Unverricht-Lundborg disease (EPM1)

Overview

Unverricht-Lundborg disease, often referred to as EPM1, is a rare form of progressive myoclonus epilepsy. This condition is characterised by a combination of involuntary muscle jerks, known as myoclonus, and epileptic seizures that typically worsen over time. The onset of symptoms commonly occurs during late childhood or early adolescence, usually between the ages of 6 and 16 years [PMID:19408104]. EPM1 affects the nervous system, leading to challenges with movement, coordination, and overall neurological function.

The progression of EPM1 can vary between individuals, but generally involves an increase in the frequency and severity of myoclonus and seizures. These symptoms can significantly impact a person's ability to perform everyday activities, such as walking, writing, and speaking. The condition is inherited, meaning it is passed down through families, and is a result of specific genetic changes [PMID:17650953]. While EPM1 is rare globally, its prevalence is notably higher in certain populations, such as Finland, where it affects approximately 1 in 20,000 people. The exact prevalence in the UK is not well established.

Symptoms & clinical features

The primary symptoms of EPM1 are progressive myoclonus and epileptic seizures. Myoclonus manifests as sudden, brief, involuntary muscle jerks that can affect any part of the body. These jerks are often triggered by movement, stress, or sensory stimuli like light or sound. Initially, myoclonus may be mild, but it typically becomes more widespread and debilitating, making fine motor tasks difficult [PMID:19408104].

Epileptic seizures in EPM1 commonly include generalised tonic-clonic seizures, which involve a loss of consciousness and widespread muscle contractions. Photosensitivity, where seizures are triggered by flashing lights, is also a common feature. As the condition progresses, individuals may experience difficulties with balance and coordination (ataxia), speech problems (dysarthria), and tremors. While cognitive decline is not always a prominent feature, some individuals may experience mild cognitive impairment or develop mood disturbances such as depression [PMID:17650953]. The severity and combination of these symptoms can significantly impact an individual's quality of life.

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Affected organs

EPM1 primarily affects the brain and central nervous system. The neurological dysfunction leads to the characteristic myoclonus, seizures, and problems with coordination. The parts of the brain involved in motor control and seizure activity are particularly impacted. While the condition does not typically cause direct damage to other organs, the neurological symptoms can have secondary effects on various bodily functions due to impaired muscle control and coordination. For instance, severe myoclonus can affect muscles used for speech and swallowing, leading to communication and feeding difficulties.

Brain

Central nervous system involvement

Cellular impact

Mechanism at cellular level

Risks & severity

EPM1 is a progressive condition, meaning its symptoms tend to worsen over time. The age of onset is typically between 6 and 16 years, with symptoms often starting subtly and gradually increasing in severity [PMID:19408104]. The progression rate can vary, but generally, myoclonus becomes more severe and widespread, and seizure control may become more challenging. While the condition can significantly affect daily life, life expectancy is often not severely reduced, though severe neurological impairment can lead to complications.

The severity of EPM1 can range from relatively mild forms, where individuals maintain a good degree of independence for many years, to more severe forms where daily activities become profoundly challenging due to relentless myoclonus and seizures. Risk factors for developing EPM1 are primarily genetic, as it is an inherited condition. Individuals with two copies of a pathogenic variant in the *CSTB* gene are at risk. There is no known way to prevent the onset of EPM1 if an individual has the causative genetic changes.

Genetic causes

Unverricht-Lundborg disease (EPM1) is caused by pathogenic variants in the *CSTB* gene. This gene provides instructions for making a protein called cystatin B. Cystatin B is a small protein that plays a crucial role in regulating the activity of a group of enzymes known as cathepsins. Cathepsins are involved in breaking down proteins within cells, a process important for normal cellular function and waste removal.

Cystatin B acts as an inhibitor, meaning it helps to control the activity of cathepsins, preventing them from becoming overactive. This regulatory function is particularly important in nerve cells, where it contributes to their development, communication, and protection. When there are pathogenic variants in the *CSTB* gene, the production of functional cystatin B can be reduced or absent. This lack of functional cystatin B leads to uncontrolled cathepsin activity, which can disrupt cellular processes, particularly in the brain [PMID:17650953]. The resulting cellular dysfunction and damage in the nervous system are thought to underlie the progressive myoclonus, seizures, and other neurological symptoms observed in EPM1.

