Background Pompe’s disease is a metabolic myopathy caused by a deficiency of acid alpha glucosidase (GAA), an enzyme that degrades lysosomal glycogen. Late-onset Pompe’s disease is characterized by progressive muscle weakness and loss of respiratory function, leading to early death. We conducted a randomized, placebo-controlled trial of alglucosidase alfa, a recombinant human GAA, for the treatment of late-onset Pompe’s disease. Methods Ninety patients who were 8 years of age or older, ambulatory, and free of invasive ventilation were randomly assigned to receive biweekly intravenous alglucosidase alfa (20 mg per kilogram of body weight) or placebo for 78 weeks at eight centers in the United States and Europe. The two primary end points were distance walked during a 6-minute walk test and percentage of predicted forced vital capacity (FVC). Results At 78 weeks, the estimated mean changes from baseline in the primary end points favored alglucosidase alfa (an increase of 28.1±13.1 m on the 6-minute walk test and an absolute increase of 3.4±1.2 percentage points in FVC; P = 0.03 and P = 0.006, respectively). Similar proportions of patients in the two groups had adverse events, serious adverse events, and infusion-associated reactions; events that occurred only in patients who received the active study drug included anaphylactic reactions and infusion-associated reactions of urticaria, flushing, hyperhidrosis, chest discomfort, vomiting, and increased blood pressure (each of which occurred in 5 to 8% of the patients). Conclusions In this study population, treatment with alglucosidase alfa was associated with improved walking distance and stabilization of pulmonary function over an 18-month period. (ClinicalTrials.gov number, NCT00158600.)

https://www.nejm.org/doi/pdf/10.1056/NEJMoa0909859

A Randomized Study of Alglucosidase Alfa in Late-Onset Pompe's Disease

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(08)61555-X.pdf

Pompe's disease.

A retrospective, multinational, multicenter study on the natural history of infantile-onset Pompe disease

Despite its being one of the most commonly observed neurological disorders, neuropathological studies of essential tremor (ET) are rare. There have been surprisingly few autopsy studies and even fewer case-control comparisons. The primary objective was to describe and quantify the pathological changes in 33 ET and 21 control brains. A secondary objective was to correlate clinical and pathological features. We examined autopsy tissue from the Essential Tremor Centralized Brain Repository. Eight (24.2%) of the 33 ET brains had Lewy bodies in the brainstem, mainly in the locus ceruleus. However, the majority of ET brains (25/33, 75.8%) had no Lewy bodies, but had pathological changes in the cerebellum. The mean number of Purkinje cells per 100× field was reduced in ET cases without Lewy bodies (6.6 ± 2.4 versus 9.6 ± 3.4, P < 0.01), and there were ∼7× more Purkinje cell torpedoes per section (12.6 ± 7.9 versus 1.7 ± 1.4, P < 0.001) compared to controls. ET cases without Lewy bodies also had degeneration of the dentate nucleus (two cases). Other findings in ET cases were Purkinje cell heterotopias and dendrite swellings. Lewy body ET cases were older than ET cases without Lewy bodies. Several trends were observed in ET cases without Lewy bodies, including a younger age of onset of tremor and higher proportions with gait difficulty and family history of ET. The pathological changes of ET seem to be heterogeneous and degenerative. The majority have cerebellar changes without Lewy bodies; a smaller proportion has brainstem Lewy bodies. The clinical differences between cases with versus without Lewy bodies require additional study.

