Metachromatic Leukodystrophy: An Assessment of Disease Burden.

Metachromatic leukodystrophy is accompanied by severe motor and cognitive dysfunction. This is the first survey of metachromatic leukodystrophy caregiver perspectives to identify relevant clinical/quality-of-life outcomes for patients/caregivers. Interviews and 1 focus group were conducted with 30 caregivers representing 23 patients. Caregivers were asked about their experiences, including diagnostic process, signs/symptoms, symptoms affecting caregivers' and patients' lives, and treatment priorities. Caregivers reported loss of physical autonomy, weight loss, limited social relationships, frequent crying, and challenging sibling relationships. Most troublesome symptoms were immobility (9/30) and respiratory difficulties (6/30). Health care visits were frequent: 8/22 patients had experienced ≥11 hospitalizations since diagnosis, and 14/22 caregivers reported that these lasted ≥4 days. Caregivers also experienced work problems, feelings of fear/sadness, and loss of social relationships. Caregivers/physicians consider a therapy that could improve decline in mobility, pain, cognitive ability, communication, or food intake as conferring the greatest benefit. In conclusion, a so-far-unreported physical/economic burden in these families is presented.

Long-term velaglucerase alfa treatment in children with Gaucher disease type 1 naïve to enzyme replacement therapy or previously treated with imiglucerase.

BACKGROUND: Gaucher Disease type 1 (GD1) often manifests in childhood. Early treatment with enzyme replacement therapy (ERT) may prevent disease complications. We report the assessment of velaglucerase alfa ERT in pediatric GD1 patients who participated in a long-term extension study (HGT-GCB-044, ClinicalTrials.gov Identifier NCT00635427). METHODS: Safety and efficacy were evaluated in pediatric patients receiving velaglucerase alfa 30-60U/kg by intravenous infusion every other week. In addition to key hematological and visceral efficacy assessments, exploratory assessments conducted specifically in pediatric patients included evaluation of height, bone age, bone marrow burden, and Tanner stage of puberty. RESULTS: The study included 24 pediatric patients. Fifteen patients were naïve to ERT on entry into the preceding trials TKT032 (12-month trial) or HGT-GCB-039 (9-month trial): in the preceding trials, ten of these 15 patients received velaglucerase alfa and five patients received imiglucerase ERT. Nine patients in the study were previously treated with imiglucerase for >30months and were switched to velaglucerase alfa in the preceding trial TKT034 (12-month trial). Cumulative ERT exposure in the clinical studies ranged from 2.0 to 5.8years. Three serious adverse events, including a fatal convulsion, were reported; none were deemed related to velaglucerase alfa. One patient tested positive for anti-velaglucerase alfa antibodies. An efficacy assessment at 24months showed that velaglucerase alfa had positive effects on primary hematological and visceral parameters in treatment-naïve patients, which were maintained with longer-term treatment. Disease parameters were stable in patients switched from long-term imiglucerase ERT. Exploratory results may suggest benefits of early treatment to enable normal growth in pediatric patients. CONCLUSION: The safety profile and clinical response seen in pediatric patients are consistent with results reported in adults.

Seven-year safety and efficacy with velaglucerase alfa for treatment-naïve adult patients with type 1 Gaucher disease.

Velaglucerase alfa is a human ß-glucocerebrosidase approved for Gaucher disease type 1 (GD1) treatment. This report summarizes the 7-year experience of the now-completed phase I/II and extension studies of adult GD1 patients who received velaglucerase alfa. Ten patients who completed the 9-month, phase I/II study entered the extension trial TKT025EXT, of which eight completed this study. Doses were reduced after a cumulative treatment period of 15 to 18 months. Although all patients experienced ≥1 adverse event, no patient withdrew due to a drug-related adverse event or required premedication. No patient developed anti-drug antibodies, compliance remained high (median 98%), and seven of eight eligible patients transitioned to home infusions under supervision by healthcare professionals. Statistically significant improvements were observed for efficacy parameters: mean percentage changes from baseline (95% confidence intervals) were 18% (12%, 24%) for hemoglobin concentration, 115% (66%, 164%) for platelet counts, and -42% (-53%, -31%) and -78% (-94%, -62%) for liver and spleen volumes, respectively. Improvements were also observed for secondary endpoints chitotriosidase and CCL18 levels and exploratory endpoints (bone mineral density [BMD], bone marrow burden [BMB] scores). Normalization to near-normalization of individuals' hemoglobin concentrations, platelet counts, liver volumes, and BMB scores was observed, and there were marked improvements in spleen volumes, biomarkers, and BMD. TKT025EXT represents the longest, prospective clinical trial for GD1 treatment to date and suggests that, despite dose reduction within 18 months of initiating therapy, velaglucerase alfa was generally well tolerated and was associated with marked improvement, including near normalization and/or normalization of key GD1 disease parameters.

