Myelin protein zero (MPZ) is a major structural protein of peripheral nerve myelin, which constitutes more than 50% of the protein and plays an important role in myelin adhesion and compaction. The MPZ gene maps to chromosome 1p36 and has 6 exons. Recent advances in molecular genetics have led to the identification of more than 120 mutations in the MPZ gene causing dominantly inherited neuropathies of various clinical patterns: Charcot–Marie–Tooth (CMT) disease, including CMT1B, CMT2, Dejerine–Sottas syndrome, and congenital hypomyelination neuropathy.1,2 We report a new 8–base pair deletion, c.160_167del, in exon 2 of the MPZ gene (mutation nomenclature according to human genome variation society guidelines with respect to National Center for Biotechnology Information reference sequence NM_000530.6) causing a frameshift, which is predicted to cause a premature termination codon, leading to late-onset demyelinating neuropathy in 2 patients with British ancestry from the same family (father and son).
A 60-year-old man was referred by his general practitioner with a history of progressive difficulty in walking and numbness affecting his toes for the past 8 years. He also noticed some balance difficulties. His medical history included ischemic heart disease and type 2 diabetes. He had normal motor development in childhood. There was a strong family history of diabetes. Clinical examination revealed bilateral foot drop with evidence of diminished vibration and joint position sense in both feet. Reflexes were relatively preserved apart from absent ankle reflexes. The patient denied any family history of peripheral neuropathy. His neurophysiological examination showed demyelinating peripheral neuropathy with uniform slowing without any evidence of conduction blocks (Table 1).
At age 31, patient 2 started complaining of sensory symptoms in his feet and over a period of a year noticed difficulty walking with a tendency to trip due to bilateral foot drop. Medical history included type 2 diabetes. He had normal motor development in childhood. He had not been in contact with his father (patient 1) since the age of 18, he was not aware of any other member of the family being affected. On examination, he had symmetrical distal muscle wasting and weakness, particularly prominent on foot dorsiflexion. He had absent ankle reflexes. Sensory examination showed reduced pinprick and loss of vibration up to his ankles. His weakness caused considerable problems to his work as a car mechanic and as a result he had to retire early. Neurophysiological assessment was different compared with his father's conduction parameters. There was excessive slowing in distal segments when compared with proximal segments, suggestive of a distal demyelinating neuropathy (Table 1). Sural nerve biopsy showed marked loss of myelinated fibers. His cerebrospinal fluid showed protein of 551 mg/L (normal range, 1–400 mg/L). Genetic testing for CMT1A was negative.
Given the apparent rapid progression of his demyelinating neuropathy and in the absence of clear family history, he was treated with a course of intravenous immunoglobulins (0.4 g·kg−1·d−1 for 5 days) without benefit. He was subsequently treated with a single course of plasma exchange (7 sessions), after which the patient reported some improvement in sensory perception. Because of this improvement, he then went onto oral prednisolone (20 mg daily, gradually reduced to 7.5 mg daily over 6 months, which was stopped when a genetic cause became apparent). Although the patient found steroid had beneficial effect, there was no clear objective improvement in his muscle power. The familial aspect of his illness was only recognized by chance when the treating neurologist noted a facial resemblance between this patient and patient 1 (both under the care of the same Neurologist but at different hospitals). The new genetic abnormality had already been identified on genetic testing of the father. With that in mind, further genetic testing of the son showed the same defect confirming the diagnosis of a hereditary neuropathy. No other members of the family reported any symptoms to suggest a neuropathy.
Blood samples were taken from both individuals of the pedigree after informed consent. Duplication or deletion of the PMP22 gene was excluded in both the patients. Sequencing of genomic DNA from both individuals detected an 8-base pair deletion in MPZ exon 2, c.160_167delTCCCGGGT, predicted to result in the p.Ser54fs protein change and thereby a premature truncation of the MPZ protein.
We report a novel mutation in exon 2 of the MPZ gene causing a demyelinating neuropathy in 2 members of the same family. There was some phenotypical variability between the patients in terms of age of onset, disease severity, and electrophysiological findings. It is difficult to tease out any contribution of the diabetes to the neuropathy. Nonetheless, both patients had good diabetic control, thus the majority of the neurophysiological findings and the corresponding disability are likely to be related to the genetic cause. Inheritance of this mutation is consistent with the autosomal dominant clinical pedigree. The deletion generates a frameshift and thence a premature termination codon 4 codons downstream predicted to result in a truncated and therefore non-functional protein. Truncating mutations in the coding region upstream of the final intron result in unstable mutant messenger RNA, which is subjected to degradation by nonsense-mediated decay (NMD). In contrast, truncating mutations downstream of this region are postulated to escape NMD and lead to the production of a mutant truncated protein with a dominant-negative effect.3 One physiological role of NMD may be to convert the dominant-negative effect of mutant protein to haploinsufficiency, thereby alleviating the severity and resulting in a milder phenotype.
MPZ mutations are known for their phenotypic variability. Most produce early-onset and commonly severe demyelinating or demyelinating CMT1B; others are associated with late-onset but often severe axonal CMT2.4 Although late-onset disease in both the patients can possibly be explained by NMD, since this mutation lies toward the 5' end of the MPZ gene, any phenotypic variability cannot be explained solely by this mechanism. It is likely that multiple factors, including type and intragenic location of the mutation, other putative gene(s) regulating MPZ gene expression, messenger RNA stability, and posttranslational protein modification may have an important effect on the ultimate clinical phenotype.
1. Warner LE, Hilz MJ, Appel SH, et al.. Clinical phenotypes of different MPZ
(P0) mutations may include Charcot-Marie-Tooth type 1B, Dejerine-Sottas, and congenital hypomyelination. Neuron. 1996;17:451–460.
3. Inoue K, Khajavi M, Ohyama T, et al.. Molecular mechanism for distinct neurological phenotypes conveyed by allelic truncating mutations. Nat Genet. 2004;36:361–369.
4. Shy ME, Jani A, Krajewski K, et al.. Phenotypic clustering in MPZ
mutations. Brain. 2004;127:371–38.