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R H Haas

Publications and source records attributed to R H Haas.

At least 37 records · Page 2Linked to original sources
PubMed1995

Oxidative metabolism in Rett syndrome: 1. Clinical studies.

The etiology of Rett syndrome (RS) remains a mystery. The clinical phenotype has similarities to that of patients with mitochondrial defects of oxidative metabolism. There is evidence of lactate and pyruvate elevations in blood and CSF in some patients. Over the last 10 years we have studied girls with RS looking for evidence of a defect in oxidative metabolism. We present data on lactate and pyruvate blood measurements in 30 patients with RS with repeated measurements performed over time in many. Taken as a whole the means of measurements of lactate and pyruvate fall within the control range, however, individual patients have marked elevation of both lactate and pyruvate with considerable fluctuation over time. Nine girls with typical RS were studied in detail using a clinical protocol designed to identify disorders of oxidative metabolism. These patients underwent fasting for 24 hours, glucose loading and alanine loading tests. Seven girls had skin and muscle biopsies performed. One patient admitted with particularly high blood lactate levels underwent hourly blood collections over a 24 hour period during which state of alertness was noted and respiratory monitoring was performed. In this patient serial blood sampling for lactate performed. In this patient serial blood sampling for lactate performed with oxypneumocardiogram recording demonstrated a fall in plasma lactate to normal levels during sleep when the respiratory pattern was normal. Such fluctuations of plasma lactate apparently correlated with sleep/wake state and respiration suggest that in some patients with RS lactate elevations may arise from respiratory abnormalities. Other positive findings included prediabetic glucose responses in three girls. Ammonia levels following alanine loading were normal in all patients.

Adolescent↗
PubMed1995

Oxidative metabolism in Rett syndrome: 2. Biochemical and molecular studies.

In an attempt to identify a possible defect of mitochondrial metabolism in Rett syndrome we studied 9 girls with typical Rett syndrome using a clinical protocol designed to identify disorders of oxidative metabolism. One girl, (RO) had marked lactic acidemia. Biochemical studies on samples from these patients included leukocyte pyruvate carboxylase assay, serum biotinidase and skin fibroblast pyruvate production, pyruvate dehydrogenase, citrate synthetase and 2-oxoglutarate dehydrogenase assay. Muscle electron transport activities were studied on samples from 4 typical Rett patients including RO. Mitochondrial DNA (mtDNA) mutational analysis for the np3243 MELAS mutation, the np8993 NARP mutation, the np8344 MERFF mutation and the 4977 kb common deletion found in Kearns-Sayre syndrome and aged tissues were tested for in 1 of the muscle samples and 2 blood samples from typical Rett patients. Western blotting of electron transport complex III was performed on mitochondrial samples obtained from autopsy brain tissue in 2 Rett patients and compared to pediatric control brain samples. No abnormalities were found in blood biotinidase or pyruvate carboxylase. Western blotting of 2 Rett brain mitochondrial samples for complex III appear normal. Pyruvate consumption in medium from 8 Rett fibroblast lines grown with and without dichloroacetate (DCA) showed a normal fall in pyruvate suggesting normal pyruvate dehydrogenase activity in these cells, however the fibroblasts from patient RO had a high pyruvate production in culture. Pyruvate dehydrogenase, 2-oxo-glutarate dehydrogenase and citrate synthetase activities in 8 Rett fibroblast lines were normal.(ABSTRACT TRUNCATED AT 250 WORDS)

Blotting, Western↗
PubMed1995

Neuropharmacology of progressive myoclonus epilepsy: response to 5-hydroxy-L-tryptophan.

Low concentrations of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) in cerebrospinal fluid (CSF) of patients with progressive myoclonus epilepsy (PME) suggest hypofunctional serotonergic neurotransmission. To study this hypothesis, we enrolled 6 patients with PME [Unverricht-Lündborg disease (U-L), mitochondrial encephalomyopathy, or Lafora disease] in a controlled, double-blinded, dose-ranging, cross-over add-on pilot clinical trial of 5-hydroxy-L-tryptophan (L-5-HTP) plus carbidopa after 2 other patients had received open-label L-5-HTP for compassionate use. Prestudy CSF 5-HIAA concentrations were low (< 20 ng/ml) in 6 patients regardless of the etiology of PME. One patient with U-L disease showed clinical improvement and a fivefold increase in CSF 5-HIAA, and 1 with Lafora disease showed a twofold increase in CSF 5-HIAA without improvement. A patient with Lafora disease reported enough improvement in myoclonus-evoked convulsions to continue chronic use of the drug. One patient with mitochondrial encephalomyopathy developed status epilepticus during treatment with L-5-HTP. As a group, patients had no statistically significant changes in myoclonus evaluation scale scores, subjective and objective measures of ataxia, seizure frequency, antiepileptic drug (AED) levels, or routine blood tests. These data suggest a serotonergic abnormality regardless of the underlying etiology of PME, but one that seldom responds to acute treatment with L-5-HTP.

