N umerous medical conditions are known to produce psychotic symptoms that resemble schizophrenia, including neurological disorders such as epilepsy, central nervous system (CNS) neoplasms, infections and trauma, and Huntington’s disease. 1 Psychosis also occurs in a number of genetic conditions, such as metachromatic leukodystrophy, Pelizaeus-Merzbacher disease, and velo-cardio-facial syndrome. Comprehensive medical and neurological assessment is essential in the investigation of new-onset psychoses but is also paramount when reviewing treatment-resistant psychotic patients to ensure that reversible diagnoses are not missed and that appropriate management and/or rehabilitation goals are instituted. 2 We describe two young men treated for schizophrenia since adolescence who developed overt neurological and cognitive impairment in early adult life, resulting in a revised diagnosis of Niemann-Pick type C disease. The third case describes a patient with known Niemann-Pick type C who presented in early adulthood with mania and hypersexuality. The pathology and variable clinical presentations of the disorder are presented, followed by discussion of how an understanding of Niemann-Pick type C may inform our understanding of the neurobiology of major neuropsychiatric disorders.
CASE 1
A 23-year-old Caucasian man with an 8-year history of schizophrenia was referred to our facility following deterioration in his mental state and the development of motor symptoms. During the neonatal period he had been jaundiced for 3 days, requiring phototherapy. He was described as a “clumsy, delicate child,” but his motor and cognitive milestones were normal. He first presented with a psychiatric illness at the age of 15 when he became intermittently mute, wandered his house at night, and responded to auditory hallucinations. Within a few days of the onset of these symptoms, he became obtunded and febrile. He was unsuccessfully treated with acyclovir for a presumed but not proven diagnosis of herpes simplex encephalitis. The diagnosis of catatonic schizophrenia was then made, and a course of electroconvulsive therapy (ECT) was prescribed to which he responded partially, such that he was able to return home and resume playing basketball and soccer with his peers. However, he continued to exhibit ongoing periods of withdrawal and odd fragmented speech. He also appeared to respond intermittently to external auditory phenomena.
Two years later, the patient again became markedly withdrawn with catatonic posturing, persecutory delusions, and auditory hallucinations. A diagnosis of Wilson’s disease was considered because of dystonia but was excluded following biochemical investigation of blood and urine, hepatic biopsy, and imaging. The patient was diagnosed with chronic schizophrenia with residual psychotic symptoms and was treated with chlorpromazine for 6 years.
Eight years following his initial presentation, the patient deteriorated further. He became withdrawn and was noted to laugh incongruously. He had difficulty bathing, shaving, feeding, and toileting himself, and he could not tie his shoelaces, which caused him to stumble while walking. On admission he presented as disinhibited with an incongruous, often fatuous affect, with poverty of speech, echopraxia, and echolalia. He appeared to be responding to internal stimuli and was unable to comply with cognitive testing. He had an ataxic gait, dysarthric speech, and dystonic posturing in the upper limbs. No tremor, chorea, or myoclonus was present. There was no obvious muscle wasting, and power was normal in all limbs. His plantar reflexes were downgoing, and he had significant dysmetria on finger-nose testing bilaterally. His ballistic tracking movements in the upper limbs were slow. There were no Kayser-Fleischer rings evident on slit-lamp examination. Vertical saccades were significantly impaired, particularly in downgaze, and horizontal saccades were slow. His left flank was dull, and his spleen tippable. In addition, there was no family history of psychiatric or neurological disease and no consanguinity.
The patient returned negative results on serum routine biochemical investigations, on cerebral spinal fluid (CSF) cell and protein count, and on urinary organic and amino acid screen. Magnetic resonance imaging (MRI) revealed marked global atrophy, particularly of the corpus callosum and frontal lobe, and single photon emission computed tomography (SPECT) scanning demonstrated diffuse frontal left parietal hypoperfusion ( Figure 1, Figure 2 ). Electroencephalogram (EEG) demonstrated bilateral nonrhythmic slowing of a nonspecific nature.
FIGURE 1. MRI Scans of Cases 1 (top left and right) and 3 (bottom left and right)
Frontal atrophy and anterior callosal thinning in Case 1, not seen in Case 3.
FIGURE 2. SPECT Scans of Cases 1 (top left and right) and 3 (bottom left and right)
Each demonstrates global cortical hypometabolism, particularly anteriorly in Case 1.