/pdf/neuropathological-changes-in-essential-tremor-33-cases-2vpizvi6t0.pdf

Neuropathological changes in essential tremor: 33 cases compared with 21 controls

Urea cycle disorders (UCDs) are inborn errors of ammonia detoxification/arginine synthesis due to defects affecting the catalysts of the Krebs-Henseleit cycle (five core enzymes, one activating enzyme and one mitochondrial ornithine/citrulline antiporter) with an estimated incidence of 1:8.000. Patients present with hyperammonemia either shortly after birth (~50%) or, later at any age, leading to death or to severe neurological handicap in many survivors. Despite the existence of effective therapy with alternative pathway therapy and liver transplantation, outcomes remain poor. This may be related to underrecognition and delayed diagnosis due to the nonspecific clinical presentation and insufficient awareness of health care professionals because of disease rarity. These guidelines aim at providing a trans-European consensus to: guide practitioners, set standards of care and help awareness campaigns. To achieve these goals, the guidelines were developed using a Delphi methodology, by having professionals on UCDs across seven European countries to gather all the existing evidence, score it according to the SIGN evidence level system and draw a series of statements supported by an associated level of evidence. The guidelines were revised by external specialist consultants, unrelated authorities in the field of UCDs and practicing pediatricians in training. Although the evidence degree did hardly ever exceed level C (evidence from non-analytical studies like case reports and series), it was sufficient to guide practice on both acute and chronic presentations, address diagnosis, management, monitoring, outcomes, and psychosocial and ethical issues. Also, it identified knowledge voids that must be filled by future research. We believe these guidelines will help to: harmonise practice, set common standards and spread good practices with a positive impact on the outcomes of UCD patients.

/pdf/suggested-guidelines-for-the-diagnosis-and-management-of-7jd0s5gqd2.pdf

Suggested guidelines for the diagnosis and management of urea cycle disorders

Glycogen storage disease type II (GSD II) is an autosomal recessive myopathy. Early and late-onset phenotypes are distinguished – infantile, juvenile and adult. Three mutations in the acid α-glucosidase gene are common in the Dutch patient population: IVS1(-13T→G), 525delT and delexon18 63% of Dutch GSD II patients carry one or two of these mutations, and the genotype–phenotype correlation is known. To determine the frequency of GSD II, we have screened an unselected sample of neonates for the occurrence of these three mutations. Based on the calculated carrier frequencies, the predicted frequency of the disease is 1 in 40 000 divided by 1 in 138 000 for infantile GSD II and 1 in 57 000 for adult GSD II. This is about two to four times higher than previously suggested, which is a reason to become more familiar with the presentation of GSD II in its different clinical forms and to adjust the risk assessment for genetic counselling.

/pdf/frequency-of-glycogen-storage-disease-type-ii-in-the-50icx4zcsa.pdf

Frequency of glycogen storage disease type II in The Netherlands: implications for diagnosis and genetic counselling.

Background: Pompe disease (acid maltase deficiency, glycogen storage disease type II; OMIM 232300) is an autosomal recessive lysosomal storage disorder characterized by acid α-glucosidase deficiency due to mutations in the GAA gene. Progressive skeletal muscle weakness affects motor and respiratory functions and is typical for all forms of Pompe disease. Cardiac hypertrophy is an additional fatal symptom in the classic infantile subtype. c.-32-13T→G is the most common mutation in adults. Objective: To delineate the disease variation among patients with this mutation and to define the c.-32-13T→G haplotypes in search for genotype–phenotype correlations. Methods: We studied 98 compound heterozygotes with a fully deleterious mutation (11 novel mutations are described) and the common c.-32-13T→G mutation. Results: All patients were Caucasian. None had the classic infantile form of Pompe disease. The clinical course varied far more than anticipated (age at diagnosis GAA gene. In 76% of the cases, c.-32-13T→G was encountered in the second most common GAA core haplotype (DHRGEVVT). In only one case was c.-32-13T→G encountered in the major GAA core haplotype (DRHGEIVT). Conclusion: Patients with the same c.-32-13T→G haplotype (c.q. GAA genotype) may manifest first symptoms at different ages, indicating that secondary factors may substantially influence the clinical course of patients with this mutation.

