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1.  Osteopoikilosis and multiple exostoses caused by novel mutations in LEMD3 and EXT1 genes respectively - coincidence within one family 
BMC Medical Genetics  2010;11:110.
Osteopoikilosis is a rare autosomal dominant genetic disorder, characterised by the occurrence of the hyperostotic spots preferentially localized in the epiphyses and metaphyses of the long bones, and in the carpal and tarsal bones [1]. Heterozygous LEMD3 gene mutations were shown to be the primary cause of the disease [2]. Association of the primarily asymptomatic osteopokilosis with connective tissue nevi of the skin is categorized as Buschke-Ollendorff syndrome (BOS) [3]. Additionally, osteopoikilosis can coincide with melorheostosis (MRO), a more severe bone disease characterised by the ectopic bone formation on the periosteal and endosteal surface of the long bones [4-6]. However, not all MRO affected individuals carry germ-line LEMD3 mutations [7]. Thus, the genetic cause of MRO remains unknown. Here we describe a familial case of osteopoikilosis in which a novel heterozygous LEMD3 mutation coincides with a novel mutation in EXT1, a gene involved in aetiology of multiple exostosis syndrome. The patients affected with both LEMD3 and EXT1 gene mutations displayed typical features of the osteopoikilosis. There were no additional skeletal manifestations detected however, various non-skeletal pathologies coincided in this group.
We investigated LEMD3 and EXT1 in the three-generation family from Poland, with 5 patients affected with osteopoikilosis and one child affected with multiple exostoses.
We found a novel c.2203C > T (p.R735X) mutation in exon 9 of LEMD3, resulting in a premature stop codon at amino acid position 735. The mutation co-segregates with the osteopoikilosis phenotype and was not found in 200 ethnically matched controls. Another new substitution G > A was found in EXT1 gene at position 1732 (cDNA) in Exon 9 (p.A578T) in three out of five osteopoikilosis affected family members. Evolutionary conservation of the affected amino acid suggested possible functional relevance, however no additional skeletal manifestations were observed other then those specific for osteopoikilosis. Finally in one member of the family we found a splice site mutation in the EXT1 gene intron 5 (IVS5-2 A > G) resulting in the deletion of 9 bp of cDNA encoding three evolutionarily conserved amino acid residues. This child patient suffered from a severe form of exostoses, thus a causal relationship can be postulated.
We identified a new mutation in LEMD3 gene, accounting for the familial case of osteopoikilosis. In the same family we identified two novel EXT1 gene mutations. One of them A598T co-incided with the LEMD3 mutation. Co-incidence of LEMD3 and EXT1 gene mutations was not associated with a more severe skeletal phenotype in those patients.
PMCID: PMC2912259  PMID: 20618940
2.  A Splice Mutation in the PHKG1 Gene Causes High Glycogen Content and Low Meat Quality in Pig Skeletal Muscle 
PLoS Genetics  2014;10(10):e1004710.
Glycolytic potential (GP) in skeletal muscle is economically important in the pig industry because of its effect on pork processing yield. We have previously mapped a major quantitative trait loci (QTL) for GP on chromosome 3 in a White Duroc × Erhualian F2 intercross. We herein performed a systems genetic analysis to identify the causal variant underlying the phenotype QTL (pQTL). We first conducted genome-wide association analyses in the F2 intercross and an F19 Sutai pig population. The QTL was then refined to an 180-kb interval based on the 2-LOD drop method. We then performed expression QTL (eQTL) mapping using muscle transcriptome data from 497 F2 animals. Within the QTL interval, only one gene (PHKG1) has a cis-eQTL that was colocolizated with pQTL peaked at the same SNP. The PHKG1 gene encodes a catalytic subunit of the phosphorylase kinase (PhK), which functions in the cascade activation of glycogen breakdown. Deep sequencing of PHKG1 revealed a point mutation (C>A) in a splice acceptor site of intron 9, resulting in a 32-bp deletion in the open reading frame and generating a premature stop codon. The aberrant transcript induces nonsense-mediated decay, leading to lower protein level and weaker enzymatic activity in affected animals. The mutation causes an increase of 43% in GP and a decrease of>20% in water-holding capacity of pork. These effects were consistent across the F2 and Sutai populations, as well as Duroc × (Landrace × Yorkshire) hybrid pigs. The unfavorable allele exists predominantly in Duroc-derived pigs. The findings provide new insights into understanding risk factors affecting glucose metabolism, and would greatly contribute to the genetic improvement of meat quality in Duroc related pigs.
