Co-occurrence of Charcot-Marie-Tooth disease type 2A and multiple sclerosis: A case report

Abstract

The pathophysiology of genetic peripheral demyelinating and axonal neuropathies typically differs from that of central demyelinating diseases. However, case reports in the literature have demonstrated instances where these distinct disorders can manifest concurrently. In our report, we describe the case of a 53-year-old woman with Charcot-Marie-Tooth disease type 2A since childhood who presented in middle age with optic neuritis. Her clinical examination, laboratory tests, and imaging results met criteria for multiple sclerosis and outpatient f/u was established in the Neuroimmunology clinic. Existing case reports for other subtypes of Charcot-Marie-Tooth have noted co-occurrence with multiple sclerosis. The underlying pathophysiology remains unknown but multiple theories and comparisons with other neurologic diseases exist. We review these and also emphasize the importance of future disease specific investigations in cases of co-occurrence to unveil new opportunities for therapeutic advancements.

Introduction

Charcot-Marie-Tooth (CMT) disease refers to a group of inherited neuropathies affecting the peripheral nervous system (PNS) which are further classified into types by the responsible genes, inheritance, as well as demyelinating and axonal sub-types. ¹ In contrast, multiple sclerosis (MS) is a disease of the central nervous system (CNS) that is an acquired autoimmune disease. As such, these diseases are usually not thought of by neurologists as occurring in the same patient. To our knowledge, this is the first reported case of CMT type 2A co-occurring with MS. Although rare cases of co-occurrence have been reported with other types of CMT, the pathophysiology of why this occurs remains unknown. We aim to bring further attention to this with our report and increase the knowledge base for different types of CMT.

Case description

A 53-year-old, right-handed woman presented to the hospital with a 3-day history of acute painful right eye vision loss and was diagnosed with optic neuritis based on fundoscopic exam and magnetic resonance imaging (MRI) of the orbits with contrast showing enhancement of the right optic nerve (Figure 1). Her past medical history was notable for CMT disease type 2A diagnosed in her 30s after having symptoms since childhood. She had a strong family history of the disease with her father, all brothers, one sister, and one paternal cousin with CMT. The patient’s genetic testing showed heterozygous mutations in NM_014874.4(MFN2):c.227T>C (p.Leu76Pro) Pathogenic; NM_022041.4(GAN):c.805C>T (p.Arg269Trp) VUS/Conflicting consistent with CMT type 2A.

Figure 1.

(a) MRI orbits axial T1 pre-contrast. (b) showing right optic nerve enhancement (red circle).

Her neurological examination findings were notable for decreased visual acuity in the right eye (visual acuity 20/100) with painful extraocular eye movements. She also had distal symmetric sensory loss and findings of pes cavus and hammer toes (which are associated with congenital neuropathy) but was able to ambulate independently. She was treated for optic neuritis with IV methylprednisolone 1 g daily for 3 days. Further diagnostic workup with MRI brain, cervical, and thoracic spine with and without contrast showed nonenhancing subcortical and periventricular demyelinating lesions in the brain and cervical spinal cord that were consistent with asymptomatic chronic demyelinating lesions (Figure 2). Serum aquaporin-4 antibody (NMO-IgG) and myelin-oligodendrocyte glycoprotein antibodies were negative. The CSF had normal cells, protein, and glucose with elevated IgG index at 2.7 and high myelin basic protein at 13.3 ng/ml. Most notably, 11 CSF-specific oligoclonal bands were present. She was therefore diagnosed with MS according to the McDonald criteria ² based on her CSF and imaging findings. Her optic neuritis resolved with IV steroid treatment and she was discharged to follow-up in Neuroimmunology clinic. She was subsequently started on disease modifying therapy but over the next 2 years had worsening balance, brain fog, and gait dysfunction (required a cane to ambulate) and ultimately was diagnosed with the subtype of secondary progressive MS.

Figure 2.

MRI brain, FLAIR sequence showing periventricular demyelinating lesions.

Discussion

Our patient demonstrates an unusual co-occurrence of a CNS demyelinating disease of MS and an inherited peripheral neuropathy. There are previous case reports linking CMT disease (particularly the demyelinating types) with relapsing forms of MS with MRI evidence of inflammatory demyelination. These case reports include a few cases of CMT type 1, X-linked CMT and one case of CMT 4J with concurrent MS.^3–5 Our literature search did not find any reported cases associated with CMT type 2A and concurrent MS or other CNS demyelinating diseases. In one study of 21 patients with MFN2 mutations (associated with CMT type 2A), 8 of them had abnormal white matter lesions on MRI brain; however, none met criteria for MS. ⁶ On a surface level, this is to be expected as CMT type 2A is the axonal subtype, and MS is classically thought of as a demyelinating disease. However, recent advances in the knowledge and pathophysiology of MS have shown that there is also gray matter involvement in MS ⁷ and that classification as a purely demyelinating disease may be insufficient. Given this, we suspect that the same may be true for the distinction between CMT type 2A and other demyelinating subtypes of CMT. Nerve biopsies in patients with CMT type 2A have also demonstrated findings that overlap with demyelinating neuropathies (such as atypical onion bulbs) ⁸ which suggest that the pathophysiology of type 2A may overlap with other demyelinating CMT types.

