Verbal and memory skills in males with Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is a progressive pediatric disorder that affects both muscle and brain. Children with DMD have mean IQ scores that are about one standard deviation lower than population means, with lower Verbal IQ than Performance IQ scores. For the present study, verbal skills and verbal memory skills were examined in males with DMD with the Clinical Evaluation of Language Fundamentals, 3rd edition, and the California Verbal Learning Test for Children. Performance of 50 males with DMD (age range 6-14 y, mean 9 y 4 mo [SD 2 y 1 mo]) was compared to normative values. Two subsets of the probands were also compared with two comparison groups: unaffected siblings (n=24; DMD group age range 6-12 y, mean 9 y 1 mo [SD 1 y 8 mo]; sibling age range 6-15 y, mean 9 y 11 mo [SD 2 y 4 mo]) and males with cerebral palsy (CP); (n=23; DMD group age range 6-9 y, mean 7 y 8 mo [SD 1 y 2 mo]; CP age range 6-8 y, mean 6 y 8 mo [SD 0 y 8 mo]). Results demonstrated that although males with DMD performed slightly more poorly than normative values, they performed comparably to the controls on most measures. Consistent deficits were observed only on tests requiring immediate repetition for verbal material (Recalling Sentences, and Concepts and Directions). On other language tasks, including tests of understanding and use of grammar, and understanding of semantic relationships, the males with DMD performed well. Moreover, the males with DMD performed well on multiple indices of verbal recall, and there was no evidence of declarative memory deficits. DMD is a single-gene disorder that is selectively associated with decreased verbal span capacity, but not impaired recall.

Poor facial affect recognition among boys with duchenne muscular dystrophy.

Children with Duchenne or Becker muscular dystrophy (MD) have delayed language and poor social skills and some meet criteria for Pervasive Developmental Disorder, yet they are identified by molecular, rather than behavioral, characteristics. To determine whether comprehension of facial affect is compromised in boys with MD, children were given a matching-to-sample test with four types of visual recognition (Object, Face, Affect, and Situation matching) developed by Lucci and Fein. Within-group analyses on 50 boys with MD found decreased Affect matching relative to the other matching conditions. Between-group comparisons on 20 sibling pairs found the boys with Duchenne performed more poorly only on the Affect-matching condition. Thus, mildly impaired facial affect recognition may be part of the phenotype associated with Duchenne or Becker MD.

[A concept of nephrologic care at the end of life]. / Ein Konzept für die nephrologische Pflege am Ende des Lebens.

BACKGROUND: A care pathway for the end-of-life had been implemented onto the two renal wards. An audit was performed to highlight potential issues and areas for development. METHOD: The audit consisted of a base review of documentation from the medical notes of 10 patients who had died an 'expected' death prior to commencing the renal Integrated Care Pathway (ICP) for the end of life and then 10 patients who had died whilst using the ICP documentation. A questionnaire was also given out to nursing staff who had used the ICP documentation. The results were collated and analysed. RESULTS: In the base review 100% of the documentation looked at did not provide a regular documented assessment of symptoms that are common in the terminal phase of life. The ICP provided a documented assessment of all of these main symptoms. The base review indicated a good response by doctors to meet the potential needs of the patient, but the ICP improved on this. This was through the use of a pre-emptive prescription. 80% of all patients were pain free, not agitated, had no nausea or vomiting or respiratory secretions. The 2 patients that had pain received further analgesia and were then pain free at the next assessment. One of the most positive aspects of the audit was that 90% of relatives were aware that the patient was dying and 100% had the plan of care discussed with them. CONCLUSION: Implementing the ICP has generated the opportunity to deliver a hospice model of care to a busy renal unit. It has allowed best practice, and a measurable standard of care, in the final stages of patients' lives. Staff find the documentation easy to use and also see it as enhancing patient care.

Aromatic L-amino acid decarboxylase deficiency: clinical features, treatment, and prognosis.

