Beyond cervical lipomas: myoclonus, gait disorder and multisystem involvement leading to mitochondrial disease

Abstract

Madelung’s disease (benign symmetric lipomatosis) is a rare syndrome in which there are multiple lipomas around the neck, upper limbs and trunk in the context of chronic alcoholism. We report on a female patient with lipomas and slightly progressive myoclonus, neuropathy, myopathy, ataxia and respiratory systemic involvement (labelled in the past as Madelung’s disease). Multisystem involvement and family history of lipomas led to the development of mitochondrial genetic tests, which can assess two concurrent mitochondrial mutations: the m.8344A>G mutation in MT-TK gene, related MERRF (myoclonic epilepsy with ragged-red fibre) phenotype and m.14484T>C mutation in the MT-ND6 gene responsible for Leber hereditary optic neuropathy phenotype.

Background

Madelung’s disease (benign symmetric lipomatosis) is a rare syndrome with multiple lipomas around the neck, upper limbs and trunk, sometimes in the context of chronic alcoholism. Besides lipomas, features such as neuropathy, myopathy and ataxia are described, relating some of them to mitochondrial mutations; however, this association has been inconsistent, perhaps due to mistaken terminology.¹ Multiple lipomas, resembling benign symmetric lipomatosis, have also been described in families with myoclonic epilepsy with ragged-red fibres (MERRF), carrying the 8344A>G mutation in the tRNALys gene of mitochondrial DNA (mtDNA).^{1 2} We show an uncommon case with myoclonus, gait disorder with systemic involvement and unexpected genetic confirmation of two different mutations of mtDNA.

Case presentation

The patient is a 63-year-old woman, consulting for a 5-year gait disorder and tremor in the arms. She has a large cervical lipoma and was diagnosed with Madelung’s disease at 32 years old (video 1). Furthermore, she reported several medical disorders over the last 10 years: jerky movements in her arms that improved with clonazepam, sensorial polyneuropathy for 6 years, asymptomatic Wolf-Parkinson-White syndrome, and 4-year progressive nightly dyspnoea treated with Bilevel Positive Airway Pressure (BI-PAP) machine. No toxic agent consumption was mentioned, except for some family history, that is, her mother and only sister also had cervical lipomas.

Video 1.

Download video file ^{(6.4MB, mp4)}

DOI: 10.1136/bcr-2016-218861.video01

A summary of the neurological examination is shown. At rest, physical appearance of cervical lipomas is remarkable (segment 1). In addition, an irregular postural kind of tremor is elicited in antigravity upper limb manoeuvres (segment 2). Also, it keeps its irregularity during action. Strictly, to be called tremor is mandatory a regular oscillation. In this case, its irregularity is due to the coexistence of two phenomena: action tremor with postural and negative myoclonus in arms. When the patient gets up, an abnormal posture with multiple lipomas around the neck, axial myoclonus while walking and dorsal deviation of trunk, with a myophatic and ataxic gait that substantially interfere her deambulation is evident (segment 3).

General examination demonstrates a large cervical lipoma. Neurological findings include action tremor in her upper limbs, with spontaneous and negative myoclonus in the arms, as well as axial myoclonus while walking and dorsal deviation of the trunk. Her gait had myopathic and ataxic features which limited her ability to walk. Thigh muscle atrophy with upper and lower girdle paresia is seen. Workup was focused on a multisystem disorder, maternally inherited, with prominent muscle involvement.