Diffusion tensor imaging has also demonstrated co-morbid cerebral white matter abnormalities in patients with multiple types of CMT, including type 2A. ⁹ The causative gene in CMT type 2A, MFN2, encodes a mitochondrial protein that regulates the balance between mitochondrial fusion and fission as part of cellular metabolism. ¹⁰ Consequently, it is widely expressed throughout the body and exerts broad effects, including on CNS function. Optic neuropathy has been reported in both CMT2A (in a minority of cases) and in CMT type 6/hereditary motor and sensory neuropathy type VI, where optic nerve atrophy is a defining feature—both forms linked to MFN2 mutations. ¹⁰ However, our case is unique in that the patient presented with optic neuritis (a specific inflammatory subset of optic neuropathy) and furthermore, optic neuritis occurring in the context of clinical and radiographic criteria consistent with MS.

For the cases of other types of CMT that have co-occurred with MS, there are various hypotheses proposed in the literature. It is proposed that myelin antigens that have not undergone central tolerance may be responsible in the process by triggering an autoimmune response against CNS myelin when presented to autoreactive T cells. ¹¹ In individuals with CMT type 1C, it is proposed that there may be shared immunogenetic mechanisms that overlap with MS. In one case report, a patient with the LITAF gene mutation involved in CMT1C also had a polymorphism in the TNF-α promoter and was diagnosed with both CMT1C and primary progressive MS. A role of TNF-α in the pathogenesis and outcome of MS has been widely demonstrated; thus, the authors’ hypothesis was that the resultant inflammation led to the co-occurrence of both conditions. ¹²

Apart from these cases, there is limited literature on the pathophysiology of CMT specifically and its overlap with CNS demyelination given its rarity. The closest comparison that came up in our literature review was chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) as an example of a peripheral neuropathy that has also been described to overlap with CNS disease. It is far from a perfect comparison as CIDP is an acquired autoimmune disease compared to CMT as an inherited one. However, since both share concurrent CNS and PNS involvement, it is possible that there could be similar underling pathophysiology. Thus, we will also review some of the relevant literature.

Overlaps have also been demonstrated between CMT and CIDP. In an animal model, knockout of protein zero (responsible for CMT1B) led to unexpected electrophysiologic and pathologic findings resembling CIDP rather than what would be expected in a genetic neuropathy. Nerve biopsies showed lymphocytic infiltration with macrophages. The authors hypothesize that there could be a proinflammatory role of mutated P0 protein that leads to a superimposed autoimmune neuropathy in CMT1B pathogenesis. ¹³ The cases of concurrent CIDP and MS are classified under the umbrella term of combined central and peripheral demyelination (CCPD). A case report detailed a patient who initially presented with a relapsing-remitting course of MS with two separate attacks of optic neuritis. This was followed by a diagnosis of CIDP 4 years later, followed by a brainstem demyelinating attack 14 months later requiring aggressive immunomodulatory treatment. ¹⁴ Both simultaneous onset of CNS and PNS demyelination and sequential cases have been reported in CCPD. Our case presented sequentially with CMT type 2A in childhood and development of optic neuritis in adulthood leading to a diagnosis of MS. A survey of CCPD patients in Japan, studied differences between these two groups and found that a monophasic course was more common in the simultaneous group versus a relapsing-remitting course in the sequential group. ¹⁵

Nodopathies are a recently defined category of autoimmune neuropathies characterized by antibodies against components of the nodes of Ranvier which mediate saltatory conduction in axons of both the CNS and PNS. ¹⁶ These have been studied as potentially playing a role as antigenic targets that result in both peripheral and central demyelination, using once again CIDP and MS as representative conditions. ¹⁶ Overall, it remains undetermined whether the hypothesized immune triggering process happens in the periphery and then affects the CNS following activated immune cell migration or is actually generated within the CNS.

Conclusions

In conclusion, our report is the first reported case of CMT type 2A specifically to co-occur with MS. It is a curious intersection of a condition often encountered in the hospital (acute demyelination) with a typically outpatient condition (CMT) that requires a broader neurologic lens and highlights the complexity of overlapping neurologic conditions. Though there is the possibility of occurring by chance, the evidence that exists for co-occurrence with other types of CMT suggests overlapping pathophysiology. Further research is required to better understand the increasing number of cases with concurrent CMT, MS, and CCPD to further clarify their connection, role of inflammation, and potential shared pathophysiology with the ultimate goal of developing targeted treatment.