Diagnosis and misdiagnosis of adult neuronal ceroid lipofuscinosis (Kufs disease)

Abstract

Objective: To critically re-evaluate cases diagnosed as adult neuronal ceroid lipofuscinosis (ANCL) in order to aid clinicopathologic diagnosis as a route to further gene discovery.Methods: Through establishment of an international consortium we pooled 47 unsolved cases regarded by referring centers as ANCL. Clinical and neuropathologic experts within the Consortium established diagnostic criteria for ANCL based on the literature to assess each case. A panel of 3 neuropathologists independently reviewed source pathologic data. Cases were given a final clinicopathologic classification of definite ANCL, probable ANCL, possible ANCL, or not ANCL.

Clinical challenges and future therapeutic approaches for neuronal ceroid lipofuscinosis

“…1 In recessive adult phenotypes (more than 16 years of age) also referred to as Kufs disease, visual loss is usually absent, and patients present with pro gressive myoclonus epilepsy (type A) or dementia with motor decline (type B) typically around age 30 years, but symptom onset could range from 16 to 50 years of age. 19 Even though all types of NCLs share a similar set of clinical features (eg, dementia, epilepsy, motor de terioration, and visual loss) their clinical severity and pre sentation often differs even for those caused by muta tions in the same gene. Delay in expressive language 9 Children with a combination of language acquisition delay and new onset of seizures should be tested for CLN2 disease.…”

“…3 Later onset forms of disease that might have a more protracted overall course also occur and some antici pated classic phenotypes might be absent as a result of milder muta tions that do not completely stop protein function (table 1). 19 There are examples of muta tions associated with a specific phenotype such as a missense mutation in CLN8 or the 1 kb intragenic deletion that underlies the most common form of NCLs, juvenile CLN3 disease. 3 The most prevalent mutations are the 1 kb deletion in CLN3 and two mutations in CLN2.…”

“…Extracerebral storage is readily detected in childhood NCLs but not necessarily in NCLs presenting in adulthood. 19 Prenatal diagnosis is available and can be offered to families with a history of NCL disease. Preimplantation genetic diagnosis 39 or a combination of enzyme assay and mutational analysis, perhaps with ultrastructural ex amination of chorionic villus samples obtained at 12-15 weeks' gestation, can provide a rapid diagnosis.…”

“…2,40 In adult onset NCLs, brain atrophy is less obvious. 2,40 Pronounced microglial and astrocytic activation precedes and per haps causes neuron loss, 19,41,42 accurately predicting its dis tribution. 41 Brain atrophy of the cerebral cortex and enlargement of the subarachnoid space and ventricles progresses throughout the disease.…”

“…40 Lipo pigments also accumulate in the CNS with increasing age, in healthy people, or neurologi cal conditions such as mucopolysaccharidoses or GM1 ganglio sidosis, 40 and careful neuropathological assess ment is needed to avoid misdiagnosis (eg, earlyonset Alzheimer's disease). 19 Mice that are genetically modified or have spontaneous mutations exist for all NCL genes, 5,46 and their char acterisation has provided insights into the staging of neuropathological changes. 6,7 This has revealed differences in the extent, timing, and nature of changes 41,42 despite leading to a similar pathological endpoint.…”