What are the NCLs?

The NCLs are a group of severe autosomal recessive inherited diseases characterised by progressive blindness and neurodegeneration, and the accumulation of autofluorescent lipofuscin-like (age pigment) material in the lysosomes of neurons and other cell types. They are the most common childhood onset neurodegenerative disorders and are currently incurable. Nine human disease gene loci have been identified. The function of most of the encoded proteins is unknown.

The NCLs were originally classified according to the clinical onset of symptoms as infantile, late-infantile, juvenile, and adult forms but now several variant forms are recognised. The underlying genes for some NCL types have not yet been identified.

CTSD encodes the proteolytic enzyme cathepsin D. Mutations in this gene cause disease evident at or before birth, with very severe brain atrophy and death occurring soon afterwards. However, disease onset may also be later, in which case the disease course is protracted, and includes progressive motor decline, loss of speech and retinal atrophy .

CLN1 encodes the enzyme palmitoyl protein thioesterase 1 (PPT1) which removes palmitate residues from proteins. Mutations in this gene cause NCL with a wide clinical spectrum - typical onset is in infancy but can be delayed until adulthood. For infants, development may slow in the first year particularly affecting fine motor skills, and infants may become irritable and difficult to comfort. Central hypotonia and decelerating head growth may be evident. Development slows further in the second year. Seizures and jerks may develop. Sleep disturbance and irritability occur in most children. Often children have characteristic hand movements rather like those seen in Rett syndrome. Mobility and language skills are lost and vision deteriorates. Spasticity of the limbs worsens later in the illness.

CLN2 encodes a lysosomal enzyme tripeptidyl peptidase (TPP1), a member of a recently defined family of serine-carboxyl proteinases, that removes tripeptides from the N terminus of small proteins. In young children, typical development may slow, particularly affecting speech. Seizures usually occur between 2-4 years of age, with myoclonic jerks and continued developmental regression. Visual failure occurs later. Some children become extremely irritable and distressed. Limb spasticity may become prominent with truncal hypotonia and loss of head control. Mutations in CLN2 cause classic late infantile NCL, and in some instances a more protracted disease with later onset.

Variant late infantile NCL can be caused by mutations in CLN5, CLN6, CLN7, CLN8 and other, as yet unknown genes. For disease caused by mutations in CLN5, initial symptoms may be clumsiness and/or difficulties in concentration noticed in the preschool and early school years. Developmental regression, visual impairment, ataxia, myoclonus and epilepsy follow. Mutations in CLN5 can also cause milder disease. For disease caused by mutations in CLN6 and CLN7, seizures and motor difficulties present before visual failure. Mutations in CLN7 can also cause milder disease. Mutations in CLN8 cause two different disease. One mutation is associated with another disease, Northern epilepsy or Progressive Epilepsy with Mental Retardation, only recently recognised as an NCL. This presents with onset of generalised tonic-clonic seizures between the ages of 5-10 years accompanied with progressive loss of cognitive skills, and loss of fine notor skills in adulthood. Vision is preserved and myoclonus does not occur. Other mutations cause typical NCL with seizures and deteriorating motor skills the leading symptoms followed by myoclonus, visual failure and loss of cognitive skills. Not all cases of NCL presenting in late infancy have been defined genetically.

Mutations in CLN3 underlie juvenile onset NCL, which presents with visual failure. Typically this progresses over 2-3 years to an appreciation of light and dark only. There is a pigmentary retinopathy and children may initially be diagnosed with retinitis pigmentosa or a cone dystrophy. In most cases, deterioration in cognitive skills, speech and mobility occurs in the early teenage years together with the onset of seizures. Seizures may be generalised tonic-clonic or partial seizures. Behaviour may become problematic at this time. Aggressiveness, psychosis, mood disturbance and anxiety often occur. Speech becomes slightly dysarthric and dysfluent with echolalia. Mobility becomes characteristically slow and shuffling with a slightly stooped posture. As the disease progresses myoclonic jerks and parkinsonian features become prominent. Communication, mobility and self-help skills are lost. Most patients carry a 1 kb intragenic deletion on at least one disease allele. Some mutations cause a mild or more protracted disease in which visual failure occurs but further symptoms can be delayed well into adulthood. A small group of patients assumed to have mutations in an unknown CLN9 gene also cause juvenile onset NCL.

Teenage and early and late adult onset cases of NCL occur. Kufs disease, an adult onset NCL, has no visual failure, and encompasses myoclonus epilepsy, dementia, ataxia, behavioural changes. Kufs type A is caused by mutations in CLN6. In a few instances late onset disease is caused by mutations in CLN1 or perhaps CLN2. Autosomal dominant adult onset NCL (Parry disease) is caused by mutations in CLN4 (DNAJC5). There are also two late onset patients carrying single mutations in CLCN6, and one with heterozygous mutations in SGSH. There are still adult onset cases (recessive and dominant) where the underlying gene defect is not yet known.