The diagnosis was confirmed by cultured skin fibroblasts. Although the rate of esterification of exogenously supplied cholesterol was above the typical affected range, filipin staining was clearly abnormal and typical of patients with the variant biochemical phenotype of Niemann-Pick type C ( Figure 3 ). Follow-up sequence analysis of the Niemann-Pick type C 1 (NPC1) gene revealed that the patient was a compound heterozygote with S940L and S954L mutations to the NPC1 protein.
FIGURE 3. Filipin Staining of Fibroblasts From a Comparison Patient (top left) Matched Against Cases 1 (top right), 2 (bottom left) and 3 (bottom right)
Patients but not comparison subjects show increased cytoplasmic staining of accumulated cholesterol.
CASE 2
A 24-year-old Caucasian man with an 8-year history of psychotic symptoms, dysarthria, and an unsteady gait was referred to our clinic. During the neonatal period, he developed a serious viral illness, which required him to remain in intensive care for 1 month. The patient was noted to be clumsy and perfectionistic as a child but had normal developmental milestones. He developed auditory and visual hallucinations and persecutory delusions at age 16 and was treated with trifluoperazine. However, he required readmission following a worsening of his psychotic symptoms. He was given eight ECT treatments and discharged on haloperidol, with a diagnosis of paranoid schizophrenia. Due to unremitting symptoms, the antipsychotic treatment was changed to olanzapine, which was progressively increased to 60 mg per day. He was later started on sodium valproate 2 g per day as an augmentation strategy. Over the 2 years leading up to his recent admission, his speech had become progressively dysarthric, and he demonstrated an increasingly unsteady gait.
The patient presented as communicative and warm and appeared euthymic but was at times fatuous and inappropriate in affect. He denied any psychotic symptoms on interview, but his cognitive function demonstrated a marked decline with impaired verbal memory, organization and planning, and a tendency to perseverate and confabulate. On physical examination, he demonstrated severe dysarthria and an ataxic gait, but had no tremor, chorea, or myoclonus. Eye movements were abnormal with marked impairment in the vertical plane, particularly in downgaze. Nystagmus was not present, and Kayser-Fleischer rings were not evident on slit-lamp examination. The patient demonstrated dysdiadochokinesia and dysmetria. Power was preserved in all limbs, and there was no evidence of muscle wasting. His plantar reflexes were downgoing, and there was no evidence of hepatosplenomegaly.
There was no known family history of psychiatric or neurological disease and no consanguinity. Comprehensive laboratory investigations were normal, including CSF examination and a bone marrow biopsy. MRI revealed marked global atrophy. Skin fibroblast culture revealed mildly deficient cholesterol esterification, which was consistent with the biochemical variant phenotype of Niemann-Pick type C, and filipin staining was abnormal ( Figure 3 ). However, mutation analysis of all exons of both known genes for Niemann-Pick type C was negative.
CASE 3
A 25-year-old Caucasian man presented with recent-onset behavioral disturbance, including disturbed sleep and appetite, sexualized behavior, and disorientation. The patient was born premature and later adopted after being given up by his teenage mother. Soon after birth he developed jaundice and was found to have cholestatic liver disease and hepatosplenomegaly. A liver biopsy was suggestive of Niemann-Pick type C disease, and he subsequently underwent fibroblast testing that confirmed markedly deficient cholesterol esterification and positive filipin staining, which is typical of the classical Niemann-Pick type C biochemical phenotype ( Figure 3 ). He was found to be homozygous for the I1061T mutation of the NPC1 protein. In addition, he was diagnosed with nephrogenic diabetes insipidus and treated with spironolactone and hydrochlorothiazide.
He attended special schools and was later employed in a sheltered setting. He also developed interests in acting and dancing. At the age of 18, he exhibited early stages of progressive cognitive decline, and his behavior became disturbed at 23. He had periods of disrupted sleep in which he stayed awake for many days. His eating patterns altered, with increased appetite every 1-2 months and interepisode euthymia. During this period, he would misidentify people familiar to him and was described as unusually aggressive to his adoptive mother. A brief trial of haloperidol in low doses was ineffective.
When referred to our clinic, the patient presented as euphoric with significant sexual disinhibition, uttering sexually suggestive and explicit comments to staff and mimicking sexual activity. He masturbated continually and could only be diverted from this with some difficulty. This behavior was not associated with aggression nor with actions imposed upon others. He appeared distractible and restless and could not follow instructions. His gait was dystonic and lurching. His affect was elevated with dysarthric speech and sexualized thought content. There were no delusions, formal thought disorder, perceptual abnormalities or ideas of harm. The patient was initially disoriented to time, place, and person, and exhibited poor verbal memory. He was unaware of his behavior, and his judgment was poor.
