Prader–willi Syndrome: Atypical Psychoses and Motor Dysfunctions

PRADER–WILLI SYNDROME: ATYPICAL PSYCHOSES AND MOTOR DYSFUNCTIONS

Willem M. A. Verhoeven*y and Siegfried Tuinier* *Vincent van Gogh Institute for Psychiatry Venray, The Netherlands y Department of Psychiatry, Erasmus University Medical Center Rotterdam, The Netherlands

I. II. III. IV. V.

Introduction Development and Behavior Psychotic Disorders Psychomotor Symptoms Conclusions References

Prader–Willi syndrome (PWS) is the result of a lack of expression of genes on the paternally derived chromosome 15q11-q13 and can be considered as a hypothalamic disorder. Its behavioral phenotype is characterized by ritualistic, stereotyped, and compulsive behaviors as well as motor abnormalities. After adolescence, recurrent aVective psychoses are relatively frequent, especially in patients with uniparental disomy. These psychotic states have a subacute onset with complete recovery and comprise an increase of psychomotor symptoms that show resemblance with catatonia. Some evidence has emerged that gammaaminobutyric acid (GABA) dysfunctionality is involved in both PWS and catatonia. Treatment of these atypical psychoses should preferably include GABA mimetic compounds like lorazepam, valproic acid, and possibly topiramate. I. Introduction

Prader–Willi syndrome (PWS) was first described in 1956 by Prader, Labhart, and Willi, and its prevalence is estimated to be 1 in 10 to 15.000. This multisystem disorder is accompanied by a variable degree of mental retardation, occurs in all races and both sexes, and arises from the lack of expression of genes on the paternally derived chromosome 15q11-q13. Candidate genes for PWS in this region are imprinted and silenced on the maternally inherited chromosome. PWS develops if the paternal alleles are defective, missing, or silenced. In 75% INTERNATIONAL REVIEW OF NEUROBIOLOGY, VOL. 72 DOI: 10.1016/S0074-7742(05)72007-9

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of the cases there is a paternal deletion of 15q11-q13, maternal uniparental disomy (UPD) occurs in 22%, imprinting errors in 3% because of either a sporadic or inherited microdeletion in the imprinting center, and there is a paternal chromosomal translocation in 1% cases. Imprinting occurs partly through parent-oV-origin allele-specific methylation of CpG residues, which is established either during or after gametogenesis and maintained throughout embryogenesis. Paternally expressed genes are particularly important for the development of the hypothalamus. Therefore, hypothalamic dysfunction is one of the key features of PWS (Nicholls and Knepper, 2001). With respect to hypothalamus-related endocrine and metabolic dysfunctions, PWS is associated with growth hormone (GH) deficiency reflected by mild prenatal growth retardation and after birth by a short stature as well as a lack of pubertal growth spurt. In addition, the levels of sex hormones are decreased as a result of an abnormal function of LH-releasing hormone neurons (Goldstone, 2004). The reduction of the number of the oxytocin-containing cells may be related to hyperphagia because oxytocin has anorexigenic properties (Shapira et al., 2005; Swaab, 1997). Finally, aberrant control of body temperature and daytime hypersomnolence are often present (Nixon and Brouillette, 2002; Swaab, 2004). Other characteristics reflect an involvement of the central nervous system (CNS) motor structures: central hypotonia in infancy, delayed psychomotor development, diYculties in motor aspects of language, and obsessive compulsive behavior. These abnormalities are thought to be related to cortical dysgenesis (Hashimoto et al., 1998; Leonard et al., 1993; Yoshii et al., 2002) and possibly to a defect in the gamma-aminobutyric acid (GABA)-type A receptor (Lucignani et al., 2004; WagstaV et al., 1991). Civardi et al. (2004) demonstrated an overall corticospinal hypoexcitability most likely as a result of hyposensitivity of GABA receptors.