Author Summary
Glycogen storage diseases (GSD) are a group of inherited disorders characterized by storage of excess glycogen, which are mainly caused by the abnormality of a particular enzyme essential for releasing glucose from glycogen. GSD-like conditions have been described in a wide variety of species. Pigs are a valuable model for the study of human GSD. Moreover, pigs affected by GSD usually produce inferior pork with a lower ultimate pH (so-called “acid meat”) and less processing yield due to post-mortem degradation of the excess glycogen. So far, only one causal variant, PRKAG3 R225Q, has been identified for GSD in pigs. Here we reported a loss-of-function mutation in the PHKG1 gene that causes the deficiency of the glycogen breakdown, consequently leading to GSD and acid meat in Duroc-sired pigs. Eliminating the undesirable mutation from the breeding stock by a diagnostic DNA test will greatly reduce the incidence of GSD and significantly improve pork quality and productivity in the pig.
PMCID: PMC4207639  PMID: 25340394
Molecular genetics and metabolism  2005;87(4):284-288.
The glycogen storage diseases comprise several inherited diseases caused by abnormalities of enzymes that regulate the synthesis or degradation of glycogen. In contrast to the classic hepatic glycogen storage diseases that are characterized by fasting hypoglycemia and hepatomegaly, the liver is not enlarged in GSD0. Patients with GSD0 typically have fasting ketotic hypoglycemia without prominent muscle symptoms. Most children are cognitively and developmentally normal. Short stature and osteopenia are common features, but other long-term complications, common in other types of GSD, have not been reported in GSD0. Until recently, the definitive diagnosis of GSD0 depended on the demonstration of decreased hepatic glycogen on a liver biopsy. The need for an invasive procedure may be one reason that this condition has been infrequently diagnosed. Mutation analysis of the GYS2 gene (12p12.2) is a non-invasive method for making this diagnosis in patients suspected to have this disorder. This mini-review discusses the pathophysiology of this disorder, use of mutation analysis to diagnose GSD0, and the clinical characteristics of all reported cases of GSD0.
PMCID: PMC1474809  PMID: 16337419
Glycogen storage disease type 0; Hepatic glycogen synthase deficiency; Ketotic hypoglycemia; Lactic acid; Mutation analysis; Hyperglycemia
4.  Two Cases of Pulmonary Hypertension Associated with Type III Glycogen Storage Disease 
JIMD Reports  2011;1:79-82.
Glycogen storage diseases (GSDs) comprise a large, heterogeneous group of disorders characterized by abnormal glycogen deposition. Multiple cases in the literature have demonstrated an association between GSD type I and pulmonary arterial hypertension (PAH). We now also report on two patients with GSD type III and PAH, a novel association. The first patient was a 16-year-old girl of Nicaraguan descent with a history of hepatomegaly and growth retardation. Molecular testing identified a homozygous 17delAG mutation in AGL consistent with GSD type IIIb. At the age of 16, she was found to have PAH and was started on medical therapy. Two years later, she developed acute chest pain and died shortly thereafter. The second patient is a 13-year-old girl of Colombian descent homozygous for the c.3911dupA mutation consistent with GSD IIIa. An echocardiogram at age 2 showed left ventricular hypertrophy, which resolved following the institution of a high protein, moderate carbohydrate diet during the day and continuous gastric-tube feeding overnight. At the age of 12, she was found to have pulmonary hypertension. She was started on sildenafil, and her clinical status has shown marked improvement including normalization of her elevated transaminases. PAH may be a rare association in patients with GSD IIIa and IIIb and should be evaluated with screening echocardiograms for cardiac hypertrophy or if they present with symptoms of right-sided heart failure such as shortness of breath, chest pain, cyanosis, fatigue, dizziness, syncope, or edema. Early diagnosis of PAH is important as increasingly effective treatments are now available.
