Neuronal Ceroid Lipofuscinosis 4 via the DNAJC5 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 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.

CLN4 is characterized by an autosomal dominant mode of inheritance, adult onset, rapid progression, and reduced life span. Symptoms start usually between the third and fourth decades of life with tonic-clonic seizures. Additional symptoms appear with the progression of the disease and include myoclonic seizures, dementia, attention deficit, memory loss, speech abnormality, tremor, voluntary movement disturbance and parkinsonian features (Burneo et al. 2003). MRI findings are consistent with cerebral and cerebellar brain atrophy. Vision is spared (Nosková et al. 2011).

CLN4 is the only neuronal ceroid lipofuscinosis that is inherited with an autosomal dominant manner. The penetrance is high. It is caused by pathogenic variants in the DNAJC5 gene. To date, only two variants have been implicated in the disorder. A missense variant (c.344T>G, p.Leu115Arg) and a three-nucleotide deletion that is predicted to result in the in-frame deletion of an adjacent residue (p.Leu116del) have been reported in a total of 8 unrelated families (Nosková et al. 2011; Benitez et al. 2011; Greaves et al. 2012; Velinov et al. 2012). These two variants accounted for about 38% of cases with unexplained adult-onset. Haplotype analyses indicate that both variants are recurrent (Cadieux-Dion et al. 2013).

The DNAJC5 gene encodes cysteine-string protein alpha (CSPalpha), which is postulated to play a neuroprotective role. DNAJC5 pathogenic variants result in synaptic dysfunction and reduced life span in mice (Schmitz F. et al. 2006).

The two pathogenic variants in the DNAJC5 gene accounted for about 38% of cases with unexplained adult-onset (Cadieux-Dion et al. 2013).

This test provides full coverage of all coding exons of the DNAJC5 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.