RET proto-oncogene mutations are restricted to codon 618 in Cypriot families with multiple endocrine neoplasia 2.

BACKGROUND: RET germline mutations predispose to the development of inherited cancer syndrome multiple endocrine neoplasia type 2 (MEN2). Several variants of the RET proto-oncogene including G691S and S904S have been suggested to act as genetic modifiers at the age of onset ofMEN2. AIM: The aim of this study is to characterize clinically and molecularly 7 Cypriot patients with familial medullary thyroid carcinoma (FMTC) and 1 with MEN2A and also to determine the allelic frequencies of the RET variants G691S and S904S. SUBJECTS AND METHODS: Seven probands from FMTC families and 1 from MEN2A were screened for the presence of RET mutations and the G691S and S904S variants. Additionally, 226 healthy Cypriots, who served as controls were analysed in an attempt to compare the frequencies of G691S and S904S RET variants to those observed in the 8 patients. RESULTS: The clinical diagnosis of the probands was based on clinical presentation and supported with biochemical findings. The germline C618R mutation of exon 10 was identified in all 8 probands and in 15 relatives from 7 different families. No significant difference in the G691S/S904S variants allele frequencies between patients (4/16 or 25%) and controls (124/452 or 27.4%) was found. CONCLUSIONS: Mutational screening of the RET gene identified a common mutation (C618R) in all 8 (7 FMTC and 1 MEN2A) unrelated Cypriot patients which may be explained by a founder effect. Additionally, no association of the G691S/S904S variants was linked with the disease.

Vertigo and imbalance caused by a small lesion in the anterior insula.

The exact location of the vestibular cortex in humans has not yet been established. Isolated lesions in the insula are exceptional. We describe a patient with recurrent episodes of vertigo and imbalance following a small lesion in the anterior insula. Myogenic and neurogenic vestibular evoked potentials were both performed using auditory stimuli. The former was recorded from the sternocleidomastoid muscle and the latter from the parietal areas on the scalp. Brainstem auditory evoked potentials, threshold latency series, pure tone audiometry and video nystagmography were also performed, as was brain MRI. All evoked potential studies and pure tone audiometry were within normal limits, ruling out peripheral and brainstem causes for the patient's symptoms. Video nystagmography revealed high slow phase velocities bilaterally with caloric stimulation, and saccadic tracking on the smooth pursuit examination. The MRI revealed a small lesion in the right anterior insula. To our knowledge this is the first reported case of vestibular symptoms and signs from a lesion in the anterior insula on MRI. In addition, its effects on the nystagmogram suggest that this area may be part of the pathway that controls smooth pursuit.

Vestibular symptoms and signs are correlated with abnormal neurogenic vestibular evoked potentials in patients with multiple sclerosis.

OBJECTIVES: Symptoms of disequilibrium in multiple sclerosis (MS) are common. Neurogenic vestibular evoked potentials (NVsEPs) are saccular responses to tone-pip acoustic stimuli and are recordable from the parietal areas ipsilaterally to the stimulated ear. We wished to determine possible correlations of abnormal findings in NVsEP with clinical neurological findings related to the vestibular system, and demyelination seen on MRI. PATIENTS AND METHODS: NVsEPs were performed by delivering a 1 kHz tone-pip stimulus monoaurally with contralateral masking noise via headphones. Brainstem auditory evoked potentials were performed in the standard manner. RESULTS: Thirty-three patients had either been diagnosed with MS or had possible MS. There is statistical evidence that the presence of symptoms is likely to give an abnormal NVsEP, but no correlation exists between the presence or absence of vestibular symptoms and signs and an abnormal BAEP. No correlation was found between the presence of brainstem lesions on MRI and an abnormal NVsEP. Correlation exists between abnormal NVsEP and the level of disability using Expanded Disability Status Scale scores. CONCLUSION: We have found that with increasing involvement of abnormal NVsEPs, there is a significant correlation with symptoms and signs that can be referred to the vestibular system.

Chromosome 17p-linked myasthenias stem from defects in the acetylcholine receptor epsilon-subunit gene.

OBJECTIVE: To identify and to characterize functionally the mutational basis of congenital myasthenic syndromes (CMS) linked to chromosome 17p. BACKGROUND: A total of 37 patients belonging to 13 CMS families, 9 of them consanguineous, were investigated. All patients were linked previously to the telomeric region of chromosome 17p. Two candidate genes in this region encode synaptobrevin 2, a presynaptic protein, and the epsilon-subunit of the acetylcholine receptor (AChR). Direct sequencing of the synaptobrevin 2 gene revealed no mutations. The authors thus searched for mutations in the epsilon-subunit gene of AChR. METHODS: Direct sequencing of the AChR epsilon-subunit, restriction analysis, allele-specific PCR, and expression studies in human embryonic kidney cells were performed. RESULTS: The authors identified two previously characterized and five novel epsilon-subunit gene mutations, all homozygous, in the 13 kinships. Two of the novel mutations are truncating (epsilon723delC and epsilon760ins8), one is a missense mutation in the signal peptide region (epsilonV-13D), one is a missense mutation in the N-terminal extracellular domain (epsilonT51P), and one is a splice donor site mutation in intron 10 (epsilonIVS10+2T-->G). Unaffected family members have no mutations or are heterozygous. Expression studies indicate that the four novel mutations in the coding region of the gene and the most likely transcript of the splice-site mutation, which skips exon 10, are low-expressor or null mutations. CONCLUSIONS: Chromosome 17p-linked congenital myasthenic syndromes are caused by low-expressor/null mutations in the AChR epsilon-subunit gene. Mutations in this gene are a common cause of CMS in eastern Mediterranean countries.

