Introduction
The clinical features of inherited neuropathies are either caused by demye- lination of the peripheral nerve and the consecutive axonal degeneration, or by the primary axonal damage caused by the specific genetic defect.
The types of neurological deficits depend on the neurologic system that is predominantly affected and might be either motor, sensory or autonomic [37]. Although we have learned much about the molecular genetic basis of inherited neuropathies over the last 15years, the biological consequences of the specific genetic alteration remain largely uncovered so far [23].
Furthermore, the glial-axonal interactions which may be disturbed by spe- cific mutations are in most forms of inherited neuropathies not sufficiently understood to serve as a basis for therapeutic interventions. Up to now, causative treatment approaches could not be developed for any form of in- herited neuropathy [33].
Based on theoretical and experimental considerations, some trials were undertaken using either antioxidant or immunomodulating agents [33].
The outcome was measured by using clinical scales or electrophysiological methods to evaluate progression of the peripheral neuropathy. These trials were mainly performed in small groups of patients suffering from the most frequent form of inherited neuropathies, the Charcot-Marie-Tooth disease type 1 (CMT1A) which is caused by a duplication on chromosome 17p11.2 harboring the peripheral myelin protein 22 gene (PMP22).
The most prominent symptom in all forms of inherited neuropathies is the progressive wasting of distal muscles, especially the peroneal muscles, and the small intrinsic muscles of the feet resulting in weakness while walking and, in the majority of cases, in foot deformities. Sensory symp- toms include tingling, burning or aching of feet, legs and sometimes hands. The autonomic system is not primarily affected; thus, autonomic dysfunction is not associated with CMT1. Erectile dysfunction may also be present due to progressive involvement of motor and sensory nerves (e.g., pudendal nerve).
CMT2 and CMTX do not differ from CMT1 concerning these main fea- tures. However, the severity of symptoms can differ between the subtypes.
of hereditary neuropathies
P. Young
A summary of treatment approaches in humans and experimental animals is given in Table 13.1.
13.1 Causative therapy
13.1.1 Genetic treatment
Attempts to treat the underlying genetic defects in CMT have to face some principal considerations as the aim should be either to correct gene dosage or to correct the change of function caused by the mutated gene, which may either be a loss of function or a toxic gain of function. Further, genet- ic therapeutical approaches have to overcome the poor accessibility of the PNS at the right time point [38] before demyelination or primary or sec- ondary axonal degeneration has started.
The most frequent form of inherited neuropathies is CMT1A. This syn- drome is caused by the overexpression of PMP22 protein in Schwann cells resulting in an impaired trafficking and accumulation of intracellular PMP22 protein [26, 27]. Thus, a reduction of the overexpression of PMP22 could be an aim of therapeutic approaches since it was shown in mice that the demyelinating phenotype can be reversed if the expression of PMP22 is normalized [31].
But how can normalization of inborn PMP22 overexpression be achieved?
Table 13.1. Medical treatment Medical treatment in humans
Agent Comment [reference]
z Corticosteroids No significant improvement in CMT1 [12]
z Lipoic acid in CMT1 Slight effect on motor deficit [15, 16, 36]
z Vitamin E in CMT1
Experimental treatment in animal models
z Neurotrophin3 in P0 mutant mice Decreased demyelination [19]
z Progesterone antagonist in PMP22
overexpressing rats Improvement in behavioral tests, decreased demyelination, reduction of PMP22 mRNA overexpression [34]
z Vitamin C in PMP22 overexpressing mice Improvement in behavioral tests, improvement of nerve conduction velocity[30]
z RNA interference Not evaluated in vivo in mice [3,10]
z RNA interference
Small interfering RNAs (siRNAs) were shown to block translation in vitro and in vivo [3, 10]. Thus, it may be possible to regulate cellular PMP22 ex- pression by using siRNAs aimed at reducing PMP22 overexpression. Ex- perimental data showing successful use of siRNAs in the PNS are still lack- ing. Many unsolved problems have to be taken into account like the man- ner of administering siRNAs in vivo and how to ensure that the peripheral nerve and especially the Schwann cells are specifically targeted by the siR- NAs. Furthermore, PMP22 is a dosage sensitive gene meaning that iatro- genic underexpression implicates the risk of a pathological state as seen in hereditary neuropathy with liability to pressure palsy (HNPP) caused by the loss of one allele of PMP22 [22].
z Adenoviral gene transfer
It was shown that by using adenoviral vectors as potential vehicles to reach Schwann cells of the PNS in vivo [19] strong incurable immune responses as seen after adenoviral injection can be circumvented. However, appropri- ate gene constructs are lacking and future clinical approaches have not been established. Suitable animal models will help to develop adenoviral approaches further.
