Enhanced markers of oxidative stress, altered antioxidants and NADPH-oxidase activation in brains from Fragile X mental retardation 1-deficient mice, a pathological model for Fragile X syndrome

Fragile X syndrome is the most common form of inherited mental retardation in humans. It originates from the loss of expression of the Fragile X mental retardation 1 (FMR1) gene, which results in the absence of the Fragile X mental retardation protein. However, the biochemical mechanisms involved in the pathological phenotype are mostly unknown. The availability of the FMR1-knockout mouse model offers an excellent model system in which to study the biochemical alterations related to brain abnormalities in the syndrome. We show for the first time that brains from Fmr1-knockout mice, a validated model for the syndrome, display higher levels of reactive oxygen species, nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase activation, lipid peroxidation and protein oxidation than brains from wild-type mice. Furthermore, the antioxidant system is deficient in Fmr1-knockout mice, as shown by altered levels of components of the glutathione system. FMR1-knockout mice lacking Fragile X mental retardation protein were compared with congenic FVB129 wild-type controls. Our results support the hypothesis that the lack of Fragile X mental retardation protein function leads to a moderate increase of the oxidative stress status in the brain that may contribute to the pathophysiology of the Fragile X syndrome.     

Factor structure of maladaptive behavior across the lifespan of persons with mental retardation

Data obtained on a sample of persons with mild to profound degrees of mental retardation (N = 8255) and ranging from birth to 98 years of age were factor analyzed to provide information on the structure of maladaptive behavior relative to age and degree of mental retardation. Using the Problem Behavior scales of the Inventory for Client and Agency Planning, two principal factors emerged for children with mild to profound degrees of retardation: Internalized Maladaptive and Externalized Maladaptive. For adolescents and young adults, a three-factor solution which varied by degree of retardation was most appropriate. For middle and older adults, three- and four-factor solutions were identified across all ages and degrees of retardation. Across all samples as many as six different types of dimensions were identified, indicating that the structure of maladaptive behavior may well be influenced by age and level of mental retardation.     

Information processing speed in patients with multiple sclerosis

We have recently proposed that the cognitive deficits of patients with multiple sclerosis (MS) share numerous characteristics associated with the syndrome of subcortical dementia. One such characteristic, slowness of mental processing, was evaluated in the present study. Thirty-six MS patients were compared to 26 normal controls of equivalent age, education, and verbal intelligence on the Sternberg memory scanning test. As anticipated, the motor-involved MS patients had an overall slower reaction time than did controls. Their scanning rate, a measure of pure cognitive speed, was also significantly slower than controls. These results suggest that MS patients exhibit a slowing of mental processing independent of motor involvement.     

Dynamical origins of stereotypy: relation of postural movements during sitting to stereotyped movements during body-rocking

The relation between the movement dynamic properties of sitting still and of seated body-rocking in adults with stereotyped movement disorder and mental retardation and a contrast group of typically developing age-matched adults was examined. Continuous measurement of sequential displacements in center-of-pressure was made using a force platform while subjects were engaged in seated body-rocking and quiet sitting. Properties of movement were compared across conditions (rocking, sitting) and groups (stereotyped movement disorder, contrast). The contrast group had the same modal frequency for both movement properties. The intrinsic dynamics of the stereotyped movement disorder group were similar to those of the contrast group for body-rocking but very different for quiet sitting. Findings support the suggestion that body-rocking in stereotyped movement disorder originates partly as an adaptation to an inability to control posture in a seated position.     

Visual preferences of students with profound mental retardation and healthy,full-term infants

Thirty students with profound mental retardation (age range: 3-5 to 19-11) and 30 healthy, full-term infants (5-8 months) were shown 12 stimuli, three times each. Four patterned stimuli were presented one to a card and each pattern appeared in black-and-white, black-and-yellow, and red-and-yellow. Both groups looked significantly longer at face patterns than other patterns. Students with profound mental retardation looked longer at black-and-white patterns than other color combinations. Infants looked longer at red and yellow cards than did students with profound mental retardation. The measurement method was practical, reliable, and sensitive to both within and between group differences. Results from this assessment method may help determine the most salient visual stimuli for evoking active-alert states for students with profound mental retardation. Individual variability was evident in the data, which demonstrates the importance of examining preferences for each individual when planning intervention. Implications for future research and intervention are discussed.     

Influence of mental retardation severity and respondent characteristics on self-reported attitudes toward mental retardation and eugenics

Eugenics refers to the investigation of means of social control to improve the mental or physical qualities of future generations. The present study investigated whether the self-reported attitudes toward mental retardation and eugenics of a sample of 572 respondents would vary as a function of (1) severity of the mental retardation attitude referent; and (2) respondent sociode-mographic characteristics. Among the respondents, 380 were health and human service providers (66% upper division undergraduate students and 34% graduate level professionals) and 192 were upper division undergraduate students majoring in fields other than health and human services. The results supported these conclusions: (1) psychometric characteristics of the scales used to measure attitudes were adequate; (2) increasing mental retardation severity was related to increasing endorsement of eugenic principles, independent of global attitudes toward people with mental retardation; and (3) respondent education was related to the expression of eugenic attitudes toward mild mental retardation, while familiarity with people with mental retardation was related to the expression of eugenic attitudes toward moderate and profound mental retardation.     