Spectrum and prevalence of prothrombotic single nucleotide polymorphism profiles in the Greek Cypriot population.

BACKGROUND: This study was performed to establish the allele, genotype and genotype combination/SNP (single nucleotide polymorphism) profile frequencies in the general population of Cyprus for 6 genes implicated in thrombotic disorders. The genes with their respective functional polymorphisms were the following: factor V (G1691A), prothrombin/factor II (G20210A), methylenetetrahydrofolate reductase (C677T), platelet glycoprotein receptor IIIa (P1A1/A2), b-fibrinogen (G/A-455) and plasminogen activator inhibitor-type 1 (4G/5G). METHODS: DNA samples from 121 unrelated individuals were used for this epidemiological study. The polymerase chain reaction followed by restriction digestion were used to genotype the 6 different polymorphic loci. Allele and genotype frequencies were established and shown to be in Hardy-Weinberg equilibrium. RESULTS: Mutant allele frequencies for the 6 genes were as follows: factor V-4%, prothrombin-2%, methylenetetrahydrofolate reductase -39%, platelet glycoprotein receptor IIIa-16%, beta-fibrinogen-17% and plasminogen activator inhibitor - type 1-46%. Combined defects occurred which may increase the risk for vascular events, 33% of individuals (39/118) had 3 or more of the above mutations. CONCLUSIONS: As in other European populations, prospective case-control studies to estimate the risk for deep vein thrombosis (DVT) and ischemic episodes with respect to genetic and environmental risk factors should be performed. Thrombophilia screening should be applied for primary and secondary prevention of thrombotic episodes in susceptible individuals on the island of Cyprus. Individuals targeted for such screening include those with the following: a positive family history for thrombosis; a previous DVT or other ischemic episode; prior exposure to circumstantial risk factors and in the presence of echolucent plaques.

Unobtainable radial nerve F-waves in a case of radial nerve conduction block.

We present here the first known case of an unobtainable radial nerve F-wave in a case of radial nerve conduction block. This case further demonstrates that F-waves are used not only to rule out neuropathy or radiculopathy, but also to detect conduction block.

Neurogenic vestibular evoked potentials in the diagnosis of multiple sclerosis.

OBJECTIVES: To determine the value of neurogenic vesibular evoked potential (NVESTEP) studies in comparison with other paraclinical tests in demonstrating dissemination in time and space in Multiple Sclerosis (MS) and in identifying clinically silent lesions. METHOD: All patients in whom MS was suspected but the diagnosis of MS was not possible based on the McDonald criteria were included in this study. We studied 14 patients and performed visual, brainstem auditory, somatosensory and neurogenic vestibular evoked potentials in all patients, together with MRI and CSF analysis of oligoclonal bands (OB). RESULTS: Two out of the thirteen patients could be movedfrom the category of "possible MS" to "MS" using the McDonald criteria based on an abnormal NVESTEP result. CONCLUSION: Neurogenic vestibular evoked potentials are potentially useful in identifying clinically silent lesions in patients with possible MS.

Brainstem lesions may be important in the development of epilepsy in multiple sclerosis patients: an evoked potential study.

OBJECTIVE: Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system, with epileptic seizures sometimes observed in the same patients. In this study, we used evoked responses to study the pathogenesis of epilepsy in MS. METHODS: Patients with a diagnosis of definite MS and who had EPs performed (visual (VEP), brainstem auditory (BAEP) and short latency somatosensory (upper (USSEP) and lower (LSSEP))) were retrospectively included in this study. They were divided into three groups; Group I: Patients with no epilepsy and who were not taking anti-epileptic drugs (AED); Group II: Patients with epilepsy and taking AEDs; and Group III: Patients with no epilepsy who were taking AEDs for symptoms related to neuropathic pain. RESULTS: Three hundred and fifty-five patients were included in this study; Group I: 229 patients (64.5%), Group II: 20 patients (5.6%) and Group III: 106 patients (29.9%). The proportion of patients with abnormal BAEP and USSEP was higher in Group II. CONCLUSIONS: A positive association exists between the presence of epilepsy in MS patients and BAEP and USSEP abnormalities. Analysis of Group III ruled out AED use as a factor. SIGNIFICANCE: Brainstem lesions may be the cause of epileptogenicity in MS.