Velaglucerase alfa (VPRIV) enzyme replacement therapy in patients with Gaucher disease: Long-term data from phase III clinical trials.

Type 1 Gaucher disease is an inherited lysosomal enzyme deficiency with variable age of symptom onset. Common presenting signs include thrombocytopenia, anemia, hepatosplenomegaly, bone abnormalities, and, additionally in children, growth failure. Fifty-seven patients aged 3-62 years at the baseline of two phase III trials for velaglucerase alfa treatment were enrolled in the single extension study. In the extension, they received every-other-week velaglucerase alfa intravenous infusions for 1.2-4.8 years at 60 U/kg, although 10 patients experienced dose reduction. No patient experienced a drug-related serious adverse event or withdrew due to an adverse event. One patient died following a convulsion that was reported as unrelated to the study drug. Only one patient tested positive for anti-velaglucerase alfa antibodies. Combining the experience of the initial phase III trials and the extension study, significant improvements were observed in the first 24 months from baseline in hematology variables, organ volumes, plasma biomarkers, and, in adults, the lumbar spine bone mineral density Z-score. Improvements were maintained over longer-term treatment. Velaglucerase alfa had a good long-term safety and tolerability profile, and patients continued to respond clinically, which is consistent with the results of the extension study to the phase I/II trial of velaglucerase alfa. EudraCT number 2008-001965-27; www.clinicaltrials.gov identifier NCT00635427.

Safety and efficacy results of switch from imiglucerase to velaglucerase alfa treatment in patients with type 1 Gaucher disease.

Gaucher disease (GD) is a lysosomal storage disorder; symptomatic patients with type 1 GD need long-term disease-specific therapy of which the standard of care has been enzyme replacement therapy (ERT). Thirty-eight of 40 patients (aged 9-71 years) clinically stable on ERT with imiglucerase, safely switched to a comparable dose of velaglucerase alfa (units/kg) during TKT034, a 12-month, open-label clinical study, and for 10-50 months in an extension study. The most common adverse events (AEs) judged to be drug-related in the extension were fatigue and bone pain. No drug-related serious AEs were reported. No AEs led to study withdrawal. At 24 months from baseline (baseline being TKT034 week 0), patients had generally stable hemoglobin, platelet, spleen, liver, and bone density parameters. Nevertheless, dose adjustment based on the achievement of therapeutic goals was permitted, and 10 patients, including seven patients who had platelet counts <100 × 10(9) /L at baseline, were given at least one 15 U/kg-dose increase during the extension. Trends indicative of improvement in platelet count and spleen volume, and decreasing levels of GD biomarkers, chitotriosidase and CCL18, were observed. Immunogenicity was seen in one patient positive for anti-imiglucerase antibodies at baseline. This patient tested positive for anti-velaglucerase alfa antibodies in TKT034, with low antibody concentrations, and throughout the extension study; however, the patient continued to receive velaglucerase alfa without clinical deterioration. In conclusion, clinically stable patients can be switched from imiglucerase to velaglucerase alfa ERT and maintain or achieve good therapeutic outcomes.

Enzyme replacement therapy with velaglucerase alfa in Gaucher disease: Results from a randomized, double-blind, multinational, Phase 3 study.

