Familial intestinal degenerative neuropathy with chronic intestinal pseudo-obstruction linked to a gene locus with duplication in chromosome 9.

Background: Intestinal degenerative neuropathy without extra-intestinal involvement occurs as familial forms (FIDN) but the genetics behind is unknown. We studied a Swedish family with autosomal dominant disease and several cases of chronic intestinal pseudo-obstruction (CIP).Methods: We included 33 members of a family sharing a male ancestor. Chronic intestinal symptoms including diarrhoea occurred in 11, four had severe CIP. DNA was analysed with SNP-microarray (Affymetrix), linkage (Allegro Software) and gene dosage (CNAG 3.0).Results: Genetic linkage was found to the short arm of Ch9 to a 9.7 Mb region with 45 protein-coding genes, 22 of which were duplicated (1.2 Mb duplication) (dup(9)(p21.3) with breaking point in the FOCAD-gene. Lod score for the region was 3.4. Fourteen subjects were duplication carriers including all 11 subjects having severe chronic symptoms/CIP. Nineteen subjects had no duplication. The occurrence of gastrointestinal symptoms in the family was strongly linked to duplication carrier-ship (p = .0005). The two branches of the family had separate maternal ancestors (A and B). Including the previous generation, severe disease (overt CIP and/or death from intestinal failure) was assessed to occur in 100% (5/5) of duplication carriers in branch A and in 21% (3/14) in branch B (p = .005). In branch B the onset of symptoms was later (median 38 vs. 24 yrs) and three duplication carriers were symptom-free.Conclusions: In this family with autosomal dominant hereditary intestinal neuropathy, the disorder is linked to a 9.7 Mb region in Ch9 including a 1.2 Mb duplication. There is a significant difference in disease expressivity between family branches, seemingly related to separate maternal ancestors.

Prevalence of Carriers of Intermediate and Pathological Polyglutamine Disease-Associated Alleles Among Large Population-Based Cohorts.

Importance: Nine hereditary neurodegenerative diseases are known as polyglutamine diseases, including Huntington disease, 6 spinocerebellar ataxias (SCAs) (SCA1, SCA2, SCA3, SCA6, SCA7, and SCA17), dentatorubral-pallidoluysion atrophy, and spinal bulbar muscular atrophy. Objective: To determine the prevalence of carriers of intermediate and pathological polyglutamine disease-associated alleles among the general population. Design, Setting, and Participants: This observational cross-sectional study included data from 5 large European population-based cohorts that were compiled between 1997 and 2012, and the analyses were conducted in 2018. In total, 16 547 DNA samples were obtained from participants of the 5 cohorts. Individuals with a lifetime diagnosis of major depression were excluded (n = 2351). In the remaining 14 196 participants without an established polyglutamine disease diagnosis, the CAG repeat size in both alleles of all 9 polyglutamine disease-associated genes (PDAGs) (ie, ATXN1, ATXN2, ATXN3, CACNA1A, ATXN7, TBP, HTT, ATN1, and AR) was determined. Exposure: The number of CAG repeats in the alleles of the 9 PDAGs. Main Outcomes and Measures: The number of individuals with alleles within the intermediate or pathological range per PDAG, as well as differences in sex, age, and body mass index between individuals carrying alleles within the normal or intermediate range and individuals carrying alleles within the pathological range of PDAGs. Results: In the 14 196 analyzed participants (age range, 18-99 years; 56.3% female), 10.7% had a CAG repeat number within the intermediate range of at least 1 PDAG. Moreover, up to 1.3% of the participants had a CAG repeat number within the disease-causing range, predominantly in the lower pathological range associated with elderly onset. No differences in sex, age, or body mass index were found between individuals with CAG repeat numbers within the pathological range and individuals with CAG repeat numbers within the normal or intermediate range. Conclusions and Relevance: These results indicate a high prevalence of individuals carrying intermediate and pathological ranges of polyglutamine disease-associated alleles among the general population. Therefore, a substantially larger proportion of individuals than previously estimated may be at risk of developing a polyglutamine disease later in life or bearing children with a de novo mutation.

New findings in facial-onset sensory and motor neuronopathy (FOSMN) syndrome.