On examination, the patient exhibited manneristic hand movements and dystonic posturing. Tone, power, reflexes, and sensation were normal peripherally. His speech was dysarthric, and he had moderate sensorineural hearing loss. There were no other abnormalities of movement noted, and he did not have Kayser-Fleischer rings. He had limited upward eye movement and no downward eye movement, although lateral eye movements were preserved; acuity was normal. His spleen was palpable 4 cm below the left costal margin, and his liver was palpable 2 cm below the right costal margin. He had no facial or axillary hair, mild gynecomastia, and small testes.
MRI of the brain showed mild generalized atrophy, prominent in cerebellar hemispheres and anterior temporal regions ( Figure 1 ). SPECT scan of the brain suggested a mild decrease in bilateral anterior temporal and inferior frontal perfusion and a lesser reduction in perfusion of the left posterior temporal lobe ( Figure 2 ). His EEG showed excess bilateral slow wave activity. Visual evoked potentials were normal, and full-scale IQ on Weschler’s Adult Intelligence Scale, edition III, revised (WAIS-III-R) testing was 64.
A trial of amisulpride was abandoned due to sedation and postural hypotension at a modest dose (100 mg/day). He was switched to sodium valproate 500 mg b.i.d., which resulted in significant improvement of mood elevation and psychosis. This was sustained at 1-year follow-up, although the patient continued to experience monthly 1-week periods of mood elevation, which responded to a brief increase in valproate dosage. His final psychiatric diagnosis was bipolar I disorder with rapid-cycling features. 3 Two years after initial assessment, periods of mood elevation had abated, and the predominant symptoms were “sundowning” in the evening, worsening episodic memory, and Alzheimer’s-like unsystematized delusions of theft.
A comparison of clinical and biochemical phenotypes with mutation analysis of the NPC1 and Niemann-Pick type C 2 (NPC2) genes is presented in Table 1 .
TABLE 1. Clinical Presentation, Biochemical Phenotype and Genotype of Cases 1, 2, and 3
DISCUSSION
Neuropathology of Niemann-Pick Type C Disease
Niemann-Pick type C disease is an autosomal recessive neurovisceral disorder of lipid storage with a frequency of 1 in 100,000 live births. 4 It is characterized by variable degrees of cognitive decline, behavioral disturbance, and neurological impairment, predominantly ataxia and vertical supranuclear opthalmoplegia. 5 The disease was first described by Niemann in 1914, 6 with its pathology characterized by Pick in 1933. 7 It is biochemically and phenotypically distinct from Niemann-Pick diseases type A and B, which result from a deficiency of lysosomal sphingomyelinase. 8, 9 Genetic analysis reveals two distinct genetic foci, with 95% of disease caused by aberrations in the NPC1 gene on 18q11, 10 coding for the lysosomal NPC1 protein. 11 The less common NPC2 variant is caused by mutations in the NPC2 gene, mapping to chromosome 14q24.3 12 and whose product resides in the Golgi apparatus and late endosomes. These proteins are involved in cyclical movement of sterols within cells, 12 – 15 performing cholesterol trafficking and homeostatic functions. 4, 16, 17 Mutation and dysfunction of NPC1 and NPC2 appears to result in late endosomal accumulation of cholesterol, some glycolipids and selected gangliosides 18, 19 leading to Alzheimer’s-like neurofibrillary tangles, neuronal degeneration, neuroaxonal dystrophy and demyelination. 15, 20 – 22 Because of this intracellular cholesterol “traffic jam” and impeded ability to transport endogenously synthesized cholesterol to distal axons, where it is required for membrane maintenance 23 and response to axonal injury, 24 axonal structures are particularly vulnerable and are affected early with axonal spheroid formation, hypomyelination and eventual demyelination. 25 As a result, white matter tracts are severely affected, 18, 26, 27 and the corpus callosum may show the most striking axonal loss. 28 Purkinje cells in the cerebellum, basal ganglia, and thalamus are the most vulnerable neurons to Niemann-Pick type C -induced neuronal dysfunction, and these gray matter regions are the first affected, with hippocampal and cortical regions affected later. 26, 29 – 31 Affected neurons, in addition to being swollen and/or affected by neurofibrillary tangle accumulation, often show ectopic dendritogenesis with stunted dendrites and greatly reduced dendritic arborization 32 as a result of altered phosphorylation of the microtubule-associated protein MAP2, which results in dendritic microtubule depolymerization 33 and a reduced availability of arborization-promoting neurosteroids secondary to cholesterol unavailability. 34 The cellular effects of Niemann-Pick type C and their structural and neuropsychiatric sequelae are demonstrated in Figure 4 .
