Infantile cerebral and cerebellar atrophy is associated with a mutation in the MED17 subunit of the transcription preinitiation mediator complex.

Primary microcephaly of postnatal onset is a feature of many neurological disorders, mostly associated with mental retardation, seizures, and spasticity, and it typically carries a grave prognosis. Five infants from four unrelated families of Caucasus Jewish origin presented soon after birth with spasticity, epilepsy, and profound psychomotor retardation. Head circumference percentiles declined, and brain MRI disclosed marked cereberal and cerebellar atrophy with severe myelination defect. A search for a common homozygous region revealed a 2.28 Mb genomic segment on chromosome 11 that encompassed 16 protein-coding genes. A missense mutation in one of them, MED17, segregated with the disease state in the families and was carried by four of 79 anonymous Caucasus Jews. A corresponding mutation in the homologous S.cerevisiae gene SRB4 inactivated the protein, according to complementation assays. Screening of MED17 in additional patients with similar clinical and radiologic findings revealed four more patients, all homozygous for the p.L371P mutation and all originating from Caucasus Jewish families. We conclude that the p. L371P mutation in MED17 is a founder mutation in the Caucasus Jewish community and that homozygosity for this mutation is associated with infantile cerebral and cerebellar atrophy with poor myelination.

Unusual clinical presentation of tuberless tuberous sclerosis complex.

Cortical tubers are the hallmark of tuberous sclerosis. Their presence is expected on brain imaging, especially when seizures begin before 1 year of age with concomitant significant developmental delay. Increased tuber counts have been reported to be associated with seizures and poor cognitive outcome. We present a 3-year-old girl with intractable seizures that started as infantile spasms at 2 months of age and who was diagnosed with clinically definitive tuberous sclerosis. Poor prognostic signs included multiple seizure types, seizure onset before 1 year of age, and multifocal electroencephalographic abnormalities. However, on repeated brain magnetic resonance imaging scans, the known radiological findings associated with tuberous sclerosis complex were absent, raising a diagnostic dilemma. Therefore, genetic analysis was performed. A mutation was detected in the TSC2 gene, confirming the diagnosis. To the best of our knowledge, this is the first reported case of tuberless tuberous sclerosis complex associated with intractable epilepsy and developmental delay.

Attention-deficit disorders and epilepsy in childhood: incidence, causative relations and treatment possibilities.

At least 20% of children with epilepsy have clinical attention-deficit hyperactivity disorder (ADHD) compared to 3% to 7% of the general pediatric population. Several mechanisms may account for the high prevalence, such as a common genetic propensity, noradrenergic system dysregulation, subclinical epileptiform discharges, or even seizures, antiepileptic drug effects, and psychosocial factors. At the same time, children with attention-deficit hyperactivity disorder have a higher than normal rate of electroencephalography abnormalities (5.6-30.1% vs. 3.5%). Methylphenidate treatment is equally efficient in children with isolated attention-deficit hyperactivity disorder and in children with attention-deficit hyperactivity disorder and epilepsy (70%-77%). Electroencephalography screening in patients with attention-deficit hyperactivity disorder in the absence of other clinical indications or before starting methylphenidate treatment is not currently indicated. Methylphenidate is considered safe for use in children who are seizure-free. However, the few reports of seizure aggravation in methylphenidate-treated children with uncontrolled epilepsy have raised concern.