Facial-onset sensory and motor neuronopathy (FOSMN) syndrome represents a rare, slowly progressive, lower motor neuron disease with sensory compromise, involving mainly the face, bulbar region and upper limbs. However, non-motor symptoms and neurogenetic studies have rarely been evaluated in large case series. In the present study, 10 unrelated Brazilian patients with FOSMN syndrome underwent extensive clinical, laboratory, neurophysiological and neurogenetic assessment. Median age at symptom onset was 52.1 years, and men and women were equally affected. Patients presented with hemifacial or bilateral facial paresthesia and weakness, which evolved with dysphagia, dysphonia, and facial and tongue atrophy and, finally, a dropped-head, upper limb weakness and syringomyelia-like sensory disturbances in the upper limbs. All 10 patients showed chronic diffuse neurogenic compromise of bulbar, cervical and thoracic myotomes, and abnormal blink reflex tests. A positive family history of neurodegeneration was identified in six cases, and revealed pathogenic gene variants in three families (involving VCP, TARDBP and CHCHD10). Thus, our case series has revealed new findings regarding FOSMN syndrome: (i) its clinical course is not always benign, with poorer prognoses associated with dropped-head syndrome and early bulbar compromise; (ii) FOSMN syndrome may be part of a complex familial neurodegenerative spectrum; and (iii) a definite genetic basis may be observed in some cases.

Huntington's disease-like disorders in Latin America and the Caribbean.

Diseases with a choreic phenotype can be due to a variety of genetic etiologies. As testing for Huntington's disease (HD) becomes more available in previously resource-limited regions, it is becoming apparent that there are patients in these areas with other rare genetic conditions which cause an HD-like phenotype. Documentation of the presence of these conditions is important in order to provide appropriate diagnostic and clinical care for these populations. Information for this article was gathered in two ways; the literature was surveyed for publications reporting a variety of genetic choreic disorders, and movement disorders specialists from countries in Latin America and the Caribbean were contacted regarding their experiences with chorea of genetic etiology. Here we discuss the availability of molecular diagnostics for HD and for other choreic disorders, along with a summary of the published reports of affected subjects, and authors' personal experiences from the regions. While rare, patients affected by non-HD genetic choreas are evidently present in Latin America and the Caribbean. HD-like 2 is particularly prevalent in countries where the population has African ancestry. The incidence of other conditions is likely determined by other variations in ethnic background and settlement patterns. As genetic resources and awareness of these disorders improve, more patients are likely to be identified, and have the potential to benefit from education, support, and ultimately molecular therapies.

Neurodegeneration beyond the primary visual pathways in a population with a high incidence of normal-pressure glaucoma.

PURPOSE: Glaucoma is the most common age-related neurodegenerative eye disease in western society. It is an insidious disease that, when untreated or detected too late, leads inevitably to blindness. An outstanding issue is whether glaucoma should be considered exclusively an eye disease or also a brain disease. To further examine it, we used Diffusion Tensor Imaging (DTI) to study white matter integrity in a Japanese glaucoma population. This population has a very high incidence of normal-pressure glaucoma, in which optic nerve damage occurs in the absence of the elevated eye pressure that characterises the more common form of glaucoma. METHODS: We performed DTI in 30 participants with normal-pressure glaucoma and 21 age-matched healthy controls. We used voxel-wise tract-based spatial statistics to compare fractional anisotropy and mean diffusivity of the white matter of the brain between patients and control group. Whole-brain and region of interest-based analyses served to find associations between diffusion indices and clinical measures of glaucomatous damage. RESULTS: Fractional Anisotropy was significantly lower in glaucoma patients in a cluster in the right occipital lobe (p < 0.05; family-wise error-corrected) comprising fibres of both the optic radiation and the forceps major. Additional analysis confirmed bilateral involvement of the optic radiations and forceps major and additionally revealed damage to the corpus callosum and parietal lobe (p < 0.09; family-wise error-corrected). The region of interest-based analysis revealed a positive association between Fractional Anisotropy of the optic radiation and optic nerve damage. CONCLUSIONS: In this specific population, glaucoma is associated with lower Fractional Anisotropy in the optic radiations, forceps major and corpus callosum. We interpret these reductions as evidence for white matter degeneration in these loci. In particular, the degeneration of the corpus callosum suggests the presence of neurodegeneration of the brain beyond what can be explained on the basis of propagated retinal and pre-geniculate damage. We discuss how this finding links to the emerging view that a brain component that is independent from the eye damage plays a role in the aetiology of glaucoma.

The Frequency of Huntington Disease and Huntington Disease-Like 2 in the South African Population.

