Section Heading section sub

Niemann-Pick Disease Type C – Example of an Inborn Error of Metabolism Producing Psychiatric Manifestations Olivier Bonnot Hospital Practitioner, Reference Centre for Rare Diseases with Psychiatric Expression, Child and Adolescent Psychiatry Department, Pitié Salpêtrière Hospitals, Paris

Abstract organic schizophrenia, or schizophrenia-like syndrome, is an important concern in psychiatry. its incidence is unknown due to difficulties in symptom recognition and changing symptoms over time. it is important to be aware that these symptoms could be the single manifestation of a specific organic disease, such as niemann-Pick disease type c (nPc). nPc is a pan-ethnic, autosomal recessive neurodegenerative disease that has been reported to cause schizophrenic symptoms in adult and adolescent patients. symptoms of early-onset schizophrenia occurring in young patients often lead to a misdiagnosis and up to a two to 10 year delay before nPc is confirmed. it is not practical to investigate all patients with schizophrenia for an organic aetiology of their disease, but it can be useful to monitor atypical signs of psychosis or minor physical signs such as vertical supranuclear ophthalmoplegia. until recently, therapy for nPc was limited to supportive measures. however, a recently licensed medication is now available to treat the psychiatric manifestations of nPc. This review article focuses on those manifestations, and describes a clinical tool developed to help clinicians identify which ones should trigger efforts to detect organic disease.

Keywords Lipid storage disorder, miglustat, neurological, neuropsychiatric disorder, niemann-Pick disease type c, organic schizophrenia Disclosure: The author has no conflicts of interest to declare. Received: 11 february 2011 Accepted: 16 June 2011 Citation: European Psychiatric Review, 2011;4(2):xx–x Correspondence: olivier Bonnot, centre référent Maladie rare à expression Psychiatrique, service de Psychiatrie de l’enfant et de l’Adolescent, groupe hospitalier Pitié salpêtrière, Assistance Publique-hôpitaux de Paris, 47-83 boulevard de l’hôpital, 75013 Paris, france. e: [email protected]

Support: The publication of this article was funded by Actelion. The views and opinions expressed are those of the author and not necessarily those of Actelion.

organic conditions associated with psychiatric symptoms or syndromes are universally studied by physicians during their training at medical school, yet are poorly diagnosed and treated in clinical practice. The association of hypothyroidism with depression, of cushing’s disease with maniac episodes or of Wilson’s disease with schizophrenia-like behaviour is well known and documented, but, sadly, many such conditions go undetected and untreated for extended periods of time. This situation needs to be improved, particularly when somatic treatments that can alleviate some, or even all, of the psychiatric symptoms arising from such organic conditions are available. in this article we will focus on the schizophrenia-like symptoms associated with niemann-Pick disease type c (nPc), which is an example of a treatable condition resulting from an inborn error of metabolism (ieM). organic schizophrenia, or schizophrenia-like syndrome, is an important concern in psychiatry1 and various medical conditions and substances may be associated with it.2 one major issue is that its incidence is unknown as a result of two important factors described below. • The extensive and exhaustive monitoring of organic schizophrenia is impossible due to difficulties in symptom recognition and the changing nature of symptoms over time. A study of 268 patients with

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a first episode of schizophrenia – one of the largest of its kind – found that less than 6 % had organic disease.3 indirect evidence of organic disease associated with catatonia or early-onset schizophrenia shows no rare organic association in these populations.4,5 • The worldwide prevalence of schizophrenia is estimated to be approximately 0.8  %, but its worldwide incidence is much higher and variable (median 15.2/100,000 population [10–90 % quantile: 7.7–43.0/100,000]) due to the chronic course of the disease.6–8 its association with rare organic diseases may therefore be coincidental, despite the conclusion of a large review in 1983 that it exceeds chance expectation in many other diseases.9 (note that this review had less technical capability to detect organic diseases than is available today.) organic disease associated with schizophrenia is an extensive subject area that goes beyond psychiatry alone and involves the nature versus nurture debate. A consensual list of diseases associated with schizophrenia (secondary or aetiological psychosis) can be found in all psychiatry manuals. 10 however, in clinical practice, these diseases frequently go unrecognised. The diagnosis of organic diseases associated with schizophrenia is an important issue in psychiatry, as well as an ethical one, especially if the diseases in question are treatable. This article provides a timely

