Case presentation

A 58-year-old right-handed man was seen in the general neurology clinic in August 2016. He reported a 7-month history of painless left ptosis, worsening as the day progressed and intermittent diplopia. He also reported long-standing numbness and tingling of the hands and feet due to a known diabetic neuropathy. His balance was worsening, but had been poor for several years, requiring bannisters and handrails at home. He had a past medical history of type 1 diabetes mellitus, diagnosed at age 25. He was known to have a sensory axonal neuropathy, a diabetic retinopathy and bilateral cataracts (right cataract surgically removed in 2015). On examination, pupils were equal and reactive and he had full visual fields. He had fatigable partial left sided ptosis with restriction of horizontal eye movements and upgaze, but spared downgaze. Facial movements were reduced, interpreted as mild bifacial weakness. Neck flexion and extension was medical research council (MRC) 5/5. Upper and lower limbs were of normal tone and power with no fatigable weakness. Reflexes were normal in the upper limbs but absent in the lower limbs. He had reduced pinprick sensation in the feet.

A provisional diagnosis of MG was made based on fatigable ptosis and diplopia and the patient was referred for single-fibre electromyography (EMG). Unfortunately, this was poorly tolerated and therefore only 14 single-fibre action potential pairs were acquired. However, two pairs showed borderline jitter and two showed pathological jitter. This was felt to be supportive of a diagnosis of MG. He also had nerve conduction studies, which revealed evidence of a significant axonal sensory neuropathy, consistent with the known history of diabetes.

He was started on trial of pyridostigmine 60 mg two times per day and bloods were sent for acetylcholine receptor antibodies, MuSK antibodies, LRP4 and low affinity antibodies which were all negative.

A CT scan of the chest showed no evidence of a thymoma. An MRI scan of the orbits showed slightly thinned optic nerves but no abnormal signal changes.

Three months later, the patient attended a routine follow-up. He reported no improvement in the ptosis or diplopia following initiation of pyridostigmine. He reported coughing with solid food and frequent nasal regurgitation to liquids. He had recurrent falls due to imbalance and he found fine dexterous tasks difficult that his wife had to help him with buttons and fastening shoelaces. Direct questioning revealed that he can be restless and can talk in his sleep but there was no suggestion of cognitive impairment. His examination was largely unchanged, but mild bradykinesia in the left upper limb was detected. A dopamine transporter (DaT) scan was performed which showed very poor uptake throughout the striata in keeping with an underlying Parkinsonian syndrome resulting from nigrostriatal dopaminergic deficiency. The patient was referred to the movement disorder clinic.

In March 2017, the patient was seen in the movement disorder clinic. He reported a number of falls, reduced volume speech and some choking episodes. Neurological examination was as above, in addition to slow, unsteady gait with bilateral reduced arm swing and bradykinesia, axial rigidity and moderate hypomimia. He had evidence of square wave jerks, restricted horizontal and up gaze with normal down gaze and hypometric slow saccades. The eye movements did not correct with doll’s eye reflex. He had asymmetric Parkinsonism and negative sign d’applause. There was no palatal tremor, apraxia, facial dyskinesias or cerebellar ataxia. A diagnosis of possible progressive supranuclear palsy (PSP) was proposed and the patient was started on levodopa.

Due to paucity of concrete evidence pointing towards a diagnosis of ocular MG a repeat EMG was performed. This demonstrated no evidence of a significant defect of neuromuscular transmission in the muscles examined including left orbicularis oculi. Pyridostigmine was stopped.

Three months later, the patient was seen by speech and language therapy and started on thickened fluids due to recurrent aspiration pneumonias. At clinic review, he reported subjective improvement in cognition and movement following commencement of levodopa. He was followed up in the atypical Parkinsonism clinic.

Over the next 2 years, he developed restless leg syndrome, poor short term memory, orthostatic hypotension, sialorrhoea and erectile dysfunction. He had ongoing problems with fine manual dexterity but less falls and he remained independently mobile. Examination including eye movements and gait remained unchanged over at least 2.5 years.

Due to the lack of progression, the presence of ptosis and preserved down-gaze, all of which are unusual in PSP, the patient was referred to the Highly Specialised Service for Rare Mitochondrial Disorders in Newcastle upon Tyne. Mild bilateral ptosis, a complex ophthalmoplegia and a relatively symmetric rigid akinetic syndrome were noted. There was no frontalis overactivity or significant cognitive deficit (Addenbrooke’s Cognitive Examination -Revised 90/100). The presence of cataracts and axonal neuropathy raised the suspicion towards POLG-related disease. A diagnostic right tibialis anterior muscle biopsy revealed an excess of cytochrome c oxidase deficiency (affecting ~10% of all fibres) and evidence of subsarcolemmal mitochondrial accumulation (figure 1A); quadruple oxidative phosphorylation immunohistochemistry4 demonstrated respiratory chain deficiencies involving both complex I and complex IV (figure 1B). Interestingly, long range PCR of muscle DNA failed to document evidence of multiple mtDNA rearrangements (figure 1C). MtDNA copy number was normal. Next-generating sequencing analysis of 18 genes associated with disorders of mtDNA maintenance revealed two heterozygous POLG gene variants (NM_002693.2: c.2209G>A p.(Gly737Arg) and c.3287G>A p.(Arg1096His)) both of which have been associated with autosomal recessive POLG disease. Familial segregation studies to establish the phase of both variants confirmed they were on different alleles.

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Figure 1

Histopathological and molecular genetic studies. (A) H&E staining, cytochrome c oxidase (COX) histochemistry, succinate dehydrogenase (SDH) histochemistry and sequential COX-SDH histochemistry demonstrate a clear mosaic pattern of COX deficiency with several fibres showing abnormal, subsarcolemmal accumulation of mitochondria. Scale bar=100 µm. (B) Quadruple immunofluorescence analysis of NDUFB8 (complex I) and COXI (Complex IV) protein expression in patient muscle. Each dot represents the measurement from an individual muscle fibre, colour co-ordinated according to its mitochondrial mass (low=blue, normal=beige, high=orange, very high=red). Grey dashed lines represent SD limits for classification of the fibres. Lines next to x-axis and y-axis represent the levels of NDUFB8 and COXI: beige=normal (>−3), light beige=intermediate positive (−3 to −4.5), light purple=intermediate negative (−4.5 to −6), purple=deficient (< −6). Bold dashed lines represent the mean expression level of normal fibres. These data confirm a loss of NDUFB8 subunit expression in many fibres, and to a lesser extent COX1 expression, consistent with a multiple mitochondrial biochemical defect consistent with recessive POLG variants. (C) Long range PCR amplification of patient muscle DNA across the major arc shows no major evidence of multiple mtDNA deletions. Mw, molecular weight markers; lane 1, patient muscle; lane 2, control muscle; lane 3, muscle from a patient with a single, large-scale mtDNA rearrangement.