PMCID: PMC3509822  PMID: 23430832
Amylo-1,6-glucosidase; Genetic; Hepatomegaly; Metabolic
5.  Involvement of endocrine system in a patient affected by Glycogen storage disease 1b: speculation on the role of autoimmunity 
Glycogen storage disease type 1b (GSD1b) is an inherited metabolic defect of glycogenolysis and gluconeogenesis due to mutations of the SLC37A4 gene and to defective transport of glucose-6-phosphate. The clinical presentation of GSD1b is characterized by hepatomegaly, failure to thrive, fasting hypoglycemia, and dyslipidemia. Patients affected by GSD1b also show neutropenia and/or neutrophil dysfunction that cause increased susceptibility to recurrent bacterial infections. GSD1b patients are also at risk for inflammatory bowel disease. Occasional reports suggesting an increased risk of autoimmune disorders in GSD1b patients, have been published. These complications affect the clinical outcome of the patients. Here we describe the occurrence of autoimmune endocrine disorders including thyroiditis and growth hormone deficiency, in a patient affected by GSD1b. This case further supports the association between GSD1b and autoimmune diseases.
PMCID: PMC3974180  PMID: 24646511
Glycogen storage disease 1b; Autoimmunity; Thyroiditis; Growth hormone deficiency; Inflammatory bowel disease
6.  Enchondromatosis: insights on the different subtypes 
Enchondromatosis is a rare, heterogeneous skeletal disorder in which patients have multiple enchondromas. Enchondromas are benign hyaline cartilage forming tumors in the medulla of metaphyseal bone. The disorder manifests itself early in childhood without any significant gender bias. Enchondromatosis encompasses several different subtypes of which Ollier disease and Maffucci syndrome are most common, while the other subtypes (metachondromatosis, genochondromatosis, spondyloenchondrodysplasia, dysspondyloenchondromatosis and cheirospondyloenchondromatosis) are extremely rare. Most subtypes are non-hereditary, while some are autosomal dominant or recessive. The gene(s) causing the different enchondromatosis syndromes are largely unknown. They should be distinguished and adequately diagnosed, not only to guide therapeutic decisions and genetic counseling, but also with respect to research into their etiology. For a longtime enchondromas have been considered a developmental disorder caused by the failure of normal endochondral bone formation. With the identification of genetic abnormalities in enchondromas however, they were being thought of as neoplasms. Active hedgehog signaling is reported to be important for enchondroma development and PTH1R mutations have been identified in ∼10% of Ollier patients. One can therefore speculate that the gene(s) causing the different enchondromatosis subtypes are involved in hedgehog/PTH1R growth plate signaling. Adequate distinction within future studies will shed light on whether these subtypes are different ends of a spectrum caused by a single gene, or that they represent truely different diseases. We therefore review the available clinical information for all enchondromatosis subtypes and discuss the little molecular data available hinting towards their cause.
PMCID: PMC2907117  PMID: 20661403
Ollier disease; Maffucci syndrome; enchondroma; metachondromatosis; enchondromatosis; central chondrosarcoma
7.  Determining mutations in G6PC and SLC37A4 genes in a sample of Brazilian patients with glycogen storage disease types Ia and Ib 
Genetics and Molecular Biology  2013;36(4):502-506.
