Germinal mosaicism for LMNA mimics autosomal recessive congenital muscular dystrophy

doi:10.1016/j.nmd.2008.09.016

Neuromuscular Disorders

Volume 19, Issue 1, January 2009, Pages 26-28

https://doi.org/10.1016/j.nmd.2008.09.016 Get rights and content

Abstract

Life-threatening cardiac and respiratory complications are common in LMNA-related myopathies and early diagnosis is important for optimal patient care. Lamin A/C related congenital muscular dystrophy (L-CMD) is often caused by de novo mutation in LMNA, affecting a single child in a family. Germinal mosaicism is a rarer variant that can lead to two children inheriting the same new heterozygous mutation from a clinically unaffected parent. Both patterns mimic autosomal recessive (AR) inheritance and the possibility of de novo L-CMD may be forgotten since most causes of congenital muscular dystrophy follow AR inheritance. To illustrate the challenge of diagnosing L-CMD, we present a consanguineous family in which two children have early onset LMNA-related myopathy likely due to paternal germinal mosaicism. This emphasises that germinal mosaicism (and de novo mutations) for LMNA can arise in any family and direct gene sequencing is required to confirm or exclude the diagnosis.

Introduction

The LMNA gene encodes two nuclear envelope proteins (lamins A and C) and is responsible for a broad spectrum of genetic disorders. Heterozygous mutations throughout the gene have been implicated in a spectrum of skeletal muscle disorders that share dystrophic histological changes and the potential for life threatening cardiac and respiratory complications, with or without lipodystrophy [1], [2]. The least severe phenotype is an adult onset limb girdle muscular dystrophy (LGMD1B) [3] while Emery-Dreifuss muscular dystrophy (EDMD) has an intermediate severity [4]. Recently, a congenital or very early onset form of LMNA-related myopathy has been defined; lamin A/C related congenital muscular dystrophy or L-CMD [5]. LMNA-related myopathies typically follow autosomal dominant inheritance but de novo mutations are very frequent, particularly in L-CMD [5], and manifest as an affected child born to clinically healthy parents, the typical pattern of autosomal recessive (AR) inheritance. Most other forms of congenital muscular dystrophy (CMD) and many forms of limb girdle muscular dystrophy (LGMD) are inherited in an autosomal recessive pattern [6]. It requires vigilance to distinguish patients with muscular dystrophies due to de novoLMNA mutations from autosomal recessive disorders so that families can receive appropriate management and genetic counselling. To demonstrate the challenges and potential pitfalls, we report a family in which two out of six children, born to healthy consanguineous parents, have an early onset muscular dystrophy due to gonadal mosaicism for a LMNA gene mutation.

Section snippets

Patients

We ascertained a consanguineous Algerian family (parents were first cousins, once removed) in which two of six children had early onset muscle weakness.

Sister 1: Forceps were required during birth for poor progression. She had congenital hypotonia, diffuse weakness and mild initial respiratory and feeding difficulties. She sat unsupported at age two years and walked independently from age 4 years with frequent falls and a waddling gait. Progressive tendo-Achilles contractures began at age three

Genetic analysis

Genomic DNA was extracted from both affected children and first degree relatives from venous blood by standard techniques. Linkage to the following genes associated with AR CMD (either homozygous by descent or heterozygous) was excluded using microsatellite markers close to the gene or disease locus: SEPN1, COL6A1/2, COL6A3, CAPN3, POMT1, FKRP, POMGNT1, FKTN and MCD1B (1p42). Classical AR inheritance was also excluded for the LMNA locus (Fig. 2). A genome-wide microsatellite analysis using 400

Discussion

Arg527Pro is a recurrent mutation that has been previously described in at least other 12 other individuals from six unrelated families, with classical EDMD or LGMD phenotypes with or without signs of familial lipodystrophy [1], [8], [9], [10], [11]. The children we describe are most typical of the EDMD phenotype (early elbow contractures, spinal rigidity, lack of marked neck weakness) rather than L-CMD. Therefore, we suspect that perinatal difficulties contributed significantly to the

Acknowledgements

We are grateful to the family for participating in this research. This work has been supported by the Association Française contre les Myopathies (AFM), Rare Disorder Network Program (#10722), GIS-Institut des Maladies Rares (#RAS05018), Institut National de la Santé et de la Recherche Médicale (Inserm) France (NC), Assistance Publique-Hôpitaux de Paris (AP-HP) France, NHMRC Australia (NC; 402861) and by the Royal Australian College of Physicians (2006 Bushell Travelling Fellowship; NC).

