Authors
F. Baas, M.D., Ph.D.
H. Bienfait, M.D., Ph.D.
Clinical features
Autosomal dominantly and X-linked inherited HMSN are characterized by distal muscle weakness and atrophy first affecting the feet and later the hands, associated with sensory disturbances in a distal distribution. Together with the presence of foot deformities this often causes instability of gait or steppage gait. Symptoms have a symmetrical distribution in the majority of cases, but occasionally, weakness and deformities can be asymmetrical. Most patients visit a physician because of symptoms of distal weakness or foot deformities as pes cavus and hammertoes and less often a claw hand. Sensory symptoms are seldom the presenting complaint. Some patients never visit a physician as they are familiar with the walking difficulties and foot deformities in the family. At clinical examination there is no difference between type 1 and 2 with exception of presence of palpable thickened nerves in occasional type 1 patients. There is a wide variation in clinical manifestations, both between and within families. The autosomal recessively inherited forms of HMSN present a more severe phenotype with proximal weakness, often leading to wheelchair dependency at a relatively young age.
Natural course and prognosis
Age at onset varies, being more often in childhood or adolescence in type 1 and relatively often in middle age or over 50 years in type 2. Disease progression is slow 36. Functional disability is mild with the majority of patients being ambulant with or without the help of a cane, ankle foot ortheses or orthopedic shoes. In more than 10% of patients with CMT1A and CMT 2 who have been examined in the Academic Medical Center there is some degree of proximal weakness. Wheelchair dependency is rare. The autosomal recessively inherited forms of HMSN present most often in early childhood with a more severe phenotype with proximal weakness leading to early development of scoliosis and wheelchair dependency.
Epidemiology
Prevalence of HMSN ranges from 10 to 36 per 100,000 persons 33-35. Type 2 comprises about one third to half of the cases, probably the prevalence of this type is underestimated because of difficulty in case ascertainment.
Differential diagnosis
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In the absence of a clear positive family history the diagnosis of HMSN type 2 can be difficult and presumably several HMSN 2 patients are misdiagnosed as chronic idiopathic axonal polyneuropathy (CIAP) or polyneuropathy caused by alcohol abuse. A history of presence of foot deformities or walking difficulties since childhood or Achilles tendon transfer in childhood may be helpful for the diagnosis. Presence of similar symptoms in the family should not only be specifically asked for, but also followed by examination of family members or reviewing their medical charts. |
Ancillary investigations
The diagnosis is based on clinical and electrophysiological examination. To recognise a hereditary neuropathy a detailed family history and sometimes a neurological examination in family members is necessary.
Electrophysiological examination is required to distinguish type 2 from type 1. Sometimes it is wise to examine several family members as there is some overlap at the electropyhysiological level. In X-linked HMSN, affected women can have near normal NCVs while affected men from the same family have NCVs in the demyelinating range.
In HMSN type 2 NCVs are slightly diminished or normal in the majority of cases. In some families NCV is more variable and can be less than 38 m/s . CMAPs and SNAPs are mostly decreased or absent in the legs in clearly affected patients. They can be in the normal range in the hands. Myography reveals high voltage, long duration motor unit action potentials as signs of reinnervation and a reduced recruitment pattern in distal leg and hand muscles. Motor unit action potentials can be absent in severely atrophied muscles. Spontaneous activity can be present.
DNA analysis: Although at the moment no causative therapy is available for any type of HMSN and phenotype-genotype correlations are poor, patients appreciate a precise diagnosis. In general, in HMSN DNA analysis can be helpful for reasons of genetic counselling or in some cases to differentiate from other causes of neuropathy. For type 2 no DNA analysis is available in the Netherlands at present. However, the MPZ gene and the CX32 gene can be analysed and when MNCV of the median nerve is < 38 m/s in at least one family member and in the others < 45 m/s one can consider analysis for the presence of a duplication on the short arm of chromosome 17 (CMT1A).
A sural nerve biopsy for diagnostic purposes has in fact become obsolete.
Genetics
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HMSN type 2 constitutes a group of clinically and genetically heterogeneous subtypes and several phenotypes with atypical or associated features . The table shows the loci and the recently identified mutations associated with the axonal type of HMSN.
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Therapy
No causative therapy is available. Treatment is symptomatic and includes prescription of ankle foot ortheses or orthopedic shoes. Referrals to a rehabilitation physician and a genetic counselling practice should take place early in the disease. Decisions about foot or hand surgery should be made after consultation of a rehabilitation physician. Strength training can increase strength and some leg-related functional performance in HMSN patients.
