Neuronal Ceroid Lipofuscinosis 7 via the MFSD8 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 the 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 mutations in CLN3.

CLN7 disease is characterized by late-infantile onset, usually between 2-7 years of age. It can be distinguished from the classical late-infantile CLN2 by more severe seizures and slower cerebral and cerebellar atrophy. Symptoms include ataxia, vision impairment and progressive cognitive and motor dysfunction (Kousi et al. 2009; Topcu et al. 2004).

Most CLNs 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). CLN7 is caused by pathogenic variants in the MFSD8 gene (Siintola et al. 2007). To date, 35 different pathogenic variants have been reported in various ethnic populations. About half of the variants are missense. The other half is predicted to result in truncated proteins and include nonsense, splicing, small insertions or deletions, and indels. No large pathogenic deletions were reported to date (Human Gene Mutation Database). Pathogenic variants in MFSD8 account for about 40% of patients with late infantile neuronal ceroid lipofuscinosis. Most causative variants are unique to single families. A founder variant, c.881C>A (p.Thr294Lys), is common in the Roma population that originated from the former Czechoslovakia (Kousi et al. 2009; Kousi et al. 2012). The MFSD8 gene encodes the Major Facilitator Superfamily Domain-containing protein-8, a lysosomal membrane protein. It is hypothesized to be a lysosomal transporter. However, the nature of the transported substrates is unknown at this time (Siintola et al. 2007; Kousi et al. 2012).

Pathogenic variants in MFSD8 were identified in about 40% of patients clinically diagnosed with late infantile ceroid lipofuscinoses (Kousi et al. 2009).

This test provides full coverage of all coding exons of the MFSD8 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.