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Niemann-Pick Disease Type C

Table 1: Characteristics of Niemann-Pick Disease Type C at Each Stage of the Disease Stage

Characteristics

Stage 0 The disease has been diagnosed biochemically, histologically or molecularly/genetically, but there is no obvious impairment or symptoms that are typical of it

Figure 1: Frequency of the symptoms most commonly seen in patients with Niemann-Pick disease type C Hearing problems

15 %

Psychiatric disorders

28 %

Sleeping problems

42 %

Epilepsy

52 %

Respiratory dysfunction

52 %

Gelsatic cataplexy

52 %

Stage I initial symptoms, such as minor movement disorders and cognitive difficulties, are present, but they are only visible at close observation •

occasional unsteady gait, but patient can climb stairs unassisted and walk unassisted for long stretches

Dysarthria

•

Mild dystonia or ataxia

Dysphagia

80 %

•

saccadic horizontal eye movements are slowed down

•

Vertical supranuclear gaze palsy is not fully developed

Vertical gaze palsy

81 %

•

slowed speech, but patient can still have differentiated

70 %

83 %

Ataxia

conversation Stage II increased cognitive impairment and easily noticeable motor disorders develop •

Learning difficulties

87 %

Clumsiness

87 %

increasingly unsteady gait, balance problems, wide-based

0

gait; patient can walk independently over short distances only and may need assistance climbing stairs •

Athetotic movements, obvious dystonia or ataxia

•

Vertical supranuclear gaze palsy

•

Dysarthria; slurred, slowed, unclear speech; conversations still possible, but patient has difficulties with articulation and with expressing own ideas

Stage III considerable cognitive impairment and motor dysfunction; nursing care required around the clock •

Walking only with support and over short distances

•

Patient needs substantial help with eating, dressing and personal hygiene

• •

incontinence substantial impairment caused by dystonia, ataxia or athetosis

•

Limited speech, one- or two-word sentences only; limited verbal expression of thoughts and emotions

Stage IV neurological deficits make walking impossible; vegetative state; patient unable to speak or articulate in a comprehensible manner Adapted from Klarner, et al., 2007.18

review of the psychiatric manifestations of nPc, as a recently licensed medication is now available to treat them.

Niemann-Pick Disease Type C The incidence of ieM was estimated to be approximately 40 cases per 100,000 live births in the population of British columbia.11 This rate, however, was probably an underestimate since the authors were not able, at the time of the study, to screen for all ieM. Today a growing number of ieM are being identified as a result of improved biochemical and analytical techniques. nPc is a pan-ethnic, autosomal recessive neurodegenerative disease with an incidence estimated between one per 120,000 and one per 150,000 live births.12 The disease is characterised by a variety of progressive and disabling neurological symptoms, including clumsiness, limb and gait ataxia, dysarthria, dysphagia and cognitive deterioration (dementia).12 The types of symptoms seen at each stage of nPc are shown in Table 1 and the frequency of the symptoms most commonly seen in the disease is shown in Figure 1.

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20

40

60

80

100

Percentage of patients Source: Garver, et al., 2007.38

unlike niemann-Pick disease type A and B, which are caused by a primary deficiency of the enzyme acid sphingomyelinase, nPc is associated with mutations of the genes NPC1 and NPC2, with no primary defect in catabolic enzymes. NPC1 gene mutations are present in 95 % and NPC2 mutations in approximately 4 % of cases; the remainder are biochemically proven cases that do not have identified mutations.13,14 These mutations give rise to characteristic abnormalities in the intracellular transport of cholesterol, glycosphingolipids and sphingosine. The impaired functioning of the NPC1 and NPC2 gene products, which normally operate cooperatively in the intracellular lipid transport, leads to the accumulation of these lipids in the late-endosomal/lysosomal intracellular compartment, and excess lipids accumulate in various tissues. unesterified cholesterol, sphingomyelin, bis(monoacylglycero)phosphate, glycosphingolipids and sphingosine are stored in excess in the liver and spleen, while levels of glucosylceramide, lactosylceramide and particularly gM2 and gM3 gangliosides are markedly increased in the brain.15 A diagram of how NPC1 and/or NPC2 gene dysfunction leads to the development of psychiatric symptoms in nPc is shown in Figure 2.

