Ceroid lipofuscinosis – Neuronal 8

Synonyms

4

Overview

Ceroid lipofuscinosis - Neuronal 8 (also known as CLN8, vLINCL, EPMR and Turkish Late Infantile Variant NCL disease) is a rare metabolic disorder that affects the nerve cells of the body and is characterized by the deposits of lipopigments (lipofuscin). Type 8 is distinguished from other types by the origin of the genetic defect.

CLN8 disease is an inherited disorder that varies in severity and primarily affects the nervous system. The condition is generally separated into less-severe and more-severe forms, based on the types of signs and symptoms that develop and life expectancy. The less-severe form of CLN8 disease appears to affect only individuals of Finnish ancestry, particularly those from the Kainuu region of northern Finland, which is why it is sometimes called Northern epilepsy. Approximately 1 in 10,000 individuals in this region have the condition. The prevalence of the more-severe form of CLN8 disease is unknown. Collectively, all forms of NCL affect an estimated 1 in 100,000 individuals worldwide.

The less-severe form of CLN8 disease, sometimes referred to as Northern epilepsy, is characterized by recurrent seizures (epilepsy) and a decline in intellectual function that begins between ages 5 and 10. The seizures in this form may be resistant to treatment and are often the generalized tonic-clonic type, which involve muscle rigidity, convulsions, and loss of consciousness. Some people with this form of CLN8 disease also experience partial seizures, which do not cause a loss of consciousness. The seizures occur approximately one to two times per month until adolescence; by early adulthood the frequency decreases to about four to six times per year. By middle age, seizures become even less frequent. In addition to seizures, affected individuals experience a gradual decline in intellectual function and develop problems with coordination and balance. Vision problems may occur in early to mid-adulthood. Individuals with the less-severe form of CLN8 disease often live into late adulthood.

The more-severe form of CLN8 disease typically begins between ages 2 and 7.The seizures in this form involve uncontrollable muscle jerks (myoclonic epilepsy). Individuals with the more-severe form have a more pronounced decline in intellectual function and usually lose the ability to speak. Vision loss is also common. People with this form of CLN8 disease have increasing difficulty walking and coordinating movements (ataxia), eventually becoming immobile. Individuals with the more-severe form of CLN8 disease usually survive only into late childhood or adolescence.

Symptoms

  • Progressive dementia
  • Seizures
  • Progressive vision failure
  • Progressive ataxia
  • Motor impairment
  • Mental regression
  • Myoclonus
  • Speech impairment
  • Personality disorders
  • Delayed psychomotor development

Causes

CLN8 disease is caused by mutations in the CLN8 gene. The CLN8 gene provides instructions for making a protein whose function is not well understood. The CLN8 protein is thought to play a role in moving materials in and out of a cell structure called the endoplasmic reticulum. The endoplasmic reticulum is involved in protein production, processing, and transport to different parts of the cell. The CLN8 protein may also play a role in helping the endoplasmic reticulum regulate levels of fats (lipids) in cells. In certain cells, including nerve cells, the CLN8 protein is thought to be active outside of the endoplasmic reticulum, but its function is unknown.

A specific mutation in the CLN8 gene is found in all individuals in northern Finland with the less-severe form of CLN8 disease. This mutation probably leads to production of a protein with reduced function. Because there is likely still some normal function of the CLN8 protein, features of this form are less severe compared to other cases of CLN8 disease. Affected individuals have a reduction in the levels of certain lipids in the brain, likely due to a decrease in CLN8 protein activity, but the effect of this reduction is unclear. Individuals with this form of CLN8 disease have mild brain abnormalities resulting from nerve cell death in the brain, but the cause of the cell death is unknown. Unlike other forms of CLN that result in the accumulation of proteins and other substances in cells, contributing to cell death, the less-severe form of CLN8 disease is associated with very little buildup in cells.

Some CLN8 gene mutations are thought to drastically reduce the function of the CLN8 protein. Other mutations likely impair transport of the protein to the endoplasmic reticulum, so that it cannot perform its function. It is unclear how a loss or reduction of CLN8 protein leads to the signs and symptoms of CLN8 disease. Unlike the less-severe form, in the more-severe form of CLN8 disease, proteins and other substances accumulate in cell structures called lysosomes. While accumulations of these substances occur in cells throughout the body, nerve cells appear to be particularly vulnerable to damage caused by the abnormal cell materials; however, it is unclear how mutations in the CLN8 gene are involved in this buildup. Widespread loss of nerve cells in CLN8 disease leads to the neurological signs and symptoms and, in the case of the more-severe form, early death.

Diagnosis

Making a diagnosis for a genetic or rare disease can often be challenging. Healthcare professionals typically look at a person's medical history, symptoms, physical exam, and laboratory test results in order to make a diagnosis. The resources presented below provide information relating to diagnosis and testing for this condition. If you have questions about getting a diagnosis, you should contact a healthcare professional.

Testing Resources: The Genetic Testing Registry (GTR) provides information about the genetic tests for this condition. The intended audience for the GTR is health care providers and researchers. Patients and consumers with specific questions about a genetic test should contact a health care provider or a genetics professional.

Prognosis

Individuals with the less-severe form of CLN8 disease often live into late adulthood. Whereas, individuals with the more-severe form of CLN8 disease usually survive only into late childhood or adolescence.

Treatment

Treatment of manifestations: Treatment is currently symptomatic and palliative only. Seizures, malnutrition, gastroesophageal reflux, pneumonia, sialorrhea, depression and anxiety, spasticity, Parkinsonian symptoms, and dystonia can be effectively managed. Antiepileptic drugs (AEDs) should be selected with caution. Benzodiazepines may help control seizures, anxiety, and spasticity. Trihexyphenydate may improve dystonia and sialorrhea. Individuals with swallowing problems may benefit from placement of a gastric (G) tube.

Surveillance: Routine medical management of children and young adults with complex neurodisability will be relevant to all those affected by CLN, and may include surveillance for swallowing difficulties and recurrent aspiration and radiograph surveillance of hip joints and spine.

Agents/circumstances to avoid: Carbamazepine and phenytoin may increase seizure activity and myoclonus and result in clinical deterioration; lamotrigine may exacerbate seizures and myoclonus.

Genetic counselling: The CLNs are inherited in an autosomal recessive manner with the exception of adult onset, which can be inherited in either an autosomal recessive or an autosomal dominant manner.

Autosomal recessive CLN. The parents of a child with an autosomal recessive form of CLN are obligate heterozygotes, and therefore carry one mutated allele. Heterozygotes have no symptoms. At conception, each sib has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives is possible if the pathogenic variants in the family are known.

Prenatal testing for pregnancies at increased risk is possible if the proband has documented deficient enzyme activity or if the pathogenic variant(s) have been identified in the family.

Resources

GHR