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BACKGROUND: The care organization of persons with profound intellectual and multiple disabilities (PIMD) varies by country according to the health care system. This study used a large sample of French individuals with severe PIMD/polyhandicap to assess: 1) the adequacy of care setting over a 5-year period and 2) health care consumption. METHODS: The longitudinal study used data from the French EVALuation PoLyHandicap (EVAL-PLH) cohort of persons with severe PIMD/polyhandicap who were receiving managed in specialized care centres and residential facilities. Two assessments were performed: wave 1 (T1) in 2015-2016 and wave 2 (T2) in 2020-2021. The inclusion criteria were as follows: age > 3 years at the time of inclusion; age at onset of cerebral lesion younger than 3 years old; and severe PIMD. The adequacy of the care setting was based on the following: i) objective indicators, i.e., adequacy for age and adequacy for health status severity; ii) subjective indicators, i.e., self-perception of the referring physician about medical care adequacy and educational care adequacy. Health care consumption was assessed based on medical and paramedical care. RESULTS: Among the 492 persons assessed at the 2 times, 50% of individuals at T1 and 46% of individuals at T2 were in an inadequate care setting based on age and severity. Regarding global subjective inadequacy, the combination of medical adequacy and educational adequacy, 7% of individuals at T1 and 13% of individuals at T2 were in an inadequate care setting. At T2, a majority of individuals were undermonitored by medical care providers (general practitioners, physical medicine rehabilitation physicians, neurologists, orthopaedists, etc.). Important gaps were found between performed and prescribed sessions of various paramedical care (physiotherapy, occupational therapy, psychomotor therapy, etc.). CONCLUSIONS: This study revealed key elements of inadequate care management for persons with severe PIMD/polyhandicap in France. Based on these important findings, healthcare workers, familial caregivers, patients experts, and health decision-makers should develop appropriate care organizations to optimize the global care management of these individuals. TRIAL REGISTRATION: NCT02400528, registered 27/03/2015.
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Personas con Discapacidad , Discapacidad Intelectual , Preescolar , Humanos , Atención a la Salud , Personas con Discapacidad/rehabilitación , Estado de Salud , Discapacidad Intelectual/terapia , Estudios LongitudinalesRESUMEN
INTRODUCTION: Parents of persons with profound intellectual and multiple disabilities (PIMD) play a major and often lifelong role in the care and support of their child. A better understanding of parents' perspectives regarding their experiences of parenting their child with PIMD is essential to support them more effectively. Although this topic has been explored extensively in Anglo-Saxon and Northern European countries, little is known about the experience of these parents in a highly institutionalized context such as that in France. OBJECTIVE: We explored parents' experiences of the activities they performed to care for their child with PIMD (namely, the 'parenting work') in the French context. METHOD: Qualitative semistructured interviews were conducted by telephone with 34 parents of persons with PIMD aged 8-35. The resulting data were analyzed using thematic analysis. RESULTS: The analysis highlighted the diversity of activities performed by parents as well as the influence of context on the forms of this parenting work. Five themes were developed: (1) navigating the challenges of obtaining medical recognition; (2) negotiating a concealed domain and becoming an expert; (3) unfolding medical and medicosocial care management; (4) navigating the challenges of daily living and (5) shaping one's child's possibilities. CONCLUSION: This study offers a better understanding of the challenges, levers and expectations of parents of children with PIMD in France. Contextual factors such as the lack of knowledge of PIMD among health professionals, access to knowledge and know-how associated with care management, the administrative complexity of access to care and equipment, institutional issues (e.g., professional turnover) and societal ableism (e.g., access to infrastructures, interpersonal discrimination) shape the work parents perform to support their child's needs. It is necessary to consider contextual aspects to better support these parents and their children. Suggestions for applications are provided in the discussion. PATIENT OR PUBLIC CONTRIBUTION: One of the researchers, a parent of a child with PIMD, supported the research design and provided feedback on the study's procedures and manuscript.
