Les signes psychiatriques des maladies neuro-métaboliques sont un des domaines d’expertise du service. Vous trouverez sur le site des présentations claires sur ce sujet, et nous mettons à votre disposition un texte complet en anglais qui vient d’être publié par notre équipe.
A range of medical conditions may be associated with schizophrenia-like psychosis.1 The landmark review of psychosis associated with organic disorders by Davison and Bagley, which utilized the 1957 WHO operational criteria for schizophrenia, highlighted a number of disorders where the association with psychosis significantly exceeded chance.2 Many of the disorders identified showed pathology in the temporal lobe and diencephalon.
A large study of 268 consecutive patients with first-episode psychosis found that 6% had organic cerebral disease that was potentially causally linked with psychiatric symptoms,3 which emphasizes the importance of a thorough diagnostic evaluation to exclude underlying medical illness at first presentation. Recently more than 60 different congenital conditions associated with psychosis were reviewed. Interestingly, some of them are not associated with dysmorphia, mental retardation or prominent neurological features which may help to trigger their search.4
The diagnosis of medical or neurological illnesses underlying psychosis is of great importance as many of these conditions are progressive or fatal, associated with significant additional medical comorbidity, and may be partially or entirely reversible with definitive treatment. Inborn errors of metabolism (IEMs) represent a particular focus for research as they are frequently under-detected or misdiagnosed, a number are treatable, and new diagnostic methods and therapies have become available.
IEMs are a group of diseases that generally result from the absence or deficiency of an intracellular component of a metabolic pathway (usually, but not exclusively, an enzyme), which may lead to altered intracellular synthesis and catabolism.5 There are hundreds of IEMs, and many remain poorly characterized. Most result in clinical disease due to the accumulation of substances that are toxic to, or interfere with, normal cellular function, or which may be due to the effects of a reduced ability to synthesize essential compounds.
The overall incidence of IEMs has been estimated to be approximately 40 cases per 100 000 live births.6 However, this rate may be an underestimation as new disorders continue to be discovered and characterized, and because diagnostic techniques continue to improve in sensitivity and accuracy.
Up to 80% of IEMs are diagnosed during childhood, but an increasing recognition of late-onset presentations has recently raised awareness and diagnoses of adult-onset forms.7 A number of adult-onset IEMs are associated with schizophrenia-like symptoms, including cerebrotendinous xanthomatosis (CTX), homocysteinemia, porphyria (POR), Wilson disease (WD), Niemann-Pick disease type C (NP-C), and urea cycle disorders (UCD).7
This article reports findings from a systematic literature review and provides a guide for the diagnosis of treatable IEMs associated with schizophrenia-like symptoms based on the review findings. The major features of IEMs that can be associated with psychosis are summarized, and a diagnostic algorithm to assist psychiatrists in the detection of atypical symptoms is proposed that may be related to underlying IEMs.
METHODS
Review Scope
A meeting was held in mid-2012 to decide which IEMs associated with psychosis are currently treatable, with the aim of conducting a systematic bibliographic search to address the clinical challenges associated with these conditions. Based on a consensus reached during that meeting, the following seven IEMs were chosen as a focus for this review: CTX, WD, homocysteinemia due to methyltetrahydrofolate reductase deficiency (MTHFR-D), homocysteinuria due to cystathionine beta-synthase deficiency (CbS-D), UCD, POR and NP-C.
Literature Search Methodology and Data Sources
The public MEDLINE database was searched according to a standard four-step protocol, as described in the following sections and summarized in Figure 1.
1. Identification
All terms, including complete names and abbreviations, for CTX, WD, MTHFR-D, CbS-D, POR, UCD and NP-C were searched alongside the generic tag, ‘psy*’ using EndNote X5 software (Thomson Reuter), which enabled the identification and deletion of any duplicates. In total, 708 potentially relevant records published between January 1967 and June 2012 were identified, from which 97 duplicate records were removed. Seven separate EndNote databases were created – one for each IEM. The numbers of articles for each IEM database were: CTX (n = 15); WD (n = 451); MTHFR-D (n = 12); CbS-D (n = 6); POR (n = 75); UCD (n = 15); and NP-C (n = 31). Six non-systematic literature reviews were also identified and included. 7-12 A total of 611 records were collated for screening.
2. Screening
Two groups worked separately in screening abstracts from relevant articles from the literature review (Group 1: MW and HHK: Group 2: OB, DC and FS). Case reports, case series with original data regarding psychiatric manifestations and cognitive impairments, and previous reviews containing relevant data were selected. Articles were excluded from full text analysis (see ‘Eligibility’ stage) according to the following exclusion criteria: 1) article just mentioned psychiatric manifestation without data in any of the seven chosen treatable diseases; 2) unrelated article, just mentioning an IEM; 3) literature reviews not containing any new data; and 4) data already reported elsewhere. Screening excluded 26 of the initial records from the POR database and 400 records from the WD database. In cases where the two analysis groups did not agree, records were kept and included in the next step.
3. Eligibility
The same two analysis groups accessed the full texts of all remaining articles (n = 185) and checked them further for eligibility according to the same exclusion criteria used in the abstract screening stage. The numbers of articles considered eligible after this process were: CTX (n = 15), WD (n = 51), MTHFR-D (n = 12), CbS-D (n = 6), POR (n = 49), UCD (n = 15) and NP-C (n = 31). The six previous reviews were also kept.
4. Inclusion
Among the eligible records, information on key IEM disease features as well as psychiatric manifestations was included from the following numbers of publications, per database: CTX (n = 14), WD (n = 11), MTHFR-D (n = 3), CbS-D (n = 2), POR (n = 12), UCD (n = 8) and NP-C (n = 9). Including the six previous reviews, this brought the final total of source articles to 59.
RESULTS
1. Disorders of Homocysteine Metabolism (DHM)
Key Features of CbS-D
Homocysteinuria due to cystathionine beta-synthase (CbS) deficiency is characterized by the involvement of the ocular, skeletal, central nervous and vascular systems. Two articles that addressed psychiatric symptoms and psychosis were identified.13, 14 The disease is an autosomal recessive disorder of methionine metabolism, caused by mutations in the CbS gene (21q22.3). CbS normally converts homocysteine to cystathionine in the trans-sulfuration pathway of the methionine cycle, and requires pyridoxal 5-phosphate as a cofactor. The other two cofactors involved in methionine remethylation include vitamin B12 and folic acid. Clinical diagnosis of CbS deficiency is confirmed by blood amino acid analysis (including total homocysteine measurement), assays of CbS enzyme activity, or screening for CBS mutations.
Patients appear normal at birth but display a progressive disease course if left untreated. Eye anomalies include ectopia lentis (in 85% of cases) and high myopia. Skeletal changes include genu valgum and pes cavus, followed by dolichostenomelia, pectus excavatum or carinatum, kyphoscoliosis and osteoporosis. A Marfan-like body habitus may occur, with tall stature and arachnodactyly. Thromboembolism affecting both large and small arteries and veins is the most striking cause of morbidity and mortality, and affects 25% of individuals by the age of 15 years. While some individuals have a normal IQ, mental retardation is common and, when present, may progress if the disorder is left untreated. Brittle hair and livedo reticularis have also been reported.
Psychiatric Signs
In one of the few studies in this field, psychiatric illness was found in 51% of cases overall, with symptoms falling into four diagnostic categories: episodic depression (10%), chronic disorders of behavior (17%), obsessive-compulsive disorder (5%), and personality disorder (19%).13 In the same study, aggressive behavior and other conduct disorders were particularly common among patients with mental retardation and those who were nonresponsive to vitamin B6. In some cases, psychiatric symptoms may be the initial presenting symptom.14
Key Features of MTHFR-D
Methyltetrahydrofolate reductase deficiency is another autonomic recessive trait, and is caused by mutations in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene (1p36.3). MTHFR deficiency results in abnormal intracellular folic acid metabolism, and prevents reduction of 5-10 methylenetetrahydrofolate to 5-methyltetrahydrofolate – the methyl donor for the remethylation of homocysteine into methionine. As a result, the disorder leads to methyltetrahydrofolate deficiency and consequently to homocysteinuria and hypomethioninemia.
