The neuronal ceroid-lipofuscinoses (NCLs) are a group of inherited, neurodegenerative, lysosomal-storage disorders characterized by progressive intellectual and motor deterioration, seizures, and early death. Visual loss is a feature of most forms. Phenotypes have been characterized clinically by age of onset and order of appearance of the clinical features: infantile neuronal ceroid-lipofuscinosis (INCL, Santavuori-Haltia), late-infantile (LINCL, Jansky-Bielschowsky), juvenile (JNCL, Batten disease, Spielmeyer-Vogt), adult (ANCL, Kuf's disease), and Northern epilepsy (NE, progressive epilepsy with intellectual disability). Children with INCL are normal at birth; symptoms usually present acutely between ages six and 24 months. Initial signs include: delayed development, myoclonic jerks and/or seizures, deceleration of head growth, and specific electroencephalographic (EEG) changes. Affected infants develop retinal blindness and seizures by age two years, followed by progressive intellectual disability. The first symptoms of LINCL typically appear between ages two and four years, usually starting with epilepsy, followed by regression of developmental milestones, dementia, ataxia, and extrapyramidal and pyramidal signs. Visual impairment typically appears at age four to six years and rapidly progresses to blindness. Life expectancy ranges from age six years to older than 40 years. The onset of JNCL is usually between ages four and ten years. Rapidly progressing visual loss resulting in total blindness within two to four years is often the first clinical sign. Epilepsy with generalized tonic-clonic seizures, complex-partial seizures, or myoclonic seizures typically appears between ages five and 18 years. Life expectancy ranges from the late teens to the 30s. Initial signs and symptoms of ANCL usually appear around age 30 years, with death occurring about ten years later. Affected individuals have either progressive myoclonic epilepsy or behavior abnormalities; and all have dementia, ataxia, and late-occurring pyramidal and extrapyramidal signs. Northern epilepsy is characterized by tonic-clonic or complex-partial seizures, intellectual disability, and motor dysfunction. Onset occurs between ages two and ten years.
The diagnosis of an NCL is often based on assay of enzyme activity and/or molecular genetic testing, and, in some instances, on electron microscopy (EM) of biopsied tissues. The diagnostic testing strategy in a proband depends on the age of onset. Mutations in eight genes (PPT1, TPP1, CLN3, CLN5, CLN6, MFSD8, CLN8, and CTSD) are known to cause NCL.
The NCLs are inherited in an autosomal recessive manner with the exception of ANCL, which can be inherited in either an autosomal recessive or an autosomal dominant manner. The parents of a child with an autosomal recessive form of NCL are obligate heterozygotes, and, therefore, carry one mutant allele. Heterozygotes have no symptoms. At conception, each sib of such a proband 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 disease-causing mutations in the family are known. Prenatal testing for pregnancies at increased risk is possible if the proband has documented deficient enzyme activity of either PPT1 or TPP-1 or if the disease-causing mutation(s) have been identified in the family.