Glycogen storage disease (GSD) comprises a group of autosomal recessive disorders characterized by deficiency of the enzymes that regulate the synthesis or degradation of glycogen. Types Ia and Ib are the most prevalent; while the former is caused by deficiency of glucose-6-phosphatase (G6Pase), the latter is associated with impaired glucose-6-phosphate transporter, where the catalytic unit of G6Pase is located. Over 85 mutations have been reported since the cloning of G6PC and SLC37A4 genes. In this study, twelve unrelated patients with clinical symptoms suggestive of GSDIa and Ib were investigated by using genetic sequencing of G6PC and SLC37A4 genes, being three confirmed as having GSD Ia, and two with GSD Ib. In seven of these patients no mutations were detected in any of the genes. Five changes were detected in G6PC, including three known point mutations (p.G68R, p.R83C and p.Q347X) and two neutral mutations (c.432G > A and c.1176T > C). Four changes were found in SLC37A4: a known point mutation (p.G149E), a novel frameshift insertion (c.1338_1339insT), and two neutral mutations (c.1287G > A and c.1076-28C > T). The frequency of mutations in our population was similar to that observed in the literature, in which the mutation p.R83C is also the most frequent one. Analysis of both genes should be considered in the investigation of this condition. An alternative explanation to the negative results in this molecular study is the possibility of a misdiagnosis. Even with a careful evaluation based on laboratory and clinical findings, overlap with other types of GSD is possible, and further molecular studies should be indicated.
PMCID: PMC3873180  PMID: 24385852
DNA-based diagnosis; glycogen storage disease; G6PC; SLC37A4; mutation
8.  Improvement of Cardiomyopathy After High-Fat Diet in Two Siblings with Glycogen Storage Disease Type III 
JIMD Reports  2014;17:91-95.
Glycogenosis type III (GSD III) is an autosomal recessive disorder due to amylo-1,6-glucosidase deficiency. This disease causes limit dextrin storage in affected tissues: liver, skeletal muscles, and heart in GSD IIIa and only liver in GSD IIIb. Cardiomyopathy is quite frequent in GSD IIIa with variable severity and progression of manifestations. It is not clear if diet manipulation may interfere with cardiomyopathy’s progression. Recent case reports showed improvement of cardiomyopathy following a ketogenic diet.
Two siblings (girl and boy), 7- and 5-year-old, both affected with GSD IIIa, developed severe and rapidly worsening left ventricular hypertrophy in the first years of life, while treated with frequent diurnal and nocturnal hyperproteic meals followed by orally administered uncooked cornstarch. Subsequently they were treated with high-fat (60%) and high-protein (25%), low-carbohydrate (15%) diet. After 12 months exertion dyspnea disappeared in the girl and biochemical blood tests, cardiac enzymes, and congestive heart failure markers improved in both (CK 3439→324, 1304→581 U/L; NT-proBNP 2084→206, 782→135 pg/mL, respectively); ultrasound assessment in both patients showed a relevant reduction of the thickness of interventricular septum (30→16, 16→11 mm, respectively) and left ventricle posterior wall (18→7, 13→8 mm, respectively) and an improvement of the outflow obstruction. A diet rich in fats as well as proteins and poor in carbohydrates could be a beneficial therapeutic choice for GSD III with cardiomyopathy. Future research is needed to confirm the beneficial effect of this treatment and to design treatment strategies with the aim to provide alternative source of energy and prevent glycogen accumulation.
PMCID: PMC4241197  PMID: 25308556
Amylo-1,6-glucosidase; Cardiac hypertrophy; GSD III; High-protein diet; Ketogenic diet; Low-carbohydrate diet
Sleep medicine  2011;13(1):52-57.
To explore how insomnia symptoms are hierarchically organized in individuals reporting daytime consequences of their sleep disturbances.
This is a cross-sectional study conducted in the general population of the states of California, New York and Texas. The sample included 8,937 individuals aged 18 years or older representative of the general population. Telephone interviews on sleep habits and disorders were managed with the Sleep-EVAL expert system and using DSM-IV and ICSD classifications. Insomnia symptoms and Global Sleep Dissatisfaction (GSD) had to occur at least three times per week for at least three months.