5-Hydroxytryptophan↗
PubMed1995

Acute basal ganglia infarction in propionic acidemia.

An 8-year-old girl with propionic acidemia had acute and rapidly fatal symmetric necrosis of the caudate, globus pallidus, and putamen. Clinical presentation was with acute aphasia, generalized hypotonia, and muscle weakness. There was no evidence of metabolic decompensation, and analysis of the organic acids of the urine indicated good metabolic control. Organic acids in the cerebrospinal fluid were unremarkable. These observations indicate that the pathophysiology of "metabolic stroke" is more complicated than previously thought.

Age of Onset↗
PubMed1995

Neuropathology of propionic acidemia: a report of two patients with basal ganglia lesions.

Propionic acidemia is a rare genetic disorder of amino acid metabolism caused by deficient activity of propionyl coenzyme A carboxylase. Neuropathologic changes previously reported in infants have been white-matter vacuolization or spongiosis. In children who survive beyond infancy, abnormalities have been found primarily in the basal ganglia. We report neuropathologic findings in two patients with propionic acidemia diagnosed in infancy who survived 35 months and 9 years, respectively. Examination of the brain of the 35-month-old boy showed vascular and parenchymal mineralization, focal pallor and spongy change, and foci of acute neuronal injury. These changes were similar to those previously described. The 9-year-old girl was in good metabolic control when she died, and presented a neuropathologic picture not previously described. She was found at autopsy to have acute hemorrhagic lesions in the caudate, putamen, and globus pallidus bilaterally and in the left ventral thalamus. There was focal neuronal loss, but no acute hypoxic/ischemic neuronal injury. Vascular proliferation and swollen endothelial cells were seen in the basal ganglia, thalamus, and substantia nigra, but not in other regions of the brain. Electron microscopy showed swelling of endothelial cells with viable adjacent brain parenchyma. The endothelial changes suggest a breakdown of the blood-brain barrier.

Basal Ganglia Diseases↗
PubMed1995

Carbidopa/levodopa and selegiline do not affect platelet mitochondrial function in early parkinsonism.

Previous studies have demonstrated impaired complex I activity in platelets from Parkinson's disease (PD) patients who were receiving levodopa and other medications for their disease. Eleven patients with early PD underwent three sequential plateletphereses: while on no medication, after receiving carbidopa/levodopa for 1 month, and after receiving carbidopa/levodopa plus selegiline for 1 additional month. As expected, carbidopa/levodopa and selegiline significantly improved motor function in these patients. Treatment with carbidopa/levodopa alone and carbidopa/levodopa plus selegiline did not affect the activities of complexes I, II/III, and IV and citrate synthetase. These observations support the hypothesis that impaired complex I activity in PD patients is a characteristic of the disease and not due to medications.

Adult↗
PubMed1994

Impairment in shifting attention in autistic and cerebellar patients.

MRI and autopsy evidence of early maldevelopment of cerebellar vermis and hemispheres in autism raise the question of how cerebellar maldevelopment contributes to the cognitive and social deficits characteristic of autism. Compared with normal controls, autistic patients and patients with acquired cerebellar lesions were similarly impaired in a task requiring rapid and accurate shifts of attention between auditory and visual stimuli. Neurophysiologic and behavioral evidence rules out motor dysfunction as the cause of this deficit. These findings are consistent with the proposal that in autism cerebellar maldevelopment may contribute to an inability to execute rapid attention shifts, which in turn undermines social and cognitive development, and also with the proposal that the human cerebellum is involved in the coordination of rapid attention shifts in a fashion analogous to its role in the coordination of movement.

Adolescent↗
PubMed1994

Abnormality of cerebellar vermian lobules VI and VII in patients with infantile autism: identification of hypoplastic and hyperplastic subgroups with MR imaging.

