CMT – also known under the term hereditary motor-sensory neuropathy (HMSN) – was first described by Charcot, Marie and Tooth in 1886. It affects approximately 1 in 2,500 individuals [22, 23]. It is represented by a heterogeneous group of different hereditary disorders whereby CMT Types Ia and IIa are to be found most frequently [24]. CMT Type Ia is associated with a duplication on chromosome 17 which contains the gene encoding peripheral myelin protein 22kD (PMP22) leading to a demyelinating neuropathy [25]. A mutation in the gene encoding kinesin, a protein that is involved in microtubule-mediated axonal transport, leads to CMT Type IIb, clinically represented by an axonal neuropathy [26]. Both CMT I and II are usually inherited as an autosomal dominant trait. Regarding further, mostly rare, types and subtypes please refer to specialist literature [27]. The classical phenotype of CMT affects individuals younger than 20 years of age and progresses slowly (Fig. 10.2). Muscle weakness/atrophy and sensory dysfunction usually starts distal-symmetric at the lower extremities, characterized by a foot drop/peroneal atrophy with steppage gait and a sock-shaped sensory impairment [28, 29]. In an advanced stage of the disease, distal and symmetric muscle weakness and atrophy of the intrinsic hand muscles (Fig. 10.3) as well as the not always glove-shaped sensory impairment may be misdiagnosed as carpal tunnel syndrome or ulnar neuropathy at the elbow. Moreover, skeletal abnormalities such as pes cavus, hammer toes and scoliosis are very characteristic [28, 29]. Beyond this classical phenotype, some variants without risk of confusion with a focal neuropathy have been described: infantile and early onset forms are characterized by a mostly severe muscle weakness (“floppy infant”), severe sensory impairment, and they may end fatally [27].

Suspected diagnosis is established by the typical clinical signs mentioned above, a positive family history, electrodiagnostic testing and high resolution ultrasound. As stated in Chap.​ 5, sensory and motor nerve conduction studies are the primary tests to distinguish between axonal and demyelinating neuropathies. CMT Type I (demyelinating) is characterized by a slowing of motor nerve conduction velocities ~20 m/s and prolonged distal motor latencies [25] (Fig. 10.4). Except for in CMT I, such slow conduction velocities regularly only occur in some neuropathies associated with a gammopathy. Moreover, in contrast to acquired neuropathies, the slowing of nerve conduction velocities in an inherited neuropathy occurs uniformly, whereas acquired neuropathies usually exhibit asymmetric or non-uniform slowing [30]. However, the axonal loss in CMT Type II results in a reduction of the amplitude of CMAP or SNAP.

The most recent diagnostic tool is the high resolution ultrasound. Individuals with CMT have a profound (CMT I) or modest (CMT II) enlargement of peripheral nerve cross-sectional area [31] (Fig. 10.5). If the evidence points to CMT disease, one of the most important issues consist of genetic testing and counselling to confirm the diagnosis [32]. There exists no curative treatment at the moment but supportive therapies may gain a partly symptom control [27]. In summary, important clues for a CMT are:

Another important hereditary neuropathy mimicking a focal neuropathy is the HNPP, a disorder that was probably first described by De Long in 1947 [33]. The disease is also inherited as an autosomal dominant trait. In contrast to CMT I it is caused by a deletion on chromosome 17, containing the gene encoding the peripheral myelin protein 22kD (PMP22) [34]. The abnormal myelin may be seen in histo-pathological studies in the form of a focal, sausage-shaped thickening of myelin sheaths, also called tomacula [35]. Typically, the disease has an early onset, and it likely occurs in adolescents and in young adults [35]. Due to the abnormal myelin protein, affected individuals suffer from multiple remitting and relapsing nerve entrapments. Just slight pressure, which nerves easily tolerate normally, may induce a nerve impairment in subjects with HNPP (Fig. 10.6). Nerve entrapment often occurs in the peroneal, ulnar and radial nerves, but it has also been described in the brachial plexus [36, 37]. The clinical manifestations include both sensory impairment and muscle weakness.

Electrophysiological studies typically demonstrate features of demyelination such as prolonged distal motor latencies, ubiquitous reduced sensory and motor nerve conduction velocities and a segmental slowing of nerve conduction across the typical entrapment sites. However, nerve conduction is not as low as in CMT I [38]. These changes may generally be observed in asymptomatic individuals at asymptomatic entrapment sites [39].

