The cognitive and behavioural phenotype of Roifman syndrome

Background Roifman syndrome (OMIM 300258) is a multi‐system disorder with a physical phenotype that includes Β‐cell immunodeficiency, intra‐uterine and postnatal growth retardation, spondyloepiphyseal dysplasia, retinal dystrophy and characteristic facial dysmorphism. So far, six cases, all boys, have been reported in the literature. Roifman postulated that the syndrome may be due to a mutation in an X‐linked gene or an autosomal gene giving rise to a sex‐limited trait, but the definitive pathogenetic mechanism has still not been elucidated. Very little is known about the cognitive and behavioural phenotype of Roifman syndrome and no standardized measures of cognitive abilities have been reported. Methods We report the seventh case of a boy with Roifman syndrome and present the first systematic documentation of the cognitive and behavioural phenotype of an individual with the syndrome. Results In spite of having been reported as appearing intellectually ‘able’, formal evaluation showed very significant intellectual disability and neuropsychological impairment across cognitive domains. Conclusions The findings suggest that Roifman syndrome may be an example of an X‐linked mental retardation syndrome (XLMRS).     

Development and behaviour in Marshall-Smith syndrome: an exploratory study of cognition, phenotype and autism

Background Marshall–Smith syndrome (MSS) is an infrequently described entity characterised by failure to thrive, developmental delay, abnormal bone maturation and a characteristic face. In studying the physical features of a group of patients, we noticed unusual behavioural traits. This urged us to study cognition, behavioural phenotype and autism in six patients. Methods Information on development, behavioural characteristics, autism symptoms, and adaptive and psychological functioning of six MSS children was collected through in‐person examinations, questionnaires, semi‐structured interviews of parents and neuropsychological assessments. Results Participants showed moderate to severe delays in mental age, motor development and adaptive functioning, with several similarities in communication, social interactions and behaviour. There was severe delay of speech and motor milestones, a friendly or happy demeanour and enjoyment of social interactions with familiar others. They exhibited minimal maladaptive behaviours. Deficits in communication and social interactions, lack of reciprocal social communication skills, limited imaginary play and the occurrence of stereotyped, repetitive behaviours were noted during assessments. Conclusions Systematic collection of developmental and behavioural data in very rare entities such as MSS allows recognition of specific patterns in these qualities. Clinical recognition of physical,developmental and behavioural features is important not only for diagnosis, prognosis and counselling of families, but also increases our understanding of the biological basis of the human physical and behavioural phenotype.     

Neurological and psychological findings in patients with Cohen syndrome: a study of 18 patients aged 11 months to 57 years

Our purpose was to perform the first systematic neurological, neurophysiological and psychological study of 18 patients with Cohen syndrome (MIM no 216550), aged 11 months to 57 years (median 27 years). All the patients had the essential features of this syndrome, i.e., typical facial and structural findings, mental retardation, microcephaly, ophthalmologic symptoms, granulocytopenia and a cheerful psychic disposition. Children with the syndrome were considered normal at birth, but upwards of 6 to 12 months, psychomotor retardation became obvious. The first symptoms were microcephaly, which manifested itself by the age of 6 months to 1 year, as well as hypotonia and delayed developmental milestones. Cohen children learned to walk at 2 to 5 years of age. Language development varied markedly. Neurological symptoms did not progress. All patients had normal EMGs. The three youngest (aged 11 months, 3 and 5 years) had normal EEGs, whereas the remainder had low-voltage EEGs. No irritative spikes or epileptoformic foci were found. Nine patients had quick beta transients. Of the 18 patients examined, 4 were profoundly, 11 severely, 1 moderately and 2 mildly retarded. On the AADM scale, Cohen patients had high scores in the positive domains, viz., self-direction, responsibility and socialisation. Maladaptive behaviour, on the other hand, was almost completely absent, except for stereotyped behaviours and odd mannerisms. Withdrawal, sexually aberrant behaviour, untrustworthy and rebellious behaviour as well as antisocial behaviour were rare. These findings are consistent with the cheerful and sociable disposition characteristic of those with Cohen syndrome.     