Type 1 Gaucher disease (GD1), resulting from glucocerebrosidase deficiency, leads to splenomegaly, hepatomegaly, anemia, thrombocytopenia, and bone involvement. Current standard treatment is enzyme replacement therapy. Velaglucerase alfa is an enzyme replacement product for GD1, with the same amino acid sequence as naturally occurring human glucocerebrosidase. This multinational, Phase 3 trial evaluated the efficacy and safety of two doses of velaglucerase alfa in 25 treatment-naïve, anemic patients with GD1 (4-62 years of age), randomized to intravenous velaglucerase alfa 60 U/kg (n=12) or 45 U/kg body weight (n=13) every other week for 12 months. The primary endpoint was change from baseline in hemoglobin concentration in the 60 U/kg arm. At 12 months, mean hemoglobin concentrations increased from baseline [60 U/kg: +23.3%; +2.43 g/dL (P<0.001); 45 U/kg: +23.8%; +2.44 g/dL (P<0.001)], as did mean platelet counts [60 U/kg: +65.9%; +50.9 × 10(9) /L (P=0.002); 45 U/kg: +66.4%; +40.9 × 10(9) /L(P=0.01)]. Mean splenic volume decreased from baseline [60 U/kg: -50.4%, from 14.0 to 5.8 multiples of normal (MN) (P=0.003); 45 U/kg: -39.9%, from 14.5 to 9.5 MN (P=0.009)]. No drug-related serious adverse events or withdrawals were observed. One patient developed antibodies. Velaglucerase alfa was generally well tolerated and effective for adults and children with GD1 in this study. All disease-specific parameters measured demonstrated clinically meaningful improvements after 12 months.

Velaglucerase alfa enzyme replacement therapy compared with imiglucerase in patients with Gaucher disease.

Enzyme replacement therapy for Gaucher disease (GD) has been available since 1991. This study compared the efficacy and safety of velaglucerase alfa with imiglucerase, the previous standard of care. A 9-month, global, randomized, double-blind, non-inferiority study compared velaglucerase alfa with imiglucerase (60 U/kg every other week) in treatment-naïve patients aged 3-73 years with anemia and either thrombocytopenia or organomegaly. The primary endpoint was the difference between groups in mean change from baseline to 9 months in hemoglobin concentration. 35 patients were randomized: 34 received study drug (intent-to-treat: 17 per arm), 20 were splenectomized. Baseline characteristics were similar in the two groups. The per-protocol population included 15 patients per arm. The mean treatment difference for hemoglobin concentration from baseline to 9 months (velaglucerase alfa minus imiglucerase) was 0.14 and 0.16 g/dL in the intent-to-treat and per-protocol populations, respectively. The lower bound of the 97.5% one-sided confidence interval in both populations lay within the pre-defined non-inferiority margin of -1.0 g/dL, confirming that velaglucerase alfa is non-inferior to imiglucerase. There were no statistically significant differences in the secondary endpoints. Most adverse events were mild to moderate. No patient receiving velaglucerase alfa developed antibodies to either drug, whereas four patients (23.5%) receiving imiglucerase developed IgG antibodies to imiglucerase, which were cross-reactive with velaglucerase alfa in one patient. This study demonstrates the efficacy and safety of velaglucerase alfa compared with imiglucerase in adult and pediatric patients with GD clinically characterized as Type 1. Differences in immunogenicity were also observed.

Safety and efficacy of velaglucerase alfa in Gaucher disease type 1 patients previously treated with imiglucerase.

Velaglucerase alfa is a glucocerebrosidase produced by gene activation technology in a human fibroblast cell line (HT-1080), and it is indicated as an enzyme replacement therapy (ERT) for the treatment of Gaucher disease type 1 (GD1). This multicenter, open-label, 12-month study examined the safety and efficacy of velaglucerase alfa in patients with GD1 previously receiving imiglucerase. Eligible patients, ≥2 years old and clinically stable on imiglucerase therapy, were switched to velaglucerase alfa at a dose equal to their prior imiglucerase dose. Infusion durations were 1 hr every other week. Forty patients received velaglucerase alfa (18 male, 22 female; four previously splenectomized; age range 9-71 years). Velaglucerase alfa was generally well tolerated with most adverse events (AEs) of mild or moderate severity. The three most frequently reported AEs were headache (12 of 40 patients), arthralgia (9 of 40 patients), and nasopharyngitis (8 of 40 patients). No patients developed antibodies to velaglucerase alfa. There was one serious AE considered treatment-related: a grade 2 anaphylactoid reaction within 30 min of the first infusion. The patient withdrew; this was the only AE-related withdrawal. Hemoglobin concentrations, platelet counts, and spleen and liver volumes remained stable through 12 months. In conclusion, adult and pediatric patients with GD1, previously treated with imiglucerase, successfully transitioned to velaglucerase alfa, which was generally well tolerated and demonstrated efficacy over 12 months' treatment consistent with that observed in the velaglucerase alfa phase 3 clinical trial program.

