J Clin Neurol.  2015 Jan;11(1):92-96. 10.3988/jcn.2015.11.1.92.

Novel Compound Heterozygous Nonsense PRX Mutations in a Korean Dejerine-Sottas Neuropathy Family

• Choi YJ
• Hyun YS
• Nam SH
• Koo H
• Hong YB
• Chung KW
• Choi BO

• KMID: 2179579
• DOI: http://doi.org/10.3988/jcn.2015.11.1.92

Abstract

BACKGROUND
Mutations in the gene encoding periaxin (PRX) are known to cause autosomal recessive Dejerine-Sottas neuropathy (DSN) or Charcot-Marie-Tooth disease type 4F. However, there have been no reports describing Korean patients with these mutations.
CASE REPORT
We examined a Korean DSN patient with an early-onset, slowly progressive, demyelinating neuropathy with prominent sensory involvement. Whole-exome sequencing and subsequent capillary sequencing revealed novel compound heterozygous nonsense mutations (p.R392X and p.R679X) in PRX. One mutation was transmitted from each of the patient's parents. No unaffected family member had both mutations, and the mutations were not found in healthy controls.
CONCLUSIONS
We believe that these novel compound heterozygous nonsense mutations are the underlying cause of DSN. The clinical, electrophysiologic, and pathologic phenotypes in this family were similar to those described previously for patients with PRX mutations. We have identified the first PRX mutation in a Korean patient with DSN.

Keyword

Dejerine-Sottas neuropathy; Charcot-Marie-Tooth disease; periaxin; whole-exome sequencing; peripheral nerve

MeSH Terms

Capillaries
Charcot-Marie-Tooth Disease
Codon, Nonsense
Hereditary Sensory and Motor Neuropathy*
Humans
Parents
Peripheral Nerves
Phenotype
Codon, Nonsense

Figure

• 

  Fig. 1 Pedigree, sequencing analysis, and distal sural nerve biopsy of the proband with compound heterozygous mutations in PRX. A: Pedigree of patient's family. Genotypes of both PRX mutations were indicated at the bottom of each examined individual. Open symbols, unaffected; filled symbol, affected; half-filled symbols, individuals possessing only a heterozygous mutation; asterisk, whole-exome sequencing performed; and arrow, proband. B: Sequencing chromatograms from the proband and her parents. Vertical arrows indicate the mutation site. * (asterisk) and X indicate the mutation codon in I-2 and and I-1, respectively. C: Transverse semi-thin sections with toluidine blue stain (×400). Light microscopy images revealed nerve fascicles that were markedly decreased in size, diffuse subendoneurial edema, and moderately to markedly decreased numbers of myelinated fibers (MFs) of all calibers with suggestive onion bulb formation and endoneurial fibrosis. D: Histogram of the sural nerve biopsy showing a unimodal distribution pattern. The mean diameter of MF (3.14 µm) and the percentage area of MFs (1.39%) were lower than in age-matched controls. E and F: Ultrastructural micrographs by electron microscopy (×1,000) revealed findings consistent with demyelinating neuropathy, such as focally folded, uncompacted, or deteriorating myelin, irregular myelin thickness, and fragmented myelin structures in Schwann cells or nearby macrophages.

• 

  Fig. 2 Hip, thigh, and lower calf MRIs of the proband (II-3) with PRX mutation. A: Coronal scan of lower limbs. T1-weighted images demonstrated no definite fatty or atrophic changes in hip and thigh muscles. B-E: Axial scans of lower limbs. B and C: At the thigh levels, MR images were normal. D and E: On the lower calf levels, we found mild fatty changes in distal peronei muscles (arrows), but, the tibialis anterior and soleus muscles were not involved.

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