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The aim of the study was to identify daytime predictors of nocturnal gas exchange anomalies in children with neuromuscular disease (NMD) and normal daytime gas exchange. Lung function tests, respiratory muscle evaluation and nocturnal gas exchange were obtained as part of routine evaluation. We included 52 consecutive children with Duchenne muscular dystrophy (n = 20), spinal muscular atrophy (n = 10) and other NMD (n = 22). 20 patients had nocturnal hypoxaemia, defined as minimal arterial oxygen saturation measured by pulse oximetry (S(p,O(2))) <90% for ≥ 2% of night time, and 22 had nocturnal hypercapnia, defined as maximal transcutaneous carbon dioxide tension (P(tc,CO(2))) >50 mmHg for ≥ 2% of night time. Forced vital capacity and helium functional residual capacity correlated with minimal nocturnal S(p,O(2)) (p = 0.009 and p = 0.01, respectively). Daytime pH correlated negatively with maximal nocturnal P(tc,CO(2)) (p=0.005) and daytime arterial carbon dioxide tension (P(a,CO(2))) correlated with the percentage of time with a P(tc,CO(2)) >50 mmHg (p = 0.02). Sniff nasal inspiratory pressure correlated with minimal nocturnal S(p,O(2)) (p = 0.02). Daytime P(a,CO(2)) was a weak predictor of nocturnal hypercapnia (sensitivity 80%; specificity 57%). Daytime lung function and respiratory muscle parameters correlate poorly with nocturnal hypoxaemia and hypercapnia in children with NMD and normal daytime gas exchange, which necessitates more systematic sleep studies in these children.
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Ritmo Circadiano/fisiología , Hipercapnia/fisiopatología , Hipoxia/fisiopatología , Enfermedades Neuromusculares/fisiopatología , Adolescente , Niño , Preescolar , Femenino , Humanos , Masculino , Oximetría , Oxígeno/sangre , Polisomnografía , Intercambio Gaseoso Pulmonar/fisiología , Pruebas de Función Respiratoria , Músculos Respiratorios/fisiopatología , Adulto JovenRESUMEN
OBJECTIVE: Mutations in the genes encoding the extracellular matrix protein collagen VI (ColVI) cause a spectrum of disorders with variable inheritance including Ullrich congenital muscular dystrophy, Bethlem myopathy, and intermediate phenotypes. We extensively characterized, at the clinical, cellular, and molecular levels, 49 patients with onset in the first 2 years of life to investigate genotype-phenotype correlations. METHODS: Patients were classified into 3 groups: early-severe (18%), moderate-progressive (53%), and mild (29%). ColVI secretion was analyzed in patient-derived skin fibroblasts. Chain-specific transcript levels were quantified by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), and mutation identification was performed by sequencing of complementary DNA. RESULTS: ColVI secretion was altered in all fibroblast cultures studied. We identified 56 mutations, mostly novel and private. Dominant de novo mutations were detected in 61% of the cases. Importantly, mutations causing premature termination codons (PTCs) or in-frame insertions strikingly destabilized the corresponding transcripts. Homozygous PTC-causing mutations in the triple helix domains led to the most severe phenotypes (ambulation never achieved), whereas dominant de novo in-frame exon skipping and glycine missense mutations were identified in patients of the moderate-progressive group (loss of ambulation). INTERPRETATION: This work emphasizes that the diagnosis of early onset ColVI myopathies is arduous and time-consuming, and demonstrates that quantitative RT-PCR is a helpful tool for the identification of some mutation-bearing genes. Moreover, the clinical classification proposed allowed genotype-phenotype relationships to be explored, and may be useful in the design of future clinical trials.
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Colágeno Tipo VII/genética , Colágeno Tipo VII/metabolismo , Enfermedades Musculares , Mutación/genética , Estadística como Asunto , Adolescente , Adulto , Células Cultivadas , Niño , Preescolar , Europa (Continente) , Femenino , Fibroblastos/metabolismo , Pruebas Genéticas/métodos , Glicina/genética , Humanos , Masculino , Músculo Esquelético/metabolismo , Enfermedades Musculares/genética , Enfermedades Musculares/metabolismo , Enfermedades Musculares/patología , Fenotipo , Adulto JovenRESUMEN
OBJECTIVE: To delineate the phenotype associated with biallelic ATAD1 variants. METHODS: We describe 2 new patients with ATAD1-related disorder diagnosed by whole-exome sequencing and compare their phenotype to 6 previous patients. RESULTS: Patients 1 and 2 had a similar distinctive phenotype comprising congenital stiffness of limbs, absent spontaneous movements, weak sucking, and hypoventilation. Both had absent brainstem evoked auditory responses (BEARs). Patient 1 carried the homozygous p.(His357Argfs*15) variant in ATAD1. In the light of the finding in patient 1, a second reading of exome data for patient 2 revealed the novel homozygous p.(Gly128Val) variant. CONCLUSIONS: Analysis of the phenotypes of these 2 patients and of the 6 previous cases showed that biallelic ATAD1 mutations are responsible for a unique congenital encephalopathy likely comprising absent BEAR, different from hyperekplexia and other conditions with neonatal hypertonia.