As in CMT, high resolution ultrasound of the peripheral nerves provides a novel tool in the diagnosis of HNPP. The average nerve CSA was greater in CMT1 than in HNPP and the most common site of nerve hypertrophy was at sites of entrapment. It is again associated with profound enlargement of peripheral nerve cross-sectional area [31]. HNPP has a favourable prognosis because of possibly spontaneous recovery within weeks or months. In some case reports it has been stated that patients also have received a benefit from surgery of the entrapped nerves [40]. However, it remains unclear whether it was due to surgery or to the natural course of the disease.

Today, it is easy to confirm the diagnosis by a genetic test, whereas meanwhile a biopsy of the sural nerve is unnecessary [41]. In summary, important clues for HNPP are:

Among the autoimmune-induced neuropathies, we have to take into account some conditions which again may be confused with a focal neuropathy. Most of them are mainly characterized by a chronic course. The classical prototype is a disease also referred to as chronic inflammatory demyelinating neuropathy (CIDP). Its etiology is completely unknown to date. However, similarity to the Guillain-Barre syndrome, as well as response to an immune-modulating therapy, suggest an autoimmune origin [42]. The primary hallmark of CIDP is demyelination followed by secondary axonal loss [43]. The prevalence has been reported to be 1–8 affected individuals within a population of 100,000 inhabitants [44]. These are likely underestimates, since the condition is not always easy to diagnose. Therefore it is supposed that a considerable percentage of the affected subjects are overlooked or misdiagnosed [45]. CIDP is characterized by predominant motor symptoms persisting for more than 2 months together with reduced or absent tendon reflexes. Either progressive or relapsing-remitting weakness may start asymmetrically at the onset of the disease, but it typically affects symmetrically the distal and/or proximal muscles of the extremities, whereas involvement of the cranial nerves is uncommon. In addition, sensory loss such as numbness may also be present. Some of the affected individuals show a self-limiting course [42]. In contrast to hereditary neuropathies, family history is negative. Besides the classical CIDP, there are conditions with an atypical clinical presentation (see below), some of which may be considered variants and others distinct disorders. Due to this heterogeneity as well as the lack of a specific diagnostic test, several diagnostic criteria have been suggested. They all have a high specificity but are less sensitive [46–48]. For instance, the frequently used criteria of the American Academy of Neurology (evidence of demyelination in nerve conduction studies, elevated CSF protein level and signs of demyelination on nerve biopsy) miss more than 50 % of the patients suffering from CIDP, but they approach a specificity of 100 % [49]. Therefore, it has been suggested to start with an immune-modulating therapy if the typical clinical symptoms mentioned above are present and if additional criteria support the diagnosis [42]. Nerve conduction studies play a key role since they since they demonstrate the underlying process of demyelination in various nerve segments by detection of slowed nerve conduction velocities, prolonged distal motor and F-wave latencies as well as conduction block or abnormal temporal dispersion (please also refer to Chap.​ 5). Electrophysiologic criteria of the American Academy of Neurology require at least three demyelinating range abnormalities in two nerves; however, they are less sensitive as stated above [46]. Moreover, in 90 % of the affected individuals, an elevated liquor protein is present, and in 29 % of patients antibodies to P0 protein were identified [50]. Furthermore, sural nerve biopsy may yield evidence of demyelination, but it is considered to be less sensitive and less specific [42].

Recently, imaging modalities have been introduced in the diagnosis of CIDP. Hypertrophy of the lumbar or cervical nerve roots as well as of the brachial or lumbosacral plexus and/or gadolinium uptake in MRI may support the diagnosis (Fig. 6.​23) [51, 52]. Additionally, high resolution ultrasound provides a cost-effective tool for the detection of focal, multifocal or generalized alterations of the peripheral nerves and plexus. Ultrasonographic findings that have been reported in CIDP cases are characterized by an modest enlargement of cervical nerve roots and non, focal or multifocal peripheral nerve enlargement (see Sect. 6.​1.​8 concerning HRUS and Sect. 6.​2.​8 concerning MRI) [53]. However, in some cases focal enlargement corresponding to sites of conduction block was demonstrated. Similar findings are reported to occur in multifocal motor neuropathy (see Sect. 10.5.2), but further investigations are required to determine the potential diagnostic value of these methods [31, 54]. Treatment is immune-modulation either with corticosteroids or alternatively with intravenous immune globulin [55, 56]. As in CMT I, chronic inflammatory demyelinating neuropathy may be confused with multiple entrapment syndromes of the upper extremities such as both-sided carpal tunnel syndrome due to prolonged distal motor latencies. Therefore, doubts concerning the diagnosis of a focal neuropathy should arise if: