Neuronal Ceroid-Lipofuscinoses type 5 (associated to CLN5)

Neuronal ceroid lipofuscinosis type 5 is a neurodegenerative disease that causes delayed psychomotor development and visual problems. The affected gene is CLN5 which produces an enzyme that regulates lysosomal trafficking.

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.

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

In neuronal ceroid lipofuscinosis type 5 the symptoms usually appear between 4 and 7 years of age. The main symptoms include motor disturbances, mental deterioration, cognitive disturbances, visual problems and epileptic seizures. Life expectancy is between 10 and 30 years of age.

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

CLN5

Bibliography

Basak I, Wicky HE, McDonald KO, et al. A lysosomal enigma CLN5 and its significance in understanding neuronal ceroid lipofuscinosis. Cell Mol Life Sci. 2021 May;78(10):4735-4763.

Moharir A, Peck SH, Budden T, Lee SY. The role of N-glycosylation in folding, trafficking, and functionality of lysosomal protein CLN5. PLoS One. 2013 Sep 10;8(9):e74299.

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.

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