ABSTRACT
The clinical care pathway for children presenting specific learning disorders, including language, motor coordination, and attention disorders is based on different levels of assessment by the professionals involved. In France, a first step of organization was established in 2002 by founding of a network of structures devoted to clinical assessment of complex cases, research, and teaching for the professionals involved. Although this organization proved to contribute an essential service, the demand largely exceeded the availability of access. A three-level organization was therefore suggested in 2013 including a first-level devoted to clinical analysis of simple cases, together with the professionals involved in rehabilitation (i.e., speech therapists, occupational therapists, psychologists), a second-level in charge of analyzing complex situations, involving comorbidities and failure of first-level care, together with the already structured third level of assessment devoted to genetic disorders, severe situations, and association with neurological conditions. To plan the practical application of these different levels, we assessed the situation of ambulatory pediatricians working in private practice, because this network appeared to be the most available in France to play these roles. A survey was therefore conducted among the main representative association of pediatricians (Association française de pédiatrie ambulatoire), including 1565 members of the 2700 in activity in France, on their level of knowledge and clinical expertise, and the drawbacks encountered in their practice in this field. Of the 481 respondents (36%), 25% were not yet in 2016 self-confident in assuming a first-level role, while 56% were ready to participate in a first-level response and 18% in a second-level response. In the 5 upcoming years, the vast majority of pediatricians intended to progress in their involvement, which should provide all regions in France with a network of professionals able to respond to the specific needs of children (48% in the first-level and 43.5% in the second-level of expertise). Specific obstacles have already been encountered by professionals who wish to play a full role in this domain: insufficient funding for medical evaluations and lack of access to specialized evaluations. This survey emphasizes the need for obtaining access to both practical and theoretical professional development programs (77.5%), funding of clinical assessment time (76%), all of which need to be answered by the French health authorities. To date, very few nationwide programs of clinical care pathways in these fields have been developed, but examples are available in France on Alzheimer disease and elderly populations, providing a model for children affected by specific development and learning difficulties. Setting up a clinical care pathway by the French Ministry of Health (Haute Autorité de santé) assumes that the needs expressed by ambulatory pediatricians will be taken into account, including the design and implementation of Medical Education programs according to the level of expertise, together with the adequate funding of diagnosis, follow-up, and care pathway coordination time.
Subject(s)
Critical Pathways , Pediatrics , Private Practice , Specific Learning Disorder/therapy , Adult , Aged , Child , Female , France , Humans , Male , Middle AgedABSTRACT
Diamond-Blackfan anemia (DBA) is a rare congenital hypoplastic anemia that usually presents early in infancy and is inherited in 10% to 20% of cases. Linkage analysis has shown that DBA in many of both dominant and recessive DBA families mapped to chromosome 19q13.2 leading to the cloning of a gene on chromosome 19q13.2 that encodes a ribosomal protein, RPS19. However, subsequently, mutations of the RPS19 gene have only been identified in 25% of all patients with DBA. This study analyzed 14 multiplex DBA families, 9 of which had 19q13.2 haplotypes inconsistent with 19q linkage. A genome-wide search for linked loci suggested the presence of a second DBA locus in a 26.4-centimorgan (cM) interval on human chromosome 8p. Subsequently, 24 additional DBA families were ascertained and all 38 families were analyzed with additional polymorphic markers on chromosome 8p. In total, 18 of 38 families were consistent with linkage to chromosome 8p with a maximal LOD score with heterogeneity of 3.55 at D8S277 assuming 90% penetrance. The results indicate the existence of a second DBA gene in the 26.4-cM telomeric region of human chromosome 8p23.3-p22, most likely within an 8.1-cM interval flanked by D8S518 and D8S1825. Seven families were inconsistent with linkage to 8p or 19q and did not reveal mutations in the RPS19 gene, suggesting further genetic heterogeneity. (Blood. 2001;97:2145-2150)
Subject(s)
Chromosomes, Human, Pair 8/genetics , Fanconi Anemia/genetics , Genetic Heterogeneity , Chromosomes, Human, Pair 19/genetics , Chromosomes, Human, Pair 8/ultrastructure , DNA Mutational Analysis , Female , Genetic Markers , Genetic Testing , Haplotypes/genetics , Humans , Lod Score , Male , Pedigree , PhenotypeABSTRACT
Diamond-Blackfan Anemia (DBA) is a rare, congenital hypoplastic anemia often diagnosed early in infancy. A moderate to severe aregenerative anemia is found in association with erythroblastopenia in an otherwise normocellular bone marrow. In 40% of these infants with DBA, diverse developmental abnormalities are also noted. A majority of patients with DBA respond to steroid therapy. Recent molecular studies have identified mutations in the gene encoding the ribosomal protein RPS19 on chromosome 19 in 25% of patients with DBA. In another subset of patients, linkage analysis has identified another locus on chromosome 8p in association with DBA. There are, however, other cases of DBA that are linked neither to the RPS19 gene nor to the locus on 8p, implying the involvement of yet-to-be-defined genetic defects in the cause of DBA. The pathogenesis of DBA is still to be fully defined and it is anticipated that further molecular studies will lead to a better understanding of this complex disease.
