Neuronal ceroid lipofuscinoses

Recommended panel testing at Breda Genetics for this condition:

Neuronal ceroid lipofuscinosis (ATP13A2, CLN3, CLN5, CLN6, CLN8, CTSD, CTSF, DNAJC5, GRN, KCTD7, MFSD8, PPT1, TPP1)


Illustration of a nerve cell on a colored background with light effects

Neuronal ceroid lipofuscinoses (NCLs) are a group of inherited neurodegenerative disorders traditionally grouped together on the basis of certain shared clinical and pathological features such as accumulation of autofluorescent storage material. They are in fact lysosomal storage diseases. Neuronal ceroid lipofuscinoses can affect children and adults, although the disorder is primarily of the childhood. Genetic mutations can affect lysosomal enzymes, transmembrane proteins, and other type of proteins.

The most common form is related to mutations in the CLN3 gene (and it is also known as juvenile neuronal ceroid lipofuscinosis – JNCL).

Mutations have been thus far identified also in the following genes: PPT1, TPP1, CLN3, CLN5, CLN6, CTSF, ATP13A2, GRN, MFSD8, CLN8, CTSD, DNAJC5, and KCTD7. The childhood form is autosomal recessively inherited, whereas the adult form can be either autosomal recessively or autosomal dominantly inherited.

It is important to remember that the most common CLN3 mutation is a large deletion of approximately 1 kb that includes exons 7 and 8 (c.461-280_677+382del) and which is not detectable by sequencing. Hence, CLN3-related lipofuscinosis cannot be excluded by negative sequencing alone. Rather, CLN3 testing should be primarily addressed by MLPA or qPCR.

Some patients remain with molecular unconfirmed ceroid lipofuscinosis.

The disease may vary in onset, severity, and progression, although most mutations associate with a typical presentation.

Progressive neuron loss, particularly in the cerebral and cerebellar cortices, with activation of the glia and innate immune system and the cerebral and extracerebral formation of lipopigments characterize the disease. Clinical features include motor problems, vision loss, seizures, and cognitive decline, culminating in premature death. Retina undergoes atrophy in all childhood forms. The first symptoms typically appear between age two and four years, usually starting with epilepsy, followed by regression of developmental milestones, myoclonic ataxia, and pyramidal signs.

Currently, no form of the disease can be treated or cured, although ground-breaking clinical trials are going, including small molecule, enzyme replacement, stem cell, and gene therapies.

Leukoencephalopathies, mitochondrial disorders, mucopolysaccharidoses, gangliosidoses, and peroxisomal disorders are all included in the differential diagnosis of neuronal ceroid lipofuscinoses.

Note: former eponyms of the various subtypes of neuronal ceroid lipofuscinoses include Haltia-Santavuori (CLN1), Janský-Bielschowsky (CLN2), Spielmeyer-Sjögren (CLN3), Kufs type A (CLN6), Kufs type B (CLN13), Finnish variant late infantile (CLN5), Lake-Cavanagh or Indian variant late infantile (CLN6), Turkish variant late infantile (CLN7), Northern epilepsy/EPMR (CLN8), and Parry (CLN4).

Recommended panel testing at Breda Genetics for this condition:

Neuronal ceroid lipofuscinosis (ATP13A2, CLN3, CLN5, CLN6, CLN8, CTSD, CTSF, DNAJC5, GRN, KCTD7, MFSD8, PPT1, TPP1)


Human NCL Neuropathology. Radke J, Stenzel W, Goebel HH. Biochim Biophys Acta. 2015 Oct;1852(10 Pt B):2262-6. PMID: 25989315

Towards a new understanding of NCL pathogenesis. Cooper JD, Tarczyluk MA, Nelvagal HR. Biochim Biophys Acta. 2015 Oct;1852(10 Pt B):2256-61. PMID: 26026924

Genetics of the neuronal ceroid lipofuscinoses (Batten disease). Mole SE, Cotman SL. Biochim Biophys Acta. 2015 Oct;1852(10 Pt B):2237-41. PMID: 26026925 

Cell biology of the NCL proteins: What they do and don’t do. Cárcel-Trullols J, Kovács AD, Pearce DA. Biochim Biophys Acta. 2015 Oct;1852(10 Pt B):2242-55. PMID: 25962910

Experimental therapies in the neuronal ceroid lipofuscinoses. Neverman NJ, Best HL, Hofmann SL, Hughes SM. Biochim Biophys Acta. 2015 Oct;1852(10 Pt B):2292-300.  PMID: 25957554

Neuronal Ceroid-Lipofuscinoses. Mole SE, Williams RE. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. 2001 Oct 10 [updated 2013 Aug 1]. PMID: 20301601

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