Neuronal Ceroid Lipofuscinosis 10 via the CTSD 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.

CLN10 has been associated with congenital onset, rapid progression and death during the first few weeks of life. Symptoms at onset include post-natal respiratory insufficiency, status epilepticus and microcephaly (Barohn et al. 1992). Previously, juvenile onset was considered to be an atypical form of CLN10 because only one case was reported in the literature (Steinfeld 2006). In this case, symptoms started during the early-school age, and included ataxia, retinitis pigmentosa and cerebral and cerebellar atrophy. Progressive cognitive and motor dysfunction developed later. Recently, two consanguineous families with a history of CLN10, similar features, and sensory axonal neuropathy were reported (Hersheson et al. 2014). In these two families symptoms started at age 8 and 15 years.

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). CLN10 is caused by compound heterozygous or homozygous pathogenic variants in the CTSD gene (Siintola et al. 2006; Steinfeld et al. 2006). Ten different pathogenic variants have been reported in various ethnic populations, including families from Somalia, Germany, the United States, and Pakistan. Eight of the variants are missense; the two remaining are expected to result in a truncated protein. No large pathogenic deletions have been reported to date (Human Gene Mutation Database).

Pathogenic variants in CTSD appear to be a rare cause of NCL. They account for about 1% of patients with a clinical diagnosis of the disorder (Santorell et al. 2013).

The CTSD gene encodes cathespsin D (CatD), a ubiquitously expressed lysosomal protease that is involved in several cellular functions, including proteolytic degradation (Baldwin et al. 1993). Complete or near complete deficiency of CatD activity causes a congenital and severe phenotype (Siintola et al. 2006; Fritchie et al. 2009); while a partial deficiency results in a juvenile phenotype (Steinfeld et al. 2006; Hersheson et al. 2014).

Pathogenic variants in CTSD appear to be a rare cause of NCL. They account for about 1% of patients with a clinical diagnosis of the disorder (Santorelli et al. 2013).

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