BACKGROUND: Deficiency of aromatic L-amino acid decarboxylase (AADC) is associated with severe developmental delay, oculogyric crises (OGC), and autonomic dysfunction. Treatment with dopamine agonists and MAO inhibitors is beneficial, yet long-term prognosis is unclear. OBJECTIVE: To delineate the clinical and molecular spectrum of AADC deficiency, its management, and long-term follow-up. RESULTS: The authors present six patients with AADC deficiency and review seven cases from the literature. All patients showed reduced catecholamine metabolites and elevation of 3-O-methyldopa in CSF. Residual plasma AADC activity ranged from undetectable to 8% of normal. Mutational spectrum was heterogeneous. All patients presented with hypotonia, hypokinesia, OGC, and signs of autonomic dysfunction since early life. Diurnal fluctuation or improvement of symptoms after sleep were noted in half of the patients. Treatment response was variable. Two groups of patients were detected: Group I (five males) responded to treatment and made developmental progress. Group II (one male, five females) responded poorly to treatment, and often developed drug-induced dyskinesias. CONCLUSIONS: The molecular and clinical spectrum of AADC deficiency is heterogeneous. Two groups, one with predominant male sex and favorable response to treatment, and the other with predominant female sex and poor response to treatment, can be discerned.

Investigation of Poor Academic Achievement in Children with Duchenne Muscular Dystrophy.

Duchenne Muscular Dystrophy (DMD) is a neurogenetic developmental disorder that presents with progressive muscular weakness. It is caused by a mutation in a gene that results in the absence of specific products that normally localize to muscle cells and the central nervous system (CNS). The majority of affected individuals have IQs within the normal range, generally with lower verbal than performance IQ scores. Prior work has demonstrated selective deficits on tests of verbal span and immediate memory. For the current study, 26 boys with DMD (and normal intellectual function) and their unaffected siblings were evaluated. Paired comparisons demonstrated that the children with DMD had significantly poorer academic achievement scores than their siblings, even though their vocabulary levels and home and educational environments were comparable. Children with DMD also had more behavioral concerns, physical disabilities, and poorer verbal memory spans. Linear regression indicated that behavioral concerns, executive function, and physical disability did not contribute substantially to academic performance, whereas performance on verbal span did. DMD presents with a selective developmental aberration in verbal span that has wide-ranging consequences on learning skills.

Selective deficits in verbal working memory associated with a known genetic etiology: the neuropsychological profile of duchenne muscular dystrophy.

Forty-one boys diagnosed with Duchenne muscular dystrophy (DMD) were each compared to an unaffected sibling on a battery of neuropsychological tests. Verbal. visuospatial, attention/memory, abstract thinking, and academic achievement skills were tested. Results indicated the boys with DMD performed similarly to their siblings on the majority of measures, indicating intact verbal, visuospatial, long-term memory, and abstract skills. However, the DMD group did significantly more poorly than their siblings on specific measures of story recall, digit span, and auditory comprehension, as well as in all areas of academic achievement (reading, writing, and math). This profile indicates that verbal working memory skills are selectively impaired in DMD, and that that likely contributes to limited academic achievement. The association between the known impact of the genetic mutation on the development of the central nervous system and boys' cognitive profile is discussed.

Poor verbal working memory across intellectual level in boys with Duchenne dystrophy.

