TUBEROUS SCLEROSIS

OVERVIEW

Tuberous sclerosis, a genetic disorder, is a common cause of malformations of cortical development, with a birth incidence of 1:6000 births. It is a disorder caused by a defect in the mTOR pathway, an intracellular pathway that regulates cell growth and differentiation, resulting in abnormalities in a number of organs, including the brain, skin, heart, kidneys and eyes.

Clinical context

Prior to the identification of the gene abnormalities associated with tuberous sclerosis, diagnosis relied on the presence of certain clinical features (Table). Many of these features appear with age and may not be present at the time of seizure onset (typically under 1 year of age). In infants, the only clinical features that may be present, in addition to structural brain abnormalities, are hypopigmented skin macules (which may need a Woods light examination to identify) and cardiac rhabdomyomas.

The frequency of epilepsy in tuberous sclerosis is high, with onset of seizures typically under 1 year of age (commonly epileptic spasms and focal seizures), but a smaller group having later (>4 years) onset of seizures, with focal seizures seen in this group. Developmental and cognitive impairments can occur, although 50% of individuals are of normal intellect.

CAUTION developmental and cognitive outcome may be worse in children with uncontrolled seizures in early life, especially if epileptic spasms or generalized seizure types appear, therefore proactive seizure control is important, this may include epilepsy surgery if seizures are not controlled with medication.

Table: Criteria for clinical diagnosis of tuberous sclerosis (2012).

Diagnosis is established as follows:

• a clinical diagnosis of definite tuberous sclerosis: 2 major features or 1 major and 2 or more minor features (lymphangioleiomyomatosis and angiomyolipomas cannot be used together as two major features)
• a clinical diagnosis of possible tuberous sclerosis: either 1 major or 2 or more minor features
• the identification of either a TSC1 or TSC2 pathogenic pathogenic variant in DNA from normal tissue is sufficient to make a definite diagnosis of tuberous sclerosis. Note that 10% to 25% of tuberous sclerosis patients have no pathogenic variant identified by conventional genetic testing, and a normal result does not exclude tuberous sclerosis