Abstracts

Rationale: Malignant Migrating Partial Seizures in Infancy (MMPSI) is a rare condition characterized by medically intractable epilepsy beginning in the first seven months of life. To date, there have been no reported familial cases. We report a consanguineous family presenting with MMPSI and evidence for genetic linkage to chromosome 4p16.1-p16.3. Methods: The family was ascertained in Saudi Arabia. DNA was extracted from blood samples obtained from 2 affected siblings, their parents, and 2 unaffected siblings. DNA was digested, amplified, and hybridized to two Affymetrix 250K single nucleotide polymorphism (SNP) arrays. Assuming an autosomal recessive mode of inheritance and a susceptibility allele frequency of 0.1 percent, we analyzed SNP data from the 6 family members to evaluate for evidence of genetic linkage using Allegro software. Results: Two affected children were reported in this autosomal recessive pedigree in which the parents were first cousins. The affected girl presented at 3 months of age with frequent seizures that had begun at 2 weeks of age. The seizures consisted of bilateral and hemi-clonic seizures, involving the right side more than the left. Phenobarbital initially resulted in partial reduction of seizures, but seizure frequency increased at 2 months of age. Physical examination was notable for mild hypotonia with brisk deep tendon reflexes. Karyotype and extensive neuro-metabolic testing were normal. MRI at 3 and 25 months showed a thin corpus callosum and delayed myelination. EEG revealed seizures arising from multiple locations in both hemispheres. Treatment with pyridoxine 100 mg IV produced no response clinically or on EEG. Carbamazepine and topiramate yielded incomplete seizure control. Development remained markedly delayed, and she died at 47 months following cardiorespratory arrest. The affected boy presented at 3 weeks of age with seizures that had begun at 1 week of age. Seizures began as hemi-convulsions on the right side; within 3 days, left-sided seizures occurred. Physical examination was notable for hypotonia with brisk deep tendon reflexes. Extensive neuro-metabolic testing and MRI at 6 weeks were normal. EEG at 1 month revealed interictal spikes in the left temporal, right temporal, and bifrontal regions. Carbamazepine was only partially effective in controlling seizures. He died at 14 months after a short febrile illness. In our genome-wide SNP analysis, we found only one region of apparent identity by descent at chromosome 4p16.1-16.3, in which SNPs were homozygous in the affected individuals but heterozygous in the unaffected individuals. Linkage analysis of this 9.6 Mb region of homozygosity resulted in a LOD score of 2, which is the maximum expected LOD score for this pedigree. Conclusions: Our data provide evidence for the first genetic locus associated with MMPSI. Future study, potentially using emerging high-throughput gene sequencing methods, should uncover the gene responsible for MMPSI and the mechanism underlying this severe form of childhood epilepsy.