Investigations

Laboratory tests indicate an increased levels of creatine kinase (1056 U/L (33–211 U/L)) and lactate (2.2 mmol/L (0.5–2.2 mmol/L)). ECG shows a pre-excitation syndrome (Wolff-Parkinson-White) with controlled ventricular response. Brain MRI demonstrated cortico–subcortical and cerebellar atrophy, while electroencephalography ruled out epileptiform activity, thus showing generalised dysrhythmia. An invasive muscle biopsy was avoided, which led to the mitochondrial genetic tests from blood and urine samples. Genetic testing by minisequencing, microfluidic PCR restriction fragment length polymorphism and direct sequencing of mtDNA in blood and urine samples identified the m.8344A>G mutation in MT-TK gene, (MERRF phenotype) (heteroplasmy levels: 83% blood, 93% urine) and m.14484T>C mutation in the MT-ND6 gene, Leber hereditary optic neuropathy phenotype (LHON) (homoplasmy) (figure 1). In view of these results, an ophthalmological study was performed showing visual acuity of 0.7 and 1, with bilateral mild signs of optic nerve atrophy. Despite a discussion about a mitochondrial study in relatives with lipomas, it could not be performed to confirm the mutations.

Figure 1.

(A, B) Sanger sequencing showing the two mitochondrial DNA mutations in patient’s tissues. (C) Heteroplasmic levels are indicated and were calculated by microfluidic PCR restriction fragment length polymorphism in bioanalyzer 2100 (Agilent).

Treatment

Unfortunately, there are no approved disease-modifying therapies available. Initially, symptomatic therapies with clonazepam to treat intense myoclonus, as well as L-carnitine and coenzyme Q-10, were used with minimal results. Subsequently, treatment with levetiracetam will be continued for myoclonus.

Outcome and follow-up

Eighteen months after the initial visit, patient presents with worse myoclonus and major gait impairment. Mitochondrial disease will inexorably advance to disability. Walking independence is delicate, and respiratory support will progressively increase as well, whereas her sight and hearing are only mildly affected.

Discussion

First, it is important to note the physical appearance, including any remarkable cervical lipomas and the lack of chronic alcohol consumption.^1–3 Second, phenomenology points to a hyperkinetic disorder with myoclonus and tremor, adult-onset, slightly progressive, accompanying red flags of a systemic metabolic disorder: myopathy, neuropathy, maternally inherited, leading to a mitochondrial disease workup. Third, the term ‘Madelung’s disease or benign symmetric lipomatosis’ can initially limit the diagnostic process (delaying the identification of an underlying mitochondrial cytopathy).¹ We remark about the value of distinguishing Madelung’s disease from mitochondrial disease when accompanying symptoms become patent and why we suggest reconsidering it.

In turn, the 8344A>G mutation in MTT-K gene is most frequent in MERRF phenotype, but the clinical phenotype is heterogeneous: myoclonus, myopathy, lipomatosis, eyelid ptosis or generalised seizures, as even asymptomatic carriers have been described.^{4 5} Hence, this patient’s syndrome can be exclusively explained by this mutation. However, finding the 14484T>C mutation in the MTND6 gene, one of three mutations commonly found in the LHON phenotype,^{6 7} was unexpected due to the lack of previous sight and related symptoms in the patient. The relationship of mild sight signs with mtDNA m.14484T>C in the MTND6 gene in this patient will be clarified prospectively. Usually, LHON onset occurs in second to third decades of life, and by 50 years old, most patients lose their sight. Rarely, individuals first manifest LHON in the seventh and eighth decades of life.⁸

To the best of our knowledge, the concurrence of both mutations was not published prior to this report, but some exclusive, concomitant LHON mutations have been found, even the LHON mutation associated with other diseases, such as progressive external ophthalmoplegia or Kearns-Sayre syndrome mutations.⁶

In conclusion, we report on a patient with bulky lipomas who presents with a slightly progressive movement disorder, maternally inherited, also demonstrating tremor, myoclonus and gait disorder with prominent myopathy including multisystem involvement, the key to its diagnosis. In patients with hereditary cervical lipomas and myoclonus, we suggest performing a mitochondrial genetic test, searching for the most common mutations.

Learning points.

• Be vigilant to lipomas in patients with concomitant myoclonus and gait disorders.

• Do not forget mitochondrial diseases, in the context of multiple lipomas with multisystem involvement.

• Two different mitochondrial mutations can coexist although it is a rare condition.