Subject(s)
Fanconi Anemia , Abnormalities, Multiple , Child, Preschool , Chromosomes, Human, Pair 19/genetics , Chromosomes, Human, Pair 8/genetics , Failure to Thrive , Fanconi Anemia/diagnosis , Fanconi Anemia/epidemiology , Fanconi Anemia/genetics , Fanconi Anemia/physiopathology , Genetic Heterogeneity , Humans , Infant , MutationABSTRACT
Lutheran blood group glycoproteins (Lu gps) are receptors for the extracellular matrix protein, laminin. Studies suggest that Lu gps may contribute to vaso-occlusion in sickle cell disease and it has recently been shown that sickle cells adhere to laminin isoforms containing the alpha5 chain (laminin 10/11). Laminin alpha5 is present in the subendothelium and is also a constituent of bone marrow sinusoids, suggesting a role for the Lu/laminin interaction in erythropoiesis. The objectives of the current study were to define more precisely the molecular interactions of the extracellular and intracellular regions of human Lu and to clone and characterize a mouse homologue. To this end, complementary DNA and genomic clones for the mouse homologue were sequenced and the mouse Lu gene mapped to a region on chromosome 7 with conserved synteny with human 19q13.2. Mouse and human Lu gps are highly conserved (72% identity) at the amino acid sequence level and both mouse and human Lu gps specifically bind laminin 10/11 with high affinity. Furthermore, the first 3, N-terminal, immunoglobulin superfamily domains of human Lu are critical for this interaction. The results indicated that the cytoplasmic domain of BRIC 221-labeled human Lu gp is linked with the spectrin-based skeleton, affording the speculation that this interaction may be critical for signal transduction. These results further support a role for Lu gps in sickle cell disease and indicate the utility of mouse models to explore the function of Lu gp-laminin 10/11 interaction in normal erythropoiesis and in sickle cell disease.
Subject(s)
Laminin/metabolism , Lutheran Blood-Group System/chemistry , Amino Acid Sequence , Animals , Binding Sites , Chromosome Mapping , Conserved Sequence , Erythrocyte Membrane/metabolism , Humans , K562 Cells , Mice , Mice, Knockout , Molecular Sequence Data , Protein Binding , Protein Structure, Tertiary , Receptors, Laminin/chemistry , Receptors, Laminin/metabolism , Recombinant Fusion Proteins/chemistry , Recombinant Fusion Proteins/metabolism , Sequence Alignment , Sequence Homology , TransfectionABSTRACT
Diamond Blackfan anemia is a rare congenital hypoplastic anemia that usually presents early in infancy. Congenital anomalies, in particular of the head and upper limbs, are present in about 25% of reported patients. The disease is characterized by a moderate to severe macrocytic anemia, occasional neutropenia or thrombocytosis, a normocellular bone marrow with erythroid hypoplasia, and an increased risk of developing leukemia. Recent genetic studies have led to the identification of mutations in the ribosomal protein RPS19 in approximately 25% of sporadic and familial cases, a second gene on chromosome 8p, and evidence for an additional locus (or loci). The pathogenesis is unknown. The majority of patients respond to prednisone, and often erythropoiesis can be maintained with low doses of the drug. Both remissions and increased resistance to steroid treatment can occur. Patients who do not respond to treatment are usually transfusion dependent, although responses to high dose steroid, androgen, and interleukin-3 have been observed. Bone marrow transplantation can be curative.
