CGG Repeat Expansion in LRP12 Causes Inherited Peripheral Neuropathy
Takahiro Hobara1, Masahiro Ando1, Yujiro Higuchi1, Akiko Yoshimura1, Jun-Hui Yuan1, Fumikazu Kojima1, Yutaka Noguchi1, Akihiro Hashiguchi1, Eiji Matsuura1, Hiroshi Takashima1
1Department of Neurology and Geriatrics, Kagoshima University
Objective:
This study aimed to identify the role of these CGG repeat expansions in Japanese patients with inherited peripheral neuropathy (IPN)
Background:

Recently, CGG repeat expansions in LRP12, GIPC1, and RILPL1 genes have been found to be associated with oculopharyngodistal myopathy (OPDM), which provides insight into various undiagnosed neurodegenerative disorders. 

Design/Methods:

We collected DNA samples from 2,424 unrelated Japanese patients with IPN and selected 1,555 unidentified cases after conducting a series of prescreening analyses. Together with eight patients diagnosed with OPDM, we screened for CGG repeat expansions in LRP12, GIPC1, and RILPL1 genes using repeat-primed polymerase chain reaction (PCR), fluorescence amplicon length analysis-PCR, and long-read sequencing technologies. We summarized the clinical, electrophysiological, radiological, and pathological features of patients with disease-causing CGG repeat expansions.

Results:

Within the IPN group, LRP12 CGG repeat expansions were identified in 44 cases (LRP12-IPN), which was the fourth most common etiology in this case series. Most cases (29/37) developed only distal limb weakness without ptosis, ophthalmoplegia, facial muscle weakness, or bulbar palsy. Neurogenic changes were commonly observed using needle electromyography (97%) and skeletal muscle biopsy (100%). The number of LRP12 CGG repeat extensions of LRP12-IPN was less than that of three LRP12-OPDM patients (76.41 ± 17.97 vs. 127.00 ± 22.87 ; p = 0.0013). Additionally, we observed selective atrophy in lower limb flexor muscles and p62-positive inclusions in skeletal muscle and peripheral nerve samples regardless of the clinical phenotype. No CGG repeat expansion was detected in GIPC1 and RILPL1.

Conclusions:
We proposed LRP12-IPN as a novel disease entity associated with shorter CGG repeats than the typical LRP12-OPDM phenotype. As the proportion of LRP12-IPN was high among patients with IPN, we strongly recommend the genetic screening of CGG repeats in LRP12, especially in undiagnosed cases.
10.1212/WNL.0000000000204787