A total of 26.2% of the sample had a GSD. Individuals with GSD reported at least one insomnia symptom in 73.1% of the cases. The presence of GSD in addition to insomnia symptoms considerably increased the proportion of individuals with daytime consequences related to insomnia. In the classification trees performed, GSD arrived as the first predictor for daytime consequences related to insomnia. The second predictor was nonrestorative sleep followed by difficulty resuming sleep and difficulty initiating sleep.
Classification trees are a useful way to hierarchically organize symptoms and to help diagnostic classifications. In this study, GSD was found to be the foremost symptom in identifying individuals with daytime consequences related to insomnia.
PMCID: PMC3249005  PMID: 22036602
10.  Glycogen storage disease type III-hepatocellular carcinoma a long-term complication? 
Journal of hepatology  2006;46(3):492-498.
Glycogen storage disease III (GSD III) is caused by a deficiency of glycogen-debranching enzyme which causes an incomplete glycogenolysis resulting in glycogen accumulation with abnormal structure (short outer chains resembling limit dextrin) in liver and muscle. Hepatic involvement is considered mild, self-limiting and improves with age. With increased survival, a few cases of liver cirrhosis and hepatocellular carcinoma (HCC) have been reported.
A systematic review of 45 cases of GSD III at our center (20 months to 67 years of age) was reviewed for HCC, 2 patients were identified. A literature review of HCC in GSD III was performed and findings compared to our patients.
GSD III patients are at risk for developing HCC. Cirrhosis was present in all cases and appears to be responsible for HCC transformation There are no reliable biomarkers to monitor for HCC in GSD III. Systematic evaluation of liver disease needs be continued in all patients, despite lack of symptoms. Development of guidelines to allow for systematic review and microarray studies are needed to better delineate the etiology of the hepatocellular carcinoma in patients with GSD III.
PMCID: PMC2683272  PMID: 17196294
Hepatocellular carcinoma; Glycogen storage disease type III; Liver cirrhosis; Debranching enzyme deficiency; Cori disease; Hepatomegaly; Hypoglycemia
11.  A Novel Mutation (A148V) in the Glucose 6-phosphate Translocase (SLC37A4) Gene in a Korean Patient with Glycogen Storage Disease Type 1b 
Journal of Korean Medical Science  2005;20(3):499-501.
We report a Korean patient with glycogen storage disease type 1b (GSD-1b) whose diagnosis was confirmed by liver biopsy and laboratory results. The patient presented with delay of puberty and short stature on admission and had typical clinical symptoms of GSD as well as chronic neutropenia and inflammatory bowel disease. Mutation analysis of the glucose 6-phosphate translocase 6-phosphate translocase (SLC37A4) gene revealed that the patient was a compound heterozygote of two different mutations including a deletion mutation (c.1042_1043delCT; L348fs) and a missense mutation (A148V). The L348fs mutation was inherited from the patient's father and has been reported in an Italian family with GSD-1b, while the A148V mutation was transmitted from the patient's mother and was a novel mutation. To the best of our knowledge, this is the first report of genetically confirmed case of GSD-1b in Korean.
PMCID: PMC2782211  PMID: 15953877
Glycogen Storage Disease; Glycogen Storage Disease Type 1; GSD-1b; Genes; SLC37A4 Gene; Mutation
12.  Polymorphisms in the Tlr4 and Tlr5 Gene Are Significantly Associated with Inflammatory Bowel Disease in German Shepherd Dogs 
PLoS ONE  2010;5(12):e15740.