II. Development and Behavior

The developmental trajectory is characterized by pre- and postnatal hypotonia, neonatal feeding problems, delayed motor milestones, and poor coordination. Adults are mildly hypotonic with decreased upper body strength. Speech is often poorly articulated. In early childhood, a characteristic behavioral profile emerges with temper tantrums, impulsiveness, stubbornness, repetitive rituals, obsessive–compulsive and ritualistic behavior, as well as diYculties with changing routine resulting in irritability and aggression (Cassidy, 2001; Clarke et al., 2002; Dykens and Shah, 2003; Wigren and Hansen, 2003). Some patients show a symptomatic form of narcolepsy, including cataplexy (Mignot et al., 2002; Tobias

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et al., 2002). Another specific behavioral abnormality is skin-picking, a stereotyped movement aimed at various parts of the skin of which the percentage of patients showing this disorder increases with age (Dimitropoulos et al., 2001; Steinhausen et al., 2004; Symons et al., 1999). Some reports suggest that the behavioral abnormalities and cognitive disabilities are more pronounced in patients with a deletion as compared with those in whom UPD etiology is present (Roof et al., 2000; Veltman et al., 2004; Whittington et al., 2004). Within the individuals with a deletion, the size of the deletion seems to be positively correlated with behavioral and psychological problems (Butler et al., 2004), although no diVerences were reported by Varela et al. (2005). Thus, some characteristics of PWS are clearly related to a hypothalamic dysfunction, whereas others point to a more general brain dysfunction. There seems to be a specific involvement of CNS motor structures expressed by stereotypies, repetitive and ritualistic behaviors, obsessive–compulsive features, as well as hypotonia and hyperactivity.

III. Psychotic Disorders

PWS patients may develop relapsing psychotic states that, in general, are characterized by a subacute onset and full recovery, as well as mood instability, polymorphous symptomatology, and a fluctuating course. All available reports on psychotic states in PWS patients are summarized in Table I. In 1966, Kollrack and Wolf described a 20-year-old male patient who developed two psychotic episodes of a few weeks duration with prominent anxiety, paranoid ideation, aVective instability, dysphoric mood, and psychomotor agitation that completely disappeared after a 10-day treatment with chlorprothixene and chlordiazepoxide. A diagnosis of schizophrenia, paranoid type was considered although a definite classification could not be made. The authors concluded that a diagnosis of ‘‘endogenous agitated depressive paranoidly coloured disorder’’ was the most appropriate diagnostic description. Until the beginning of 1990s, only two questionnaire surveys including 40 (Bray et al., 1983) and 35 (Whitman and Accardo, 1987) PWS patients respectively were published, which were mainly focused on behavioral and emotional symptoms. In the study by Bray et al. (1983), two patients could be identified with psychotic symptoms, particularly auditory hallucinations and fluctuating behavioral inhibition or disinhibition that were short-lived and self-limited. In their review on quantitative psychiatric manifestations, obtained by administering the Survey Diagnostic Instrument to the parents, Whitman and Accardo (1987) found in about one-third of the cases mild and/or recurrent psychotic symptoms such as auditory and visual hallucinations as well as strange and paranoid

TABLE I REPORTS ABOUT PSYCHOTIC SYMPTOMS IN PRADER–WILLI SYNDROME Authors

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Kollrack and WolV, 1966* Bray et al., 1983*

N

Duration and course

2 out of 40 35 survey

Anxiety, mood alterations, paranoid ideas, hallucinations Social withdrawal, hallucinations, uncontrollable anger Hallucinations, paranoid ideation

Recurrent short episodes with full recovery Short-lived and self-limiting —

3

Dysphoric mood, anxiety

—

Jerome, 1993*

1

24 h, 2–4 times per month

Bartolucci and Younger, 1994*

4 out of 9

Cyclic mood change, sleep disturbances, skin-picking behavior Delusional thinking, hallucinations, dysphoric mood

Clarke, 1993*; Clarke et al., 1995,* 1998b*

8

Whitman and Accardo, 1987* Tu et al., 1992*

1

Symptoms

Anxiety, abnormal believes, auditory and visual hallucinations, paranoid ideation

Cyclic course, fluctuating behavioral traits

Acute onset, short lasting with full recovery, recurrent

Treatment

Diagnosis

Chlorprothixene þ chlordiazepoxide None

Paranoid-hallucinatory syndrome Emotional problems

—

Behavioral symptoms

Carbamazepine (n ¼ 1) Lithium

—

Low doses of antipsychotics, antidepressants or lithium Low doses of antipsychotics, carbamazepine (n ¼ 2)

