Neuronal Ceroid-Lipofuscinoses – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY

NOTE: THIS PUBLICATION HAS BEEN RETIRED. THIS ARCHIVAL VERSION IS FOR HISTORICAL REFERENCE ONLY, AND THE INFORMATION MAY BE OUT OF DATE.

Clinical characteristics: 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. Clinical phenotypes have been characterized traditionally according to the age of onset and order of appearance of clinical features into infantile, late-infantile, juvenile, adult, and Northern epilepsy (also known as progressive epilepsy with mental retardation [EPMR]). There is however genetic and allelic heterogeneity; a proposed new nomenclature and classification system has been developed to take into account both the responsible gene and the age at disease onset; for example, CLN1 disease, infantile onset and CLN1 disease, juvenile onset are both caused by pathogenic variants in PPT1 but with differing age of onset.

The most prevalent NCLs are CLN3 disease, classic juvenile and CLN2 disease, classic late infantile (although prevalence varies by ethnicity and country of family origin):

CLN2 disease, classic late infantile. The first symptoms typically appear between age two and four years, usually starting with epilepsy, followed by regression of developmental milestones, myoclonic ataxia, and pyramidal signs. Visual impairment typically appears at age four to six years and rapidly progresses to light /dark awareness only. Life expectancy ranges from age six years to early teenage.

CLN3 disease, classic juvenile. Onset is usually between ages four and ten years. Rapidly progressing visual loss resulting in severe visual impairment within one to two years is often the first clinical sign. Epilepsy with generalized tonic-clonic seizures and/or complex-partial seizures typically appears around age ten years. Life expectancy ranges from the late teens to the 30s.

Other forms of NCL may present with behavior changes, epilepsy, visual impairment, or slowing of developmental progress and then loss of skills. The course may be extremely variable. Some genotype-phenotype information is available.

Diagnosis/testing: The diagnosis of an NCL is increasingly based on assay of enzyme activity and molecular genetic testing. In unusual cases diagnosis relies on electron microscopy (EM) of biopsied tissues. The diagnostic testing strategy in a proband depends on the age of onset. Pathogenic variants in thirteen genes — PPT1, TPP1, CLN3, CLN5, CLN6, MFSD8, CLN8, CTSD, DNAJC5, CTSF, ATP13A2, GRN, KCTD7 — are known to cause NCL.

Management: Treatment of manifestations: Treatment is currently symptomatic and palliative only. Seizures, malnutrition, gastroesophageal reflux, pneumonia, sialorrhea, depression and anxiety, spasticity, Parkinsonian symptoms, and dystonia can be effectively managed. Antiepileptic drugs (AEDs) should be selected with caution. Benzodiazepines may help control seizures, anxiety, and spasticity. Trihexyphenydate may improve dystonia and sialorrhea. Individuals with swallowing problems may benefit from placement of a gastric (G) tube. Antidepressants and antipsychotic agents are sometimes indicated for those with CLN3 disease.

Surveillance: Routine medical management of children and young adults with complex neurodisability will be relevant to all those affected by NCL, and may include surveillance for swallowing difficulties and recurrent aspiration; radiograph surveillance of hip joints and spine; screening ECG for those with CLN3 disease who are older than age 16 years.

Agents/circumstances to avoid: Carbamazepine and phenytoin may increase seizure activity and myoclonus and result in clinical deterioration; lamotrigine may exacerbate seizures and myoclonus, especially in CLN2 disease.

Genetic counseling: The NCLs are inherited in an autosomal recessive manner with the exception of adult onset, which can be inherited in either an autosomal recessive or an autosomal dominant manner.

Autosomal recessive NCL. The parents of a child with an autosomal recessive form of NCL are obligate heterozygotes, and therefore carry one mutated allele. Heterozygotes have no symptoms. At conception, each sib 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 pathogenic variants in the family are known.

Prenatal testing for pregnancies at increased risk is possible if the proband has documented deficient enzyme activity or if the pathogenic variant(s) have been identified in the family.