Congenital myaesthenic syndrome

Gene: LRP4

I don't know

Review and rating from Michael Oldridge (Oxford Medical Genetics Laboratories Oxford University Hospitals NHS Foundation Trust), submitted by Tracy Lester (Oxford Medical Genetics Laboratories Oxford University Hospitals NHS Foundation Trust) on behalf of Wessex and West Midlands GLH for GMS Neurology specialist test group.

Created: 30 Apr 2019, 9:30 a.m.

Green List (high evidence)

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Created: 29 Apr 2019, 4:33 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Congenital myasthenic syndrome; Myasthenic syndrome, congenital, 17, 616304

Comment on list classification: Updated rating from grey to Green based on 1 Green rating from expert reviewer and discussion with curation team. 2 unrelated cases plus mouse model.

Created: 7 Feb 2017, 4:17 p.m.

Mouse models: Shen et al. (2013, 24200689) found that mice with anti-Lrp4 antibodies showed symptoms associated with myasthenia gravis (254200), including muscle weakness. Barik et al. (2014, PMID:25319686) found that conditional knockdown of the Lrp4 gene in adult mouse skeletal muscle resulted in progressive loss of muscle mass and strength, scoliosis, and ultimately death, consistent with a myasthenic phenotype.

Created: 2 Feb 2017, 2:59 p.m.

Comment on phenotypes: Mutations in LRP4 also cause the bone diseases Cenani-Lenz syndactyly syndrome (MIM:212780) and Sclerosteosis 2 (MIM:614305).

Created: 2 Feb 2017, 2:18 p.m.

Comment on mode of inheritance: Mode of inheritance confirmed by PMID:24234652 and PMID:26052878.

Created: 2 Feb 2017, 2:17 p.m.

Selcen et al., 2015 (PMID:26052878) identified a second case of CMS due to mutations in LRP4. They investigated two adult sisters with CMS affecting the limb-girdle muscles, and identified a homozygous p.Glu1233Ala mutation in LRP4 in both patients. The unaffected brother and the mother are heterozygous for the mutation.

Created: 2 Feb 2017, 2:16 p.m.

Ohkawara et al., 2014 (PMID:24234652) propose LRP4 as a new congenital myasthenic syndromes (CMS) gene, and describe a patient harboring two heteroallelic loss-of-function mutations (c.3697G>A, p.Glu1233Lys and c.3830G>A, p.Arg1277His) in LRP4. The father was heterozygous for p.Glu1233Lys. A half-brother carried no mutaion. No DNA was available from the mother.

Created: 2 Feb 2017, 2:16 p.m.

Green List (high evidence)

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Congenital myasthenic syndrome; Cenani-Lenz syndrome; Congental syndactyly

Publications

• PMID: 24234652
• PMID: 26052878