Efficacy of sapropterin dihydrochloride in increasing phenylalanine tolerance in children with phenylketonuria: a phase III, randomized, double-blind, placebo-controlled study.

OBJECTIVE: To evaluate the ability of sapropterin dihydrochloride (pharmaceutical preparation of tetrahydrobiopterin) to increase phenylalanine (Phe) tolerance while maintaining adequate blood Phe control in 4- to 12-year-old children with phenylketonuria (PKU). STUDY DESIGN: This international, double-blind, randomized, placebo-controlled study screened for sapropterin response among 90 enrolled subjects in Part 1. In Part 2, 46 responsive subjects with PKU were randomized (3:1) to sapropterin, 20 mg/kg/d, or placebo for 10 weeks while continuing on a Phe-restricted diet. After 3 weeks, a dietary Phe supplement was added every 2 weeks if Phe control was adequate. RESULTS: The mean (+/-SD) Phe supplement tolerated by the sapropterin group had increased significantly from the pretreatment amount (0 mg/kg/d) to 20.9 (+/-15.4) mg/kg/d (P < .001) at the last visit at which subjects had adequate blood Phe control (<360 micromol/L), up to week 10. Over the 10-week period, the placebo group tolerated only an additional 2.9 (+/-4.0) mg/kg/d Phe supplement; the mean difference from the sapropterin group (+/-SE) was 17.7 +/- 4.5 mg/kg/d (P < .001). No severe or serious related adverse events were observed. CONCLUSIONS: Sapropterin is effective in increasing Phe tolerance while maintaining blood Phe control and has an acceptable safety profile in this population of children with PKU.

Clinical and molecular heterogeneity in patients with the cblD inborn error of cobalamin metabolism.

OBJECTIVES: To describe 3 patients with the cblD disorder, a rare inborn error of cobalamin metabolism caused by mutations in the MMADHC gene that can result in isolated homocystinuria, isolated methylmalonic aciduria, or combined homocystinuria and methylmalonic aciduria. STUDY DESIGN: Patient clinical records were reviewed. Biochemical and somatic cell genetic studies were performed on cultured fibroblasts. Sequence analysis of the MMADHC gene was performed on patient DNA. RESULTS: Patient 1 presented with isolated methylmalonic aciduria, patient 3 with isolated homocystinuria, and patient 2 with combined methylmalonic aciduria and homocystinuria. Studies of cultured fibroblasts confirmed decreased synthesis of adenosylcobalamin in patient 1, decreased synthesis of methylcobalamin in patient 3, and decreased synthesis of both cobalamin derivatives in patient 2. The diagnosis of cblD was established in each patient by complementation analysis. Mutations in the MMADHC gene were identified in all patients. CONCLUSIONS: The results emphasize the heterogeneous clinical, cellular and molecular phenotype of the cblD disorder. The results of molecular analysis of the MMADHC gene are consistent with the hypothesis that mutations affecting the N terminus of the MMADHC protein are associated with methylmalonic aciduria, and mutations affecting the C terminus are associated with homocystinuria.

Safety and efficacy of 22 weeks of treatment with sapropterin dihydrochloride in patients with phenylketonuria.

Phenylketonuria (PKU) is an inherited metabolic disease characterized by phenylalanine (Phe) accumulation, which can lead to neurocognitive and neuromotor impairment. Sapropterin dihydrochloride, an FDA-approved synthetic formulation of tetrahydrobiopterin (6R-BH4, herein referred to as sapropterin) is effective in reducing plasma Phe concentrations in patients with hyperphenylalaninemia due to tetrahydrobiopterin (BH4)-responsive PKU, offering potential for improved metabolic control. Eighty patients, > or =8 years old, who had participated in a 6-week, randomized, placebo-controlled study of sapropterin, were enrolled in this 22-week, multicenter, open-label extension study comprising a 6-week forced dose-titration phase (5, 20, and 10 mg/kg/day of study drug consecutively for 2 weeks each), a 4-week dose-analysis phase (10 mg/kg/day), and a 12-week fixed-dose phase (patients received doses of 5, 10, or 20 mg/kg/day based on their plasma Phe concentrations during the dose titration). Dose-dependent reductions in plasma Phe concentrations were observed in the forced dose-titration phase. Mean (SD) plasma Phe concentration decreased from 844.0 (398.0) micromol/L (week 0) to 645.2 (393.4) micromol/L (week 10); the mean was maintained at this level during the study's final 12 weeks (652.2 [382.5] micromol/L at week 22). Sixty-eight (85%) patients had at least one adverse event (AE). All AEs, except one, were mild or moderate in severity. Neither the severe AE nor any of the three serious AEs was considered related to sapropterin. No AE led to treatment discontinuation. Sapropterin is effective in reducing plasma Phe concentrations in a dose-dependent manner and is well tolerated at doses of 5-20 mg/kg/day over 22 weeks in BH4-responsive patients with PKU.