The onset of MTHFR deficiency usually occurs during the first year of life, characterized by severe neurological signs, recurrent apnea, microcephaly and convulsions without megaloblastic anemia. However, there are some forms with onset during childhood, adolescence or adulthood that present with mental regression, ataxia and schizophrenia-like psychosis. Other symptoms such as sub-acute degeneration of the spinal cord have been reported.
Diagnoses of DHM are made through analysis of amino acids by chromatography and total plasma homocysteine measurement; an elevated level is defined at >100 micromol/L.15 Methionine levels may be useful, as they are decreased in MTHFR deficiency and increased in CbS.
There are currently three recognized treatment modalities for DHM. For pyridoxine-responsive patients, treatment with pharmacological doses of pyridoxine combined with folic acid and vitamin B12 supplements is recommended. In pyridoxine non-responsive patients, the treatment should comprise a methionine-restricted, cysteine-supplemented diet in combination with the pyridoxine, folic acid and vitamin B12 supplementation. Betaine anhydrous is a methyl donor that may lead to lowering of homocysteine levels in MTHFR deficiency patients, and can be used as an adjunct to such a diet.
Homocysteine is cleared by transulfuration to cysteine and glutathione, an important antioxidant. Transulfuration requires vitamins B6 and B12. Treatment with vitamin B6, a precursor of homocysteine, can be effective in treating psychiatric symptoms if instituted early.7
Psychiatric Signs
Three articles were identified from the systematic literature review.16-18 Psychiatric symptoms are not uncommon in MTHFR deficiency, and may be the presenting symptom.16 Their onset may be acute or may follow a more insidious course.17 Acute manifestations occur mainly after surgery, and present with visual and/or auditory hallucinations, thought disorder and delusions. Non-psychotic illness has also been associated with folate metabolism disorders.
A recent meta-analysis examining the association between MTHFR gene polymorphisms and psychiatric disorders demonstrated a strong association between the MTHFR C677T gene variant and unipolar depression, schizophrenia and bipolar disorders, with odds ratios of 1.36, 1.44 and 1.82, respectively.18 Notably, the metabolic syndrome secondary to antipsychotic medication may be more frequent in patients with reduced MTHFR activity associated with schizophrenia-like psychosis.19
It is well documented that aberrant methylated compounds are linked to mental state and behavior. A recent review of the ‘one-carbon metabolism hypothesis’ described a range of factors that can contribute to folate and/or vitamin B12 deficiency.20 Moreover, folic acid is a water-soluble B-vitamin involved in the synthesis, repair and methylation of DNA, leading to epigenetic regulation of crucial developmental genes implicated in the pathogenesis of schizophrenia.21, 22 Deficiency of B-vitamins leads to an increased level of homocysteine, which is a highly toxic metabolite to neural and vascular development.23 Elevated serum levels of homocysteine have also been shown to be associated with schizophrenia, although the evidence is far from conclusive.24, 25
2. Urea Cycle Disorders (UCD)
Key Features
The urea cycle is the metabolic process by which the body eliminates nitrogen. Six enzymes take part in this process; a deficiency of any one of them disrupts this pathway and results in excess nitrogen accumulating in the body in the form of ammonia. The six UCDs include deficiency of: 1) carbamyl phosphate synthetase; 2) n-acetylglutamate synthetase; 3) ornithine transcarbamylase; 4) argininosuccinic acid synthetase (also called citrullinemia); 5) argininosuccinase acid lyase; and 6) arginase.
If the enzyme deficiency is severe, symptoms will be present at birth and can present as irritability, nausea and vomiting followed by lethargy, seizures and poor muscle tone. If left untreated, patients can develop respiratory distress or fall victim to coma or premature death due to pathological levels of ammonia in the blood.
If the enzyme deficiency is partial, symptom onset may not occur until childhood or adulthood. In such cases, symptoms may include nausea and vomiting associated with headache and a clouded sensorium in the context of infection or a high-protein diet. Medications may worsen or trigger the disease, particularly corticosteroids and sodium valproate.
There is no cure for the UCDs, although prompt diagnosis allows measures to be taken that can reduce the consequences of hyperammonemia. Measurement of plasma ammonemia is key to the diagnosis of UCDs, and treatment consisting of a protein-restricted diet and special supplements is essential.26 In addition, several medications including sodium benzoate, sodium phenylacetate and sodium phenylbutyrate can bind with ammonia and remove it from the circulation. Hemodialysis may represent an alternative treatment, especially in emergency situations.27
Psychiatric Signs
Eight relevant articles were identified in the literature review.28, 29. 30-35 Psychiatric presentations including delusions and disorganized behavior have been described.29 Atypical major depressive disorder has also been reported.28 Interestingly, late-onset UCD may present with behavioral and hallucinatory psychiatric and organic signs, often featuring vomiting.32-34
3. Acute Porphyria
Key Features
Porphyrias comprise a group of eight hereditary metabolic diseases characterized by intermittent neurovisceral manifestations, cutaneous lesions, or the combination of both. All porphyrias are caused by a deficiency in one of the enzymes of the heme biosynthesis pathway. These deficiencies result in an accumulation of porphyrins and/or their precursors – delta-aminolevulinic acid (ALA) and porphobilinogen (PBG) – in the liver or bone marrow. Neurological manifestations are caused by the neurotoxic effects of these precursors, particularly ALA.
Enzyme deficiencies in the porphyrias result from mutations of the correspondingly coded genes, and transmission of hereditary porphyrias occurs in either an autosomal dominant fashion with weak penetrance, or in a recessive manner with complete penetrance.
Clinical signs of disease usually appear in adulthood although some porphyrias affect children. Porphyrias are classified into two groups – hepatic and erythropoietic – according to the main location of the metabolic anomaly. Chronic hepatic porphyrias and erythropoietic porphyrias manifest with bullous cutaneous lesions or acute pain in areas exposed to the sun, without neurological symptoms. However, neuro-visceral attacks occur in patients with acute hepatic porphyrias, manifesting as intense abdominal pain (often associated with nausea, vomiting and constipation), and neurological and psychological symptoms. Two acute hepatic porphyrias (variegate porphyria and hereditary coproporphyria) may also present with cutaneous photosensitivity.
Diagnosis is mainly based on the measurement of porphyrins and their precursors in biological samples such as urine, stools, and blood. The key diagnostic procedure is the measurement of delta aminolevulinic acid and porphobilinogen in urine. Genetic counseling should be offered to affected families to identify individuals susceptible to developing and transmitting the disease. Acute attacks should be treated urgently with an injection of human hemin and/or perfusion of carbohydrates.