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Cited by (22)

Floppy infant syndrome as a first manifestation of LMNA-related congenital muscular dystrophy
2021, European Journal of Paediatric Neurology
Citation Excerpt :
In family 3 mosaicism (20% in DNA isolated from blood) for the novel mutation c.121C > G (p.Arg41Gly) was found in clinically asymptomatic father. Mosaicism for LMNA gene has been already described in L-CMD (paternal) and HGPS (maternal) – both parents, who transmitted the LMNA mutation, were asymptomatic [35,36]. Mosaicism for the LMNA gene should be encountered in genetic counselling, as it might mimics autosomal recessive trait of inheritance [24].
LMNA-related congenital muscular dystrophy (L-CMD) is the most severe phenotypic form of skeletal muscle laminopathies. This paper reports clinical presentation of the disease in 15 Polish patients from 13 families with genetically confirmed skeletal muscle laminopathy. In all these patients floppy infant syndrome was the first manifestation of the disease. The genetic diagnosis was established by next generation sequencing (targeted panel or exome; 11 patients) or classic Sanger sequencing (4 patients). In addition to known pathogenic LMNA variants: c.116A > G (p.Asn39Ser), c.745C > T (p.Arg249Trp), c.746G > A (p.Arg249Gln), c.1072G > A (p.Glu358Lys), c.1147G > A (p.Glu383Lys), c.1163G > C (p.Arg388Pro), c.1357C > T (p.Arg453Trp), c.1583C > G (p.Thr528Arg), we have identified three novel ones: c.121C > G (p.Arg41Gly), c.1127A > G (p.Tyr376Cys) and c.1160T > C (p.Leu387Pro). Eleven patients had de novo mutations, 4 – familial. In one family we observed intrafamilial variability of clinical course: severe L-CMD in the male proband, intermediate form in his sister and asymptomatic in their mother. One asymptomatic father had somatic mosaicism. L-CMD should be suspected in children with hypotonia in infancy and delayed motor development, who have poor head control, severe hyperlordosis and unstable and awkward gait. Serum creatine kinase may be high (~1000IU/l). Progression of muscle weakness is fast, leading to early immobilization. In some patients with L-CMD joint contractures can develop with time. MRI shows that the most frequently affected muscles are the serratus anterior, lumbar paraspinal, gluteus, vastus, adductor magnus, hamstrings, medial head of gastrocnemius and soleus. Ultra-rare laminopathies can be a relatively common cause of generalized hypotonia in children. Introduction of wide genome sequencing methods was a breakthrough in diagnostics of diseases with great clinical and genetic variability and allowed approach “from genotype do phenotype”. However target sequencing of LMNA gene could be considered in selected patients with clinical picture suggestive for laminopathy.
Muscle diseases with prominent joint contractures: Main entities and diagnostic strategy
2013, Revue Neurologique
Citation Excerpt :
In apparently sporadic cases with an identified LMNA mutation, both parents have to be tested to confirm whether it is a de novo mutation, which are particularly frequent in LMNA-EDMD (about 50% probands) (Bonne et al., 2000). In other families, germinal mosaicism (Makri et al., 2009) or minimal expression of the disease in a parent carrying the mutation, indicating variable penetrance, have been observed (Vytopil et al., 2002). Digenism has been reported in some patients harbouring EMD and LMNA mutations (Muntoni et al., 2006; Ben Yaou et al., 2007) or EMD and desmin gene mutations (Muntoni et al., 2006).
Muscle diseases may have various clinical manifestations including muscle weakness, atrophy or hypertrophy and joint contractures. A spectrum of non-muscular manifestations (cardiac, respiratory, cutaneous, central and peripheral nervous system…) may be associated. Few of these features are specific. Limb joint contractures or spine rigidity, when prevailing over muscle weakness in ambulant patients, are of high diagnostic value for diagnosis orientation. Within this context, among several disorders, four groups of diseases should systematically come to mind including the collagen VI-related myopathies, the Emery–Dreifuss muscular dystrophies, the SEPN1 and FHL1 related myopathies. More rarely other genetic or acquired myopathies may present with marked contractures. Diagnostic work-up should include a comprehensive assessment including family history, neurological, cardiologic and respiratory evaluations. Paraclinical investigations should minimally include muscle imaging and electromyography. Muscle and skin biopsies as well as protein and molecular analyses usually help to reach a precise diagnosis. We will first describe the main muscle and neuromuscular junction diseases where contractures are typically a prominent symptom of high diagnostic value for diagnosis orientation. In the following chapters, we will present clues for the diagnostic strategy and the main measures to be taken when, at the end of the diagnostic work-up, no definite muscular disease has been identified.
