Discussion
Correct diagnostic investigation is a prerequisite for ensuring that patients with inflammatory polyneuropathy receive immunomodulatory therapy and that patients with hereditary disease avoid futile, expensive and potentially harmful treatment. A genetic diagnosis also allows the opportunity for genetic counselling.
Although clinical findings in inflammatory and hereditary polyneuropathy may overlap, certain features point more towards one or the other (Table 1). No cause is found in 50 % of patients with sensory-predominant chronic polyneuropathy, despite thorough investigation. The likelihood of finding a cause is greater in patients with motor-predominant symptoms (8, 11). Hereditary neuropathy with no known family history and with demyelinating pattern on neurography can be misdiagnosed as chronic inflammatory demyelinating polyneuropathy (9, 12). Both clinical experience and retrospective studies suggest that overdiagnosis of the disease is common (13). Factors that frequently lead to this are misinterpretation of neurophysiological findings and transient efficacy of immunomodulatory therapy (13, 14). A retrospective study at 16 European university hospitals revealed that 35 (3.2 %) of 1104 patients diagnosed with chronic inflammatory demyelinating polyneuropathy had Charcot-Marie-Tooth disease. The mean duration of immunomodulatory therapy in misdiagnosed patients was 17 months (10).
Table 1
Clinical and investigational features of Charcot-Marie-Tooth disease and chronic inflammatory demyelinating polyneuropathy. The table is based on the authors' clinical experience, international recommendations and review articles (5, 8– 10).
| Feature | Charcot-Marie-Tooth disease | Chronic inflammatory demyelinating polyneuropathy |
|---|
| Age at onset | Often early | All |
| Family history | Often positive | Negative |
| Course | Slow progression | Progressive or relapsing |
| Muscles involved | Distal more than proximal | Proximal and distal |
| Skeletal deformities | Common | Rare |
| Nerve conduction abnormalities | Diffuse and homogenous motor conduction slowing without conduction block | Heterogeneous motor conduction slowing and conduction block |
| Cerebrospinal fluid | Normal | Often elevated protein levels |
| Efficacy of immunomodulatory therapy | No | Yes |
In our patient, the main focus was on family history and neurography findings. However, there is a large amount of overlap in the neurography findings in acquired and hereditary demyelinating polyneuropathy. Prolonged distal motor latencies, reduced motor nerve conduction velocities and prolonged F-responses occur in both cases. Furthermore, negative family history is not unheard of in hereditary polyneuropathy. A relatively recent study revealed a pathogenic genetic variant in 30 out of 200 patients with neuropathy of unclear aetiology. In 6 of these 30 positive results, hereditary neuropathy had not been suspected based on the family history and clinical findings (14). Another study revealed PMP22 mutations in 10 out of 111 patients diagnosed with chronic inflammatory demyelinating polyneuropathy (12).
Hereditary neuropathies are classified on the basis of clinical findings (sensory or motor), inheritance, neurography findings and genetics (Table 2). Charcot-Marie-Tooth disease is the most common type. A population-based study in the former Akershus county found a prevalence of 1 case per 1214 people (20). Severity varies considerably, and this can lead to false negative family history since family members with few symptoms are often not diagnosed. Some patients have a de novo mutation or recessive inheritance and therefore no known family history (15). Around 10 % of patients with PMP22 duplication (Charcot-Marie-Tooth disease type 1A) have a de novo mutation and milder clinical symptoms (21).
Table 2
Affected genes, inheritance and clinical and neurophysiological features of the most common hereditary neuropathies. The table is based on the authors' experience with clinical and genetic diagnostic investigation of people with neuropathy, and international databases and review articles (15–19).
| Neuropathy | Most commonly affected genes | Inheritance | Clinical and neurophysiological features |
|---|
| Charcot-Marie-Tooth disease, type 1 (CMT1) | PMP22 (duplication), MPZ, SH3TC2 | Usually autosomal dominant, more rarely recessive | Demyelinating, low nerve conduction velocities.
Most commonly hereditary neuropathy.
