PPT1 – Infantile Neuronal Ceroid Lipofuscinosis

Infantile Neuronal Ceroid Lipofuscinosis (INCL) is a severe autosomal recessive lysosomal storage disorder characterized by progressive psychomotor deterioration, early visual loss, seizures, cognitive decline, brain atrophy, myoclonus, and premature death. Biallelic mutations in the CLN1 gene, encoding the lysosomal enzyme palmitoyl-protein thioesterase 1 (PPT1), underlie INCL (Infantile Neuronal Ceroid Lipofuscinosis). Onset typically occurs around 12–18 months of age with rapid neurodegeneration.

Genetic evidence includes a novel homozygous single-base insertion c.169dup (p.Met57fs) segregating with disease in an Italian patient and carrier parents, absent in controls (PMID:9571187). A multi-center series of 32 unrelated U.S. and Canadian families identified PPT1 deficiency in 57 of 58 alleles, including a recurrent nonsense mutation c.451C>T (p.Arg151Ter) in 40% of alleles and missense alleles (T75P) associated with protracted course (PMID:9664077). First-trimester prenatal diagnosis by fluorometric PPT enzyme assay and homozygous C451T detection underscores diagnostic reliability (PMID:10416973).

The variant spectrum encompasses >30 pathogenic alleles: nonsense, frameshift, splice-site, and missense mutations. Frameshift mutations accounting for classical INCL include c.169dup (p.Met57fs) and c.20_47del (p.Leu7HisfsTer21), while missense changes such as c.236A>G (p.Asp79Gly) and c.364A>T (p.Arg122Trp) correlate with residual enzyme activity and attenuated phenotypes. A founder R122W allele predominates in Finnish patients, and multiple private alleles have been described worldwide.

Functional studies demonstrate loss of PPT1 activity leads to defective endocytosis, saposin A/D accumulation in fibroblasts (PMID:16542649), structural insights from the crystal structure reveal an α/β-hydrolase fold with catalytic triad Ser115–His289–Asp233 explaining the impact of missense alleles (PMID:10781062), and Ppt1 knockout mice recapitulate INCL neuropathology with spasticity, seizures, storage material, and reduced lifespan (PMID:11717424). AAV2-mediated intravitreal gene therapy restores PPT1 activity in retina and brain, improving histology and function (PMID:15979943).

Therapeutic proof‐of‐concept includes treatment with the thioesterase‐mimetic N-(tert-butyl)hydroxylamine (NtBuHA) in Ppt1(−/−) mice, which depletes lysosomal ceroid, suppresses neuronal apoptosis, and extends lifespan (PMID:24056696). In vitro read-through of premature stop codons by PTC124 induces PPT1 activity, reduces thioester load, and protects patient cells (PMID:21704547). A pilot clinical trial of oral cysteamine bitartrate and N-acetylcysteine demonstrated delayed isoelectric EEG and granular osmiophilic deposit depletion (PMID:24997880).

Integration of robust genetic and functional data, including extensive segregation, multi‐family mutation screening, animal models, and therapeutic rescue experiments, establishes a Definitive gene–disease relationship. Clinically, PPT1 mutation analysis and enzyme assay are essential for early diagnosis, genetic counseling, and eligibility for emerging therapies. Key Take-home: Bi-allelic PPT1 mutations reliably predict INCL, guiding diagnostic workflows and informing targeted therapeutic strategies.

References

• Biochemical and Biophysical Research Communications • 1998 • A novel insertion mutation (A169i) in the CLN1 gene is associated with infantile neuronal ceroid lipofuscinosis in an Italian patient. PMID:9571187
• The Journal of Clinical Investigation • 1998 • Molecular genetics of palmitoyl-protein thioesterase deficiency in the U.S. PMID:9664077
• Prenatal Diagnosis • 1999 • First-trimester diagnosis of infantile neuronal ceroid lipofuscinosis (INCL) using PPT enzyme assay and CLN1 mutation analysis. PMID:10416973
• Experimental Cell Research • 2006 • Palmitoyl protein thioesterase 1 (PPT1) deficiency causes endocytic defects connected to abnormal saposin processing. PMID:16542649
• Proceedings of the National Academy of Sciences of the United States of America • 2000 • The crystal structure of palmitoyl protein thioesterase 1 and the molecular basis of infantile neuronal ceroid lipofuscinosis. PMID:10781062
• Proceedings of the National Academy of Sciences of the United States of America • 2001 • Disruption of PPT1 or PPT2 causes neuronal ceroid lipofuscinosis in knockout mice. PMID:11717424
• Molecular Therapy • 2005 • AAV2-mediated ocular gene therapy for infantile neuronal ceroid lipofuscinosis. PMID:15979943
• Nature Neuroscience • 2013 • Neuroprotection and lifespan extension in Ppt1(-/-) mice by NtBuHA: therapeutic implications for INCL. PMID:24056696
• Molecular Genetics and Metabolism • 2011 • Stop codon read-through with PTC124 induces palmitoyl-protein thioesterase-1 activity, reduces thioester load and suppresses apoptosis in cultured cells from INCL patients. PMID:21704547
• The Lancet Neurology • 2014 • Oral cysteamine bitartrate and N-acetylcysteine for patients with infantile neuronal ceroid lipofuscinosis: a pilot study. PMID:24997880

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