Neuronal ceroid lipofuscinosis type 1 (PPT1 gene)
Neuronal ceroid lipofuscinoses (NCLs) or Batten disease are a group of inherited, neurodegenerative, smooth storage disorders characterized by progressive intellectual and motor impairment, seizures, and premature death. Visual loss is a feature of most forms. The clinical phenotypes are traditionally characterized according to the age of onset and the order of appearance of the clinical features in infantile, late childhood, juvenile, and adult epilepsy.
Pathogenic variants in thirteen genes (PPT1, TPP1, CLN3, CLN5, CLN6, MFSD8, CLN8, CLN8, CTSD, DNAJC5, CTSF, ATP13A2, GRN, KCTD7) are known to cause NCL. The diagnosis of NCL is based on enzyme activity assay and molecular genetic testing. In unusual cases, diagnosis is based on electron microscopy of biopsied tissues. The diagnostic testing strategy depends on the age of onset.
The diagnostic test strategy depends on the age of onset.
NCLs reach the highest incidence values in Northern Europe and the USA with 1 case per 12,500 population.
Symptoms
Most patients with NCLs (except those associated with the CTSD gene) have normal psychomotor development before the first symptoms appear. NCLs usually appear in childhood and patients have a short life expectancy, although there are also cases of late onset, after the age of 60, with milder symptomatology and better prognosis.
At least two of the following symptoms are present in NCLs: dementia, epilepsy, motor impairment, and visual loss. The remaining manifestations and timing will depend on the patient's mutations in one of the 13 related genes.
In the classic infantile form or associated with the PPT1 gene, symptoms appear before the first year of age and progress rapidly. Developmental skills are not acquired or there is a gradual loss. In some cases, the disease appears around 5 or 6 years of age and has a slower progression.
Disease management
Available treatments focus on relieving symptoms. Anticonvulsant drugs are used to prevent or treat seizures. Associated psychiatric and motor disorders can also be controlled when they occur.
In recent years, significant advances have been made toward potential treatments for NCLs such as gene therapy and enzyme replacement therapy. Despite the efforts, only one NCL2-specific drug called Cerliponase alfa (Brineura; Biomarin Pharmaceutical, USA) has been approved in 2017.
Genes analyzed
Bibliography
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Das AK, Becerra CH, Yi W, et al.Molecular genetics of palmitoyl-protein thioesterase deficiency in the U.S. J Clin Invest. 1998 Jul 15;102(2):361-70.
Kousi M, Lehesjoki AE, Mole SE. Update of the mutation spectrum and clinical correlations of over 360 mutations in eight genes that underlie the neuronal ceroid lipofuscinoses. Hum Mutat. 2012 Jan;33(1):42-63.
Mole SE, Anderson G, Band HA, et al. Clinical challenges and future therapeutic approaches for neuronal ceroid lipofuscinosis. Lancet Neurol. 2019 Jan;18(1):107-116.