Presentation and Diagnostic Clues nPc has an extremely heterogeneous clinical presentation characterised by a wide range of symptoms that are not specific to the disease and that arise and progress over various periods of time.12,16 This complicates diagnosis and is likely to be an important factor in the underdetection of nPc and, in some cases, in its misdiagnosis. in the first decade of life, the most common presentations are neurological, although early-onset patients are often diagnosed based on isolated systemic manifestations. Many cases are also diagnosed in adulthood (as late as the seventh decade of life). The age at onset of neurological symptoms has a major influence on disease progression; if neurological symptoms arise early in life, the rate of deterioration is generally faster and premature death occurs sooner. generally, cases of early nPc (before the third month) present with: enlarged liver and spleen (sometimes with ascites and hepatic failure),

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Section Heading section sub Figure 2: How NPC1/2 Gene Dysfunction Leads to Psychiatric Symptoms

NPC1/2 dysfunction

Impeded cholestrol transport and availability

Impaired myelination, axonal growth and remyelination

Axonal dystrophy and eventual loss

Cholesterol and ganglioside accumulation

Alterations in dendritic microtubular proteins

Altered kinase activity and protein phosphorylation

Increased γ-secretase activity and increased Aβ42 formation

Reduced production of neurosteroids

Ectopic dendritogenesis, reduced dendritic arborisation

Neuronal amyloid deposition

Neuronal disconnection

Hyperphosphorylation of tau

Neuronal neurofibrillary tangle formation

Neuronal dysfunction and loss

Psychosis ± mania Early

Dementia Late

This diagram shows the effects of NPC1 and/or NPC2 gene dysfunction on cellular and axonal function, and how this leads to the development of psychiatric symptoms in Niemann-Pick disease type C. Adapted from Walterfang, et al., 2006.39

extended cholestasis, foetal hydrops and respiratory failure;12 however, at this stage, there are normally no neurological signs. cases may present with all the clinical signs or only some of them. Juvenile, adolescent and adult cases usually present only with an enlarged spleen, but neurological signs may gradually appear. These signs may be: central hypotonia, deafness and progressive ataxia, sometimes with dystonia, dysarthria or dysphagia. There may also be catalepsy or, more rarely, epilepsy. Vertical supranuclear gaze palsy is a quasipathognomonic sign that could be present at the early stages of the disease, although this remains a controversial issue among specialists.12 Developmental delay in nPc is classically observed between six and 15 years of age and should be looked for in a patient’s medical history.17 it is associated with learning disorders and difficulties at school.16,18 There has been no systematic review of intellectual deficiency in nPc, but our clinical experience at the reference centre for rare Diseases with Psychiatric expression within the groupe hospitalier Pitié salpêtrière in Paris, france, shows that it causes mostly mild impairment (intelligence quotient level 50–75). consequently, learning disability may be an isolated symptom of the disease that sometimes appears in primary school. in cases of nPc, an analysis of patients’ histories typically shows anomalies such as: • impaired fine and gross motor skills associated with slurred articulation; • impaired logical thinking and abstraction processes associated with decreased attention; • limited working memory and concentration; • word retrieval difficulties and use of stereotypical expressions; and • progressive loss of ability to perform daily activities and lack of distance in relationships (mainly sexually uninhibited behaviour).19

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however, despite these signs, when a cognitive test battery was used to assess a small cohort of 15 patients, the authors found no specific cognitive profile for nPc patients, even in cases where working memory seemed particularly impaired.18 Literature on nPc cognitive impairment is scarce and further studies are needed on larger patient populations to determine whether there is a cognitive profile that is characteristic of the disease.

Reported Cases several cases of nPc presenting with schizophrenic symptoms have been reported in adolescent and adult patients.20–26 in all cases there was a long delay of between two and 10 years before nPc was diagnosed; in some cases, the diagnosis was made only after the appearance of neurological symptoms. A typical example is that of a 30-year-old man with no history of psychiatric or organic disease and no developmental delay who started suffering from paranoid psychosis. nPc was diagnosed after eight years, when movement disorders such as ataxia and chorea developed, leading to a neurological examination that detected vertical supranuclear ophthalmoplegia (Vso). interestingly, treatment with phenothiazin was poorly effective. 23 it is worth noting that treatment with antipsychotic medications may create confusion, since dystonia and dysarthria may arise as a result of it.21 cases of child and adolescent nPc have also been reported. such cases can be confusing for the physician, especially when symptoms of early-onset schizophrenia occur in a young patient with known pervasive developmental disorder (PDD). sandu et al. reported the case of an eight-year-old boy with PDD,22 which was confirmed using the revised Autism Diagnostic interview.27 The patient presented with auditory hallucinations and, seven years later, was given a clear diagnosis of paranoid schizophrenia consistent with the Diagnostic and Statistical Manual of Mental Disorders - Fourth Edition. Quietapin

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Niemann-Pick Disease Type C

treatment was inefficient and risperidone partially reduced the hallucinations. The diagnosis of nPc was not made until the patient was 16 years old, when a neurological examination revealed Vso.