Subject(s)
Fanconi Anemia , Combined Modality Therapy , Erythropoiesis/genetics , Fanconi Anemia/diagnosis , Fanconi Anemia/genetics , Fanconi Anemia/therapy , Humans , Infant , Infant, Newborn , Molecular Sequence Data , Mutation , Sequence Homology, Amino AcidABSTRACT
Mutations of the ribosomal protein S19 (RPS19) gene were recently identified in 10 patients with Diamond Blackfan anemia (DBA). To determine the prevalence of mutations in this gene in DBA and to begin to define the molecular basis for the observed variable clinical phenotype of this disorder, the genomic sequence of the 6 exons and the 5' untranslated region of the RPS19 gene was directly assessed in DBA index cases from 172 new families. Mutations affecting the coding sequence of RPS19 or splice sites were found in 34 cases (19.7%), whereas mutations in noncoding regions were found in 8 patients (4.6%). Mutations included nonsense, missense, splice sites, and frameshift mutations. A hot spot for missense mutations was identified between codons 52 and 62 of the RPS19 gene in a new sequence consensus motif W-[YFW]-[YF]-x-R-[AT]-A-[SA]-x-[AL]-R-[HRK]-[ILV]-Y. No correlation between the nature of mutations and the different patterns of clinical expression, including age at presentation, presence of malformations, and therapeutic outcome, could be documented. Moreover, RPS19 mutations were also found in some first-degree relatives presenting only with isolated high erythrocyte adenosine deaminase activity and/or macrocytosis. The lack of a consistent relationship between the nature of the mutations and the clinical phenotype implies that yet unidentified factors modulate the phenotypic expression of the primary genetic defect in families with RPS19 mutations.
Subject(s)
Fanconi Anemia/genetics , Mutation , Ribosomal Proteins/genetics , Adolescent , Adult , Amino Acid Sequence , Base Sequence , Child, Preschool , Fanconi Anemia/physiopathology , Female , Humans , Infant , Male , Molecular Sequence Data , PedigreeABSTRACT
Diamond-Blackfan anemia (DBA) is a constitutional disease characterized by a specific maturation defect in cells of erythroid lineage. We have assembled a registry of 229 DBA patients, which includes 151 patients from France, 70 from Germany, and eight from other countries. Presence of malformations was significantly and independently associated with familial history of DBA, short stature at presentation (before any steroid therapy), and absence of hypotrophy at birth. Two hundred twenty-two patients were available for long-term follow-up analysis (median, 111.5 mo). Of these individuals, 62.6% initially responded to steroid therapy. Initial steroid responsiveness was found significantly and independently associated with older age at presentation, familial history of DBA, and a normal platelet count at the time of diagnosis. Severe evolution of the disease (transfusion dependence or death) was significantly and independently associated with a younger age at presentation and with a history of premature birth. In contrast, patients with a familial history of the disease experienced a better outcome. Outcome analysis revealed the benefit of reassessing steroid responsiveness during the course of the disease for initially nonresponsive patients. Bone marrow transplantation was successful in 11/13 cases; HLA typing of probands and siblings should be performed early if patients are transfusion dependent, and cord blood should be preserved. Incidence of DBA (assessed for France over a 13-y period) is 7.3 cases per million live births without effect of seasonality on incidence of the disease or on malformative status. Similarly, no parental imprinting effect or anticipation phenomenon could be documented in families with dominant inheritance.
