Orthostatic hypotension from sympathetic denervation in Parkinson's disease.

BACKGROUND: Patients with PD often have signs or symptoms of autonomic failure, including orthostatic hypotension. Cardiac sympathetic denervation occurs frequently in PD, but this has been thought to occur independently of autonomic failure. METHODS: Forty-one patients with PD (18 with and 23 without orthostatic hypotension) and 16 age-matched healthy volunteers underwent PET scanning to visualize sympathetic innervation after injection of 6-[(18)F]fluorodopamine. Beat-to-beat blood pressure responses to the Valsalva maneuver were used to identify sympathetic neurocirculatory failure and plasma norepinephrine to indicate overall sympathetic innervation. RESULTS: All patients with PD and orthostatic hypotension had abnormal blood pressure responses to the Valsalva maneuver and septal and lateral ventricular myocardial concentrations of 6-[(18)F]fluorodopamine-derived radioactivity >2 SD below the normal mean. In contrast, only 6 of the 23 patients without orthostatic hypotension had abnormal Valsalva responses (p < 0.0001 compared with patients with orthostatic hypotension), and only 11 had diffusely decreased 6-[(18)F]fluorodopamine-derived radioactivity in the left ventricular myocardium (p = 0.0004). Of the 12 remaining patients without orthostatic hypotension, 7 had locally decreased myocardial radioactivity. Supine plasma norepinephrine was lower in patients with than in those without orthostatic hypotension (1.40 +/- 0.15 vs 2.32 +/- 0.26 nmol/L, p = 0.005). 6-[(18)F]fluorodopamine-derived radioactivity was less not only in the myocardium but also in the thyroid and renal cortex of patients with PD than in healthy control subjects. CONCLUSIONS: In PD, orthostatic hypotension reflects sympathetic neurocirculatory failure from generalized sympathetic denervation.

Clinical and therapeutic observations in aromatic L-amino acid decarboxylase deficiency.

OBJECTIVES: To elucidate the phenotype in aromatic L-amino acid decarboxylase (AADC) deficiency, a rare autosomal recessive disorder of neurotransmitter synthesis, and report preliminary treatment observations with directed therapy of the associated neurotransmitter deficiencies. BACKGROUND: AADC is a required enzyme in dopamine, norepinephrine, epinephrine, and serotonin biosynthesis. Five patients have been previously reported. Responses to treatment interventions in these patients have been mixed. METHODS: Clinical and biochemical evaluation and therapeutic trials were performed in two children over a 26-month period. RESULTS: Characteristic features included axial hypotonia, hypokinesia, and athetosis, with superimposed episodes of ocular convergence spasm, oculogyric crises, dystonia, and limb rigidity. Catecholamine deficiency was manifest by ptosis, nasal congestion, paroxysmal diaphoresis, temperature instability, and blood pressure lability. Abnormal sleep, feeding difficulties, and esophageal reflux were typical. Significant therapeutic benefit was observed in one child with a combination of pergolide, trihexyphenidyl, and tranylcypromine. Preliminary trials using serotonin receptor agonists or reuptake inhibitors resulted in adverse effects. CONCLUSIONS: The movement disorder in AADC deficiency, particularly the characteristic eye movement abnormalities, should facilitate the identification of patients with this rare but possibly underrecognized disorder. Directed therapy of the underlying dopamine and norepinephrine deficiency may be beneficial in some cases.

Chronic and discrete stress as predictors of children's adjustment.

Diabetes, as a chronic stressor, and negative life events (NLEs), as a discrete stressor, were related to children's behavioral adjustment, along with moderating effects of the family environment. Diabetes and NLEs predicted both higher internalizing (INT) and externalizing (EXT) behavior problems, suggestive of nonspecific distress. Higher family conflict and lower cohesion each predicted more behavior problems (INT-EXT). However, conflict was the sole moderator of the stressors. Higher family conflict and diabetes exacerbated children's EXT behavior problems, with clinically elevated scores. Higher family conflict and higher NLEs resulted in clinically elevated INT-EXT behaviors. Conversely, low family conflict protected children's behavioral functioning from the stressors. Family cohesion was the sole predictor of children's social competencies but did not moderate the stressors.

Behavior problems in children with diabetes: disentangling possible scoring confounds on the Child Behavior Checklist.