Neuropsychological Findings: Myoclonic Astatic Epilepsy (MAE) and Lennox-Gastaut Syndrome (LGS)

Summary:  Purpose: To identify a specific neuropsychological profile associated with myoclonic astatic epilepsy (MAE) and Lennox-Gastaut syndrome (LGS).
Methods: Seven patients diagnosed with MAE and four patients diagnosed with LGS were selected from patients referred to our Child Neurology Unit. The patients were assessed both clinically (awake, sleep, Holter EEG, seizures frequency, and semiology) and neuropsychologically (IQ, language, attention, visuospatial and visuomotor abilities, and behavior). One representative case of each syndrome is presented here.
Results: The clinical picture of the MAE patient resembled that of an MAE condition associated with transitory epileptic encephalopathy. The neuropsychological findings suggest that electroclinical anomalies can temporarily affect cognitive and behavioral functioning. Early effective antiepileptic drug (AED) treatment was found to improve cognitive outcome. In contrast, LGS was associated with mental retardation, which persisted after seizure control.
Conclusions: At present, it remains difficult to delineate a precise neuropsychological profile associated with MAE and LGS. The cognitive outcome of MAE is variable and depends on the clinical pattern. With regard to LGS, the hypothesis of a genetic predisposition underlying both the epilepsy and the mental retardation is still valid. Alternatively, exposure to subclinical electrophysiological anomalies during a critical period of cerebral development may be responsible for the mental retardation. At the time the clinical manifestations appear, drug treatment, even if effective, would have only limited impact on cognitive outcome. However, early multidisciplinary intervention may help to improve behavior and communicative abilities, enhancing the quality of life of these children and their families.     

Bradykinesia in motoneuron diseases

ObjectiveOnly few studies investigated voluntary movement abnormalities in patients with motoneuron diseases (MNDs) or their neurophysiological correlates. We aimed to kinematically assess finger tapping abnormalities in patients with amyotrophic lateral sclerosis (ALS) and primary lateral sclerosis (PLS), as compared to healthy controls (HCs), and their relationship with motoneuron involvement.MethodsFourteen ALS and 5 PLS patients were enrolled. Finger tapping was assessed by a motion analysis system. Patients underwent a central motor conduction time assessment, a motor nerve conduction study, and needle electromyography. Data were compared to those of 79 HCs using non-parametric tests. Possible relationships between clinical, kinematic, and neurophysiological data were assessed in patients.ResultsAs a major finding, ALS and PLS patients performed finger tapping slower than HCs. In both conditions, movement slowness correlated with muscle strength. In ALS, movement slowness also correlated with the amplitude of the compound muscle action potential recorded from the muscles involved in the task and with denervation activity. No correlations were found between slowness, measures of upper motoneuron involvement, and other clinical and neurophysiological data.ConclusionsThis study provides novel information on voluntary movement abnormalities in MNDs.SignificanceThe results highlight the pathophysiological role of motoneurons in generating movement slowness.     

Midline-crossing inhibition: an indicator of developmental delay

In normal development midline crossing integration is usually attained by eight or nine years of age. The inability to attain this developmental milestone is called midline crossing inhibition (MCI). A new method to detect MCI was used to examine the presence of MCI in a group of subjects with mental retardation. Seventeen subjects with mental retardation and an equal number of non-disabled peers participated in the study. Choice response time measurements consisting of reaction time and movement time were the dependent variables. These variables were recorded when subjects executed ipsilateral, midline and contralateral movements with each leg. Analysis of data revealed for both dependent variables significant differences between the two groups of subjects. Only the group with mental retardation exhibited contralateral times that were significantly slower than ipsilateral times. Midline crossing inhibition was evident with these developmentally delayed subjects. This new method shows promise for assessing developmental and neurological anomalies.     

DSM-III-R and persons with dual diagnoses: conceptual issues and strategies for future research

Diagnosis of mental health needs in people with mental retardation using the DSM-III-R manual was critically reviewed. Conceptual issues included the interaction of different diagnosis categories; the cognitive and linguistic competencies often required for diagnosis; the potential mismatch between psychopathology in people with mental retardation and the DSM-III-R nosology; and issues relating to multi-axial classification. Strategies identified to explore and resolve these issues include better documentation of the frequency and nature of these problems when using unmodified DSM-III-R criteria, better empirical piloting of modified diagnostic criteria with people with severe and profound mental retardation, and the use of social validity data to identify potential mismatches between psychopathology in people with mental retardation and DSM-III-R diagnoses.     