Can sodium valproate improve learning in children with epileptiform bursts but without clinical seizures?

This study aimed to determine whether sodium valproate (VPA) improves cognitive performance and behaviour in children with learning and behavioural problems associated with electrographic epileptiform discharges but without clinical seizures. A randomized, double-blind, single-crossover trial was carried out with VPA or placebo on eight participants with different learning and behaviour problems. Participants also underwent neuropsychological testing under video EEG and the parent and teacher Behaviour Check List (CBCL; Achenbach 1991a, b) during each treatment phase. Clinically none of the children improved on VPA. On formal testing children were more distractable, had increased delay in response time, and showed lower memory scores while on VPA. In addition, parents reported higher internalizing scores on the CBCL while children were on VPA. Our data do not support the use of VPA in similar patients.     

Cognitive, anxiety and mood disorders in the fragile X-associated tremor/ataxia syndrome

OBJECTIVE: We evaluated patients with fragile X-associated tremor/ataxia syndrome (FXTAS), a neurodegenerative disorder associated with a CGG repeat expansion in the premutation range in the fragile X mental retardation 1 (FMR1) gene. METHODS: Neurological, psychiatric and neuropsychological evaluations were performed on 15 male patients with FXTAS. RESULTS: Seven cases were diagnosed with dementia, and seven others were diagnosed with mood and/or anxiety disorders. Twelve subjects demonstrated deficits on neuropsychological testing. CONCLUSIONS: Physicians assessing dementia patients are urged to consider this newly described syndrome, especially in patients with dementia associated with a movement disorder and in those with a family history of mental retardation. If FXTAS is a possible diagnosis, physicians may carry out FMR1 DNA testing; patients who test positive on DNA testing should undergo magnetic resonance imaging, be referred to neurology and receive genetic counseling.     

Algorithmic approach for methyl-CpG binding protein 2 (MECP2) gene testing in patients with neurodevelopmental disabilities

Methyl-CpG binding protein 2 gene (MECP2) testing is indicated for patients with numerous clinical presentations, including Rett syndrome (classic and atypical), unexplained neonatal encephalopathy, Angelman syndrome, nonspecific mental retardation, autism (females), and an X-linked family history of developmental delay. Because of this complexity, a gender-specific approach for comprehensive MECP2 gene testing is described. Briefly, sequencing of exons 1 to 4 of MECP2 is recommended for patients with a Rett syndrome phenotype, unexplained neonatal encephalopathy, an Angelman syndrome phenotype (with negative 15q11-13 analysis), nonspecific mental retardation, or autism (females). Additional testing for large-scale MECP2 deletions is recommended for patients with Rett syndrome or Angelman syndrome phenotypes (with negative 15q11-13 analysis) following negative sequencing. Alternatively, testing for large-scale MECP2 duplications is recommended for males presenting with mental retardation, an X-linked family history of developmental delay, and a significant proportion of previously described clinical features (particularly a history of recurrent respiratory infections).     

Focal polymicrogyria,continuous spike-and-wave discharges during slow-wave sleep and Cohen syndrome: a case report

Cohen syndrome is a rare genetic disorder consisting of truncal obesity, hypotonia, mental retardation, characteristic facial appearance and ocular anomalies. Other diagnostic clinical features include narrow hands and feet, low growth parameters, neutropenia and chorioretinal dystrophy. Here, we report an 18-year-old male with Cohen syndrome associated with focal polymicrogyria and continuous spike-and-wave discharges during slow-wave sleep.     

Neuropsychological rehabilitation in a case of Cornelia de Lange syndrome

Cornelia de Lange syndrome is a rare congenital disorder. Symptoms include a characteristic facial structure, pre- and post-natal growth deficiency, hypertrichosis, and visceral and cardiovascular anomalies. Behavioural problems and moderate to severe mental retardation are also present. In this paper, we report a mild case of Cornelia de Lange syndrome. The neuropsychological rehabilitation of this patient is also described. It was structured on the patient's specific areas of strength and weakness in order to facilitate the development of adaptive cognitive abilities. To maximise the learning potential of these children, we recommend specific interventions with a multidimensional neuropsychological approach, which considers developmental abilities and disabilities as related to the global reality of the child.     

