Description, Causes and Risk Factors:
A progressive myoclonic epilepsy; one of the degenerative gray matter disorders characterized by myoclonus and generalized seizures, with progressive neurologic and intellectual decline; age of onset between 8-13 years of age; autosomal recessive inheritance, caused by mutation in the cystatin B gene (CSTB) on 21q22.
Mutations in the CSTB gene cause Unverricht-Lundborg disease. The CSTB gene provides instructions for making a protein called cystatin B. This protein reduces the activity of enzymes called cathepsins. Cathepsins help break down certain proteins in the lysosomes (compartments in the cell that digest and recycle materials). While the specific function of cystatin B is unclear, it may help protect the cells' proteins from cathepsins that leak out of the lysosomes.
In almost all affected individuals, Unverricht-Lundborg disease is caused by an increase in size of the CSTB gene. One region of the CSTB gene has a particular repeating sequence of 12 DNA building blocks (nucleotides). This sequence is normally repeated two or three times within the gene and is called a dodecamer repeat. Most people with this disorder have more than 30 repeats of the dodecamer sequence in both copies of the CSTB gene. A small number of people with Unverricht-Lundborg disease carry other mutations.
The increased number of dodecamer repeats in the CSTB gene seems to interfere with the production of the cystatin B protein. Levels of cystatin B in affected individuals are only 5 to 10 percent of normal, and cathepsin levels are significantly increased. These changes are believed to cause the signs and symptoms of Unverricht-Lundborg disease, but it is unclear how a reduction in the amount of cystatin B leads to the features of this disorder.
Studies have shown that it affects approximately 4 persons in 100,000. In addition, there does not seem to be a difference in the number of girls versus boys that inherit Unverricht-Lundborg disease.
The progression of the disease is slow and patients usually maintain normal cognitive functioning for a long time with slow intellectual decline spanning 10 - 20 years. Usually, some years after onset, ataxia, in-coordination, intentional tremor, and dysarthria develop. The disease is inevitably progressive. Although mentally alert for many years, patients show emotional lability and depression. Long term studies suggest that many patients are incapacitated by ataxia and myoclonus at the end of the disease. Today, patients may live into their sixties or seventies with proper medication and therapies.
Affected individuals also usually have seizures involving loss of consciousness, muscle rigidity, and convulsions (tonic-clonic or grand mal seizures). Like the myoclonic episodes, these may increase in frequency over several years but may be controlled with treatment. After several years of progression, the frequency of seizures may stabilize or decrease.
Eventually people with Unverricht-Lundborg disease may develop problems with balance and coordination (ataxia), involuntary rhythmic shaking that worsens during movement (intentional tremor), difficulty speaking (dysarthria), depression, and a slow, mild decline in intellectual functioning.
The diagnosis of ULD is made on the basis of family history, age at onset, the geographical and ethnic context, and on the typical features of myoclonus and epilepsy, in the absence of cognitive and sensory deficits. Neurophysiological evaluation yields interesting, but unspecific results. There are no biological or pathological markers for ULD. Molecular biology easily confirms the diagnosis in most patients. Genetic counseling and even prenatal diagnosis are possible, although seldom performed, if the mutation has been identified.
EEG abnormalities are more pronounced at initial diagnosis when disease onset may be accompanied by generalized tonic clonic seizures. Any physiological sleep patterns that are initially observed disappear in about one-half of the patient after 16 years of having the disease.
Clinical diagnosis should be complemented with genetic testing, which is commercially available at genetic testing centers.
The primary therapeutic approaches for ULD patients include rehabilitation and symptomatic pharmacologic management. Pharmacologic management includes:
Antiepileptic Medications: The most reliable seizure medication for seizure and myoclonus control is valproic acid, which decreases myoclonus and the frequency of generalized seizures. Clonazepam and piracetam are effective as add-on therapy to valproic acid. However, piracetam is not available in the States.
Some of the newer medications such as levetiracetam, lamotrigine, topiramate and zonisamide, may reduce seizure frequency, but are not as well studied as valproic acid and clonazepam. Recent data revealed that some medications are completely ineffective in the treatment of Unverricht-Lundborg disease such as phenytoin and carbamazepine. In fact, phenytoin is believed to worsen the course of Unverricht-Lundborg.
Also, psychological therapy may be needed for emotional issues, which are commonly associated with the disease, and is especially true during the teenage years. Some experts recommend clinical and psychosocial follow-up at 6-month intervals for teenage patients. Suicide is increased in patients with Unverricht-Lundborg disease and close watch of depression should be performed.
NOTE: The above information is educational purpose. The information provided herein should not be used during any medical emergency or for the diagnosis or treatment of any medical condition.
DISCLAIMER: This information should not substitute for seeking responsible, professional medical care.
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