Bipolar aVective disorder Psychotic disorder, atypical depression

Atypical psychotic disorder

Takhar and Malla, 1997*

1

123

Periods of confusion, impaired attention and concentration, hallucinations, ideas of reference Delusional convictions, anxiety, hallucinations, perplexity

Recurrent episodes with subacute onset and full recovery Acute onset, short lasting with full recovery

Low doses of clozapine

Whittaker et al., 1997*

1

Dhossche and Bouman, 1997*

1

Catatonic symptoms, anxiety, visual hallucinations, delusional ideas

Acute onset, short lasting with full recovery

Beardsmore et al., 1998

5

Recurrent episodes

Cycloid psychosis

Pereda Bikandi et al., 2001*

1

Acute onset, short lasting with full recovery

Low doses of olanzapine

Atypical psychotic disorder

Vogels et al., 2003, 2004

10 out of 14

Acute onset, recurrent episodes

—

Atypical psychotic disorder

Boer et al., 2002

6 and 6 out of 15

Delusions and/or hallucinations, depressive symptoms, anxiety, lability of mood Anxiety, hallucinations, confusion, delusional convictions, mood disorders Hyper/hypoactivity, anxiety, dysphoric mood, delusions, hallucinations Hypokinesia, paranoid ideation, anxiety, confusion, delusions, delusional convictions, hallucinations

Low doses of antipsychotic and lorazepam —

Subacute onset, recurrent episodes

Various antipsychotics carbamazepine (n ¼ 3)

Psychotic disorder

*For references see: Verhoeven et al., 2003a,b.

Low doses of antipsychotic

Psychosis and drug-induced parkinsonism Acute confusional state, paranoid psychotic illness Catatonia

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ideation. Tu et al. (1992) described three patients with prominent anxiety and dysphoric mood of whom one was treated successfully with carbamazepine in a daily dose of 1200 mg. In none of the three patients a psychiatric diagnosis was specified. Jerome (1993) reported a 31-year-old female patient with long lasting cyclic mood changes who responded to treatment with lithium. In this case, a diagnosis of bipolar aVective disorder was considered to be the most appropriate. In four out of nine patients, Bartolucci and Younger (1994) observed a cyclic pattern of psychopathological symptoms, especially mood and motor disturbances in both directions, auditory and visual hallucinations, delusional ideas usually accompanied by fear, and occasionally elated and mystical feelings. No clear psychiatric diagnosis and classification was made. In two single case reports, Whittaker et al. (1997) and Takhar and Malla (1997) described female patients aged 17 and 51 years, respectively, who developed a short lasting psychotic state with full recovery on treatment with low doses of antipsychotics. Characteristic symptoms included confusion, perplexity, anxiety, and delusional convictions. In both cases, a diagnosis of paranoid psychosis was made. Beardsmore et al. (1998) described in their report on aVective psychoses in 23 PWS patients, 1 patient with a delusional disorder and 4 with a mixture of aVective and psychotic symptoms. Clarke et al. (1993, 1995, 1998a) reported eight patients who developed an acute short-lasting psychosis with full recovery after treatment with low doses of antipsychotics. Psychotic symptomatology consisted of pan-anxiety, motility disturbances, abnormal beliefs not syntonic with mood, paranoid ideation, and hallucinations. The diVerential diagnosis included psychosis within the schizophrenic spectrum, atypical psychosis, and cycloid psychosis. Other investigators published 14 patients of whom 10 were diagnosed with atypical psychoses and 4 with a bipolar aVective disorder. Apart from psychotic symptoms, the clinical picture included hyper- and hypoactivity (Descheemaeker et al., 2002; Vogels et al., 2003, 2004). Finally, Boer et al. (2002) reported a population-based study with 25 adult PWS patients of whom 15 had a complete neuropsychiatric examination. In six patients, psychotic symptoms were observed. A previous study described six patients with a psychotic disorder. Four of the case descriptions make special reference to motor disturbances, especially hypokinesia and disinhibition (Clarke et al., 1998a). Over the past years, 27 PWS patients (mean age: 31 years; 12 males, 15 females) were referred to for neuropsychiatric evaluation to the first author because of long lasting or recurrent behavioral problems and psychotic symptoms (mean age of onset: 24 years). Out of this group, 23 patients were published previously (Verhoeven et al., 1998, 2000, 2002, 2003a,b). In all patients, a standard psychiatric examination was performed, and additional data about history and course were collected from all available sources. Tentative formal psychiatric diagnoses were established according to the clinical descriptions and diagnostic guidelines of the Interclassification of Diseases, 10th revision (ICD-10).