Figure 3: Filipin Staining of Skin Fibroblasts from three Patients with Niemann-Pick Disease Type C (top right, bottom left and bottom right) and a Control Patient (top left)

further interesting cases of nPc occurred in two siblings.26 A boy aged 16 with no history of organic or psychiatric disease except some obsessive traits presented with visual and auditory hallucinations. At the age of 18, dysarthria and ataxia developed, but were considered to be side effects from olanzapine treatment aggravating his neurological state. When he was 24, however, he underwent a neurological examination and a diagnosis of nPc was made in which Vso was the main orienting symptom. his sister also had nPc with the same mutation, but had less severe biochemical, neuroimaging and ocular motor parameters, and had associated cognitive and motor disturbances. one major difficulty in nPc is the complexity of the biological diagnosis. A skin biopsy and a fibroblast culture are required to perform a filipin test (that is, cell biology performed twice).28 This diagnostic test requires specialist skills and can therefore only be undertaken at a dedicated centre. comparative filipin staining of skin fibroblasts from three patients with nPc and a control patient is shown in Figure 3. nPc is a rare and probably misdiagnosed disease. nPc patients presenting with psychiatric symptoms may be encountered more frequently than was previously thought and could benefit from treatment during the early stages of the disease, before neurological signs start developing. All case reports strongly suggest that nPc may present with schizophrenic symptoms in adults or adolescents, even in patients without any indicative psychiatric or medical history. Vso is present in almost all cases of nPc and this symptom must be looked for in any suspected case of schizophrenia, especially where there is resistance to treatment.

A Recently Approved Medication until recently, therapy for nPc was limited to supportive measures, including pharmacotherapy to alleviate neurological symptoms. 19 since nPc was first identified, there has been a large unmet clinical need for specific disease-modifying therapies that would stabilise patients by slowing down or stopping the progression of their neurological symptoms. Miglustat has recently been approved for use in nPc. Miglustat (n-butyldeoxynojirimycin) is a synthetic analogue of D-glucose that inhibits glucosylceramide synthase, the enzyme that catalyses the first committed step of glycosphingolipid synthesis. it was approved in the eu in 2009 and is approved in canada, south Korea, Brazil, russia and Australia – but not in the us. 29 This medication both improves symptoms and has putative disease-modifying effects. 30

A Clinical Tool to Guide Metabolic Investigations reviewing the literature reporting nPc associated with psychiatric symptoms leads to two observations: • the literature on this subject is scarce and the topic largely unstudied; and • in almost all reported cases, the psychiatric symptoms and/or the evolution of the disease are atypical; this observation may also be true for many organic diseases, including treatable ieM.31

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The patients with Niemann-Pick disease type C show increased cytoplasmic staining of accumulated cholesterol compared with the control patient. Source: Walterfang, et al., 2006.39

Which atypical psychiatric features should trigger a search for an ieM? in this section i briefly describe a proposed clinical tool for clinicians to identify psychiatric features that should trigger efforts to detect organic disease. The development of this tool was justified by the findings of several studies of schizophrenic patients. one such study analysed the phenomenology of 74 patients with either organic or non-organic schizophrenia, and found that visual hallucination and mild confusion were more frequently seen in organic disease.32 in other studies, similar features were found in elderly schizophrenia populations.33,34 A comprehensive review of psychiatric manifestations in ieM carried out by our team provided a diagnostic strategy to guide metabolic investigations.35 our clinical tool focuses on psychiatric features that justify a search for treatable disease, and includes key physical examinations orienting the specific ieM diagnosis. it requires little time or resources to complete. it is not practical to search for ieM in all patients with schizophrenia, especially not in those with a long history of the disease. The key objective is to identify patients with atypical psychiatric symptoms. our clinical tool is a simple means of doing this. it requires to distinguish first-order from second-order atypical psychiatric symptoms. To be considered atypical, second-order symptoms need to be associated with first-order ones. • The first order of atypical psychiatric symptoms includes: visual hallucinations; mental confusion; catatonia (which is strongly associated with organic disorders, especially during childhood or adolescence); 36,37 fluctuating symptoms; progressive cognitive decline; unusual response to treatment (mostly excitement). • The second order of atypical psychiatric symptoms includes: acute symptoms; early onset; inefficacy of treatment with antipsychotics; intellectual disability.

