engleski

CONGENITAL MYASTHENIC SYNDROME (CMS) IN TWO SIBLINGS DUE TO A HOMOZYGOUS SPLICE MUTATION OF THE EPSILON-ACETYLCHOLIN RECEPTOR (AchR)SUBUNIT GENE

Objective. To present a brother and sister at the age of 4 and 6 years from a consanguineous Croatian family with CMS caused by a homozygous splice site mutation of intron 7 in epsilon-AchR subunit gene. In both sibs generalized mild and fatigable muscle weakness, ophtalmoparesis and feeding difficulties were present since birth as well as delayed motor development. Background. CMS are genetically determined disorders affecting safety margins of neural transmission at presynaptic, postsynaptic and synaptic level. Various mutations of the epsilon-AchR subunit gene have been reported in CMS. In general, nonsense or frame shifting mutations cause CMS by decreased or absent protein expression and are inherited in autosomal recessive traits. In contrast, missense mutations of the channel pore lining domains may alter the electrophysiogical properties of the channel resulting in the so-called Slow Channel Congenital Myasthenic Syndrome (SCCMS). SCCMS are usually inherited as autosomal dominant traits. Delayed pupillary response and hand and wrist extensor weakness are regarded as clinical clues pointing towards SCCMS. Design/Methods. Clinical examination, EMG, edrophonium test, and molecular genetic analysis were performed in both sibs. Results. On clinical examination both siblings present with waddling gait, positive Gowers maneuver, myopathic face, bilateral ophtalmoplegia, delayed pupillary reflexes, pharyngeal, hand and wrist extensor weakness. Lower limb girdle muscle weakness showed slight progression during 3 years of follow up. EMG showed slight myopathy and decremental response on repetitive stimulation in both siblings. Edrophonium test was positive. Pyridostigmine treatment improved proximal muscle weakness in brother, while the external ophtalmoplegia remained unchanged. Analysis of the epsilon-AChR subunit gene showed homozygosity for a splice site mutation of intron 7 (IVS7 -2A/G) in both siblings. Both parents are clinically unaffected and are heterozygous for the mutation. Epsilon mRNA analysis by RT-PCR and direct sequencing is underway. Conclusion. Both siblings suffer from an autosomal recessive CMS caused by a splice site mutation of the epsilon-AchR subunit gene. We hypothesize the mutation is resulting in altered splice products which may not be expressed as functional receptors at the cell surface. Clinical symptoms might indicate the presence of SCCMS in both siblings, i.e. expression of a channel with altered functional characteristics.

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