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All but two patients (insuYcient data in the medical record) had a history of mood instability paralleled by fluctuating behavioral problems. With respect to the actual psychopathology, six patients met the criteria for a bipolar aVective disorder, in that they showed an episodic pattern of euphoria, hyperactivity and sleep disturbances, or depressed mood and inactivity. In the other 21 patients, the psychiatric symptomatology included emotional turmoil, anxieties, irritability, confusion, (rapid) mood swings, hallucinatory experiences, and paranoid ideation with a variable intensity and subacute onset. Therefore, a diagnosis of cycloid psychosis was considered to be the most appropriate (Table II). Treatment with one or a combination of mood stabilizers, such as lithium (0.8 mMol/l) and/or valproic acid (60 mg/l), resulted in most patients in full recovery and prevention of relapses of both psychotic episodes and mood and behavioral instability. Concerning the genetic etiology, three patients had a deletion, and a clinical diagnosis was made in four patients. Three patients were genetically confirmed but not diVerentiated. In the remaining 17 patients, a UPD was demonstrated. In a population of PWS patients, the expected percentage of deletions and UPD is about 75 and 25, respectively (Vogels and Fryns, 2002), whereas in the present group, excluding those with a clinical diagnosis or a not specified genetic etiology, percentages of 15 and 85 are found. These results indicate a three- to fourfold overrepresentation of UPD patients in a group of PWS patients with a psychotic illness. This association is described in two other reports that deal with smaller groups (Boer et al., 2002; Vogels et al., 2003). Focusing on the cross-sectional assessment of psychopathology, however, may conceal the history of aVective instability in these patients. Descriptions of instability of mood and behavior in patients with intellectual disabilities have been published since the beginning of the last century and meet, depending on the presence of mood elevation, the criteria of either cyclothymia or unstable

TABLE II SYMPTOMS OF 21 PWS PATIENTS WITH RELAPSING ATYPICAL PSYCHOSES Symptoms and course

Number

Percentage

Auditory hallucinations Perceptual disturbances Paranoid ideation Confusion Anxieties Mood swings Emotional turmoil Increased obsessive rituals Agitation/hyperactivity Subacute onset

10 4 16 19 20 20 17 18 13 21

48 19 76 90 95 95 80 85 62 100

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mood disorder (Verhoeven and Tuinier, 2001). Since aVective symptoms are frequently expressed as mood swings, irritability, impulsivity, aggression, and self injury, a diagnosis of depression is often overseen (Verhoeven et al., 2004). Although the literature on psychopathology in PWS frequently refers to aVective symptoms, there is no information about the lifetime prevalence of aVective disorders in this syndrome. In the reported 27 patients, the psychosis was characterized by symptoms like confusion, auditory hallucinations, and paranoid behavior on the one hand and an increase of obsessive rituals, anxieties, and mood swings on the other and was preceded by aVective instability for many years. Even though the actual psychopathology justifies a diagnosis of cycloid psychosis, longitudinal evaluation points toward an atypical bipolar disorder. It can, therefore, be hypothesized that the psychopathological phenotype of PWS patients with a UPD etiology comprises also an increased risk for a bipolar aVective disorder (Verhoeven et al., 2003b). In these patients signs of cyclothymia or unstable mood disorder should be treated with mood stabilizers in order to prevent psychotic deterioration. Formal categorical diagnoses in PWS patients with psychiatric symptoms are rather futile since the psychopathological symptom profile varies longitudinally and comprises an increase of preexistent behavioral abnormalities including motor symptoms. It is, therefore, advocated to use the term Prader–Willi psychiatric syndrome (Verhoeven et al., 2000). Since the clinical picture is very polymorphous and fluctuating over time, the clinician easily ignores the motor symptoms that may indicate the existence of catatonia. Nonetheless, these symptoms have been described in several reports.