Broad spectrum of Pompe disease in patients with the same c.-32-13T→G haplotype

To the Editor: The article by Laforêt et al.1 on French patients with juvenileand adult-onset glycogen storage disease type II (GSD II) compels us to react to their main conclusions, which we consider inaccurate. We think that their way of measuring -glucosidase activity in leukocytes is not the most reliable diagnostic feature for GSD II. In contrast, we argue that this assay, using an artificial substrate in conjunction with immunologic procedures, is error prone. This is best illustrated by the authors’ observation that 8 of the 19 adult patients in the study have zero levels of -glucosidase activity, whereas the literature consistently reports residual activities of 5 to 25% of normal in patients with adult GSD II.2 Moreover, six of these eight patients with zero activity are compound heterozygote for the frequent IVS1( 13T3G) mutation, which is known to preserve 10 to 20% of fully normal -glucosidase.3 In our opinion, these discrepancies are due to limitations of the authors’ complex immunologic procedure used to discriminate between lysosomal and nonlysosomal -glucosidases. Also, based on our own experience, we recommend abandoning the use of artificial substrates for measuring the lysosomal -glucosidase activity of leukocytes. The natural substrate glycogen can be used for diagnostic purposes, provided that -glucosidase deficiency is confirmed in fibroblasts. -Glucosidase determinations in fibroblasts, with both artificial and natural substrate, are the gold standard in the diagnostic process of GSD II.4 This reliable assay has previously shown that the clinical phenotype of GSD II is determined primarily by the level of residual -glucosidase activity, which in turn is dictated by the type and combination of mutations in the -glucosidase gene. The sum of these observations provides the genotype–phenotype correlation.2,5,6 In contrast, the authors firmly conclude that a correlation is absent. Moreover, this conclusion cannot be drawn from the data presented, as the majority of the patients were not fully genotyped, leaving uncertainty as to the functional effect of the second mutation. Sixteen of 21 patients are compound heterozygotes for the IVS1( 13T3G) mutation and 15 of these 16 show a similar clinical pattern. If the second allele carries a fully deleterious mutation, as in other studies on late-onset GDS II,5,6 these patients have, in essence, the same “functional genotype.” The logical conclusion would then be that the GSD II genotype– phenotype correlation stands out impressively against the background of the estimated 30,000 other genes constituting the human genome.

Juvenile and adult-onset acid maltase deficiency in France: Genotype-phenotype correlation. Authors' reply

ease, including neuropsychological testing; (3) research to obtain insight into people's knowledge, beliefs, feelings, and behaviour related to genetic disease, genetic risk, and genetic testing. "Prediction" of how many people will use specific genetic tests and delineation of predictor variables is part of the latter role. We want to stress that the mere prediction of future uptake rates or other preventive behaviour is not the main purpose of our study. The study is aimed at a description of adolescents' present opinions about genetic risk information, prenatal diagnosis, and

https://jmg.bmj.com/content/jmedgenet/32/10/836.2.full.pdf

Glycogen storage disease type II: frequency of three common mutant alleles and their associated clinical phenotypes studied in 121 patients.

To analyze the diagnostic value of various laboratory tests for the confirmation of adult-onset glycogen storage disease type II (GSD II), we performed a clinical, biochemical, and genetic study of 18 patients with this disease. Measurement of acid alpha-glucosidase (GAA) activity in muscle and histopathologic analysis of muscle tissue appeared to have no additional value when GAA activity in leukocytes was clearly deficient. Our study showed that creatine kinase elevation is a sensitive marker of GSD II. A diagnostic protocol is formulated.

M.G.E.M. Ausems

Papers

Frequency of glycogen storage disease type II in The Netherlands: implications for diagnosis and genetic counselling.

Broad spectrum of Pompe disease in patients with the same c.-32-13T→G haplotype

Juvenile and adult-onset acid maltase deficiency in France: Genotype-phenotype correlation. Authors' reply

Glycogen storage disease type II: frequency of three common mutant alleles and their associated clinical phenotypes studied in 121 patients.

A diagnostic protocol for adult-onset glycogen storage disease type II