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.

Mapping of the familial infantile myasthenia (congenital myasthenic syndrome type Ia) gene to chromosome 17p with evidence of genetic homogeneity.

Familial infantile myasthenia is an autosomal recessive disorder, recently classified as congenital myasthenic syndrome type Ia. Onset of symptoms is at birth to early childhood with significant myasthenic weakness and possible respiratory distress, followed later in life by symptoms of mild to moderate myasthenia. Thirty-six patients of 12 families, seven of them consanguineous, were used to map the familial infantile myasthenia gene. A combination of linkage search through the genome, DNA pooling and homozygosity mapping were employed resulting in the localisation of this disease locus to the telomeric region of chromosome 17p. A maximum lod score of 9.28 at theta = 0.034 was obtained between the disease locus and marker locus D17S1537. Haplotype analysis showed all families to be consistent with linkage to this region thus providing evidence for genetic homogeneity of familial infantile myasthenia. Multipoint linkage analysis mapped the disease gene in the approximately 4.0 cM interval between marker loci D17S1537 and D17S1298 with a maximum multipoint lod score of 12.07. Haplotype analysis and homozygosity by descent in affected individuals of the consanguineous families revealed results in agreement with the confinement of the familial infantile myasthenia region within the interval between marker loci D17S1537 and D17S1298.

Multiple sclerosis in Arabs in Jordan.

In a 2-year hospital-based study (1992 and 1993), there were 131 multiple sclerosis patients attending 2 large referral hospitals in Jordan. Based on MS/ALS case ratios an overall rate of 32.1 (95% CI 19.7-55.2) was estimated. There were 126 Arabs of whom 84 were Palestinians and 36 indigenous Jordanians. Comparison of these subgroups, which had a similar age distribution revealed that the disease was twice as frequent in Palestinians (estimated 42.0/100,000 (CI 2.8-90.8)) among Jordanians (estimated 20.0/100,000 (CI 9.5-47.2)). Clinical presentation, pattern of disease, disability and HLA association were similar to that in the disease reported in Caucasians in the West. All investigations including neurophysiology and imaging were also very similar to Western reports.

Hyperexcitability of cutaneous afferents during the supernormal period. Relevance to paraesthesiae.

The excitability of cutaneous afferents in the median nerve of 20 normal human subjects was investigated using a supramaximal conditioning stimulus and a submaximal test stimulus that produced an afferent volley of 20 to 40% of maximum. The intensity of the test stimuli was 1.1 to 1.25 times threshold for the first recruited axons (defined as a compound action potential of approximately 0.5 microV). The amplitude of the test volley did not reach the control amplitude until conditioning-test intervals of 3.4 ms. This was followed by a period of increased axonal excitability which reached a peak at intervals of 5 to 8 ms and declined gradually into a late phase of subnormality at 15 to 20 ms. The amplitude of the submaximal test potential was potentiated by, on average, 47% (range 9-146%) during the supernormal period. There were no significant changes in latency. The time course and the degree of potentiation were reproducible in the same subject on separate occasions. When the limb was cooled, the latency of the onset of supernormality was increased and the degree of supernormality was decreased and ultimately abolished. There was an inverse relationship between the degree of potentiation and the size of the test volley. High-frequency repetitive stimulation of the digital nerves for 10 min modified axonal excitability and produced spontaneous paraesthesiae that lasted for 20 min after the stimulation. Following this prolonged stimulus train, single submaximal stimuli evoked larger cutaneous afferent potentials than before the train, and the extent of the potentiation during the supernormal period was increased. It is concluded that prolonged repetitive stimulation of cutaneous afferents has two effects, one on axonal threshold, the second on the supernormal period. It is suggested that, in this experimental model, paraesthesiae result from ectopic impulses generated when axonal excitability is highest, namely at the peak of the supernormal period.