Inflammatory bowel disease (IBD) is considered to be the most common cause of vomiting and diarrhoea in dogs, and the German shepherd dog (GSD) is particularly susceptible. The exact aetiology of IBD is unknown, however associations have been identified between specific single-nucleotide polymorphisms (SNPs) in Toll-like receptors (TLRs) and human IBD. However, to date, no genetic studies have been undertaken in canine IBD. The aim of this study was to investigate whether polymorphisms in canine TLR 2, 4 and 5 genes are associated with IBD in GSDs. Mutational analysis of TLR2, TLR4 and TLR5 was performed in 10 unrelated GSDs with IBD. Four non-synonymous SNPs (T23C, G1039A, A1571T and G1807A) were identified in the TLR4 gene, and three non-synonymous SNPs (G22A, C100T and T1844C) were identified in the TLR5 gene. The non-synonymous SNPs identified in TLR4 and TLR5 were evaluated further in a case-control study using a SNaPSHOT multiplex reaction. Sequencing information from 55 unrelated GSDs with IBD were compared to a control group consisting of 61 unrelated GSDs. The G22A SNP in TLR5 was significantly associated with IBD in GSDs, whereas the remaining two SNPs were found to be significantly protective for IBD. Furthermore, the two SNPs in TLR4 (A1571T and G1807A) were in complete linkage disequilibrium, and were also significantly associated with IBD. The TLR5 risk haplotype (ACC) without the two associated TLR4 SNP alleles was significantly associated with IBD, however the presence of the two TLR4 SNP risk alleles without the TLR5 risk haplotype was not statistically associated with IBD. Our study suggests that the three TLR5 SNPs and two TLR4 SNPs; A1571T and G1807A could play a role in the pathogenesis of IBD in GSDs. Further studies are required to confirm the functional importance of these polymorphisms in the pathogenesis of this disease.
PMCID: PMC3009732  PMID: 21203467
13.  Nosology and Classification of Genetic Skeletal Disorders – 2010 Revision& 
Genetic disorders involving the skeletal system arise through disturbances in the complex processes of skeletal development, growth and homeostasis and remain a diagnostic challenge because of their variety. The Nosology and Classification of Genetic Skeletal Disorders provides an overview of recognized diagnostic entities and groups them by clinical and radiographic features and molecular pathogenesis. The aim is to provide the Genetics, Pediatrics and Radiology community with a list of recognized genetic skeletal disorders that can be of help in the diagnosis of individual cases, in the delineation of novel disorders, and in building bridges between clinicians and scientists interested in skeletal biology.
In the 2010 revision, 456 conditions were included and placed in 40 groups defined by molecular, biochemical and/or radiographic criteria. Of these conditions, 316 were associated with mutations in one or more of 226 different genes, ranging from common, recurrent mutations to “private” found in single families or individuals. Thus, the Nosology is a hybrid between a list of clinically defined disorders, waiting for molecular clarification, and an annotated database documenting the phenotypic spectrum produced by mutations in a given gene.
The Nosology should be useful for the diagnosis of patients with genetic skeletal diseases, particularly in view of the information flood expected with the novel sequencing technologies; in the delineation of clinical entities and novel disorders, by providing an overview of established nosologic entities; and for scientists looking for the clinical correlates of genes, proteins and pathways involved in skeletal biology.
PMCID: PMC3166781  PMID: 21438135
14.  Nosology and Classification of Genetic Skeletal Disorders: 2010 Revision 
Genetic disorders involving the skeletal system arise through disturbances in the complex processes of skeletal development, growth and homeostasis and remain a diagnostic challenge because of their variety. The Nosology and Classification of Genetic Skeletal Disorders provides an overview of recognized diagnostic entities and groups them by clinical and radiographic features and molecular pathogenesis. The aim is to provide the Genetics, Pediatrics and Radiology community with a list of recognized genetic skeletal disorders that can be of help in the diagnosis of individual cases, in the delineation of novel disorders, and in building bridges between clinicians and scientists interested in skeletal biology. In the 2010 revision, 456 conditions were included and placed in 40 groups defined by molecular, biochemical, and/or radiographic criteria. Of these conditions, 316 were associated with mutations in one or more of 226 different genes, ranging from common, recurrent mutations to “private” found in single families or individuals. Thus, the Nosology is a hybrid between a list of clinically defined disorders, waiting for molecular clarification, and an annotated database documenting the phenotypic spectrum produced by mutations in a given gene. The Nosology should be useful for the diagnosis of patients with genetic skeletal diseases, particularly in view of the information flood expected with the novel sequencing technologies; in the delineation of clinical entities and novel disorders, by providing an overview of established nosologic entities; and for scientists looking for the clinical correlates of genes, proteins and pathways involved in skeletal biology. © 2011 Wiley-Liss, Inc.