Psychiatric Signs
Twelve relevant articles were included from the systematic literature review. Psychiatric manifestations are widely known and well-documented,36-39 occurring in 24–70% of patients in acute porphyria series.40, 41 The most common manifestations reported are delirium, psychosis and depression, with some authors suggesting that 40% of acute porphyrias present with delirium and hallucinations.42 Catatonia has also been reported in some cases.39 Coproporphyria might also be a presenting symptom and must be recognized, especially in children and young adults.43-47
4. Wilson disease
Key Features
Wilson disease (WD) is an autosomal recessive disorder with a prevalence of 1–4 per 100 000 of the general population. A mutation in the ATP7B gene coding for a key copper transport protein leads to copper accumulation in the liver, brain, kidney and skeletal system, caused by reduced excretion in the bile.48
In approximately half of patients, computerized tomography reveals characteristic hypodensities in the basal ganglia.49 Virtually all patients show magnetic resonance imaging (MRI) abnormalities, including T2-weighted hyperintensities in the thalamus, brainstem, and lenticular nuclei.50 Functional imaging generally shows significant hypometabolism in the lenticular nuclei.51
Classically, symptoms of WD appear between the ages of 6 and 20 years. Approximately one-third of patients initially present with hepatic disease, one-third with neurological symptoms, and one-third with psychiatric symptomatology. Between one- and two-thirds of patients report psychiatric symptoms at the time of initial presentation.52-54 Psychiatric signs are present in almost 50% of patients at any one time,55 and present before motor signs in 20% of cases; up to half of patients may be seen initially by a psychiatrist.56 Four main psychiatric symptom clusters have been identified: mood and affective change, behavior and personality change, psychosis, and cognitive impairment.57 Personality changes are very common, particularly irritability and aggression.52, 58 Mood disturbance, including both depression and mania, is the most common formal neuropsychiatric illness.59-64
Psychiatric Signs
Eleven relevant case reports or case series (psychiatric or general including psychiatric patients) were identified, and data from most of these were included in a large review.53 Psychosis, delusional states and catatonia, while less frequent in WD, can be extremely disabling.52, 53, 56, 57, 65 Schizophrenia-like symptoms were reported to be present in up to 10% of patients,59 but were less prevalent in one case series (2.4%).66 Whilst delusions in WD have been reported to be uncommon,56 a number of psychotic presentations meeting criteria for delusional disorder have recently been described.67-70
Deteriorating academic performance or work function is another key neurological feature of WD. Neurologically symptomatic patients display a range of cognitive difficulties including impairments of executive function, aspects of memory and visuospatial processing.55, 71, 72 In contrast, no such deficits are found in neurologically asymptomatic patients.73 Lesions within the basal ganglia seem to be of central importance in cognitive change due to their interruption of frontal-subcortical circuits.73, 74
After initiating treatment with chelation therapy, the disease often stabilizes or improves, but disease progression during treatment is more likely for neuropsychiatric symptoms than for hepatic symptoms.75 Resolution of neuropsychiatric illness following chelation has been reported.64, 70, 76, 77
The use of neuroleptic medication may be problematic due to the increased risk of movement disorder side effects in the setting of degenerative basal ganglia disease.78-81 However, some reports suggest the relatively safe use of atypical medications such as olanzapine, risperidone, quetiapine and clozapine, which each have a lower propensity to cause movement disorders.69, 80, 82, 83 Nevertheless, these agents should be used with caution because of the increased risk of agranulocytosis in the presence of hypersplenism or penicillamine treatment.
Treatment of mania with mood stabilizers can be difficult because valproate or carbamazepine may be contraindicated in the presence of significant hepatic impairment.81 Lithium may also be contraindicated in the presence of renal tubular acidosis,81 although successful lithium treatment without metabolic compromise has been reported.83, 84
Electroconvulsive therapy (ECT) has been successfully used in cases of catatonia,85 psychosis86 and depression.87-89
Depression has been reported as responding to both tricyclic antidepressants and selective serotonin reuptake inhibitors,88-90 although treatment-resistance to traditional antidepressants has also been described.88 A manic switch in response to antidepressant therapy has also been described in one patient.90
5. Cerebrotendinous xanthomatosis
Key Features
Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive disease of bile acid synthesis. It is caused by mutations in the CYP27A1 gene, which is localized on the long arm of chromosome 2 and codes for the mitochondrial enzyme, sterol-27-hydroxylase. This enzyme is involved in the synthesis of chenodeoxycholic and cholic acids from cholesterol. The metabolic block resulting from the mutant gene causes a progressive storage of cholesterol and its poorly soluble by-product, cholestanol, which is deposited in many tissues including the brain and tendons.91 A recent review found more than 300 patients with CTX reported worldwide, and identified 50 different mutations in the CYP27A1 gene associated with this disease.92
Clinical presentations of CTX are quite variable. The initial symptoms typically begin in childhood with non-specific mild mental retardation, juvenile cataract, chronic diarrhea or epilepsy. Progressive neurological deterioration follows in adolescence or adulthood with acute psychiatric signs,10, 93 progressive spastic paraparesis, cerebellar ataxia, polyneuropathy, epilepsy and cognitive deficits leading to severe handicap or death. These neurological signs can be accompanied by the appearance of tendon xanthomata, which are usually visible at the level of the Achilles’ tendons. An MRI of the brain typically shows a specific pattern with high signals in the dentate nuclei of the cerebellum on T2-weighted sequences.94
Chenodeoxycholic acid is the primary treatment for CTX. This agent blocks the accumulation of cholestanol by replenishing the pool of bile acid in the liver and hepatic circulation, and shuts down the abnormal hepatic bile acid synthesis pathway. Although it is efficient at normalizing circulating levels of cholestanol, and clearly stabilizes disease progression, it does not improve already existing neurological signs. In addition, xanthomata do not decrease in size.
Psychiatric Signs
Fourteen articles were identified in the systematic literature review.10, 93 Psychiatric manifestations in CTX have only been described in sporadic reports and two patient series.93, 95-107 Unfortunately, many of these cases are poorly documented.
Acute psychotic episodes have been described, but most psychiatric symptoms are non-specific and occur during childhood and/or adolescence.10, 93 Hyperactivity is the most common syndrome seen during youth, and is associated with cognitive impairments in speech and comprehension.108
6. Niemann Pick type C Disease
Key Features
NP-C is a panethnic, autosomal recessive neurodegenerative disease with an incidence estimated between 1 case per 150,000 and 1 case per 120 000 live births.109, 110 The disease is characterized by a variety of progressive, disabling neurological symptoms including clumsiness, limb and gait ataxia, dysarthria, dysphagia and cognitive deterioration.109, 111
NP-C is associated with mutations of the NPC1 and NPC2 genes, with no primary defect in catabolic enzymes. NPC1 gene mutations are present in 95% of cases and NPC2 mutations are present in approximately 4%. At the cellular level, these mutations give rise to characteristic abnormalities in the intracellular transport of cholesterol, glycosphingolipids and sphingosine. Impaired function of the NPC1 and NPC2 gene products, which normally function cooperatively in intracellular lipid transport, leads to the accumulation of these lipids in the late-endosomal/lysosomal intracellular compartment, and excess bulk build up 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 above all, GM2 and GM3 gangliosides are markedly increased in the brain.112
NP-C has an extremely heterogeneous clinical presentation characterized by a wide range of symptoms that are not specific to the disease, and which arise and progress over varied periods of time.109, 113 This complicates diagnosis, and is likely an important factor in the under-detection of the NP-C and, in some cases, 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, up to the seventh decade of life.114
The age at onset of neurological symptoms has a major influence on disease progression;115 if neurological symptoms arise early in life the rate of deterioration is generally faster and premature death occurs sooner. Patients with the perinatal-onset form present during the first 3 months of life with an enlarged liver and spleen, prolonged cholestasis, hydrops fetalis and/or respiratory failure,109, 110 usually without presenting neurological signs. Infantile, juvenile and adolescent/adult forms usually present with neurological signs including progressive ataxia, dystonia, dysarthria, dysphagia, deafness, cataplexy or, more rarely, epilepsy. Most notably, vertical supranuclear gaze palsy (VSGP) – particularly paresis of downgaze – is a highly specific and highly prevalent sign that may be present at an early stage of the disease.109, 111 VSGP or discrete slowing of saccades is present in almost all cases at some point during the disease course.
