Mutations in the gene encoding GlyT2 (SLC6A5) define a presynaptic component of human startle disease.

Hyperekplexia is a human neurological disorder characterized by an excessive startle response and is typically caused by missense and nonsense mutations in the gene encoding the inhibitory glycine receptor (GlyR) alpha1 subunit (GLRA1). Genetic heterogeneity has been confirmed in rare sporadic cases, with mutations affecting other postsynaptic glycinergic proteins including the GlyR beta subunit (GLRB), gephyrin (GPHN) and RhoGEF collybistin (ARHGEF9). However, many individuals diagnosed with sporadic hyperekplexia do not carry mutations in these genes. Here we show that missense, nonsense and frameshift mutations in SLC6A5 (ref. 8), encoding the presynaptic glycine transporter 2 (GlyT2), also cause hyperekplexia. Individuals with mutations in SLC6A5 present with hypertonia, an exaggerated startle response to tactile or acoustic stimuli, and life-threatening neonatal apnea episodes. SLC6A5 mutations result in defective subcellular GlyT2 localization, decreased glycine uptake or both, with selected mutations affecting predicted glycine and Na+ binding sites.

Mutations in genes encoding ribonuclease H2 subunits cause Aicardi-Goutières syndrome and mimic congenital viral brain infection.

Aicardi-Goutières syndrome (AGS) is an autosomal recessive neurological disorder, the clinical and immunological features of which parallel those of congenital viral infection. Here we define the composition of the human ribonuclease H2 enzyme complex and show that AGS can result from mutations in the genes encoding any one of its three subunits. Our findings demonstrate a role for ribonuclease H in human neurological disease and suggest an unanticipated relationship between ribonuclease H2 and the antiviral immune response that warrants further investigation.

Aicardi-Goutières syndrome (AGS).

In 1984, Jean Aicardi and Françoise Goutières described 8 children showing both severe brain atrophy and chronic cerebrospinal fluid lymphocytosis, with basal ganglia calcification in at least one member of each affected family. The course was rapid to death or a vegetative outcome. Aicardi and Goutières correctly predicted that the disorder would be genetic, but emphasised that "some features, especially the pleocytosis, may erroneously suggest an inflammatory condition". The increased interferon-alpha in affected children (Pierre Lebon, Paris) mimicked congenital viral infection, but the associated chilblains (pernio) pointed to lupus erythematosus and an autoimmune mechanism. Genetic research led by Yanick Crow has clarified these puzzling relationships in Aicardi-Goutières syndrome, a syndrome that now includes conditions previously known as microcephaly-intracranial calcification syndrome, pseudo-TORCH and Cree encephalitis. At the time of writing, Crow's team has discovered that over 80% of families with Aicardi-Goutières syndrome have mutations in one of four nuclease genes, the exonuclease TREX1 and the genes for all three subunits of the ribonuclease H2 enzyme complex. Aicardi-Goutières syndrome is both genetically and phenotypically heterogeneous, with a range of severity from life-threatening perinatal illness to mild late infancy onset. All infants of whatever genotype have increased interferon-alpha in the first year of life and this appears to be the final common pathway that links Aicardi-Goutières syndrome, congenital virus infection and systemic lupus erythematosus.

Clinical diagnosis of syncopes (including so-called breath-holding spells) without electroencephalography or ocular compression.

A recent article in this journal suggested that ocular compression during electroencephalography was useful in distinguishing "breath-holding spells and syncope" from epileptic seizures. The method proposed involved measurement of the RR interval on the simultaneously recorded electrocardiographic trace and determining both the absolute RR lengthening and the change in RR interval as compared with the baseline value. It is argued by the present author that this is not an appropriate way to come to a diagnosis in episodic loss of consciousness in children. It is pointed out that so-called "breath-holding spells" are reflex syncopes and that the diagnosis of reflex syncopes should be by clinical history, even if this means delaying the diagnosis until a future consultation. Published evidence on the nature and clinical diagnosis of reflex syncopes in infants and children is reviewed in depth. It is concluded that routine electroencephalography is not an appropriate investigation when the diagnosis of episodic loss of consciousness is in doubt and has the implicit danger of false positive "abnormality". Aside from scientific exploration of the developing autonomic nervous system, the only current indication for diagnostic ocular compression is to induce a syncope so that its nature may be better understood. Such a circumstance might be a history of an apparent reflex syncope but with atypical features, including prolonged post-syncopal unconsciousness such as might indicate epileptic absence status. Several additional investigations of a primarily cardiological nature may be indicated in some cases, but a wait-and-see policy is usually to be preferred.

Autonomic seizures in 18q- syndrome.

The 18q- syndrome is due to (terminal) deletion in the long arm of chromosome 18 with variable break points. The phenotype is also variable, with a variety of dysmorphisms, neurological deficits possibly related to haploinsufficiency of the gene for myelin basic protein, and frequent cardiac problems. The diagnosis of paroxysmal events in 18q- syndrome presents difficulties because both epileptic seizures and cardiac syncopes might be expected to occur. Autonomic seizures are epileptic seizures consisting of episodic alterations of autonomic function that are elicited by activation of autonomic cortical centres. In such events confusion with syncope is even more likely. A previous case of autonomic seizures masquerading as syncope in an adult has been reported. The present report is the first to describe autonomic seizures in 18q- syndrome in a child. Very frequent episodes of prolonged apnoea with profound oxygen desaturation was associated with a focal EEG discharge, arising from either the right temporal or left temporal region. As in the adult patient referred to, the seizures ceased on carbamazepine. No systematic studies of incidence have been published, but autonomic epileptic seizures simulating non-epileptic syncopes may be a feature of 18q- syndrome.

