A recurrent TMEM106B mutation in hypomyelinating leukodystrophy: A rapid diagnostic assay
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Published on: March 29, 2017
Satoru Ikemoto1, Shin-Ichiro Hamano2, Kenjiro Kikuchi1
1Division of Neurology, Saitama Children's Medical Center, Saitama-City, Saitama 330-8777, Japan; Department of Pediatrics, Jikei University School of Medicine, Minato-ku, Tokyo 105-8471, Japan.
Introduction:
Hypomyelinating leukodystrophies (HLDs) are genetically heterogeneous syndromes, presenting abnormalities in myelin development in the central nervous system. Recently, a recurrent de novo mutation in TMEM106B was identified to be responsible for five cases of HLD. We report the first Japanese case of TMEM106B gene mutation.
Case Study:
A 3-year-old patient presented with nystagmus and muscle hypotonia in his neonatal period, followed by delayed psychomotor development. Brain magnetic resonance images showed delayed myelination. Wave III and subsequent components were not presented by his auditory brainstem response. These features were similar to those observed in Pelizaeus-Merzbacher disease (PMD).
Methods:
Proteolipid protein 1 (PLP1) gene screening, Mendelian disease panel exome, and whole-exome sequencing (WES) were sequentially performed.
Results:
After excluding mutations in either PLP1 or other known HLD genes, WES identified a mutation c.754G > A, p.(Asp252Asn) in TMEM106B, which appeared to occur de novo, as shown by Sanger sequencing and SalI restriction enzyme digestion of PCR products.
Discussion:
This is the sixth case of HLD with a TMEM106B mutation. All six cases harbored the same variant. This specific TMEM106B mutation should be investigated when a patient shows PMD-like features without PLP1 mutation. Our PCR-SalI digestion assay may serve as a tool for rapid HLD diagnosis.
Insights
Hypomyelinating leukodystrophies (HLDs) are rare genetic disorders affecting myelin development. A recurrent de novo mutation in the TMEM106B gene was identified in the sixth HLD case, presenting with Pelizaeus-Merzbacher disease-like features.
Area of Science:
- Genetics
- Neurology
- Biochemistry
Background:
- Hypomyelinating leukodystrophies (HLDs) are a group of genetic disorders characterized by impaired myelin development in the central nervous system.
- The genetic heterogeneity of HLDs necessitates comprehensive diagnostic approaches.
- A recurrent de novo mutation in the TMEM106B gene has recently been implicated in five HLD cases.
Observation:
- A 3-year-old Japanese patient presented with neonatal nystagmus, hypotonia, and delayed psychomotor development.
- Brain MRI revealed delayed myelination, and auditory brainstem response showed absent Wave III and subsequent components, mimicking Pelizaeus-Merzbacher disease (PMD).
- Genetic analysis, including PLP1 screening, Mendelian disease panel exome, and whole-exome sequencing (WES), was performed.
Findings:
- WES identified a de novo mutation (c.754G>A, p.(Asp252Asn)) in the TMEM106B gene.
- This represents the sixth reported case of HLD associated with a TMEM106B mutation, with all cases sharing the identical variant.
- Sanger sequencing and a PCR-SalI digestion assay confirmed the de novo status of the mutation.
Implications:
- The specific TMEM106B mutation should be considered in patients exhibiting PMD-like features without PLP1 mutations.
- This finding expands the known genetic spectrum of HLDs.
- The developed PCR-SalI digestion assay offers a potential tool for rapid HLD diagnosis.