Maternal glutaric acidemia, type I identified by newborn screening.

We report two women with glutaric acidemia type I in whom the diagnosis was unsuspected until a low carnitine level was found in their newborn children. Both mothers had low carnitine in plasma. In the first, organic acid analysis was only done after fibroblast studies revealed normal carnitine uptake. Having learned from the first family, organic acid analysis was done immediately in the mother of family 2. In both, the plasma acylcarnitine profile was normal but both excreted the metabolites typical of their disorder. One of the women was a compound heterozygote for distinct mutations in the glutaric acid dehydrogenase gene, whereas the second was either homozygous or hemizygous for a mutation in Exon 6 of the gene.

Expanded newborn screening identifies maternal primary carnitine deficiency.

Primary carnitine deficiency impairs fatty acid oxidation and can result in hypoglycemia, hepatic encephalopathy, cardiomyopathy and sudden death. We diagnosed primary carnitine deficiency in six unrelated women whose unaffected infants were identified with low free carnitine levels (C0) by newborn screening using tandem mass spectrometry. Given the lifetime risk of morbidity or sudden death, identification of adult patients with primary carnitine deficiency is an added benefit of expanded newborn screening programs.

Duplication of the Down syndrome critical region does not predict facial phenotype in a baby with a ring chromosome 21.

Ring chromosomes represent a rare type of chromosomal anomaly that can lead to multiple malformations. Although rings may occur with any chromosome, ring chromosome 21 is of particular interest due to the association of this chromosome with Down syndrome. Individuals with a ring chromosome 21, containing duplicated material, typically have a phenotype consistent with Down syndrome. We report an infant with a ring chromosome 21 containing a duplication of most of the long arm, including the Down syndrome critical region [46,XX,r(21)(p11.2q22.3)]. Fluorescence in situ hybridization analyses of the ring showed one chromosome 21 centromere, two copies each of the AML1 gene (q22) and the Down syndrome critical region, and deleted subtelomeric material. The patient has some Down syndrome characteristics including a high arched palate, a secundum atrial septal defect, and duodenal stenosis, but lacks the typical Down syndrome facial features, nuchal folds, and hand/foot anomalies. The phenotype of this patient supports the hypothesis that the duplication of the Down syndrome critical region alone is not sufficient to recapitulate the classical Down syndrome craniofacial phenotype.

Hyperargininemia due to liver arginase deficiency.

The urea cycle is a series of six reactions necessary to rid the body of the nitrogen generated by the metabolism, primarily of amino acids, from the diet or released as the result of endogenous protein catabolism. Arginase is the sixth and final enzyme of this cycle. Arginase catalyzes the conversion of arginine to urea and ornithine, the latter recycled to continue the cycle. Hyperargininemia due to arginase deficiency is inherited in an autosomal recessive manner and gene for arginase, designated AI, has been cloned. Unlike the other urea cycle enzymes, a second gene encoding arginase, with similar structural properties and enzyme characteristics, exists and has been named Arginase II (AII). Comprehensive histories and physical examinations confirm a strikingly uniform clinical picture and one notably different from patients with other urea cycle disorders. This condition rarely presents in the neonatal period and first symptoms typically present in children between 2 and 4 years of age. First symptoms are often neurologically based. If untreated, symptoms are progressive with a gradual loss of developmental milestones. With adherence to a dietary and drug regimen, a favorable outcome can be expected, with cessation of further neurological deterioration and in some instances, of improvement. This article summarizes the clinical course of selected patients who represent the full spectrum of presentations of arginase deficiency. In addition to the clinical characterization of this disorder; the biochemical, enzymatic, and molecular evidence of disease is summarized. Treatment and prenatal diagnosis are also discussed.