Neuronal Ceroid Lipofuscinosis 12 via the ATP13A2 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.

CLN12 is characterized by juvenile onset and slow progression. To date, one single family with four affected individuals has been documented in the literature. Symptoms started around the age of 8 years with learning difficulties. As the disease progressed additional symptoms appeared and included bradykinesia, limb stiffness, gait disturbances, dysarthria, clumsiness, spasticity, myotonic jerks, seizures, slow eye movements, and peripheral neuropathy. MRI findings indicated brain atrophy. In this family, the diagnosis of neuronal ceroid lipofuscinosis was confirmed by the presence of lipofuscin deposits in post-mortem pathological studies of the brain and retina (De Volder et al. 1990; Bras et al. 2012).

Most CLNs, including CLN12, 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).

CLN12 is caused by pathogenic variants in the ATP13A2 gene. A homozygous missense variant, c.2429T>G (p.Met810Arg), was found in the one reported family (Bras et al. 2012; De Volder et al. 1990). Support for the pathogenicity of this variant include its segregation with the disease in the described family; and its absence from control populations in various databases. Importantly, a homozygous truncating variant, c.1620delG, in the ATP13A2 gene was previously reported in a dog model of late onset lethal form of NCL. This variant causes exon skipping as the result of a broken exonic splicing enhancer motif (Wöhlke et al. 2011; Farias et al. 2011).

The ATP13A2 gene encodes a lysosomal transport protein that is part of the P-type superfamily of ATPases (Schultheis et al. 2004).

Pathogenic variants in ATP13A2 appear to be a rare cause of NCL. Only one NCL family with such variants has been reported to date (Bras et al. 2012).

Pathogenic variants in ATP13A2 appear to be a rare cause of NCL. Only one NCL family with a pathogenic ATP13A2 variant has been reported to date (Bras et al. 2012).

This test provides full coverage of all coding exons of the ATP13A2 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).