Nonambulatory persons with profound mental retardation: Physical, developmental, and behavioral characteristics

Although profound mental retardation is generally associated with various organic etiologies that result in substantial cognitive and behavioral deficits, little is known about specific subgroups of persons with profound mental retardation. This study presents data on the physical, developmental, and behavioral characteristics of a group of 203 nonambulatory persons with profound mental retardation residing within a specialized service setting. The results indicate that nonambulatory persons with profound mental retardation have a high prevalence of physical and medical problems along with high rates of self-injurious, stereotypic, and aggressive behavior. Assessment results from the Stanford-Binet (L-M), Bayley Scales of Infant Development-Mental Scale, and Vineland Adaptive Behavior Scale reveal a high degree of variability in cognitive and adaptive functioning. However, developmental age-equivalent scores of cognitive ability, communication, daily living, socialization, and motor skills for the group fell below the 1-year level. The data illustrate the complexity of needs in providing habilitative services to nonambulatory persons with profound mental retardation.     

A nonsense mutation of the ATRX gene causing mild mental retardation and epilepsy

Mutations in the X-encoded gene ATRX are known to give rise to profound syndromal mental retardation (MR). Here, we describe a pedigree, including 4 affected family members with a 324C-->T nonsense mutation in the ATRX gene. Although 2 patients have moderate to profound MR and the typical facial features of ATR-X syndrome, the other 2 patients presented with mild MR and epilepsy but without the characteristic facial dysmorphism. Mutations in the ATRX gene should be considered as a cause of mild MR in male patients lacking specific diagnostic features.     

Muscle slowness in a family with nemaline myopathy

All patients of a large family with nemaline myopathy complained of slowness in movement. We confirmed this clinical complaint physiologically by showing lower contractile speed in quadriceps muscle. Electrically evoked contractions of the quadriceps muscle elicited a lower rate of relaxation and a tendency for slower torque generation. Here, we demonstrate for the first time slow muscle characteristics as a physiological correlate for the clinical complaint of slowness.     

Clinical neurophysiology of akinesia

Akinesia refers to failure of willed movement to occur, and bradykinesia refers to slowness of movement that is ongoing. One mechanism of bradykinesia is failure to energize muscles up to the level necessary to complete a movement in a standard amount of time. Akinesia may occur for two possible reasons. One is that the movement is so slow (and so small) that it cannot be seen. A second is that the time needed to initiate the movement becomes excessively long; this can be studied by evaluation of reaction time. One simple factor in prolongation of reaction time is present in patients with rest tremor, who appear to have to wait for a beat of tremor in the agonist muscle of the willed movement in order to initiate the movement. Reaction time studies in patients with Parkinson's disease demonstrate that simple reaction time is delayed, while choice reaction time is normal. Additionally, there does not appear to be any slowness of thinking or difficulty with storage of a motor program. Hence, the difficulty with reaction time in these patients appears to be the time that it takes to execute a motor program. Studies with magnetic stimulation of the motor cortex during the reaction time period seem to support this hypothesis. Slowness of activation of the motor cortex to trigger a movement may well be analogous in mechanism to the slowness of bradykinesia.     

The clinical profile and service needs of hospitalized adults with mental retardation and a psychiatric diagnosis

OBJECTIVE: This study compared patients with both mental retardation and a psychiatric diagnosis with patients who did not have co-occurring mental retardation who were served in Ontario's tertiary mental health care system in terms of demographic characteristics, symptom profile, strengths and resources, and clinical service needs. METHODS: A secondary analysis of data from the Colorado Client Assessment Record (CCAR) that were collected between 1999 and 2003 from all tertiary psychiatric hospitals in Ontario, Canada, was completed for a random sample of 3,927 cases, representing 12,470 patients receiving psychiatric services. RESULTS: Patients with both mental retardation and a psychiatric diagnosis differed from those who did not have mental retardation in terms of demographic characteristics, diagnostic and symptom profile, resources, and recommended level of care. More specifically, patients with both mental retardation and a psychiatric diagnosis had significantly worse ratings across nearly all CCAR functional domains and were assessed as requiring more than the recommended levels of care compared with other patients. CONCLUSIONS: Patients who have both mental retardation and a psychiatric diagnosis constitute a sizeable subgroup of an already underserved psychiatric hospital population. Greater attention is required to meet the unique clinical and service needs of this challenging group.     

FMR1 gray‐zone alleles: Association with Parkinson's disease in women?

