Case studyProgeria caused by a rare LMNA mutation p.S143F associated with mild myopathy and atrial fibrillation
Introduction
Hutchinson-Gilford progeria syndrome (HGPS) described by Jonathan Hutchinson and Hastings Gilford in 1886–1887 and characterized by premature aging of children, is a rare genetic disease with an estimated incidence of 1 per 4–8 millions. Progeria is a multisystem disorder affecting various tissues and organs: bone, muscle, skin, subcutaneous tissue, vessels and heart. Children with progeria are usually normal at birth, but characteristic signs of progeria appear at the age of 6–18 months. A typical phenotype includes delayed growth, short stature, low weight, bird-like face appearance, craniofacial disproportion, beaked nose, micrognathia and sparse grey hair, wrinkled skin with mottled pigmentation, prominent vessels and sometimes scleroderma-like changes, pear-shaped thorax and coxa valga. Atherosclerosis developing in the first decade of life may result in early-onset coronary heart disease and cerebral stroke. The average lifespan is about 13 years. Since 2003, progeria has been recognized as a laminopathy, as it is associated with mutations in the LMNA gene encoding lamin A/C, the main component of the nuclear lamina. The most frequent mutation in HGPS is a heterozygous single base g.1824C>T substitution in exon 11, which creates silent point mutation at codon 608 (p.G608G) and activates cryptic splice site leading to truncated lamin A –progerin, lacking 50 amino acids at the C-terminal end.1, 2 There are few reports on progeria with atypical clinical course, which may share some phenotypical features with other known multisystem laminopathies, i.e. mandibuloacral dysplasia (MAD) or restrictive dermatopathy (RD), lethal genodermatosis. Mutations associated with atypical progeria occur both in LMNA or/and in ZMPSTE-24, which encodes FACE-1 responsible for maturation of lamin A. The trait of inheritance may be dominant or recessive.1, 3, 4, 5, 6, 7
In this report, we present a girl with progeria, myopathy and atrial fibrillation, associated with a point mutation in the exon 2 of the LMNA gene.
Section snippets
Case report
A 6-year-old girl was born at term to non-consanguineous, healthy parents, as the oldest child among three sisters. Pregnancy was complicated by fetal hypotrophy and gestation was terminated by the Cesarean section because of breech presentation. She weighted 3000 g (10–25th percentile), her length was 54 cm (25–50th percentile), and the Apgar score was 10. At the age of 2 months she started failing to thrive, having poor appetite and constipation. First freckles appeared at the age of 12 months,
Discussion
We describe a girl with signs of progeria in whom we have found a mutation in the exon 2 of the LMNA gene. The phenotype of 6-year old patient fulfills some clinical criteria to recognize this case as atypical progeria8: hair loss is not complete, craniofacial disproportion is not prominent, subcutaneous adipose tissue is quite well-preserved on face (cheeks), and growth retardation is less severe than in classic HGPS. Furthermore, our patient presented myopathy involving mild proximal muscle
Acknowledgements
This work has been supported by a grant from the Polish Committee for Scientific Research 2P05B10629. We thank Ms. Jadwiga Kędzierska and Ms. Zofia Glinka for technical assistance.
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A novel nonsense mutation in LMNA gene identified by Exome Sequencing in an atrial fibrillation family
2016, European Journal of Medical GeneticsCitation Excerpt :Several mutations in LMNA have been proved associated with AF previously (Brauch et al., 2009; Sebillon et al., 2003; Pan et al., 2009; Beckmann et al., 2010; Saj et al., 2012; Madej-Pilarczyk et al., 2008). Most of these mutations were detected in AF families (Pan et al., 2009; Beckmann et al., 2010; Saj et al., 2012; Madej-Pilarczyk et al., 2008). This variant we detected is a novel mutation and has not yet been reported for any actual databases.
A recurrent homozygous LMNA missense variant p.Thr528Met causes atypical progeroid syndrome characterized by mandibuloacral dysostosis, severe muscular dystrophy, and skeletal deformities
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