FIGURE 4. A Model for the Relationship Between Cellular and Axonal Abnormalities Occurring in Niemann-Pick type C and Resultant Psychiatric Symptoms
The diagnosis of Niemann-Pick type C can be confirmed by demonstrating a low esterification rate of exogenous cholesterol in cultured skin fibroblasts or by testing for lysosomal accumulation of free cholesterol by filipin staining. 35 The classical biochemical phenotype shows markedly reduced esterification and >70%–80% of cells staining positive for filipin, whereas the variant phenotype shows near-normal esterification rates and lower filipin-positive cell counts while still demonstrating clinical symptoms. 36
Niemann-Pick type C may present in infancy, adolescence, or adulthood 37 with a clinically variable picture, although its core features include dementia, dysarthria, ataxia, vertical supranuclear opthalmoplegia and hepatosplenomegaly. It may also commonly present with dystonia and choreoathetosis, 37, 38 although it may occasionally occur without organomegaly. 39 Seizures, dysphagia, and pyramidal signs may appear with disease progression. 37, 38 The range of NPC1 and NPC2 mutations results in marked heterogeneity of clinical presentations. 40 As can be seen by comparison of the clinical phenotype and genotype of cases one and three ( Table 1 ), differing mutations to the same gene may result in disparate neuroradiological, biochemical and psychiatric presentations.
Neuropsychiatric Presentations of Niemann-Pick Type C
Psychosis is not an uncommon sign later in the presentation of adolescent or adult-onset Niemann-Pick type C, but may present alongside motor symptoms and cognitive impairment as an initial manifestation, in perhaps 25%–40% of adult-onset cases. 35, 41 – 45 When psychosis has been reported, features have included persecutory delusions, auditory hallucinations and ideas of reference, as well as behavioral disorganization. 35, 41, 42, 44 – 47 A small number of cases have been reported where psychosis was the sole initial manifestation; 35, 41, 42, 46 however, there have been only three cases where a diagnosis of schizophrenia was made and the patient was treated with neuroleptics alone for a number of years before gait impairment resulted in a revision of the diagnosis. 41, 45 Mood elevation as seen in case three has not been previously reported by other groups. Additionally, the chronology of neuropsychiatric symptoms in case three, whereby initial psychiatric symptoms are supervened by dementia, illustrates the temporal development of neuropathology in the disorder, where neuroaxonal dystrophy occurs early and is supervened by Alzheimer’s-type pathology as the illness develops.
Structural imaging in Niemann-Pick type C commonly shows diffuse cerebral and/or cerebellar atrophy 37, 41, 48 – 51 or callosal pathology, 27, 52 although white matter lesions may be found, 37, 50 – 53 which may radiologically mimic multiple sclerosis. 52 SPECT and positron emission tomography (PET) imaging may show hypoperfusion in frontal regions, 39, 44, 51 while magnetic resonance spectroscopy (MRS) in psychotic and nonpsychotic patients shows reductions in N -acetyl-aspartate—creatine ratios suggestive of pathology in the frontal and parietal cortices and basal ganglia, 48, 50 where changes appear to correlate with clinical dysfunction. 50 Some of these features overlap with those found in schizophrenia, including hypofrontality, 54 striatal pathology 55 and white matter changes. 56 Electro-encephalography (EEG) commonly demonstrates diffuse slowing. 37, 41, 44, 46, 49, 53 Neuropsychological testing in adolescent/adult-onset cases often reveals a steady decline in function throughout adulthood with significant deficits in executive function and memory. 41, 44, 46, 48