OBJECTIVE: Infantile autism is a neurobehavioral disorder that is widely believed to have etiologically distinct subtypes, including subtypes with a genetic basis, but no neuroanatomic evidence firmly supports this belief. To date, only one type of cerebellar abnormality has been identified in patients with autism: hypoplasia of the vermis and hemispheres. By using a large sample of autistic patients and healthy volunteers along with precise MR imaging and quantitative procedures, we sought to replicate previous reports of cerebellar vermian hypoplasia in autism and to identify additional subtypes of cerebellar abnormality. MATERIALS AND METHODS: Using MR technology, we imaged and measured posterior and anterior vermian regions in 50 autistic patients (2-40 years old) and 53 healthy control subjects (3-37 years old). The autistic patients had social, language, cognitive, behavioral, and medical history characteristics that were typical of the general autistic population. By using precise procedures for positioning and aligning MR slices, we obtained comparable MR images within and across subject groups. RESULTS: Statistical analyses showed two subgroups of autistic patients, one (86% of the patients) with findings consistent with vermian hypoplasia and another (12% of the patients) with evidence of vermian hyperplasia. The hypoplasia subgroup included 43 patients whose mean midsagittal area for vermian lobules VI and VII was 237 +/- 38 mm2, and the hyperplasia subgroup included six patients whose mean area was 377 +/- 12 mm2. Thus, the area of lobules VI and VII in the hypoplasia subgroup was 16% smaller than the mean area in the control subjects (282 +/- 42 mm2) (p < .0001), whereas that in the hyperplasia subgroup was 34% larger (p < .0001). Analyses showed that these two subtypes of vermian abnormalities were present across all ages of autistic patients studied. CONCLUSION: Two different subtypes of autistic patients can be identified on the basis of the presence of vermian hypoplasia or hyperplasia as seen on MR images. Possible origins for vermian hypoplasia include environmental trauma and genetic factors.

Adolescent↗
PubMed1992

Cerebellar and cerebral abnormalities in Rett syndrome: a quantitative MR analysis.

Rett syndrome is a neurodegenerative disease of young girls that begins in early childhood with autismlike behavior and loss of language skills, and progresses with marked deterioration of the motor system in the second decade of life. The purpose of this study was to determine if neuroanatomic changes detected with MR imaging could help to explain the clinical presentation and progression of signs and symptoms in these patients. Accordingly, computer-assisted planimetry was used to measure various dimensions of cerebral, cerebellar, and brainstem structures on sagittal and transverse MR images of 13 patients with Rett syndrome and 10 healthy volunteers. Dimensions of the cerebrum, basal ganglia, cerebellum, and brainstem were measured on transverse images. Areas of cerebellar vermian lobules, the fourth ventricle, the pituitary gland, and the corpus callosum were measured on sagittal images. Fourteen dimensions and areas were measured in each patient and each control subject; according to two-tailed Student's t tests, all but two values were significantly smaller in the patients with Rett syndrome than in control subjects. Graphing the measurements against age by using simple linear regression revealed progressive cerebellar atrophy without evidence of atrophy of the brainstem or cerebrum. Our results indicate that patients with Rett syndrome have global hypoplasia of the brain and progressive cerebellar atrophy increasing with age. Cerebellar atrophy with age may contribute to the deterioration of the motor system seen in older patients with Rett syndrome.

Adolescent↗
PubMed1989

Cardiac function, substrate utilization, and myocardial energy metabolism studied with 31-P NMR spectroscopy during acute hypoglycemia and hyperketonemia.

Whether severe hypoglycemia alone or in combination with hyperketonemia might cause deterioration of cardiac function has been controversial. Therefore, the influence of acute hypoglycemia (mean 33 mg/dL) with and without hyperketonemia (mean 1.3 and 3.3 mM) on cardiac function, substrate utilization, and myocardial high energy phosphate levels was studied in 10 mongrel dogs. After 45 min of hypoglycemia, mean aortic pressure, total peripheral resistance, and myocardial oxygen consumption had increased significantly, but other hemodynamic parameters and regional myocardial function had not changed. Additional infusion of 3-hydroxybutyrate did not affect hemodynamic variables significantly. During both metabolic interventions in vivo phosphorus-31 nuclear magnetic resonance spectroscopy showed stable levels of myocardial phosphocreatinine, ATP, as well as the phosphocreatinine/ATP (3.0-3.2) ratio. Biochemical measurements revealed that hyperketonemia led to significant alterations in arterial concentrations and arteriocoronary venous differences of selected citric acid cycle intermediates, thus confirming previous reports which suggested a blockade of the 2-oxoglutarate-dehydrogenase reaction induced by ketone body oxidation. However, despite this blockade, the energy supply to the heart was not impaired as shown by normal nuclear magnetic resonance spectroscopy and cardiac performance. It is speculated, that the blockade might be due to an enhanced NADH/NAD ratio.

Adenosine Triphosphate↗
PubMed1988

High-performance liquid chromatographic measurement of selected blood citric acid cycle intermediates.

