Epilepsy and Neurodevelopmental Comorbidities in Tuberous Sclerosis Complex: A Natural History Study.

BACKGROUND: We studied the natural history, genotype influence, and inter-relationship of epilepsy and neuropsychiatric disorders in tuberous sclerosis complex. METHODS: Patients were identified using the TSC Natural History Database, the largest repository of longitudinally studied patients enrolled by the TSC Clinics Consortium. RESULTS: A cohort of 1657 TSC Natural History Database patients was analyzed. Eighty-eight percent patients (91% TSC2 vs 82% TSC1; P = 0.002) had epilepsy; TSC2 was more frequent with epilepsy onset at age less than two years (TSC2 82% vs TSC1 54%; P < 0.001) and infantile spasms (TSC2 56% vs TSC1 27%; P < 0.001). Frequency of intellectual disability (intelligence quotient less than 70) was higher when epilepsy coexisted (P < 0.001), but was not impacted by genotype (P = 0.08). Severe intellectual disability (intelligence quotient less than 50) was associated with epilepsy onset at age less than two years (P = 0.007), but not with the epilepsy duration (P = 0.45). Autism was diagnosed in 23% and was associated with epilepsy (P < 0.001), particularly with epilepsy onset at age less than two years (P = 0.02) but not with genotype (P = 0.06). Attention-deficit/hyperactivity disorder (age greater than four years) was diagnosed in 18% and was associated with epilepsy (P < 0.001), but genotype made no difference. Nine percent had anxiety (age greater than seven years) and 6% had depression (age greater than nine years), but neither showed association with epilepsy or genotype. CONCLUSIONS: Epilepsy is associated with intellectual disability, and when epilepsy begins before age two years the frequency and severity of intellectual disability is much higher. Epilepsy is also associated with autism and attention-deficit/hyperactivity disorder but not with anxiety and depression. Additional trials, blinded, prospective, and adequately powered, will help clarify if early and effective treatment of epilepsy may also mitigate intellectual disability, autism, and attention-deficit/hyperactivity disorder.

Hydrops fetalis and pulmonary lymphangiectasia due to FOXC2 mutation: an autosomal dominant hereditary lymphedema syndrome with variable expression.

UNLABELLED: Non-immune hydrops fetalis may find its origin within genetically determined lymphedema syndromes, caused by mutations in FOXC2 and SOX-18. We describe a newborn girl, diagnosed with non-immune hydrops fetalis at a gestational age of 30 weeks. Family history revealed the presence of an autosomal dominant late-onset form of lymphedema of the lower limbs in her father, associated with an aberrant implantation of the eyelashes in some individuals. The newborn, hydropic girl suffered from severe pulmonary lymphangiectasia, resulting in terminal respiratory failure at the age of 3 months. Genetic analysis in both the father and the newborn girl demonstrated a heterozygous FOXC2 mutation, i.e., c.939C>A, p.Tyr313X. Her two older sisters are currently asymptomatic and the parents decided not to test them for the FOXC2 mutation. CONCLUSION: Patients with a mutation in the FOXC2 transcription factor usually show lower limb lymphedema with onset at or after puberty, together with distichiasis. However, the eye manifestations can be very mild and easily overlooked. The association between FOXC2 mutation and neonatal hydrops resulting in terminal respiratory failure is not reported so far. Therefore, in sporadic patients diagnosed with non-immune hydrops fetalis, lymphangiogenic genes should be systematically screened for mutations. In addition, all cases of fetal edema must prompt a thorough analysis of the familial pedigree, in order to detect familial patterns and to facilitate adequate antenatal counseling.