Multiple Symmetrical Lipomatosis — A mitochondrial disorder of brown fat
Introduction
Multiple Symmetrical Lipomatosis (MSL) is an unusual disorder characterized by the presence of non-encapsulated axial lipomas (Berkovic et al., 1991a). Since Brodie's original phenotypic description of the condition in 1846 (Brodie, 1846), it has been variously labeled as Benign Symmetrical Lipomatosis (Gonzalez-Garcia et al., 2004), Ekbom's Syndrome (Ekbom, 1975), Madelung's Disease (Madelung, 1888), and Launois-Bensaude Syndrome (Launois and Bensaude, 1898) — but the pathogenesis of lipoma formation in MSL remains unclear. A leading hypothesis is that MSL is fundamentally a mitochondrial disorder (Berkovic et al., 1991a). Three lines of evidence support this: i) Phenotypic — the midline location of the lipomas (neck, mediastinum, axillae, periaortic, perirenal, suprapubic) mirrors the distribution of brown fat, a tissue known to be rich in mitochondria (Kodish et al., 1974, Nechad, 1986); ii) Genetic — MSL has a well documented clinico-pathologic association with known mitochondrial cytopathies, such as myoclonic epilepsy and ragged red fibers (MERRF) (Austin et al., 1998, Berkovic et al., 1991a, Berkovic et al., 1991b, Gamez et al., 1998, Klopstock et al., 1994, Naumann et al., 1997), and mitochondrial mutations have been isolated from lipoma tissue in MSL (Nisoli et al., 2002, Traff et al., 1995, Vila et al., 2000); iii) Molecular-uncoupling protein 1 (UCP-1), a mitochondrial carrier protein unique to brown fat (Ricquier et al., 1991), has been detected in MSL lipomas (Nisoli et al., 2002, Ricquier et al., 1991, Vila et al., 2000).
There are two riders here: i) Alcohol appears to be a risk factor for MSL (Berkovic et al., 1991a, Haller and Knochel, 1984), and ii) some investigators have failed to identify mitochondrial mutations in patients with MSL (Heckmann et al., 2000, Klopstock et al., 1997, Matthews et al., 1995).
This long-term study has two aims — 1) to examine the clinical outcome in MSL, 2) to re-examine the twin hypotheses that MSL is a mitochondrial disorder and that MSL lipomas are derived from vestigial brown fat.
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Material and methods
Seven cases with Multiple Symmetrical Lipomatosis (MSL) were followed for a mean period of 12 years (8–20 years) by clinical history, serial examination and investigation. All were of Australasian heritage except Patient 4, who was born in India. Mean interval from symptom-onset to diagnosis was 11.5 years (2–30 years). Investigations included magnetic resonance imaging (MRI) brain, electroencephalography (EEG), nerve conduction studies (NCS), electromyography (EMG), muscle biopsy, mitochondrial
Results
Table 1 summarizes the clinical data.
Patient 1: (Fig. 1) a female, presented at age 53 years with multiple axial lipomas, proximal myopathy and peripheral neuropathy. Past history included hypertension, diabetes mellitus (DM) type 2 and hyperlipidaemia. A posterior neck mass was first noted 10 years earlier and progressive enlargement caused neck and shoulder pain. Lipoma tissue was confirmed on post-resection histology. Within two years to presentation the neck mass had recurred and bilateral
MSL clinical features and disease course
The range of clinical features seen across the cohort (Table 1) underscores the phenotypic heterogeneity of this disorder for both clinical presentation and disease course. Diagnostic delay was common — while the mean age at presentation was 45.7 years (36–63 years), symptoms had been present for some time (2–30 years). All patients had cervical lipomas seated at the posterior neck. These varied from subtle midline lesions to large disfiguring masses. Without exception, lipoma resection (for neck
Conclusion
This study on a cohort of seven patients with Multiple Symmetrical Lipomatosis with long-term follow-up underscores the phenotypic heterogeneity of the disorder. Beyond the development of midline lipomas, affected patients can carry an array of associated clinical features including myoclonic epilepsy, proximal myopathy, peripheral neuropathy and cerebellar ataxia. Disease progression is the rule. Our clinical, histological, and genetic findings support the hypothesis that MSL is a
Competing interests
Nil.
Funding
Nil.
Contributorship
As corresponding author, I confirm that all Authors listed met the ICMJE criteria for authorship.
Acknowledgments
We would like to thank the staff of the following laboratories for their assistance: Nerve and Muscle Laboratory, University of Sydney (including Dr. Min Wang for providing photographs of muscle biopsies), St Vincent's and Austin Hospitals Melbourne, Concord Hospital Sydney, and Auckland City Hospital Pathology Departments, and the Musculoskeletal Pathology Department, Nuffield Orthopedic Centre, Oxford.
References (41)
- et al.
Clinical spectrum of mitochondrial DNA mutation at base pair 8344
Lancet
(1991) Mitochondrial neuropathy
Clin. Neurol. Neurosurg.
(2005)- et al.
Multiple symmetrical lipomatosis (Madelung's disease)
Surgery
(2001) - et al.
Skeletal muscle disease in alcoholism
Med. Clin. North Am.
(1984) - et al.
Development of a monoclonal antibody to the aP2 protein to identify adipocyte precursors in tumours of adipose differentiation
Pathol. Res. Pract.
(1999) - et al.
Benign symmetric lipomatosis: functional sympathetic denervation of adipose tissue and possible hypertrophy of brown fat
Metabolism
(1974) - et al.
Morphological and immunohistochemical features of brown adipocytes and preadipocytes in a case of human hibernoma
Nutr. Metab. Cardiovasc. Dis.
(2010) - et al.
Uncoupling protein-1 mRNA expression in lipomas from patients bearing pathogenic mitochondrial DNA mutations
Biochem. Biophys. Res. Commun.
(2000) - et al.
Madelung's disease
N. Engl. J. Med.
(2011) - et al.
Defective kinetics of cytochrome c oxidase and alteration of mitochondrial membrane potential in fibroblasts and cytoplasmic hybrid cells with the mutation for myoclonus epilepsy with ragged-red fibres (‘MERRF’) at position 8344 nt
Biochem. J.
(1999)
Expanding the phenotype of the 8344 transfer RNAlysine mitochondrial DNA mutation
Neurology
Alterations in beta-adrenergic receptor binding during ethanol withdrawal
Nature
Immunohistochemical identification of tumours of adipocytic differentiation using an antibody to aP2 protein
J. Clin. Pathol.
Mitochondrial dysfunction in Multiple Symmetrical Lipomatosis
Ann. Neurol.
Diagnostic criteria for respiratory chain disorders in adults and children
Neurology
Lectures Illustrative of Various Subjects in Pathology and Surgery
Single large-scale mitochondrial DNA deletion in a patient with mitochondrial myopathy associated with multiple symmetric lipomatosis
Neurology
Mitochondrial G8363A mutation presenting as cerebellar ataxia and lipomas in an Italian family
Neurology
Mitochondrial respiratory-chain diseases
N. Engl. J. Med.
Hereditary ataxia, photomyoclonus, skeletal deformities and lipoma
Acta Neurol. Scand.
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