Diagnosis of NP-C requires a skin biopsy and a fibroblast culture in a specialized center, with the resulting cultured cells stained with filipin (which binds excess cholesterol) and tested for cholesterol esterification. However, data suggest that plasma oxysterol measurements may represent simpler screening and/or diagnostic method in the coming years.116
Therapy for NP-C has, until recently, been limited to supportive measures, including pharmacotherapy to alleviate neurological and psychiatric symptoms.109, 111, 117 Miglustat, an iminosugar compound that reversibly inhibits glucosyl ceramide synthetase and thus inhibits the formation of excess gangliosides, is a substrate-reduction therapy that has been shown to stabilize neurological manifestations in children and adults.118-120
Psychiatric signs
Numerous cases of NP-C presenting with schizophrenia-like symptoms have been reported in adolescent and adult patients, and nine cases series and reports were identified and included in this literature analysis.121-129 Definitive diagnoses are commonly delayed in patients with adult psychiatric presentations of NP-C, sometimes by up to 10 years.130
Psychotic presentations among children and adolescents with NP-C have been reported, and may be comorbid with a pervasive developmental disorder (PDD). Sandu et al reported a case of an 8 year-old with PDD who presented with auditory hallucinations and 7 years later developed a typical paranoid schizophrenic illness that was partially responsive to risperidone.128 One notable report described two siblings with psychosis.131 The male sibling presented at 16 years old with visual and auditory hallucinations, and later developed dysarthria and ataxia leading to a definitive diagnosis at the age of 24 years when vertical supranuclear ophthalmoplegia was discovered. His sister developed schizophrenia-like symptoms a decade later, but diagnosis was made rapidly when she was examined for vertical supranuclear ophthalmoplegia based on the family history. Notably, her later onset and lower antipsychotic dosage required to effect symptom resolution mirrored the gender dimorphism seen in typical schizophrenia, which raises the possibility of a gender effect in presentation and progression of NP-C.131
The onset of developmental delay is commonly seen between 6 and 15 years of age in NP-C, and may result in a learning disorder and/or impaired school performance.113, 132, 133 Patients commonly display cognitive impairments involving logical thinking and abstraction, impaired attentional processes, poor working memory, word retrieval difficulties, and a lack of interpersonal ‘distance’.117, 133 The typical cognitive profile in adult patients is one of significant executive dysfunction and impaired working memory.111, 133
DISCUSSION
This article is the first systematic review in this field. Widely unknown and neglected by psychiatrists, IEMs represent a growing field in research that interfaces with clinical psychiatry due to the fact that a number of disorders may initially present to psychiatrists. New treatments are available for a number of these diseases.134
One key finding of this literature review is that the clinical signs of IEMs are poorly documented in terms of both quantity (only 63 articles with original data for seven different disorders) and quality (non-systematic clinical evaluations, lack of standardized clinical scales, sparse clinical description). A second clear finding is that many cases of WD, MTHFR deficiency and NP-C are strongly associated with psychotic illness.
Common psychiatric practice for affected patients, especially those with intellectual disabilities (ID) who tend to have a poor healthcare environment, is difficult and medical diagnosis is sometimes inaccurate. It is well known that people with ID have a higher level of health needs compared with the general population, which is often unmet.135 It is not realistic, and probably unnecessary due to the rarity of the association, to consider IEMs in all psychiatric patients. It is also not beneficial to train psychiatrists to become metabolism specialists. However, it is crucial for all professionals working in psychiatry to be aware of the large variety of organic disorders that may be associated with psychiatric diseases, especially in the case of IEMs.
When we focus our interests on such rare diseases it is almost impossible to be sure that an IEM could be directly linked to schizophrenia-like symptoms. If prevalence rates are higher than 0.8–1.0% (the general population prevalence for schizophrenia)136, 137 an association may be considered relevant, as in the case of 22q11 micro-deletion syndrome which is seen in around 15% of patients with schizophrenic disorders.138, 139 When treatment of organic conditions leads to an improvement in schizophrenic symptoms, a relevant association can be considered. However, this does not say anything about the potential organic origins of schizophrenia. There is a wide consensus regarding the neurodevelopmental hypothesis of schizophrenia,140, 141 as well as complex genetic determinism associated with cofactors.142 Questions remain open as to whether organic psychoses represent schizophrenia-like disorders of ‘real’ schizophrenia per se. Historically, the term ‘schizophrenia-like’ is usually employed when possible organic origins are associated.143
Data regarding organic psychosis and its specific associated symptoms are scarce. One study, which was not specific for IEMs, analyzed the phenomenology of 74 patients with ‘organic schizophrenia’ compared with ‘non-organic schizophrenia’.144 Visual hallucinations and confusion were seen more often among patients with organic schizophrenia, and comparable features have been observed in elderly schizophrenia patients.145, 146 An acute onset of psychiatric manifestations, which is well known to be associated with drug abuse, may also raise suspicion of IEMs (e.g. urea circle disorders, porphyria or homocysteinemia with CbS deficiency). It is also notable that data indicate a high degree of association of catatonia with organic disorders, especially if it occurs during childhood or adolescence.147 An unusually high proportion of patients with organic disorders has been reported in large series of patients with early-onset schizophrenia, which suggests that an early-onset of schizophrenia-like symptoms is another indicator for possible organic origin of disease, especially if associated with progressive cognitive decline, which is a common feature in IEMs.148 Finally, treatment resistance is frequently associated with IEMs, again suggesting its possible use as an indicator for possible organic disease.
In summary, this review highlighted six easily recognizable features that should trigger suspicion of organicity associated with schizophrenia-like symptoms: 1) confusion; 2) visual hallucinations; 3) catatonia; 4) progressive cognitive decline; 5) early or acute onset; 6) treatment resistance (see Table 1). Table 2 provides a summary that encompasses the main clinical signs of 6 treatable IEMs, and highlights the main clinical, contextual, ophthalmologic symptoms. It is important for psychiatrists and other associated professionals to be specifically aware of potential IEMs when patients present with such indicators (organic signs and atypical psychiatric symptoms) of possible organic psychosis.
CONCLUSIONS
Our work is based on a three main observations. First, schizophrenia or schizophrenia-like syndromes can be associated with a range of organic disorders. Second, some IEMs are treatable (sometimes simply with vitamin replacement or supplementation) and new treatments continue to appear. Finally, clinical studies indicate that treatments are most effective during the early stages of disease in certain IEMs, during which psychiatric symptoms may be evident.
When patients present with psychiatric symptoms it can be difficult to consider IEMs as a possible underlying cause due to infrequency of such cases. It is hoped that his review summarizing seven easily assessed features that might trigger suspicion of organicity in patients with psychosis will help to detect patients with the treatable IEMs as early as possible during their disease course. While not intended to replace specialized psychiatric and neurological examination and measurements, our proposed algorithm is a pragmatic tool that can be used to reduce the risk of mistaken diagnoses among patients with atypical psychiatric signs and treatable IEMs.
Acknowledgements
Matthew Reilly PhD, associated with InTouch Medical Ltd, provided editorial assistance in the preparation of the final draft of this manuscript, paid for by Actelion Pharmaceuticals Ltd.
References
1.Price G,Ron MA. Schizophrenia and schizophrenia-like psychosis, in Neurology and Clinical Neuroscience (First Edition), A.H.V. Schapira, Editor. 2003, Elsevier-Mosby: St Louis. p. 223-233.
2.Davison K. Schizophrenia-like psychoses associated with organic cerebral disorders: a review. Psychiatr Dev 1983;1(1):1-33.
3.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.
4.Lauterbach MD, Stanislawski-Zygaj AL,Benjamin S. The differential diagnosis of childhood and young adult onset disorders that include psychosis. Journal of Neuropsychiatry and Clinical Neurosciences 2008;20(4):409-418.