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Section Heading section sub if a patient shows at least one first-order or two second-order symptoms, then it is legitimate to perform a simple medical examination designed to identify key symptoms and confirm the diagnosis. our work is mostly empirical and based on our experience. The tool is currently in use at our centre, but no assessment of its performance has yet been completed. once established, the tool may expedite the diagnosis of ieM diseases and thus hasten the start of an appropriate therapy. The tool could also be used in psychiatric diseases other than those of ieM origin.

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Beer MD, The dichotomies: psychosis/neurosis and functional/organic: a historical perspective, Hist Psychiatry, 1996;7(26):231–55. Price g, ron MA, schizophrenia and schizophrenia-like psychosis. in: schapira AhV (ed), Neurology and Clinical Neuroscience 1st edn, Philadelphia: elsevier-Mosby, 2007;223–33. Johnstone ec, Macmillan Jf, crow TJ, The occurrence of organic disease of possible or probable aetiological significance in a population of 268 cases of first episode schizophrenia, Psychol Med, 1987;17(2):371–9. Lahutte B, cornic f, Bonnot o, et al., Multidisciplinary approach of organic catatonia in children and adolescents may improve treatment decision making, Prog Neuropsychopharmacol Biol Psychiatry, 2008;32(6):1393–8. remschmidt h, Theisen fM, schizophrenia and related disorders in children and adolescents, J Neural Transm Suppl, 2005;(69):121–41. Andreasen nc, The evolving concept of schizophrenia: from Kraepelin to the present and future, Schizophr Res, 1997;28(2–3):105–9. Mcgrath J, saha s, Welham J, et al., A systematic review of the incidence of schizophrenia: the distribution of rates and the influence of sex, urbanicity, migrant status and methodology, BMC Med, 2004;2:13. Van os J, Driessen g, gunther n, Delespaul P, neighbourhood variation in incidence of schizophrenia. evidence for person-environment interaction, Br J Psychiatry, 2000;176:243–8. Davison K, schizophrenia-like psychoses associated with organic cerebral disorders: a review, Psychiatr Dev, 1983;1(1):1–33. sadock BJ, sadock VA, ruiz P (eds), Kaplan and Sadock’s Comprehensive Textbook of Psychiatry 9th edn, Philadelphia: Lippincott Williams and Wilkins, 2009. Applegarth DA, Toone Jr, Lowry rB, incidence of inborn errors of metabolism in British columbia, 1969-1996, Pediatrics, 2000;105(1):e10. nP-c guidelines Working group, Wraith Je, Baumgartner Mr, Bembi B, et al., recommendations on the diagnosis and management of niemann-Pick disease type c, Mol Genet Metab, 2009;98(1–2):152–65. carstea eD, Morris JA, coleman Kg, et al., niemann-Pick c1 disease gene: homology to mediators of cholesterol

Conclusion schizophrenia-like symptoms are common in psychiatry. it is important to be aware that they may be the single manifestation of a specific organic disease, especially an ieM such as that causing nPc. it is not practical to investigate all patients with schizophrenia for an organic aetiology of their disease, but looking for atypical signs of psychosis or minor physical signs such as Vso, or using the clinical tool described here, may be extremely useful in the rare cases of treatable disease. n

