The Castang Foundation, Bath Unit for Research in Paediatrics, National Institute of Health Research, the Royal United Hospitals Bath NHS Foundation Trust, BRONNER-BENDER Stiftung/Gernsbach, University Children's Hospital Zurich.

We have studied 23 children from 13 families with a clinical diagnosis of Aicardi-Goutières syndrome. Affected individuals had developed an early-onset progressive encephalopathy that was characterized by a normal head circumference at birth, basal ganglia calcification, negative viral studies, and abnormalities of cerebrospinal fluid comprising either raised white cell counts and/or raised levels of interferon-alpha. By means of genomewide linkage analysis, a maximum-heterogeneity LOD score of 5.28 was reached at marker D3S3563, with alpha=.48, where alpha is the proportion of families showing linkage. Our data suggest the existence of locus heterogeneity in Aicardi-Goutières syndrome and highlight potential difficulties in the differentiation of this condition from pseudo-TORCH (toxoplasmosis, rubella, cytomegalovirus, and herpes simplex virus types 1 and 2) syndrome.

Glycinergic neurotransmission is a major inhibitory influence in the CNS and its disruption triggers a paediatric and adult startle disorder, hyperekplexia. The postsynaptic α(1)-subunit (GLRA1) of the inhibitory glycine receptor (GlyR) and the cognate presynaptic glycine transporter (SLC6A5/GlyT2) are well-established genes of effect in hyperekplexia. Nevertheless, 52% of cases (117 from 232) remain gene negative and unexplained. Ligand-gated heteropentameric GlyRs form chloride ion channels that contain the α(1) and β-subunits (GLRB) in a 2α(1):3β configuration and they form the predominant population of GlyRs in the postnatal and adult human brain, brainstem and spinal cord. We screened GLRB through 117 GLRA1- and SLC6A5-negative hyperekplexia patients using a multiplex-polymerase chain reaction and Sanger sequencing approach. The screening identified recessive and dominant GLRB variants in 12 unrelated hyperekplexia probands. This primarily yielded homozygous null mutations, with nonsense (n = 3), small indel (n = 1), a large 95 kb deletion (n = 1), frameshifts (n = 1) and one recurrent splicing variant found in four cases. A further three cases were found with two homozygous and one dominant GLRB missense mutations. We provide strong evidence for the pathogenicity of GLRB mutations using splicing assays, deletion mapping, cell-surface biotinylation, expression studies and molecular modelling. This study describes the definitive assignment of GLRB as the third major gene for hyperekplexia and impacts on the genetic stratification and biological causation of this neonatal/paediatric disorder. Driven principally by consanguineous homozygosity of GLRB mutations, the study reveals long-term additive phenotypic outcomes for affected cases such as severe apnoea attacks, learning difficulties and developmental delay.

L earning difficulties have a very significant effect on individuals and on society. The affected individual will have difficulties in thinking, acquisition, and processing of new information and knowledge. As a result of these difficulties many individuals require additional care, education, and medical services. In some cases affected individuals will never achieve personal independence and the need for care will persist throughout their lifetime.In the UK the term learning difficulty (or learning difficulties) is now preferred to older terms such as mental handicap or mental retardation. The term learning disorder is used slightly differently in the USA where it usually refers to specific learning difficulties such as dyslexia.Learning difficulty is not a specific diagnosis-it refers to a collection of disorders in all of which impaired cognitive functioning is a common feature. This review will briefly discuss the causes of learning difficulty and will give guidance as to appropriate investigation of individuals who present with learning difficulty. It will also highlight some of the issues in management of the learning difficulties, particularly at the transition between paediatric services and adult learning disability services. EPIDEMIOLOGYIncidence and prevalence figures for learning difficulties vary throughout the world and within social class. The prevalence of mild learning difficulties is higher in developing countries than developed countries 1-3 and this is thought to reflect poor socioeconomic conditions. The overall incidence of mild and severe learning difficulty in Western countries is around 8 per 1000, although this figure varies depending on the method of ascertainment 2 3 with population based studies yielding higher rates. For example, in a one year cohort of Norwegian children followed until 14 years of age the overall prevalence of children with IQ < 70 was 11.9 per 1000. 4 Mild learning difficulty is approximately twice as common as severe learning difficulty, but the prevalence changes with age. Thus, although rates of severe learning difficulty are stable from about 3 years of age (because of the fact that it is usually recognised early), the rates of mild learning difficulty increase throughout the school years as more subtle difficulties become apparent.It is well recognised that learning difficulty is more common in boys than girls with ratios varying between 3:1 and 1.9:1. This is mainly explained by the occurrence of specific X linked conditions (such as fragile X syndrome) in boys. AETIOLOGYThere is a very wide range of conditions that may lead to learning difficulties. These include numerous medical conditions, both congenital and acquired, and social and environmental factors. The relative frequency of these various factors varies with the severity of the learning difficulty and with the socioeconomic background.Aetiology is usually far more easy to establish in individuals with severe learning difficulty than in those with only mild learning difficulty or borderline intelle...

Background: Aicardi-Goutières syndrome (AGS) is an autosomal recessive, early onset encephalopathy characterised by calcification of the basal ganglia, chronic cerebrospinal fluid lymphocytosis, and negative serological investigations for common prenatal infections. AGS may result from a perturbation of interferon a metabolism. The disorder is genetically heterogeneous with approximately 50% of families mapping to the first known locus at 3p21 (AGS1). Methods: A genome-wide scan was performed in 10 families with a clinical diagnosis of AGS in whom linkage to AGS1 had been excluded. Higher density genotyping in regions of interest was also undertaken using the 10 mapping pedigrees and seven additional AGS families.Results: Our results demonstrate significant linkage to a second AGS locus (AGS2) at chromosome 13q14-21 with a maximum multipoint heterogeneity logarithm of the odds (LOD) score of 5.75 at D13S768. The AGS2 locus lies within a 4.7 cM region as defined by a 1 LOD-unit support interval. Conclusions: We have identified a second AGS disease locus and at least one further locus. As in a number of other conditions, genetic heterogeneity represents a significant obstacle to gene identification in AGS. The localisation of AGS2 represents an important step in this process.