PMCID: PMC3166781  PMID: 21438135
skeletal genetics; osteochondrodysplasias; nosology; dysostoses; molecular basis of disease
15.  Ollier disease 
Enchondromas are common intraosseous, usually benign cartilaginous tumors, that develop in close proximity to growth plate cartilage. When multiple enchondromas are present, the condition is called enchondromatosis also known as Ollier disease (WHO terminology). The estimated prevalence of Ollier disease is 1/100,000. Clinical manifestations often appear in the first decade of life. Ollier disease is characterized by an asymmetric distribution of cartilage lesions and these can be extremely variable (in terms of size, number, location, evolution of enchondromas, age of onset and of diagnosis, requirement for surgery). Clinical problems caused by enchondromas include skeletal deformities, limb-length discrepancy, and the potential risk for malignant change to chondrosarcoma. The condition in which multiple enchondromatosis is associated with soft tissue hemangiomas is known as Maffucci syndrome. Until now both Ollier disease and Maffucci syndrome have only occurred in isolated patients and not familial. It remains uncertain whether the disorder is caused by a single gene defect or by combinations of (germ-line and/or somatic) mutations. The diagnosis is based on clinical and conventional radiological evaluations. Histological analysis has a limited role and is mainly used if malignancy is suspected. There is no medical treatment for enchondromatosis. Surgery is indicated in case of complications (pathological fractures, growth defect, malignant transformation). The prognosis for Ollier disease is difficult to assess. As is generally the case, forms with an early onset appear more severe. Enchondromas in Ollier disease present a risk of malignant transformation of enchondromas into chondrosarcomas.
PMCID: PMC1592482  PMID: 16995932
16.  Cardiac Involvement in Glycogen Storage Disease Type IV: Two Cases and the Two Ends of a Spectrum 
Case Reports in Medicine  2012;2012:764286.
Glycogen storage disease type IV (GSD IV) is an autosomal recessive disorder due to the deficiency of α 1,4-glucan branching enzyme, resulting in an accumulation of amylopectin-like polysaccharide in various systems. We describe two cases, a 23-year-old girl with dilated cardiomyopathy who presented with progressive dyspnea and fatigue and a 28-year-old girl with hypertrophic cardiomyopathy who was asymptomatic, secondary to the accumulation of amylopectin-like fibrillar glycogen, in heart. In both patients, the diagnosis was confirmed by enzyme assessment. Our patients showed that GSD IV is not only liver or skeletal muscle disease, but also it can be presented in different form of the spectrum of cardiomyopathy from dilated to hypertrophic and from asymptomatic to decompensated heart failure. Also, to our knowledge, this is the first hypertrophic cardiomyopathy case due to GSD IV in the literature.
PMCID: PMC3463931  PMID: 23056054
17.  Glycogen Storage Disease type 1a – a secondary cause for hyperlipidemia: report of five cases 
Background and aims
Glycogen storage disease type Ia (GSD Ia) is a rare metabolic disorder, caused by deficient activity of glucose-6-phosphatase-α. It produces fasting induced hypoglycemia and hepatomegaly, usually manifested in the first semester of life. Besides, it is also associated with growth delay, anemia, platelet dysfunction, osteopenia and sometimes osteoporosis. Hyperlipidemia and hyperuricemia are almost always present and hepatocellular adenomas and renal dysfunction frequent late complications.
The authors present a report of five adult patients with GSD Ia followed in internal medicine appointments and subspecialties.