BACKGROUND: Huntington disease (HD) has most recently been estimated to affect between 10.6 and 13.7 per 100,000 individuals in European populations. However, prevalence is known to differ geographically. In South Africa, the only published estimates are from a survey performed in the 1970s, an era when the disease was believed to be rare or absent in black individuals and molecular confirmation was absent. The disease phenotype in South Africa is currently attributable to mutations in both the huntington and junctophilin-3 genes, which underlie the well-known HD and the rarer HD-like 2 (HDL2) respectively. This study aimed at providing improved minimum estimates of disease frequency in South Africa, based on molecular genetic testing data. METHODS: A review of all testing records for HD and HDL2 over a 20-year period was undertaken. HDL2 is virtually indistinguishable on clinical features, thus necessitating its inclusion. RESULTS: Based on molecular diagnostic records, minimum estimates of disease frequency are: 5.1, 2.1 and 0.25 (per 100,000 individuals) for the white, mixed ancestry and black population groups respectively. CONCLUSION: Although ascertainment remains incomplete, these minimum estimates suggest that disease frequencies are significantly higher than those previously reported in South Africa.

Huntington disease and Huntington disease-like in a case series from Brazil.

The aim of this study was to identify the relative frequency of Huntington's disease (HD) and HD-like (HDL) disorders HDL1, HDL2, spinocerebellar ataxia type 2 (SCA2), SCA17, dentatorubral-pallidoluysian degeneration (DRPLA), benign hereditary chorea, neuroferritinopathy and chorea-acanthocytosis (CHAC), in a series of Brazilian families. Patients were recruited in seven centers if they or their relatives presented at least chorea, besides other findings. Molecular studies of HTT, ATXN2, TBP, ATN1, JPH3, FTL, NKX2-1/TITF1 and VPS13A genes were performed. A total of 104 families were ascertained from 2001 to 2012: 71 families from South, 25 from Southeast and 8 from Northeast Brazil. There were 93 HD, 4 HDL2 and 1 SCA2 families. Eleven of 104 index cases did not have a family history: 10 with HD. Clinical characteristics were similar between HD and non-HD cases. In HD, the median expanded (CAG)n (range) was 44 (40-81) units; R(2) between expanded HTT and age-at-onset (AO) was 0.55 (p=0.0001, Pearson). HDL2 was found in Rio de Janeiro (2 of 9 families) and Rio Grande do Sul states (2 of 68 families). We detected HD in 89.4%, HDL2 in 3.8% and SCA2 in 1% of 104 Brazilian families. There were no cases of HDL1, SCA17, DRPLA, neuroferritinopathy, benign hereditary chorea or CHAC. Only six families (5.8%) remained without diagnosis.

Implementación de un programa piloto de servicios farmacéuticos en una población rural de Veracruz (México) con alta prevalencia de enfermedades crónico-degenerativas / Implementation of a pilot program of pharmaceutical services in a rural population of Veracruz (Mexico) with high prevalence in chronic-degenerative diseases

Objetivo: Implementar un programa piloto de servicios farmacéuticos de carácter comunitario en una población rural de la zona centro de Veracruz (México) con una alta prevalencia de enfermedades crónico-degenerativas. Material y métodos: Consistió en dos fases: 1) identificación y caracterización de la población, y 2) implementación del programa piloto de los servicios farmacéuticos. El análisis estadístico se realizó con paquete estadístico STATA (versión 9.0). Resultados: Se le ofreció el servicio a una población de 904 personas, de las que 897 participaron; de estas últimas, 436 presentaron valores alterados de las patologías incluidas en el estudio. Para evaluar el efecto de la intervención farmacéutica sobre la efectividad de los tratamientos farmacológicos, se observó que en el grupo con hipertrigliceridemia, hipercolesterolemia y diabetes mellitus tipo 2 se produjo una disminución estadísticamente significativa de las concentraciones séricas de triglicéridos, colesterol y glucosa (p <0,001), respectivamente. De igual manera, se observó una reducción de la presión arterial diastólica y sistólica (p <0,001) después de la intervención. La evaluación clínica de los pacientes al final del tratamiento que incluyó servicios farmacéuticos fue en sentido favorable, ya que el 82,56% de la población de estudio refirió valores controlados dentro de las patologías de estudio y valores estadísticamente significativos (p <0,001). Los resultados negativos asociados a la medicación identificados fueron del tipo inefectividad cuantitativa, y se detectaron 14 reacciones adversas a medicamentos tipo A. Conclusiones: La atención farmacéutica es una estrategia idónea para actuar en el complejo proceso de generación y protección de la salud en comunidades vulnerables, como son las rurales con poblaciones con enfermedades crónico-degenerativas (AU)