The movement disorders of Coffin-Lowry syndrome.

Coffin-Lowry syndrome (CLS) is an X-linked semi-dominant condition with learning difficulties and dysmorphism caused by mutations in the gene RSK2. Originally, epilepsy was reported as a feature. We and others have since described predominantly sound-startle induced drop attacks that have been labelled 'cataplexy', abnormal startle response and hyperekplexia. We sought to clarify why there should be controversy over the type of paroxysmal events. Review of the literature and our patients confirmed that each centre had studied only a small numbers of individuals (mean = 2). The type of movement disorder varied both with age and between individuals. One individual might have more than one movement disorder. One of our adult patients had several types of movement disorder and epilepsy that merged seamlessly: there was true cataplexy triggered by telling a joke, something close to cataplexy ('cataplexy') triggered by sound-startle, a predominantly hypertonic reaction varying from hyperekplexia to a more prolonged tonic reaction resembling startle epilepsy, and true unprovoked epileptic seizures. In the large database of the Coffin-Lowry Syndrome Foundation family support group, 34 of 170 (20%) individuals with CLS and known age had 'drop attacks' and an additional 9 (5%) of these had additional epileptic seizures. The onset of such events was usually after age 5 years, prevalence peaking at 15-20 years (27%). Many became wheelchair bound as a result. This unique combination of more than one non-epileptic movement disorder and epilepsy deserves further semiological and genetic study both for the patients with CLS and for the wider implications.

Electro-clinical phenotypes of chromosome disorders associated with epilepsy in the absence of dysmorphism.

Chromosome imbalances are associated with epilepsy but electro-clinical phenotypes are lacking for all but the best-known syndromes. Scanty information is contained in older case reports published in genetics journals that describe children with severe patterns of malformation and dysmorphism. From a larger series of children with chromosome abnormalities and epilepsy, we identified 10 patients with associated dysmorphism without malformation. Electro-clinical features are described for each patient. We found that these patients are at greater risk of delayed diagnosis, particularly when there are no learning difficulties at the onset of epilepsy, as in ring chromosome 20 syndrome. Chromosome studies should be ordered on all children with learning difficulties and epilepsy, and on children with atypical non-lesional epilepsy, even in the absence of learning difficulties or dysmorphism.

Syncopes and other paroxysmal events.

Paroxysmal nonepileptic disorders are very frequent in infants and children and pediatric neurologists need to be as familiar with them as with epileptic seizures. Syncopes are the most important of these episodic disorders and amongst the syncopes the various subtypes of so-called neurally mediated syncopes (vagal, vasovagal, and so forth) predominate. In such syncopes there is almost always a trigger or provoking situation and this is the major clinical clue to the diagnosis. Whatever the mechanism of a syncope it is commonly "convulsive" in that there is a motor element, with tonic extensions and arrhythmic nonepileptic spasms ("jerks"). This everyday situation must be distinguished from the much less common combination of a syncope and a true epileptic seizure. In such anoxic-epileptic seizures the epileptic component is usually clonic, with rhythmic or semi-rhythmic jerks quite different from the arrhythmic spasms of the usual nonepileptic convulsive syncope. Syncope from compulsive Valsalva maneuver may be extremely frequent in affected (usually autistic) children. Diagnosis is easy if one obtains a video recording with audio: the premonitory hyperventilation stops leaving 11 seconds of silence before the tonic extension that signifies the syncope. Syncopes of more serious kind include those in long QT syndrome, hyperekplexia, paroxysmal extreme pain disorder, and congenital myasthenia; each has recognizable characteristics. Other nonsyncopal nonepileptic paroxysmal disorders are described further in the text.

Mutations in CTC1, encoding conserved telomere maintenance component 1, cause Coats plus.

Coats plus is a highly pleiotropic disorder particularly affecting the eye, brain, bone and gastrointestinal tract. Here, we show that Coats plus results from mutations in CTC1, encoding conserved telomere maintenance component 1, a member of the mammalian homolog of the yeast heterotrimeric CST telomeric capping complex. Consistent with the observation of shortened telomeres in an Arabidopsis CTC1 mutant and the phenotypic overlap of Coats plus with the telomeric maintenance disorders comprising dyskeratosis congenita, we observed shortened telomeres in three individuals with Coats plus and an increase in spontaneous γH2AX-positive cells in cell lines derived from two affected individuals. CTC1 is also a subunit of the α-accessory factor (AAF) complex, stimulating the activity of DNA polymerase-α primase, the only enzyme known to initiate DNA replication in eukaryotic cells. Thus, CTC1 may have a function in DNA metabolism that is necessary for but not specific to telomeric integrity.