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Updated: May 27, 2025
State of the Art Cranial Ultrasound Imaging in Neonates
Published on: February 2, 2015
Delineating the Clinical and Brain Imaging Characteristics of the Neonatal Form of CSTB -Related Neurodevelopmental
Mohamed S Abdel-Hamid1, Sherif F Abdel-Ghafar1, Inas S M Sayed2
1Medical Molecular Genetics Department, Human Genetics and Genome Research Institute, National Research Centre, Cairo, Egypt.
Insights
Genetic variants in the Cystatin B gene (CSTB) are linked to a severe neonatal neurodevelopmental disorder characterized by microcephaly and hypomyelination, distinct from the childhood epilepsy form.
Area of Science:
- Genetics
- Neuroscience
- Developmental Biology
Background:
- The Cystatin B gene (CSTB) is primarily associated with progressive myoclonic epilepsy (EPM1A), a common childhood-onset epilepsy.
- Recent studies identified biallelic CSTB variants in neonates presenting with microcephaly, hypomyelination, and dyskinesia, suggesting a distinct neonatal phenotype.
Purpose of the Study:
- To clinically and molecularly characterize five additional patients with neonatal onset neurodevelopmental disorders.
- To investigate the association between specific CSTB variants and this neonatal phenotype.
- To differentiate this neonatal presentation from the classic EPM1A.
Main Methods:
- Exome sequencing was performed to identify genetic variants.
- Clinical data, including neurological examination and brain imaging, were collected and analyzed.
- Molecular characterization of identified CSTB variants (c.67-1G>C and c.10G>C) was conducted.
Main Results:
- Five patients presented with progressive microcephaly, developmental delay, and dyskinesia.
- Brain imaging revealed diffuse hypomyelination and progressive cerebral/cerebellar atrophy in most patients.
- Specific CSTB variants, previously linked to EPM1A, were identified in these patients, with only one developing seizures.
Conclusions:
- CSTB variants are associated with a distinct neonatal neurodevelopmental phenotype characterized by microcephaly, hypomyelination, and dyskinesia.
- This neonatal form of CSTB-related disorder shares features with other genetic conditions involving microcephaly and hypomyelination.
- Further research is warranted to fully understand the genotype-phenotype correlation and the underlying mechanisms.
Abstract:
Cystatin B gene (CSTB) is responsible for the most common childhood onset type of progressive myoclonic epilepsy (EPM1A). More recently, biallelic CSTB variants were described in four patients with a neonatal onset phenotype of microcephaly, diffuse hypomyelination, brain atrophic changes, and dyskinesia. Herein, we describe the clinical and molecular characterization of five additional patients in whom exome sequencing detected a splice variant (c.67-1G>C) in Family I and II and a missense variant (c.10G>C, p.Gly4Arg) in Family III and IV. Interestingly, these variants were described before in patients with EPM1A. However, all our patients had progressive microcephaly, developmental delay, and dyskinesia. In addition, only one patient developed seizures. Brain imaging showed mainly diffuse hypomyelination and progressive cerebral and cerebellar atrophy of variable severity. Interestingly, one patient showed intracranial calcification and another showed congenital distal arthrogryposis. Our findings support the association between CSTB variants and the neonatal form as a distinct neurodevelopmental phenotype. This newly characterized neonatal onset of the CSTB shares many overlapping features with genetic disorders encompassing microcephaly and hypomyelination.
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