5.Saudubray JM. Neurometabolic disorders. J Inherit Metab Dis 2009;32(5):595-6.
6.Applegarth DA, Toone JR,Lowry RB. Incidence of inborn errors of metabolism in British Columbia, 1969-1996. Pediatrics 2000;105(1):e10.
7.Sedel F, Baumann N, Turpin JC, Lyon-Caen O, Saudubray JM,Cohen D. Psychiatric manifestations revealing inborn errors of metabolism in adolescents and adults. J Inherit Metab Dis 2007;30(5):631-41.
8.Wilson WP,Nashold BS, Jr. Psychiatric considerations of certain neurological diseases treated neurosurgically. Int Psychiatry Clin 1967;4(2):189-204.
9.Bonnot O,Cohen D. [Psychiatric and cognitive signs associated with inborn errors of metabolism]. Rev Neurol (Paris) 2011;167(12):881-5.
10.Estrov Y, Scaglia F,Bodamer OA. Psychiatric symptoms of inherited metabolic disease. J Inherit Metab Dis 2000;23(1):2-6.
11.Martins AM. Inborn errors of metabolism: a clinical overview. Sao Paulo Med J 1999;117(6):251-65.
12.Trifiletti RR,Packard AM. Metabolic disorders presenting with behavioral symptoms in the school-aged child. Child Adolesc Psychiatr Clin N Am 1999;8(4):791-806.
13.Abbott MH, Folstein SE, Abbey H,Pyeritz RE. Psychiatric manifestations of homocystinuria due to cystathionine beta-synthase deficiency: prevalence, natural history, and relationship to neurologic impairment and vitamin B6-responsiveness. Am J Med Genet 1987;26(4):959-69.
14.Li SC,Stewart PM. Homocystinuria and psychiatric disorder: a case report. Pathology 1999;31(3):221-4.
15.Baric I. Inherited disorders in the conversion of methionine to homocysteine. J Inherit Metab Dis 2009;32(4):459-71.
16.Mattson MP,Shea TB. Folate and homocysteine metabolism in neural plasticity and neurodegenerative disorders. Trends Neurosci 2003;26(3):137-46.
17.Roze E, Gervais D, Demeret S, Ogier de Baulny H, Zittoun J, Benoist JF, Said G, et al. Neuropsychiatric disturbances in presumed late-onset cobalamin C disease. Arch Neurol 2003;60(10):1457-62.
18.Gilbody S, Lewis S,Lightfoot T. Methylenetetrahydrofolate reductase (MTHFR) genetic polymorphisms and psychiatric disorders: a HuGE review. Am J Epidemiol 2007;165(1):1-13.
19.Ellingrod VL, Miller DD, Taylor SF, Moline J, Holman T,Kerr J. Metabolic syndrome and insulin resistance in schizophrenia patients receiving antipsychotics genotyped for the methylenetetrahydrofolate reductase (MTHFR) 677C/T and 1298A/C variants. Schizophr Res 2008;98(1-3):47-54.
20.Frankenburg FR. The role of one-carbon metabolism in schizophrenia and depression. Harv Rev Psychiatry 2007;15(4):146-60.
21.Friso S,Choi SW. Gene-nutrient interactions in one-carbon metabolism. Curr Drug Metab 2005;6(1):37-46.
22.Sharma RP. Schizophrenia, epigenetics and ligand-activated nuclear receptors: a framework for chromatin therapeutics. Schizophr Res 2005;72(2-3):79-90.
23.Regland B. Schizophrenia and single-carbon metabolism. Prog Neuropsychopharmacol Biol Psychiatry 2005;29(7):1124-32.
24.O'Donnell C,Stephens T. The significance of homocysteine levels in schizophrenia. Am J Psychiatry 2005;162(7):1387-8; author reply 1388-9.
25.Muntjewerff JW, Kahn RS, Blom HJ,den Heijer M. Homocysteine, methylenetetrahydrofolate reductase and risk of schizophrenia: a meta-analysis. Mol Psychiatry 2006;11(2):143-9.
26.Singh RH. Nutritional management of patients with urea cycle disorders. J Inherit Metab Dis 2007;30(6):880-7.
27.Smith W, Kishnani PS, Lee B, Singh RH, Rhead WJ, Sniderman King L, Smith M, et al. Urea cycle disorders: clinical presentation outside the newborn period. Crit Care Clin 2005;21(4 Suppl):S9-17.
28.Arn PH, Hauser ER, Thomas GH, Herman G, Hess D,Brusilow SW. Hyperammonemia in women with a mutation at the ornithine carbamoyltransferase locus. A cause of postpartum coma. N Engl J Med 1990;322(23):1652-5.
29.Enns GM, O'Brien WE, Kobayashi K, Shinzawa H,Pellegrino JE. Postpartum "psychosis" in mild argininosuccinate synthetase deficiency. Obstet Gynecol 2005;105(5 Pt 2):1244-6.
30.Bachmann C. Outcome and survival of 88 patients with urea cycle disorders: a retrospective evaluation. Eur J Pediatr 2003;162(6):410-6.
31.Krivitzky L, Babikian T, Lee HS, Thomas NH, Burk-Paull KL,Batshaw ML. Intellectual, adaptive, and behavioral functioning in children with urea cycle disorders. Pediatr Res 2009;66(1):96-101.
32.Legras A, Labarthe F, Maillot F, Garrigue MA, Kouatchet A,Ogier de Baulny H. Late diagnosis of ornithine transcarbamylase defect in three related female patients: polymorphic presentations. Crit Care Med 2002;30(1):241-4.
33.Myers JH,Shook JE. Vomiting, ataxia, and altered mental status in an adolescent: late-onset ornithine transcarbamylase deficiency. Am J Emerg Med 1996;14(6):553-7.
34.Panlaqui OM, Tran K, Johns A, McGill J,White H. Acute hyperammonemic encephalopathy in adult onset ornithine transcarbamylase deficiency. Intensive Care Med 2008;34(10):1922-4.
35.Thurlow VR, Asafu-Adjaye M, Agalou S,Rahman Y. Fatal ammonia toxicity in an adult due to an undiagnosed urea cycle defect: under-recognition of ornithine transcarbamylase deficiency. Ann Clin Biochem 2010;47(Pt 3):279-81.
36.Cashman MD. Psychiatric aspects of acute porphyria. Lancet 1961;1(7168):115-6.
37.Tishler PV, Woodward B, O'Connor J, Holbrook DA, Seidman LJ, Hallett M, Knighton DJ. High prevalence of intermittent acute porphyria in a psychiatric patient population. Am J Psychiatry 1985;142(12):1430-6.
38.Boon FF,Ellis C. Acute intermittent porphyria in a children's psychiatric hospital. J Am Acad Child Adolesc Psychiatry 1989;28(4):606-9.
39.Santosh PJ,Malhotra S. Varied psychiatric manifestations of acute intermittent porphyria. Biol Psychiatry 1994;36(11):744-7.
40.Goldberg A. Acute intermittent porphyria: a study of 50 cases. Q J Med 1959;28(110):183-209.
41.Stein JA,Tschudy DP. Acute intermittent porphyria. A clinical and biochemical study of 46 patients. Medicine (Baltimore) 1970;49(1):1-16.
42.Bonkowsky HL,Schady W. Neurologic manifestations of acute porphyria. Semin Liver Dis 1982;2(2):108-24.
43.Brodie MJ, Thompson GG, Moore MR, Beattie AD,Goldberg A. Hereditary coproporphyria. Demonstration of the abnormalities in haem biosynthesis in peripheral blood. Q J Med 1977;46(182):229-41.