OBJECTIVE: The Child Behavior Checklist (CBCL; T. M. Achenbach, 1991), when used to assess the behavior of children with diabetes, may contain confounds because some behavioral items can have a physiologic etiology, and may skew reports of behavioral disturbance. METHODS: Two techniques were used to disentangle possible scoring confounds in the behavioral ratings of children with and without diabetes: (1) the Somatic Complaints scale was deleted, or (2) Diabetes Items, identified a priori with 89% agreement by nine medical personnel, were deleted. RESULTS: As expected, with traditionally scored protocols, children with diabetes obtained higher Internalizing and Total Behavior Problem scores than controls. This group difference persisted whether the Somatic Complaints scale or the Diabetes Items were deleted. CONCLUSIONS: Compared to controls, children with diabetes obtained mildly elevated scores on six of the eight CBCL scales, regardless of scoring method, suggesting that their mildly elevated behavioral profile is not confounded by physiologic symptomatology.

Monoaminergic effects of high-dose corticotropin in corticotropin-responsive pediatric opsoclonus-myoclonus.

Children with the opsoclonus-myoclonus syndrome (OMS) usually respond to corticotropin (adrenocorticotrophic hormone, ACTH) treatment but the mechanism of benefit is unknown. We previously showed that both cerebrospinal fluid (CSF) homovanillic acid (HVA) and 5-hydroxyindole-acetic acid (5-HIAA) concentrations are low in pediatric OMS. In this study, we measured levels of CSF Dopa, catecholamines, deaminated metabolites of catecholamines, as well as HVA and 5-HIAA in eight patients before and during treatment with ACTH. All the children were ACTH-responsive with 50-70% improvement in multiple clinical features of OMS. ACTH treatment reduced the HVA concentration in every child by a mean of 21% (p < 0.001). Treatment with ACTH was associated with significant correlations between dopaminergic markers such as HVA, dihydroxyphenylacetic acid (DOPAC), and Dopa. There were no significant changes in the CSF concentrations of the noradrenergic markers norepinephrine (NE) and dihydroxyphenylglycol (DHPG), or the serotonergic marker 5-HIAA. The only child with a marked inflammatory pattern in CSF, which was reversed by ACTH, was atypical for a large increase in NE and decrease in 5-HIAA during ACTH treatment. Beneficial effects of ACTH in OMS are not associated with normalization of HVA or 5-HIAA levels. The pattern of decreased HVA and unchanged DOPAC levels could reflect decreased extraneuronal uptake of catecholamines (which steroids inhibit) or decreased 0-methylation of catecholamines in nonneuronal cells.

Sociodemographic risk factors to disease control in children with diabetes.

This study examined the effects of sociodemographic variables such as ethnicity, socioeconomic status (SES), and family structure on disease control in 58 children with diabetes stratified by ethnicity and SES. Three dependent variables were chosen to evaluate the disease control of the study participants, including HbA1 values averaged over the year prior to study participation, number of hospitalizations, and number of hypoglycaemic blackouts. SES and family structure, but not ethnicity, were the primary risk factors to disease control. Children from low SES families were in poorer glycaemic control (mean HbA1 = 12.6%) and experienced more episodes of hypoglycaemia-related loss of consciousness (mean = 0.5 per patient) than did children from middle income families (mean HbA1 = 10.4%; mean blackouts = 0.1 per patient). In addition, children from middle-class, two-parent families were in better metabolic control than all other groups. These results indicate that it may not be ethnicity per se, but other factors that often covary with ethnic status, that may pose a risk to the disease status of children and adolescents with diabetes.

Successful early copper therapy in Menkes disease associated with a mutant transcript containing a small In-frame deletion.

Classical Menkes disease is a fatal X-linked neurodegenerative disorder caused by defects in a gene (MNK) that encodes a copper-transporting ATPase. Treatment with parenteral copper has been proposed for patients identified before symptoms develop. We recently described suboptimal outcomes despite early copper replacement in two classical Menkes patients whose mutation predicts little if any functional copper transporter. Here, we describe successful copper replacement therapy in a patient with Menkes disease with a splice acceptor site mutation (IVS8,AS,dup5) that causes exon-skipping and generates a mutant transcript with a small in-frame deletion in a noncritical region. The patient was diagnosed by analysis of neurochemical levels in cord blood, and parenteral copper replacement was begun at 8 days of life. Throughout infancy, he showed normal head growth, brain myelination, and age-appropriate neurodevelopment, including independent walking at 14 months of age. In contrast, his affected half-brother and first cousin with the same mutation, but who were not diagnosed and treated from an early age, showed arrested head growth, cerebral atrophy, delayed myelination, and abnormal neurodevelopment. We propose that the successful neurological outcome in this patient was related to early repletion of circulating copper levels, in combination with residual copper transport by a partially functional MNK ATPase containing the small deletion. We hypothesize that raising plasma copper concentrations in patients with Menkes disease with some residual functional gene product can increase the ligand: transporter ratio and thus alter favorably the kinetics of copper transport into and within the brain.

