Cathepsin D deficiency causes juvenile-onset ataxia and distinctive muscle pathology

Abstract

CATHEPSIN D DEFICIENCY CAUSES JUVENILE-ONSET ATAXIA AND DISTINCTIVE MUSCLE PATHOLOGYThe neuronal ceroid lipofuscinoses (NCLs) are a heterogeneous group of neurodegenerative disorders with the most common phenotype consisting of early-onset progressive motor deterioration, cognitive decline, visual failure, epilepsy, cerebellar ataxia, and premature death. Mutations in the lysosomal protein cathepsin D (CatD/CTSD) underlie one subtype of NCL (CLN10) and were initially associated with a severe, congenital form resulting in early death, 2 with a single juvenileonset CLN10 disease subsequently reported. 3 We report additional novel mutations in cathepsin D in 2 consanguineous pedigrees, both with a juvenile onset of NCL and associated with characteristic muscle pathology.Methods. Ethical approval to undertake this study was given by the National Hospital for Neurology and Neurosurgery/Institute of Neurology ethics committees and informed consent was obtained from all participating family members.Exome sequencing and homozygosity mapping were carried out in a large recessive consanguineous pedigree with complex ataxia and retinitis pigmentosa, which identified a homozygous missense mutation in CTSD in the index case of family A. We subsequently screened a cohort of complex ataxia cases all with associated retinitis pigmentosa and found a further homozygous missense mutation in CTSD in a second family. To support the pathogenicity of these variants, we carried out a kinetic assay of CatD activity in patient fibroblasts and performed detailed pathologic examination of patient muscle biopsies. See appendix e-1 on the Neurology ® Web site at Neurology.org for additional details on the above methods.Results. A summary of the clinical features of both pedigrees is shown in the table and pedigrees are shown in figure e-1.

Cathepsins in the Pathophysiology of Mucopolysaccharidoses: New Perspectives for Therapy

“…According to the ClinVar Database, 21 mutations have been identified related to CLN10 and affecting the CTSD gene; they include 19 single nucleotide variants, one insertion, and one duplication. Among the 21 mutations, only nine mutations have been confirmed to be pathogenic and linked to the development of CLN10: six missense mutations (p.Phe229Ile, p.Trp383Cys [42], p.Gly149Val, p.Arg399His [124], p.Ser100Phe [125], p.Glu69Lys [126]), a nonsense mutation (c.764dup, p.Tyr255Ter [127]), an insertion (c.268_269insC, p.Gln90fs [128]), and one deletion (p.Phe229del [129]). All different mutations result in neuropathogenesis whose extension is determined by the degree of CTSD gene function loss.…”

“…All different mutations result in neuropathogenesis whose extension is determined by the degree of CTSD gene function loss. Therefore, while complete loss of CTSD activity translates in an early infantile form of CLN10 with patients dying within hours to weeks after birth, patients with residual CTSD activity develop late infantile, juvenile, or adult CLN10 with milder phenotypes [43,121,124]. It is not yet clear how CTSD deficiency causes neuropathies; however, experimental evidence suggests defective autophagy might be in part responsible, as CTSD is essential in degrading cellular components during macroautophagy [130].…”

Human NCL Neuropathology

“…The neuronal ceroid lipofuscinoses (NCL) are diagnosed by muta- 40 tions, but defined by morphological features − though diagnosed by 41 morphology when genetics are not available. The morphological criteria Distribution and severity of cellular loss will best be appreciated by 48 autopsy which, however, will hardly inform about the dynamics of the Reduced brain weights in the individual CLN forms are given in Table 1.…”

A Short Commentary of Neuronal Ceroid Lipofuscinoses; Phenotypes in Congenital to Preschooler

“…Patients with CLN10, the earliest onset form of NCL, is congenital [10,11]. Its specific clinical symptoms are microcephaly due to brain atrophy, absence of neonatal reflexes and respiratory insufficiency.…”

“…Infants with CLN10 disease rarely live more than a few days. The causal gene is located at 11p15.5 (CLN10/CTSD) [10,11]. Mutations in CLN10 cause a deficiency in the activity of the lysosomal enzyme of the aspartic protease cathepsin D. Late infantile-onset and juvenile-onset forms have also been reported [11].…”