Eveline C. Traeger, MD
DESCRIPTION 
- Neuronal ceroid lipofuscinoses (NCL forms 1–10) are a group of neurodegenerative disorders, characterized by progressive dementia, visual loss, epilepsy, and intralysosomal accumulation of a membrane-bound fluorescent lipopigment in neurons and other cells. Signs and symptoms are confined to the CNS.
- NCLs are a clinically and genetically heterogeneous group of disorders. 8 of the 10 forms of NCL have been molecularly characterized and are associated with gene mutations.
EPIDEMIOLOGY
Prevalence
- The NCLs are the most common group of neurodegenerative disorders. 25,000 families in the US are affected with a form of NCL.
- Prevalence is highest in the Scandinavian countries, especially Finland.
RISK FACTORS
Genetics
Autosomal recessive mode of inheritance except for a rare adult-onset variant that is autosomal dominant. Gene identification is available for NCL1, NCL2, NCL3, NCL5, NCL6, NCL7, NCL8, and NCL10. Prenatal diagnosis is available if the proband has a documented enzyme deficiency or a disease-causing mutation.
PATHOPHYSIOLOGY
Apoptosis and dysregulated sphingolipid metabolism.
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HISTORY
- Congenital NCL: Microcephalic at birth with seizures, spasticity, and central apnea.
- Infantile NCL (INCL): Dramatic onset of psychomotor deterioration, seizures, and blindness during the first year of life. The common ocular abnormality is optic atrophy; retinal abnormalities have been reported.
- Late-Infantile NCL (LINCL): Onset between 2 and 5 years of age, with psychomotor deterioration and intractable seizures. Blindness associated with optic atrophy or retinitis pigmentosa. Vegetative state ensues after symptoms have been present for about 1 year.
- Juvenile NCL (JNCL): Onset between 5 and 15 years of age, with either gradual visual loss resulting in blindness within 3–5 years and/or behavioral symptoms. There is macular degeneration, optic atrophy, or retinitis pigmentosa. Some time after the onset of the visual disturbance, motor dysfunction (apraxia and ataxia), seizures, and slow dementia are noted.
- Northern epilepsy (NE): Onset with frequent tonic–clonic seizures between 5 and 10 years of age followed by progressive mental retardation. Visual loss is not a prominent feature.
- Adult NCL (ANCL): Average onset at 30 years, with a steadily progressive dementia and seizures that ultimately become refractory. Vision is not usually affected.
PHYSICAL EXAM
- Progressive cognitive decline.
- Variable visual loss. Funduscopic evaluation may reveal optic atrophy, retinitis pigmentosa, or macular degeneration.
- Progressive motor dysfunction may include spasticity, extra pyramidal symptoms, or ataxia.
DIAGNOSTIC TESTS AND INTERPRETATION
Lab
Initial Lab Tests
- EEG, electroretinogram, visual evoked potentials, and somatosensory evoked potentials may add supportive evidence. Electron microscopic identification of characteristic ultrastructural abnormalities in lymphocytes or tissue biopsy of skin or conjunctiva.
- Histologic inclusions:
- Granular osmiophilic deposits (GROD) in NCL1, NCL9, NCL10
- Curvilinear inclusion bodies (CV) in NCL2, NCL6, NCL7, NCL9
- Fingerprint inclusions (FP) in NCL3, NCL5, NCL6, NCL7
- Mixed-type inclusions (CV, FP, GROD) in NCL4, NCL8
Imaging
Initial Approach
Neuroimaging may reveal cerebral and/or cerebellar atrophy.
Diagnostic Procedures/Other
- Molecular genetic testing for the 8 genes known to be associated with NCL. The following phenotype–genotype correlations should help guide molecular testing:
- Congenital NCL: NCL10
- INCL: NCL1
- LINCL: NCL2 (most common), NCL5 (most common in Finland), NCL1, NCL6, NCL7, NCL8, NCL10
- JNCL: NCL3 (most common), NCL1, NCL2, NCL9
- NE: NCL8
- ANCL: NCL1, NCL3, NCL4, NCL5, NCL10
- Enzyme activity of palmitoyl-protein thiesterase 1 for NCL1, tripeptidyl-peptidase 1 for NCL2, Cathepsin D for NCL10
DIFFERENTIAL DIAGNOSIS
The NCLs are easily distinguished from the other known inherited metabolic neurodegenerative diseases based on physical examination, funduscopic evaluation, and clinical course. It is important to confirm the diagnosis to rule out other neurodegenerative disorders.
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MEDICATION
First Line
No medications are available to reverse the symptoms of these disorders.
ADDITIONAL TREATMENT
General Measures
Patients and their families require emotional support.
COMPLEMENTARY AND ALTERNATIVE THERAPIES
- Symptomatic treatment
- Correction of associated visual refractive errors.
- Antiepileptic drugs should be selected with caution.
- Psychotropic drugs for treatment of behavior problems.
- Adjunctive treatment
- Braille training and visual impairment education.
IN-PATIENT CONSIDERATIONS
Admission Criteria
Patients usually are admitted for evaluation and treatment of the complications of their disease.
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FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
Patient follow-up is guided by the predicted course and potential complications of the particular disease.
PATIENT EDUCATION
- Batten Disease Support and Research Association, 2600 Parsons Avenue, Columbus, OH 43207. Phone: 800-448-4570.
- Children's Brain Diseases Foundation, 350 Parnassus Avenue, Suite 900, San Francisco, CA 94117. Phone: 415-565-5402.
- National Batten Disease Registry, 1050 Forest Hill Road, Staten Island, NY 10314-6399. Phone: 800-952-9628.
PROGNOSIS
- Congenital NCL: Death soon after birth.
- INCL: Rapid and severe neurologic devastation. Usually fatal before the end of the first decade.
- LINCL: Rapidly progressive. Usually fatal before the end of the first decade.
- JNCL: May remain ambulatory and able to attend school until the late teens, although 25% of patients die in their teens after a more rapidly dementing course with prominent seizures.
- NE: Epileptic seizures decrease after puberty. Slow cognitive decline continues throughout life. Some individuals have lived beyond 60 years of age.
- ANCL: Slow progression. Duration of illness 20–30 years.
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