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ADVANCE (NCT01526785) presented an opportunity to obtain a more nuanced understanding of motor function changes in treatment-experienced children with Pompe disease receiving 4000L-production-scale alglucosidase alfa for 52 weeks. To estimate minimal detectable change (MDC) and effect size on Gross Motor Function Measure-88 (GMFM-88) after 52 weeks of 4000L alglucosidase alfa (complete data N =  90). The GMFM-88 mean total % score changes, MDC, and effect size were analyzed post hocby Pompe Motor Function Level at enrollment, age groups at enrollment, and fraction of life on pre-study 160L-production-scale alglucosidase alfa. Overall, participants aged < 2 years surpassed MDC at Week 52 (change [mean±standard deviation] 21.1±14.1, MDC range 5.7–13.3, effect size 1.1), whereas participants aged≥2 years did not attain this (change –0.9±15.3, MDC range 10.8–25.2, effect size –0.03). In participants aged < 2 years, improvements surpassed the MDC for walkers (change 17.1±13.3, MDC range 3.0–6.9, effect size 1.7), supported standers (change 35.2±18.0, MDC range 5.9–13.7, effect size 1.8) and sitters (change 24.1±12.1, MDC range 2.6–6.2, effect size 2.7). Age-independent MDC ranges were only attained by walkers (change 7.7±12.3, MDC range 6.4–15.0, effect size 0.4) and sitters (change 9.9±17.2, MDC range 3.3–7.7, effect size 0.9). These first GMFM-88 minimal-detectable-change estimates for alglucosidase alfa-treated Pompe disease offer utility for monitoring motor skills. ClinicalTrials.gov; NCT01526785; Registered 6 February 2012; https://clinicaltrials.gov/ct2/show/NCT01526785

AbstractPompe disease results from lysosomal acid α-glucosidase deficiency, which leads to cardiomyopathy in all infantile-onset and occasional late-onset patients. Cardiac assessment is important for its diagnosis and management. This article presents unpublished cardiac findings, concomitant medications, and cardiac efficacy and safety outcomes from the ADVANCE study; trajectories of patients with abnormal left ventricular mass z score at enrolment; and post hoc analyses of on-treatment left ventricular mass and systolic blood pressure z scores by disease phenotype, GAAgenotype, and “fraction of life” (defined as the fraction of life on pre-study 160 L production-scale alglucosidase alfa). ADVANCE evaluated 52 weeks’ treatment with 4000 L production-scale alglucosidase alfa in ≥1-year-old United States of America patients with Pompe disease previously receiving 160 L production-scale alglucosidase alfa. M-mode echocardiography and 12-lead electrocardiography were performed at enrolment and Week 52. Sixty-seven patients had complete left ventricular mass z scores, decreasing at Week 52 (infantile-onset patients, change −0.8 ± 1.83; 95% confidence interval −1.3 to −0.2; all patients, change −0.5 ± 1.71; 95% confidence interval −1.0 to −0.1). Patients with “fraction of life” <0.79 had left ventricular mass z score decreasing (enrolment: +0.1 ± 3.0; Week 52: −1.1 ± 2.0); those with “fraction of life” ≥0.79 remained stable (enrolment: −0.9 ± 1.5; Week 52: −0.9 ± 1.4). Systolic blood pressure z scores were stable from enrolment to Week 52, and no cohort developed systemic hypertension. Eight patients had Wolff–Parkinson–White syndrome. Cardiac hypertrophy and dysrhythmia in ADVANCE patients at or before enrolment were typical of Pompe disease. Four-thousand L alglucosidase alfa therapy maintained fractional shortening, left ventricular posterior and septal end-diastolic thicknesses, and improved left ventricular mass z score.Trial registry:ClinicalTrials.gov Identifier: NCT01526785 https://clinicaltrials.gov/ct2/show/NCT01526785.Social Media Statement:Post hoc analyses of the ADVANCE study cohort of 113 children support ongoing cardiac monitoring and concomitant management of children with Pompe disease on long-term alglucosidase alfa to functionally improve cardiomyopathy and/or dysrhythmia.

