A MT-ATP6 Mutation Causes a Slowly Progressive Myeloneuropathy

INTRODUCTION

Charcot-Marie-Tooth disease (CMT) is the term that is best reserved for inherited neuropathies that are not part of a syndrome. Mutations in more than 90 different genes cause CMT, with dominant, recessive, and X-linked inheritance. Mutations in more than 200 additional genes cause inherited neuropathies that are typically part of syndromes that have other manifestations [1]. Here we report on a 53-year-old man with a myeloneuropathy that insidiously progressed over 20 years to more typical picture of CMT, and found that this was caused by a homoplasmic m.9176T>C/p.Leu217Pro mutation in MT-ATP6.

CASEREPORT

The proband is a 53-year-old man who has had high arches since childhood, and developed hammertoes in his second decade. He presented to a neurologist at the age of 32 with 10-year history of progressive lower extremity weakness and stiffness, as well as hyperhydrosis of the right hand. He had hammer toes, high arches, absent reflexes at the ankles but brisk reflexes in the arms and knees, prominent extensor plantar reflexes, normal strength in the arms and legs, reduced pinprick in a stocking distribution, and “slightly reduced vibration at the toes”. Nerve conduction studies showed severely reduced CMAPs in the feet and a normal sural amplitude; EMG showed severe, chronic denervation in distal leg muscles (Table 1). These electrophysiological results were interpreted as showing a motor greater than sensory axonal neuropathy; his clinical diagnosis was a myeloneuropathy. Very long chain fatty acids, B12, vitamin E levels, and MRI of the spinal cord and brain wereallnormal. At age 34, a right sympathectomy (at the level of the second rib) relieved the hyperhidrosis of the right hand, and a genetic test for Friedreich ataxia was normal. The remainder of his review of systems was negative.

Table 1.

Summary of nerve conductions for affected family members (left/right)

Age at EMG (y)	ulnar CMAP ≥ 6 mV	median CMAP ≥ 4 mV	peroneal CMAP ≥ 2 mV	tibial CMAP ≥ 4 mV	median SNAP (O) ≥ 10 μV	ulnar SNAP (O) ≥ 7 μV	radial SNAP (A) ≥ 15 μV	sural SNAP (A) ≥ 6 μV	peroneal SNAP (A) ≥ 6 μV
proband 32	−/−	−/−	0.3/−	0.2/1.1	−/−	−/−	−/−	6.0/8.3	−/−
proband 52	8.6/−	11.1/−	NR/−	NR/−	2.2/−	NR/−	9.2/−	3.1/−	NR/−
mother 68	−/7.2	−/9.7	NR/NR	1.5/2.1	−/11	−/23	−/27	12/10	−/−

CMAP= compound muscle action potential; SNAP = sensory nerve action potential; O= orthodromic; A= antidromic; – = not done; NR= no response.

At age 52, he reported more difficulty ambulating, particularly in initiating walking, and had fallen several times. His exam showed minimally worsened deficits: strength (MRC scale) was 4 + /5 in ankle dorsiflexion and in intrinsic hand muscles, reflexes were less pronounced at the knees, vibration sense (Rydel-Seiffer tuning fork) was absent at the toes, pinprick sensation was reduced to above the knees, and he had subtle extensor plantar responses. Nerve conductions (Table 1) showed little change from the prior study 20 years earlier, and EMG showed severe, chronic denervation in distal leg muscles. His CMT neuropathy score was 17. Serum B12, methylmalonic acid, and copper levels were normal.

His mother was examined at age 68, and considered herself to be asymptomatic. She had hammertoes, mild(4 + /5)weakness in extensor hallicus longus and tibialis anterior, absent vibration in her toes (Rydel-Seiffer tuning fork), and bilateral extensor plantar responses. Her nerve conductions (Table 1) showed reduced motor but not sensory amplitudes in the feet, and EMG showed moderate, chronic denervation in distal leg muscles. The neurological status of other family members is unknown.

A hereditary neuropathy panel of the proband at age 54 through GeneDx identified a variant of uncertain significance (c.2215 A > G; p.Ile739 Val) in in SCN9A (NM 002977.3). Reflex testing to whole exome sequencing with mitochondrial sequencing identified a homoplasmic pathogenic variant in the mitochondrial genome, MT-ATP6 - m.9176T>C/p. Leu217Pro in the proband and subsequently in his mother.

DISCUSSION

We identified a m.9176T>C MT-ATP6 mutation in a patient with an indolently progressive, motor greater than sensory, axonal neuropathy as well as myelo-pathic features that faded over 20 years such that the patient could have been diagnosed with CMT. The presence of sural responses indicates that the loss of vibratory sensation in the toes may result from a distal axonopathy in the dorsal columns and not from the loss of myelinated mechanoreceptor axons in the distal nerves. These findings add to the evidence that MT-ATP6 mutations can present as CMT or evolve into a CMT-like presentation. The mitochondrial genome is maternally inherited and the level of heteroplasmy effects expression of disease phenotype, therefore, the presence of a mitochondrial mutation changes the genetic counseling and risk assessment for a patient.

The m.9176T>C mutation has been previously described to cause Leigh syndrome, bilateral striatal necrosis [2], hereditary spastic paraplegia [3], and CMT [4, 5]. Ng et al. (2019) recently summarized a national registry (125 affected people from 60 families) of well characterized patients with MT-ATP6 mutations. The 9176T>C mutation was the fourth (13%) most common mutation, with 6/10 and 5/10 patients having clinical findings of a myelopathy and neuropathy, respectively, and the probability of being clinically affected was 100% if the blood heteroplasmy was more than 75%. Some affected members of the family described by Verny et al. (2010), were similar to our proband, with adult-onset, static or slowly progressive myelopathy and axonal neuropathy, but not all family members were found to have neuropathy by clinical neurophysiology. The affected members of the kindred reported by Synofzik et al. (2012) were not noted to have a myelopathy. A motor more than sensory neuropathy was not described in these other reports.

The other common MT-ATP6 mutations, m.8993T>C (27%), m.8993T>G (25%), m.9185T>C (20%), and m.9035T>C (9%), also cause an axonal neuropathy [4]. The m.9185T>C mutation was reported to cause Leigh syndrome or neuropathy/ataxia in one family [6], and has been subsequently found to account for 1% of CMT in a large cohort of undiagnosed CMT patients [7]. The m.9185T>C mutation is recognized to cause a motor greater than sensory axonal neuropathy [7].

Clinical genetic testing for conditions such as CMT and hereditary spastic paraplegia typically include a next generation sequencing panel based approach of nuclear genes, but not mitochondrial genes. Our findings add strong support for the idea that mitochondrial sequencing should be part of a complete evaluation of CMT and hereditary spastic paraplegia.