We have presented 2 cases where psychosis was the sole manifestation of variant Niemann-Pick type C for many years prior to the emergence of frank motor symptoms, presenting as a phenocopy of schizophrenia. The third reported case is unique in describing a cyclical illness with psychosis and mood elevation. Other authors have reported cases of Niemann-Pick type C presenting as a psychotic illness, but there are only a small number of cases reported where the diagnosis of schizophrenia preceded the diagnosis of Niemann-Pick type C by a number of years. These cases highlight the importance of continued diagnostic review in patients presenting with a combination of psychosis, cognitive and motor impairments. When neurological symptoms supervene in a preexisting psychosis, or present concomitantly, the clinician needs to undertake a thorough neurological and medical examination and utilize appropriate imaging and investigative techniques. However, psychotropic medication is frequently the major cause of motor symptoms in psychotic patients and should be considered in the first instance. In addition, a number of patients with schizophrenia may also have minor motor abnormalities that coexist with their illness and that do not represent harbingers of an additional neurodegenerative disorder. 57, 58
Genotype-Phenotype Correlations
This is the second report describing Niemann-Pick type C patients presenting with psychiatric disturbance where genotype, biochemical phenotype and clinical presentations are reported. Previously, Battisti et al. 51 described a case of a 25-year-old male presenting with obsessive-compulsive symptoms, gait disturbance and cognitive decline in whom MRI demonstrated mild global atrophy and where functional imaging showed frontal and cerebellar hypometabolism. This patient was a compound heterozygote for two mutations in NPC1, P1007A and I1061T and presented with a classical biochemical picture. In our series of patients, the detected mutations predicted the biochemical (variant versus classical) and clinical phenotype (see Table 1 ). In case one, the two mutations seen (S940L and S954L) occur in the NPC1-specific cysteine-rich region, which is associated with the variant biochemical phenotype, milder illness and/or later onset. 59 The I1061T mutation seen in case three is the most commonly reported mutation in Niemann-Pick type C patients (in up to 20% of alleles). In homozygotes, it is generally associated with the “classical” biochemical phenotype of the illness (as seen in this patient’s markedly reduced esterification rate), juvenile onset, and survival into adulthood with cognitive impairment and typical neurological signs. 60 Whether case three’s nephrogenic diabetes insipidus is related to his Niemann-Pick type C is unclear, although glomerulonephritis has been reported with Niemann-Pick type C 61 and central diabetes insipidus would be theoretically possible due to the possible disruption of function of hypothalamic neurons due to neurofibrillary tangles accumulation in this region. 62 Similarly, his hypogonadal state is likely to be a result of direct effect of mutant NPC1 on steroidogenesis in the Leydig cells of the testis 63 or disruption to the hypothalamic-pituitary-gonadal loop as a whole. 64 No other reports of neuropsychiatric Niemann-Pick type C have correlated genotype, biochemical phenotype and neuropsychiatric presentation.
Mutations associated with the variant biochemical phenotype seen in cases one and two may cause milder impairments to sterol metabolism, which impinge on neural function at a point in adolescent neurodevelopment that predisposes individuals to major mental illness prior to the onset of neurological and cognitive dysfunction. Case three, homozygous for a mutation known to cause the classical phenotype, had infantile onset but a slower than expected course, and this may have been responsible not only for his unexpected survival into adulthood but also his unusual presentation and the development of a major mental disorder after the onset of neurological illness.
Why case two presented with clinical features of the disorder in addition to demonstrating a variant biochemical phenotype, in the absence of detectable mutations to NPC1 and NPC2 despite repeat exon analysis, is unclear. It is known that NPC1 and NPC2 operate in a coordinated fashion and that mutations to either gene can produce an identical biochemical phenotype, raising the possibility that dysfunction to another protein involved in sterol metabolism may be implicated in this case. One such candidate may be the cation-independent mannose-6-phosphate receptor (MPR215), which regulates NPC2; cells lacking MPR215, like cells lacking NPC1 or NPC2, accumulate cholesterol in late endosomes. 65 Testing for mutations or deficient expression of MPR215 was not available to our unit.
