TY - JOUR
T1 - Novel truncating RAPSN mutations causing congenital myasthenic syndrome responsive to 3,4-diaminopyridine
AU - Banwell, Brenda L.
AU - Ohno, Kinji
AU - Sieb, Joern P.
AU - Engel, Andrew G.
N1 - Funding Information:
This work was supported by NIH Grant NS6277 (to A.G.E.) and by a grant from the Muscular Dystrophy Association (to A.G.E.).
PY - 2004/3
Y1 - 2004/3
N2 - Rapsyn is essential for clustering the acetylcholine receptor at the postsynaptic membrane of the neuromuscular junction. Direct sequencing of RAPSN in two children with congenital myasthenic syndromes with no mutation in any of the AChR subunits identified two heterozygous recessive mutations in each: a previously characterized N88K mutation in both, and a second frameshifting mutation in Patient (Pt) 1 and a nonsense mutation in Pt 2. An intercostal muscle biopsy in Pt 1 revealed decreased AChRs per endplate and decreased amplitude of the miniature endplate potential, predicted consequences of rapsyn deficiency. Clinically, both children manifested with hypomotility in utero, fatigable ocular and limb weakness since birth, decreased strength during viral illness, decremental response on electromyography, and absence of AChR antibodies. Pt 1, however, had a more severe clinical course with recurrent episodes of respiratory failure, contractures, and craniofacial malformations. In both patients, treatment with pyridostigmine was of some benefit, but the addition of 3,4-diaminopyridine led to significant clinical improvement. Thus, rapsyn deficiency predicting similar consequences at the cellular level can result in phenotypes with marked differences in severity of symptoms, risk of respiratory failure, and presence of contractures and craniofacial malformations.
AB - Rapsyn is essential for clustering the acetylcholine receptor at the postsynaptic membrane of the neuromuscular junction. Direct sequencing of RAPSN in two children with congenital myasthenic syndromes with no mutation in any of the AChR subunits identified two heterozygous recessive mutations in each: a previously characterized N88K mutation in both, and a second frameshifting mutation in Patient (Pt) 1 and a nonsense mutation in Pt 2. An intercostal muscle biopsy in Pt 1 revealed decreased AChRs per endplate and decreased amplitude of the miniature endplate potential, predicted consequences of rapsyn deficiency. Clinically, both children manifested with hypomotility in utero, fatigable ocular and limb weakness since birth, decreased strength during viral illness, decremental response on electromyography, and absence of AChR antibodies. Pt 1, however, had a more severe clinical course with recurrent episodes of respiratory failure, contractures, and craniofacial malformations. In both patients, treatment with pyridostigmine was of some benefit, but the addition of 3,4-diaminopyridine led to significant clinical improvement. Thus, rapsyn deficiency predicting similar consequences at the cellular level can result in phenotypes with marked differences in severity of symptoms, risk of respiratory failure, and presence of contractures and craniofacial malformations.
KW - 3,4-Diaminopyridine
KW - Congenital myasthenic syndrome
KW - Human rapsyn deficiency
KW - Therapy
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U2 - 10.1016/j.nmd.2003.11.004
DO - 10.1016/j.nmd.2003.11.004
M3 - Article
C2 - 15036330
AN - SCOPUS:1242316360
SN - 0960-8966
VL - 14
SP - 202
EP - 207
JO - Neuromuscular Disorders
JF - Neuromuscular Disorders
IS - 3
ER -