• CSTB
  cystatin B
  CSTB encodes cystatin B, a protein that regulates enzyme activity in cells and protects nerve cells from damage.

Inheritance pattern

EPM1 has an autosomal recessive inheritance pattern. This means that a person must inherit two copies of a pathogenic variant in the *CSTB* gene - one copy from each parent - to develop the condition. Individuals who inherit only one pathogenic variant in *CSTB* are known as carriers. Carriers typically do not show symptoms of EPM1 because they still have one working copy of the gene, which is usually sufficient to produce enough functional cystatin B.

When two carrier parents have a child, there is a 25% chance with each pregnancy that the child will inherit two copies of the pathogenic variant and develop EPM1. There is a 50% chance the child will be a carrier like their parents, and a 25% chance the child will inherit two normal copies of the gene and will not have the condition or be a carrier. Family members of an affected individual may wish to consider genetic counselling to understand their own carrier status and the risks for future children.

Diagnosis & testing

A diagnosis of EPM1 is typically suspected based on characteristic clinical symptoms, including progressive myoclonus and seizures, especially with onset in childhood or adolescence. A neurological examination will assess motor skills, coordination, and reflexes. Electroencephalography (EEG), which measures brain activity, often shows generalised epileptic activity and sometimes photosensitivity. Magnetic resonance imaging (MRI) of the brain may also be performed, though it may initially appear normal and specific changes may only be seen later in the disease course.

Genetic testing is the definitive method to confirm a diagnosis of EPM1. This involves analysing the *CSTB* gene to identify pathogenic variants. In the UK, genetic testing for EPM1 is usually accessed through the NHS Genomic Medicine Service (GMS). Referral to a clinical genetics service or a neurologist specialising in epilepsy or movement disorders is generally required to initiate genetic testing. The relevant NHS National Genomic Test Directory R-code for testing related to progressive myoclonus epilepsy, which includes EPM1, would typically be used to guide testing decisions.

Management & lifestyle

While there is currently no cure for EPM1, management focuses on controlling symptoms and improving quality of life. Treatment often involves a combination of anticonvulsant medications to help reduce the frequency and severity of seizures and myoclonus. Medications like valproate, levetiracetam, and piracetam are commonly used, though individual responses can vary [PMID:19408104]. Close monitoring by a neurologist is essential to adjust medication dosages and manage side effects.

Supportive therapies are also crucial. Physiotherapy can help maintain mobility and muscle strength, while occupational therapy can provide strategies and adaptations to assist with daily activities. Speech and language therapy may be beneficial for individuals experiencing communication or swallowing difficulties. Regular follow-up with a multidisciplinary team, including neurologists, genetic counsellors, and therapists, is important to address the evolving needs of individuals with EPM1. Genetic counselling can provide information and support to affected individuals and their families regarding the inheritance pattern and implications for family planning.

UK care pathway

In the UK, individuals suspected of having a rare genetic condition like EPM1 would typically enter the NHS Genomic Medicine Service (GMS) pathway. This pathway begins with a referral from a GP or specialist, such as a neurologist, to a clinical genetics service. Clinical geneticists and genetic counsellors provide expert assessment, diagnosis, and support. Genetic testing for EPM1, guided by the NHS National Genomic Test Directory R-codes for epilepsies, would be arranged through the GMS.

Genetic counsellors play a vital role in explaining the genetic basis of EPM1, its inheritance pattern, and implications for family members. They can also provide emotional support and help families navigate the complex information associated with a genetic diagnosis. Management of the condition itself would involve ongoing care from a neurologist and a multidisciplinary team, ensuring access to appropriate therapies and medication.

Related conditions

EPM1 belongs to a group of conditions known as progressive myoclonus epilepsies (PMEs). Other PMEs, such as Lafora disease or neuronal ceroid lipofuscinoses, share overlapping symptoms like myoclonus and seizures, but are caused by pathogenic variants in different genes and often have distinct additional features and progression patterns. Differentiating EPM1 from other PMEs requires careful clinical evaluation and specific genetic testing.

Other conditions that may present with seizures and movement disorders, such as certain metabolic disorders or other forms of epilepsy, also need to be considered during diagnosis. The precise genetic diagnosis of EPM1 is crucial because it helps to confirm the specific type of PME, inform prognosis, and guide appropriate management strategies, as treatments can vary between these conditions.

Frequently asked questions

References

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