Peripheral myelin protein 22 p.Tll8M point mutation in a family with no clinical phenotypes of Charcot-Marie-Tooth disease

INTRODUCTION

Charcot-Marie-Tooth disease (CMT) is a group of peripheral nerve disorders with clinical and genetic heterogeneity predominantly characterized by distal muscle weakness and atrophy, sensory loss, and reduced deep tendon reflex.^[1-3] CMT is categorized into primary peripheral demyelinating neuropathy or CMT Type 1 and primary peripheral axonal neuropathy or CMT Type 2.^[2] Mutations in peripheral myelin protein 22 (PMP22) gene that is mapped on chromosome 17p12-p11.2 are associated with CMT disease.^[4] The most frequent form is a demyelinating neuropathy/CMT Type 1 associated with a tandem duplication of the chromosome 17p11.2-p12 region.^[3] The deletion of the same region is less common and causes hereditary neuropathy with liability to pressure palsies (HNPP);^[5] and point mutations in PMP22 are also less common and may cause either cause CMT1 or HNPP.^[6] The PMP22 mutations are inherited in an autosomal dominant pattern,^[7] which cause a diversity of phenotypes of neuropathy.^[4] The PMP22 gene encodes the PMP22, which is a major element of myelin in peripheral nervous system produced primarily by Schwann cells.^[6] Expression of altered dosage of the PMP22 protein in Schwann cells is a major cause of inherited peripheral neuropathies.^[8] In this study, we report the detection of PMP22 c.353C>T p.T118M mutation in two cases with cerebral palsy (CP).

CASE REPORT

Two siblings, a male aged 15 years (Case 1) and his younger sister aged 6 years (Case 2) affected with CP, were referred to the All India Institute of Speech and Hearing (AIISH) for speech and hearing impairment assessment and therapy. Their parents were consanguineous and were delivered after a normal prenatal period through vaginal delivery. Case 1 was epileptic with a delayed motor milestones; muscle hypertonicity, poor standing posture, poor developmental delay, and poor mental ability. Case 2 had low muscle tone, poor dynamic and posture control, and inadequate speech and mental ability. Their reports showed no earlier diagnosis for CMT disease. The affected siblings have a normally developed full sibling.

DISCUSSION

The p.T118M (rs104894619) substitution in the PMP22 gene has been detected in a number of families with CMT disease. This paper discusses the detection of PMP22 p.T118M mutation in two siblings (Case 1 and Case 2) affected with CP. This mutation at codon 118 of the PMP22 gene is a single-nucleotide variant that produces a threonine to methionine amino acid substitution (p.T118M) which has been reported in the context of familial neuropathy and in CMT disease.^[9,10] In the siblings, the PMP22 p.T118M was identified in a heterozygous state, with an autosomal dominant transmission which is arisen from the paternal line; the father and the other normally developed full sibling were also heterozygous for the PMP22 p.T118M mutation; and the mother was wild-type [Figure 1]. Several investigations have identified the p.T118M mutation in unaffected parents of neuropathy patients.^[11,12]

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Figure1:

Chromatogram showing the PMP22 gene mutation at nucleotide position c.353C>T

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The PMP22 gene encodes a 22 kDa specific integral membrane protein named PMP22, which is a major component of myelin in peripheral nervous system.^[13] The p.T118M mutation is not 100% penetrant when expressed under heterozygous condition^[7,14,15] and some heterozygous carriers do not present with CMT or related peripheral neuropathies; some heterozygous subjects have moderately decreased nerve conduction velocity, while others exhibit normal nerve conduction.^[16] However, homozygous p.T118M mutation might disrupt normal Schwann cell axonal interactions without altering myelin formation; causing severe axonal neuropathy^[14] and patients with homozygous PMP22 mutations are rare.^[6] CMT has an estimated incidence of 10–40/100,000 individuals.^[17] The p.T118M variant is more common in European lineage than other ethnic groups.^[16] In India, inherited neuropathies are not quite reported in the literature and genetic basis of CMT is limited.^[18-20]

Moreover, the clinical significance of p.T118M variant has been divisive,^[16,21,22] while some studies have reported p.T118M variant to be a causative mutation in many CMT cases.^[7,9,11,12] The genetic analysis of the two cases with CP and the family described in this study showed no significant influence of the p.T118M variant on the phenotype, as reported by earlier studies.^[21,22] In consideration with aforementioned studies, the p.T118M variant can be benign or cause partial loss of function, but can be disease-causing and/or disease-modifying in the appropriate conditions.

CONCLUSION

Despite the absence of clinical phenotypes associated with CMT disease in the south Indian family carrying the PMP22 p.T118M point mutation, factors such as gene expression, incomplete penetrance, modifier genes, environmental influences, and phenotypic variability may likely contribute to the lack of symptoms. We report that the p.T118M variant is common in the human population, which may be a risk factor for CMT rather than a complete penetrant cause of this disorder. Further genetic analysis and functional studies could enhance our understanding of this mutation’s implications and the potential for future clinical manifestations.