Ceroid lipofuscinosis - Neuronal 6 (also known as CLN6 and Variant late infantile neuronal ceroid lipofuscinosis) is a rare metabolic disorder that affects the nervous system. It is characterized by intracellular accumulation of autofluorescent liposomal material, and clinically by seizures, dementia, visual loss, and/or cerebral atrophy. CLN6 disease is caused by changes (mutations) in the CLN6 gene and is inherited in an autosomal recessive manner. The lipopigment patterns observed most often in CLN6 comprise mixed combinations of granular, curvilinear, and fingerprint profiles. It occurs predominantly in people of Portuguese, Indian, Pakistani, or Czech ancestry. The incidence of CLN6 disease is unknown; more than 125 cases have been described in the scientific literature.
Signs and symptoms of the condition generally develop between ages 18 months and 8 years, although later onset cases have been reported. Affected people may experience loss of muscle coordination (ataxia), seizures that do not respond to medications, muscle twitches (myoclonus), visual impairment, and developmental regression (loss of previously acquired skills). Treatment options are limited to therapies that can help relieve some of the symptoms.
- Progressive dementia
- Progressive vision failure
- Loss of strength
- Progressive loss of ability to move
- Loss of language
- Behavioural changes
CLN6-NCL is caused by changes (mutations) in the CLN6 gene and is inherited in an autosomal recessive manner. More than 70 mutations in the CLN6 gene have been found to cause CLN6 disease. This condition impairs motor and mental development, typically starting in early to late childhood, causing gradually worsening problems with movement and a decline in intellectual function. In some cases, signs and symptoms of CLN6 disease do not appear until adulthood.
Most CLN6 gene mutations result in the production of an abnormal CLN6 protein that is quickly broken down (degraded). As a result, there is a severe reduction in the amount of functional CLN6 protein in cells. While it is not known how the loss of this protein causes the signs and symptoms of CLN6 disease, it is likely that the protein's quick degradation contributes to the childhood onset of CLN6 disease.
In the cases in which CLN6 disease develops in adulthood, CLN6 gene mutations often change single protein building blocks (amino acids), resulting in a CLN6 protein with reduced function. Research suggests that these CLN6 gene mutations allow enough functional protein to be produced so that signs and symptoms of the disorder do not develop until later in life.
CLN6 disease is characterized by the accumulation of proteins or peptides and other substances in lysosomes. These accumulations occur in cells throughout the body; however, nerve cells seem to be particularly vulnerable to their effects. The accumulations can cause cell damage leading to cell death. The progressive death of nerve cells in the brain and other tissues leads to the signs and symptoms of CLN6 disease. However, it is unclear how mutations in the CLN6 gene are involved in the buildup of substances in lysosomes in CLN6 disease. These accumulations occur in more cells throughout the body in children with CLN6 disease than in affected adults.
Treatment options are limited to therapies that can help relieve some of the symptoms.
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.
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.