Leukoencephalopathy and conduction blocks in PLEKHG5-associated intermediate CMT disease

Area of Science:

• Genetics
• Neurology
• Molecular Biology

Background:

• Biallelic variants in the PLEKHG5 gene are linked to Lower Motor Neuron Disease (LMND) and intermediate Charcot-Marie-Tooth disease (CMT).
• Previous reports highlight a spectrum of phenotypes associated with PLEKHG5 mutations.

Purpose of the Study:

• To describe four patients from two families with intermediate CMT and atypical clinical and para-clinical findings.
• To identify novel variants in the PLEKHG5 gene associated with this phenotype.

Main Methods:

• Clinical evaluation of four patients with predominant distal weakness and mild sensory involvement.
• Nerve conduction studies (NCS) to assess nerve conduction velocities, sensory amplitudes, and conduction blocks.
• Biochemical analysis including creatine kinase (CK) levels and cerebrospinal fluid (CSF) protein.
• Genetic analysis to identify variants in the PLEKHG5 gene.

Main Results:

• Patients presented with distal weakness, mild sensory involvement, and remained ambulant.
• NCS revealed intermediate motor nerve conduction velocities, reduced sensory amplitudes, and multiple conduction blocks.
• Strikingly elevated CK levels (1611-3867 U/L) were observed in all patients.
• Three novel frameshift variants (c.1835_1860del, c.2308del, and c.104del) in the PLEKHG5 gene were identified.

Conclusions:

• PLEKHG5-associated disease presents a spectrum from pure motor phenotypes to intermediate CMT with distal motor and mild sensory involvement.
• Leukoencephalopathy, elevated CK levels, and conduction blocks with intermediate velocities on NCS are significant indicators for suspecting PLEKHG5-related neuropathy.
• Recognition of these features can prevent misdiagnosis and unnecessary treatments.