Faculty Bibliography

Globoid cell leukodystrophy is an autosomal recessive inherited disease caused by deficiency of the lysosomal enzyme galactocerebrosidase (GALC). Although the severe, rapidly progressing infantile form is the most common, late-onset forms have been described. We investigated the molecular basis of GALC deficiency in a patient with a late-life mild form of globoid cell leukodystrophy who survived into the eighth decade. Since material suitable for mutation analysis was no longer available from the proband, her GALC genotype was reconstructed by analyzing this gene in her six obligate carrier offspring. One allele contained the mutation 809G>A (G270D) in the 1637C background, while the other allele contained three sequence variants: 1609G>A (G537R), 1873G>A (A625T), and 1650T>A (V550V) in the 1637T background. These mutations were confirmed in the proband's genomic DNA isolated from a sural nerve biopsy. Expression studies indicated that the G537R is a disease-causing mutation, as it resulted in no GALC activity, either alone or together with the A625T. This A625T sequence variant did not affect the enzyme activity, at least when expressed in the 1637T background. The mild clinical phenotype was likely to be associated with the 809G>A, since residual GALC activity, about 17% of the control activity, was detected in the expression studies of this mutation. This mutation has been found in several other patients with late-onset GLD.

Quantitative Thermotesting evaluates peripheral small nerve fiber function. The method of limits is a widely used algorithm of perception threshold determination. Normative data are needed to apply the method of limits in children and juveniles. In 225 healthy boys and girls, aged 7 to 17.9 years, warm and cold perception thresholds were established with the method of limits at the volar distal forearm, the thenar eminence, the lower medial calf, the lateral dorsal foot, and the cheek. A 1 degree C/s stimulus velocity, a 32 degrees C thermode baseline, and a 1.5-cm x 2.5-cm Thermotest stimulator were used. Accuracy of stimulus perception was studied by comparing the lowest to the highest response of five consecutive stimuli. The influence of different stimulator sizes on thresholds was tested at the lower calf and distal forearm with an additional 2.5-cm x 5.0-cm thermode. To determine the impact of the pretest skin temperature on thresholds, skin temperature was correlated with thresholds. Results showed good intratrial reproducibility of thresholds. The large thermode yielded lower thresholds than the small probe. Skin temperature had only minor influence on thresholds. The large probe should be used at body sites where it adjusts planely

BACKGROUND: Timely diagnosis and continued monitoring of patients with type I Gaucher disease is critical because skeletal involvement can permanently disable patients and visceral organ involvement can lead to abdominal pain and secondary hematologic and biochemical complications. OBJECTIVE: To seek clinical consensus for minimum recommendations for effective diagnosis and monitoring of patients with type I Gaucher disease. PARTICIPANTS, EVIDENCE, AND CONSENSUS PROCESS: Contributing authors collaborated in quarterly meetings over a 2-year period to synthesize recommendations from peer-reviewed publications and their own medical experiences. These physicians care for most patients with Gaucher disease in the United States and serve as the US Regional Coordinators for the International Collaborative Gaucher Group Registry, the world's largest database for this disorder. CONCLUSIONS: The definitive method of diagnosis is enzyme assay of beta-glucocerebrosidase activity. Schedules differ for monitoring complications of type I Gaucher disease, depending on symptoms and whether enzyme replacement therapy is used. Hematologic and biochemical involvement should be assessed by complete blood cell count, including platelets, acid phosphatase, and liver enzymes, at baseline and every 12 months in untreated patients and every 3 months and at enzyme replacement therapy changes in treated patients. Visceral involvement should be assessed at diagnosis using magnetic resonance imaging or computed tomographic scans. Skeletal involvement should be assessed at diagnosis using T1- and T2-weighted magnetic resonance imaging of the entire femora and plain radiography of the femora, spine, and symptomatic sites. Follow-up skeletal and visceral assessments are recommended every 12 to 24 months in untreated patients, and every 12 months and at enzyme replacement therapy changes in treated patients

OBJECTIVE: Patients with familial dysautonomia have an increased risk of sudden death. In some patients with familial dysautonomia, sympathetic cardiac dysfunction is indicated by prolongation of corrected QT (QTc) interval, especially during stress tests. As many patients do not tolerate physical stress, additional indices are needed to predict autonomic risk. In familial dysautonomia there is a reduction of both sympathetic neurons and peripheral small nerve fibres which mediate temperature perception. Consequently, quantitative thermal perception test results might correlate with QTc values. If this assumption is correct, quantitative thermotesting could contribute to predicting increased autonomic risk. METHODS: To test this hypothesis, QTc intervals were determined in 12 male and eight female patients with familial dysautonomia, aged 10 to 41 years (mean 21.7 (SD 10.1) years), in supine and erect positions and postexercise and correlated with warm and cold perception thresholds assessed at six body sites using a Thermotest. RESULTS: Due to orthostatic presyncope, six patients were unable to undergo erect and postexercise QTc interval assessment. The QTc interval was prolonged (>440 ms) in two patients when supine and in two additional patients when erect and postexercise. Supine QTc intervals correlated significantly with thermal threshold values at the six body sites and with the number of sites with abnormal thermal perception (Spearman's rank correlation p<0.05). Abnormal Thermotest results were more frequent in the four patients with QTc prolongation and the six patients with intolerance to stress tests. CONCLUSION: The results suggest that impaired thermal perception correlates with cardiac sympathetic dysfunction in patients with familial dysautonomia. Thus thermotesting may provide an alternative, albeit indirect, means of assessing sympathetic dysfunction in autonomic disorders