RELEVANCE TO MAJOR MENTAL DISORDERS
Schizophrenia and Bipolar Disorder
The core neuropathology of schizophrenia remains elusive, although it has been seen increasingly as a disorder of connectivity, 66, 67 particularly between frontal and temporal cortical regions and subcortical structures. 68 Much evidence points to the role of dendritic and synaptic connections as anatomical substrates of this disconnectivity. 69 – 71 Myelinated axon structures are another key carrier of much CNS connectivity; hence, pathology in myelinated structures may also play a role. 56, 72 The lipid-rich nature of myelinated axons, which are dependent on endogenous cholesterol, 73 renders them highly vulnerable to disturbances of cholesterol metabolism 23 and disturbances in lipid biology have been seen as central to the underpinning neurobiology of schizophrenia. 74 Similarly, bipolar disorder leaves no neurobiological “smoking gun” although evidence points to a disorder of cellular signal transduction. 75 It does share some overlap with schizophrenia, including prefrontal cortical volume loss, 76 increased white matter hyperintensities, 77 and alterations to myelin-related gene expression. 78
The adolescent or early adulthood form of Niemann-Pick type C may disrupt neurodevelopmental processes occurring during this period of CNS development, such as frontotemporal myelination, 79 impairing frontotemporal connectivity that may lead to psychosis. 66 Pathology in the striatum could also disrupt frontal-subcortical connectivity, which has also been linked to psychosis in schizophrenia. 80 The rates of psychosis in adult-onset Niemann-Pick type C seem to approach those of adolescent/adult-onset metachromatic leukodystrophy, a disorder predominantly affecting white matter, where up to 50% of cases in this age group present with psychosis. 81, 82 In metachromatic leukodystrophy, psychotic symptoms may be a result of impaired CNS function during a critical period of development of the CNS. 83 In adult-onset adrenoleukodystrophy, where disruptions to myelination predominantly affect posterior zones, mania or affective psychosis occurs more commonly than schizophrenia-like psychosis. 84 The reduced dendritic arborization that occurs in Niemann-Pick type C 85 also bears some homology to that seen in schizophrenia 69, 70 and may be an additional psychotogenic factor through its contribution to cortical disconnectivity at a microstructural level. 85 The progression of the clinical picture from psychosis/mania to dementia and movement disorder in most cases may reflect an initial disconnectivity syndrome, resulting from dysfunction in axonal structures prior to degeneration, which is then followed by frank axonal loss and neurodegeneration in cortical and subcortical structures. Why case three presented with mania rather than psychosis is unclear, although it may be that NPC1 mutations in the presence of other susceptibility genes for major mental illness that also affect CNS development may modify the neuropsychiatric presentation of the disease.
Alzheimer’s Disease
It is also noteworthy that a number of the neuropathological, and later clinical, abnormalities in Niemann-Pick type C show overlap with Alzheimer’s disease, which in it itself is not surprising as there is a strong link between cholesterol metabolism and Alzheimer’s disease. The presence of the E4 allele of apolipoprotein E (ApoE4), essential to the metabolism of cholesterol, confers an elevated risk for the development of Alzheimer’s disease 86 and elevated low density lipoprotein (LDL) cholesterol accelerates the accumulation of the most common isoform of amyloid β-protein in senile plaques, the poorly soluble and readily aggregating Aβ42. 87 In Niemann-Pick type C neurons, it was initially thought that Aβ42 coaccumulated with cholesterol in late endosomes, 88 a process apparently accelerated by ApoE4. 22 More recent work however suggests it accumulates independently of cholesterol in early endosomes, 89 where the earliest yet known pathological changes occur in Alzheimer’s disease. 90 This may occur as a result of redistribution of presenilin-1 to early endosomes in Niemann-Pick type C with a subsequent increase in γ-secretase activity, which accelerates formation of Aβ42. 91 In addition to amyloid plaque formation, Niemann-Pick type C neurons show dysregulation of cyclin-dependent kinase 5, which results in hyperphosphorylation of the cytoskeletal protein tau and the formation of neurofibrillary tangles from phosphorylated tau aggregates 92 that again shows considerable overlap with the neurofibrillary tangles characteristically seen in Alzheimer’s disease. 93 Although Purkinje cells of the cerebellum are affected early in Niemann-Pick type C, they remain relatively resistant to neurofibrillary tangles due to their low levels of tau,94 and the neurotoxic effect of neurofibrillary tangless likely occurs later in the illness as other cortical regions are affected.
This significant early neuropathological overlap between Niemann-Pick type C and Alzheimer’s disease offers tantalizing insights into the core biology of both illnesses and of the contribution of endosomal-lysosomal dysfunction to neurodegenerative disease 23 and may even predict novel treatments for both diseases. 92 The illness does not present as a direct phenocopy of Alzheimer’s disease due to the fact that axonal structures are affected early and Purkinje cells are the most vulnerable neurons, resulting in ataxia and motor abnormalities. When hippocampal and cortical neurons are then affected by Alzheimer’s disease-type pathology, frank dementia ensues. This temporal sequence of events is illustrated in Figure 4 .
Patients diagnosed with chronic psychotic or affective illnesses who have concomitant neurological impairment and evidence of moderate cognitive impairment, many of whom will be in rehabilitation or long-stay settings, should be reviewed with the possibility that they may be suffering an adolescent or early adulthood form of Niemann-Pick type C. Awareness and understanding of illnesses that may initially present as a phenocopy of a major mental illness cannot only lead the clinician to an appropriate diagnosis but may also aid in revealing the neuropathologies at the core of psychiatric disorders.
