Summary Neuronal ceroid lipofuscinoses (NCLs) are a group of inherited lysosomal storage disorders – most commonly occurring in childhood – characterized by progressive, widespread neurodegeneration and intra-neuronal accumulation of autofluorescent lipopigments. Adult-onset NCL (also referred to as Kufs disease) is the rarest entity of this group, with an incidence of 1 in 1,000,000 worldwide.
The clinical presentation of Kufs disease involves any combination of progressive dementia, epilepsy, myoclonus, cerebellar and/or extrapyramidal signs. Behavioural changes are also common and visual loss is infrequent; however, the condition invariably leads to death within 15 years of the onset of symptoms.
The diagnostic challenges posed by patients with Kufs disease are two-fold. Firstly, their clinical presentation can mimic several other rare causes of progressive myoclonic epilepsy or dementia with motor deterioration. Secondly, unlike other forms of NCL, extra-neural accumulation of the hallmark lipopigments is unreliable for confirming a diagnosis of Kufs disease. This diagnosis is most reliably confirmed by invasive brain biopsy.
Mutations in the DNAJC5 gene, which has a key role in synaptic transmission, are a known cause of autosomal dominant Kufs disease. This gene encodes for cysteine string protein (CSP-α), which is located on pre-synaptic vesicles and enables the formation of SNARE-complexes – the key mediators of pre-synaptic vesicular fusion and exocytosis at the synaptic cleft. Causative mutations reduce synaptic levels of CSP-α, therefore impairing synaptic transmission.
This presentation will describe the clinical features and genetic analysis of a patient diagnosed with autosomal dominant Kufs disease in the UK.