INTRODUCTION: The concept of the mucolipidoses developed as the result of encounters with patients whose clinical appearance suggested a mucopolysaccharidosis, i.e. coarse facies, short stature, skeletal dysplasia, joint contractures and lysosomal accumulations but did not have an excess of mucopolysaccharides in their urine. DEVELOPMENT: This clinical phenotype embraces the early onset forms of sialidosis (mucolipidosis I), as well as I-cell disease (mucolipidosis II) and pseudoHurler polydystrophy (mucolipidosis III). Two disorders that were later added to the mucolipidoses, the Cherry-red Spot Myoclonus Epilepsy Syndrome (sialidosis type I) and mucolipidosis IV differ in that the facial appearance is normal and they do no have skeletal dysmorphism. Enzyme deficiencies have been identified in mucolipidosis I, II and III. The basic molecular cause of mucolipidosis IV is not known but linkage analysis is underway to identify the chromosomal map position of the defective gene. Precise diagnosis of these autosomal recessively inherited diseases depends upon radiographic studies for skeletal dysplasias, analyses of urine for sialyloligosaccharides, morphologic studies of bone marrow and skin biopsy specimens and enzymatic determinations of sialidase and UDP-N-acetylglucosamine: lysosomal enzyme N-acetylglucosamine-1-phosphotransferase. CONCLUSIONS: Case descriptions from the author's experience are presented to illustrate the use of a decision tree employing these diagnostic modalities. The existence of naturally-occurring animal models for sialidase deficiency (SM/J mouse) and the phosphotransferase deficiency (mucolipidosis III cat) provide opportunities to develop new therapeutic approaches

BACKGROUND: Earlier approaches to pallidotomy for refractory Parkinson's disease had significant complication rates. More recent approaches show fewer complications, but the effect of pallidotomy on cognition is unclear. The current study was conducted to examine the neuropsychological effects of unilateral pallidotomy. METHODS: Neuropsychological testing was performed on patients with medically refractory, predominantly unilateral Parkinson's disease at baseline and after unilateral ventral pallidotomy (n=28) or after an equivalent period without surgery in control patients (n=10). RESULTS: Pallidotomy patients showed no significant changes from baseline to retesting relative to the control group for any measure. Across all of the tests administered, only five of the surgery patients showed a significant decline, and of these five none declined on more than one test. Depression did not relate to preoperative or postoperative cognition. The pallidotomy group showed a significant improvement in motor functioning and activities of daily living whereas the control group did not. These measures were not associated with the neuropsychological test scores at baseline or retest. CONCLUSIONS: Stereotactic unilateral ventral pallidotomy does not seem to produce dramatic cognitive declines in most patients

The clinical features of four families with autosomal dominant spastic paraparesis (FSP) are described, along with the results of linkage analysis to markers from the regions of chromosomes 2, 14, and 15 which are known to contain spastic paraplegia genes. All families had 'pure' spastic paraparesis (FSP), but the severity of symptoms varied widely among families, and other mild neurologic signs were observed in some subjects. Although no family individually yielded a lod score >3.0, all families yielded positive lod scores with chromosome 2 markers, and a maximal lod score of 5.7 was obtained for the families combined using marker D2S352. There was no evidence of linkage to chromosome 14 or 15 in any of the families

BACKGROUND: Globoid-cell leukodystrophy is caused by a deficiency of galactocerebrosidase, which results in progressive central nervous system deterioration. We investigated whether allogeneic hematopoietic stem-cell transplantation can provide a source of leukocyte galactocerebrosidase and thereby prevent the decline of central nervous system function in patients with the disease. METHODS: Five children with globoid-cell leukodystrophy (one with the infantile type and four with late-onset disease) were treated with allogeneic hematopoietic stem-cell transplantation. Measurement of leukocyte galactocerebrosidase levels, neurologic examinations, neuropsychological tests, magnetic resonance imaging of the central nervous system, cerebrospinal fluid protein assays, and neurophysiologic measurements were performed before and after transplantation, with follow-up ranging from one to nine years. RESULTS: Engraftment of donor-derived hematopoietic cells occurred in all patients and was followed by restoration of normal leukocyte galactocerebrosidase levels. In the four patients with late-onset disease, the central nervous system deterioration was reversed, and in the patient with the infantile form of the disease, signs and symptoms have not appeared. Magnetic resonance imaging showed a decrease in signal intensity in the three patients with late-onset disease who were assessed both before and after transplantation. Abnormalities in cerebrospinal fluid total protein levels were corrected in three patients with late-onset disease and substantially reduced in the patient with the infantile form. CONCLUSIONS:Central nervous system manifestations of globoid-cell leukodystrophy can be reversed by allogeneic hematopoietic stem-cell transplantation