TY - JOUR
T1 - Recessive congenital myasthenic syndrome caused by a homozygous mutation in SYT2 altering a highly conserved C-terminal amino acid sequence
AU - Maselli, Ricardo A.
AU - van der Linden, Hélio
AU - Ferns, Michael
PY - 2020/7/1
Y1 - 2020/7/1
N2 - Defects in the gene encoding synaptotagmin 2 (SYT2) have been linked to a presynaptic congenital myasthenic syndrome (CMS) and motor neuropathies. However, to date only dominant forms of the disease have been described. We report here a consanguineous patient with a severe recessive form of presynaptic CMS and denervation atrophy caused by the homozygous mutation c.1191delG, p.Arg397Serfs*37 in SYT2. The affected 2-year-old girl had profound weakness and areflexia with moderate bulbar deficit. Repetitive nerve stimulation revealed an extreme reduction of compound muscle action potential amplitudes at rest, with a striking facilitation followed by a progressive decline at fast stimulation rates. These findings were reminiscent, but not identical to those seen in the Lambert–Eaton myasthenic syndrome. 3,4 diaminopyridine and pyridostigmine were effective to ameliorate muscle fatigue, but albuterol was ineffective. Modeling of the mutation using the rat Syt1 C2B x-ray structure revealed that Arg397Serfs*37 disrupts a highly conserved amino acid sequence at the bottom face of the C2B domain not directly involved in calcium binding, but crucial for synaptotagmin-SNARE interaction and exocytosis. Thus, this report describes a recessive form of synaptotagmin 2-CMS and highlights the importance of the synaptotagmin C-terminal on synaptic vesicle fusion and exocytosis.
AB - Defects in the gene encoding synaptotagmin 2 (SYT2) have been linked to a presynaptic congenital myasthenic syndrome (CMS) and motor neuropathies. However, to date only dominant forms of the disease have been described. We report here a consanguineous patient with a severe recessive form of presynaptic CMS and denervation atrophy caused by the homozygous mutation c.1191delG, p.Arg397Serfs*37 in SYT2. The affected 2-year-old girl had profound weakness and areflexia with moderate bulbar deficit. Repetitive nerve stimulation revealed an extreme reduction of compound muscle action potential amplitudes at rest, with a striking facilitation followed by a progressive decline at fast stimulation rates. These findings were reminiscent, but not identical to those seen in the Lambert–Eaton myasthenic syndrome. 3,4 diaminopyridine and pyridostigmine were effective to ameliorate muscle fatigue, but albuterol was ineffective. Modeling of the mutation using the rat Syt1 C2B x-ray structure revealed that Arg397Serfs*37 disrupts a highly conserved amino acid sequence at the bottom face of the C2B domain not directly involved in calcium binding, but crucial for synaptotagmin-SNARE interaction and exocytosis. Thus, this report describes a recessive form of synaptotagmin 2-CMS and highlights the importance of the synaptotagmin C-terminal on synaptic vesicle fusion and exocytosis.
KW - congenital myasthenic syndrome
KW - recessive
KW - synaptic vesicles
KW - synaptotagmin 2
UR - http://www.scopus.com/inward/record.url?scp=85082932258&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85082932258&partnerID=8YFLogxK
U2 - 10.1002/ajmg.a.61579
DO - 10.1002/ajmg.a.61579
M3 - Article
C2 - 32250532
AN - SCOPUS:85082932258
VL - 182
SP - 1744
EP - 1749
JO - American Journal of Medical Genetics, Part A
JF - American Journal of Medical Genetics, Part A
SN - 1552-4825
IS - 7
ER -