Reconstruction of a pedigree of these 24 patients with common clinical phenotypes of MS found that “the shortest connection to a common ancestor between two individuals with MS was significantly more often through their nonaffected mother than through their nonaffected father, suggesting a maternal parent-of-origin effect” that was specific for MS, noted Dr. Hoppenbrouwers and colleagues. “Mothers of the 24 MS patients were also more closely related to each other than their fathers.”
Maternal transmission of MS can be a result of genetic factors, environmental factors, or both. These data suggest that “the most likely explanation is a gene-environment effect that takes place in utero,” the researchers concluded. “Dense genotyping in this pedigree can help to unravel the genetic combination, thus aiding in resolving the nature-nurture dilemma in MS.”
Malformations of Cortical Development
In another study from the Erasmus Medical Center–Sophia Children’s Hospital, Rotterdam, Marie Claire Yvette de Wit, MD, of the Department of Pediatric Neurology, and colleagues evaluated the etiology of malformations of cortical development in children to determine whether a combined radiologic, clinical, and syndrome classification could provide a molecularly confirmed diagnosis.
A case series of 113 children who had a radiologic diagnosis of malformations of cortical development from 1992 to 2006 was included in the study. Each child had a complete radiologic, clinical, and neurologic assessment and was tested for phenotypically appropriate genes known to be involved in the pathogenesis of malformations of cortical development.
An etiologic diagnosis was established in 45 of the 113 children (40%). Diagnoses included molecular and/or genetic confirmation in 21 patients (19%) of Miller-Dieker syndrome; LIS1, DCX, FLNA, EIF2AK3, or KIAA1279 mutations; or an inborn error of metabolism. A syndrome with an unknown genetic defect was diagnosed in 17 children (15%), and evidence of gestational insult was found in seven (6%). “Of the remaining 68 patients, 34 probably have a yet-unknown genetic disorder based on the presence of multiple congenital anomalies (15 patients), a family history of multiple affected persons (12 patients), or consanguineous parents (seven patients),” the investigators wrote.
Most patients were diagnosed as having malformations of cortical development when they developed seizures; 26 of 63 patients (41%) were previously misdiagnosed, demonstrating that “a quality MRI of the brain and a skilled neuroradiologist are essential for a correct classification and the choice of diagnostic tests.”
Dr. de Wit’s group concluded that “classification based on radiological, clinical genetic, and neurological examinations combined with genetic testing can yield important information about monogenetic, syndromal, and metabolic causes and can lead to improvement of patient care and genetic counseling. This requires a multidisciplinary team specialized in neuroradiology, pediatric neurology, and genetics. Even then, the underlying cause remains elusive in more than 50% of patients, and the suspicion of an underlying genetic cause remains in many of our unclassified cases. This encourages exploitation of new genome-wide techniques.”
Additional articles in the theme issues also focused on stem cells, the human HapMap, primary and amyotrophic lateral sclerosis, Huntington’s disease, frontotemporal disease, Parkinson’s disease, cryptogenic epileptic syndromes, fragile X, spinocerebellar ataxia, Machado-Joseph disease, Troyer syndrome, MELAS, Leigh syndrome, and hereditary spastic paraplegia.
—Debra Hughes