Elsevier

Mitochondrion

Volume 13, Issue 4, July 2013, Pages 269-276
Mitochondrion

Multiple Symmetrical Lipomatosis — A mitochondrial disorder of brown fat

https://doi.org/10.1016/j.mito.2013.03.003Get rights and content

Highlights

  • Seven cases of Multiple Symmetrical Lipomatosis, MSL, are followed for 8–20 years.

  • We provide evidence that MSL is a mitochondrial cytopathy.

  • We substantiate the hypothesis that MSL lipomas are derived from vestigial brown fat.

Abstract

Multiple Symmetrical Lipomatosis (MSL) is an unusual disorder characterized by the development of axial lipomas in adulthood. The pathoetiology of lipoma tissue in MSL remains unresolved. Seven patients with MSL were followed for a mean period of 12 years (8–20 years). All patients had cervical lipomas ranging from subtle lesions to disfiguring masses; six patients had peripheral neuropathy and five had proximal myopathy. Myoclonus, cerebellar ataxia and additional lipomas were variably present. All patients showed clinical progression. Muscle histopathology was consistent with mitochondrial disease. Five patients were positive for mtDNA point mutation m.8344A > G, three of whom underwent lipoma resection — all samples were positive for uncoupling protein-1 mRNA (unique to brown fat). Lipoma from one case stained positive for adipocyte fatty-acid protein-2 (unique to brown fat and immature adipocytes). This long-term study hallmarks the phenotypic heterogeneity of MSL's associated clinical features. The clinical, genetic and molecular findings substantiate the hypothesis that lipomas in MSL are due to 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.

Section snippets

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)

  • S.A. Austin et al.

    Expanding the phenotype of the 8344 transfer RNAlysine mitochondrial DNA mutation

    Neurology

    (1998)
  • S.P. Banerjee et al.

    Alterations in beta-adrenergic receptor binding during ethanol withdrawal

    Nature

    (1978)
  • J.H. Bennett et al.

    Immunohistochemical identification of tumours of adipocytic differentiation using an antibody to aP2 protein

    J. Clin. Pathol.

    (1995)
  • S.F. Berkovic et al.

    Mitochondrial dysfunction in Multiple Symmetrical Lipomatosis

    Ann. Neurol.

    (1991)
  • F.P. Bernier et al.

    Diagnostic criteria for respiratory chain disorders in adults and children

    Neurology

    (2002)
  • B. Brodie

    Lectures Illustrative of Various Subjects in Pathology and Surgery

    (1846)
  • Y. Campos et al.

    Single large-scale mitochondrial DNA deletion in a patient with mitochondrial myopathy associated with multiple symmetric lipomatosis

    Neurology

    (1996)
  • C. Casali et al.

    Mitochondrial G8363A mutation presenting as cerebellar ataxia and lipomas in an Italian family

    Neurology

    (1999)
  • S. DiMauro et al.

    Mitochondrial respiratory-chain diseases

    N. Engl. J. Med.

    (2003)
  • K. Ekbom

    Hereditary ataxia, photomyoclonus, skeletal deformities and lipoma

    Acta Neurol. Scand.

    (1975)
  • Cited by (56)

    • Increased trunk volume

      2023, Revue de Medecine Interne
    • Self-initiated lifestyle interventions lead to potential insight into an effective, alternative, non-surgical therapy for mitochondrial disease associated multiple symmetric lipomatosis

      2020, Mitochondrion
      Citation Excerpt :

      Variable phenotypic penetrance and expressivity within and between generations is a hallmark of the disease that is related to differences in the location of the mutation (nuclear vs mitochondrial genome), the nuclear and mitochondrial genetic background, environmental factors, and, for mitochondrial DNA mutations, heteroplasmy level within the individual patient’s tissues (Wallace, 2018). Multiple symmetric lipomatosis may be a manifestation of some mitochondrial disease syndromes including MFN2, large scale or multiple mitochondrial DNA deletions and myoclonic epilepsy with ragged red fibres (MERRF) (Capel et al., 2018; Plummer et al., 2013; Munoz-Malaga et al., 2000). Two unrelated Canadian families with MERRF and MSL have been reported in the past decade (Perera et al., 2018; Kazakos et al., 2012).

    • Obesity, mitochondrial dysfunction, and obstructive lung disease

      2018, Mechanisms and Manifestations of Obesity in Lung Disease
    View all citing articles on Scopus
    View full text