Les signes cliniques des affections musculaires sont variés : faiblesse et/ou fatigabilité, atrophie et/ou hypertrophie musculaires mais aussi rétractions tendineuses, de topographie variable. Peuvent s’y associer des symptômes extramusculaires (cardiaques, respiratoires, neurologiques centraux ou périphériques, ophtalmologiques, métaboliques, cutanés). Parmi les symptômes clés qui orientent la démarche clinique, les rétractions tendineuses peuvent être d’un apport décisif pour poser un diagnostic précis quand elles sont au premier plan. Leur existence et leur topographie (axiale et/ou au niveau des membres), notamment chez un patient encore ambulatoire, apportent un élément d’orientation important à l’équation clinique. Dans ce cadre, quatre groupes d’affections musculaires sont à évoquer systématiquement : les myopathies liées aux collagène VI, les myopathies de type Emery-Dreifuss, les myopathies liées aux gènes FHL1 et SEPN1. D’autres affections musculaires héréditaires ou acquises sont plus rarement en cause. La conduite à tenir doit comporter une évaluation aussi complète que possible de l’histoire familiale et de l’état neuro-cardiorespiratoire. Les investigations paracliniques devront comprendre au moins une imagerie musculaire et un examen électromyographique complet. Les biopsies musculaire et cutanée ainsi que les études protéiques ad hoc et les analyses génétiques en biologie moléculaire permettent souvent de poser un diagnostic précis. Au terme d’une démarche diagnostique rigoureuse, les cas restant sans diagnostic bénéficieront de l’apport des techniques d’analyses moléculaires en haut débit récemment mises au point. Dans cet article, nous décrivons d’abord les principales entités cliniques où les rétractions tendineuses au premier plan contribueront à orienter le diagnostic. Nous présenterons ensuite les principaux éléments de la stratégie diagnostique.
Muscular Dystrophies and Allied Disorders IV: Emery-Dreifuss Muscular Dystrophy and Similar Syndromes
2013, Muscle Biopsy: A Practical Approach Expert Consult; Online and Print
A novel mutation in the LMNA gene causes congenital muscular dystrophy with dropped head and brain involvement
2012, Neuromuscular Disorders
Citation Excerpt :
This duplication was not found in 100 control Japanese DNA samples. Reports of L-CMD with a dropped head are rare, and all of them have been from Europe [2–6]. Here we describe the first Asian patient with L-CMD accompanied by a dropped head caused by a novel mutation in the LMNA.
We describe a 22-month-old girl with axial muscle and diaphragmatic weakness as well as motor developmental delay without mental retardation. The striking clinical feature was a dropped head, although she could walk unaided. T2/FLAIR brain MRI revealed a focal abnormality with high signal intensity in the white matter including U-fibers. A muscle biopsy showed active necrotic and regenerative processes. These distinct clinical findings prompted a mutational analysis of the lamin A (LMNA) gene, and we identified a novel heterozygous mutation in LMNA (c.1330_1338dup9). This is the first report of an Asian patient with LMNA-related congenital muscular dystrophy (L-CMD) and a dropped head.
Congenital Fiber-Type Disproportion
2011, Seminars in Pediatric Neurology
Citation Excerpt :
If 2 siblings are the only affected members of their family, an autosomal recessive inheritance pattern is most likely. Gonadal mosaicism for a dominant mutation in one or the other parent who appears unaffected can result in the same pattern but is rare.43 X-linked inheritance has only been reported in 1 family to date and appears rare.18