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Inverted duplications with terminal deletions have been reported for an increasing number of chromosome ends. The best characterized and most frequent rearrangement reported involves the short arm of chromosome 8. It derives from non-allelic homologous recombination (NAHR) between two inverted LCRs (low copy repeats) of the olfactory receptor (OR) gene cluster during maternal meiosis. We report here on the cytogenetic characterization of the first inversion duplication deletion involving the short arm of chromosome 20 (inv dup del 20p) in an 18-month-old boy presenting with clinical signs consistent with 20p trisomy syndrome. This abnormality was suspected on karyotyping, but high-resolution molecular cytogenetic investigations were required to define the breakpoints of the rearrangement and to obtain insight into the mechanism underlying its formation. The duplicated region was estimated to be 18.16 Mb in size, extending from 20p13 to 20p11.22, and the size of the terminal deletion was estimated at 2.02 Mb in the 20p13 region. No single copy region was detected between the deleted and duplicated segments. As neither LCR nor inversion was identified in the 20p13 region, the inv dup del (20p) chromosome abnormality probably did not arise by NAHR. The most likely mechanism involves a break in the 20p13 region, leading to chromosome instability and reparation by U-type exchange or end-to-end fusion.
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Aberraciones Cromosómicas , Trastornos de los Cromosomas/genética , Inversión Cromosómica , Cromosomas Humanos Par 20/genética , Análisis Citogenético , Rotura Cromosómica , Cromosomas Artificiales Bacterianos , Discapacidades del Desarrollo/genética , Colorantes Fluorescentes/metabolismo , Humanos , Hibridación Fluorescente in Situ , Indoles/metabolismo , Lactante , Discapacidad Intelectual/genética , Cariotipificación , Masculino , Modelos Genéticos , Hibridación de Ácido Nucleico , Recombinación Genética , TrisomíaRESUMEN
BACKGROUND: Carpal tunnel syndrome (CTS) is a common complication of the mucopolysaccharidoses. In severe or attenuated mucopolysaccharidoses patients, clinical symptoms of CTS usually appear at a late stage of median nerve compression. Relying on CTS symptoms is often too late and there is a risk of axonal damage and further irreversible sequelae. Electroneurography is a powerful technique to detect the initial preclinical signs of median nerve compression. In a retrospective series of 13 children with mucopolysaccharidoses (10 Hunter, one Hurler-Scheie and 2 Hurler children), we describe the electroneurography progression of CTS (43 hand evaluations) and the severity of median nerve damage. RESULTS: The average age at mucopolysaccharidoses diagnosis was 33.6 months (11-66 months). Clinical signs of CTS appeared on average 44.6 months (0-73 months) after diagnosis of mucopolysaccharidoses. Electroneurography anomalies suggestive of CTS appeared as early as the age of 3.5 years and probably preceded clinical signs of CTS. Median nerve compression was bilateral and distal, initially on the sensory pathway then becoming motor-sensory. Beyond a threshold of 14 m/sec median distal motor nerve conduction velocity (MNCVd) and index of terminal latency (MNCVd/MNCVp) of 0.27, there was true distal conduction slowdown. CONCLUSIONS: To prevent irreversible sequelae of median nerve compression, we suggest annual electroneurography testing for mucopolysaccharidoses patients starting as early as 3 years of age, including both motor and sensory nerve pathways, on median and, in reference to the ulnar nerves, bilaterally at the wrist and the elbow. Timely surgical intervention can greatly improve the overall function and quality of life of these patients.
