Clinical Reasoning: Blurred vision and dancing feet
Restless legs syndrome presenting in mitochondrial disease
H. Aitken,
G. Gorman, MRCP,
R. McFarland, MRCPCH,
M. Roberts, FRCP,
R. W. Taylor, FRCPat and
D. M. Turnbull, FRCP
From Mitochondrial Research Group (H.A., G.G., R.M., R.W.T., D.M.T.), The Medical School, Newcastle University, Newcastle upon Tyne; and Department of Neurology (M.R.), Hope Hospital, Salford, UK.
Address correspondence and reprint requests to Professor D.M. Turnbull, Mitochondrial Research Group, 4th Floor, The Medical School, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK d.m.turnbull{at}ncl.ac.uk
A 58-year-old woman presented to a neuro-ophthalmologist witha 5-year history of progressively blurred vision, diplopia,and longstanding bilateral ptosis. She described occasionalchoking episodes after eating as well as fatigue and shortnessof breath after minimal exertion. Her older sibling had receivedcorrective eyelid surgery for ptosis and two nieces had ptosisand proximal myopathy and were being investigated in anothercenter.
Direct and consensual pupillary light reflexes were normal withno rapid alternating pupillary defect. Visual acuity was 20/20on the right and 20/30 on the left. She had bilateral symmetricptosis obscuring two-thirds of the pupil and restriction ofeye movements below 60% of normal in all directions of gaze.Lower limb examination revealed symmetric proximal limb weakness(Medical Research Council grade 4+) with reduced reflexes andflexor plantars. Tandem gait was hesitant.
The initial differential diagnosis included Graves thyroid eyedisease, a neuromuscular junction disorder (myasthenia gravisor botulism), oculopharyngeal muscular dystrophy, Miller Fishervariant of Guillain-Barré syndrome, and progressive musculardystrophy.
Free thyroxin and thyroid stimulating hormone levels were normal.Thyroid antibodies were negative. Acetylcholine receptor antibodyassay was negative and repetitive nerve stimulation to excludea neuromuscular junction disorder was normal. Electromyographyof proximal upper limb muscles revealed an increased numberof short duration motor units consistent with borderline myopathy.Nerve conduction velocities were normal, reducing the likelihoodof an immune-mediated inflammatory neuropathy.
Due to the chronicity of symptoms, presence of gaze paresis,myopathic findings on neurophysiologic assessment, and familyhistory of ocular complications suggestive of dominant inheritance,a muscle biopsy was performed. Polyadenylate binding-proteinnuclear 1 (PABPN1) gene mutation analysis to exclude oculopharyngealmuscular dystrophy was deferred pending muscle biopsy analysis.
The muscle biopsy showed 13% cytochrome c oxidase (COX)–deficientfibers, significant numbers of ragged red fibers but no excessof lipid or glycogen accumulation, and subsarcolemmal accumulationof abnormal mitochondria suggestive of a mitochondrial cytopathy(figure 1A). Testing for common mitochondrial DNA (mtDNA) pointmutations (MELAS m.3243A>G [mitochondrial encephalopathy,lactic acidosis and stroke-like episodes], MERRF m.8344A>G[myoclonic epilepsy with ragged red fibers], and NARP m.8993T>G/C[neuropathy, ataxia, and retinitis pigmentosa]) did not revealany abnormalities. Long-range PCR, however, revealed multiplemtDNA deletions in muscle (figure 1B).
Figure 1 Histochemical and mitochondrial genetic investigations in patient muscle
(A) Sequential cytochrome c oxidase (COX)/succinate dehydrogenase (SDH) histochemistry in the muscle biopsy from our patient reveals significant numbers (13%) of COX-deficient fibers, some of which show clear subsarcolemmal accumulation of abnormal mitochondria (marked with an asterisk). (B) Long-range PCR clearly demonstrates the presence of multiple mitochondrial DNA (mtDNA) deletions in patient muscle DNA (lane 4) compared to muscle DNA extracted from two age-matched controls (lanes 1 and 2); lane 3 shows muscle DNA amplified from a patient with a single large-scale mtDNA deletion for comparison. M = size marker.
Questions for consideration:
What is your differential diagnosis at this point?
What additionaldiagnostic tests would you consider at thistime?