OBJECTIVE: To determine whether all boys with Duchenne muscular dystrophy (DMD) have a similar verbal and memory profile of skills, or whether only a subset is affected, and to determine whether the weak areas in their profile are substantially different from a control group. METHODS: Performance of patients with DMD on neuropsychological tests of verbal and memory skills was examined in two ways. Standardized test scores for 80 boys with DMD (estimated IQ range, 70 to 160) were ranked individually from worst to best, and the individual rankings were compared across the group using Friedman rank analysis. Additionally, performance of 41 boys with DMD was compared with that of their sibling control subjects of similar age and estimated IQ using multivariate analysis of variance. RESULTS: Individual cognitive profiles were significantly similar among the subjects with DMD, such that for most subjects digit span, story recall, and comprehension were the tests on which each performed most poorly. This finding remained true regardless of whether they were of high or low intellectual function. In contrast, no significant cognitive profile was found among their sibling control subjects, and when compared with their siblings, the DMD group scored significantly more poorly on digit span, comprehension, and story recall, but not on other verbal and memory measures. CONCLUSIONS: Boys with DMD have a specific cognitive profile, regardless of their general level of cognitive function. Specifically, boys with DMD performed more poorly on tests requiring attention to complex verbal information than they did on other verbal or memory measures. The possibility that the missing dystrophin brain products may contribute to selective cognitive processing is considered.

Premutation female carriers of fragile X syndrome: a pilot study on brain anatomy and metabolism.

OBJECTIVE: It was thought that premutation carriers of fragile X syndrome (FraX) have no neurobiological abnormalities, but there have been no quantitative studies of brain morphometry and metabolism. Thus the authors investigated brain structure and metabolism in premutation carriers of FraX. METHOD: Eight normal IQ, healthy female permutation FraX carriers aged 39 +/- 9 years (mean +/- SD) and 32 age-sex-handedness-matched controls (39 +/- 10 years) were studied; in vivo brain morphometry was measured using volumetric magnetic resonances imaging, and regional cerebral metabolic rates for glucose were measured using positron emission tomography and (18F)-2-fluoro-2-deoxy-D-glucose. RESULTS: Compared with controls, FraX premutation carriers had a significant (1) decrease in volume of whole brain, and caudate and thalamic nuclei bilaterally; (2) increase in volume of hippocampus and peripheral CSF bilaterally, and third ventricle; (3) relative hypometabolism of right parietal, temporal, and occipital association areas; (4) bilateral relative hypermetabolism of hippocampus; (5) relative hypermetabolism of left cerebellum; and (6) difference in right-left asymmetry of the Wernicke and Broca language areas. CONCLUSIONS: Premutation carriers of FraX, as defined by analysis of peripheral lymphocytes, have abnormalities in brain anatomy and metabolism. The biological basis for this is unknown, but most likely it includes tissue heterogeneity for mutation status. The findings may be of relevance to people counseling families with FraX and to understanding other neuropsychiatric disorders which are associated with expansion of triplet repeats and genetic anticipation.

Early developmental outcome after the Norwood procedure for hypoplastic left heart syndrome.

OBJECTIVE: To assess intellect and adaptive behavior in children with hypoplastic left heart syndrome (HLHS) who had undergone at least two surgical stages of the Norwood procedure. METHODS: Fourteen children with HLHS >3 years of age participated in the study. The patients underwent intelligence quotient (IQ) testing, and their parents were interviewed regarding their children's adaptive behavior. Results were compared with those of 10 family controls. Outcomes were studied for possible correlation with perioperative variables. RESULTS: Among the HLHS patients, the median scores for full scale IQ and adaptive behavior were 88 and 91, respectively (normal = 100 +/- 15). One child met criteria for mental retardation. Family controls scored generally higher than did HLHS patients, but only differences in adaptive behavior were statistically significant. A negative correlation was found between stage I circulatory arrest time and full scale IQ. CONCLUSIONS: Children with HLHS most often function in the low-normal range of intelligence and adaptive behavior. A prolonged circulatory arrest time may result in decreased intellectual function.

Maximum interlabial pressures in normal speakers.

It has been hypothesized that typical speech movements do not involve large muscular forces and that normal speakers use less than 20% of the maximum orofacial muscle contractile forces that are available (e.g., Amerman, 1993; Barlow & Abbs, 1984; Barlow & Netsell, 1986; DePaul & Brooks, 1993). However, no direct evidence for this hypothesis has been provided. This study investigated the percentage of maximum interlabial contact pressures (force per unit area) typically used during speech production. The primary conclusion of this study is that normal speakers typically use less than 20% of the available interlabial contact pressure, whether or not the jaw contributes to bilabial closure. Production of the phone [p] at conversational rate and intensity generated an average of 10.56% of maximum available interlabial pressure (MILP) when jaw movement was not restricted and 14.62% when jaw movement was eliminated.