Background:Smith-Lemli-Opitz syndrome (SLOS) is a multiple malformation/cognitive impairment syndrome characterized by the accumulation of 7-dehydrocholesterol, a precursor sterol of cholesterol. Simvastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor that crosses the blood–brain barrier, has been proposed for the treatment of SLOS based on in vitro and in vivo studies suggesting that simvastatin increases the expression of hypomorphic DHCR7 alleles.Methods:Safety and efficacy of simvastatin therapy in 23 patients with mild to typical SLOS were evaluated in a randomized, double-blind, placebo-controlled trial. The crossover trial consisted of two 12-month treatment phases separated by a 2-month washout period.Results:No safety issues were identified in this study. Plasma dehydrocholesterol concentrations decreased significantly: 8.9 ± 8.4% on placebo to 6.1 ± 5.5% on simvastatin (P < 0.005); we observed a trend toward decreased cerebrospinal fluid dehydrocholesterol concentrations. A significant improvement (P = 0.017, paired t-test) was observed on the irritability subscale of the Aberrant Behavior Checklist–C when subjects were taking simvastatin.Conclusion:This article reports what is, to our knowledge, the first randomized, placebo-controlled trial designed to test the safety and efficacy of simvastatin therapy in SLOS. Simvastatin seems to be relatively safe in patients with SLOS, improves the serum dehydrocholesterol–to–total sterol ratio, and significantly improves irritability symptoms in patients with mild to classic SLOS.Genet Med 19 3, 297–305.

Smith-Lemli-Opitz syndrome (SLOS) is a multiple malformation/cognitive impairment syndrome characterized by the accumulation of 7-dehydrocholesterol, a precursor sterol of cholesterol. Simvastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor that crosses the blood–brain barrier, has been proposed for the treatment of SLOS based on in vitro and in vivo studies suggesting that simvastatin increases the expression of hypomorphic DHCR7alleles.

Neonatal hypotonia is a common problem in the neonatal intensive care unit. The genetic differential diagnosis is broad, encompassing primary muscular dystrophies, chromosome abnormalities, neuropathies, and inborn errors of metabolism. Recognition of hypotonia is relatively straightforward, but determining the cause can be challenging. It is important for the neonatologist to have an organized approach to the assessment of neonatal hypotonia. Physical examination and history alongside basic laboratory testing and imaging aid in the differential diagnosis. Identification of the cause is essential for determining prognosis, associated morbidities, and recurrence risk. The prevailing therapeutic modality is physical, occupational, speech/feeding, and respiratory therapy.

We sought to examine the prevalence of EEG abnormalities in Smith-Lemli-Opitz syndrome (SLOS) as well as the relationship between interictal epileptiform discharges (IEDs) and within-subject variations in attentional symptom severity.

Hermansky–Pudlak syndrome (HPS) is an autosomal recessive disorder characterized by oculocutaneous albinism, a bleeding disorder, and, in some patients, granulomatous colitis and/or a fatal pulmonary fibrosis. There are eight different subtypes of HPS, each due to mutations in one of eight different genes, whose functions are thought to involve intracellular vesicle formation and trafficking. HPS has been identified in patients of nearly all ethnic groups, though it has primarily been associated with patients of Puerto Rican, Northern European, Japanese and Israeli descent. We report on the diagnosis of HPS type 1 in two African‐American patients. Both brothers carried compound heterozygous mutations in HPS1: previously reported p.M325WfsX6 (c.972delC) and a novel silent mutation p.E169E (c.507G > A), which resulted in a splice defect. HPS may be under‐diagnosed in African‐American patients and other ethnic groups. A history of easy bruising or evidence of a bleeding disorder, combined with some degree of hypopigmentation, should prompt investigation into the diagnosis of HPS. Published 2009 Wiley‐Liss, Inc.

We report on a case of a phenotypic male infant who was referred to the genetics service due to dysmorphic features and congenital cardiac anomalies. Dysmorphic features included low‐set, posteriorly rotated ears with squared, simple helices, midface hypoplasia, a broad nasal root with wide nasal alae, small mouth, micrognathia, short neck, overlapping fingers, rocker‐bottom feet, prominent heels, and hypoplastic toenails. The phallus was normal and no testes were palpable in the scrotal sac. Cardiac anomalies included tricuspid atresia and a ventricular septal defect. The karyotype was 46,XX. Diagnostic microarray demonstrated evidence for trisomy 9 mosaicism, metaphase FISH revealed trisomy 9 on 7% of cultured cells, and interphase FISH analysis of a peripheral blood smear showed trisomy 9 in 78% of the cells examined. This is the first reported case of XX sex reversal in a patient with trisomy 9 mosaicism. © 2007 Wiley‐Liss, Inc.

