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CLN8 Disease, EPMR and late infantile variant

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What is the cause?

The gene called CLN8 lies on chromosome 8.  CLN8 disease is inherited as an autosomal recessive disorder, which means that both chromosomes carry mutations in the CLN8 gene, and both parents are unaffected carriers.  The gene was discovered in 1999.  CLN8 normally directs production of a protein that is embedded in internal cell membranes.  The cells cannot function as they should and symptoms develop.

 

How is it diagnosed?

The diagnosis is usually made by histological and genetic (CLN8) tests on blood samples.  A skin biopsy may be necessary.  The characteristic storage bodies at the electron microscope level often show a mixture of fingerprint profiles (FPP) and curvilinear bodies (CVB).

 

How does the disease progress?  Genotype/phenotype correlations

Epilepsy with Progressive Mental Retardation (EPMR) or Northern Epilepsy

This disease is caused by mutations in CLN8 but has seldom been described outside Scandinavian countries.  Symptoms usually start between the ages of 5 and 10 years, with seizures.  Cognitive decline occurs at around the same time.  Seizure frequency increases until puberty.  Cognitive deterioration is more rapid during puberty.  Behavioural disturbances can occur, eg: irritability, restlessness, inactivity and these features may continue into adulthood.  Epilepsy is partially responsive to treatment.  The number of seizures decreases spontaneously after puberty, even with no change in treatment, and by the second-third decade they become relatively sporadic.  Cognitive decline continues and in some cases loss of speech has been reported.  Motor function is also impaired.  In a number of cases, visual acuity is reduced (without evidence of retinal degeneration).  The disease has a chronic course and survival to the sixth or seventh decade has been reported.  EPMR is very unusual amongst the NCLs of childhood onset in this respect.

 

CLN8 disease, variant late infantile

All children have developmental delay before the onset of symptoms at 2-7 years of age:  myoclonic seizures and an unsteady gait are commonly the initial symptoms; other seizures follow soon after.   Cognitive decline and visual impairment usually occur.  Behavioural abnormalities are frequent.  Rapid disease progression with loss of cognitive skills is observed over two years from the time of diagnosis.  By the age of 8-10 years severe deterioration of neurological and cognitive skills is apparent together with medication resistant epilepsy.  Spasticity, dystonic posturing, tremors, and other extrapyramdal signs are also observed commonly.  In the second decade of life children are unable to walk or stand without support.  The life-expectancy of children affected by this disease is not yet known.  The eldest patients know are now in their second decade, and their general health remains good.

Dr Ruth Williams (NCL2012 Abstract Book, Clinical Summaries, 2012)