Subject(s)
Abnormalities, Multiple/genetics , Fanconi Anemia/genetics , Abnormalities, Multiple/epidemiology , Fanconi Anemia/epidemiology , Female , Follow-Up Studies , France/epidemiology , Humans , Infant , Infant, Newborn , Male , Medical History Taking , Prevalence , Prognosis , Registries , Treatment OutcomeABSTRACT
Diamond-Blackfan anaemia (DBA) is a constitutional erythroblastopenia characterized by absent or decreased erythroid precursors. The disease, previously mapped to human chromosome 19q13, is frequently associated with a variety of malformations. To identify the gene involved in DBA, we cloned the chromosome 19q13 breakpoint in a patient with a reciprocal X;19 chromosome translocation. The breakpoint occurred in the gene encoding ribosomal protein S19. Furthermore, we identified mutations in RPS19 in 10 of 40 unrelated DBA patients, including nonsense, frameshift, splice site and missense mutations, as well as two intragenic deletions. These mutations are associated with clinical features that suggest a function for RPS19 in erythropoiesis and embryogenesis.
Subject(s)
Fanconi Anemia/genetics , Mutation , Ribosomal Proteins/genetics , Amino Acid Sequence , Chromosomes, Human, Pair 19/genetics , Cosmids , Female , Humans , Male , Molecular Sequence Data , Pedigree , Ribosomal Proteins/biosynthesis , Ribosomal Proteins/chemistry , Sequence Analysis, DNA , Translocation, Genetic , X Chromosome/geneticsABSTRACT
Phenotypic characterization of Diamond Blackfan Anemia (DBA) patients and their relatives was performed in 54 families. Complete blood count, fetal hemoglobin level, erythrocyte i antigen expression, and erythrocyte adenosine deaminase (eADA) activities were quantitated in patients and relatives. eADA was elevated in 28 of 34 transfusion-independent DBA patients, whereas persistence of erythrocyte i antigen was noticed in only 10 of 20 DBA patients. High eADA activities were also found in 14 of 149 healthy family members, allowing us to identify an isolated high eADA phenotype in these families. In contrast, increase in erythrocyte i antigen expression, elevated fetal hemoglobin levels, and macrocytosis were much less frequently noted in nonaffected members of the DBA families studied. Importantly, isolated high eADA phenotype was found to be significantly associated with genetic markers on chromosome 19 that segregate with the DBA phenotype. Isolated high eADA phenotype thus seems to reflect a silent phenotype of DBA in affected families. These findings suggest that elevated eADA activity in unaffected individuals needs to be taken into account during genetic assessment of DBA families and could be used for accurate assessment of mode of inheritance.
Subject(s)
Adenosine Deaminase/blood , Chromosomes, Human, Pair 19 , Fanconi Anemia/enzymology , Fanconi Anemia/genetics , Genetic Markers , Fanconi Anemia/blood , Female , Haplotypes , Humans , Male , PedigreeABSTRACT
Diamond-Blackfan anemia (DBA) is a rare pure red-cell hypoplasia of unknown etiology and pathogenesis. A major DBA locus has previously been localized to chromosome 19q13.2. Samples from additional families have been collected to identify key recombinations, microdeletions, and the possibility of heterogeneity for the disorder. In total, 29 multiplex DBA families and 50 families that comprise sporadic DBA cases have been analyzed with polymorphic 19q13 markers, including a newly identified short-tandem repeat in the critical gene region. The results from DNA analysis of 29 multiplex families revealed that 26 of these were consistent with a DBA gene on 19q localized to within a 4.1-cM interval restricted by loci D19S200 and D19S178; however, in three multiplex families, the DBA candidate region on 19q13 was excluded from the segregation of marker alleles. Our results suggest genetic heterogeneity for DBA, and we show that a gene region on chromosome 19q segregates with the disease in the majority of familial cases. Among the 50 families comprising sporadic DBA cases, we identified two novel and overlapping microdeletions on chromosome 19q13. In combination, the three known microdeletions associated with DBA restrict the critical gene region to approximately 1 Mb. The results indicate that a proportion of sporadic DBA cases are caused by deletions in the 19q13 region.