Organophosphorus (OP) compound-induced inhibition of acetylcholinesterase (AChE) and neuropathy target esterase explains the rapid onset and delayed neurotoxic effects, respectively, for OP insecticides and related compounds but apparently not a third or intermediate syndrome with delayed onset and reduced limb mobility. This investigation tests the hypothesis that fatty acid amide hydrolase (FAAH), a modulator of endogenous signaling compounds affecting sleep (oleamide) and analgesia (anandamide), is a sensitive target for OP pesticides with possible secondary neurotoxicity. Chlorpyrifos oxon inhibits 50% of the FAAH activity (IC50 at 15 min, 25°C, pH 9.0) in vitroat 40–56 nM for mouse brain and liver, whereas methyl arachidonyl phosphonofluoridate, ethyl octylphosphonofluoridate (EOPF), oleyl-4H-1,3,2-benzodioxaphosphorin 2-oxide (oleyl-BDPO), and dodecyl-BDPO give IC50s of 0.08–1.1 nM. These BDPOs and EOPF inhibit mouse brain FAAH in vitrowith ≥200-fold higher potency than for AChE. Five OP pesticides inhibit 50% of the brain FAAH activity (ED50) at <30 mg/kg 4 h after ip administration to mice; while inhibition by chlorpyrifos, diazinon, and methamidophos occurs near acutely toxic levels, profenofos and tribufos are effective at asymptomatic doses. Two BDPOs (dodecyl and phenyl) and EOPF are potent inhibitors of FAAH in vivo(ED50 0.5–6 mg/kg). FAAH inhibition of ≥76% in brain depresses movement of mice administered anandamide at 30 mg/kg ip, often leading to limb recumbency. Thus, OP pesticides and related inhibitors of FAAH potentiate the cannabinoid activity of anandamide in mice. More generally, OP compound-induced FAAH inhibition and the associated anandamide accumulation may lead to reduced limb mobility as a secondary neurotoxic effect.

Chloropicrin (CCl3NO2) is a widely used soil fumigant with an unknown mechanism of acute toxicity. We investigated the possible involvement of dechlorination in CCl3NO2toxicity by considering its metabolism, inhibition of pyruvate and succinate dehydrogenases, cytotoxicity in cultured cells, and interaction with hemoproteins. In a newly discovered pathway, CCl3NO2is metabolized to thiophosgene, which is characterized as the cyclic cysteine adduct (raphanusamic acid) in the urine of mice. CCl3NO2inhibits porcine heart pyruvate dehydrogenase complex (IC‐50 4 μM) and mouse liver succinate dehydrogenase complex (IC‐50 13 μM), whereas its dehalogenated metabolites (CHCl2NO2and CH2ClNO2are more than 10 times less effective. The inhibitory potency of CCl3NO2for these dehydrogenase complexes is similar to that of captan, folpet, and dichlone fungicides (IC‐50 2–6 μM). CCl3NO2cytotoxity with Hepa 1c1c7 mouse hepatoma cells (IC‐50 9 μM) is not correlated with glutathione depletion. Mice treated intraperitoneally with CCl3NO2at 50 mg/kg but not with an equivalent dose of CHCl2NO2show increased concentrations of oxyhemoglobin in liver. The acute toxicity of CCl3NO2in mice is due to the parent compound or metabolites other than CHCl2NO2or CH2ClNO2and may be associated with inhibition of the pyruvate dehydrogenase complex and elevated oxyhemoglobin. © 1999 John Wiley & Sons, Inc. J Biochem Toxicol 14: 26–32, 2000

Succinylcholine is the most important rapid-acting depolarizing muscle relaxant during anesthesia. Its desirable short duration of action is controlled by butyrylcholinesterase, the detoxifying enzyme. There are two reported cases of prolonged paralysis from succinylcholine in patients poisoned with the organophosphorus insecticides parathion and chlorpyrifos. The present study examines the possibility that other organophosphorus and methylcarbamate pesticides might also prolong succinylcholine action by inhibiting butyrylcholinesterase using mice treated intraperitoneally as a model and relating inhibition of blood serum hydrolysis of butyrylthiocholine to potentiated toxicity (mouse mortality). The organophosphorus plant defoliant tribufos (4 h pretreatment, 160 mg/kg) and organophosphorus plant growth regulator ethephon (1 h pretreatment, 200 mg/kg) potentiate the toxicity of succinylcholine by seven- and fourfold, respectively. Some other pesticides or analogs are more potent sensitizers for succinylcholine toxicity with threshold levels of 0.5, 1.0, 1.7, 8, 10, and 67 mg/kg for phenyl saligenin cyclic phosphonate, profenofos, methamidophos, tribufos, chlorpyrifos, and ethephon, respectively. Enhanced mortality from succinylcholine is generally observed when serum butyrylcholinesterase is inhibited 55–94%. Mivacurium, a related nondepolarizing muscle relaxant also detoxified by butyrylcholinesterase, is likewise potentiated by at least threefold on 4 hour pretreatment with tribufos (25 mg/kg) or profenofos (10 mg/kg). © 1998 John Wiley & Sons, Inc. J Biochem Toxicol 13: 113–118, 1999

