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Benedetti and colleagues  reported two dominant LMNA mutations,
one missense and one 4-nt deletion, leading to combined muscular dystrophy
and peripheral neuropathy. We would like to present some commentaries in
order to analyse the nosological implications of this nice case report and
to provide a more complete point of view to the readers of the JNNP.
Laminopathies are a group of disorders...
Laminopathies are a group of disorders caused by mutation in the LMNA
gene encoding Lamins A/C, components of the nuclear envelope. They include
diseases affecting striated muscle including Emery-Dreifuss Muscular
dystrophy (EDMD), Limb Girdle Muscular Dystrophy type 1B (LGMD 1B) and an
isolated form of dilated cardiomyopathy with conduction system defects
(DCM-CD), as well as diseases involving peripheral nerves (autosomal
recessive and autosomal dominant axonal CMT or ARCMT2B1) and adipose
tissue (partial lipodystrophy of Dunnigan type).
The first case reported by Benedetti and Colleagues (family A,
predicted p.R571C substitution in Lamin C) present with combined axonal
neuropathy and muscular dystrophy (patient DE) or very mild axonal
involvement without myopathic features (MG, mother of DE). Even if the
authors have not underlined this point, the 2 patients also show clinical
features of partial lipodystrophy. In our opinion, this is one of the
major contributions of this interesting paper: the authors show that nerve
involvement can be found together with lipodystrophic features as it has
been demonstrated for striated muscle involvement.[3-5] We
previously reported a combination of axonal neuropathy and muscular
dystrophy associated with cardiac disease and leuconychia in a single
French family. More recently, we observed another family showing a
clinical mixture of neuropathy and cardiac involvements (c.1496delC LMNA
gene mutation leading to p.A499V FsX48, G. Bonne & P. Richard,
Unpublished data). Any way, the fact that a mutation involving the same
codon but leading to another substitution (p.R571S) have been identified
in a family with DCMM-CD  argues for a regular cardiac assessment of
this family mutated members.
The second case (Family B, c.864_867del LMNA gene mutation) shows
evidence for a LGMD 1B phenotype with proximal muscle involvement without
contractures in the four limbs and severe atrio-ventricular heart block
requiring pacemaker implantation. Interestingly, electroneuromyography
(ENMG) revealed myopathic features without nerve conduction abnormalities
and muscle biopsy showed mild neuropathic and myopathic abnormalities.
Although ENMG can be neuropathic in chronic muscular dystrophies due to
functional denervation  we think that these findings are important in
this context. In fact, we recently reported a German family showing
clinical features of a neurogenic variant of Emery-Dreifuss muscular
dystrophy (EDMD) due to deletion of the LMNA initiator codon. We also
observed neuropathic ENMG features in some instance (p.R249Q EDMD, p.R377H
LGMD1B, c.IVS8-2 A>G EDMD, G. Bonne & P. Richard, Unpublished
data). These findings are also similar to those published before the
identification of the molecular basis of EDMD (10), initially causing some
difficulties for the classification of this entity. Like Benedetti and
colleagues, we believe that these features might be indicative of a
subclinical neuropathic process that may become manifest in the course of
the disease. However, it might also be indicative of a nerve involvement
which is not accessible using the routine electroneuromyographic
In all cases, these findings corroborate our previous observations
(6) and highlight the possible common pathway of nerve and muscle
involvements in laminopathies. However the pathophysiological link between
all these conditions remains to be established.
Thus, peripheral nerve involvement in laminopathies seems to occur 1)
as pure conditions in AR-CMT2B1 disease, as neurogenic forms
of “myopathies” as reported by Benedetti and colleagues or by others,
3) as mixed phenotypes combining neuropathy with muscular dystrophy and
other laminopathic traits as lipodystrophy and cardiac conduction disease
due to dominant LMNA mutations. Consequently, laminopathies seem
to comprise a real continuum of neuromuscular diseases.
In conclusion, these observations prompt to include LMNA in the
spectrum of genes responsible for autosomal dominant and recessive axonal
neuropathies, especially when combined with muscular dystrophy, cardiac
abnormalities, altered fat distribution and leukonychia.
The authors declare no competing financial interests.
1. Benedetti S, Bertini E, Iannaccone S, Angelini C, Trisciani M,
Toniolo D, et al. Dominant LMNA mutations can cause combined muscular
dystrophy and peripheral neuropathy. J Neurol Neurosurg Psychiatry
2. Ben Yaou R, Muchir A, Arimura T, Massart C, Demay L, Richard P, et
al. Genetics of laminopathies. Novartis Found Symp 2005;264:81-90;
discussion 90-97, 227-30.
3. van der Kooi AJ, Bonne G, Eymard B, Duboc D, Talim B, Van der Valk
M, et al. Lamin A/C mutations with lipodystrophy, cardiac abnormalities,
and muscular dystrophy. Neurology 2002;59(4):620-3.
4. Garg A, Speckman RA, Bowcock AM. Multisystem dystrophy syndrome
due to novel missense mutations in the amino-terminal head and alpha-
helical rod domains of the lamin A/C gene. Am J Med 2002;112(7):549-55.
5. Vantyghem MC, Pigny P, Maurage CA, Rouaix-Emery N, Stojkovic T,
Cuisset JM, et al. Patients with familial partial lipodystrophy of the
Dunnigan type due to a LMNA R482W mutation show muscular and cardiac
abnormalities. J Clin Endocrinol Metab 2004;89(11):5337-46.
6. Goizet C, Ben Yaou R, Demay L, Richard P, Bouillot S, Rouanet M,
et al. A new mutation of the lamin A/C gene leading to autosomal dominant
axonal neuropathy, muscular dystrophy, cardiac disease, and leuconychia. J
Med Genet 2004;41(3):E29.
7. Fatkin D, MacRae C, Sasaki T, Wolff MR, Porcu M, Frenneaux M, et
al. Missense Mutations in the Rod Domain of the Lamin A/C Gene as Causes
of Dilated Cardiomyopathy and Conduction-System Disease. N Engl J Med
8. Mastaglia FL, Laing NG. Investigation of muscle disease. J Neurol
Neurosurg Psychiatry 1996;60(3):256-74.
9. Walter MC, Witt TN, Weigel BS, Reilich P, Richard P, Pongratz D, et al.
Deletion of the LMNA initiator codon leading to a neurogenic variant of
autosomal dominant Emery-Dreifuss muscular dystrophy. Neuromuscul Disord
10. Rowland LP, Fetell M, Olarte M, Hays A, Singh N, Wanat FE. Emery-
Dreifuss muscular dystrophy. Ann Neurol 1979;5(2):111-117.
11. De Sandre-Giovannoli A, Chaouch M, Kozlov S, Vallat JM, Tazir M,
Kassouri N, et al. Homozygous defects in LMNA, encoding lamin A/C nuclear-
envelope proteins, cause autosomal recessive axonal neuropathy in human
(Charcot- Marie-Tooth Disorder Type 2) and mouse. Am J Hum Genet
12. Tazir M, Azzedine H, Assami S, Sindou P, Nouioua S, Zemmouri R,
et al. Phenotypic variability in autosomal recessive axonal Charcot-Marie-
Tooth disease due to the R298C mutation in lamin A/C. Brain 2004;127(Pt