Subject(s)
Chromosomes, Human, Pair 19 , Fanconi Anemia/genetics , Polymorphism, Genetic , Sequence Deletion , Chromosome Mapping , Female , Genetic Carrier Screening , Genetic Markers , Humans , Lod Score , Male , Molecular Sequence Data , Nuclear Family , Pedigree , Recombination, GeneticABSTRACT
Diamond-Blackfan anemia, although rare, has been the focus of much attention with respect to both its clinical features and the characterization of the in vitro erythroid defect. Despite this, its pathophysiology is still unclear, and the treatment of steroid-refractory patients is still unsatisfactory. The recent chromosomal localization of a gene for familial Diamond-Blackfan anemia represents an important step forward toward the elucidation of this disorder. Therapeutic advances will depend on the development of collaborative studies, employing consensus criteria for diagnosis and response to therapy.
Subject(s)
Fanconi Anemia , Child, Preschool , Fanconi Anemia/complications , Fanconi Anemia/diagnosis , Fanconi Anemia/etiology , Fanconi Anemia/physiopathology , Fanconi Anemia/therapy , Humans , InfantABSTRACT
Magnetic resonance imaging was used to determine total fat mass of patients with neuromuscular disorders, accounting for intramuscular fat. Nineteen boys aged 9 to 12 (eight with Duchenne muscular dystrophy, three with type II spinal muscular atrophy and eight control subjects) underwent whole-body magnetic resonance imaging examination and anthropometric measurements. Whole-body fat mass was deduced from automated analysis of images normalized by a reference signal. Intramuscular and subcutaneous fat masses were deduced from manual analysis of twelve reference slices. Affected children significantly differed from control subjects for higher total fat mass, mostly related to intramuscular fat mass. Shorter protocols validated from whole-body data were shown to be more accurate than fat mass estimation derived from anthropometric measurements.
Subject(s)
Body Composition , Magnetic Resonance Imaging/methods , Muscular Atrophy, Spinal/complications , Muscular Dystrophies/complications , Adipose Tissue , Anthropometry/methods , Child , Electronic Data Processing , Humans , Male , Muscular Atrophy, Spinal/physiopathology , Muscular Dystrophies/physiopathologyABSTRACT
To ascertain the patients' perception of the consequences of elbow flexion contractures and better understand the circumstances at their inception, we surveyed 405 spinal muscular atrophy and congenital myopathy patients. Diagrams of various elbow angles and questions concerning the effect of elbow contractures on daily activities were part of the survey. Of 108 completed responses, effectively a 24% response rate, 49 reported elbow flexion contractures. Thirteen of the 49 patients reported first noting them during extended periods of inactivity. Elbow flexion contractures greater than 25 degrees were intractable and were reported to hamper 17% (77 of 410) of specifically considered daily activities for the 49 subjects. Twenty-nine of the 49 (59%) subjects with contractures complained of contracture-associated hindrance of at least one daily function. Perceived contracture-associated difficulties increased significantly as a function of contracture severity. Elbow contractures were perceived to be useful by 12% of the respondents. The correlation between contracture severity and upper limb discomfort was also striking. We conclude that elbow flexion contractures are common and perceived to be associated with disability and discomfort for about one-half of spinal muscular atrophy and congenital myopathy patients.