Two proposed modes of toxic action of the molluscicide metaldehyde are considered here by studies in orally treated mice of symptomatology, acetaldehyde and metaldehyde concentrations in tissues, and characteristics of the γ-aminobutyric acid (GABA) receptor complex. An earlier proposal that metaldehyde-induced poisoning is due to acetaldehyde liberation is not supported by either their different symptomatology or tissue analyses. Unmetabolized metaldehyde is excreted to the extent of 8% and the urinary metabolites from [13C]metaldehyde and [13C]acetate are consistent with primary degradation of metaldehyde via acetaldehyde and acetate. Poisoning signs are initiated at ∼12 ppm metaldehyde in brain, progressing to tonic convulsions and death at ∼40 ppm and lessened by diazepam and phenobarbital without greatly altering the tissue levels of metaldehyde. Possible involvement of the GABAergic system in metaldehyde toxicity is suggested by the lowered levels of GABA in the brain of poisoned mice determined by (1) earlier chemical analysis of the whole brain (Homeida and Cooke,J. Vet. Pharmacol. Ther.5,77 (1982)) and (2) the presently observed reduced effect of endogenous inhibitors (primarily GABA) in preventing binding of [3H]ethynylbicycloorthobenzoate ([3H]EBOB) to brain membranes. Metaldehyde (1 mM) does not: (1) inhibit [3H]EBOB bindingin vitroat the noncompetitive blocker site, (2) alter the coupled effects on [3H]EBOB binding of GABA as an inhibitor (acting at the GABA recognition site) and the amidine steroid RU 5135 in reversing this inhibition (acting primarily as a competitive antagonist), or (3) inhibit glutamic acid decarboxylase activity. Thus, the toxicity of metaldehyde is not due to degradation to acetaldehyde but instead may result from disrupting the GABAergic system by a mechanism which remains to be determined.

Succinylcholine is the most important rapid‐acting depolarizing muscle relaxant during anesthesia. Its desirable short duration of action is controlled by butyrylcholinesterase, the detoxifying enzyme. There are two reported cases of prolonged paralysis from succinylcholine in patients poisoned with the organophosphorus insecticides parathion and chlorpyrifos. The present study examines the possibility that other organophosphorus and methylcarbamate pesticides might also prolong succinylcholine action by inhibiting butyrylcholinesterase using mice treated intraperitoneally as a model and relating inhibition of blood serum hydrolysis of butyrylthiocholine to potentiated toxicity (mouse mortality). The organophosphorus plant defoliant tribufos (4 h pretreatment, 160 mg/kg) and organophosphorus plant growth regulator ethephon (1 h pretreatment, 200 mg/kg) potentiate the toxicity of succinylcholine by seven‐ and fourfold, respectively. Some other pesticides or analogs are more potent sensitizers for succinylcholine toxicity with threshold levels of 0.5, 1.0, 1.7, 8, 10, and 67 mg/kg for phenyl saligenin cyclic phosphonate, profenofos, methamidophos, tribufos, chlorpyrifos, and ethephon, respectively. Enhanced mortality from succinylcholine is generally observed when serum butyrylcholinesterase is inhibited 55–94%. Mivacurium, a related nondepolarizing muscle relaxant also detoxified by butyrylcholinesterase, is likewise potentiated by at least threefold on 4 hour pretreatment with tribufos (25 mg/kg) or profenofos (10 mg/kg). © 1998 John Wiley & Sons, Inc. J Biochem Toxicol 13: 113–118, 1999

Hereditary inclusion body myopathy (HIBM) is an autosomal recessive neuromuscular disorder associated with mutations in uridine diphosphate (UDP)-N-acetylglucosamine (GlcNAc) 2-epimerase (GNE)/N-acetylmannosamine (ManNAc) kinase (MNK), the bifunctional and rate-limiting enzyme of sialic acid biosynthesis. We developed individual GNE and MNK enzymatic assays and determined reduced activities in cultured fibroblasts of patients, with HIBM harboring missense mutations in either or both the GNE and MNK enzymatic domains. To assess the effects of individual mutations on enzyme activity, normal and mutated GNE/MNK enzymatic domains were synthesized in a cell-free in vitro transcription–translation system and subjected to the GNE and MNK enzymatic assays. This cell-free system was validated for both GNE and MNK activities, and it revealed that mutations in one enzymatic domain (in GNE, G135V, V216A, and R246W; in MNK, A631V, M712T) affected not only that domain’s enzyme activity, but also the activity of the other domain. Moreover, studies of the residual enzyme activity associated with specific mutations revealed a discrepancy between the fibroblasts and the cell-free systems. Fibroblasts exhibited higher residual activities of both GNE and MNK than the cell-free system. These findings add complexity to the tightly regulated system of sialic acid biosynthesis. This cell-free approach can be applied to other glycosylation pathway enzymes that are difficult to evaluate in whole cells because their substrate specificities overlap with those of ancillary enzymes.