Niemann-Pick Disease Type C in Adulthood – A Psychiatric and Neurological Disorder
attributed to the effects of medication, particularly dystonia in the setting of antipsychotic medication usage.
The fact that adult patients often present with neuropsychiatric illness prior to exhibiting motor and/or cognitive impairments12
may relate to
the differential effect of the underlying pathophysiology on white and grey matter structures. There is some evidence for this from a recent neuroimaging study showing widespread white matter deficits and relatively restricted grey matter deficits in adult-onset disease,31 and this hypothesis is also supported by a study using the NPC knockout mouse that shows significant axonal changes occurring prior to neuronal loss.32
This may provide at least a partial explanation as to why adult patients often present with neuropsychiatric illness prior to exhibiting motor and/or cognitive impairments. Early disruption to ‘macroconnectivity’ (due to disrupted axonal and myelin structure) and ‘microconnectivity’ (due to altered synaptic structure and function) leads to a functional disconnection that predisposes to major mental illness such as schizophrenia. This is then followed by more widespread neuronal dysfunction and loss that results in frank movement disorder and cognitive impairment.12
The characteristic
vertical gaze palsy is caused by a striking vulnerability of neurons in the rostral interstitial nucleus of the medial longitudinal fasciculus to disrupted intracellular lipid storage.33
Ataxia results from an apparent
Cognitive impairment, which usually involves significant memory and executive dysfunction, may result from the disruption to cellular functioning, including the deposition of neurofibrillary tangles, in major structures involved in these functions, such as the hippocampus, thalamus and higher cortex.36–38
vulnerability of cerebellar Purkinje neurons to the underlying disease process.34,35
Considering the heterogeneous presentation of NPC, particularly in adults, it is not surprising that individuals with this illness are often misdiagnosed. As previously discussed, NPC is characterised by a wide variety of symptoms that can appear at different points during the disease course.41,45
diagnostic delay of 6.2±6.4 years.9 In the presence of
trained in the filipin-staining diagnostic process involves the assay of circulating oxidised forms of cholesterol, some forms of which are markedly elevated in both childhood and adult-onset NPC disease (Daniel Ory, personal communication).
A review of adult NPC cases demonstrated a mean Adult-onset patients will often
present with some subtle signs and be diagnosed with schizophrenia for many years before being recognised as having NPC.12
It is possible that covert signs may be present prior to more obvious symptomatic disease, which strongly indicates the need for a thorough neurological examination for ataxia and vertical gaze palsy in all patients presenting with a psychotic illness.
The Natural History of Niemann-Pick Disease Type C A recent study by Wraith et al.49
Differences Between the Symptoms of Childhood and Adult Niemann-Pick Disease Type C Childhood-onset patients often present with intellectual retardation, seizures and more obvious visceral signs, such as hepatospleno- megaly, compared with adults.39,40
disease course and deteriorate more quickly.41–43
Children experience a more rapid This is partially
related to the nature of the mutation in the individual patient (with I1061T being a common cause of juvenile-onset illness),8 other factors including gender may be involved.44 have a slower disease progression45 often clinically missed.46
although Adults generally and milder splenomegaly that is
Diagnosis of Niemann-Pick Disease Type C The most common and most reliable test for diagnosing NPC is filipin staining of fibroblast cells,46
whereby skin fibroblasts are cultured in
Individuals with the variant phenotype tend to exhibit a lower, more variable level of storage that can lead to difficulties in diagnosis.47,48
However, incubation with LDL under specific conditions can optimise test results and facilitate NPC identification.48
While filipin staining remains the accepted standard for the diagnosis of NPC, other options are available, including the detection of any reduction in the rate of cholesterol esterification and genotyping.46 Mutation analysis of the gene to determine the illness associated with mutations is definitive, although clinically filipin staining is often sufficient to make a diagnosis of NPC. A more recent development that may obviate the need for skin biopsy and specialised laboratories
EUROPEAN NEUROLOGICAL REVIEW
LDL-enriched medium, fixed and stained. Cholesterol-filled perinuclear vesicles of NPC cells are observed under fluorescence microscopy. Approximately 85% of cases possess this classic pattern of lipid storage.46
major psychiatric illness, the development of any motor signs may be incorrectly attributed to psychotropic medication, further delaying proper testing and diagnosis. This often lengthy diagnostic delay highlights the need for better clinician awareness of the signs and symptoms of NPC. Recognition that isolated splenomegaly or hepatosplenomegaly could indicate NPC should allow for earlier detection of the disease prior to neurological involvement. However, as NPC can present purely as a psychiatric disorder, accurate diagnosis is often challenging.9
focused on the progression of NPC in
adults and children, assessing the course of neurological deterioration in 57 patients. This retrospective observational cohort study asked physicians to complete online questionnaires for their patients at diagnosis and at up to three follow-up visits. Disease progression was measured using an NPC-specific disability scale that consisted of four parameters of neurological disease progression: ambulation, manipulation, language and swallowing. The annual rate of change in each parameter and the composite score using a linear mixed model analysis was calculated to determine disease progression. Patients were also classified based on the number of worsening parameters during the observation period.
The rate of deterioration was found to be similar across all four parameters and the mean annual disease progression was +0.12 units (95% confidence interval [CI]). Of the patients with at least one year between diagnosis and last visit (n=49), 42 (86%) had disease progression and only seven (14%) had stable disease. The authors concluded that there was progression in all four parameters of the disability scale that demonstrated a continuous progression of neurological manifestations. In keeping with previous reports, disease progression was more rapid in patients diagnosed in early childhood relative to those diagnosed later in life,49
suggesting that early-onset
disease follows a more rapid and fulminant course. A review of 94 NPC cases in the UK45
further confirmed the wide
phenotypic variability of NPC. The recognition of late-onset disease is improving as biochemical diagnosis is increasingly being applied in adult neurology clinics. This report underscored the progressive nature of NPC and the neurological and (in some patients) neuropsychiatric decline seen in individuals with NPC. Understanding the natural history of NPC is necessary to prepare for the future
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