlapping hypofunction in ventral striatal and orbitofrontal regions in depression and schizophrenia during unexpected reward receipt, and for a relationship between unexpected reward processing in the medial prefrontal cortex and the generation of motivational states.
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Anhedonia/fisiología , Trastorno Depresivo/fisiopatología , Lóbulo Frontal/fisiopatología , Recompensa , Esquizofrenia/fisiopatología , Psicología del Esquizofrénico , Estriado Ventral/fisiopatología , Adulto , Mapeo Encefálico , Femenino , Juegos Experimentales , Humanos , Imagen por Resonancia Magnética , Masculino , Motivación , Vías Nerviosas/fisiopatologíaRESUMEN
In the research domain framework (RDoC), dysfunctional reward expectation has been proposed to be a cross-diagnostic domain in psychiatry, which may contribute to symptoms common to various neuropsychiatric conditions, such as anhedonia or apathy/avolition. We used a modified version of the Monetary Incentive Delay (MID) paradigm to obtain functional MRI images from 22 patients with schizophrenia, 24 with depression and 21 controls. Anhedonia and other symptoms of depression, and overall positive and negative symptomatology were also measured. We hypothesized that the two clinical groups would have a reduced activity in the ventral striatum when anticipating reward (compared to anticipation of a neutral outcome) and that striatal activation would correlate with clinical measures of motivational problems and anhedonia. Results were consistent with the first hypothesis: two clusters in both the left and right ventral striatum were found to differ between the groups in reward anticipation. Post-hoc analysis showed that this was due to higher activation in the controls compared to the schizophrenia and the depression groups in the right ventral striatum, with activation differences between depression and controls also seen in the left ventral striatum. No differences were found between the two patient groups, and there were no areas of abnormal cortical activation in either group that survived correction for multiple comparisons. Reduced ventral striatal activity was related to greater anhedonia and overall depressive symptoms in the schizophrenia group, but not in the participants with depression. Findings are discussed in relation to previous literature but overall are supporting evidence of reward system dysfunction across the neuropsychiatric continuum, even if the specific clinical relevance is still not fully understood. We also discuss how the RDoC approach may help to solve some of the replication problems in psychiatric fMRI research.
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We report two unrelated patients with a multisystem disease involving liver, eye, immune system, connective tissue, and bone, caused by biallelic mutations in the neuroblastoma amplified sequence (NBAS) gene. Both presented as infants with recurrent episodes triggered by fever with vomiting, dehydration, and elevated transaminases. They had frequent infections, hypogammaglobulinemia, reduced natural killer cells, and the Pelger-Huët anomaly of their granulocytes. Their facial features were similar with a pointed chin and proptosis; loose skin and reduced subcutaneous fat gave them a progeroid appearance. Skeletal features included short stature, slender bones, epiphyseal dysplasia with multiple phalangeal pseudo-epiphyses, and small C1-C2 vertebrae causing cervical instability and myelopathy. Retinal dystrophy and optic atrophy were present in one patient. NBAS is a component of the synthaxin-18 complex and is involved in nonsense-mediated mRNA decay control. Putative loss-of-function mutations in NBAS are already known to cause disease in humans. A specific founder mutation has been associated with short stature, optic nerve atrophy and Pelger-Huët anomaly of granulocytes (SOPH) in the Siberian Yakut population. A more recent report associates NBAS mutations with recurrent acute liver failure in infancy in a group of patients of European descent. Our observations indicate that the phenotypic spectrum of NBAS deficiency is wider than previously known and includes skeletal, hepatic, metabolic, and immunologic aspects. Early recognition of the skeletal phenotype is important for preventive management of cervical instability.