Cohen syndrome with insulin resistance and seizure

Cohen syndrome is a rare, genetic, connective-tissue disorder with the genetic abnormality linked to chromosome 8q22. The diagnosis of Cohen syndrome is based on the recognition of certain clinical findings, which include mental retardation, typical morphologic stigmata (e.g., truncal obesity, hypotonia, short philtrum, prominent frontal incisors, high-arched palate, narrow hands and feet), and characteristic ophthalmologic abnormalities. We report a patient manifesting the typical characteristics of Cohen syndrome with seizure and hyperinsulinemia.     

Neuropsychological profiles of persons with mental retardation and dementia

This study examined the use of neuropsychological tests to assist in the differential diagnosis of dementia among persons with mental retardation. The author compared performances of persons with mental retardation and dementia (n = 10) to persons with mental retardation without dementia (n = 12). Participants were matched by IQ (mild or moderate mental retardation), age, presence of Down syndrome, and gender. In addition, all participants in the dementia group had corroborative medical tests (i.e., imaging, EEG, or high tau low AB42 protein testing) consistent with diagnosis of dementia. Test performance was compared on measures of attention and executive functions, language, memory and learning, and a dementia screening. Results from MANOVAs and nonparametric tests revealed significantly lower performance for persons with mental retardation and dementia in all areas assessed. Cut-off scores were also developed for the sample in order to maximize sensitivity and specificity for the test battery. Despite the small sample size, these findings suggest that there are significant measurable differences in several neurocognitive domains between the two groups.     

Spatial learning, contextual fear conditioning and conditioned emotional response in Fmr1 knockout mice

Fmr1 knockout mice are an animal model for fragile X syndrome, the most common form of heritable mental retardation in humans. Fmr1 knockout mice exhibit macro-orchidism and cognitive and behavioural deficits reminiscent of the human phenotype. In the present study additional behavioural and cognitive testing was performed. Knockouts and control littermates were subjected to a spatial learning test using a plus-shaped water maze. Animals had to learn the position of a hidden escape platform during training trials. The position of this platform was changed during subsequent reversal trials. Previously reported deficits in reversal learning were replicated, but we also observed significant differences during the acquisition trials. A plus-shaped water maze experiment with daily changing platform positions failed to provide clear evidence for a working memory impairment, putatively underlying the spatial learning deficits. Two different test settings were used to examine the reported deficit of Fmr1 knockout mice in fear conditioning. Conditioned fear responses were observed in a contextual fear test, and the ability to acquire an emotional response was tested by means of response suppression in a conditioned emotional response procedure. Neither protocol revealed significant differences between controls and knockouts.     

MRI of the brain in the Cohen syndrome: a relatively large corpus callosum in patients with mental retardation and microcephaly

Our purpose was to perform the first systematic brain magnetic resonance imaging (MRI) study of a substantial number of Cohen syndrome (MIM n:o 216550) patients. 18 Cohen patients and 26 healthy volunteers were examined by MRI (1.0 T). All Cohen patients had essential features of this syndrome: typical facial and structural features, mental retardation, microcephaly, ophthalmologic symptoms, granulocytopenia and cheerful psychic disposition. All our patients belong to the recently published study of refined mapping of the Cohen syndrome gene by linkage disequilibrium. As visual analysis of MR images revealed an impression of a large corpus callosum (CC), quantitative analysis was performed. Sagittal diameter of the body of the CC was larger than that of controls (p = 0.02), whereas all sagittal diameters of the brain stem were markedly smaller (p < 0.0001), as was the midline internal skull surface (MISS) (p < 0.0001). The CC surface did not significantly differ from that of controls significantly. Our main finding, a relatively enlarged corpus callosum, has not previously been reported to associate with mental retardation. Though MRI alone can not confirm the diagnosis and no definite measurements can be recommended for clinical use, any clinical suspicion of this syndrome receives reinforcement through MRI: a relatively enlarged corpus callosum in a microcephalic head and normal signal intensities of the grey and white matters.     

