Fact sheet on tuberous sclerosis and comorbid disorders with Aspergers and Autism, two Autism Spectrum Disorders


Tuberous sclerosis (TS) is a hereditary neurological condition that affects all ages. The name arises from the potato stem-shaped growths that occur in the brain, also known as tubers. These growths often involve overgrowth of nerves or the connective tissue within them, which is described by the term sclerosis.


Tuberous sclerosis is also known by the names tuberous sclerosis complex and Bourneville's disease. Neurological symptoms may include tubers and other non-cancerous growths in the brain, cancerous brain tumors, seizures, and intellectual disability or developmental delay.


Autism is seen in about 25 to 50% of people with Tuberous sclerosis, and this is felt to have a major influence on an individual's daily functioning. Parents of children with Tuberous sclerosis often raise concerns about autism or autistic-type characteristics, because this has a significant impact on routine activities like attending school. Though scientific studies have been done to find exact neurological causes for autism in Tuberous sclerosis, none has provided consistent results.


Nearly everyone with Tuberous sclerosis has some symptoms affecting their skin. These include light-colored patches called ash-leaf spots, acne-type growths on the face, nail beds, and the body, and shagreen patches. Other common symptoms of Tuberous sclerosis are kidney cysts, kidney growths, and heart tumors that may develop at a very young age or even before birth.


Demographics of Tuberous sclerosis

According to the National Institute of Neurological Disorders and Stroke (NINDS),Tuberous sclerosis affects about 1 in 6,000 newborns. As many as 25,000 to 45,000 people in the United States and 1-2 million people worldwide have the disorder. Its true incidence may be higher because mildly affected individuals may not come to medical attention. Tuberous sclerosis has been reported in all ethnic groups and races with equal frequency. Two genes for Tuberous sclerosis have been identified, and males and females are equally affected with the condition. About one third of people with Tuberous sclerosis have an affected parent as well.


Causes and symptoms of Tuberous sclerosis

Always known to be hereditary, mutations in two different genes are now known to cause Tuberous sclerosis. These genes are TSC1 and TSC2, and were discovered in 1993 and 1997 on chromosomes 16 and 9 respectively. Tuberous sclerosis is inherited in an autosomal dominant manner, meaning that an affected individual has a 50/50 chance to pass a disease-causing mutation to his or her children, regardless of their gender. As a result, strong family histories of Tuberous sclerosis are common.


TSC1 and TSC2 normally code for specific proteins, hamartin and tuberin, which are felt to be necessary for neurological functioning. Reduced amounts of these proteins in the brains of people with Tuberous sclerosis may contribute to the neurological complications associated with the condition.


The most common neurological symptoms in Tuberous sclerosis include seizures, learning and behavioral problems, and hydrocephalus. Seizures affect about 85% of people at some point in their lives. They can begin in very early childhood as infantile spasms, sometimes with hypsarrhythmia. The presence of these spasms at an early age often means more significant learning problems and more significant epilepsy later on.


Learning problems are not a certainty with Tuberous sclerosis; about 50% of people with the condition are known to have developmental delay or intellectual disability. People with Tuberous sclerosis have an increased chance to develop certain behavioral disorders.


A unique brain finding in Tuberous sclerosis is the cortical tuber, which is seen in about 90% of people with the condition. The number and size of tubers in a person can correlate with the degree of learning problems and seizures they may experience. Other brain findings in Tuberous sclerosis include subependymal hamartomas. Some of these may grow in childhood and block the normal flow of spinal fluid, causing hydrocephalus. Brain tumors like subependymal giant cell astrocytomas are a cause of health complications and death in Tuberous sclerosis.


Since skin changes are so common in Tuberous sclerosis, they can be some of the first signs of the condition that are noticed. Ash-leaf spots are the most common skin finding, followed by facial angiofibromas. These angiofibromas may cause slight disfigurement, but more often are a cosmetic concern. Darkened skin patches called cafe-au-lait spots may also occur, along with skin tags. Fortunately, none of the skin symptoms usually cause serious medical complications.


Kidney disease can be a serious medical concern in Tuberous sclerosis; it is the most frequent cause of death in people with Tuberous sclerosis older than 30 years. The most common renal finding is the angiomyolipoma, which is more commonly found in women at a younger age. Though these growths are non-cancerous, they can enlarge and disturb normal kidney function. Kidney cysts may occur, again more commonly in younger women. These cysts may be numerous and similarly disrupt normal kidney function as a result. Renal cell carcinoma can be a further symptom of Tuberous sclerosis, and kidney transplants may be necessary for any significant renal complication.


Cardiac rhabdomyomas are typically seen in early childhood, but occasionally may even be seen on a prenatal ultrasound. Most rhabdomyomas disappear with age, remaining stable and causing no symptoms; others may cause heart rhythm problems. Vascular disease may also be a part of Tuberous sclerosis, with some people having aneurysms of the abdomen and other areas of the body.


Lung problems are a part of Tuberous sclerosis, and affect women more often. Lymphangioleimyomas of the lung are common and affect about 1-4% of people with Tuberous sclerosis by interfering with normal lung function. Hormones may be a factor because pregnancy, menstruation, and estrogen have been associated with a worsening of these symptoms in some women. Interestingly, pulmonary problems have been associated with a milder case of Tuberous sclerosis, often with fewer learning problems and seizures.