Congenital fiber-type disproportion is a form of congenital myopathy that may be best viewed as a syndrome rather than as a formal diagnosis. The central histologic abnormality is that type 1 fibers are consistently smaller than type 2 fibers by at least 35%-40%. Care is needed in diagnosing patients, as this histologic abnormality can occur in other congenital myopathies and in other neuromuscular disorders. Many of the genetic causes have been identified. Careful surveillance of respiratory function is required in all patients until the specific genetic cause is known and advice can be individualized.
Germline Mosaicism for KIF21A Mutation (p.R954L) Mimicking Recessive Inheritance for Congenital Fibrosis of the Extraocular Muscles
2010, Ophthalmology
Citation Excerpt :
Postzygotic mutations that give rise to mosaicism can affect either somatic cells, germ cells, or both, depending on the timing of the event.9–11 The fact that the parents have no ophthalmic findings and no detectable KIF21A mutation in peripheral blood leukocytes suggests that there is little if any somatic component9,12; however, in any individual, somatic mosaicism can never be ruled out entirely because all cells of the body cannot be tested.9–11 The percentage of apparent de novo mutations that in fact are the result of germline mosaicism in a parent varies depending on the disorder and is difficult determine, especially if only 1 affected child is born to unaffected parents.
To document the genotype for familial congenital fibrosis of the extraocular muscles (CFEOM) with apparent autosomal recessive inheritance.
Interventional family study.
Two affected siblings, 3 asymptomatic siblings, and their 2 asymptomatic parents.
Ophthalmologic examination and candidate gene analysis (KIF21A and PHOX2A from venous blood samples) of the 2 affected siblings and their parents; confirmatory testing for 3 available asymptomatic siblings.
Significant clinical observations and results of gene testing.
The 2 affected siblings had large-angle exotropia, moderate bilateral hypotropia, moderate bilateral ptosis, sluggish pupils, and almost complete ophthalmoloplegia with some abnormal synkinesis. The asymptomatic parents were not related and had unremarkable ophthalmic examinations. Four other siblings were normal by history; 3 underwent venous blood sampling for confirmatory testing. Candidate gene testing of PHOX2A, the gene for recessive CFEOM (CFEOM2), did not reveal mutation in the 2 patients or their parents. Sequencing of KIF21A, the gene for dominant CFEOM (CFEOM1), revealed heterozygous p.R954L in both affected individuals but in not in their parents or 3 asymptomatic siblings, consistent with parental germline mosaicism. Haplotype analysis suggested paternal inheritance but was not conclusive.
Parental germline mosaicism can mimic recessive inheritance in CFEOM and likely is underrecognized. Ophthalmologists should be aware of this phenomenon when counseling parents of children with apparent recessive (or de novo) hereditary eye disease. Unlike other reported KIF21A mutations that cause CFEOM1, the p.R954L variant seems to be associated with abnormal pupils.
The author(s) have no proprietary or commercial interest in any materials discussed in this article.

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¹: These authors contributed equally to this research.

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Case reportGerminal mosaicism for LMNA mimics autosomal recessive congenital muscular dystrophy

Abstract

Introduction

Section snippets

Patients

Genetic analysis

Discussion

Acknowledgements

Biochim Biophys Acta

Rev Neurol (Paris)

Mutations in the gene encoding lamin A/C cause autosomal dominant Emery-Dreifuss muscular dystrophy

Nat Genet

Nuclear lamins: laminopathies and their role in premature ageing

Physiol Rev

Identification of mutations in the gene encoding lamins A/C in autosomal dominant limb girdle muscular dystrophy with atrioventricular conduction disturbances (LGMD1B)

Hum Mol Genet

Clinical and molecular genetic spectrum of autosomal dominant Emery-Dreifuss muscular dystrophy due to mutations of the lamin A/C gene

Ann Neurol

De novo LMNA mutations cause a new form of Congenital Muscular Dystrophy (L-CMD)

Ann Neurol

Lamin A/C mutations with lipodystrophy, cardiac abnormalities, and muscular dystrophy

Neurology

Case report
Germinal mosaicism for LMNA mimics autosomal recessive congenital muscular dystrophy