Carriers of fragile X mental retardation 1 repeat expansions in the premutation range (55–200 CGG repeats), especially males, often develop tremor, ataxia, and parkinsonism. These neurological signs are believed to be a result of elevated levels of expanded CGG‐repeat fragile X mental retardation 1 mRNA. The purpose of this study was to determine the prevalence of fragile X mental retardation 1 repeat expansions in a movement disorder population comprising subjects with all types of tremor, ataxia, and parkinsonism. We screened 335 consecutive patients with tremor, ataxia, or parkinsonism and 273 controls confirmed to have no movement disorders. There was no difference in fragile X mental retardation 1 premutation size expansions in the cases compared with controls. Eleven percent of the women with Parkinson's disease had fragile X mental retardation 1 gray‐zone expansions compared with 4.4% of female controls (odds ratio of 3.2; 95% confidence interval, 1.2–8.7). Gray‐zone expansions in patients with other phenotypes were not overrepresented in comparison with controls. Fragile X mental retardation 1 premutation range expansions are not more common in a mixed movement disorder population compared with controls. Our results, however, suggest that fragile X mental retardation 1 gray‐zone alleles may be associated with Parkinson's disease in women. © 2011 Movement Disorder Society     

Fluoxetine treatment of depression and associated self-injury in two adults with mental retardation

ABSTRACT. The use of fluoxeiine to treat chronic depression and associated self-injurious behaviour (SIB) in a woman with severe mental retardation and a man with profound mental retardation is reported. In the first case, behavioural monitoring of treatment response revealed a dramatic decrease in SIB and a normalization of the woman's sleep disturbance. In the second case, SIB and the use of mechanical restraint decreased substantially. In both cases, anecdotal reports also indicated a diminution of other depressive symptoms. These cases highlight the need to consider an affective disorder as a cause of SIB in persons with severe and profound developmental disabilities. The behaviour monitoring system proved to be a practical aid in the diagnosis of depression and evaluation of antidepressant treatment in individuals who were incapable of self-report.     

Naltrexone attenuates self-injurious behavior in mentally retarded subjects

The effect of naltrexone on the frequency of self-injurious behavior (SIB) was investigated in 6 male subjects with profound mental retardation. Following a double-blind placebo-controlled crossover design, naltrexone was administered in a dose of 50 mg once daily for 3 consecutive weeks. In 2 of 5 subjects, a significant decrease of SIB frequency could be demonstrated, and in 1, a tendency to a reduction was found. No effect on duration of restrain time was found in 3 subjects. These data suggest that disturbances of the endogenous opioid systems may be involved in the pathophysiology of SIB of certain patients.     

Electrophysiological and behavioral correlates of psychomotor responsivity in depression

Psychomotor retardation is a frequently observed clinical feature of depressive states. This study attempted to assess the relationship between response slowness and central nervous system (CNS) activity by examining cortical evoked potentials (EPs) during psychomotor task performance. Patients consisted of 21 women who met Research Diagnostic Criteria (RDC) and exhibited a minimum Hamilton Rating Scale for Depression score of 18 at the end of a drug washout period, the scheduled time of testing. The same number of normal women with no history of psychiatric illness were employed as controls. Cortical EPs from Cz and integrated electromyogram (EMG) from the dominant forearm extensor were recorded and time-locked to warning and imperative stimuli of a standard, two-choice, fixed foreperiod reaction time (RT) task, which yielded behavioral measures of decision time (DT) and movement time (MT). Analysis focused on behavioral RTs, latency and amplitudes of EMG, sensory and slow cortical (CNV) EPs, and measures of input time (IPT), central processing time (CPT), and motor execution time (MET), derived from combinations of EP and EMG peak latencies. Patients exhibited slower DT and MT response times, delayed EMG latencies, and attenuated EP amplitudes. The derived CPT measure was also significantly longer in patients. These findings support the view that a central dysfunction is implicated in psychomotor retardation, and the results are discussed in relation to information processing theory.     

Fronto-parietal and cerebellar contributions to motor dysfunction in Williams syndrome: a review and future directions

Williams syndrome (WS) is a rare genetically based neurodevelopmental disorder which is associated with mental retardation and a distinctive cognitive and behavioural profile, including weaknesses in visuospatial processing but preserved language abilities and face recognition. Relative to the cognitive characteristics of WS, there is a dearth of research into the movement problems associated with this syndrome. This is despite the evidence from clinical and experimental studies that indicate disordered movement may be an important neuromotor characteristic of WS. This article reviews the current neuroanatomical and behavioural literature on visuomotor deficits in WS, and examines the differential role of fronto-parietal and cerebellar regions in motor dysfunction. The role of these brain regions in disturbances of visuomotor control is discussed in the context of the important interaction with attention, executive and planning deficits in WS. Finally, directions are provided for future research emphasising the need to examine developmental changes in motor functioning across a range of movement parameters and to investigate the functional correlates of abnormal neural connectivity in WS. It is concluded that further investigation of motor dysfunction in WS may provide us with a greater understanding of how important movement-related brain regions develop and operate.