Due to the presence of multiple mtDNA deletions indicative ofan mtDNA maintenance defect, polymerase (POLG1) gene amplificationand sequencing was performed. This detected two previously describedheterozygous mutations in compound p.T251I and p.P587L, frequentlyfound in cis and subsequently confirmed as showing an autosomaldominant pattern of inheritance. No mutations were identifiedin the PEO1 (Twinkle) and SLC25A4 (ANT1) genes.
The patient presented 10 months later with an unpleasant "jumping"sensation in her feet when at rest which was relieved by movement.Symptoms were worse at night and she also described sudden involuntarymovements of her lower limbs. These symptoms did not subjectivelyimpact on sleep hygiene. Family history was negative for thesesymptoms.
Questions for consideration:
What condition is this patient describing?
What additionaltests would you consider at this time?
This patient’s symptoms were consistent with restlesslegs syndrome (RLS) and periodic limb movements of sleep. Medicationsincluded ubiquinone only. Initial blood tests including fullblood count, iron, ferritin, glucose, renal and liver profiles,thyroid function tests, and vitamin B12 levels were normal.Nerve conduction studies were normal excluding a peripheralneuropathy. Due to the risks associated with developing a dopaminedeficient syndrome with POLG mutations, 123-I Ioflupane DatSCANimaging was performed.
This showed asymmetric uptake of tracer in the putamen withrelative reduced uptake in the right putamen compared to theleft side (figure 2) consistent with impairment of the dopaminetransporter mechanism suggestive of parkinsonism. She declinedpharmacologic intervention for symptom control. The resultsof POLG1 gene analysis in the affected relatives revealed thesame heterozygous mutations.
Figure 2 Dopamine transporter scan showing asymmetric uptake of tracer in the putamen with relative reduced uptake in the right putamen compared to the left side, consistent with impairment of the dopamine transporter mechanism
Mutations of the POLG1 gene are thought to account for up to25% of adult mitochondrial disease presentations.1 This patientpresented with gaze paresis, multiple mtDNA deletions in skeletalmuscle, and a family history of ptosis. It is widely acceptedthat this constellation of factors warrants consideration ofPOLG1 as a possible diagnosis.1 Autosomal dominant progressiveexternal ophthalmoplegia (adPEO) caused by a mutation in POLG1was first described in 2001.2 Pathogenic mutations in the genesencoding POLG, the enzyme that synthesizes mitochondrial DNA,have been described in patients with dominant, recessive, andsporadic PEO, as well as in patients presenting with parkinsonism,neuropathy, late onset ataxia, and Alpers syndrome.3 Mitochondrialdysfunction has been linked to Parkinson disease (PD) with mtDNAdeletions and rearrangements found in the substantia nigra ofpatients with PD and individuals with POLG mutations.4,5
RLS is a common yet underdiagnosed condition with multiple causes.6Secondary causes excluded in this patient include iron deficiency,pregnancy, and end-stage renal failure.7 The patient fulfilledthe essential criteria for RLS: the urge to move the legs whichis initiated or worsened by inactivity, relieved by movementand worse at night.6,8 High prevalence of RLS is reported inthis patient’s age group and gender (women, aged 50–59years).9 Associated features are a family history of RLS, apositive therapeutic response to dopaminergic drugs, periodiclimb movements in sleep, and sleep disturbance.6
Pathophysiologic concepts for RLS include dysfunction of thedopaminergic system based on clinical observation and responseto dopamine and dopamine agonists. RLS symptoms may be prevalentin PD; however, an etiologic link has not been shown. UnlikePD, RLS is not a degenerative disorder and there is little evidenceof degeneration of dopaminergic neurons, although neuroimagingshows a subtle functional impairment of the dopaminergic systemwith reduced dopamine binding in the caudate and putamen.10Although extrapyramidal features have been described in POLG1mutations, moreover, an association with RLS has yet to be reported.
The patient we describe has an unusual presentation of a commonlyoccurring syndrome, RLS, and extends the ever-evolving spectrumof clinical phenotypes attributable to mutation of the POLG1gene.
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(POLG1) gene amplification and sequencing was performed. This detected two previously described heterozygous mutations in compound p.T251I and p.P587L, frequently found in cis and subsequently confirmed as showing an autosomal dominant pattern of inheritance. No mutations were identified in the PEO1 (Twinkle) and SLC25A4 (ANT1) genes. 
