What is tuberous sclerosis?

Risk Factors

The mutation occurs spontaneously in people with no family history for unknown reasons (in two-thirds of cases) or may be inherited as an autosomal dominant trait (familial; one-third of cases). The estimated prevalence of TS is 1 in 6,000 newborns, according to the National Institutes of Health. It affects males and females equally, and there is 50 percent chance that the defective gene will be passed on to their offspring. There are no identified risk factors.

Etiology and Genetics

Mutations that render the TSC1 and TSC2 genes inactive may be missense, nonsense, deletions, or insertions. Studies have demonstrated that mutations in TSC2 are about five times more common than mutations in TSC1 in the sporadic TS population. There is no clearly identified “hotspot” (preferred site) for mutations; more than four hundred different mutations are known in the TSC1 gene and approximately 1,100 different mutations in the TSC2 gene, according to the National Institutes of Health. Any particular mutation accounts for around 1 percent of the disease in the affected population. The TSC genes are located on two different chromosomes with TSC1 on chromosome 9 (9q34) and TSC2 on chromosome 16 (16p13.3).

The harmartin and tuberin proteins have been shown to form heterodimers that play a role in cell division and the production of tumor-suppressor proteins. One particular downstream protein cascade is affected by the pathogenesis of the disease; the pathway of the mammalian target of rapamycin (mTOR). mTOR detects signals of nutrient availability, hypoxia, or growth factor stimulation and is part of many cell processes, such as cell-cycle progression, transcription and translation control, and nutrient uptake. Tuberin and hamartin form an intracellular complex that reduces mTOR stimulation.

In families with more than one child with TS complex, no extended family history, and no clinical features of the TS complex, germline mosaicism is the likely explanation. Germ-line mosaicism
is when the individual’s eggs or sperm may carry the mutation, even though it is absent from the somatic cells. The carrier of germ-line mosaicism may be asymptomatic or may present with various symptoms of the disease.

Symptoms

The symptoms of tuberous sclerosis vary from person to person. The most common presentation is seizures in infancy or early childhood, particularly infantile spasms. Delayed development and skin lesions usually appear shortly after birth but may remain very discrete in children. Other manifestations include kidney and lung disease, skin abnormalities, and vision problems. Some affected individuals have normal intelligence and no seizures. Others have severe retardation, serious tumors, or difficult-to-control seizures.

Screening and Diagnosis

Diagnosis of TS is usually based on clinical and radiological findings; however, no single feature of TS is diagnostic. Therefore, an evaluation including all clinical features is necessary. The clinical manifestations of TS appear at distinct developmental points. For example, cortical tubers and cardiac rhabdomyomas form during embryogenesis and are typical in infancy. Skin lesions are detected at all ages in more than 90 percent of patients. Hypopigmented macules (formerly known as ash-leaf spots) are generally detected in infancy or early childhood, whereas the so-called shagreen patch is identified with increasing frequency after the age of five. Ungual fibromas typically appear after puberty and may develop in adulthood.

DNA testing for either of the two genes that cause this disease (TSC1 or TSC2) is available. Molecular diagnosis using DNA-based testing is not yet routinely available, however, but it could be developed in the future. It would help to identify patients at increased or decreased risk for particular complications.

Treatment and Therapy

There is no specific treatment for TS. Because the disease can differ from person to person, treatment is based on the symptoms. Finding the right medications to control seizures is often difficult. Depending on the severity of the mental retardation, the child may need special education.

Small growths on the face may be removed by laser treatment, but tend to come back, making repeat treatments necessary. Rhabdomyomas commonly disappear after puberty, so surgery is usually not necessary.

A multidisciplinary team approach is useful to address the many organ systems that may be affected.

Prevention and Outcomes

Molecular genetic testing of the TSC1 and TSC2 genes is complicated by the large size of the two genes and the large number of disease-causing mutations. Genetic counseling for families with one affected child should include a small (1 to 2 percent) possibility of recurrence, even for parents without evidence of TS after a thorough diagnostic evaluation.

Prognosis for people with TS can range depending on the severity of symptoms. Individuals with mild forms do not have a shortened life expectancy, while individuals with more severe forms may have serious disabilities. Currently, there is no cure for TS. However, with appropriate medical care (such as lung transplant or surgical removal of tumors) most individuals with the disorder can look forward to a normal life expectancy.

Bibliography

Crino, P. B., K. L. Nathanson, and E. P. Henske. “The Tuberous Sclerosis Complex.” New England Journal of Medicine 355 (2006): 1345–356. Print.

Curatolo, P., R. Bombardieri, and S. Jozwiak. “Tuberous Sclerosis.” Lancet 372 (2008): 657–68. Print.

Kothare, Sanjeev V., et al. "Severity of Manifestations in Tuberous Sclerosis Complex in Relation to Genotype." Epilepsia 55.7 (2014): 1025–029. Print.

Murray, Michael F., et al. Clinical Genomics: Practical Applications in Adult Patient Care. New York: McGraw-Hill Education/Medical, 2014. Print.

Puri, Neerja. "A Study on Clinical Manifestations of Tuberous Sclerosis." Journ. of Pakistan Assoc. of Dermatologists 23.4 (2013): 365–70. Print.