44.Mandoki MW,Sumner GS. Psychiatric manifestations of hereditary coproporphyria in a child. J Nerv Ment Dis 1994;182(2):117-8.
45.Crimlisk HL. The little imitator--porphyria: a neuropsychiatric disorder. J Neurol Neurosurg Psychiatry 1997;62(4):319-28.
46.Kuhnel A, Gross U,Doss MO. Hereditary coproporphyria in Germany: clinical-biochemical studies in 53 patients. Clin Biochem 2000;33(6):465-73.
47.Gross U, Puy H, Meissauer U, Lamoril J, Deybach JC, Doss M, Nordmann Y, et al. A molecular, enzymatic and clinical study in a family with hereditary coproporphyria. J Inherit Metab Dis 2002;25(4):279-86.
48.Pfeffer RF. Wilson's disease. Semin Neurol 2007;27(2):123-132.
49.Williams J,Walshe J. Wilson's disease: an analysis of the cranial computerized tomographic appearances found in 60 patients and the changes in response to treatment with chelating agents. Brain 1981;104:735-752.
50.Roh JK, Lee TG, Wie BA, Lee SB, Park SH,Chang KH. Initial and follow-up brain MRI findings and correlation with the clinical course in Wilson's disease. Neurology 1994;44(6):1064-8.
51.Hawkins RA, Mazziotta JC,Phelps ME. Wilson's disease studied with FDG and positron emission tomography. Neurology 1987;37(11):1707-11.
52.Barthel W,Markwardt F. Aggregation of blood platelets by adrenaline and its uptake. Biochem Pharmacol 1975;24(20):1903-4.
53.Dening TR. The neuropsychiatry of Wilson's disease: a review. Int J Psychiatry Med 1991;21(2):135-48.
54.Schwartz M, Fuchs S, Polak H,Sharf B. [Psychiatric manifestations in Wilson's disease]. Harefuah 1993;124(2):75-7, 120.
55.Rathbun JK. Neuropsychological aspects of Wilson's disease. Int J Neurosci 1996;85(3-4):221-9.
56.Dening TR,Berrios GE. Wilson's disease. Psychiatric symptoms in 195 cases. Arch.Gen.Psychiatry 1989;46(12):1126-1134.
57.Dening TR. Psychiatric aspects of Wilson's disease. Br J Psychiatry 1985;147:677-82.
58.Coscia L, Causa P, Giuliani E,Nunziata A. Pharmacological properties of new neuroleptic compounds. Arzneimittelforschung 1975;25(9):1436-42.
59.Akil M,Brewer GJ. Psychiatric and behavioral abnormalities in Wilson's disease. Adv Neurol 1995;65:171-8.
60.Akil M, Schwartz JA, Dutchak D, Yuzbasiyan-Gurkan V,Brewer GJ. The psychiatric presentations of Wilson's disease. J Neuropsychiatry Clin Neurosci 1991;3(4):377-82.
61.Dening TR,Berrios GE. Wilson's disease: a longitudinal study of psychiatric symptoms. Biol Psychiatry 1990;28(3):255-65.
62.Dening TR,Berrios GE. Wilson's disease. Psychiatric symptoms in 195 cases. Arch Gen Psychiatry 1989;46(12):1126-34.
63.Medalia A,Scheinberg IH. Psychopathology in patients with Wilson's disease. Am J Psychiatry 1989;146(5):662-4.
64.Srinivas K, Sinha S, Taly AB, Prashanth LK, Arunodaya GR, Janardhana Reddy YC, Khanna S. Dominant psychiatric manifestations in Wilson's disease: a diagnostic and therapeutic challenge! J Neurol Sci 2008;266(1-2):104-8.
65.Renaud B, Buda M, Lewis BD,Pujol JF. Effects of 5,6-dihydroxytryptamine on tyrosine-hydroxylase activity in central catecholaminergic neurons of the rat. Biochem Pharmacol 1975;24(18):1739-42.
66.Taly AB, Meenakshi-Sundaram S, Sinha S, Swamy HS,Arunodaya GR. Wilson disease: description of 282 patients evaluated over 3 decades. Medicine (Baltimore) 2007;86(2):112-21.
67.Sagawa M, Takao M, Nogawa S, Mizuno M, Murata M, Amano T, Koto A. [Wilson's disease associated with olfactory paranoid syndrome and idiopathic thrombocytopenic purpura]. No To Shinkei 2003;55(10):899-902.
68.Wichowicz H, Cubala W,Slawek J. Wilson's disease asociated with delusional disorder. Psychiatry Clin Neurosci 2006;60:758-760.
69.Spyridi S, Diakogiannis I, Michaelides M, Sokolaki S, Iacovides A,Kaprinis G. Delusional disorder and alcohol abuse in a patient with Wilson's disease. Gen.Hosp.Psychiatry 2008;30(6):585-586.
70.Stiller P, Kassubek J, Schonfeldt-Leucona C,Connemann B. Wilson's disease in psychiatric patients. Psychiatry Clin Neurosci 2008;56:649.
71.Medalia A, Isaacs-Glaberman K,Scheinberg IH. Neuropsychological impairment in Wilson's disease. Arch Neurol 1988;45(5):502-4.
72.Isaacs-Glaberman K, Medalia A,Scheinberg IH. Verbal recall and recognition abilities in patients with Wilson's disease. Cortex 1989;25(3):353-61.
73.Ardenne M,Reitnauer PG. [Demonstration of tumor inhibiting properties of a strongly immunostimulating low-molecular weight substance. Comparative studies with ifosfamide on the immuno-labile DS carcinosarcoma. Stimulation of the autoimmune activity for approx. 20 days by BA 1, a N-(2-cyanoethylene)-urea. Novel prophylactic possibilities]. Arzneimittelforschung 1975;25(9):1369-79.
74.Kroger H, Donner I,Skiello G. Influence of a new virostatic compound on the induction of enzymes in rat liver. Arzneimittelforschung 1975;25(9):1426-9.
75.Smith RJ,Bryant RG. Metal substitutions incarbonic anhydrase: a halide ion probe study. Biochem Biophys Res Commun 1975;66(4):1281-6.
76.Walter G,Lyndon B. Depression in hepatolenticular degeneration (Wilson's disease). Aust N Z J Psychiatry 1997;31(6):880-2.
77.Machado A, Deguti M, Caixeta L, Spitz M, Lucato L,Barbosa E. Mania as the first manifestation of Wilson's disease. Bipolar Disord 2008;10:447-450.
78.Tu J. The inadvisability of neuroleptic medication in Wilson's disease. Biol Psychiatry 1981;16(10):963-8.
79.Hoogenraad T. Wilson's Disease. Major Problems in Neurology. 1996, London: Saunders.
80.Chroni E, Lekka NP, Tsibri E, Economou A,Paschalis C. Acute, progressive akinetic-rigid syndrome induced by neuroleptics in a case of Wilson's disease. J Neuropsychiatry Clin Neurosci 2001;13(4):531-2.
81.Varghese ST, Narayanan D,Dinesh D. Mania in a patient with Wilson's disease awaiting liver transplant. J Neuropsychiatry Clin Neurosci 2008;20(4):501-2.
82.Krim E,Barroso B. [Psychiatric disorders treated with clozapine in a patient with Wilson's disease]. Presse Med 2001;30(15):738.
83.Kulaksizoglu IB,Polat A. Quetiapine for mania with Wilson's disease. Psychosomatics 2003;44(5):438-9.
84.Longanathan S, Nayak R, Sinha S, Taly A, Math S,Varghese M. Treating mania in Wilson's disease with lithium. J Neuropsychiatry Clin Neurosci 2008;20:487-489.
