Kufs Disease, the Major Adult Form of Neuronal Ceroid Lipofuscinosis, Caused by Mutations in CLN6

Abstract

The molecular basis of Kufs disease is unknown, whereas a series of genes accounting for most of the childhood-onset forms of neuronal ceroid lipofuscinosis (NCL) have been identified. Diagnosis of Kufs disease is difficult because the characteristic lipopigment is largely confined to neurons and can require a brain biopsy or autopsy for final diagnosis. We mapped four families with Kufs disease for whom there was good evidence of autosomal-recessive inheritance and found two peaks on chromosome 15. Three of the families were affected by Kufs type A disease and presented with progressive myoclonus epilepsy, and one was affected by type B (presenting with dementia and motor system dysfunction). Sequencing of a candidate gene in one peak shared by all four families identified no mutations, but sequencing of CLN6, found in the second peak and shared by only the three families affected by Kufs type A disease, revealed pathogenic mutations in all three families. We subsequently sequenced CLN6 in eight other families, three of which were affected by recessive Kufs type A disease. Mutations in both CLN6 alleles were found in the three type A cases and in one family affected by unclassified Kufs disease. Mutations in CLN6 are the major cause of recessive Kufs type A disease. The phenotypic differences between variant late-infantile NCL, previously found to be caused by CLN6, and Kufs type A disease are striking; there is a much later age at onset and lack of visual involvement in the latter. Sequencing of CLN6 will provide a simple diagnostic strategy in this disorder, in which definitive identification usually requires invasive biopsy.

Clinical Reasoning: Progressive cognitive decline, cerebellar ataxia, recurrent myoclonus, and epilepsy

“…NCLs are a group of inherited neurodegenerative disorders characterized by lysosomal lipopigment storage mainly in neurons, and the retina is usually involved (except in the adult form of NCL, Kufs disease) 3 ; however, lysosomal lipopigment has also been reported among extracerebral tissues, including lymphocytes, skin, rectum, and skeletal muscle. Cytoplasmic vacuoles of lymphocytes may also be revealed in a blood smear examination using light microscopy.…”

“…5 Disease onset is usually in the third decade of life but onset in teenagers has also been reported. 3,4 Two gene mutations have been reported to account for the majority of patients: DNAJC5 mutations lead to the autosomal dominant inherited type Kufs disease and CLN6 mutations cause the autosomal recessive inherited type Kufs disease. 6 Cerebral MRI usually shows brain atrophy.…”

“…Mutations of CLN6 were identified in variant of lateinfantile NCL (vLNCL) and recessive Kufs disease type A. 3,4 Patients with vLNCL experience symptom onset at an age between 18 months and 5 years, with loss of vision. Since our patient did not show visual impairment as a teenager, we excluded vLNCL.…”

Neuronal ceroid-lipofuscinoses

“…The putative gene loci CLN4A and CLN4B were only recently mapped. The autosomal recessive Kufs disease, CLN4A, has been shown to be caused by mutations in the CLN6 gene [25], while the autosomal dominant Kufs disease, CLN4B, has been shown to be caused by mutations in DNAJC5 that encodes cysteine-string protein alpha (CSP␣) [26]. Other NCLs that may rarely present with adult onset disease include CLN1, CLN10, CLN5, CLN13, and CLN11.…”

“…Another group of researchers has shown a correlation between the CLN3P expression and the synthesis of bis (monoacylglycerol) phosphate (BMP) and suggested that CLN3P may play a role in the biosynthesis of BMP [24]. CLN4A (Kufs disease, autosomal recessive) has been shown to be caused by mutations in the CLN6 gene [25]. CLN4B (Kufs disease, autosomal dominant) has been shown to be caused by mutations in DNAJC5 that encodes cysteine-string protein alpha (CSP␣) [26].…”