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Anomalías Múltiples/genética , Mutación , Proteínas de Neoplasias/genética , Anomalías Múltiples/etiología , Niño , Preescolar , Femenino , Humanos , Sistema Inmunológico/fisiopatología , Lactante , Hepatopatías/genética , Masculino , Atrofia Óptica/genética , Anomalía de Pelger-Huët/etiología , Embarazo , Retina/patología , Piel/patologíaRESUMEN
We report a toddler affected with Angelman syndrome and isovaleric acidemia (IVA). Such association was due to paternal uniparental isodisomy (UPD) of chromosome 15 in which the proband inherited two paternal copies of an IVA gene point mutation. As both diseases may have severe impact on neurodevelopment, adequate treatment of IVA should be discussed. In our patient however, the variant identified likely causes asymptomatic organic aciduria. Such findings emphasize that paternal UPD 15 can rarely lead to co-occurrence of Angelman syndrome and potentially treatable inborn errors of metabolism.
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Negative symptoms occur in several major mental health disorders with undetermined mechanisms and unsatisfactory treatments; identification of their neural correlates might unveil the underlying pathophysiological basis and pinpoint the therapeutic targets. In this study, participants with major depressive disorder (n = 24), schizophrenia (n = 22), and healthy controls (n = 20) were assessed with 10 frequently used negative symptom scales followed by principal component analysis (PCA) of the scores. A linear model with the prominent components identified by PCA was then regressed on gray and white-matter volumes estimated from T1-weighted magnetic resonance imaging. In depressed patients, negative symptoms such as blunted affect, alogia, withdrawal, and cognitive impairment, assessed mostly via clinician-rated scales were inversely associated with gray matter volume in the bilateral cerebellum. In patients with schizophrenia, anhedonia, and avolition evaluated via self-rated scales inversely related to white-matter volume in the left anterior limb of internal capsule/anterior thalamic radiation and positively in the left superior longitudinal fasiculus. The pathophysiological mechanisms underlying negative symptoms might differ between depression and schizophrenia. These results also point to future negative symptom scale development primarily focused on detecting and monitoring the corresponding changes to brain structure or function.
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BACKGROUND: Hepatorenal tyrosinaemia (Tyr 1) is a rare inborn error of tyrosine metabolism. Without treatment, patients are at high risk of developing acute liver failure, renal dysfunction and in the long run hepatocellular carcinoma. The aim of our study was to collect cross-sectional data. METHODS: Via questionnaires we collected retrospective data of 168 patients with Tyr 1 from 21 centres (Europe, Turkey and Israel) about diagnosis, treatment, monitoring and outcome. In a subsequent consensus workshop, we discussed data and clinical implications. RESULTS: Early treatment by NTBC accompanied by diet is essential to prevent serious complications such as liver failure, hepatocellular carcinoma and renal disease. As patients may remain initially asymptomatic or develop uncharacteristic clinical symptoms in the first months of life newborn mass screening using succinylacetone (SA) as a screening parameter in dried blood is mandatory for early diagnosis. NTBC-treatment has to be combined with natural protein restriction supplemented with essential amino acids. NTBC dosage should be reduced to the minimal dose allowing metabolic control, once daily dosing may be an option in older children and adults in order to increase compliance. Metabolic control is judged by SA (below detection limit) in dried blood or urine, plasma tyrosine (<400 µM) and NTBC-levels in the therapeutic range (20-40 µM). Side effects of NTBC are mild and often transient. Indications for liver transplantation are hepatocellular carcinoma or failure to respond to NTBC. Follow-up procedures should include liver and kidney function tests, tumor markers and imaging, ophthalmological examination, blood count, psychomotor and intelligence testing as well as therapeutic monitoring (SA, tyrosine, NTBC in blood). CONCLUSION: Based on the data from 21 centres treating 168 patients we were able to characterize current practice and clinical experience in Tyr 1. This information could form the basis for clinical practice recommendations, however further prospective data are required to underpin some of the recommendations.
