Muscle Glycogenosis type 0 (GSD0B) is an extremely rare disorder first recognized in 2007 in three siblings with childhood onset and severe cardiomyopathy. Since then, a few cases with severe cardiac involvement and premature death have been reported. We describe two unrelated cases presenting with an adult-onset myopathy with no heart involvement. Clinical features were quite similar in both patients, mainly characterized by early fatigability, myalgia and muscle weakness. Muscle biopsy revealed marked glycogen depletion in nearly all myofibers. Biochemical assay demonstrated a marked reduction of Glycogen Synthase (GS) activity. Sequence analysis of GYS1 revealed two new variants: a homozygous G to C substitution in the splice donor consensus site (c.678+1G>C) in patient1 and a homozygous missense variant c.630G>C in exon 3 (p. Asp145His) in patient 2. This study describes a new phenotype of muscle GSD0B presenting with adult onset, proximal myopathy, no cardiac abnormalities and a quite benign disease course. This report highlights the importance of a systematic diagnostic approach that includes muscle morphology and enzymatic assay to facilitate the identification of adult patients with GSD0B.

Muscle phosphorylase kinase b deficiency (PhK) is a rare disorder of glycogen metabolism characterized by exercise-induced myalgia and cramps, myoglobinuria and progressive muscle weakness. PhK deficiency is due to mutations in the PHKA1 gene inherited in an X-linked manner and is associated to glycogenosis type VIII (GSD VIII also called GSD IXd). PHKA1 gene codes for the αM subunit of the PhK, a multimeric protein complex responsible for the control of glycogen breakdown in muscle. Until now, few patients have been reported with X-linked recessive muscle PhK deficiency due to PHKA1 mutations. All reported patients presented with exercise intolerance and mild myopathy and one of them had cognitive impairment, leading to speculate about a central nervous system involvement in GSD VIII. Here we report in a sibling a novel mutation in the PHKA1 gene associated with a progressive myopathy, exercise intolerance, muscle hypertrophy and cognitive impairment as an associated feature. This report expands the genetic and clinical spectrum of the extremely rare PHKA1-related PhK deficiency and presents new evidences about its involvement in brain development.

This case report investigated exercise metabolism and the effect of oral sucrose and intravenous glucose supplementation in a 30-year-old, mildly affected man with muscle phosphorylase b kinase (PHK) deficiency caused by a novel c.586G>A mutation in the PHKA1 gene. Only 12 patients with PHK deficiency have been reported and it is unclear to what extent patients exhibit symptoms during exercise. Carbohydrate and fat metabolism were measured during 30 min of exercise at ∼ 70% of peak oxidative capacity using stabile isotope technique and signaling proteins and enzymes in the energy pathway were analyzed by Western blot. Results were compared to four healthy subjects. These studies show that neither oral nor intravenous glucose improved exercise tolerance in this patient with PHK deficiency. Despite Western blots indicated affected metabolism on protein level, systemic substrate turnover studies showed that carbohydrate and fatty acid oxidations were normal.

Glycogen storage disorder type III (GSDIII), or debranching enzyme (GDE) deficiency, is a rare metabolic disorder characterized by variable liver, cardiac, and skeletal muscle involvement. GSDIII manifests with liver symptoms in infancy and muscle involvement during early adulthood. Muscle biopsy is mainly performed in patients diagnosed in adulthood, as routine diagnosis relies on blood or liver GDE analysis, followed by AGL gene sequencing. The GSDIII mouse model recapitulate the clinical phenotype in humans, and a nearly full rescue of muscle function was observed in mice treated with the dual AAV vector expressing the GDE transgene.In order to characterize GSDIII muscle morphological spectrum and identify novel disease markers and pathways, we performed a large international multicentric morphological study on 30 muscle biopsies from GSDIII patients. Autophagy flux studies were performed in human muscle biopsies and muscles from GSDIII mice. The human muscle biopsies revealed a typical and constant vacuolar myopathy, characterized by multiple and variably sized vacuoles filled with PAS-positive material. Using electron microscopy, we confirmed the presence of large non-membrane bound sarcoplasmic deposits of normally structured glycogen as well as smaller rounded sac structures lined by a continuous double membrane containing only glycogen, corresponding to autophagosomes. A consistent SQSTM1/p62 decrease and beclin-1 increase in human muscle biopsies suggested an enhanced autophagy. Consistent with this, an increase in the lipidated form of LC3, LC3II was found in patients compared to controls. A decrease in SQSTM1/p62 was also found in the GSDIII mouse model.In conclusion, we characterized the morphological phenotype in GSDIII muscle and demonstrated dysfunctional autophagy in GSDIII human samples.These findings suggest that autophagic modulation combined with gene therapy might be considered as a novel treatment for GSDIII.

The field of glycogenosis has been greatly expanded over the past few years with the discovery of new metabolic diseases that have allowed new metabolic pathways to be deciphered. Described here are the clinical and pathological features of four recently described muscle glycogenoses caused by GYS1, GYG1, RBCK1 and PGM1 gene mutations. The initial steps of glycogen synthesis are involved in deficiencies of glycogenin-1 (GYG1) and muscle glycogen synthase (GYS1). Phosphoglucomutase deficiency disrupts two metabolic pathways: the connection between galactose and glycogen on the one hand, and glucose metabolism on the other. However, the metabolic consequences of mutations in the ubiquitin ligase gene RBCK1 are still poorly understood.