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Mucopolisacaridosis/diagnóstico , Síndrome del Túnel Carpiano/diagnóstico , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Mucopolisacaridosis/fisiopatología , Conducción Nerviosa/fisiología , Estudios RetrospectivosRESUMEN
INTRODUCTION: Upper limb evaluation of patients with Duchenne Muscular Dystrophy is crucially important to evaluations of efficacy of new treatments in non-ambulant patients. In patients who have lost ambulation, there are few validated and informative outcome measures. In addition, longitudinal data demonstrating sensitivity to clinical evolution of outcome measures over short-term periods are lacking. PATIENTS AND METHODS: We report here the results of a one-year multicenter study using specifically designed tools to assess grip, pinch strength, and hand function in wheelchair-bound patients. Our study assessed 53 non-ambulant patients with Duchenne muscular dystrophy aged 17.1 ± 4.8 years (range: 9 - 28.1 years). The average Brooke functional score of these patients was 4.6 ± 1.1. The average forced vital capacity was 44.5% predicted and 19 patients used non-invasive ventilation. Patients were assessed at baseline, 6 months, and one year using the Motor Function Measure and innovative devices (namely the MyoSet composed of MyoGrip, MyoPinch, and MoviPlate). RESULTS: Our study confirmed preliminary data previously reported regarding feasibility of use and of reliability of the MyoSet and the correlation at baseline between distal strength and clinical outcomes such as FVC, Brooke score, age, and duration since loss of ambulation. A significant correlation was observed between the distal upper limb strength and clinical variables. The sensitive dynamometers (MyoGrip and MyoPinch) and MoviPlate captured a 12-month change in non-ambulant Duchenne muscular dystrophy patients of all ages. TRIAL REGISTRATION: ClinicalTrials.gov NCT00993161 NCT00993161.
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Fuerza Muscular , Distrofia Muscular de Duchenne/fisiopatología , Recuperación de la Función , Extremidad Superior/fisiopatología , Adolescente , Adulto , Niño , Femenino , Estudios de Seguimiento , Humanos , Masculino , Fuerza Muscular/efectos de los fármacos , Distrofia Muscular de Duchenne/tratamiento farmacológico , Recuperación de la Función/efectos de los fármacos , Adulto JovenRESUMEN
Assessment of the upper limb strength in non-ambulant neuromuscular patients remains challenging. Although potential outcome measures have been reported, longitudinal data demonstrating sensitivity to clinical evolution in spinal muscular atrophy patients are critically lacking. Our study recruited 23 non-ambulant patients, 16 patients (males/females = 6/10; median age 15.4 years with a range from 10.7 to 31.1 years) with spinal muscular atrophy type II and 7 patients (males/females = 2/5; median age 19.9 years with a range from 8.3 to 29.9 years) with type III. The Brooke functional score was on median 3 with a range from 2 to 6. The average total vital capacity was 46%, and seven patients required non-invasive ventilation at night. Patients were assessed at baseline, 6 months, and 1 year using the Motor Function Measure and innovative devices MyoGrip, MyoPinch, and MoviPlate, which assess handgrip strength, key pinch strength, and hand/finger extension-flexion function, respectively. The study demonstrated the feasibility and reliability of these measures for all patients, and sensitivity to negative changes after the age of 14 years. The younger patients showed an increase of the distal force in the follow-up period. The distal force measurements and function were correlated to different functional scales. These data represent an important step in the process of validating these devices as potential outcome measures for future clinical trials.
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Atrofia Muscular Espinal/fisiopatología , Extremidad Superior/fisiopatología , Adolescente , Adulto , Niño , Femenino , Estudios de Seguimiento , Fuerza de la Mano/fisiología , Humanos , Masculino , Ventilación no Invasiva , Fuerza de Pellizco/fisiología , Atrofias Musculares Espinales de la Infancia/fisiopatología , Adulto JovenRESUMEN
The molecular basis underlying the clinical variability in symptomatic Duchenne muscular dystrophy (DMD) carriers are still to be precised. We report 26 cases of early symptomatic DMD carriers followed in the French neuromuscular network. Clinical presentation, muscular histological analysis and type of gene mutation, as well as X-chromosome inactivation (XCI) patterns using DNA extracted from peripheral blood or muscle are detailed. The initial symptoms were significant weakness (88%) or exercise intolerance (27%). Clinical severity varied from a Duchenne-like progression to a very mild Becker-like phenotype. Cardiac dysfunction was present in 19% of the cases. Cognitive impairment was worthy of notice, as 27% of the carriers are concerned. The muscular analysis was always contributive, revealing muscular dystrophy (83%), mosaic in immunostaining (81%) and dystrophin abnormalities in western blot analysis (84%). In all, 73% had exonic deletions or duplications and 27% had point mutations. XCI pattern was biased in 62% of the cases. In conclusion, we report the largest series of manifesting DMD carriers at pediatric age and show that exercise intolerance and cognitive impairment may reveal symptomatic DMD carriers. The complete histological and immunohistological study of the muscle is the key of the diagnosis leading to the dystrophin gene analysis. Our study shows also that cognitive impairment in symptomatic DMD carriers is associated with mutations in the distal part of the DMD gene. XCI study does not fully explain the mechanisms as well as the wide spectrum of clinical phenotype, though a clear correlation between the severity of the phenotype and inactivation bias was observed.
