Neuronal Ceroid-Lipofuscinoses type 7 (associated to MFSD8)

It is a lysosomal storage disease in which the MFSD8 gene, which produces a protein involved in the transport of ions across the lysosome membrane, is affected.

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.

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 7, symptoms may appear in infancy, between 2 and 7 years of age. Affected children present with severe neurological symptoms, such as progressive neurodevelopmental disorders and microcephaly, visual impairment, ataxia, speech disturbances and frequent seizures.

The patterns of lipofuscin acómules most frequently observed microscopically in neuronal ceroid lipofuscinosis type 7 comprise mixed combinations of granular, curvilinear, dactyl, and straight profiles.

Disease management

The treatments available 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

MFSD8

Bibliography

Canafoglia L, Gilioli I, Invernizzi F, et al. Electroclinical spectrum of the neuronal ceroid lipofuscinoses associated with CLN6 mutations. Neurology. 2015 Jul 28;85(4):316-24.

Gao H, Boustany RM, Espinola JA, et al. Mutations in a novel CLN6-encoded transmembrane protein cause variant neuronal ceroid lipofuscinosis in man and mouse. Am J Hum Genet. 2002 Feb;70(2):324-35.

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.

Clinical challenges and future therapeutic approaches for neuronal ceroid lipofuscinosis.

Rus CM, Weissensteiner T, Pereira C, et al. Clinical and genetic characterization of a cohort of 97 CLN6 patients tested at a single center. Orphanet J Rare Dis. 2022 May 3;17(1):179.

Clinical and genetic characterization of a cohort of 97 CLN6 patients tested at a single center.

Trivisano M, Ferretti A, Calabrese C, et al. Neurophysiological Findings in Neuronal Ceroid Lipofuscinoses. Front Neurol. 2022 Feb 25;13:845877.

Neuronal Ceroid Lipofuscinoses.

Tuermer A, Mausbach S, Kaade E, et al. CLN6 deficiency causes selective changes in the lysosomal protein composition. Proteomics. 2021 Oct;21(19):e2100043.

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