Subject(s)
Activities of Daily Living , Contracture/physiopathology , Elbow/physiopathology , Muscular Atrophy, Spinal/physiopathology , Neuromuscular Diseases/congenital , Adolescent , Adult , Analysis of Variance , Child , Data Collection , Female , Humans , Male , Neuromuscular Diseases/physiopathology , Pain/etiology , Pilot Projects , Self Concept , ShoulderABSTRACT
Feeding problems in patients with neuromuscular diseases are frequently underestimated and poorly analyzed. To gain a better understanding of the most common complaints, we surveyed 451 patients and received 409 responses representing seven disorders. Difficulties in the pre-oral phase of swallowing were encountered primarily in Duchenne muscular dystrophy (DMD), limb-girdle muscular dystrophy (LGMD), facio-scapulo-humoral muscular dystrophy (FSHMD), and spinal muscular atrophy (SMA). A limitation in the ability to open the mouth was also noted in SMA. Some features are characteristic of certain diseases such as macroglossia in DMD and dryness of the mouth in dermatomyositis and polymyositis (DMPM) and myasthenia gravis (MG). Posterior swallowing time is especially affected in MG, dermatomyositis and polymyositis, LGMD, and SMA. Overall prevalence of feeding disability in five disorders (SMA, myotonic dystrophy [MD], DMPM, FSHMD, MG) was 34.9%. A better understanding of the swallowing problems associated with these disorders may help in choosing treatment possibilities, technical aids, adaptation of the consistency of foods, swallowing rehabilitation, and nutritional support by the non-oral route.
Subject(s)
Deglutition Disorders/etiology , Neuromuscular Diseases/complications , Adolescent , Adult , Dermatomyositis/complications , Female , Humans , Male , Middle Aged , Muscular Atrophy, Spinal/complications , Muscular Dystrophies/complications , Myasthenia Gravis/complications , Neuromuscular Diseases/physiopathology , Neuromuscular Diseases/rehabilitation , Nutritional Status , Nutritional Support , Polymyositis/complications , Temporomandibular Joint/physiopathologyABSTRACT
Thirty-four patients with an identified muscular disease were referred to our department for assessment and treatment of swallowing difficulties. Their ages ranged from 16 to 91 years (mean 59). The diagnoses were oculopharyngeal dystrophy in 17 patients, Steinert myotonic dystrophy in 6, mitochondrial myopathies in 4, polymyositis in 3, and other types in 4 patients. The main consequences of the dysphagia were weight loss (12 patients), pulmonary infections (15 patients), modified food consistency (18 patients) and non-oral feeding (3 patients). Several techniques were used to assess the different stages of deglutition: physical examination during swallowing, videofluoroscopy, pharyngoesophageal manometry, videofibroscopy of the pharynx during swallowing. Major pathological features found in the pharynx were decreased pharynx peristaltis and impaired UES relaxation. Cricopharyngeal myotomy was performed in 11 myopathic patients (median follow-up 24.9 months), while it was unnecessary, refused or contraindicated in the other patients. The procedure was successful in 8 patients whose dysphagia was dramatically improved, and failed in 3 patients. Pharyngeal perstaltis was severely impaired only in the 3 failures and was partly preserved in the improved cases. We conclude that pharyngeal function is the major prognostic factor. Cricopharyngeal myotomy is an effective treatment in those cases where cricopharyngeal dysfunction is a predominant problem or where pharyngeal peristaltis is partly impaired, since the procedure removes one obstacle. It is contraindicated when pharynx propulsion is severely impaired.
Subject(s)
Cricoid Cartilage/surgery , Deglutition Disorders/diagnosis , Muscular Diseases/diagnosis , Muscular Diseases/surgery , Pharynx/surgery , Adolescent , Adult , Aged , Deglutition Disorders/complications , Deglutition Disorders/etiology , Female , Fluoroscopy , Humans , Male , Manometry , Middle Aged , Muscular Diseases/complications , Pneumonia, Aspiration/etiologyABSTRACT
A specific-weight chart and simple clinical tools are sufficient to obtain an accurate diagnosis of undernutrition or obesity among patients with Duchenne muscular dystrophy (DMD). The authors collected weight-for-age measures from a sample of 252 boys and anthropometric data from 109 of those boys with DMD. The data confirm the accuracy of the DMD ideal-weight chart previously proposed by Griffiths and Edwards (1988). Obesity may occur from the age of seven years; its prevalence seems to reach 54 per cent by the age of 13 years. Undernutrition occurs after the age of 14 years, involving 54 per cent of boys at about 18 years of age. Obese boys show a centralized body-fat distribution, in agreement with other obese populations.