Miglustat in late-onset Tay-Sachs disease: a 12-month, randomized, controlled clinical study with 24 months of extended treatment.

PURPOSE: To evaluate the safety and efficacy of miglustat in patients with GM2 gangliosidosis. METHODS: A randomized, multicenter, open-label, 12-month study involving patients aged 18 years or older, randomized 2:1 to miglustat (200 mg TID) or "no miglustat treatment." This study was followed by 24 months of extended treatment during which all patients received miglustat. Primary efficacy endpoints were change in eight measures of isometric muscle strength in the limbs and isometric grip strength, evaluated at baseline, and months 12 and 36. Secondary efficacy endpoints included gait, balance, disability, and other neurological assessments. Safety evaluations included adverse event reporting. RESULTS: Thirty patients (67% male, age range 18-56 years) with late-onset Tay-Sachs disease were enrolled; 20 were randomized to miglustat and 10 to "no miglustat treatment." Muscle and grip strength generally decreased over the study period. No differences were observed between the two groups in any efficacy measure, either during the 12-month randomized phase or the full 36 months. The most common treatment-related adverse events were decrease in weight and diarrhea. CONCLUSION: Miglustat treatment was not shown to lead to measurable benefits in this cohort of patients with late-onset Tay-Sachs disease. The observed safety profile was consistent with that of the approved dose (100 mg TID) in type 1 Gaucher disease.

Clinical features of MCI: motor changes.

Mild cognitive impairment (MCI) is a classification reserved for nondemented elderly individuals at increased risk for future decline to dementia, compared to those with normal cognition. Cognitive tests, particularly those assessing verbal recall, have been found to be useful in the identification of elderly people with MCI. We argue that a variety of motor/psychomotor evaluations are also sensitive to MCI. Motor assessments described as complex correctly categorize normal versus MCI elderly with comparable accuracies to those obtained by cognitive tests. Unlike performance on verbally based cognitive measures, motor-test scores appear to be relatively independent of educational attainment, indicating that the use of certain motor tests may be particularly valuable in the identification of MCI among elderly with widely varying educational backgrounds.

MR imaging and proton spectroscopy of neuronal injury in late-onset GM2 gangliosidosis.

BACKGROUND AND PURPOSE: Despite the ubiquity of G(M2) gangliosides accumulation in patients with late-onset G(M2) gangliosidosis (G(M2)G), the only clinical MR imaging-apparent brain abnormality is profound cerebellar atrophy. The goal of this study was to detect the presence and assess the extent of neuroaxonal injury in the normal-appearing gray and white matter (NAGM and NAWM) of these patients. METHODS: During a single imaging session, 9 patients with late-onset G(M2)G and 8 age-matched normal volunteers underwent the following protocol: (1) T1- and T2-weighted and fluid-attenuated inversion recovery MR images, as well as (2) multivoxel proton MR spectroscopy (1H-MR spectroscopy) to quantify the distribution of the n-acetylaspartate (NAA), creatine (Cr), and choline (Cho), were obtained. RESULTS: The patients' NAA levels in the thalamus (6.5 +/- 1.9 mmol/L) and NAWM (5.8 +/- 2.1 mmol/L) were approximately 40% lower than the controls' (P = .003 and P = .005), whereas the Cr and Cho reductions ( approximately 30% and approximately 26%) did not reach significance (P values of .06-.1). All cerebellar metabolites, especially NAA and Cr, were much (30%-90%) lower in the patients, which reflects the atrophy. CONCLUSION: In late-onset G(M2)G, NAA decreases are detectable in NAGM and NAWM even absent morphologic (MR imaging) abnormalities. Because the accumulation of G(M2) gangliosides can be reduced pharmacologically, 1H-MR spectroscopy might be a sensitive and specific for detecting and quantifying neuroaxonal injury and monitoring response to emerging treatments.

Late-onset Tay-Sachs disease: phenotypic characterization and genotypic correlations in 21 affected patients.