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Ciclohexanonas/uso terapéutico , Inhibidores Enzimáticos/uso terapéutico , Tamizaje Neonatal/métodos , Nitrobenzoatos/uso terapéutico , Tirosinemias/diagnóstico , Tirosinemias/terapia , Adolescente , Niño , Preescolar , Estudios Transversales , Ciclohexanonas/efectos adversos , Inhibidores Enzimáticos/efectos adversos , Femenino , Estudios de Seguimiento , Humanos , Lactante , Recién Nacido , Fallo Hepático/diagnóstico , Fallo Hepático/cirugía , Trasplante de Hígado , Masculino , Nitrobenzoatos/efectos adversos , Enfermedades Raras/diagnóstico , Enfermedades Raras/tratamiento farmacológico , Insuficiencia Renal/diagnóstico , Insuficiencia Renal/cirugía , Estudios Retrospectivos , Encuestas y Cuestionarios , Resultado del Tratamiento , Adulto JovenRESUMEN
Mutations in the CACNA1A gene, encoding the α1 subunit of the voltage-gated calcium channel Ca(V)2.1 (P/Q-type), have been associated with three neurological phenotypes: familial and sporadic hemiplegic migraine type 1 (FHM1, SHM1), episodic ataxia type 2 (EA2), and spinocerebellar ataxia type 6 (SCA6). We report a child with congenital ataxia, abnormal eye movements and developmental delay who presented severe attacks of hemiplegic migraine triggered by minor head traumas and associated with hemispheric swelling and seizures. Progressive cerebellar atrophy was also observed. Remission of the attacks was obtained with acetazolamide. A de novo 3 bp deletion was found in heterozygosity causing loss of a phenylalanine residue at position 1502, in one of the critical transmembrane domains of the protein contributing to the inner part of the pore. We characterized the electrophysiology of this mutant in a Xenopus oocyte in vitro system and showed that it causes gain of function of the channel. The mutant Ca(V)2.1 activates at lower voltage threshold than the wild type. These findings provide further evidence of this molecular mechanism as causative of FHM1 and expand the phenotypic spectrum of CACNA1A mutations with a child exhibiting severe SHM1 and non-episodic ataxia of congenital onset.
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Ataxia/complicaciones , Ataxia/genética , Edema Encefálico/complicaciones , Edema Encefálico/genética , Canales de Calcio/genética , Ataxia Cerebelosa/complicaciones , Ataxia Cerebelosa/genética , Trastornos Migrañosos/complicaciones , Trastornos Migrañosos/genética , Acetazolamida/uso terapéutico , Adolescente , Animales , Ataxia/tratamiento farmacológico , Edema Encefálico/tratamiento farmacológico , Canales de Calcio/fisiología , Ataxia Cerebelosa/tratamiento farmacológico , Niño , Preescolar , Femenino , Predisposición Genética a la Enfermedad/genética , Humanos , Lactante , Imagen por Resonancia Magnética , Potenciales de la Membrana , Trastornos Migrañosos/tratamiento farmacológico , Mutación Missense/genética , Neuroimagen , Oocitos , Xenopus laevisRESUMEN
Spondylo-megaepiphyseal-metaphyseal dysplasia (SMMD; OMIM 613330) is a dysostosis/dysplasia caused by recessive mutations in the homeobox-containing gene, NKX3-2 (formerly known as BAPX1). Because of the rarity of the condition, its diagnostic features and natural course are not well known. We describe clinical and radiographic findings in six patients (five of which with homozygous mutations in the NKX3-2 gene) and highlight the unusual and severe changes in the cervical spine and the neurologic complications. In individuals with SMMD, the trunk and the neck are short, while the limbs, fingers and toes are disproportionately long. Radiographs show a severe ossification delay of the vertebral bodies with sagittal and coronal clefts, missing ossification of the pubic bones, large round "balloon-like" epiphyses of the long bones, and presence of multiple pseudoepiphyses at all metacarpals and phalanges. Reduced or absent ossification of the cervical vertebrae leads to cervical instability with anterior or posterior kinking of the cervical spine (swan neck-like deformity, kyknodysostosis). As a result of the cervical spine instability or deformation, five of six patients in our series suffered cervical cord injury that manifested clinically as limb spasticity. Although the number of individuals observed is small, the high incidence of cervical spine deformation in SMMD is unique among skeletal dysplasias. Early diagnosis of SMMD by recognition of the radiographic pattern might prevent of the neurologic complications via prophylactic cervical spine stabilization.