Objective: Implement a pilot program of pharmaceutical services of communitarian character in a rural population of the central region of Veracruz (México) with high prevalence in chronic degenerative diseases. Methods: It consisted of two phases: 1) identification and characterization of the population, and 2) implementation of the pilot program of pharmaceutical services. Statistical analyses were done using STATA software (version 9.0). Results: The study population was of 904 people, of which 897 signed the informed consent. Fortunately, only 436 participants presented altered values related to the pathologies of study. To evaluate the effect of pharmaceutical intervention on the effectiveness of drug treatments was observed for the group with hypertriglyceridemia, hypercholesterolemia and diabetes mellitus type 2 had a statistically significant decrease in serum triglyceride, cholesterol and glucose concentrations (p <0.001). Similarly there was a reduction of systolic and diastolic blood pressure (p <0.001) after intervention. The clinical evaluation of patients at the end of treatment that included pharmaceutical services was in a positive in favorable way for the participants, since the 82.56% of the study population referred controlled values among the study pathologies and statistically significant values (p <0.001). The identifi ed negative outcomes associated with medication were of quantitative ineffectiveness type and 14 adverse drug reactions type A were detected. Conclusions: Pharmaceutical attention is a suitable strategy to act in the complex process of generation and protection of health in vulnerable communities such as the rural ones with chronic degenerative diseases (AU)

Evolución de la nutrición enteral domiciliaria en Madrid 2002-2007 / Evolution of home-based enteral nutrition in Madrid 2002-2007

Introducción: La Nutrición Enteral Domiciliaria en Madrid utiliza como soporte la receta oficial lo que facilita el uso de sistemas de información para el análisis de su consumo y evolución. Objetivos: Análisis cualitativo y cuantitativo de la evolución del consumo de NED de 2002 a 2007. Tendencia e identificación de los productos con mayor impacto en el periodo 2006-2007. Características de los pacientes. Métodos: Selección de recetas facturadas de productos de NED, clasificación por tipos y análisis de la evolución en importe y en envases para el periodo 2002 -2007. Estudio de la evolución consumo 2006-2007 identificando los productos con mayor impacto, la distribución de su prescripción y las características de los pacientes a los que se indica. Resultados: En el periodo 2002-2007, los envases han aumentado más del doble y el importe económico se ha triplicado, observándose un desplazamiento hacia las dietas completas hiperproteicas. El análisis 2006-2007 de las mismas nos lleva a identificar 5 productos cuyo incremento en envases ha superado el 210%. La edad media de los pacientes es 60,33 años, siendo los diagnósticos más frecuentes oncológicos y neurológicos. El 69% de los tratamientos están prescritos como suplementos a una dieta de consumo ordinario. Discusión: En los últimos 6 años se evidencia la tendencia al alza y el desplazamiento hacia dietas del tipo completas hiperproteicas que suponen ya en 2007 casi la tercera parte del consumo. Dos terceras partes de los tratamientos están dirigidos a pacientes geriátricos con patologías oncológicas o degenerativas del sistema nervioso central (AU)

Introduction: Home-based enteral nutrition in Madrid uses the official prescription form which facilitates the use of information systems for analysing consumption and evolution. Objectives: Qualitative and quantitative analysis of the evolution of HBEN use from 2002 to 2007. Trend and identification of the products with higher impact for the period 2006-2007. Patients characteristics. Methods: Selection of invoiced prescriptions of HBEN products, classification by type, and analysis of price and pack number evolution for the period 2002 -2007. Study of the consumption evolution 2006-2007 identifying those products with higher impact, the prescription distribution, and the characteristics of the patients in whom HBEN is prescribed. Results: In the period 2002-2007, the number of packs has increased more than twice and the costs have tripled, observing a shift towards complete hyperproteinic diets. When analysing these diets in the period 2006-2007, there are five products that have increased the number of packs by more than 210%. The mean patients age was 60.33 years. The most frequent diagnoses were oncologic and neurologic. 69% of the treatments are prescribed as dietary supplements for an ordinary diet. Discussion: For the last 6 years, an increasing trend is observed as well as a shift towards complete hyperproteinic diets, which in 2007 accounted for almost a third of the whole consumption. Two thirds of the therapies are focused on geriatric patients with oncologic or central nervous system degenerative pathologies (AU)

Monogenic Mendelian disorders in general neurological practice.

An observational study of monogenic Mendelian disorders seen in general neurology outpatient clinics over a 6-year period was undertaken. Fifty-three patients with 16 different diagnoses were identified, the commonest being Huntington's disease and neurofibromatosis type 1. This low frequency of monogenic Mendelian disorders has implications for both continuing medical education and for neurological training. All such patients are probably best referred to specialist clinics where expertise in diagnosis, genetic counselling and testing, and management has been developed.

