Ceroid lipofuscinosis - Neuronal 5 (also known as CLN5, Neuronal ceroid lipofuscinosis Finnish variant and Finnish variant late infantile neuronal ceroid lipofuscinosis) is a rare metabolic disorder that affects the nervous system. It is characterised by the deposits of lipopigments (lipofuscin). CLN5-NCL is caused by changes (mutations) in the CLN5 gene and is inherited in an autosomal recessive manner.
Although the incidence of CLN5 disease is unknown; more than 85 cases have been described in the scientific literature. CLN5 disease was originally thought to affect only the Finnish population as they were the first individuals to be diagnosed with the condition. However, research has since shown that CLN5 disease affects populations worldwide. CLNs, including CLN5 disease, are still most common in Finland, where approximately 1 in 12,500 individuals are affected. Collectively, all forms of NCL affect an estimated 1 in 100,000 individuals worldwide.
Signs and symptoms of the condition generally develop between ages 4.5 and 7 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 cognitive/motor decline. Treatment options are limited to therapies that can help relieve some of the symptom(s).
- Progressive dementia
- Progressive vision failure
- Cerebellar atrophy
- Abnormal nervous system electrophysiology
- Autosomal recessive inheritance
- Curvilinear intracellular accumulation of autofluorescent lipopigment storage material
- Developmental regression
CLN5 is caused by homozygous or compound heterozygous mutation in the CLN5 gene (608102) on chromosome 13q22. It is characterized by the intracellular accumulation of autofluorescent lipopigment storage material in different patterns ultrastructurally. The lipopigment patterns observed most often in CLN5 comprise mixed combinations of 'granular,' 'curvilinear,' and 'fingerprint' profiles.
At least 35 mutations in the CLN5 gene have been found to cause CLN5 disease. Most of the mutations that cause CLN5 disease make changes in the CLN5 protein that interfere with the processing of the preprotein or alter the structure of the protein. The resulting proteins cannot be transported to the lysosomes. Other mutations lead to production of abnormal proteins that are quickly broken down. One such mutation, known as Finmajor, is responsible for almost all cases of CLN5 disease in people of Finnish descent. The Finmajor mutation replaces the protein building block (amino acid) tyrosine with a signal to stop protein production prematurely (written as Tyr392Ter or Y392X).
A lack of functional CLN5 protein within lysosomes probably impairs the breakdown of certain proteins, which then likely accumulate in cells throughout the body. While these accumulations can damage any cells, nerve cells appear to be particularly vulnerable. Widespread loss of nerve cells in CLN5 disease leads to severe signs and symptoms and early death.
This condition impairs mental and motor development causing difficulty with walking and intellectual function. In addition, affected children often develop recurrent seizures (epilepsy) and vision loss. Signs and symptoms of CLN5 disease typically appear around age 5 but can begin in adolescence or adulthood. In the cases in which CLN5 disease develops in adolescence or adulthood, it is thought that the CLN5 gene mutations lead to a CLN5 protein with reduced function that is broken down earlier than normal. Because the altered CLN5 protein can function for a small amount of time, some damaged or unneeded proteins may be broken down in lysosomes. Since it takes longer for these substances to accumulate and cause nerve cell death, the signs and symptoms of CLN5 disease in these individuals occur later in life.
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.
The prognosis for people with the disease is poor. They will be profoundly mentally disabled and unable to speak or move some time after the age of 10. The average life expectancy is about 20 years, though the lifespan of people with the disease has ranged from 14 to 39 years.
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; 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
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.
NCBI; GARD; GHR