Mitochondrial cytopathies are multisystem disorders in which different gene defects can produce the same clinical syndrome; and, different clinical syndromes can be associated with the same gene defect. Multiple symmetric lipomatosis is an unusual disorder characterized by the development of axial lipomas in adulthood. Here, we report the case of a patient who presented with multiple neurological manifestations such as proximal myopathy, peripheral neuropathy, and ataxia along with significant non-neurological features such as impaired glucose tolerance and axial lipomatosis. The presence of multiple symmetric axial lipomatosis often serves as a clinical marker of mitochondrial disease and may also indicate the most likely mitochondrial deoxyribose nucleic acid (DNA) mutation.
A 45-year old female patient presented with a history of weakness of all four limbs of one year duration. The weakness predominantly involved the proximal muscles of all four limbs with mild weakness of distal muscles. She also had neck and trunk muscle weakness. The weakness was insidious in onset and gradually progressive. She had generalized thinning of limbs associated with flailness [Figure 1] and [Figure 2]. She also had unsteadiness of gait with a sway to either side while walking. History of benumbed perception of all modalities of sensation over the distal extremities was present. History of walking on cotton wool sensation was present. She complained of multiple painful boggy swellings over the nape of neck and shoulder regions.
On examination, the patient appeared ill built and ill nourished. She had generalized muscle wasting [Figure 1] and [Figure 2] and hypotonia of all 4 limbs. She also had multiple, large, tender, firm swellings over the nape of the neck and shoulder regions [Figure 3], [Figure 4], [Figure 5].
The power of muscles around the proximal joints was 3/5, and around the distal joints was 4/5. She had weakness of neck and trunk muscles [Figure 6]. Deep tendon reflexes were absent. She had a typical waddling gait. Sensory system examination showed evidence of graded sensory loss over both upper limbs and lower limbs for all modalities of sensation. Romberg's test was positive. She had stance and gait ataxia. Exaggerated lumbar lordosis was present.
Nerve conduction studies showed features suggestive of diffuse sensorimotor axonal neuropathy. Needle electromyogram revealed a myopathic pattern. Complete blood count with peripheral smear study showed microcytic hypochromic anemia. Renal function tests, fasting and postprandial blood sugars, serum electrolytes, liver function tests, lipid profile, and urine analysis were normal. Serum creatine phosphokinase was 925 units/l. Serum lactate dehydrogenase was 420 mg/dl. Serum calcium, phosphorus, and alkaline phosphatase were normal. Serum thyroid profile was normal. Serum antinuclear antibody, C-reactive protein, rheumatoid factor, and extractable nuclear antigen profiles were negative. Glucose tolerance test revealed impaired glucose tolerance. Serum and cerebrospinal fluid (CSF) lactate were elevated. The lactate pyruvate ratio was high. Chest X-ray and electrocardiogram (ECG) were normal. Cardiac evaluation including echocardiogram analysis was normal. Ophthalmological and ear, nose, throat (ENT) evaluation were normal. Ultrasonogram of the abdomen and pelvis were normal. Biopsy of the neck swelling showed features of lipomatosis. Muscle biopsy done on the vastus lateralis muscle showed evidence of ragged blue fibres, which was suggestive of mitochondrial myopathy.
Our patient, a middle-aged female patient, presented with multiple neurological manifestations such as proximal myopathy, peripheral neuropathy, and ataxia as well as multiple symmetric axial lipomatosis and impaired glucose tolerance.
Mitochondrial cytopathy is a neurometabolic syndrome with varied clinical manifestations involving multiple sites along the neuraxis.
Multiple symmetric lipomatosis has been alternatively referred to as Madelung's disease, Brodie's disease, and Launois–Bensaude syndrome. A limited number of cases have been reported so far in the world literature. An autosomal dominant mode of inheritance had been postulated. These fat masses are unencapsulated and penetrate deep into the surrounding tissues.
A study done by Plummer et al., on seven patients with multiple symmetric lipomatosis, followed up for a period of 8–20 years, revealed that multiple symmetric lipomatosis is a mitochondrial cytopathy and that the axial lipomas were derived from vestigial brown fat. Muscle biopsy was consistent with mitochondrial disease. Five patients were positive for mitochondrial (mt)DNA point mutation m. 8344 A>G. Three patients underwent lipoma resection; all were positive for uncoupling protein-1 mRNA (ribose nucleic acid), which is unique to brown fat. Lipoma from one patient was positive for adipocyte fatty acid protein-2, which is also unique to brown fat. The authors hypothesized that multiple symmetric lipomatosis (MSL) was due to a mitochondrial disorder of brown fat.
Another analysis done by Campos et al., in a nonalcoholic woman with multiple symmetric lipomatosis, showed ragged red fibers and cytochrome C oxidase negative fibers in muscle histochemistry along with a single deletion of mitochondrial DNA in southern blot analysis. They concluded that multiple symmetric lipomatosis is a rare manifestation of the wide clinical spectrum of mitochondrial disorders, specifically those associated with single mtDNA deletions.
Gamez et al., described familial multiple symmetric lipomatosis in a pedigree harboring the 8344 mutation in the T RNA Lys gene of mitochondrial DNA (mtDNA).
Klopstock et al., studied 11 patients with multiple symmetric lipomatosis. Muscle biopsy showed evidence of pathologic subsarcolemmal aggregates of mitochondria and decrease of cytochrome C oxidase activity. Southern blot analysis revealed multiple deletions of mitochondrial DNA. They concluded that mitochondrial dysfunction was common in multiple symmetric lipomatosis and may be based on mitochondrial genomic defects.,
Kratz et al., reported the cases of two children with multiple symmetric lipomatosis (MSL), and concluded that multiple symmetric lipomatosis is a new neurometabolic disorder with heterogenous clinical expression.
Mitochondrial cytopathy has been associated with changes in lipid metabolism such as the acquisition of an abnormal adipocyte phenotype observed in multiple symmetric lipomatosis, or triglyceride accumulation in muscles associated with the myoclonic epilepsy with ragged red fiber syndrome, according to Sebastien et al.,
Two cases of multiple symmetric lipomatosis with ragged red fibres and molecular features (A8344G mutation) of mitochondrial disease were analyzed by Chong.
In a longitudinal study of 31 patients with MSL (mean follow-up of 14.5 ± 5.0 years), Enzi et al., (2002) confirmed the association of the disorder with a high ethanol intake. A substantial morbidity related to the occupation of the mediastinal space by the lipomatous tissue was observed.,
Most cases of multiple symmetric lipomatosis reported so far in the literature were predominantly found in males who had a history of alcohol consumption. However, our patient was a female subject with no history of alcohol intake. Genetic analysis could not be done in our patient due to logistical reasons, although the definite association of multiple symmetric lipomatosis with mitochondrial myopathy could be established.
Multiple symmetric lipomatosis is a rare clinical syndrome whose etiopathogenesis has not been well elucidated. The clinical association of this syndrome with mitochondrial cytopathy has promoted better understanding of the pivotal role played by mitochondria in lipid metabolism. The presence of multiple symmetric lipomatosis may even give a clue to the most likely mtDNA mutation; however, this requires more research. The presence of multiple symmetric lipomatosis in a given case is a strong clinical marker of mitochondrial cytopathy.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]