Cognitive and behavioral assessment in the early stages of neurodegenerative extrapyramidal syndromes.

Parkinson's disease (PD), Dementia with Lewy Bodies (DLB), Progressive Supranuclear Palsy (PSP) and Corticobasal Degeneration Syndrome (CBDS) are the most common neurodegenerative extrapyramidal syndromes. Beyond motor symptoms, cognitive dysfunctions and behavioral disturbances are reported. Neuropsychological and neuropsychiatry features in the early stages, however, are under-investigated, and few comparison studies are available yet. The aim of the present study was to evaluate the cognitive and behavioral profile in the early stages of neurodegenerative extrapyramidal syndromes. Thirty-nine PD, 27 DLB, 16 CBDS, and 24 PSP were recruited. Groups were matched for global cognitive and motor impairment. The overall sample showed a common neuropsychological core characterized by visuospatial deficits. Although in the early stage of the disease, a high presence of behavioral disturbances was detected, depression and anxiety were the most common disorders, followed by apathy and sleep disturbances. The observation of overlapping clinical entities points the attention on the need of adjunctive diagnostic markers for early differential diagnosis.

Atención al niño de otras culturas / Care for children of other cultures

No disponible

Fibroblast growth factor receptor 1 is required for the proliferation of hippocampal progenitor cells and for hippocampal growth in mouse.

Fibroblast growth factor receptor 1 (Fgfr1) is expressed at high levels by progenitor cells of the ventricular zone (VZ) within the hippocampal primordium. To investigate the role of Fgfr1 in these cells, in vivo Cre recombination of "floxed" Fgfr1 alleles was directed to cells of the radial glial lineage by using the human glial fibrillary acidic protein promoter. Radial glial-like cells of the hippocampal VZ are the progenitors of pyramidal neurons and granule cells of hippocampal dentate gyrus (DG). Mice carrying null Fgfr1 alleles (Fgfr1(Deltaflox)) in cells of this lineage showed a dramatic loss of Fgfr1 gene expression throughout the embryonic dorsal telencephalon. These Fgfr1(Deltaflox) mice exhibited a approximately 30% decrease in dividing radial glial progenitor cells in the hippocampal VZ and DG in the late embryonic period, progressing to a approximately 50-60% loss at birth, without any changes in cell survival. In addition, no FGF2-sensitive neural stem cells could be isolated from the Fgfr1(Deltaflox) hippocampal neuroepithelium, whereas epidermal growth factor-sensitive neural stem cells were not affected. The number of hippocampal pyramidal neurons and DG granule cells was approximately 30-50% decreased from the perinatal period through adulthood, and the number of parvalbumin-containing interneurons was similarly decreased in both the DG and pyramidal cell fields. We conclude that Fgfr1 is necessary for hippocampal growth, because it promotes the proliferation of hippocampal progenitors and stem cells during development.

Localization of the gene for a novel autosomal recessive neurodegenerative Huntington-like disorder to 4p15.3.

A consanguineous family affected by an autosomal recessive, progressive neurodegenerative Huntington-like disorder, was tested to rule out juvenile-onset Huntington disease (JHD). The disease manifests at approximately 3-4 years and is characterized by both pyramidal and extrapyramidal abnormalities, including chorea, dystonia, ataxia, gait instability, spasticity, seizures, mutism, and intellectual impairment. Brain magnetic resonance imaging (MRI) findings include progressive frontal cortical atrophy and bilateral caudate atrophy. Huntington CAG trinucleotide-repeat analyses ruled out JHD, since all affected individuals had repeat numbers within the normal range. The presence of only four recombinant events (straight theta=.2) between the disease and the Huntington locus in 20 informative meioses suggested that the disease localized to chromosome 4. Linkage was initially achieved with marker D4S2366 at 4p15.3 (LOD 3.03). High-density mapping at the linked locus resulted in homozygosity for markers D4S431 and D4S394, which span a 3-cM region. A maximum LOD score of 4.71 in the homozygous interval was obtained. Heterozygosity at the distal D4S2366 and proximal D4S2983 markers defines the maximum localization interval (7 cM). Multiple brain-related expressed sequence tags (ESTs) with no known disease association exist in the linkage interval. Among the three known genes residing in the linked interval (ACOX3, DRD5, QDPR), the most likely candidate, DRD5, encoding the dopamine receptor D5, was excluded, since all five affected family members were heterozygous for an intragenic dinucleotide repeat. The inheritance pattern and unique localization to 4p15.3 are consistent with the identification of a novel, autosomal recessive, neurodegenerative Huntington-like disorder.