13.1.2 Prevention of axonal degeneration
The pathobiological hallmarks of hereditary neuropathies are either de- myelination and secondary axonal damage, or primary axonal loss with consecutive muscle atrophy. Medical treatment could aim at preventing the axon from degenerating [24]. Another aim in therapeutic approaches could be the rescue of the axon and possibly the neuron, too [8]. Survival of the demyelinated axon resulting in reduced progression of muscular atrophy and paresis would be an approach of choice in several forms of hereditary neuropathies in which demyelination is the primary pathogenetic step.
z Neurotrophic factors
Several neurotrophic factors are known to rescue neurons and their axons from degeneration [17]. The usefulness of neurotrophic factors to prevent axonal degeneration was shown by adenoviral transfer of neurotrophin3 in MPZ deficient mice [19]. Local application like intramuscular injection was shown to be efficient in reducing progressive motor neuropathy in a mouse model for spinal muscular atrophy [35]. Therapeutic problems resulting from systemic use are not solved. One has to take into account that sys- temic application of neurotrophic factors may have severe side effects which can be more harmful than the symptoms of hereditary neuropathies.
As it was shown in the development of therapeutic strategies in amyo- trophic lateral sclerosis (ALS), the systemic use of brain derived neuro- trophic factors had unpredictable side effects [28].
z Antioxidant reagents
There are a few reports in which antioxidants were used in patients suffer- ing from CMT1 and CMT2 [15, 16, 36]. The rationale for this approach was to prevent the axon from degeneration by reducing oxidative stress.
The size of these studies is too small to show that these therapeutic strate- gies can be used as a standard therapy in CMT syndromes. As antioxidant reagents, lipoic acid and vitamin E were used analogous to the treatment of ALS [2].
Therapy with vitamin C has become a new perspective based on the ob- servation that a mouse model of CMT1A improved significantly under high dosage vitamin C treatment. In how far this therapy regimen is successful in humans suffering from CMT1A has to be evaluated in future studies [30].
z Immunotherapeutics
In the early 1980s, two small studies evaluated the benefit of corticosteroids in CMT1 patients [12]. These studies showed no consistent results regard- ing the improvement of CMT1 symptoms in these patients. Temporary im- provement was not stable and muscle wasting could not be stopped by the treatment regimen used. Further studies have not been initiated so far. Re- cently, the observation that, in CMT1B and CMTX mouse models, the im- mune system has an influence on the degree of demyelination [6, 25] led to the question if suppression of the immune system could improve the symp- toms of patients suffering from CMT1B caused by mutations in MPZ and CMTX patients carrying mutations in GJB1. Up to now no studies have been started.
z Progesterone antagonists
In a rat model of CMT1A, it was shown that the use of the progesterone an- tagonist onapristone reduced demyelination and even improved histopatho- logical changes [34]. This improvement could be correlated with the reduc- tion of PMP22 mRNA and protein. Besides morphological improvements be- havioral tasks were also improved, giving hope that clinically detectable pa- rameters of patients with hereditary neuropathies might improve as well.
Although using progesterone antagonists in human CMT1A syndrome is still at the first step, it is feasible to think about using it in selected patients [5, 9].
13.2 Symptomatic therapy
13.2.1 Neuropathic pain
As for acquired neuropathies, membrane stabilizing (antiepileptic) drugs like gabapentin and carbamazepine can also be used to reduce neuropathic pain in patients suffering from inherited neuropathies. Furthermore, anti- depressive agents such as desipramine, amitriptyline and a number of other agents can be used to reduce neuropathic pain in patients with he- reditary neuropathies [11]. The response of patients suffering from differ- ent forms of hereditary neuropathies has not yet been evaluated in con- trolled studies. Recommended dosages are equivalent to the dosages used in acquired neuropathies like diabetic or paraneoplastic neuropathies [29].
13.2.2 Autonomic dysfunction
Autonomic dysfunction is the main feature of hereditary sensory and auto- nomic neuropathies (HSAN), but patients with a HMSN/CMT syndrome may in some cases also suffer from moderate autonomic dysfunction. The most frequent autonomic symptom in patients with HMSN/CMT is erectile dysfunction. Besides hereditary neuropathies which affect mainly the auto- nomic nervous system like HSAN/HSN, patients with a HMSN/CMT syn- drome also rarely suffer from moderate autonomic dysfunction. The thera- py of erectile dysfunction in patients with hereditary neuropathies does not differ from therapies in patients with other neuropathies, e.g. diabetic neuropathy. Phosphodiesterase-5inhibitors like sildenafil and its derivates are medications of choice with regard to possible contraindications and side effects [4, 7, 20].
In CMTX, excessive sweating can be observed in some patients. Like in noninherited neuropathies, local injections of botulinum toxin is the thera- py of choice [21, 32]. Botulinum toxin should be used by physicians who are experienced in its administration. Side effects like initial weakness of arm muscles after axillary injection should be monitored carefully.
13.2.3 Surgery of foot deformities
Some CMT syndromes are associated with foot deformities which lead to further immobilization. Especially early manifestation of pes cavus and short- ened Achilles tendon can lead to severe handicaps reducing mobility in young patients. Thus, besides conservative orthopedic treatment, surgery of foot muscles and tendons of leg muscles may be an appropriate method. After completion of length growth in adolescence, orthopedic surgery can be re- commended for achieving better stability and improvement of walking [13,
14, 18]. Some studies were published showing a clear benefit from surgical correction of foot deformities in different CMT syndromes if associated with pes cavus [28]. Further details can be found in chapter 14 in this book.
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