Early copper therapy in classic Menkes disease patients with a novel splicing mutation.

To correlate genotype with response to early copper histidine therapy in Menkes disease, an X-linked disorder of copper transport, we performed mutational analysis in 2 related males who began treatment at the age of 10 days and prenatally at 32 weeks' gestation, respectively. A G to T transversion at the -1 exonic position of a splice donor site was identified, predicting a glutamine to histidine substitution at codon 724 of the Menkes copper-transporting ATPase gene. The Q724H mutation disrupts proper splicing and generates five mutant transcripts that skip from one to four exons. None of these transcripts is predicted to encode a functional copper transport protein. Copper histidine treatment normalized circulating copper and ceruloplasmin levels but did not improve the baseline deficiency of dopamine-beta-hydroxylase, a copper-dependent enzyme. At the age of 36 months, the first patient was living and had neurodevelopmental abilities ranging from 10 to 15 months. The second patient also showed delayed neurodevelopment and died of pulmonary complications at the age of 5 1/2 months. We conclude that early copper histidine therapy does not normalize neurological outcome in patients with the Q724H splicing mutation, and suggest that preservation of some residual Menkes ATPase activity may be a general prerequisite for significant clinical efficacy from such treatment.

Family environment and the interrelation of family structure, child behavior, and metabolic control for children with diabetes.

Examined perceptions of the family environment in a cross-regional sample of 90 families who had children with diabetes and 89 controls. Families were classified as either traditional (intact) or nontraditional (single-parent or blended families). Parents of children with diabetes reported less family expressiveness, which was a predictor of clinically higher levels of child behavior problems than controls. Parents in nontraditional families reported lower levels of organization, less emphasis on active-recreational pursuits, and more child behavior problems than traditional families. An additive effect of diabetes and nontraditional family structure was found for children with diabetes from nontraditional families, who reported substantially less cohesion than all other groups. Nontraditional family structure was more disruptive for children with diabetes than for controls; it was the best predictor of behavior problems and was related to poorer metabolic control.

Occipital horn syndrome and a mild Menkes phenotype associated with splice site mutations at the MNK locus.

We have found mutations in the Menkes disease gene (MNK) which impair, but do not abolish, correct mRNA splicing in patients with less severe clinical phenotypes. In one family, four males aged 2-36 years with a distinctive Menkes variant have a mutation at the +3 position of a splice donor site near the 3' end of the Menkes coding sequence that is associated with exon skipping and a stable mutant transcript. In an unrelated 15-year-old male with typical occipital horn syndrome, a point mutation at the -2 exonic position of a splice donor site in the middle of the gene causes exon-skipping and activation of a cryptic splice acceptor site. In both mutations, maintenance of some normal splicing is demonstrable by RT-PCR, cDNA sequencing and ribonuclease protection.

Postpubertal disease status in diabetes and factor structure anomaly on the WISC-R.

Diabetic children have been found to display an anomalous factor structure on the Wechsler Intelligence Scale for Children-Revised (WISC-R) (Holmes, Cornwell, Dunlap, Chen, & Lee, 1992). The present study sought to extend this finding with a larger cross-regional sample of children to determine which, if any, demographic or disease factor(s) might be related to the anomalous structure. Results revealed that groups of older (> = 12 years) children and those with late disease onset (> = 5 years) exhibited an anomalous four-factor structure in which the traditional Perceptual Organization factor (II) split into two factors: Picture Completion and Picture Arrangement formed a visual discrimination factor; and Block Design and Object Assembly created a spatial conceptual factor. It is postulated that diabetic performance on this visual discrimination factor may reflect mild visual neuropathies, often associated with adolescence and postpubertal disease status.

Gender differences in the learning status of diabetic children.

