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Biomedical subjects

John B P Stephenson

Publications and source records attributed to John B P Stephenson.

11 recordsLinked to original sources
PubMed2006

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.

Amino Acid Sequence↗
PubMed2006

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.

Amino Acid Sequence↗
PubMed2005

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.

Autonomic Nervous System Diseases↗
PubMed2005

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.

Brain↗
PubMed2005

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.

Adolescent↗
PubMed2003

Phenotypic comparison of two Scottish families with mutations in different genes causing autosomal dominant nocturnal frontal lobe epilepsy.

PURPOSE: Mutations in genes coding for the alpha 4 and beta 2 subunits of the neuronal nicotinic acetylcholine receptor receptor (CHRN) are known to cause autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). Here we examined the phenotypes in two families, from the same ethnic and geographic backgrounds, with ADNFLE as a result of mutations in these two different subunits of CHRN. METHODS: All affected family members underwent a detailed clinical evaluation and review of available EEG, neuroimaging, and videotapes of seizures. The molecular study of family D is reported here; family S has a previously reported mutation in the beta 2 subunit of CHRN. RESULTS: A total of 16 individuals with ADNFLE were identified in the two families. In both families, seizure semiology, age at seizure onset, and the natural history of the seizure disorder was similar. Intrafamilial variation in terms of severity of epilepsy syndrome was present in both families. A significant number of individuals from each family had a history of psychological problems. The molecular study of family D revealed a Ser248Phe mutation in the alpha 4 subunit of CHRN. CONCLUSIONS: The epilepsy phenotype is not distinguishable in the two families who have ADNFLE as a result of mutations in genes coding for different CHRN subunits. This is likely to be due to the similar functional consequences of each mutation on the CHRN receptor.

Adolescent↗