Footnote
Received October 25, 2004; revised March 31, 2005; accepted April 8, 2005. From the Neuropsychiatry Unit, Royal Melbourne Hospital, Melbourne, Australia; Genetic Health Services Victoria, Royal Children’s Hospital, Melbourne, Australia; and Department of Biochemical and Molecular Genetics, Women’s and Children’s Hospital, Adelaide, Australia. Address correspondence to Dr. Walterfang, Neuropsychiatry Unit, Level 2, John Cade Building, Royal Melbourne Hospital, Melbourne 3050, Australia; [email protected] (E-mail).
Pentchev P, Vanier M, Suzuki K, et al: Niemann-Pick Disease Type C: a Cellular Cholesterol Lipidosis, in The Metabolic and Molecular Bases of Inherited Disease. Edited by Valle D. New York, McGraw-Hill, 1995, pp 2625–2639
Millat G, Marcais C, Rafi M, et al: Niemann-Pick C1 disease: the I1061T substitution is a frequent mutant allele in patients of Western European descent and correlates with a classic juvenile phenotype. Am J Human Genet 1999; 65:1321–1329
Kobayashi T, Beuchat M, Lindsay M, et al: Late endosomal membranes rich in lysobisphosphatidic acid regulate cholesterol transport. Nat Cell Biol 1999; 1:113–118
Zervas M, Dobrenis K, Walkley S: Neurons in Niemann-Pick type C accumulate gangliosides as well as unesterified cholesterol and undergo dendritic and axonal alterations. J Neuropathol Exp Neurol 2001; 60:49–64
Blom T, Linder M, Snow K, et al: Defective endocytic trafficking of NPC1 and NPC2 underlying infantile Niemann-Pick type C disease. Hum Mol Genet 2003; 12:257–272
Saito Y, Suzuki K, Nanba E, et al: Niemann-Pick type C disease: accelerated neurofibrillary tangle formation and amyloid B deposition associationed with apolipoprotein E4 homozygosity. Ann Neurol 2002; 52:351–355
Goodrum J, Pentchev P: Cholesterol reutilization during myelination of regenerating PNS axons is impaired in Niemann-Pick disease type C mice. J Neurosci Res 1997; 49:389–392
Elleder M, Jirasek A, Smid F, et al: Niemann-Pick disease type C: study on the nature of the cerebral storage process. Acta Neuropathol 1985; 66:325–366
Harzer K, Schlote W, Peiffer J, et al: Neurovisceral lipidosis compatible with Niemann-Pick disease type C: morphological and biochemical studies of a late infantile case and enzyme and lipid assays in a prenatal case of the same family. Acta Neuropathol 1978; 43:97–104
March P, Thrall M, Brown D, et al: Gabaergic neuroaxonal dystrophy and other cytopathological alterations in feline Niemann-Pick disease type C. Acta Neuropathol 1997; 94:164–172
Fan Q-W, Yu W, Gong J-S, et al: Cholesterol-dependent modulation of dendrite outgrowth and microtubule stability in cultured neurons. J Neurochem 2002; 80:178–190
Sakamoto H, Ukena K, Tsutsu K: Effects of progesterone synthesized de novo in the developing purkinje cell on its dendritic growth and synaptogenesis. J Neurosci 2001; 16:6221–6232
Vanier M, Rodriguez-Lafrasse C, Rousson R, et al: Typc C niemann pick disease: biochemical aspects and phenotypic heterogeneity. Dev Neurosci 1991; 13:307–314
Vanier M, Rodriguez-Lafrasse C, Rousson R, et al: Type C Niemann-Pick disease: spectrum of phenotypic variation in disruption of intracellular LDL-derived cholesterol processing. Biochim Biophys Acta 1991; 1096:328–337
Hulette C, Earl N, Anthony D, et al: Adult onset Niemann-Pick disease type C presenting with dementia and absent organomegaly. Clin Neuropathol 1992; 11:293–297
Millat G, Chikh K, Naureckienne S, et al: Niemann-Pick disease type C: spectrum of HE1 mutations and genotype/phenotype correlations in the NPC2 group. Am J Human Genet 2001; 69:1013–1021
Turpin J, Goas N, Masson M, et al: Type C Niemann-Pick disease: supranuclear ophthalmoplegia associated with deficient biosynthesis of cholesterol esters. Rev Neurol (Paris) 1991; 147:28–34
Campo J, Stowe R, Slomka G, et al: Psychosis as a presentation of physical disease in adolescence: a case of Niemann-Pick disease type C. Dev Med Child Neurol 1998; 40:126–129
Josephs K, Van Gerpen M, Van Gerpen J: Adult-onset Niemann-Pick disease type C presenting with psychosis. J Neurol Neurosurg Psychiatry 2003; 74:528–529