We describe a high-performance liquid chromatographic (HPLC) method for analysis of the intermediates of the citric acid cycle. Using two Aminex HPX-87H columns in series at 36 degrees C, the early eluting compounds cis-aconitate, oxaloacetate, alpha-ketoglutarate and citrate-isocitrate can be resolved. Acetonitrile is used for extraction of citric acid cycle intermediates from blood as interfering ultraviolet absorbing peaks are present with perchloric acid or trichloroacetic acid extraction. Acetonitrile extraction is compared with perchloric acid extraction of citric acid cycle intermediates from plasma. Low recovery of some organic acids from blood seems not to be due to enzymatic degradation. Storage of acetonitrile extracts in liquid nitrogen led to a small but significant decrease in pyruvate levels in human blood. However, significant changes in other organic acids were not seen. HPLC methodology allows study of the citric acid cycle in tissue samples as well as blood and promises to facilitate the investigation of human disorders of energy metabolism.

Acetonitriles↗
PubMed1988

Pyruvate dehydrogenase activity in osmotically shocked rat brain mitochondria: stimulation by oxaloacetate.

Pyruvate dehydrogenase complex activity (PDHC) measured by CO2 release isotopic assay has generally been much lower than activity measured by the spectrophotometric arylamine acetyltransferase assay (ArAT). Decarboxylation of [1-14C]pyruvate was measured in osmotically shocked rat brain cortical mitochondria. Activity is dependent on the concentration of the substrate pyruvate. Activity of 74.6 units +/- 12.3 SD (n = 22) was observed at 4 mM pyruvate (1 unit = 1 nmol pyruvate decarboxylated/min/mg protein). Activity was dependent on added NAD, CoA, and thiamine pyrophosphate, implying increased mitochondrial permeability after osmotic shock. Freeze/thaw with sonication of the mitochondrial preparation reduced PDHC activity to 11.5 units +/- 3.0 SD (n = 4). Oxaloacetate produced a marked stimulation of activity. The optimal assay contained 3 mM oxaloacetate, and without oxaloacetate activity fell to 15.4 units +/- 9.9 SD (n = 8). These studies highlight the importance of optimal substrate concentrations in the CO2 release isotopic PDHC method. Higher PDHC activity is found with intact mitochondria and thus activity values should be interpreted in the light of the presence or absence of intact mitochondria in individual preparations.

Animals↗
PubMed1988

The history and challenge of Rett syndrome.

Rett syndrome was first described in 1966 by Dr Andreas Rett, who reported in German his findings in 22 patients. Recognition of the syndrome grew slowly until 1983, when a series of 35 patients from several countries was reported in English. By 1987, the number of known cases had grown to over 1,250 worldwide, the International Rett Syndrome Association had been founded, and international conferences on the syndrome were being held regularly. Although a developmental staging system has been devised, many questions remain concerning the course of the disease. Rett syndrome poses a challenge to the physicians, therapists, psychologists, educators, and families involved with affected patients, as well as to researchers investigating the syndrome.

Ammonia↗
PubMed1988

Cognitive profile of Rett syndrome.

We report preliminary studies in 18 girls with Rett syndrome (15 typical, three atypical cases) who were studied using a number of neuropsychologic measures. Results indicate a relative preservation of gross motor and daily living skills at the developmental level of the age of onset of the condition. Other adaptive functions were more depressed. Higher levels of object permanency were found in this population than reported previously. Our results indicate that islands of motor and intellectual function persist in Rett syndrome patients. These data may be useful for therapeutic intervention.

Adolescent↗
PubMed1988

Peripheral nerve findings in Rett syndrome.

Sural nerve and peroneus brevis muscle biopsies were studied in 12 patients with Rett syndrome, ten with the typical form of the disorder according to 1985 criteria, and two with atypical features. Ages ranged from 23 months to 25 years. All stages of the disease were represented. There was evidence of a mild axonal neuropathy in seven of 12 patients. Degenerative and occasional regenerative changes were seen in five sural nerve biopsies, including one from the youngest patient in the series, who was normally nourished and fully ambulatory. Occasional nonspecific ultrastructural abnormalities were present, including accumulation of pi granules in Schwann cells and Hirano bodies within axons. However, morphometric analysis of the four nerves in which these alterations were most prominent showed a normal density and size distribution of myelinated fibers. Enzyme histochemistry of the peroneus brevis biopsies demonstrated abnormal predominance of type II muscle fibers in three of the 12 biopsies and atrophy of type I fibers in one patient.

Adolescent↗
PubMed1988

The nutritional aspects of Rett syndrome.

Nutrition is a major problem for the Rett patient. We have studied 21 girls with Rett syndrome (19 typical, two atypical). We report our experience in this population with the nutritional aspects of Rett syndrome, the typical dietary habits, and various nutritional deficiencies. Further experience with the use of high fat diets is reported.

Adolescent↗