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

CLINICAL REPORT

The finding of a clinical report was established in a 5 and half-month-old boy referred to the Department of Pediatric Neurology at the Mofid Children’s Hospital, Tehran, Iran due to bilateral ptosis. He was the product of consanguineous marriage with an uneventful birth history. Ptosis started when he was 2 months old and was exacerbated by crying and breast feeding, which led to fatigue and lack of sleep during this period. The family history for neuromuscular disorders tested negative. In a neurological examination, the patient showed hypotonia bilateral ptosis but normal mental development in terms of normal facial phenotypic expression followed by a social smile (Figure 1). In order to rule out the etiology of intracranial involvement, at first, we did a brain magnetic resonance imaging (MRI) and the result was within normal limits. According to the above history and physical examination, the top list of our diagnosis was CMS. Therefore, electromyography (EMG) and nerve conduction velocity (NCV), in the right and left deltoid, biceps, triceps, extensor digitrum communis and first dorsal interosseous in upper extremities and in right and left gluteus medius, vastus medialis, tibialis anterior and gastrocnemius (medial head in lower extremities evaluated a 2+ fibrillation, normal NCV and low-amplitude pattern were detected, although it showed some myopathic pattern but the repetitive nerve stimulation (RNS) test in abductor digiti minimi muscle did not show any decremental pattern. This response could be due to the young age of the patient. Creatine phosphokinase was normal and antibody against the AChR was negative. Neurometabolic disorders such as mitochondrial disease would probably be given little attention because of the early symptoms of ptosis and motor delay. We evaluated serum urine and cerebral spinal fluid and the results were within normal limits. Metabolic screenings, tandem mass spectro chromatography, high performance liquid chromatography of amino acids, urine organic acids, ammonia and venous blood gas (VBG), were all within normal limits. For confirmation of our diagnosis, we did a genetic study of CMS. Informed consent for the genetic studies and publication of medical information was obtained from patient’s parents. Venous blood sample was obtained from the patient as well as from all his family members for segregation analysis. Molecular analysis was designed based on the mutation frequencies in genes responsible for post-synaptic CMSs. The family were screened for pathogenic variants in the CHRNE gene. Genomic DNA was extracted from peripheral leukocytes using standard procedures. Polymerase chain reaction (PCR) was carried out in a final volume of 50 μL using PCR Master Mix (Ampliqon A/S, Odense, Denmark). The PCR reactions were performed in a thermal cycler (Techne ® Prime; Techne, Cambridge, Cambridgeshire, UK) for 5 min. at 95 °C followed by 30 cycles of denaturation for 30 seconds at 95 °C, annealing for 30 seconds depended on the melting temperature of primers, primer extension for 1 min. at 72 °C, with a final 5 min. extension at 72 °C. The PCR product was evaluated on an 1.5% agarose gel. Then, sequencing was carried out using an ABI PRISM® 3100 capillary sequencer (Thermo Fisher, Waltham, MA, USA). Sequences data were analyzed by comparing these results with the reference wild-type sequence (GenBank CHRNE accession numbers: NM_000080.3) using the Finch TV program (version 1.4.0; Geospiza Inc., Seattle, WA, USA). Bioinformatics Analysis. To predict the possible structural and functional effects of the newly identified mutation in the CHRNE gene, the PolyPhen (Polymorphism phenotyping-2) [5], MutationTaster [6] and SIFT (Sorting Intolerant from Tolerant) [7] programs were used. These are the most frequently used tools for variant effect prediction. In order to classify the mutation, we used the 2015 American College of Medical Genetics and Genomics/ Association for Molecular Pathology (ACMG/AMP) guideline as implemented in the InterVar Web-server.

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