Lossos A, Schlesigner I, Okon E, et al: Adult-onset Niemann-Pick type C disease: clinical, biochemical and genetic study. Arch Neurol 1997; 54:1536–1541
Tedeschi G, Bonavita S, Barton N, et al: Proton magnetic resonance spectroscopic imaging in the clinical evaluation of patients with Niemann-Pick type C disease. J Neurol Neurosurg Psychiatry 1998; 65:72–79
Battisti C, Tarugi P, Dotti M, et al: Adult-onset Niemann-Pick type C disease: a clinical, neuroimaging, and molecular genetic study. Mov Disord 2003; 18:1405–1409
Grau A, Brandt T, Weisbrod M, et al: Adult Niemann-Pick disease type C mimicking features of multiple sclerosis. J Neurol Neurosurg Psychiatry 1997; 63:522–525
Velakoulis D, Pantelis C: What have we learned from functional imaging studies in schizophrenia? the role of frontal, striatal and temporal areas. Aust NZ J Psychiatry 1996; 30:195–209
Bartzokis G: Schizophrenia: breakdown in the well-regulated lifelong process of brain development and maturation. Neuropsychopharmacology 2002; 27:672–683
McCreadie R, Thara R, Padmavati R, et al: Structural brain differences between never-treated patients with schizophrenia, with and without dyskinesia, and normal control subjects: a magnetic resonance imaging study. Arch Gen Psychiatry 2002; 59:332–336
Yamamoto T, Ninomiya H, Matsumoto M, et al: Genotype-phenotype relationship of Niemann-Pick disease type C: a possible correlation between clinical onset and levels of NPC1 protein in isolated skin fibroblasts. J Med Genet 2000; 37:707–712
Park W, O’Brien J, Lundquist P, et al: Identification of 58 novel mutations in Niemann-Pick disease type C: correlation with biochemical phenotype and importance of PTC1-like domains in NPC1. Hum Mutation 2003; 22:313–325
Philit J-B, Queffeulou G, Walker F, et al: Membranoproliferative glomerulonephritis type II and Niemann-Pick disease type C. Nephrol Dialysis Transplant 2002; 17:1829–1831
Reaves B, Row P, Bright N, et al: Loss of cation-independent mannose 6 phosphate receptor expression promotes the accumulation of lysobisphosphatidic acid in multilamellar bodies. J Cell Sci 2000; 133:4099–4108
Rosoklija G, Toomayan G, Ellis S, et al: Structural abnormalities of subicular dendrits in subjects with schizophrenia and mood disorders: preliminary findings. Arch Gen Psychiatry 2000; 57:349–356
Davis K, Stewart D, Friedman J, et al: White matter changes in schizophrenia: evidence for myelin-related dysfunction. Arch Gen Psychiatry 2003; 60:443–456
Strittmatter W, WB Saunders A, Schmechel D, et al: Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci USA 1993; 90:1977–1981
Kuo Y-M, Emmerling M, Bisgaier C, et al: Elevated low-density lipoprotein in Alzheimer’s disease correlates with brain abeta 1–42 levels. Biochem Biophys Res Commun 1998; 252:711–715
Yamakazi T, Chang T-Y, Haass C, et al: Accumulation and aggregation of amyloid beta protein in late endosomes of Niemann-Pick type C cells. J Biol Chem 2001; 276:4454–4460
Jim L-W, Maezawa I, Vincent I, et al: Intracelular accumulation of amyloidogenic fragments of amyloid-beta precursor protein in neurons with Niemann-Pick type C defects is associated with endosomal abnormalities. Am J Pathol 2004; 164:975–985
Cataldo A, Peterhoff C, Troncoo J, et al: Endocytic pathway abnormalities precede amyloid beta deposition in sporadic Alzheimer’s disease and down syndrome: differential effects of apoe genotype and presenelin mutations. Am J Pathol 2000; 157:277–286
Burns M, Gaynor K, Olm V, et al: Presenilin redistribution associated with aberrant cholesterol transport enhances beta amyloid production in vivo. J Neurosci 2003; 23:5645–5649
Bu B, Li J, Davies P, et al: Deregulation of cdk5, hyperphosphorylation, and cytoskeletal pathology in the Niemann-Pick type C murine model. J Neurosci 2002; 22:6515–6525
Bu B, Klunemann K, Suzuki K, et al: Niemann-Pick disease type C yields possible clue for why cerebellar neurons do not form neurofibrillary tangles. Neurobiol Dis 2002; 11:285–297
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