High prevalence of arrhythmic and myocardial complications in patients with cardiac glycogenosis due to PRKAG2 mutations.

AIMS: Mutations in PRKAG2, the gene encoding for the γ2 subunit of 5'-AMP-activated protein kinase (AMPK), are responsible for an autosomal dominant glycogenosis with a cardiac presentation, associating hypertrophic cardiomyopathy (HCM), ventricular pre-excitation (VPE), and progressive heart block. The aim of this study was to perform a retrospective time-to-event study of the clinical manifestations associated with PRKAG2 mutations. METHODS AND RESULTS: A cohort of 34 patients from 9 families was recruited between 2001 and 2010. DNA were sequenced on all exons and flanking sequences of the PRKAG2 gene using Sanger sequencing. Overall, four families carried the recurrent p.Arg302Gln mutation, and the five others carried private mutations among which three had never been reported. In the total cohort, at 40 years of age, the risk of developing HCM was 61%, VPE 70%, conduction block 22%, and sudden cardiac death (SCD) 20%. The global survival at 60 years of age was 66%. Thirty-two per cent of patients (N = 10) required a device implantation (5 pacemakers and 5 defibrillators) at a median age of 66 years, and two patients required heart transplant. Only one patient presented with significant skeletal muscle symptoms. No significant differences regarding the occurrence of VPE, ablation complications, or death incidence were observed between different mutations. CONCLUSION: This study of patients with PRKAG2 mutations provides a more comprehensive view of the natural history of this disease and demonstrates a high risk of cardiac complications. Early recognition of this disease appears important to allow an appropriate management.

Outcomes of liver transplantation for glycogen storage disease: a matched-control study and a review of literature.

BACKGROUND: The clinical characteristics and outcomes of patients with glycogen storage disease (GSD) who undergo liver transplantation (LT) have not been well defined. In this study, our objective was to determine the outcome of LT in patients with GSD and compare it with a comparable group of patients without GSD (matched controls). METHODS: UNOS data from 1986 to 2007 were used for this study. For each GSD patient (n = 95; men 62%) who was transplanted, three patients (n = 285, men 60%) without GSD (case controls) matched for age ± five yr, year of transplantation and donor risk index (DRI) ± 0.2 were identified from the UNOS database in a random manner. Unadjusted patient survival was determined by Kaplan-Meier survival analysis and significance determined by log-rank test. RESULTS: The mean age of the group was 17.9 yr. GSD patients had lower BMI (22 vs. 24, p = 0.002), lower serum bilirubin (2.7 vs. 13.5 mg/dL, p < 0.0001), higher serum albumin (3.7 vs. 3.1 g/dL, p < 0.0001), and higher wait-list time (239 vs. 74 d, p < 0.0001) compared to case controls. Recipient age and DRI were similar between the groups. Tumors were more common in GSD group (13.7% vs. 5%). Patient survival was significantly better (p = 0.024) in GSD group at one, five, and 10 yr (82%, 76%, and 64%) than non-GSD (73%, 65%, and 59%) group. CONCLUSIONS: In this matched-control study, patients who underwent LT for GSD had a better long-term survival than a comparable group of patients without GSD.

Immune protection of auxiliary liver to other allograft: report of 3 cases.

OBJECTIVE: To assess the immune status of auxiliary liver transplantation and to clarify the immune protection of auxiliary liver to other allograft. METHODS: Immunological markers and pathological changes in 3 patients undergoing auxiliary liver transplantation were analysed. RESULTS: The lower the concentration of immunosuppressive agent, the less the rejection and the milder the intensity in the 3 patients. The function of allograft after auxiliary liver transplantation was excellent. CONCLUSIONS: Patients are in a low immune reaction state after auxiliary liver transplantation. Auxiliary liver can protect other allografts by related immunological mechanisms. The side-effects of low-concentration immunosuppressive agents on auxiliary liver and other allografts are mild.

Pulmonary interstitial glycogenosis: a new variant of neonatal interstitial lung disease.

We present the clinical, radiologic, and pathologic findings in lung biopsies from seven infants with atypical neonatal lung disease. All seven infants presented with tachypnea, hypoxemia, and diffuse interstitial infiltrates with overinflated lungs on chest radiographs in the first month of life. Lung biopsies from all cases showed similar pathology, with expansion of the interstitium by spindle-shaped cells containing periodic acid-Schiff positive diastase labile material consistent with glycogen. Immunohistochemical staining showed these cells to be vimentin positive but negative for leucocyte common antigen, lysozyme, and other macrophage markers. Electron microscopy revealed primitive interstitial mesenchymal cells with few cytoplasmic organelles and abundant monoparticulate glycogen. Minimal or no glycogen was seen in the alveolar lining cells. Five cases were treated with pulse corticosteroids; hydroxychloroquine was added in one case. Six of seven infants have shown a favorable clinical outcome. One infant died from complications of extreme prematurity and bronchopulmonary dysplasia. Three cases that have been followed for at least 6 years have shown clinical resolution and radiographic improvement. We propose the term "pulmonary interstitial glycogenosis" of the neonate for this new entity to be differentiated from other forms of interstitial lung disease. Because abundant glycogen is not normally found in pulmonary interstitial cells, we postulate an abnormality in lung cytodifferentiation involving interstitial mesenchymal cells.

[Long-term course of hepatic glycogenosis. A retrospective study of 76 cases]. / Evolution à long terme des glycogénoses hépatiques. Etude rétrospective de 76 observations.

In order to study the long term outcome of hepatic glycogen storage diseases, a national retrospective inquiry gathered 76 patients older than 12 years. In adolescents and adults, hypoglycemia, failure to thrive, pubertal delay, hepatomegaly and metabolic disturbances are major in type I, intermediary in type III and mild in type "VI+IX". Spontaneous improvement of these symptoms is noted in older patients. Beside these classical signs, anemia, high blood pressure, renal failure and persistent hypercholesterolemia were reported in some type I glycogen storage disease and bad school and professional results in type III. The knowledge of these complications should lead to a better management of these patients.

[The myocardiopathies of glycogenosis]. / Myocardiopathies des glycogénoses.

Thirty-three patients with glycogen abnormalities and myocardial disease were studied. 27 of them has type II glycogen disorders (Pompe's disease, with an intralysozymal deficit of acid maltase) and 6 with type III glycogen disorders Forbes disease, with a deficit in amylo-1-6-glucosidase). The picture of a type II abnormality in the infant is very standard: early onset, often neonatally; the association with asystole and muscular hypotonia and a characteristics clinical picture; invariable cardiomegaly and typical ECG findings (short PR interval, high voltage complexes). Death occurs before one year of age, treatment has limited effect, and attention is centred on the early discovery of heterozygotes and of diagnosis antenatally. The possibility of an obstructive type (4 out of 24) and a type with endocardial fibroelastosis (3 out of 24) must be emphasised. In the late onset myopathic form of type II disorder (3 cases), involvement of the myocardium is always found, but is of secondary importance in determining the clinical picture and natural history. The same can be said of type III disorders in which, despite the infrequency of asystole or significant cardiomegaly, a hypertrophic cardiomyopathy which may be obstructive can lead to sudden death in infancy (2 cases out of 6).