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Survival of a male patient harboring CASK Arg27Ter mutation to adolescence
Konark Mukherjee1, Paras A Patel1, Deepa S Rajan2
1Fralin Biomedical Research Institute at Virginia Tech Carilion, Roanoke, VA, USA.
Background:
CASK is an X-linked gene in mammals and its deletion in males is incompatible with life. CASK heterozygous mutations in female patients associate with intellectual disability, microcephaly, pontocerebellar hypoplasia, and optic nerve hypoplasia, whereas CASK hemizygous mutations in males manifest as early infantile epileptic encephalopathy with a grim prognosis. Here, we report a rare case of survival of a male patient harboring a CASK null mutation to adolescent age.
Methods:
Trio whole exome sequencing analysis was performed from blood genomic DNA. Magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS), and electroencephalogram (EEG) analyses were performed to determine anomalies in brain development, metabolite concentrations, and electrical activity, respectively.
Results:
Trio-WES analysis identified a de novo c.79C>T (p.Arginine27Ter) mutation in CASK causing a premature translation termination at the very N-terminus of the protein. The 17-years, and 11-month-old male patient displayed profound intellectual disability, microcephaly, dysmorphism, ponto-cerebellar hypoplasia, and intractable epilepsy. His systemic symptoms included overall reduced somatic growth, dysautonomia, ventilator and G tube dependence, and severe osteopenia. Brain MRI revealed a severe cerebellar and brain stem hypoplasia with progressive cerebral atrophy. EEG spectral analysis revealed a global functional defect with generalized background slowing and delta waves dominating even in the awake state.
Conclusion:
This case study is the first to report survival of a male patient carrying a CASK loss-of-function mutation to adolescence and highlights that improved palliative care could extend survival. Moreover, the genomic position encoding Arg27 in CASK may possess an increased susceptibility to mutations.
Insights
This study reports a rare case of a male surviving into adolescence with a CASK null mutation, highlighting potential for extended survival with advanced palliative care and identifying a mutation hotspot.
Area of Science:
- Genetics
- Neurology
- Developmental Biology
Background:
- CASK is an X-linked gene crucial for male survival; mutations cause severe neurodevelopmental disorders.
- Male CASK mutations typically lead to early infantile epileptic encephalopathy with a poor prognosis.
- Female CASK mutations are associated with intellectual disability, microcephaly, and pontocerebellar hypoplasia.
Observation:
- A rare male patient with a CASK null mutation survived to adolescence.
- The patient exhibited profound intellectual disability, microcephaly, dysmorphism, pontocerebellar hypoplasia, and intractable epilepsy.
- Systemic symptoms included growth reduction, dysautonomia, ventilator/G-tube dependence, and severe osteopenia.
Findings:
- Trio whole exome sequencing identified a de novo CASK mutation (c.79C>T) causing premature termination.
- Brain MRI revealed severe cerebellar and brainstem hypoplasia with progressive cerebral atrophy.
- EEG analysis showed global functional defects with generalized background slowing.
Implications:
- This case is the first documenting survival of a male with a CASK loss-of-function mutation into adolescence.
- Improved palliative care may extend survival in male CASK mutation patients.
- The Arg27 position in CASK may be a mutational hotspot.