85.Rodrigues AC, Dalgalarrondo P,Banzato CE. Successful ECT in a patient with a psychiatric presentation of Wilson's disease. J ECT 2004;20(1):55.
86.Shah N,Kumar D. Wilson's disease, psychosis, and ECT. Convuls Ther 1997;13(4):278-9.
87.Negro P,Louza Neto M. Results of ECT for a case of depression in Wilson disease. J Neuropsychiatry Clin Neurosci 1995;7:384.
88.Sechi G, Antonio Cocco G, Errigo A, Deiana L, Rosati G, Agnetti V, Stephen Paulus K, et al. Three sisters with very-late-onset major depression and parkinsonism. Parkinsonism Relat Disord 2007;13(2):122-5.
89.Chan K, Cheung R, Au-Yeung K, Mak W, Cheng T,Ho S. Wilson’s disease with depression and parkinsonism. J Clin Neurosci 2004;12:303-305.
90.Keller R, Torta R, Lagget M, Crasto S,Bergamasco B. Psychiatric symptoms as late onset of Wilson's disease: neuroradiological findings, clinical features and treatment. Ital J Neurol Sci 1999;20:49-54.
91.Moghadasian MH, Salen G, Frohlich JJ,Scudamore CH. Cerebrotendinous xanthomatosis: a rare disease with diverse manifestations. Arch Neurol 2002;59(4):527-9.
92.Gallus GN, Dotti MT,Federico A. Clinical and molecular diagnosis of cerebrotendinous xanthomatosis with a review of the mutations in the CYP27A1 gene. Neurol Sci 2006;27(2):143-9.
93.Berginer VM, Foster NL, Sadowsky M, Townsend JA, 3rd, Siegel GJ,Salen G. Psychiatric disorders in patients with cerebrotendinous xanthomatosis. Am J Psychiatry 1988;145(3):354-7.
94.Barkhof F, Verrips A, Wesseling P, van Der Knaap MS, van Engelen BG, Gabreels FJ, Keyser A, et al. Cerebrotendinous xanthomatosis: the spectrum of imaging findings and the correlation with neuropathologic findings. Radiology 2000;217(3):869-76.
95.Philippart M,Van Bogaert L. Cholestanolosis (cerebrotendinous xanthomatosis). A follow-up study on the original family. Arch Neurol 1969;21(6):603-10.
96.Shapiro S. Depression in a patient with dementia secondary to cerebrotendinous xanthomatosis. J Nerv Ment Dis 1983;171(9):568-71.
97.Burnstein M, Buckwalter KA, Martel W, McClatchey KD,Quint D. Case report 427: Cerebrotendinous xanthomatosis. Skeletal Radiol 1987;16(4):346-9.
98.Laurent A, Dairou F, Luc G, Truffert J, Lapresle J,de Gennes JL. [Van Bogaert's cerebrotendinous xanthomatosis. A study of 3 cases]. Ann Med Interne (Paris) 1988;139(6):395-402.
99.Wevers RA, Cruysberg JR, Van Heijst AF, Janssen-Zijlstra FS, Renier WO, Van Engelen BG, Tolboom JJ. Paediatric cerebrotendinous xanthomatosis. J Inherit Metab Dis 1992;15(3):374-6.
100.Soffer D, Benharroch D,Berginer V. The neuropathology of cerebrotendinous xanthomatosis revisited: a case report and review of the literature. Acta Neuropathol 1995;90(2):213-20.
101.Verrips A, Steenbergen-Spanjers GC, Luyten JA, van den Heuvel LP, Keyser A, Gabreels FJ, Wevers RA. Two new mutations in the sterol 27-hydroxylase gene in two families lead to cerebrotendinous xanthomatosis. Hum Genet 1996;98(6):735-7.
102.Sperhake JP, Matschke J, Orth U, Gal A,Puschel K. Sudden death due to cerebrotendinous xanthomatosis confirmed by mutation analysis. Int J Legal Med 2000;113(2):110-3.
103.Dotti MT, Rufa A,Federico A. Cerebrotendinous xanthomatosis: heterogeneity of clinical phenotype with evidence of previously undescribed ophthalmological findings. J Inherit Metab Dis 2001;24(7):696-706.
104.Lee Y, Lin PY, Chiu NM, Chang WN,Wen JK. Cerebrotendinous xanthomatosis with psychiatric disorders: report of three siblings and literature review. Chang Gung Med J 2002;25(5):334-40.
105.Guyant-Marechal L, Verrips A, Girard C, Wevers RA, Zijlstra F, Sistermans E, Vera P, et al. Unusual cerebrotendinous xanthomatosis with fronto-temporal dementia phenotype. Am J Med Genet A 2005;139A(2):114-7.
106.Price Evans DA, Salah KA, Mobrad MA, Mitchell WD, Olin M,Eggertsen G. Cerebrotendinous xanthomatosis in a Saudi Arabian family-genotyping and long-term follow-up. Saudi Med J 2007;28(7):1113-8.
107.Gonzalez-Cuyar LF, Hunter B, Harris PL, Perry G, Smith MA,Castellani RJ. Cerebrotendinous xanthomatosis: case report with evidence of oxidative stress. Redox Rep 2007;12(3):119-24.
108.Bonnot O, Fraidakis MJ, Lucanto R, Chauvin D, Kelley N, Plaza M, Dubourg O, et al. Cerebrotendinous xanthomatosis presenting with severe externalized disorder: improvement after one year of treatment with chenodeoxycholic Acid. CNS Spectr 2010;15(4):231-6.
109.Group N-CGW, Wraith JE, Baumgartner MR, Bembi B, Covanis A, Levade T, Mengel E, et al. Recommendations on the diagnosis and management of Niemann-Pick disease type C. Mol Genet Metab 2009;98(1-2):152-65.
110.Vanier MT. Niemann-Pick disease type C. Orphanet J Rare Dis 2010;5:16.
111.Patterson MC, Hendriksz CJ, Walterfang M, Sedel F, Vanier MT, Wijburg F, on behalf of the NPCGWG. Recommendations for the diagnosis and management of Niemann-Pick disease type C: An update. Mol Genet Metab 2012;106(3):330-344.
112.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.
113.Sevin M, Lesca G, Baumann N, Millat G, Lyon-Caen O, Vanier MT, Sedel F. The adult form of Niemann-Pick disease type C. Brain 2007;130(Pt 1):120-33.
114.Trendelenburg G, Vanier MT, Maza S, Millat G, Bohner G, Munz DL, Zschenderlein R. Niemann-Pick type C disease in a 68-year-old patient. J Neurol Neurosurg Psychiatry 2006;77(8):997-8.
115.Wraith JE, Guffon N, Rohrbach M, Hwu WL, Korenke GC, Bembi B, Luzy C, et al. Natural history of Niemann-Pick disease type C in a multicentre observational retrospective cohort study. Mol Genet Metab 2009;98(3):250-4.
116.Porter FD, Scherrer DE, Lanier MH, Langmade SJ, Molugu V, Gale SE, Olzeski D, et al. Cholesterol oxidation products are sensitive and specific blood-based biomarkers for Niemann-Pick C1 disease. Sci Transl Med 2010;2(56):56ra81.
117.Patterson MC,Platt F. Therapy of Niemann-Pick disease, type C. Biochim Biophys Acta 2004;1685(1-3):77-82.
118.Patterson MC, Vecchio D, Prady H, Abel L,Wraith JE. Miglustat for treatment of Niemann-Pick C disease: a randomised controlled study. Lancet Neurol 2007;6(9):765-72.
119.Wraith JE, Vecchio D, Jacklin E, Abel L, Chadha-Boreham H, Luzy C, Giorgino R, et al. Miglustat in adult and juvenile patients with Niemann-Pick disease type C: long-term data from a clinical trial. Mol Genet Metab 2010;99(4):351-7.