Benign myoclonic epilepsy in infancy: neuropsychological and behavioural outcome

Benign myoclonic epilepsy in infancy (BMEI) is a rare syndrome of idiopathic generalized epilepsies with onset below 3 years of age. It has been reported that BMEI is associated with a good prognosis, however, recently some studies suggest less favourable neuropsychological outcome. We report a long-term follow-up of seven patients with BMEI. Seizure outcome and neuropsychological, cognitive, and behavioural evolution were discussed for each of them. At the end of follow-up, 86% of children showed neuropsychological and intellectual disorders: two children had mental retardation, three patients achieved a borderline IQ and one normal but low IQ. All but one displayed neuropsychological disabilities including fine motor skill deficits, attention deficits, and language impairment and learning disorders. Our clinical data and the previous reports suggest that the early onset of the seizures may be one of the main factors of the illness giving rise to a less favourable outcome. Additional interacting factors such as delayed start of treatment, and efficacy of the drugs may play an important role, too. We believe that BMEI does not exert, different from some epileptic encephalopathies, a quick destroying effect but may interfere with the growth of developing functions, which results in long-term neuropsychological disabilities.     

Klinefelter syndrome in a military population. Electroencephalographic, endocrine, and psychiatric status.

In a study of nine Klinefelter syndrome patients obtained from a military population, all were found to have normal electroencephalograms (EEGs), all were clinically euthyroid, and had normal thyroid function test results. All had normal verbal and nonverbal IQs and no evidence of neurologic dysfunction on psychological testing. There was a high incidence of personality maladjustment as indicated by both the Minnesota Multiphasic Personality inventory and individual psychiatric evaluation. No particular personality pattern appeared typical for the group as a whole. Neurologic dysfunction, as manifest by EEG abnormality, mental retardation, or neuropsychological test deficits, and hypothyroidism are not necessarily associated with Klinefelter syndrome. Likewise, although the incidence of personality disorders may be strongly associated with this disorder, no specific personality type appears especially characteristic of the syndrome.     

Weight,lipids, glucose,and behavioral measures with ziprasidone treatment in a population with mental retardation

BACKGROUND: Atypical antipsychotics effectively reduce maladaptive behavior in individuals with mental retardation, yet bring significant weight gain and metabolic anomalies. Ziprasidone, a weight-neutral antipsychotic in patients with schizophrenia or schizoaffective disorder, has not been studied in a population with mental retardation and maladaptive behaviors. METHOD: Forty patients with mental retardation and maladaptive behaviors who had gained excessive weight or were inadequately responsive to other agents were switched to ziprasidone. Weight, total cholesterol, HDL, LDL, triglycerides, and frequency of maladaptive behavior were recorded at baseline and after 6 months of ziprasidone treatment. RESULTS: Ziprasidone treatment was associated with a significant weight loss of 8.1 lb (3.6 kg) as well as a significant reduction in total cholesterol and triglycerides (p < or =.05). The monthly frequency of the maladaptive behavior remained unchanged or improved in 72% (18/25) of the patients in whom maladaptive behavior was assessed. CONCLUSION: Ziprasidone effectively reduces the frequency of maladaptive behavior in a patient group with mental retardation without causing weight gain or metabolic disturbances.     

Behaviour problems of the mentally retarded.

The behaviour profiles of 176 mentally retarded individuals from two reception centres and nine group homes were assessed. The correlations between behaviour and age, sex, degree of mental retardation, etiology of mental retardation and medical diagnosis were assessed using the Revised Child Behaviour Profile. The severity of behaviour disturbance did not vary with age or medical diagnosis. The moderately retarded subjects presented with more severe behaviour problems, such as aggression, than the severely mentally retarded subjects. The variable most predictive of behavioural problems was etiology of the disorder. Individuals with Down's syndrome had significantly fewer behaviour disturbances and those with autism and pervasive developmental disorder had significantly more behaviour disturbances than other subjects. A psychiatric disorder was found in 10.2% of the sample. The implications of these findings are discussed with respect to public policy.     

