A Neonate With MuSK Congenital Myasthenic Syndrome Presenting With Refractory Respiratory Failure

Abstract

This was a Chinese neonatal congenital myasthenic syndromes case caused by muscle skeletal receptor tyrosine kinase gene mutations, which have not been recorded in the Human Gene Mutation Database. The newborn girl had refractory respiratory failure from birth to death, and failed extubation seven times. She had two heterozygous mutations: a non-sense mutation c.2062C>T (p.Q688X) inherited from father and a missense mutation c.2324T>C (p.F775S) inherited from mother, which was predicted pathogenic and harmful by bioinformatic softwares SIFT, PolyPhen_2 and REVEL. She positively responded to Neostigmine, but her parent quitted treatment when Pyridostigmine Bromide (2 mg/kg Q12 h) had been given for 8 days. She died 2 days after she was taken home by her parents on age of 56 days.

Keywords: Chinese; MUSK gene; congenital myasthenic syndrome; neonate; respiratory failure.

Figure 1

Anterio-posterial Chest and abdominal X-ray on DOL 23. The anterio-posterial chest and abdominal X-ray on DOL23 showed a slightly decreased lung volume with normal lung parenchyma and heart image. The right diaphragm was at the right 6–7 intercostal space and was 1 intercostal space higher than the left side.

Figure 2

MUSK mutation analysis and models of the predicted protein structure of MuSK. (A,B) show the MUSK mutations in the patient and her parents, as confirmed by Sanger sequencing. The patient harbored compound heterozygous mutations c.2062C>T (p.Q688X) and c.2324T>C (p.F775S) of the MUSK at exon 14. (A) In the patient, one allele bears the non-sense mutation c.2062C>T (p.Q688X), which was inherited from her father. (B) The other allele bears the c.2324T>C (p.F775S) missense mutation, which was inherited from her mother. (C–E) are the re-constructed three-dimensional (3D) structure of normal MuSK and the predicted MuSK protein structures caused by the 2 mutations. (C) Total view of the 3D structure of normal MuSK. The green dotted line indicates hydrogen bonds between groups. The Phe-775 forms a hydrogen bond with the backbone atoms of Pro-771. (D) The mutation c.2062C>T (p.Q688X) results in a truncation of the protein and disruption of the protein kinase domain structure. (E) The 3D model of the MuSK amino acid substitution of p.F775S (c.2324T>C), from phenylalanine to serine, highlighted by the yellow arrow. The two hydrogen bonds interacting with Pro-771 are formed when Phe-775 is mutated to Ser, which is different from the wild type.