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.

Results: Of the 47 cases, only 16 fulfilled the Consortium's criteria of ANCL (5 definite, 2 probable, 9 possible). Definitive alternate diagnoses were made in 10, including Huntington disease, early-onset Alzheimer disease, Niemann-Pick disease, neuroserpinopathy, prion disease, and neurodegeneration with brain iron accumulation. Six cases had features suggesting an alternate diagnosis, but no specific condition was identified; in 15, the data were inadequate for classification. Misinterpretation of normal lipofuscin as abnormal storage material was the commonest cause of misdiagnosis.

Conclusions: Diagnosis of ANCL remains challenging; expert pathologic analysis and recent molecular genetic advances revealed misdiagnoses in >1/3 of cases. We now have a refined group of cases that will facilitate identification of new causative genes.

Figure. Pathologic diagnosis and misdiagnosis of adult-onset neuronal ceroid lipofuscinosis (ANCL)

(A) Electron micrograph of KC33 shows one of many deposits of lipofuscin in a cortical neuron. These deposits were originally considered to represent granular osmiophilic deposits (GRODs), leading to a diagnosis of ANCL. Lipid vacuoles, as seen here, are numerous in lipofuscin, but not in GRODs, and the granules in lipofuscin are coarser and less uniform (bar = 5 μm). The patient had cognitive decline beginning at age 28 years; NPC1 mutation was later found (table 3). (B) This electron micrograph of KC15 shows fingerprint profiles from an eccrine secretory cell. The basic paired parallel line pattern even at this magnification tends to appear as a single wide slightly fuzzy line, but the spacing, the wheeling ranks, and the focal crystalline pattern where the ranks intersect (at the left of the asterisk) are very characteristic (bar = 1 μm). Disease onset was at 18 years with stimulus-sensitive and action-induced myoclonus, dementia, and parkinsonism on the background of normal development. This case met out criteria for classification as definite ANCL. The molecular basis remains unknown.