Metabolic syndrome manifestations in Cohen syndrome: description of two new patients

We report on sporadic cases that have the proposed diagnostic criteria for Cohen syndrome associated with metabolic syndrome. The patients, aged 14 and 16 years, had truncal obesity, mild mental retardation, hypotonia, narrow hands and feet, a high-arched palate, prominent upper central incisors, a high nasal bridge, and ocular abnormalities. Both had impaired glucose tolerance, with marked hyperinsulinemia exhibited by an oral glucose tolerance test. Moreover, they had the other metabolic syndrome features of hyperlipidemia and hypertension. We suggest that it is necessary to consider the possibility of metabolic syndrome in a case of Cohen syndrome.     

A profile of cognitive deficit in females from fragile X families

Fragile X, a recently discovered X-linked syndrome, is usually associated with mental retardation in affected males. Less consistent findings have been described for females. neuropsychological evaluation of seven nonretarded females from fragile X families suggested a characteristic profile: on Wechsler IQ tests, a positive Verbal-Performance score difference and lower subtest scaled scores on Arithmetic, Digit Span, Block Design, and Object Assembly; on the Wide Range Achievement Test, a lower score on Arithmetic than on Reading or Spelling; and on the Benton Visual Retention Test, defective recall. These results suggest the existence of X-linked learning disability in females.     

A neuropsychological assessment of frontal cognitive functions in Prader–Willi syndrome

Background Prader–Willi syndrome (PWS) is associated with a characteristic behavioural phenotype whose main features are, alongside compulsive hyperphagia, deficits in social behaviour: social withdrawal, temper tantrums, perseverative speech and behaviour, mental rigidity, stereotyped behaviour, impulsiveness, etc. Similar symptoms may also be found in autistic spectrum disorders and lesional pathologies of the frontal lobe. In both cases, such symptoms have been related to dysfunctions in frontal cognitive processes such as attention, working memory and executive functions. This study uses standardized neuropsychological instruments to analyse the degree to which these processes are affected in PWS. Methods The sample comprised 16 individuals with a genetically confirmed PWS diagnosis. Subjects’ IQ (Wechsler Adult Intelligence Scale), academic level, laterality and body mass index (BMI) were calculated. Attention, memory and executive functions were analysed using standard, widely employed neuropsychological tests. We compared the results of the sample group with the general population. Correlation analyses were carried out with IQ, academic level and BMI. Results In all the neuropsychological measures focusing on attention, executive functions and visuoperceptual organization, the study sample scored significantly lower than the normative reference population. The scores of the tests used for measuring immediate memory were also significantly lower when trials required sequential processing, although not when they required simultaneous processing. In the memorization of a list of words, subjects showed an initial deficit which disappeared with repetition, enabling them to obtain scores similar to the reference population. No significant correlations were found with BMI, and a higher IQ or academic level did not improve scores in the majority of tests. Conclusions The study shows a deficit in elementary frontal cognitive processes in PWS patients. This deficit may be involved in the social behaviour disorders that characterize such patients, as described in other development or frontal syndrome pathologies. However, we cannot affirm that the deficits found are specific to PWS; they could also occur in other causes of intellectual disability. Although in the study sample IQ did not correlate with frontal deficits, further research is needed to establish whether the neuropsychological alterations described form part of a cognitive phenotype for PWS. We believe that our understanding of the social behaviours typical of PWS may be improved by taking into consideration the cognitive functioning models of the prefrontal lobe, particularly those applied to pervasive developmental disorders.     

Expanding the clinical picture of Simpson-Golabi-Behmel syndrome

This report describes a 14-year-old male with Simpson-Golabi-Behmel overgrowth syndrome. He was born via cesarean section because of macrocephaly and subsequently exhibited significant developmental delay in motor, language, and cognitive skills with mental retardation and epilepsy. He manifests the characteristic dysmorphic ("bulldog") facial features of Simpson-Golabi-Behmel syndrome. His molecular genetic testing has substantiated the clinical diagnosis of Simpson-Golabi-Behmel syndrome; however, he is unique in that he has mental retardation, hydrocephalus, and epilepsy, which have not been previously documented in Simpson-Golabi-Behmel syndrome in the literature.