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Niemann-Pick disease type C is a panethnic autosomal recessive neurovisceral storage disorder characterised by a unique error in cellular trafficking of exogenous cholesterol. The most typical phenotype is characterised by hepatosplenomegaly, vertical supranuclear ophthalmoplegia, progressive ataxia, dystonia, and dementia and manifests in late childhood. Adult onset Niemann-Pick disease type C often includes psychosis and dementia.1 2 We report an adult female patient with biochemically verified Niemann-Pick disease type C in whom the initial diagnosis of multiple sclerosis was questionable because of a persistent splenomegaly.
The 33 year old woman was referred to the Psychiatry Department of the University of Heidelberg in December 1994. She complained of progressive difficulties with memory and concentration, increasing social isolation, and problems with daily activities. The patient was unsure about the onset of her problems but suggested that they had started after the birth of her daughter three years previously. History, family history, and the patient’s fetal and childhood development were unremarkable. Her parents are non-consanguineous. School performance was satisfactory initially but later her learning behaviour became erratic and she failed her examinations after 10 school years. She worked as a saleswoman and after giving birth she lived on social support. With time she no longer managed to educate her daughter and neglected her housekeeping. The patient′s mother reported that her problems with memory and concentration had been variably apparent since school but progressively deteriorated after her pregnancy.
On neurological examination, cranial nerves were unremarkable. Guided and voluntary eye movements were normal; fast saccadic movements were slightly dysmetric. Optokinetic nystagmus was absent vertically but normal horizontally. The patient had a slight paresis of her left leg, tendon reflexes were brisker in the left than the right leg but symmetric in both arms. Plantar response was flexor. There was a slight ataxia in both legs. Sensory testing was normal. Snout or palmomental reflexes were absent. The patient was inattentive but well oriented to time, person, and place. She had difficulties in retrieving past and storing new information. There was no aphasia or dysarthria but her speech was vague and circuitous with many meaningless phrases. Thinking was slowed, impoverished in content, and reduced in flexibility. She was emotionally labile, her behaviour was disorganised, and her judgment was impaired.
Psychometric tests resulted in an estimated IQ of 71 on the Hamburg-Wechsler test. An amnesia score (Berliner Amnesietest-Kurzform) and the d2 test were highly pathological. Cranial MRI showed considerable cerebral atrophy and multiple non-enhancing hyperintense areas on T2 weighted images localised in the periventricular white matter and the corpus callosum (figure). Follow up examination in spring 1996 showed no changes. Protein concentration (0.36 g/l) and cell count (1 cell/ml) in CSF were normal; oligoclonal bands were positive in CSF but negative in serum. Somatosensory evoked potentials to both legs and transcortical magnetic evoked potential to the left leg were delayed. Abdominal sonography disclosed an enlarged (vertical diameter 17 cm) and inhomogeneously structured spleen. Liver size was borderline. Routine hematological and biochemical analyses were normal except for transient thrombopenia. Vasculitis screening, serum tests for copper, coeruloplasmin, vitamin B12, folic acid, basic endocrinological tests including thyroid function assessment, testing for HIV and syphilis, very long chain fatty acids, arylsulphatase A, and other serum lysosomal enzyme activities were normal.
Considering the MRI and CSF findings we first diagnosed multiple sclerosis with a prominent picture of progressive dementia. Treatment with steroids did not improve the clinical status. The patient was referred to a rehabilitation hospital. There, CSF analysis was normal and oligoclonal bands were absent.
In August 1995, the patient was readmitted in a state of severe depression and helplessness. Her dementia had deteriorated, neurological examination was unchanged, still showing slight lower limb ataxia and left leg paresis. Because control sonography disclosed persistent splenomegaly, we considered the diagnosis of Niemann-Pick disease type C or Gaucher disease. Cytology of a bone marrow aspirate disclosed so-called sea blue histiocytes and Niemann-Pick cells, a result strongly suggestive of Niemann-Pick disease type B or C. Biochemical studies on cultured skin fibroblasts confirmed the diagnosis of Niemann-Pick disease type C. The intracellular low density lipoprotein induced esterification of cholesterol was reduced (330 (controls 2950 (SD 1200)) pmol/mg cell protein of cholesteryl oleate formed after 4.5 h).
Cytochemical staining with filipin showed a significant but not massive accumulation of unesterified cholesterol in perinuclear vesicles. These combined findings were consistent with an “intermediate” biochemical phenotype of Niemann-Pick disease type C.2
The clinical picture in our patient corresponds well to late onset Niemann-Pick disease type C. Although her disease may have insidiously started during childhood or adolescence, definite dementia only developed around the age of 30. Progressive dementia is the most often reported sign, and limb ataxia and splenomegaly are other prominent features in adult onset Niemann-Pick disease type C. Vertical supranuclear ophthalmoplegia, which was absent in our patient, is an important sign in infantile and juvenile Niemann-Pick disease type C, but it is often missing in adult disease1
Findings on MRI and in CSF had initially suggested a diagnosis of multiple sclerosis in our patient. Dementia may occasionally be the leading or even only symptom in multiple sclerosis and features of dementia in multiple sclerosis resemble those in our patient. In Niemann-Pick disease type C, neuroimaging is usually normal or shows non-specific cerebral atrophy, but some cases with periventricular white matter lesions have been described.3Neuropathological studies occasionally showed demyelination in infantile cases.2 4 Therefore, clinical and neuroradiological findings in our patient were compatible with a diagnosis of Niemann-Pick disease type C. However, to our knowledge oligoclonal bands have not been reported in the disease. Increased CSF immunoglobulin concentrations are often found in adrenoleukodystrophy,5 indicating that inborn errors of metabolism can be associated with an immune response. Accordingly, oligoclonal bands in our patient may also represent an immunological response to cerebral damage caused by Niemann-Pick disease type C. In our patient, Niemann-Pick disease type C mimicked features of multiple sclerosis. Therefore, in patients with suspected multiple sclerosis in whom dementia or psychosis are the leading symptoms, Niemann-Pick disease type C should be considered as differential diagnosis.