The neuronal ceroid lipofuscinoses (NCL) are a heterogeneous group of genetic lysosomal storage diseases causing dementia, epilepsy, motor deterioration and mostly also visual loss through retinal degeneration. Similarities of the different NCL also concern elements of their pathophysiology, which is characterized by loss of neurons and accumulation of a material called ceroid lipofuscin. The single NCL forms differ significantly by the age at manifestation, and the progression of neurological deterioration.
The neuronal ceroid lipofuscinoses (NCL) are a heterogeneous group of genetic lysosomal disorders characterized by the accumulation of a waxy intracellular storage material termed ceroid lipofuscin and progressive neurological deterioration, usually associated with dementia and epilepsy, frequently also with visual loss due to retinopathy. Most NCL forms are transmitted autosomal recessively. As a group, NCL represent one of the most frequent etiologies of dementia in children and young adults [1-3]. The classification of the NCL disorders is based on the different genes involved (CLN1-CLN14) and on the age at clinical onset, which can be anytime between the infantile and young adult age. The major NCL forms are shortly described below according to the age at manifestation.
NCL with infantile onset (1st year of life)
Infantile NCL is usually caused by CLN1 mutations. Early development appears normal until around six months of age. At onset, there is typically a decreased muscle tone and decreased social interaction followed by dramatically progressive psychomotor decay, myoclonus, seizures, spasticity and visual failure. By two years of age, blindness has developed with optic atrophy and retinal abnormalities. Patients rapidly reach a vegetative state.
NCL with late-infantile onset (age 2 to 5 years)
The onset of an NCL disease at this age is usually caused by CLN2 mutations, but mutations of other genes are possible. Children with CLN2 disease appear initially healthy and normally developed. Acquisition of speech may be retarded. First symptoms occur generally between the ages of 2 and 4 years and consist in motor decline with clumsiness and ataxia, deterioration of speech and/or epilepsy. Seizures (partial, generalized tonic-clonic, secondarily generalized, or other) are the first symptom in 75% of patients. Non-epileptic myoclonus frequently coexists and has to be distinguished from epileptic seizures as it is treated differently. After the third year of life, loss of motor function and of language ability progress rapidly and uniformly. MR imaging shows progressive brain atrophy. Visual ability declines gradually and leads to blindness. Limb spasticity, truncal hypotonia, and loss of head control lead to complete loss of independent mobility. Children lose the ability to swallow and frequently receive tube feeding. Death usually occurs at the age of 10-15 years.
NCL with juvenile onset (age 5 to 15 years)
Juvenile NCL is mostly caused by CLN3 mutations, rarely also by mutations of other genes. The disease usually starts between ages 4 and 7 years with insidious onset of visual failure due to a pigmentary retinopathy. For several years, patients are regarded as visually handicapped only. Progressive cognitive decline and behavioral problems (angry outbursts, physical violence, and anxiety with features of depression) follow. Seizures develop at around 10 years of age, mostly as generalized tonico-clonic seizures, which are usually well-controlled by medication, at least initially. Any other type of epilepsy may occur, from subtle partial seizures to myoclonic status. A parkinsonian movement disorder develops. Speech becomes affected by a severe dysarthria. Swallowing difficulties frequently lead to tube feeding. A cardiac conduction abnormality is detectable in the second decade of life. Age at death is usually in the third decade.
NLC with onset in adults
Adult onset forms of NCL are all very rare and can be caused by mutations of a variety of genes. In the past, the term Kufs disease was used to designate some of them. Onset is typically at around 30 years of age. Clinical features include ataxia, dementia, progressive myoclonus epilepsy, but in contrast to most other NCL, there is usually no loss of vision.