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Microcephaly with simplified gyral pattern in six related children
A Peiffer1, N Singh, M Leppert
1Department of Human Genetics, University of Utah, Salt Lake City, 84112-5330, USA.
Insights
This study details a rare genetic disorder in six related children with congenital microcephaly and severe intellectual disability. The findings suggest a novel neuronal proliferation disorder not linked to known genetic loci.
Area of Science:
- Genetics
- Neuroscience
- Pediatrics
Background:
- Congenital microcephaly, seizures, and severe mental retardation (MR) can result from various genetic and environmental factors.
- Known cortical malformation syndromes like lissencephaly types I and II present distinct clinical and neuroradiological features.
Purpose of the Study:
- To characterize the clinical, neurophysiological, and genetic findings in a family with a unique presentation of microcephaly and severe MR.
- To investigate potential genetic linkages to known microcephaly and lissencephaly loci.
Main Methods:
- Clinical examination and neurophysiological assessments were performed on affected children.
- Neuroradiological studies including MRI were conducted.
- Karyotypic analysis and genetic linkage studies were performed for LIS1, LIS2, and MCPH1 loci.
Main Results:
- Six related children (five girls, one boy) presented with congenital microcephaly, early-onset seizures, and severe MR.
- Physical and neuroradiological findings excluded known lissencephaly types and showed simplified gyral patterns without pachygyria.
- Genetic analyses ruled out linkage to LIS1, LIS2, and MCPH1, indicating a novel genetic cause.
Conclusions:
- The affected children likely have an unmapped neuronal proliferation disorder.
- This family's unique genetic and clinical profile expands the understanding of microcephaly and intellectual disability disorders.
Abstract:
We describe clinical and neurophysiological findings in six related children with congenital microcephaly, seizures that began within the first 2-4 months of life, and severe mental retardation (MR). These affected children (five girls and one boy), born to two women who are half-sisters, inherited the disease as an autosomal recessive trait. Physical examination of these children did not show any of the anomalies in the known cortical malformation syndromes such as lissencephaly types I and II. Neuroradiological studies in these children documented microcephaly and a simplified gyral pattern with no pachygyria. Chromosomal analysis showed neither karyotypic abnormalities nor a microdeletion at 17p13.3, site of the lissencephaly type I gene locus (LIS1). Genetic studies failed to show linkage of this family to LIS1, LIS2 (a region on chromosome 2p homologous to LIS1), or MCPH1 (a locus for primary autosomal recessive microcephaly). The unique clinical and genetic findings in this family suggest that these children may be affected by an as-of-yet unmapped neuronal proliferation disorder.