Abstract
Defects in genes encoding the isoforms of the laminin alpha subunit have been linked to various phenotypic manifestations, including brain malformations, muscular dystrophy, ocular defects, cardiomyopathy, and skin abnormalities. We report here a severe defect of neuromuscular transmission in a consanguineous patient with a homozygous variant in the laminin alpha-5 subunit gene (LAMA5). The variant c.8046C>T (p.Arg2659Trp) is rare and has a predicted deleterious effect. The affected individual, who also carries a rare homozygous sequence variant in LAMA1, had muscle weakness, myopia, and facial tics. Magnetic resonance imaging of brain showed mild volume loss and periventricular T2 prolongation. Repetitive nerve stimulation revealed 50% decrement of compound muscle action potential amplitudes and 250% facilitation immediately after exercise, Endplate studies identified a profound reduction of the endplate potential quantal content and endplates with normal postsynaptic folding that were denuded or partially occupied by small nerve terminals. Expression studies revealed that p.Arg2659Trp caused decreased binding of laminin alpha-5 to SV2A and impaired laminin-521 cell-adhesion and cell projection support in primary neuronal cultures. In summary, this report describing severe neuromuscular transmission failure in a patient with a LAMA5 mutation expands the list of phenotypes associated with defects in genes encoding alpha-laminins.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 2240-2245 |
| Number of pages | 6 |
| Journal | American Journal of Medical Genetics, Part A |
| Volume | 173 |
| Issue number | 8 |
| DOIs | |
| State | Published - Aug 1 2017 |
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Keywords
- congenital myasthenic syndrome (CMS)
- LAMA5
- laminin α5
- presynaptic
ASJC Scopus subject areas
- Genetics
- Genetics(clinical)
Cite this
Presynaptic congenital myasthenic syndrome with a homozygous sequence variant in LAMA5 combines myopia, facial tics, and failure of neuromuscular transmission. / University of Washington Center for Mendelian Genomics.
In: American Journal of Medical Genetics, Part A, Vol. 173, No. 8, 01.08.2017, p. 2240-2245.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Presynaptic congenital myasthenic syndrome with a homozygous sequence variant in LAMA5 combines myopia, facial tics, and failure of neuromuscular transmission
AU - University of Washington Center for Mendelian Genomics
AU - Maselli, Ricardo A
AU - Arredondo, Juan
AU - Vázquez, Jessica
AU - Chong, Jessica X.
AU - Bamshad, Michael J.
AU - Nickerson, Deborah A.
AU - Lara, Marian
AU - Ng, Fiona
AU - Lo, Victoria L.
AU - Pytel, Peter
AU - McDonald, Craig M
PY - 2017/8/1
Y1 - 2017/8/1
N2 - Defects in genes encoding the isoforms of the laminin alpha subunit have been linked to various phenotypic manifestations, including brain malformations, muscular dystrophy, ocular defects, cardiomyopathy, and skin abnormalities. We report here a severe defect of neuromuscular transmission in a consanguineous patient with a homozygous variant in the laminin alpha-5 subunit gene (LAMA5). The variant c.8046C>T (p.Arg2659Trp) is rare and has a predicted deleterious effect. The affected individual, who also carries a rare homozygous sequence variant in LAMA1, had muscle weakness, myopia, and facial tics. Magnetic resonance imaging of brain showed mild volume loss and periventricular T2 prolongation. Repetitive nerve stimulation revealed 50% decrement of compound muscle action potential amplitudes and 250% facilitation immediately after exercise, Endplate studies identified a profound reduction of the endplate potential quantal content and endplates with normal postsynaptic folding that were denuded or partially occupied by small nerve terminals. Expression studies revealed that p.Arg2659Trp caused decreased binding of laminin alpha-5 to SV2A and impaired laminin-521 cell-adhesion and cell projection support in primary neuronal cultures. In summary, this report describing severe neuromuscular transmission failure in a patient with a LAMA5 mutation expands the list of phenotypes associated with defects in genes encoding alpha-laminins.
AB - Defects in genes encoding the isoforms of the laminin alpha subunit have been linked to various phenotypic manifestations, including brain malformations, muscular dystrophy, ocular defects, cardiomyopathy, and skin abnormalities. We report here a severe defect of neuromuscular transmission in a consanguineous patient with a homozygous variant in the laminin alpha-5 subunit gene (LAMA5). The variant c.8046C>T (p.Arg2659Trp) is rare and has a predicted deleterious effect. The affected individual, who also carries a rare homozygous sequence variant in LAMA1, had muscle weakness, myopia, and facial tics. Magnetic resonance imaging of brain showed mild volume loss and periventricular T2 prolongation. Repetitive nerve stimulation revealed 50% decrement of compound muscle action potential amplitudes and 250% facilitation immediately after exercise, Endplate studies identified a profound reduction of the endplate potential quantal content and endplates with normal postsynaptic folding that were denuded or partially occupied by small nerve terminals. Expression studies revealed that p.Arg2659Trp caused decreased binding of laminin alpha-5 to SV2A and impaired laminin-521 cell-adhesion and cell projection support in primary neuronal cultures. In summary, this report describing severe neuromuscular transmission failure in a patient with a LAMA5 mutation expands the list of phenotypes associated with defects in genes encoding alpha-laminins.
KW - congenital myasthenic syndrome (CMS)
KW - LAMA5
KW - laminin α5
KW - presynaptic
UR - http://www.scopus.com/inward/record.url?scp=85023187786&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85023187786&partnerID=8YFLogxK
U2 - 10.1002/ajmg.a.38291
DO - 10.1002/ajmg.a.38291
M3 - Article
C2 - 28544784
AN - SCOPUS:85023187786
VL - 173
SP - 2240
EP - 2245
JO - American Journal of Medical Genetics
JF - American Journal of Medical Genetics
SN - 1552-4825
IS - 8
ER -