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Charcot-Marie-Tooth disease (CMT) is the most common type of hereditary peripheral neuropathy. It is classified into two types based on pathological and electrophysiological findings: type 1 and type 2. CMT type 1 gene loci have been mapped to chromosome 17 (CMT1A), chromosome 1 (CMT1B),1 another unknown chromosome, (CMT1C) and the X chromosome (CMTX). CMT1B is a rare form of CMT1 associated with mutations of the myelin protein zero (P0) gene. Mutations in the P0 gene have recently been recognised in Dejerine-Sottas disease, peripheral neuropathy with an early onset in childhood, and a more severe phenotype than CMT1. CMT1 and Dejerine-Sottas disease are characterised by thickening of peripheral nerves, and thickening of the cauda equina, nerve roots, and ganglia have often been found.2 3 Although cranial nerves are generally spared in CMT, thickening of the acoustic or optic nerve has been reported in some cases. We report here on a Japanese patient who exhibited severe polyneuropathy, bilateral trigeminal thickening on MRI, and an abnormality of the auditory brain stem response. Gene analysis disclosed a novel missense mutation (His81Arg) of P0. The cranial nerve involvements in this patient may be associated with the novel missense mutation of P0(His81Arg).
A 15 year old Japanese girl presented with CMT disease. She showed delayed motor development. Although she became ambulant at 1 year and 8 months of age, she was never able to run. She was referred to our hospital due to progression of her gait abnormality. Her mentality and higher brain function were normal. Neurological examination disclosed weakness in both proximal and distal muscles of the legs, decreased grasping power, sensory disturbance of distal limbs, and generalised areflexia. Facial sensation, mastication power, and hearing acuity were normal. She also had atrophy of the lower limbs, drop foot, a steppage gait, claw hands and pes cavus deformities. Optic atrophy, incoordination, autonomic dysfunction, and cardiac involvement were not evident.
In laboratory findings, creatinine kinase was 343 IU/l. A peripheral nerve conduction study showed undetectable sensory and motor action potentials in all limbs. Auditory brain stem response showed abnormal prolongation of the I-III interpeak (2.81 ms on the right side, 2.88 ms on the left side). Brain MRI (figure) showed significant thickness of bilateral trigeminal nerves (7 mm) compared with that of controls (3.15 ± 1.62 mm (mean ± 2 SD), n=20). However, other cranial, spinal nerves and roots were not thick on physical examination or MRI study. Sural nerve biopsy was not performed.
Although no detailed familial information was available, her mother (49 years old) showed normal findings on neurological examination and peripheral nerve conduction study.
Blood samples were obtained from the patient and her mother with informed consent. DNA was extracted from the blood by a standard phenol/chloroform protocol.
The six exons of the P0 gene were amplified by the polymerase chain reaction using primers, and analysed by single strand conformational polymorphism (SSCP) and sequencing analyses. DNA sequencing of exon 3 showed a novel point mutation (A242 to C at codon 81) resulting in amino acid substitutions of arginine for histidine only in the patient. A DNA duplication in chromosome 17p11.2-p12, including the peripheral myelin protein-22 (PMP 22) gene, was not present. The patient’s mother did not show any mutations in the P0 gene.
CMT type 1 is caused by abnormalities in myelin protein of Schwann cells. Repeated demyelinating and remyelinating responses in the peripheral nerve produce diffusely enlarged diameters of nerves in CMT type 1, and thickening of the cauda equina, nerve roots, and ganglia has also been found.2 3 Although blepharoptosis, ophthalmoplegia, facial weakness, deafness, dysphagia, and dysphonia in CMT have been previously reported,2 clinical involvement in the cranial nerves is rare and thickening of cranial nerves has not been reported except for the acoustic or optic nerves in some cases.
In the present study, our patient showed severe clinical manifestations of early onset and undetectable conduction velocities. Therefore, this patient was considered to have a severe variant of CMT1 or Dejerine-Sottas disease. Although her facial sensation, mastication power, and hearing acuity were normal, the thickness of bilateral trigeminal nerves on MRI and prolongation of the I-III interpeak intervals in auditory brain stem response were found. The I-III interpeak interval represents the conduction time from the eighth nerve to the pontomedullary portions of the auditory pathway. Prolongation of the auditory brain stem response suggested peripheral conduction delay of the auditory nerve.
Trigeminal neuralgia with CMT has been reported.4 In these rare cases, trigeminal neuralgia was inherited, suggesting a partial symptom of CMT. Although some patients were surgically treated, it was not clear whether a thickened trigeminal nerve was present. Moreover, on electrophysiological studies of facial and trigeminal nerves in CMT, Kimura5 reported that the sensory component of the trigeminal nerve was relatively spared, despite extremely delayed conduction of the facial nerve. However, the MRI study of our patient suggested that the fifth cranial nerves were subjected to the same pathological process that affects other peripheral nerves.
Our patient showed no DNA duplication on chromosome 17p11.2 and we found a novel mutation (A to C) representing an Arg81 to His substitution in the P0 gene. Histidine 81 is conserved among many other species, including cows, rats, chickens, and sharks. This mutant allele was absent in the DNA from 100 controls. Therefore we identified this mutation as pathogenic. Arg81His was located in exon 3, which codes for the extracellular domain of P0. The extracellular domain plays a part in myelin compaction by homophilic interaction and many mutations in this area have been reported. Although the phenotypic variability is related to the position and nature of the P0 mutation, patients with cranial nerve involvement are rare in CMT with a P0mutation. Therefore, the unique thickening of trigeminal nerves and the clinical severity in this patient may be related to this novel missense mutation. A careful comparison of the clinical, electrophysiological, and histopathological data between patients with CMT should be conducted.
We are indebted to the families studied for their cooperation and support. This work was partly supported by Uehara Memorial Foundation, the Sasakawa Health Science Foundation, the Primary Amyloidosis Research Committee, and the Ministry of Education, Science and Culture of Japan 10832002, 18832993.