homeostasis, Science, 1997;277(5323):228–31. 14. naureckiene s, sleat De, Lackland h, et al., identification of he1 as the second gene of niemann-Pick c disease, Science, 2000;290(5500):2298–301. 15. Vanier MT, Lipid changes in niemann-Pick disease type c brain: personal experience and review of the literature, Neurochem Res, 1999;24(4):481–9. 16. sévin M, Lesca g, Baumann n, et al., The adult form of niemann-Pick disease type c, Brain, 2007;130(Pt 1):120–33. 17. van de Vlasakker cJ, gabreëls fJ, Wijburg hc, Wevers rA, clinical features of niemann-Pick disease type c. An example of the delayed onset, slowly progressive phenotype and an overview of recent literature, Clin Neurol Neurosurg, 1994;96(2):119–23. 18. Klarner B, Klünemann hh, Lürding r, et al., neuropsychological profile of adult patients with niemannPick c1 (nPc1) mutations, J Inherit Metab Dis, 2007;30(1):60–7. 19. Patterson Mc, Platt f, Therapy of niemann-Pick disease, type c, Biochim Biophys Acta, 2004;1685(1–3):77–82. 20. campo JV, 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(2):126–9. 21. Josephs KA, Van gerpen MW, Van gerpen JA, Adult onset niemann-Pick disease type c presenting with psychosis, J Neurol Neurosurg Psychiatry, 2003;74(4):528–9. 22. sandu s, Jackowski-Dohrmann s, Ladner A, et al., niemann-Pick disease type c1 presenting with psychosis in an adolescent male, Eur Child Adolesc Psychiatry, 2009;18(9):583–5. 23. shulman LM, Lang Ae, Jankovic J, et al., case 1, 1995: psychosis, dementia, chorea, ataxia, and supranuclear gaze dysfunction, Mov Disord, 1995;10(3):257–62. 24. Turpin Jc, Baumann n, [Presenting psychiatric and cognitive disorders in adult neurolipidoses], Rev Neurol (Paris), 2003;159(6–7 Pt 1):637–47. 25. Tyvaert L, stojkovic T, cuisset JM, et al., [Presentation of niemann-Pick type c disease with psychiatric disturbance in an adult], Rev Neurol (Paris), 2005;161(3):318–22. 26. Walterfang M, fietz M, Abel L, et al., gender dimorphism in siblings with schizophrenia-like psychosis due to niemannPick disease type c, J Inherit Metab Dis, 2009;180:1–6. 27. Lord c, Pickles A, McLennan J, et al., Diagnosing autism: analyses of data from the Autism Diagnostic interview,

J Autism Dev Disord, 1997;27(5):501–17. 28. Ledvinová J, elleder M, filipin test for diagnosis of niemannPick disease type c, Sb Lek, 1993;94(2):137–43. 29. niemann Pick Disease foundation, Treatment options for nPc, 2099. Available at: www.nnpdf.org/npdisease_09.html (accessed 8 november 2011). 30. Patterson M, niemann-Pick Disease Type c, genereviews, Bookshelf iD: nBK1296, PMiD: 20301473. Available at: www.ncbi.nlm.nih.gov/books/nBK1296/ (accessed 21 september 2011). 31. Walterfang M, Mocellin r, Velakoulis D, The neuropsychiatry of neurometabolic and neuroendocrine disorders. in: sadock BJ, sadock VA and ruiz P (eds), Kaplan and Sadock’s Comprehensive Textbook of Psychiatry 9th edn, Philadelphia: Lippincott Williams and Wilkins, 2009;592–618. 32. cutting J, The phenomenology of acute organic psychosis. comparison with acute schizophrenia, Br J Psychiatry, 1987;151:324–32. 33. Barak y, Aizenberg D, Mirecki i, et al., Very late-onset schizophrenia-like psychosis: clinical and imaging characteristics in comparison with elderly patients with schizophrenia, J Nerv Ment Dis, 2002;190(11):733–6. 34. horiguchi J, Miyaoka T, shinno h, Pathogenesis and symptomatology of hallucinations (delusions) of organic brain disorder and schizophrenia, Psychogeriatrics, 2009;9(2):73–6. 35. sedel f, Baumann n, Turpin Jc, et al., Psychiatric manifestations revealing inborn errors of metabolism in adolescents and adults, J Inherit Metab Dis, 2007;30(5):631–41. 36. cohen D, nicolas JD, flament Mf, et al., clinical relevance of chronic catatonic schizophrenia in children and adolescents: evidence from a prospective naturalistic study, Schizophr Res, 2005;76(2–3):301–8. 37. cornic f, consoli A, Tanguy ML, et al., Association of adolescent catatonia with increased mortality and morbidity: evidence from a prospective follow-up study, Schizophr Res, 2009;113(2–3):233–40. 38. garver Ws, francis gA, Jelinek D, et al., The national niemann-Pick c1 disease database: report of clinical features and health problems, Am J Med Genet A, 2007;143A(11):1204–11. 39. Walterfang M, fietz M, fahey M, et al., The neuropsychiatry of niemann-Pick type c disease in adulthood, J Neuropsychiatry Clin Neurosci, 2006;18:158–70.

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