Mitochondrial disease mimicking Charcot–Marie Tooth disease

Patient 1 was a 24‐year‐old woman with a 12‐year history of a progressive sensorimotor peripheral neuropathy associated with pes cavus and bilateral foot drop. She had no family history of neuromuscular disease. At the age of 20 years she underwent nerve conduction studies (NCS), which showed absent motor and sensory responses in the lower limbs, with reduced upper limb motor conduction velocities (table). Upper limb sensory nerve action potentials (SNAP) were also absent. Interestingly, she had a lumbar puncture that showed no cells but a raised protein concentration of 1.56 mmol/l. A sural nerve biopsy showed active chronic axonal neuropathy with some segmental demyelination, not consistent with chronic inflammatory demyelinating polyneuroapthy (CIDP). Her muscle biopsy showed neuropathic changes with a mild inflammatory infiltrate. Genetic testing for X‐linked Charcot–Marie Tooth disease (CMT) 1A, 1B and X‐linked was negative. Four years later, she developed an external ophthalmoplegia, increasing abdominal borborygmi, pain, nausea, vomiting and diarrhoea, associated with considerable weight loss. Urinary thymidine levels (92 μmol/mmol creatinine) and deoxyuridine (168 μmol/mmol creatinine) were markedly raised. DNA sequencing showed compound heterozygotic mutations (G106T and del‐G at nucleotide 1444) in the thymidine phosphorylase gene, confirming the diagnosis of mitochondrial myopathy, neuropathy and gastrointestinal encephalopathy (MNGIE) syndrome.

Table Representative nerve conduction studies of patients 1–3.

	Patient 1			Patient 2			Patient 3
	Latency (ms)	Amplitude (mV)	C vel (m/S)	Latency	Amplitude	Velocity	Latency	Amplitude	Velocity
Motor nerve conduction studies
Peroneal nerve ankle‐EDB		Absent		7	1.6		7.1	0.7
Peroneal nerve knee‐EDB					0.5	27		0.7	19
Tibial nerve ankle‐AH		Absent		7.3	2.2		6	8.2
Tibial nerve knee‐AH					1.9	25		4.9	21
Median nerve wrist‐APB	6.4	8.4		5.7	5.6		5.2	12.4
Median nerve elbow‐APB		4.6	21		3.7	32		5.6	25
Sensory NCS
Sural nerve		Absent			Absent			Absent
Median nerve wrist‐index		Absent		5.2	13			Absent
Median nerve elbow‐index				10.4	3	42

AH, abductor hallicus; APB, abductor pollicis brevis; C vel, conduction velocity; EDB, extensor digitorum brevis; NCS, nerve conduction studies.

Patient 2 is a 38‐year‐old man who first noticed weakness and cramping of his legs at the age of 27 years. NCS carried out at the time of presentation showed mildly reduced motor amplitudes and slowed motor conduction velocities (table), worse in the lower limbs than in the upper limbs, suggestive of a demyelinating rather than axonal peripheral neuropathy. SNAPs were absent in the lower limbs, but were normal in the upper limbs. The diagnosis of CMT was made on the basis of the clinical and neurophysiological findings, but genetic testing did not confirm this diagnosis. At the age of 35 years, the patient began to develop cramping abdominal pains associated with a decrease in appetite, early satiety and marked weight loss. He recalled having prominent borborygmi throughout childhood. He is the third of four boys, whose parents are first cousins. His second eldest brother had diabetes and died at the age of 27 years from a “ruptured diverticulum”. On examination, he was markedly cachectic, with bilateral pes cavus and clawed toes. He had an external ophthalmoplegia with bilateral ptosis, and facial, proximal and distal limb muscle weakness. He had low thymidine phosphorylase activity in the buffy coat, associated with an increased concentration of plasma thymidine (11.9 μmol/l) and deoxyuridine (6.7 μmol/l). DNA sequencing showed a homozygotic 20 base‐pair deletion in exon 10 of the thymidine phosphorylase gene, thus confirming the diagnosis of MNGIE syndrome.

Patient 3 is a 30‐year‐old man, with no family history of neuromuscular disease. At age 25 years, he presented with walking difficulties, muscle weakness and exercise intolerance. On examination, he had evidence of peripheral wasting, clawed toes and bilateral pes cavus. His upper and lower limb motor NCS studies showed relatively preserved motor amplitudes with reduced conduction velocities (table). Sensory responses were absent in both the upper and lower limbs. His symptoms progressed over 5 years and he developed an external ophthalmoplegia, bilateral ptosis, proximal limb weakness and mild limb ataxia. These new neurological signs prompted a needle muscle biopsy, which showed numerous COX negative ragged‐red fibres on the combined cytochrome c oxidase succinate dehydrogenase stain, confirming the diagnosis of a mitochondrial myopathy. Unfortunately, DNA available was insufficient to perform a Southern blot to confirm an mtDNA genetic abnormality.

Discussion

Mitochondrial diseases can affect multiple organs, but have a predilection for organs with high‐energy requirements such as the muscles or brain.¹ Thus they may present in a wide variety of ways, including myopathy, external ophthalmoplegia, diabetes mellitus, short stature or hearing loss. Although peripheral neuropathy is often a component of mitochondrial disease,²,³ it is rarely the presenting symptom. Previous reports have not emphasised the possible confusion between mitochondrial disease and CMT disease when peripheral neuropathy is the dominant feature.

Peripheral neuropathy in mitochondrial disease may occur in up to 50% of affected patients² but is often subclinical.³ In most studies, the axonal form predominates, although demyelinating forms have also been reported.³,⁴ The symptoms of MNGIE syndrome have also been reported to mimic those of CIDP.⁴ Over 30% of the patients seen in our neurogenetics clinic with genetically or biopsy‐proved mitochondrial myopathy have a peripheral neuropathy on NCS, but <5% of these are demyelinating. The three patients discussed here are the only patients to initially present with the primary problem of a neuropathy, with distal weakness, pes cavus and clawed toes. The severity of sensorimotor peripheral neuropathy with slowed conduction velocities led clinicians to consider the possibility of CMT. On electrophysiological grounds alone, it would be difficult to distinguish CMT from mitochondrial disease, as both of these conditions have axonal and demyelinating forms. Clinical features distinguishing our patients from patients with CMT included external ophthalmoplegia and bilateral partial ptosis. In the two patients with MNGIE syndrome, severe gastrointestinal involvement prompted further investigation. Although not specific for mitochondrial disease, these clinical features are exceedingly rare manifestations of CMT disease, and we note that recently there has been a case report of a Taiwanese family with probable CMT and ptosis.⁵ These ophthalmological and gastrointestinal clinical features were not initially present in our patients and thus it is important to follow up patients with undiagnosed peripheral neuropathies and negative genetic studies for CMT, particularly if the conduction velocities are slowed. On development of these features, a measurement of thymidine phosphorylase activity in the buffy coat and plasma thymidine levels for MNGIE syndrome, genetic studies and muscle biopsies confirmed the diagnosis of mitochondrial disease.

In conclusion, young patients with CMT‐like peripheral neuropathies and negative CMT genetic studies should undergo close clinical follow‐up. The development of any atypical clinical features, such as ptosis, external ophthalmoplegia or prominent gastrointestinal symptoms, should prompt consideration of the diagnosis of a mitochondrial cytopathy. In these cases, a muscle biopsy or relevant genetic studies should be carried out.