R. Kiefer, E.B. Ringelstein
2.2 Specific features in the history of patients
2.2.1 Chief complaint and functional deficits noted by the patient Patients may seek medical advice for a number of different reasons which vary depending on the type of hereditary neuropathy. The most common causes of seeking medical advice are summarized in Table 2.2. It should al-ways be remembered that only CMT1A and B, CMTX, CMT2 and HNPP are diseases which are regularly encountered in neurological practice, while all other forms are extremely rare and may occur only in certain populations.
The most common chief complaint in patients with hereditary neuropa-thy is disturbance of gait. Gait may be impaired due to weakness, proprio-ceptive loss, foot deformity or contracture of the Achilles tendon. Patients may fall over their feet due to weakness of peroneal muscles, while the ability to stand on the toes is usually preserved for some time. Walking on uneven ground may become difficult with distal weakness, and frequent ankle sprains may be another consequence of distal weakness.
Proximal weakness is indicated by complaints of difficulties climbing stairs or raising from a chair. Proximal weakness, however, is an unusual feature of hereditary neuropathy and occurs only late in the disease in few cases, with the exception of the most severe forms such as Djerine-Sottas syndrome (DSS), some forms of CMT4 and the very rare hereditary motor and sensory neuropathy proximal type (HMSN-P) and is otherwise rather suggestive of acquired inflammatory polyradiculoneuropathy.
z R. Kiefer, E.B. Ringelstein 18
Weakness of the hands with difficulties in writing, turning a key or grasp-ing fine objects is rarely the presentgrasp-ing complaint in hereditary neuropathy but may occur later in the course of the disease. Exceptions are patients with CMT2D and the hereditary motor neuropathies type 5(HMN V) as well as HMN VIIB whose illness begins in the hands with initially normal function of the legs.
Progressive muscle wasting of the lower legs or hands may be another chief complaint while weakness may not have been noted. While the above complaints are typical for CMT and distal HMN patients, patients with HNPP usually report disturbances of gait due to uni- or bilateral peroneal palsy. Other peripheral nerves of the lower limb are less frequently af-fected, and quadriceps weakness is not a usual feature of this disease. Pa-tients with HNPP may also complain of acute weakness and sensory loss in one or both arms which only on physical examination turn out to follow the distribution of individual nerves, mostly the ulnar nerve. Weakness is frequently triggered by repetitive movements, forced positions of the af-fected limbs for a prolonged period of time, or minor pressure on the nerve along its course. Further questioning may reveal similar insults at earlier times and evidence of an additional generalized neuropathy, the symptoms of which may only be reported when specifically asked for. Also, the history may reveal the preexisting diagnoses of multiple entrapment syndromes or surgery for carpal tunnel syndrome. In hereditary neuralgic amyotrophy (HNA), weakness is rarely the presenting complaint, but rather severe shoulder pain, followed by weakness and atrophy within days to weeks. Usually the pain subsides while weakness and atrophy set in.
Sensory deficits in CMT patients add to postural imbalance and gait dis-turbance which are accentuated in the dark. Sensory loss may, however, go Table 2.2. Common presenting complaints in patients with hereditaryneuropathies
CMT and distal HMN phenotype z Disturbance of gait
z Weakness
z Sensoryloss (not distal HMN) z Foot deformities
HNPP and HNA phenotype z Recurrent focal weakness z Foot deformities z Shoulder pain (HNA) HSAN phenotype (rare) z Pain
z Excessive or lost sweating All hereditary neuropathies z Affected familymembers
unnoticed for many patients with CMT, particularly in CMT2. Some pa-tients may even insist on feeling normal sensation despite having total loss of vibration sense at the toes and severe sensory abnormalities on neuro-physiological testing. The history alone may therefore not provide the nec-essary clues to differentiate between CMT and distal SMA. The very slow occurrence of deficits is the likely cause of unnoticed sensory loss in CMT and is a suggestive feature differentiating it from acquired neuropathies of shorter duration. In HNPP, sensory loss is focally distributed along the sensory fields of individual peripheral nerves. In addition, there may be distal sensory loss similar to that in CMT patients due to the underlying generalized neuropathy in HNPP.
Pain is a prominent complaint in hereditary sensory and autonomic neuropathy type 1 (HSAN1). Also, it is highly characteristic of HNA where acute onset of uni- or bilateral shoulder pain is the chief complaint fol-lowed by weakness. Specific questioning may reveal similar episodes in the past.
Loss of pain and distal loss of sweating are characteristics of HSAN ex-cept HSAN3 where excessive sweating is a feature. Some HSAN patients may also present because of poor wound healing and painless ulcers, or mutilations.
Foot deformities including hammertoes and pes cavus are another fre-quent cause to seek medical advice, and such patients may first be seen by orthopedic surgeons rather than neurologists. When evaluating patients with longstanding polyneuropathy, a history of orthopedic surgery on the feet and ankles in earlier days may suggest a hereditary neuropathy. Foot deformities are seen in CMT1 and 2, CMTX, distal HMN patients and less frequently in HNPP.
Finally, patients with affected family members may seek medical advice despite the absence of any physical complaints to find out whether they are also affected, and to obtain genetic counseling. In some individuals, the ill-ness may then be detected by physical examination and neurophysiological testing.
2.2.2 Onset and time course of disease
Although a lifelong disease, patients with CMT and distal HMN usually do not seek medical advice before the end of the first decade or in the second decade. Earlier onset points towards severe disease such as DSS, in which weakness is often present from birth, or one of the forms of CMT4. On the other hand, onset may be so insidious and progression so slow that it may remain unnoticed for many years. Some symptoms may only retrospec-tively be recognized when specifically asked for. In neuropathy patients with suspected hereditary neuropathy, it is therefore very important to spe-cifically ask for early symptoms during childhood and adolescence and in-quire about indirect hints for abnormal function. Low physical activity as z R. Kiefer, E.B. Ringelstein
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a child or a dislike for wild play may provide clues, as do poor grades in sports at school. Affected persons will frequently report that they always had been slower than their peers. A child regularly assigned as goalkeeper when playing soccer may indicate poor running abilities. It may also be re-membered that the feet looked funny from the early days and that shoes that fit were always difficult to buy, indicating that foot deformities had preexisted for years.
In contrast, patients with HNPP and HNA may have been healthy until the first bout of disease, but again, this needs to be specifically asked for and may have gone unnoticed at first.
2.2.3 Concomitant diseases
Medical conditions causing acquired peripheral neuropathy should be sought for as part of establishing a differential diagnosis. Their existence does, however, not preclude hereditary neuropathy. The time course of the disease and characteristic elements of the physical examination may help distinguish between the two.
2.2.4 Family history
A considerable number of patients have no family history of neuropathy, amounting to 20% in CMT1. A negative family history, therefore, does not preclude the diagnosis of hereditary neuropathy. Also, affected family members may not have even noted their disease. It is therefore necessary to specifically ask for weakness, gait disturbance, foot deformities and other features of the disease in family members. It is also mandatory to ex-plore a complete family tree including brothers and sisters, the parents and their brothers and sisters, the cousins, and the grandparents. A large family who all lived until old age will be informative. On the other hand, the ab-sence of affected family members does not exclude even an autosomal dominant genetic trait. Potentially informative family members may have died early or were lost for other reasons. This may be particularly true in populations where families were destroyed or dispersed during war times.
Finally, adoption or false paternity may obscure a genetic trait. Another not uncommon possibility is that the disease is caused by a de novo muta-tion and therefore the patient is the first affected member of the family.