Other symptoms of Tuberous sclerosis include growths on the retinas called hamartomas, which are not usually problematic. There have been no typical ages in which eye involvement occurs in Tuberous sclerosis.


Diagnosis of Tuberous sclerosis

Up until the discovery of TSC1 and TSC2, the diagnosis of Tuberous sclerosis was made on a clinical basis. Criteria for clinical diagnosis were updated in 1998 at the Tuberous Sclerosis Complex Consensus Conference. The major features include:

• facial angiofibromas or forehead plaque
• non-traumatic ungual or periungual fibroma
• hypomelanotic macules (more than three)
• shagreen patch
• multiple retinal nodular hamartomas
• cortical tuber
• subependymal nodule
• subependymal giant cell astrocytoma
• cardiac rhabdomyoma, single or multiple
• lymphangioleimyomatosis
• renal angiomyolipoma.


The minor features include:

• multiple randomly distributed pits in dental enamel
• bone cysts
• cerebral white matter radial migration lines
• gingival fibromas
• non-renal hamartoma
• retinal achromic patch
• "confetti" skin lesions
• multiple renal cysts.


Most brain findings in Tuberous sclerosis can be identified with magnetic resonance imaging (MRI) or computed tomography (CT) scans. Seizures can be documented from electroencephalogram (EEG) monitoring. Skin changes are often found by using a Woods lamp, which makes them more obvious during a physical examination. Routine ultrasounds of the kidney often find and help monitor cysts and angiomylipomas. Cardiac involvement may be seen as early as a prenatal ultrasound, or with an echocardiogram in early life. Electrocardiograms may be necessary to help detect heart rhythm problems. For women in particular, a CT scan of the chest is important to detect lung lymphangiomyomatosis. For all, an ophthalmology examination is important to detect retinal involvement.


Genetic testing is available for Tuberous sclerosis via gene sequencing. It is useful for confirming a clinical diagnosis, prenatal diagnosis, or family testing when there is an identified TSC mutation in the family. Sequencing of the TSC1 and TSC2 genes is not perfect; it detects about 80% of people with Tuberous sclerosis. An informative test result is one that identifies a known mutation in either gene, and this confirms that the person has Tuberous sclerosis. A negative test result does not identify a mutation in either gene. This either means that the tested individual does not have Tuberous sclerosis, or has a mutation that cannot be found through testing and truly has the diagnosis.


Treatment for Tuberous sclerosis

Treatment for people with Tuberous sclerosis is usually very specific to the person, since symptoms vary greatly. The typical treatment team for someone with Tuberous sclerosis may include a neurologist, neurosurgeon, medical geneticist, genetic counselor, dermatologist, cardiologist, pulmonologist, nephrologist, ophthalmologist, social worker, and a primary care provider. Often times there are pediatric specialists in these fields who aid in the care for children. Care providers in pediatric development are particularly important, such as speech-language therapists and pediatric neuropsychologists.


There is no cure for Tuberous sclerosis. Therefore, treatment is based upon symptoms. Seizures may be treated with various anti-epilepsy medications. Those with significant seizures may be tried on a ketogenic diet, which consists of frequent meals of high-fat foods. While challenging, the ketogenic diet yields good results in some cases.


Learning or behavioral problems are often serious issues, but awareness and developmental interventions often help families with Tuberous sclerosis. Pediatricians who have an interest in child development are a good resource, particularly if a child with Tuberous sclerosis is showing signs of autism.


Hydrocephalus can be serious and even lead to learning problems if left untreated, so surgery to drain accumulated fluid in the brain may be necessary. While most growths in the brain are non-cancerous, brain tumors are typically treated as they would be in someone without Tuberous sclerosis.


Since most skin complications of Tuberous sclerosis cause no medical problems, treatment is not often necessary. Some angiofibromas, particularly on the face, may be problematic and require removal. Laser treatments may also be effective to reduce the appearance of some skin changes.


Many kidney growths cause no health problem in Tuberous sclerosis, but some individuals may have kidney cysts similar to those found in polycystic kidney disease (Type 1). In these cases, kidney function may be disturbed and the person might need a kidney transplant after some time. Those with renal cell carcinoma would be treated as anyone with this complication.


Most rhabdomyomas cause no problems, but some may need surgery to keep their hearts working well. Surgery may also be required for someone with a severe heart rhythm problem.


People with lung function problems may need to be treated with medications, hormone therapy, or surgery if necessary.


Visual complaints are not as common for people with Tuberous sclerosis, since retinal growths do not usually cause symptoms. In rarer cases, vision may be disturbed and treated like someone without Tuberous sclerosis.


Prognosis for Tuberous sclerosis

Prognosis for someone with tuberous sclerosis is highly dependent upon symptoms they experience. Those who die may do so as a result of significant neurological, pulmonary or cardiac complications. People with Tuberous sclerosis often have routine medical appointments dealing with symptoms as they arise.


Many people with Tuberous sclerosis survive into adulthood, and studies are attempting to learn more about long-term prognosis as people with Tuberous sclerosis age. It is challenging to gain this information because older people with milder forms of Tuberous sclerosis may not present for medical care frequently, or may not even know they have the condition.

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This autism fact sheet is licensed under the GNU Free Documentation. It is derivative of an article on Tuberous sclerosis at Wikipedia.

Tuberous sclerosis (TS) is a hereditary neurological condition that, although rare, is linked with Autism and the autism spectrum