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Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant disorder, the molecular basis of which is a 1.5 mb deletion in chromosome 17p11.2 including the peripheral myelin protein-22 (PMP-22) gene.1 HNPP typically presents recurrent pressure palsies of peripheral nerves, such as the axillary, median, radial, ulnar, or peroneal nerves, at common entrapment sites. Respiratory muscle weakness has not been previously reported in HNPP. We describe a patient with HNPP in whom respiratory failure and proximal muscle weakness were prominent features.
The patient started to have dyspnoea on exertion at the age of 44. At the age of 47, he noticed a slowly progressive weakness of the pelvic girdle and lower limbs. At the age of 57, he experienced difficulty in going up stairs. However, he was almost independent in daily life At the age of 60, he was admitted to Narita Red Cross Hospital as an emergency patient with a coma due to CO2 narcosis (PCO2 117.6, PO2 64.0). Responding to mechanical ventilatory support, he completely recovered consciousness within a day. His respiratory condition in the daytime improved to that previously. However, he needed mechanical ventilation during sleep because of nocturnal hypoventilation.
The patient had no history of diabetes mellitus, pulmonary disease, or other medical problems. There was no familial history of neurological disorder, including entrapment neuropathies. After a few months, he noted that in his teens he had experienced some episodes of right peroneal and right axillary nerve palsies which resolved themselves over a few months.
In a neurological examination, the patient's mental state and cranial nerves were normal. Evidence of muscular atrophy and lumbar lordosis was found. The muscular atrophy was prominent in the shoulder girdle, intercostal muscles, paravertebral muscles, and pelvic girdle, and moderate atrophy was present in all four limbs (figure). There was moderate weakness of the shoulder and pelvic girdle and mild weakness of the distal limbs. The thorax showed poor respiratory movement, and the patient showed paradoxical movement of the abdomen in the supine position. Tendon reflexes were hypoactive in all limbs. The patient's sensations of touch and pain were mildly impaired in the four distal limbs. His position sensation was normal. His vital capacity was 1.9 l (55% of the normal mean) in the sitting position, but 1.3 l (38%) in the supine position. The percentage of forced expiratory volume in 1 second was normal (99%). Chest radiography at inspiration and expiration showed poor movement of the diaphragm but no abnormality in the lung field. Routine haematological and serological studies gave normal results. No monoclonal or polyclonal proteins were detected. IgG and IgM antibodies to gangliosides GM1 and GD1b were negative. Analysis of CSF showed 1 lymphocyte/mm3 and 25 mg/dl protein. Motor nerve conduction studies showed prolonged distal latencies in the right median (8.8 m/s (normal value in our laboratory <4.6)) and ulnar (6.2 ms (normal<3.6)) nerves, and moderate decreased conduction velocities in the right median (40 m/s (normal>45)), ulnar (45 m/s (normal>49)), tibial (35 m/s (normal>38)), and peroneal (29 m/s (normal>41)) nerves. There were moderate decreases in the amplitude of compound action potentials in all the nerves tested, and an amplitude reduction of 50% was detected across the cubital tunnel of the right ulnar nerve. Minimum F wave latencies were prolonged in all the nerves tested. The latency in the right phrenic nerve was slightly delayed (8.7 ms (normal<8.0)). Sensory nerve conduction studies showed a reduced amplitude of sensory nerve action potentials and conduction slowing in all the nerves tested. Electromyography carried out in the supraspinatus, deltoid, biceps, flexor carpi ulnaris, brachioradialis, quadriceps femoris, biceps femoris, tibialis anterior, and gastrocnemius muscles showed polyphasic motor unit potentials of long duration, but denervation potentials were rare. A left sural nerve biopsy showed scattered tomaculous thickening of the myelin sheath and some abnormally thin axonal myelin sheaths. The density of myelinated fibres was reduced (5726/mm2). A gene analysis disclosed a 53% gene dose of PMP-22 related to normal controls, using Southern blots of DNA digested with EcoRI.
Given the possibility of superimposing demyelinating neuropathy, especially chronic inflammatory demyelinating polyneuropathy, oral prednisolone (60 mg/day) was given for 1 month. However, the patient's clinical condition did not respond to this treatment. Pulmonary dysfunction and proximal muscle weakness were almost steady during the next 3 years.
We examined the patient's elder sister (64 years old), elder brother (62 years old), and younger sister (58 years old), although they had no neurological complaints. All of them had experienced generalised hyporeflexia or areflexia but no weakness or sensory loss, and nerve conduction studies showed moderate conduction slowing with accentuation at the common entrapment sites, suggesting demyelinating neuropathy.
Our patient recalled experiencing recurrent episodes of transit entrapment mononeuropathies, and the familial occurrence of asymptomatic entrapment neuropathy was detected by nerve conduction studies. The presence of tomacula, and genetic analysis confirmed a diagnosis of HNPP. However, the patient's dominant clinical features—respiratory failure and proximal muscle weakness—were atypical for HNPP. Although respiratory muscle weakness has been reported in hereditary motor and sensory neuropathy (HMSN),2-4 there has been no report of respiratory insufficiency associated with HNPP to our knowledge.
The weakness of the truncal muscles, including the respiratory accessory muscle, is a possible cause of respiratory failure in our patient. On the other hand, he had experienced hypoventilation in the supine posture and paradoxical movement of the abdomen, which suggested diaphragmatic weakness.2 Also, chest radiography showed poor movement of the diaphragm. Although the prolongation of distal latency in the phrenic nerve was mild considering the severity of respiratory failure, assessment of axonal loss is not possible with phrenic nerve stimulation. In fact, phrenic nerve latency is not necessarily associated with pulmonary dysfunction in HMSN.4
Diffuse proximal weakness in our patient is an uncommon finding as for HNPP. Mancardi et al 5reported on three patients with progressive sensory-motor polyneuropathy associated with 17p11.2 deletion, and the initial symptom of one patient was proximal weakness in one arm. We propose that our patient represents a clinical phenotypic variability among HNPP. It may be necessary to pay attention to respiratory function in HNPP.
We thank Dr T Yamamoto from the University of Occupational and Environmental Health for the gene analysis and Mr T Nagase from Chiba University for his technical help with the sural nerve biopsy.