Adult fragile X syndrome: neuropsychology, brain anatomy, and metabolism.

To understand the implications of suboptimal gene expression in fragile X syndrome -fra(X)-, we sought to define the central nervous abnormalities in fra(X) syndrome to determine if abnormalities in specific brain regions or networks might explain the cognitive and behavioral abnormalities in this syndrome. Cranial and ventricular volumes were measured with quantitative computed tomography (CT), regional cerebral metabolic rates for glucose (rCMRglc) were measured with [18-F]-2-fluoro-2-deoxy-D-glucose (18FDG), and patterns of cognition were determined with neuropsychological testing in ten healthy, male patients with karyotypically proven fra(X) syndrome (age range 20-30 yr). Controls for the CT studies were 20 healthy males (age range 21-37 yr), controls for the PET studies were 9 healthy males (age range 22-31 yr), and controls for the neuropsychological tests were 10 young adult, male Down syndrome (DS) subjects (age range 22-31 yr). The mean mental age of the fra(X) syndrome group was 5.3 yr (range 3.5-7.5 yr; Stanford-Binet Intelligence Scale). Despite comparable levels of mental retardation, the fra(X) subjects showed poorer attention/short term memory in comparison to the DS group. Further, the fra(X) subjects showed a relative strength in verbal compared to visuospatial attention/short term memory. As measured with quantitative CT, 8 fra(X) subjects had a significant (P < 0.05) 12% greater intracranial volume (1,410 +/- 86 cm3) as compared to controls (1,254 +/- 122 cm3). Volumes of the right and left lateral ventricles and the third ventricle did not differ between groups. Seven of eight patients had greater right lateral ventricle volumes than left, as opposed to 9 out of 20 controls (P < 0.05). Global gray matter CMR-glc in nine fra(X) patients was 9.79 +/- 1.28 mg/100 g/minute and did not differ from 8.84 +/- 1.31 mg/100 g/minute in the controls. R/L asymmetry in metabolism of the superior parietal lobe was significantly higher in the patients than controls. A preliminary principal component analysis of metabolic data showed that the fra(X) subjects tended to form a separate subgroup that is characterized by relative elevation of normalized metabolism in the lenticular nucleus, thalamus, and premotor regions. Further, a discriminant function, that reflected rCMRglc interactions of the right lenticular and left premotor regions, distinguished the fra(X) subjects from controls. These regions are part of a major group of functionally and anatomically related brain regions and appear disturbed as well in autism with which fra(X) has distinct behavioral similarities. These results show a cognitive profile in fra(X) syndrome that is distinct from that of Down syndrome, that the larger brains in fragile X syndrome are not accompanied by generalized cerebral cortical atrophy or hypoplasia, and that distinctive alterations in resting regional glucose metabolism, measured with 18 FDG and PET, occur in fra(X) syndrome.

Cognitive and molecular aspects of fragile X.

The relationships among parental origin of the fragile X gene, gene structure, and specific cognitive deficits were evaluated in nonretarded adult female fragile X carriers to determine whether: (1) origin influences gene structure and cognitive function, (2) mild cognitive impairments are associated with altered gene structure, and (3) specific cognitive domains are affected. Results indicated that 56% of women with maternally inherited, but none with paternally inherited, fragile X showed large genomic structural alterations and selective deficits on measures of visual attention. Thus, molecular status of the fragile X gene appears to be linked to parental origin and may selectively affect specific cognitive skills.

Parameter estimation of labial movements in speech production: implications for speech motor control.

