A 2-year-old, 3.4 kg male neutered domestic shorthair cat presented to the University of Liverpool Small Animal Teaching Hospital with a 2 week history of progressive weight loss, altered mentation, blindness and suspected focal epileptic seizures. Relevant history included a single visit to the referring veterinary surgeon 6 months prior to presentation for non-specific behavioural changes. On neurological examination, the cat’s mentation was obtunded and disorientated. The menace response was markedly reduced bilaterally with intact pupillary light reflexes. Jaw clattering and hypersalivation were demonstrated intermittently, consistent with focal epileptic seizure activity. Stimulus resulted in hyper-reactivity and hypertonicity of all limbs, thus hindering a comprehensive neurological examination, including ophthalmological and visual assessment. Gait analysis was not possible owing to the cat’s obtunded status and hyper-reactivity. The remaining general examination was unremarkable. Based on the clinical signs and limited neurological examination, a diffuse forebrain neurolocalisation was suspected. The main differential diagnoses for a 2-year-old cat with diffuse forebrain neurolocalisation included metabolic disease (lysosomal storage disease, thiamine deficiency, hepatic encephalopathy), infectious causes (feline infectious peritonitis, toxoplasmosis, bacterial meningitis), immune-mediated disease (meningoencephalitis of unknown origin), developmental disease (lissencephaly, microencephaly) and degenerative disease (neuroaxonal dystrophy and leukoencephalomyelopathy). Biochemistry, including fasting ammonia and pre-prandial bile acids, and haematology were within normal limits. Serological testing for feline leukaemia virus, feline immunodeficiency virus, feline coronavirus and toxoplasmosis were negative. Cerebrospinal fluid analysis, including total protein, total nucleated cell count and cytology, was unremarkable. MRI of the brain was performed using a 1.5 T magnet (Philips Ingenia CX). All slices were 3 mm thick with a 0.3 mm slice gap. Sagittal, dorsal and transverse T2-weighted (T2W) images were acquired. Transverse images for fluid-attenuated inversion recovery (FLAIR), T2*W, T1-weighted before and after intravenous administration of contrast medium (gadobutrol 0.1 mmol/kg bodyweight [Gadovist; Bayer]) and proton-density weighted sequences were obtained. On all sequences there was thinning of the cerebral and cerebellar cortices with widening of the corresponding sulci, demonstrating diffuse cortical atrophy. The corpus callosum was markedly thin and only partially visualised with absence of a visible rostrum, genu and body. Moderate, generalised symmetrical dilation of the ventricular system was present, with complete suppression of contents on FLAIR, indicating that the cerebrospinal fluid was not markedly abnormal. Mild, generalised, symmetrical and homogeneous increased T2W signal intensity of the cerebral white matter was visible, with consequent decrease in the distinction between the white and grey matter (). The pachymeninges were mildly and diffusely thickened. There were no regions of abnormal contrast enhancement. Generalised and marked thickening of the calvarium and osseous tentorium cerebelli was visible (calvarial hyperostosis) with reduction of the fat signal of the diploe (). The remaining bones of the skull were normal. Given the MRI findings and the signalment of the cat the presumptive diagnosis was an inherited neurodegenerative disorder, most likely neuronal ceroid lipofuscinosis or other lysosomal storage disease. Following the presumptive diagnosis of neurodegenerative lysosomal storage disease and worsening of clinical signs the cat was euthanased on humane grounds and underwent a full post-mortem examination. Grossly, the meninges were diffusely moderately thickened and the brain showed moderate diffuse and bilateral cortical atrophy with narrowing of gyri and widening of sulci (). Subjectively, a mild dilation of the ventricular system was observed. Sections of meninges and relevant areas of the brain and cerebellum, including motor, somatosensory, limbic, vestibular and visual system, were sampled for histopathology and transmission electron microscopy (TEM). Samples of the spinal cord at the level of the cervical and lumbosacral intumescences (C5–T1 and L3–L6, respectively) were also obtained for histopathology. Meninges showed diffuse moderate thickening due to deposition of palely eosinophilic mature collagen interpreted as fibrosis and confirmed with Masson’s trichrome stain. All cerebral areas examined showed mild-to-moderate gliosis and moderate loss of neurons (more severe in cortical areas) with numerous neurons distended and enlarged by botryoid, palely acidophilic to glassy cytoplasmic inclusions (), with frequent marginalisation of nuclei. Intracytoplasmic vacuoles resulted markedly positive to Luxol fast blue stain (), moderately positive to periodic acid–Schiff () and stained red with Masson’s trichrome (). When observed under a fluorescent microscope (excitation 465–495 nm) the cytoplasmic material showed green autofluorescence (). The cerebellum and the spinal cord were the least affected areas with well-represented neuronal cells showing few (very rare in the spinal cord) intracytoplasmic inclusions. Ultrastructural examination of the intracytoplasmic neuronal deposits in the occipital cortex showed electron-dense, membrane-bound material () composed of small curvilinear lamellar stacks () and electron-dense, variably sized granular material (), consistent morphologically with previously described intra-neuronal lipofuscins in cats. No further gross and histopathological changes were observed in the main thoracic and abdominal organs, including autonomic ganglia. Furthermore, both eyes were thoroughly examined to rule out the presence of retinal neuronal inclusions and to confirm the suspect of central blindness. Neither eye showed histopathological changes.