120.Patterson MC, Vecchio D, Jacklin E, Abel L, Chadha-Boreham H, Luzy C, Giorgino R, et al. Long-term miglustat therapy in children with Niemann-Pick disease type C. J Child Neurol 2010;25(3):300-5.
121.Shulman LM, Lang AE, Jankovic J, David NJ,Weiner WJ. Case 1, 1995: psychosis, dementia, chorea, ataxia, and supranuclear gaze dysfunction. Mov Disord 1995;10(3):257-62.
122.Campo JV, Stowe R, Slomka G, Byler D,Gracious B. 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.
123.Turpin JC,Baumann N. [Presenting psychiatric and cognitive disorders in adult neurolipidoses]. Rev Neurol (Paris) 2003;159(6-7 Pt 1):637-47.
124.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.
125.Tyvaert L, Stojkovic T, Cuisset JM, Vanier MT, Turpin JC, De Seze J, Vermersch P. [Presentation of Niemann-Pick type C disease with psychiatric disturbance in an adult]. Rev Neurol (Paris) 2005;161(3):318-22.
126.Walterfang M, Fietz M, Fahey M, Sullivan D, Leane P, Lubman DI, Velakoulis D. The neuropsychiatry of Niemann-Pick type C disease in adulthood. The Journal of neuropsychiatry and clinical neurosciences 2006;18(2):158-70.
127.Walterfang M, Fietz M, Abel L, Bowman E, Mocellin R,Velakoulis D. Gender dimorphism in siblings with schizophrenia-like psychosis due to Niemann-Pick disease type C. J Inherit Metab Dis 2009.
128.Sandu S, Jackowski-Dohrmann S, Ladner A, Haberhausen M,Bachmann C. Niemann-Pick disease type C1 presenting with psychosis in an adolescent male. Eur Child Adolesc Psychiatry 2009;18(9):583-5.
129.Walterfang M, Kornberg A, Adams S, Fietz M,Velakoulis D. Post-ictal psychosis in adolescent Niemann-Pick disease type C. J Inherit Metab Dis 2010.
130.Klunemann HH, Santosh PJ,Sedel F. Treatable metabolic psychosis that go undetecd: What Niemann Pick type C can teach us. International Journal of Psychiatry in Clinical Practice 2012:1-8.
131.Walterfang M, Fietz M, Abel L, Bowman E, Mocellin R,Velakoulis D. Gender dimorphism in siblings with schizophrenia-like psychosis due to Niemann-Pick disease type C. Journal of inherited metabolic disease 2009.
132.van de Vlasakker CJ, Gabreels 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.
133.Klarner B, Klunemann HH, Lurding R, Aslanidis C,Rupprecht R. Neuropsychological profile of adult patients with Niemann-Pick C1 (NPC1) mutations. J Inherit Metab Dis 2007;30(1):60-7.
134.Talele SS, Xu K, Pariser AR, Braun MM, Farag-El-Massah S, Phillips MI, Thompson BH, et al. Therapies for inborn errors of metabolism: what has the orphan drug act delivered? Pediatrics 2010;126(1):101-6.
135.Cooper SA, Morrison J, Melville C, Finlayson J, Allan L, Martin G, Robinson N. Improving the health of people with intellectual disabilities: outcomes of a health screening programme after 1 year. J Intellect Disabil Res 2006;50(Pt 9):667-77.
136.Andreasen NC. The evolving concept of schizophrenia: from Kraepelin to the present and future. Schiz. Res. 1997;%19;28(2-3):105-9.
137.van Os J, Driessen G, Gunther N,Delespaul P. Neighbourhood variation in incidence of schizophrenia. Evidence for person-environment interaction. Br.J.Psychiatry 2000;176:243-58.
138.Boer H, Holland A, Whittington J, Butler J, Webb T,Clarke D. Psychotic illness in people with Prader Willi syndrome due to chromosome 15 maternal uniparental disomy. Lancet 2002;359(9301):135-6.
139.Vogels A, Matthijs G, Legius E, Devriendt K,Fryns JP. Chromosome 15 maternal uniparental disomy and psychosis in Prader-Willi syndrome. J Med Genet 2003;40(1):72-3.
140.Weinberger DR. From neuropathology to neurodevelopment. Lancet 1995;346(8974):552-7.
141.Van Gorkom HJ, Pulles MP,Wessels JS. Light-induced changes of absorbance and electron spin resonance in small photosystem II particles. Biochim Biophys Acta 1975;408(3):331-9.
142.van Os J,Kapur S. Schizophrenia. Lancet 2009;374(9690):635-645.
143.Velakoulis D, Walterfang M, Mocellin R, Pantelis C,McLean C. Frontotemporal dementia presenting as schizophrenia-like psychosis in young people: clinicopathological series and review of cases. Br J Psychiatry 2009;194(4):298-305.
144.Cutting J. The phenomenology of acute organic psychosis. Comparison with acute schizophrenia. Br J Psychiatry 1987;151:324-32.
145.Horiguchi J, Miyaoka T,Shinno H. Pathogenesis and symptomatology of hallucinations (delusions) of organic brain disorder and schizophrenia. Psychogeriatrics 2009;9(2):73-6.
146.Barak Y, Aizenberg D, Mirecki I, Mazeh D,Achiron A. 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.
147.Cornic F, Consoli A, Tanguy ML, Bonnot O, Perisse D, Tordjman S, Laurent C, 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.
148.Remschmidt H,Theisen F. Early-onset schizophrenia. Neuropsychobiology 2012;66(1):63-9.
Figure 1. Summary of literature review process
Figure 2. Diagnostic algorithm for diagnosing inborn errors of metabolism in patients with schizophrenia-like symptoms
MRI = magnetic resonance imaging; MTHFR-CbS = methylenetetrahydrofolate reductase-cystathionine beta-synthase.
Table 1. Atypical psychiatric features which should trigger a search for Inborn error of metabolism in patients with schizophrenia
First level atypical feature (Atypical by their own)
Second level atypical features (atypical when associated with first level)
Confusion
Acute onset
Visual hallucinations
Early onset
Catatonia
Intellectual deficiency
Progressive cognitive decline
Mental retardation
Treatment resistance
Unusual or severe side effects
Fluctuating schizophrenia core symptoms
Table 2. Synthesis of main clinical, contextual, ophthalmologic symptoms associated with 7 treatable IEM associated with schizophrenia-like symptoms.
Disorder
Clinical signs
Context
Eye exam
Biomarkers
Wilson disease
Tremor
Dystonia
Dysarthria
–
Kayser-Fleischer ring
Coeruloplasmin
Urea cycle disorders
Confusion
Abdominal pain
Nausea/vomiting
Protein diet
Post surgery
Drugs*
–
Ammoniemia
Homocysteinemia (MTHFR)
Ataxia
Mental regression
–
–
Homocysteinemia
Methioninemia
Homocysteinemia (CbS)
Thromboembolism
Scoliosis
Marfan-like
Cerebellar signs
Protein diet
Post surgery
Severe myopia
Ectopic lens
Homocysteinemia
Methioninemia
Niemann-Pick disease type C
Dystonia + ataxia Dysarthria
Splenomegaly
Neonatal icterus
Slow progression
Supranuclear vertical
gaze palsy
Skin biopsy
Filipin test
NPC1 and NPC2 gene test
Cerebrotendinous
xanthomatosis
Chronic diarrhea
Spastic paralysis
–
Juvenile cataract
Cholesteanoemia
Porphyria
Black or red urine
Constipation
Confusion
Abdominal pain
Nausea/vomiting
Periodic
–
Porphobilinogens (URINE)
*Example drugs: valproate/corticoids.