Central to theories of speech motor control are estimates on magnitudes of lip activity expressed in terms of central tendency, variability, and interrelatedness. In fact, the tenability of each of two competing theories of motor control for speech production rests solely on the observation of the predicted direction of the correlation coefficient (one positive and one negative) that indexes the relationship of concurrent lip activity. Each theory, however, predicts a relationship that is the complete opposite of the relationship predicted by the other. That is, one theory proposes that the labial system functions on the basis of complementary variation, whereas the other assumes positive covariation, or complementary modulation. In apparent contradiction, each prediction has been observed under laboratory conditions. The explanation for this apparent contradiction resides in the small sample sizes upon which each estimate was based. The minimum number of observations that are necessary to achieve accurate estimates of lip displacement parameters has remained unclear. This paper addresses three fundamental questions: (a) how many observations of on-task behavior are necessary to accurately estimate mean and variance values for the magnitude of upper lip displacement in a speech production experiment?, (b) what is the analogous number of observations for estimating the same values of lower lip displacement (together with the mandible) in the same context?, and (c) how many observations are necessary to accurately estimate the correlation coefficient indexing the relationship of lip displacements during the production of speech? Answers to these questions are accomplished through a review of estimator properties, a Monte Carlo computer simulation, and through laboratory observations.(ABSTRACT TRUNCATED AT 250 WORDS)

Relationships between integrated oral-nasal differential pressure and velopharyngeal closure.

Oral-nasal differential pressures are derived measures that incorporate both active (e.g., articulatory) and passive (e.g., nasal structure) components. This study was designed to examine integrated oral-nasal differential pressures in speakers with different levels of velopharyngeal closure. Integrated oral-nasal differential pressure data were obtained from 20 noncleft adults with normal speech and 166 speakers with repaired palatal clefts. Velopharyngeal competency for the cleft subjects, as determined by aerodynamic assessment, ranged from adequate to grossly incompetent. Results of the data analysis indicate that integrated pressures are not maintained at a consistent level across all groups. This lack of consistency across all degrees of velopharyngeal opening may reflect the flexibility, as well as structural limitations, of a speech pressure regulating system.

Individual, but not simultaneous, glucagon and cholecystokinin infusions inhibit feeding in men.

Pancreatic glucagon and cholecystokinin octapeptide (CCK-8) were intravenously infused (1 ml/min for 10 min) alone or in combination beginning 15 min after normal-weight men had eaten a 500-ml tomato soup preload and 5 min before they were served a lunch of macaroni and beef with tomato sauce. Infusion of approximately 3 ng.kg-1.min-1 glucagon or approximately 2 ng.kg-1.min-1 CCK-8 each reduced test meal size. However, simultaneous infusion of these peptide doses reduced meal size less than the sum of the peptides' individual effects. Infusions of approximately 1.5 ng.kg-1.min-1 glucagon or approximately 1 ng.kg-1.min-1 CCK-8 had neither individual nor interactive effects on meal size. Psychophysical ratings failed to detect nonspecific side effects after any of the infusions. That exogenous glucagon and CCK-8 each reduced meal size without side effects suggests that these peptides may participate in the physiological control of human appetite; that their simultaneous infusion resulted in an infra-additive reduction in meal size suggests that they can interact antagonistically.

Validation of a modern miniature transducer for measurement of interlabial contact pressure during speech.

The response characteristics of the Entran Flatline pressure transducer (EPL-2001-10) and its potential for use in studies of speech production were investigated. Data from a model simulating bilabial closure and from 2 human subjects indicate that this transducer is an appropriate tool for measurement of interlabial pressure during production of bilabial consonants. That is, the onset of the pressure pulse corresponds to the initiation of lip contact between the upper and lower lips, and the return to baseline represents complete lip separation, thus eliminating the need to infer lip contact from records of lip movement. Transducer output is not influenced significantly by temperature fluctuations or changes in the configuration and stiffness of the lips. The frequency response and level of sensitivity are linear over the range of pressures produced during speech. The subjects in this study typically generated interlabial pressures of 1.0-3.0 kPa during production of [p] in a carrier phrase.