The learning status of 95 diabetic boys and girls and 97 matched controls was evaluated using the Wechsler Intelligence Scale for Children--Revised IQ factors and school histories. Of interest was whether diabetic boys would evidence more learning difficulties. Results indicated that diabetic boys had significantly lower Freedom From Distractibility scores compared with scores of diabetic girls and control Ss and lower Perceptual Organization scores compared with scores of control boys. Although group scores were still within the average range of functioning, a significantly high percentage of diabetic boys (40%) compared with diabetic girls (16%) had learning problems that warranted either special instructional services or grade retention. Diabetic children experienced more learning difficulties (24%) than controls (13%), supporting research findings that diabetes is associated with increased risk of learning problems.

Blood glucose control and visual and auditory attention in men with insulin-dependent diabetes.

Assessment of 16 young men with insulin-dependent diabetes mellitus was undertaken with neuropsychological measures of attention, decision-making, and motor tasks. Those patients in very good, or near-normal, blood glucose control demonstrated decreased attention on visual and auditory simple reaction-time tasks, compared with those in moderate blood glucose control. Patient groups did not differ in their decision-making performance; nor did they differ in motor skill performance. These results replicate earlier findings of differences in visual attention in groups of patients according to degree of blood glucose control and show between-group differences with an auditory reaction time measure. The results suggest that patients with near-normal blood glucose control may exhibit slowed simple attention, whether information presentation is visual or aural.

Psychosocial aspects of disease duration and control in young adults with type I diabetes.

Self-report questionnaires completed by young adults with Type I diabetes were examined to determine if individuals differing in recent metabolic control (Poor, Moderate or Very Good) or disease duration (Long, Short) also vary in either occurrence or type of life events during the past year or occurrence of recent emotional distress. Subjects in Poor control reported more positive and neutral life events during the past year, suggesting even those life changes individuals view benignly may be associated with metabolic control difficulties. Individuals in Poor control also reported more recent symptoms of depression, anxiety and hostility than did individuals in Moderate or Very Good control--symptomatology which may further impair their ability to adhere to a complex self-care regimen. Individuals with Long disease duration reported more positive and negative recent life experiences than did subjects with Short disease duration, but did not evidence concomitant disruptions in metabolic control. The role experience with a chronic disease may play in this finding was unclear, however. Although more research is required to clarify the exact relation of psychosocial variables and diabetic control, these findings suggest that clinically relevant subgroup parameters, subjects' perceptions of life change, and demographic variables may be important factors to assess.

Metabolic control and auditory information processing at altered glucose levels in insulin-dependent diabetes.

Previous work with a visual reaction time (RT) paradigm showed rate of mental processing to be slowed during a state of brain energy depletion (i.e., hypoglycemia). The present study employed an analog auditory RT paradigm to determine if modality differences in processing information might occur in response to glucose alteration. A balanced crossover design was used in which men with insulin-dependent diabetes completed RT tasks of increasing complexity at each of the following glucose levels: hypoglycemia (60 mg/dL), normoglycemia/control (110 mg/dL), and hyperglycemia (300 mg/dL). Results revealed two performance groups. A convergent group displayed slower RT responding during hypoglycemia, consistent with the visual RT pattern of results. A divergent group displayed better responding on one RT measure during hypoglycemia, and generally poorer responding on all RT measures during the other glucose conditions. Subjects in the divergent group maintained more stringent metabolic control and tended to have experienced more episodes of hypoglycemic unconsciousness. The present results provide the first evidence that more stringent metabolic control may be related to generally slower rates of processing auditory information. Possible explanations for these findings include hypotheses of immutable structual derangement, state-dependent performance effects, and a U-shaped response curve.

Simple versus complex performance impairments at three blood glucose levels.

By using a visual reaction time paradigm, we sought to determine if disruption of relatively simple responding (finger tapping or letter recognition) or more complex responding (choice reaction time) would occur in response to blood glucose deviations. Glucose levels were maintained in 24 male diabetics to within 4% of the following targeted concentrations: 55 mg/dl (hypoglycemia), 110 mg/dl (euglycemia/control), and 300 mg/dl (hyperglycemia). The results indicate that simple motor and perceptual skills were not affected by blood glucose alterations, while more complex cognitive processing required significantly longer response latencies during hypoglycemia. Performance impairments occurred independently of disease duration and control, and without documented neuropathy, underscoring the sensitivity of some cognitive skills to acute glucose fluctuations.