Predominantly motor.
Foot drop, pes cavus and hammer toes. |
| Charcot-Marie-Tooth disease, type 2 (CMT2) | AARS1, GARS1, HSPB1, LRSAM1, MFN2, MME, MPZ, SORD | Autosomal dominant or recessive | Axonal, almost normal nerve conduction velocities.
Less pronounced foot deformities than in CMT1. |
| Charcot-Marie-Tooth disease, type X (CMTX) | GJB1 | X-linked dominant or recessive | Demyelinating or axonal.
Second most common form of CMT.
Affects males more severely.
Hearing loss, optic neuropathy, transient hemiparesis, monoparesis or quadriparesis can occur in younger patients. |
| Hereditary motor neuropathy (HMN) | BSCL2, HSPB1, GARS1 | Autosomal dominant/ recessive or X-linked | Slow progression. Exclusively motor. |
| Hereditary sensory and autonomic neuropathy | SPTLC1, SPTLC2, ATL1, DNMT1 | Autosomal dominant or recessive | Hearing loss, development of dementia and loss of sensation.
Open painless sores occur. Autonomic involvement with orthostatic hypotension. |
| Hereditary neuropathy with liability to pressure palsies | PMP22 (deletion) | Autosomal dominant | Triggered by compression of peripheral nerves. Recurrent, transient focal mononeuropathies.
Cranial nerve involvement and loss of hearing may occur.
Foot drop common. |
The symptoms of Charcot-Marie-Tooth disease type 1 often present before the age of 25 years, while symptoms generally present later in type 2. Many patients report symptoms of weakness in the lower legs, ankles or soles of the feet, and are not able to run as fast as their peers. Some patients have mild symptoms that are not noticed for several years, and it is often difficult to say when the symptoms began. Sensory symptoms are often subtle. Walking difficulties gradually become predominant and are due to a combination of paresis and sensory ataxia. Neuropathic pain is uncommon, but pain on exertion occurs frequently. Some people eventually also develop symptoms in their hands. Examination often reveals foot drop and pes cavus. Hammer toes and thickened palpable nerves occur. Disease progression is usually slow, and few patients require a wheelchair.
Neurography plays an important role in diagnostic investigation and grading of severity. Neurography often reveals more serious pathology than expected from clinical examinations. Charcot-Marie-Tooth disease type 1 is demyelinating and characterised by considerably reduced nerve conduction velocity (<38 m/s). Secondary axonal degeneration with reduced amplitudes occurs (22).
A Norwegian study analysed 52 neuropathy genes and identified a genetic cause in one-third of patients with unexplained polyneuropathy (23). The first step in genetic testing for neuropathies is usually PMP22 duplication and deletion analysis. If this is normal, more than 100 known neuropathy genes are analysed with deep sequencing. Good information about clinical findings, inheritance and neurography findings is useful in assessing whether the variants detected are likely to be pathogenic or not. Gene panels for peripheral neuropathies are available at Haukeland University Hospital, Telemark Hospital, the University Hospital of North Norway and Oslo University Hospital (24).
There is as yet no specific treatment for Charcot-Marie-Tooth disease. A combination of baclofen, naltrexone and sorbitol is currently being trialled in phase 3 studies. Personalised treatment with allele-specific RNA interference has shown promising results in an animal model (25).
Many patients benefit from physical activity and orthopaedic devices, and some patients benefit from surgery for foot deformities. To prevent worsening of the neuropathy, it is recommended that patients limit alcohol consumption and avoid neurotoxic medications. Pregnant women with Charcot-Marie-Tooth disease have been found to have a higher rate of placenta previa, abnormal presentations and preterm deliveries (26).
Our patient had no family history or typical findings such as pes cavus and hammer toes. However, in retrospect, we can see that the combination of slowly progressive demyelinating polyneuropathy and normal cerebrospinal fluid should have raised suspicion of a genetic cause much sooner. Genetic testing should have been performed before initiation of immunoglobulin treatment, and certainly after there was no effect after six months of treatment.