Ceroid Lipofuscinosis, Neuronal, 13

A number sign (#) is used with this entry because neuronal ceroid lipofuscinosis-13 (CLN13) is caused by homozygous or compound heterozygous mutation in the CTSF gene (603539) on chromosome 11q13.

Description

Neuronal ceroid lipofuscinosis-13 is an autosomal recessive neurodegenerative disorder characterized by adult onset of progressive cognitive decline and motor dysfunction leading to dementia and often early death. Some patients develop seizures. Neurons show abnormal accumulation of autofluorescent material (summary by Smith et al., 2013).

Adult-onset neuronal ceroid lipofuscinosis is sometimes referred to as Kufs disease.

For a discussion of genetic heterogeneity of neuronal ceroid lipofuscinosis (CLN), see CLN1 (256730).

Clinical Features

Smith et al. (2013) reported 2 Italian sibs, born of unrelated parents, with adult onset of CLN. At age 20 years, the proband developed a progressive cerebellar syndrome manifest as tremor, ataxia, and dysarthria. She later developed tonic-clonic seizures and progressive cognitive impairment with emotional lability turning into dementia. She died at age 42. Neuropathologic examination showed diffuse cerebral atrophy with neuronal loss and astrogliosis. There was abundant autofluorescent material in the cytoplasm of neurons in the cerebral cortex, thalamus, striatum, brainstem nuclei, and Purkinje cells. This storage material was immunoreactive for ubiquitin and contained fingerprint profiles. The patient's older sister developed depression associated with cognitive decline at age 32 years. She had rare seizures from age 41, and later showed ataxia, dysarthria, and pyramidal and extrapyramidal signs. She was bedridden at age 51. Brain MRI showed diffuse cerebral atrophy; skin biopsy was unremarkable. An unrelated woman, born of consanguineous French Canadian parents, had occasional focal seizures in her twenties. At age 35, she showed progressive dementia with mood disturbance and motor features, including tremor, ataxia, and extrapyramidal rigidity with mild hyperreflexia. In her forties, she had dementia and became wheelchair-bound. Brain biopsy showed autofluorescent material in neurons. A 35-year-old Australian woman had a similar disorder, with cognitive decline and dysarthria followed by at least 1 seizure and mild ataxia with tremor.

Di Fabio et al. (2014) reported an Italian family in which 4 individuals had Kufs disease. The proband presented with tonic-clonic seizures at age 23. From age 30, she showed progressive cognitive decline associated with myoclonic jerks, facial dyskinesia, axial hypotonia, postural tremor, hyperreflexia, and extensor plantar responses with frontal release signs. At age 40, she was wheelchair-bound and totally dependent for activities of daily living. Brain imaging showed severe cortical and cerebellar atrophy and periventricular hyperintensities on T2-weighted images. The patient's deceased mother and living cousin had a similar disease course, with onset of seizures in their twenties or early thirties, followed by progressive cognitive decline, behavioral and personality changes, and dementia. An affected aunt had later onset of similar symptoms in her mid-sixties. Skin fibroblasts from 2 of the patients showed aggresome-like osmiophilic cytoplasmic inclusions suggestive of NCL, and Western blot analysis of 1 patient's cells showed increased expression of polyubiquitinated proteins. Two additional deceased family members reportedly had a phenotype consistent with the disorder. Di Fabio et al. (2014) noted that the transmission pattern in this family initially resembled an autosomal dominant disorder, but the family was from an isolated community with a high degree of inbreeding (Fondi, in central Italy), and detailed family history was consistent with autosomal recessive inheritance.

Inheritance

The transmission pattern of CLN13 in the families reported by Smith et al. (2013) was consistent with autosomal recessive inheritance.

Molecular Genetics

In affected members of 2 unrelated families with Kufs disease, Smith et al. (2013) identified homozygous or compound heterozygous mutations in the CTSF gene (603539.0001-603539.0003). The mutations, which were found by linkage analysis combined with exome sequencing, segregated with the disorder and were not found in several large control databases. Sequencing of the CTSF gene in 22 unrelated probands with suspected Kufs disease identified compound heterozygous mutations (603539.0004-603539.0005) in 1 patient. Molecular modeling predicted that the mutations were pathogenic, and Smith et al. (2013) noted that Ctsf-null mice develop a similar neurodegenerative disorder (Tang et al., 2006). The findings implicated CTSF dysfunction in this disorder.

In affected members of an Italian family with CLN13, Di Fabio et al. (2014) identified a homozygous splice site mutation in the CTSF gene (603539.0006).

Animal Model

Tang et al. (2006) found that Ctsf-null mice developed normally, but had onset of a progressive neurologic disorder between 12 and 16 months of age. Mutant mice showed progressive difficulty walking, with hind leg weakness, decline in motor coordination, and general wasting. Other features included tonic hind leg extension, poor balance, tremor, and spasticity. Some mice had seizures. Ctsf-null mice died within 4 to 6 months of symptom onset. Postmortem examination showed substantial gliosis in the brain and spinal cord, neuronal loss, and an accumulation of cytoplasmic eosinophilic and autofluorescent granules in neurons and glial cells. Ultrastructural analysis confirmed membrane-bound lamellar inclusions in fingerprint patterns, consistent with lipofuscin. The phenotype was reminiscent of human adult-onset neuronal ceroid lipofuscinosis.