CLN1 disease

CLN1 disease, also known as neuronal ceroid lipofuscinosis type 1 or palmitoyl-protein thioesterase 1 (PPT1) deficiency, is a severe inherited neurodegenerative disorder belonging to the group of neuronal ceroid lipofuscinoses (NCLs), which are collectively the most common neurodegenerative diseases of childhood. It was historically referred to as infantile neuronal ceroid lipofuscinosis or Santavuori-Haltia disease. The condition is caused by mutations in the PPT1 gene, which encodes the lysosomal enzyme palmitoyl-protein thioesterase 1. Deficiency of this enzyme leads to the accumulation of lipopigments (ceroid and lipofuscin) within lysosomes of neurons and other cells, resulting in progressive neuronal death. The classic infantile form typically presents between 6 and 24 months of age with developmental regression, including loss of previously acquired motor and language skills. Affected children develop progressive visual impairment leading to blindness, seizures (often myoclonic and tonic-clonic), cognitive decline, and movement abnormalities including ataxia and spasticity. Brain MRI shows progressive cerebral and cerebellar atrophy. The disease follows a relentless neurodegenerative course, and children with the classic infantile form typically become vegetative by age 3-4 years. Later-onset forms (late-infantile, juvenile, and adult) have also been described with PPT1 mutations, presenting with a more protracted clinical course. There is currently no cure for CLN1 disease. Management is primarily supportive and symptomatic, including antiepileptic medications for seizure control, nutritional support, physical therapy, and palliative care. Cerliponase alfa (Brineura), an enzyme replacement therapy approved for CLN2 disease, is not indicated for CLN1. Research into gene therapy, enzyme replacement therapy, and small molecule approaches for CLN1 is ongoing. In April 2022, the FDA granted approval for clinical trials investigating intrathecal enzyme replacement therapy for CLN1 disease, representing a potential future therapeutic avenue.

Common questions about CLN1 disease