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A novel PLP1 frameshift mutation causing a milder form of Pelizaeus-Merzbacher disease
Takashi Shiihara1, Mio Watanabe1, Kengo Moriyama1
1Department of Neurology, Gunma Children's Medical Center, Gunma 377-8577, Japan.
Background:
Pelizaeus-Merzbacher disease (PMD), a hypomyelinating leukodystrophy, and the related but less severe allelic spastic paraplegia 2 (SPG2) are caused by mutations in the proteolipid protein 1 (PLP1) gene. Magnetic resonance imaging (MRI) is pivotal for diagnosing these disorders. The severity of PMD/SPG2 varies, and for a milder form of PMD, there have been some reports of near-normal findings in T1-weighted images but abnormal findings in T2-weighted images.
Patient:
We report the case of a 5-year-old boy diagnosed with a milder form of PMD caused by a novel PLP1 mutation in exon 3: c.300delC (p.I100IfsX13). He had delayed development from several months of age and was able to walk with support at 19 months in spite of the spasticity in his lower extremities. Hypomyelination was noted at 12 months by brain MRI. Motor nerve conduction studies showed decreased velocities with reduced amplitudes. Follow-up MRI at 1-year intervals from 18 months until 55 months of age showed gradual myelination progress.
Discussion:
The single nucleotide deletion identified in this patient can cause a frameshift and premature termination of PLP1. Via the nonsense-mediated mRNA decay mechanism of this mutation will result in loss-of-function, leading to a milder form of PMD. The present case is compatible with previously reported cases of milder form of PMD. We incidentally identified progressive myelination in this patient by T1-weighted images obtained by serial MRI. This finding adds to our understanding of the pathological stages of a milder form of PMD.
Insights
A novel mutation in the PLP1 gene causes a milder form of Pelizaeus-Merzbacher disease (PMD). Serial MRI revealed progressive myelination, offering new insights into PMD pathology.
Area of Science:
- Neuroscience
- Genetics
- Radiology
Background:
- Pelizaeus-Merzbacher disease (PMD) and spastic paraplegia 2 (SPG2) are hypomyelinating leukodystrophies linked to mutations in the proteolipid protein 1 (PLP1) gene.
- Diagnosis relies heavily on Magnetic Resonance Imaging (MRI), with milder PMD forms sometimes showing subtle T1-weighted and abnormal T2-weighted findings.
Observation:
- A 5-year-old boy presented with delayed development and spasticity, diagnosed with a milder PMD.
- A novel PLP1 mutation (c.300delC) in exon 3 was identified.
- Brain MRI at 12 months showed hypomyelination; motor nerve conduction studies revealed reduced velocities and amplitudes.
Findings:
- The identified PLP1 mutation leads to a frameshift, premature termination, and loss-of-function via nonsense-mediated mRNA decay, consistent with milder PMD.
- Serial MRI follow-up from 18 to 55 months demonstrated gradual myelination progress, particularly noted on T1-weighted images.
Implications:
- This case expands the understanding of PLP1 mutations and their phenotypic spectrum in PMD.
- The incidental finding of progressive myelination on serial T1-weighted MRI provides valuable insights into the pathological progression of milder PMD forms.
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