PURPOSE: The purpose of this study was to describe the phenotype (and corresponding genotype) of adult patients with late-onset Tay-Sachs disease, a clinical variant of the GM2-gangliosidoses. METHODS: A comprehensive physical examination, including neurological assessments, was performed to establish the current disease pattern and severity. In addition, the patients' past medical histories were reviewed. The patients' alpha-subunit mutations (beta-Hexosaminidase A genotype) were determined and correlated with their corresponding clinical findings and disease course. RESULTS: Twenty-one patients (current mean age: 27.0 years; range: 14-47 years) were identified. The pedigree revealed a relative with the "classic" infantile or late-onset form of Tay-Sachs disease in four (out of 18) unrelated families. The patients were predominantly male (15/21 individuals) and of Ashkenazi Jewish ancestry (15/18 families). Mean age at onset was 18.1 years; balance problems and difficulty climbing stairs were the most frequent presenting complaints. In several cases, the diagnosis was delayed (mean age at diagnosis: 27.0 years). Analysis of the beta-hex A gene revealed the G269S mutation as the most common disease allele; found in homozygosity (N = 1) or heterozygosity (N = 18; including 2 sib pairs). Disease onset (age 36 years) was delayed and progression relatively slower in the homozygous G269S patient. Two siblings (ages 28 and 31 years), of non-Jewish ancestry, were compound heterozygotes (TATC1278/W474C); their clinical course is dominated by psychiatric problems. Brain imaging studies revealed marked cerebellar atrophy in all patients (N = 18) tested, regardless of disease stage. CONCLUSIONS: Late-onset Tay-Sachs disease is an infrequent disorder and the diagnosis is often missed or delayed (by approximately 8 years). Early on, the majority of patients develop signs of either cerebellar or anterior motor neuron involvement. Affected individuals may also develop psychotic episodes. In most cases, the later-onset of expression results from the presence of at least one allele (usually the G269S mutation), associated with residual enzyme (beta-hexosaminidase A) activity. A positive family history is a valuable clue, enabling early diagnosis. Nonspecific cerebellar atrophy on brain imaging is another important finding. This entity should be considered among patients presenting with speech, gait, and balance problems, and those with psychiatric disorders even when focal neurologic deficits may be initially absent. Accurate diagnosis will permit appropriate genetic counseling regarding disease prognosis and reproductive risks.

Test-retest reliability of the seated Functional Rotation Test in people with Parkinson's disease: a preliminary study.

This study established the test-retest reliability of a seated Functional Rotation Test monitoring hand-pointing, together with head and trunk-rotation performance, in people with Parkinson's disease. An ancillary purpose was to establish the concurrent validity between the Functional Rotation Test and an electrogoniometer. 10 males with Parkinson's disease (M age=70.5 yr.; Hoehn and Yahr staging severity ranging from II to IV) were recruited. Subjects were fitted with laser-pointing devices, sat in the Functional Rotation room, and were instructed to turn actively and point to their right (or left) as far as they could comfortably manage. Tagged projections were scored (in degrees). Testing was repeated after a brief interval. Electrogoniometer projected locations were compared with Functional Rotation Test scores. Intraclass correlation coefficients (.91 to .97) indicated excellent test-retest reliability. There was also excellent agreement between electrogoniometric and Functional Rotation Test values (Intraclass correlation coefficients=.99). Thus the Functional Rotation Test provides a replicable measure of axial rotation of head, trunk, and hand-pointing in seated subjects with Parkinson's disease.

Test-retest reliability in performance of persons with hemiparesis tracking by means of compatibly displayed myoelectric feedback derived from upper limb muscles.

The aim of this study was to assess whether persons with hemiparesis will yield statistically reliable test-retest tracking performance on a procedure using limb-generated, compatibly displayed, myoelectric video feedback. A convenience sample of 50 inpatients and outpatients with upper extremity involvement of at least six months were recruited. 30 had hemiparesis and had both upper extremities tested. 20 had hemiplegia and had the nonparetic upper extremity tested. Tracking skill was measured as mean tracking error. Repeated measures analysis of variance yielded statistically significant effects of main factors: Response mode, Cursor Feedback, and Session. Extremity tested was not significant. Performance with involved limb, uninvolved limb, isometric mode, and isotonic mode all yielded positive rest-retest correlations. The reliable range of tracking error obtained from subjects with hemiparesis performing a task requiring modulation of compatibly displayed myoelectric output supports the therapeutic rationale for employing compatibly displayed video feedback in the rehabilitation of motor control.

Test-retest reliability of the functional rotation test in healthy adults.

Test-retest reliability and concurrent validity for a Functional Rotation Test, developed as a clinical tool for quantifying the extent of body rotation while sitting or standing, were evaluated with healthy adults in this study. Participants, ages 20 to 72 years (n = 36) donned laser-pointing devices, stood or sat in the center of a room calibrated for the test, and actively turned and pointed to the right (or left) as far as they could comfortably. The locations of the lasers were recorded and subsequently scored. Testing was repeated after a brief rest. Concurrent measurements between a clinical goniometer and the Functional Rotation Test were also compared. Intraclass correlation coefficients (ICCs) indicated good to excellent test-retest reliability indices, ranging from .89 to .96 for standing and .87 to .95 for sitting tests. Agreement between the Functional Rotation Test and the goniometer was excellent (ICC = 1.0). The relevance and possible applications of the Functional Rotation Test are discussed.