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Distrofina/genética , Heterocigoto , Músculos/metabolismo , Distrofia Muscular de Duchenne/genética , Adolescente , Adulto , Edad de Inicio , Anciano , Biopsia , Western Blotting , Niño , Preescolar , Trastornos del Conocimiento/genética , Trastornos del Conocimiento/patología , Distrofina/metabolismo , Femenino , Francia/epidemiología , Humanos , Inmunohistoquímica , Persona de Mediana Edad , Músculos/patología , Distrofia Muscular de Duchenne/epidemiología , Distrofia Muscular de Duchenne/patología , Mutación , Inactivación del Cromosoma X , Adulto JovenRESUMEN
Natural killer (NK)/lymphokine-activated killer (LAK) cell-based immunotherapy could be beneficial against major histocompatibility complex class I-negative tumor residual disease such as neuroblastoma (NB), provided that interleukin 2 (IL-2) or surrogate nontoxic NK cell stimulatory factors could sustain NK cell activation and survival in vivo. Here we show that human monocyte-derived dendritic cells (MD-DCs) promote potent NK/LAK effector functions and long-term survival, circumventing the need for IL-2. This study demonstrates (1) the feasibility of differentiating granulocyte colony-stimulating factor-mobilized hematopoietic peripheral blood stem cells (PBSCs) into high numbers of functional MD-DCs and NK/LAK cells in a series of 12 children with stage 4 neuroblastoma (NB); (2) potent DC-mediated NK cell activation in autologous settings; (3) the reciprocal capacity of NK/LAK cells to turn immature DCs into maturing cells electively capable of triggering NK cell functions; and (4) the unique capacity of maturing DCs to sustain NK cell survival, superior to that achieved in IL-2. These data show a reciprocal interaction between DCs and NK/LAK cells, leading to the amplification of NK cell effector functions, and support the implementation of DC/NK cell-based immunotherapy for purging the graft and/or controlling minimal residual disease after autologous stem cell transplantation.
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Células Dendríticas/inmunología , Inmunoterapia/métodos , Células Asesinas Activadas por Linfocinas/inmunología , Células Asesinas Naturales/inmunología , Activación de Linfocitos , Neuroblastoma/terapia , Supervivencia Celular/inmunología , Niño , Preescolar , Humanos , Inmunofenotipificación , Activación de Linfocitos/inmunología , Monocitos/inmunología , Neuroblastoma/inmunologíaRESUMEN
Oligophrenin-1 (OPHN-1) gene disruption is known as responsible for so called "non-specific" X-linked mental retardation (MR) Billuart et al. [1998: Nature 392:923-926]. In order to search for a possible specific clinical and radiological profile for mutation in the OPHN-1 gene, clinical and 3D brain MRI studies were performed in the two families with a known mutation in OPHN-1 reported so far: a 19-year-old female with an X;12 balanced translocation encompassing OPHN-1, and four affected males of family MRX60 sharing a frameshift mutation in OPHN-1. Clinical data shared by affected individuals were neonatal hypotonia with motor delay but no obvious ataxia, marked strabismus, early onset complex partial seizures, and moderate to severe MR. Brain MRIs performed in three individuals exhibited a specific vermian dysgenesis including an incomplete sulcation of anterior and posterior vermis with the most prominent defect in lobules VI and VII. In addition, a non-specific cerebral cortico-subcortical atrophy was also observed. These clinical and radiological features suggest a distinct clinico-radiological syndrome. These preliminary data need to be confirmed in other families and will be helpful for further targeted mutation screening of the OPHN-1 gene in male patients with similar clinico-radiological features. In addition, OPHN-1 inactivation should be considered as a relevant model of developmental vermis disorganization, leading to a better understanding of the possible role of the cerebellum in MR.