Cln1

CLN1 refers to pathogenic variants in the CLN1 gene, encoding palmitoyl-protein thioesterase 1 (PPT1), a lysosomal hydrolase. PPT1 removes palmitoyl groups from S-palmitoylated proteins, enabling their degradation.

PPT1 functions in lysosomes; deficiency causes accumulation of palmitoylated proteins and ceroid lipofuscin-like material in neurons and other cells, leading to neurodegeneration. CLN1 is one form of neuronal ceroid lipofuscinoses (NCLs).

Genetics: CLN1 disease is inherited in an autosomal recessive manner. It is the infantile form of the NCL spectrum, with onset typically in infancy or early childhood.

Clinical features: CLN1 presents with rapidly progressive neurodegeneration including seizures, myoclonus, cognitive and motor decline, and visual loss. Other features may include hypotonia that progresses to spasticity. Onset is often before age 2, and survival is usually into early childhood, though outcomes vary.

Diagnosis: Diagnosis is suspected from clinical features and confirmed by genetic testing identifying CLN1 variants and by demonstrating reduced PPT1 enzyme activity in leukocytes or fibroblasts. Neuroimaging may show brain atrophy, and tissue studies can reveal lysosomal storage material consistent with NCLs.

Management and prognosis: There is no cure for CLN1 disease; care is supportive and multidisciplinary, focusing on seizure control, nutrition, vision support, and physical therapy. Several experimental approaches, including gene therapy and enzyme replacement strategies, have been explored in preclinical and early clinical studies, emphasizing CNS delivery and disease modification.