Brief screening questionnaire for determining affected state in fragile X syndrome: a consensus recommendation.

New molecular research has provided strong evidence for different forms of the fragile X mutation. These findings suggest the need to develop a more standardized and sensitive method for determining neurobehavioral effects of the fragile X gene(s), particularly for molecular studies of patients who do not have obvious mental retardation. This report describes a brief screening questionnaire designed to increase the detection of neurobehavioral dysfunction in individuals from fragile X families who are included in new molecular studies. Improved detection of the affected state in fragile X syndrome will allow more valid clinical data to be correlated with the important molecular information currently being collected.

Mode of inheritance influences behavioral expression and molecular control of cognitive deficits in female carriers of the fragile X syndrome.

The effect of mode of inheritance on expression of fragile X syndrome [fra(X)] was investigated in nonretarded female carriers. Examination included cognitive and molecular measures. A priori predictions about cognitive impairment and size of an unstable region of DNA containing a CGG repeat on the X chromosome were tested in age and education matched heterozygotes grouped according to parental inheritance. Nine carriers with a maternal fra(X) chromosome, 11 carriers with a paternal fra(X) chromosome and 15 control mothers of children with non X-linked developmental disabilities were tested. Inheritance was established through DNA linkage analysis. Cognitive skills were assessed using the Wechsler Adult Intelligence Scale-Revised and the Benton Visual Retention Test. Molecular status was assessed by Southern blot analysis of genomic DNA digested with Eco RI and Eag I, and probed with StB 12.3. Results supported the inheritance models' predictions. Heterozygotes who inherited the fra(X) from their fathers appeared to be a homogeneous group. They were indistinguishable from controls on cognitive measures and all had genomic insertions of less than 500 base pairs. In contrast, heterozygotes who inherited the fra(X) chromosome from their mothers appeared to be made up of 2 sub-populations. They were as a group deficient in measures of attention and visual memory, but not other measures, with scores of some women consistently below the other subjects. Further, they had some members with greater than 500 base pair inserts.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of neocortex in three males with the fragile X syndrome.

Fragile X [fraX] syndrome is a common hereditary disorder associated with a fragile site marker at Xq27.3 which clinically presents as a form of mental retardation (MR). Postmortem investigation of 3 fraX positive males with mild to moderate MR did not document any gross neuropathological changes. Golgi analysis of neocortical dendritic spine morphology extended our previous observations of immature, long, tortuous spines in one adult case of fraX (Rudelli, et al., Acta Neuropathologica 67:289-295, 1985) to 2 new cases. Evidence for similar dendritic spine abnormalities was found, although Golgi analysis was less than optimal because of incomplete dendritic stain impregnation. Neocortical intra-layer cell density was also investigated in all 3 cases. Cresyl violet stained neurons were counted in 10 randomly selected fields in neocortical layers II-VI of cingulate and temporal association areas (Brodmann's areas 23 and 38). Neuron counts in fraX and control neocortex showed no significant differences. Thus, abnormal dendritic spine morphology with preservation of neuronal density appears to characterize the neocortex in individuals with this common form of mental retardation.

Maintenance of intraoral pressure during speech after maxillary resection.

Although structural defects such as cleft palate and severe anterior open bite alter vocal tract resistance, compensatory responses usually result in maintaining consonant pressures at an adequate level. The purpose of the present study was to determine if individuals with an acquired palatal defect spontaneously develop similar compensatory behaviors. The pressure-flow technique was used to measure aerodynamic variables associated with consonant production after surgery and obturation. Although intraoral pressures decreased considerably immediately after surgery, pressures were maintained at a mean level of 3.5-cm H2O. Respiratory volumes increased as much as fourfold without obturation and were normal with obturation. Voice-voiceless differences in air volumes among consonants were maintained even in the presence of the defect. These findings suggest that compensatory responses are directed toward maintaining an appropriate level of intraoral pressure for consonant production.