Faculty Bibliography

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

Abstract BACKGROUND:: The substrate synthesis inhibitor miglustat (N-butyldeoxynojirimycin) is the first oral agent to receive regulatory approval for the treatment of type I Gaucher disease (GD). OBJECTIVES:: The aims of this study were to further assess previous observations of the effects of miglustat in adult patients with mild to moderate type I GD and to evaluate the tolerability and safety profile of this drug. METHODS:: This was a noncomparative, open-label study in adult patients with type I GD (confirmed by genotyping and glucocerebrosidase assay) who were unwilling or unable to receive enzyme replacement therapy (ERT) or who had discontinued ERT for at least 3 months. Patients received miglustat 100 mg TID for 12 months, with the option of continuing treatment for a further 12 months. The primary end point was the percentage change in liver volume. Secondary end points included the percentage change in spleen volume and changes in hematologic parameters (hemoglobin, platelets), chitotriosidase activity (a surrogate marker of disease burden), and bone assessments (dual-energy X-ray absorptiometry, magnetic resonance imaging, and radiography). Clinical safety was monitored, including assessment of neurologic status at baseline and throughout the study using a comprehensive battery of standardized neurologic tests (eg, Purdue Pegboard Test, Mini-Mental State Examination, nerve conduction studies) and neuropsychological tests. RESULTS:: Of the 10 patients (7 men, 3 women) who received at least 1 dose of miglustat, 7 completed 24 months of treatment. Patients were aged between 32 and 62 years (mean, 46.3 years) and weighed between 55 and 88 kg (mean, 72.4 kg). All patients had at least 1 manifestation of GD, including 10 with splenomegaly (mean size, 8.1 times normal; range, 3.9-15.9 times normal), 9 with thrombocytopenia, and 8 with hepatomegaly (mean size, 1.5 times normal; range, 1.0-2.0 times normal). At baseline, hemoglobin concentrations ranged from 11.5 to 15.1 g/dL (mean, 13.2 g/dL), platelet counts from 55 to 161 x 10(9)/L (mean, 83.8 x 10(9)/L), and chitotriosidase activity from 526 to 29636 nmol/mL . h (mean, 8143.7 nmol/mL . h). In the 8 patients comprising the efficacy set, significant mean percentage changes from baseline in liver volume were seen at 6 months (-8.4%; P = 0.036; 95% CI, -16.1 to -0.7) and 18 months (-15.1%; P = 0.022; 95% CI, -27.1 to -3.0). Although not statistically significant, the 95% CIs for the percentage changes in liver volume at 12 months (-9.4%; 95% CI, -19.5 to 0.6) and 24 months (-5.6%; 95% CI, -12.1 to 1.0) were similar to those at 6 and 18 months, supporting a consistent clinical effect. Significant mean percentage reductions in spleen volume were observed at 6 months (-19.0%; P = 0.006; 95% CI, -30.4 to -7.6) and 18 months (-24.3%; P = 0.001; 95% CI, -33.6 to -15.1). Mean hemoglobin concentrations, which were normal at baseline, remained stable over the course of the study. There were no significant changes in bone status. There was a significant mean increase in absolute platelet count at 12 months (by 13.9 x 10(9)/L; P = 0.030; 95% CI, 1.8 to 26.0); at 24 months, the mean percentage increase from baseline (23.0%) was not statistically significant. The mean percentage reduction from baseline in chitotriosidase activity at 24 months was 25.3%. Treatment was well tolerated, and the incidence of most adverse events decreased with time. Gastrointestinal and central nervous system adverse events reported during 3-month periods at the beginning (0-3 months) and end (>21-24 months) of the study were flatulence (10 and 2 patients, respectively), diarrhea (9 and 0), abdominal pain (7 and 1), tremor (4 and 1), paresthesia (3 and 0), headache (2 and 3), and abdominal distention (2 and 0). No evidence of clinically significant adverse effects on neurologic or neuropsychological function was found during the study. CONCLUSIONS:: In this small study in symptomatic adult patients with type I GD, miglustat treatment resulted in a significant decrease in liver and spleen volume at 6 and 18 months, with clinical improvement noted over 24 months. Bone involvement and platelet and hemoglobin values remained stable, with no significant changes noted during the observation period. The effects of treatment were consistent with those of earlier studies of miglustat in type I GD

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

Globoid cell leukodystrophy is an inherited metabolic disorder of the central nervous system caused by deficiency of the lysosomal enzyme galactocerebrosidase. Haematopoietic stem cell transplantation is the only available effective treatment. The engraftment from normal donors provides competent cells able to correct the metabolic defect. Umbilical cord blood cells have proved to significantly decrease complications and improve engraftment rate compared to adult marrow cells in haematopoietic stem cell transplantation. Umbilical cord blood cells must be of sufficient activity to provide central nervous system recovery after engraftment is obtained. Galactocerebrosidase activity is known to be affected by two polymorphic alleles found at nucleotides 502 and 1637 of the cDNA for this gene. This enzyme activity and the polymorphic alleles noted above were analysed in 83 random samples of umbilical cord blood. The activity, assayed with the fluorogenic substrate 6-hexadecanoylamino-4-methylumbelliferyl-beta-galactopyranoside, in those with neither polymorphic allele was 4.6 +/- 1.7 units (nmol/h per mg protein). This optimal choice of cord blood was found in only 24% of specimens. Homozygotes for 1637T > C with activity of only 1.5 +/- 0.4 units represented 16% of the samples. Those heterozygous for 1637T > C with slightly better activity (2.3 +/- 0.7 units) represented 52% of the samples. Choice of umbilical cord blood for haematopoietic stem cell transplantation, therefore, requires consideration not only of cell quantity and HLA compatibility but also selection for normal alleles to obtain maximal enzymatic activity for central nervous system correction

For patients with type 1 Gaucher disease, challenges to patient care posed by clinical heterogeneity, variable progression rates, and potential permanent disability that can result from untreated or suboptimally treated hematologic, skeletal, and visceral organ involvement dictate a need for comprehensive, serial monitoring. An updated consensus on minimum recommendations for effective monitoring of all adult patients with type 1 Gaucher disease has been developed by the International Collaborative Gaucher Group (ICGG) Registry coordinators. These recommendations provide a schedule for comprehensive and reproducible evaluation and monitoring of all clinically relevant aspects of this disease. The initial assessment should include confirmation of deficiency of beta-glucocerebrosidase, genotyping, and a complete family medical history. Other assessments to be performed initially and at regular intervals include a complete physical examination, patient-reported quality of life using the SF-36 survey, and assessment of hematologic (hemoglobin and platelet count), visceral, and skeletal involvement, and biomarkers. Specific radiologic imaging techniques are recommended for evaluating visceral and skeletal pathology. All patients should undergo comprehensive regular assessment, the frequency of which depends on treatment status and whether therapeutic goals have been achieved. Additionally, reassessment should be performed whenever enzyme therapy dose is altered, or in case of significant clinical complication