IV. Psychomotor Symptoms

There is an ongoing debate on how to classify or characterize the psychiatric symptomatology in patients with PWS. A great variety of diagnostic vignettes is applied as a result of the fluctuating and heterogeneous clinical picture. Most prominent, however, are aVective and anxiety symptoms associated with an increase of the syndrome-specific motor dysfunctions like skin-picking, stereotypies, perseverations, compulsions, excitement, and aggression. This polymorphous symptomatology is sometimes attributed to a bipolar aVective disorder or, in the acute phase, a cycloid psychosis although these diagnoses do not account for the prominent changes in motor-related symptoms. The latter points to the presence of a psychomotor syndrome associated with an aVective psychosis. In a few PWS cases, catatonic symptoms have been described, but they have not been systematically assessed and, therefore, may have remained unrecognized (Dhossche, 2004).

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It is not surprising that the psychomotor aspects of the recurrent psychoses in PWS are relatively neglected. A similar disregard has taken place in psychiatry in general. Over the past century, the prevalence of the diagnosis catatonic schizophrenia apparently dropped from 10–30% to 2–10% (Morrison, 1974; Stompe et al., 2002; Taylor and Fink, 2003). This decline has been explained by diVerences in patient samples, changes in diagnostic criteria, improvement of the diagnosis of neurological and somatic disorders, as well as the implementation of rehabilitation programs. Whether the introduction of antipsychotics has contributed to this phenomenon is still a matter of debate (Mahendra, 1981). More fundamental, however, could be the so-called ‘‘conflict of paradigms’’ that has emerged as a result of the separation of neurology and psychiatry after which motor disorders were no longer a major part of the psychiatric spectrum (Fink, 2001; NorthoV, 1992; Pichot, 1997; Rogers, 1985). Interpretation became more influential at the expense of clinical observation and description. In a Dutch psychiatric hospital, the prevalence rate of catatonic schizophrenia over the last decades of the past century dropped from 7.8% to 1.3%. Evaluation of psychotic patients with a specific screening instrument for catatonia, however, revealed a much higher percentage (Van der Heijden et al., 2005). These figures suggest that the decline of catatonic symptoms is the result of selective observation. Since the genes coding for the GABAA-receptor subunits are localized within the deleted chromosomal segment in PWS patients, it can be hypothesized that some of the CNS abnormalities, like psychomotor dysfunctions, may arise from an altered gene expression or from a dysfunction of the GABAA-receptor (Lucignani et al., 2004). An involvement of GABAA has been postulated in catatonia as well (NorthoV, 2002; NorthoV et al., 1999). This hypothesis emerged from the frequently observed therapeutic potential of the GABA-agonist lorazepam in acute catatonia (Fink, 2001; Gaind et al., 1994; Ungvari et al., 2001). In our patient group, treatment with the GABAergic anticonvulsant valproic acid appeared to result in a clinically relevant reduction of aVective and psychomotor symptoms and prevention of relapse (Verhoeven et al., 1998, 2003a). One case report describes the eVect of valproic acid in catatonia (Kru¨ger and Bra¨unig, 2001). It has been suggested that treatment with topiramate, an anticonvulsant with among others GABAergic eVects, may be eVective in reducing stereotyped and compulsive behaviors in PWS patients (Shapira et al., 2002, 2004; Smathers et al., 2003).

V. Conclusions

PWS is associated with the occurrence of atypical psychoses after adolescence, especially in patients with UPD genetic etiology, which are characterized by a subacute onset, relapsing course, and the absence of residual symptoms. The

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clinical profile comprises aVective symptoms and an increase of preexistent motor symptoms. Motoric abnormalities are part of the behavioral phenotype and should therefore not be considered as emotion-driven, goal-oriented behaviors. Most preferably, pharmacological treatment is targeted at an enhancement of the GABA function, resulting in an eVect on aVective and motor symptoms. It is advocated to abandon categorical diagnoses and establish a long-term prophylactic treatment regimen with GABA mimetic compounds.

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