Neuronal Ceroid Lipofuscinosis 13 via the CTSF Gene

The neuronal ceroid lipofuscinoses (NCLs) are inherited neurodegenerative lysosomal storage disorders caused by the accumulation of ceroid and lipofuscin in various cell types, mainly cells of the cerebral cortex, cerebellar cortex, and retina (Dyken et al. 1988; Williams and Mole 2012). Characteristic features at onset include clumsiness; deterioration of vision and psychomotor functions; seizures; and behavioral changes. Progression of clinical features results ultimately in total disability, blindness and premature death. Although NCL affects primarily children, age of onset of symptoms varies from infancy to adulthood. The incidence of NCL is variable and ranges from 1.3 to 7 per 100,000 (Mole and Williams 2013). However, it is more common in northern European populations, particularly Finland where the incidence may reach 1 in 12,500 individuals and a carrier frequency of 1 in 70 (Rider and Rider 1988). NCLs are clinically and genetically heterogeneous. A nomenclature and classification based both on the age of onset of symptoms and the disease-causing gene has been recently developed, which classifies NCLs into thirteen subtypes (CLN1-8, 10-14) (Williams and Mole 2012). The causative gene for the CLN9 phenotype has not been identified yet (Schulz et al. 2004).

Of note, NCLs were previously known as Batten disease. However, in recent nomenclature, Batten disease only applies to NCL caused by pathogenic variants in CLN3.

CLN13, also referred to as Kufs’ disease Type B, is characterized by a later age of onset, usually around the age of 30; although earlier and later onsets have been reported. Premature death occurs as the result of dementia, with an average clinical course of 12.5 years. Behavioral changes, dementia and motor disturbances with no visual impairment are the distinguishing clinical features. Facial dyskinesia is seen in some, but not all patients (Berkovic et al. 1988). MRI findings include frontal and parietal cortical atrophy, cerebellar atrophy, and ventricular enlargement (Smith et al. 2013).

Most CLNs, including CLN13, are inherited in an autosomal recessive manner. Thirteen genes have been implicated in the disorder: PPT1, TPP1, CLN3, CLN5, CLN6, MFSD8, CLN8, CTSD, DNAJC5, CTSF, ATP13A2, GRN, and KCTD7 (Mole and Williams 2013).

CLN13 is caused by pathogenic variants in the CTSF gene. Six pathogenic variants, that include 4 missense, one splice site, and one small deletion, have been reported (Smith et al. 2013; Di Fabio et al. 2014). The splice site variant, c.213+1G>C, was found in the homozygous state in a large consanguineous family from Italy. Additional support for the involvement of CTSF gene in CLN13 is provided by the development, in a ctsf knock-out mouse model, of a phenotype and pathological findings similar to that of human adult-onset neuronal ceroid lipofuscinosis (Tang et al. 2006).

The CTSF gene encodes a lysosomal cysteine protease. The natural substrates of this protease are not known at this time (Smith et al. 2013).

Pathogenic variants in CTSF appear to be a rare cause of NCL. They were found in a minority of patients with Kufs’ disease Type B (Smith et al. 2013).

This test provides full coverage of all coding exons of the CTSF gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).