Balkan Journal of Medical Genetics

A NOVEL c.973G>T MUTATION IN THE ε-SUBUNIT OF THE ACETYLCHOLINE RECEPTOR CAUSING CONGENITAL MYASTHENIC SYNDROME IN AN IRANIAN FAMILY
Karimzadeh P1,2, Parvizi Omran S3, Ghaedi H4, Omrani MD4,*
*Corresponding Author: Mir Davood Omrani, Ph.D., Department of Medical Genetics, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Koodakyar Street, Daneshjoo Boulevard, Evin, Chamran Highway, Tehran, Islamic Republic of Iran, 1985717443. E-mail: davood_omrani@sbmu.ac.ir
page: 95

DISCUSSION

We present the clinical and molecular findings of a patient with CMS due to a CHRNE gene mutation. Analysis of the whole ε-subunit gene by PCR-sequencing was likely purported to be the novel missense mutation NM_ 000080.3 (CHRNE): p.Val325Leu in an Iranian family. The possible impact of the mutation on protein structure or function has been supported by three different in silico prediction programs. Segregation analysis from the parents also validated the pathogenicity of the mutation. This mutation has not been detected in CMS patients of any ethnic group before. We know that CHRNE gene mutations caused by postsynaptic defects represent the most common forms of CMS. Postsynaptic defects tend to be less severe in comparison with other forms of CMS. Two major abnormalities of post synaptic form are slow-channel form and fast-channel form. The slow-channel form of autosomal dominant type is a late onset form and the clinical manifestation of this form are more typical than the other types of CMS. But the clinical onset of this syndrome varies ranging from infancy to adulthood. On the other hand, fast-channel syndromes are related to autosomal recessive forms of mutations. Patients become symptomatic during early infancy. Common disorders of these post synaptic syndromes are brief channel activation episodes and reduced channel opening in response to AChRs [11,12]. Fluoxetine that normalizes abnormality of prolonged AChR activation episodes in cell cultures expressing mutated receptors can improve the clinical and electrophysiological disorders. Therefore, we used fluoxetine and we had good response in this patient after starting Prozac syrup. The patient showed improvement in his neurodevelopmental milestones and ptosis. When he was 11 months old, he could crawl and sit independently. At the last patient visit, he was 2 and a half years old and had normal developmental milestones with bilateral ptosis. The AChR ε-subunit deficiency showed as first cause of CMS worldwide, which were inherited mostly in an autosomal recessive form [4]. The mutated CHRNE gene was previously reported in an Iranian family with CMS [13]. Our findings highlight the contribution of the CHRNE gene in pathogenesis of CMS. This implies that genetic assessment of CMS cases may lead to the discovery of new CHRNE variations that could expand the clinical management of the disease. It is noteworthy that mutations in the CHRNE gene tend to be in different exons or introns or arising as a founder effect in particular geographic regions. For instance, the 1267delG frameshift mutation occurs on at least one allele of 60.0% of patients [13,4]. This mutation has been repeatedly identified in a series of Roma families in which the disease course was progressive [14]. Moreover, 1293insG was a common founder mutation in patients originating from North Africa [15]. In conclusion, we report an Iranian family carrying a CHRNE gene mutation. As expected, screening for CHRNE variants could be an effective approach to identify genetic lesion in patients with CMS. Thus, whenever clinical data are suggestive for CMS, screening the appropriate gene may help establish a significant genetic diagnosis. For further studies, the clinical and functional impacts of different CHRNE mutations may provide important insights into the roles of this gene in development of CMSs treatment.

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