Four out of five patients were diagnosed in the first 6 months of life, while the other one was diagnosed in adult life after the discovery of hepatocellular adenomas. In two cases genetic tests were performed, being identified the missense mutation R83C in one, and the mutation IVS4-3C > G in the intron 4 of glucose-6-phosphatase gene, not previously described, in the other. Growth retardation was present in 3 patients, and all of them had anemia, increased bleeding tendency and hepatocellular adenomas; osteopenia/osteoporosis was present in three cases. All but one patient had marked hyperlipidemia and hyperuricemia, with evidence of endothelial dysfunction in one case and of brain damage with refractory epilepsy in another case. Proteinuria was present in two cases and end-stage renal disease in another case. There was a great variability in the dietary measures; in one case, liver transplantation was performed, with correction of the metabolic derangements.
Hyperlipidemia is almost always present and only partially responds to dietary and drug therapy; liver transplantation is the only definitive solution. Although its association with premature atherosclerosis is rare, there have been reports of endothelial dysfunction, raising the possibility for increased cardiovascular risk in this group of patients. Being a rare disease, no single metabolic center has experience with large numbers of patients and the recommendations are based on clinical experience more than large scale studies.
PMCID: PMC3688353  PMID: 23738826
Glycogen storage disease type Ia; Glucose-6-phosphatase-α; Hypoglycemia; Hyperlactacidemia; Hyperlipidemia; Hyperuricemia
18.  HLA-A and -B alleles and haplotypes in 240 index patients with common variable immunodeficiency and selective IgG subclass deficiency in central Alabama 
We wanted to quantify HLA-A and -B phenotype and haplotype frequencies in Alabama index patients with common variable immunodeficiency (CVID) and selective IgG subclass deficiency (IgGSD), and in control subjects.
Phenotypes were detected using DNA-based typing (index cases) and microlymphocytotoxicity typing (controls).
A and B phenotypes were determined in 240 index cases (114 CVID, 126 IgGSD) and 1,321 controls and haplotypes in 195 index cases and 751 controls. Phenotyping revealed that the "uncorrected" frequencies of A*24, B*14, B*15, B*35, B*40, B*49, and B*50 were significantly greater in index cases, and frequencies of B*35, B*58, B*62 were significantly lower in index cases. After Bonferroni corrections, the frequencies of phenotypes A*24, B*14, and B*40 were significantly greater in index cases, and the frequency of B*62 was significantly lower in index cases. The most common haplotypes in index cases were A*02-B*44 (frequency 0.1385), A*01-B*08 (frequency 0.1308), and A*03-B*07 (frequency 0.1000), and the frequency of each was significantly greater in index cases than in control subjects ("uncorrected" values of p < 0.0001, 0.0252, and 0.0011, respectively). After performing Bonferroni corrections, however, the frequency of A*02-B*44 alone was significantly increased in probands (p < 0.0085). Three other haplotypes were also significantly more frequent in index cases (A*03-B*14, A*31-B*40, and A*32-B*14). The combined frequencies of three latter haplotypes in index patients and control subjects were 0.0411 and 0.0126, respectively ("uncorrected" value of p < 0.0002; "corrected" value of p = 0.0166). Most phenotype and haplotype frequencies in CVID and IgGSD were similar. 26.7% of index patients were HLA-haploidentical with one or more other index patients. We diagnosed CVID or IgGSD in first-degree or other relatives of 26 of 195 index patients for whom HLA-A and -B haplotypes had been ascertained; A*01-B*08, A*02-B*44, and A*29-B*44 were most frequently associated with CVID or IgGSD in these families. We conservatively estimated the combined population frequency of CVID and IgGSD to be 0.0092 in adults, based on the occurrence of CVID and IgGSD in spouses of the index cases.
CVID and IgGSD in adults are significantly associated with several HLA haplotypes, many of which are also common in the Alabama Caucasian population. Immunoglobulin phenotype variability demonstrated in index cases and family studies herein suggests that there are multiple gene(s) on Ch6p or other chromosomes that modify immunoglobulin phenotypes of CVID and IgGSD. The estimated prevalence of CVID and IgGSD in central Alabama could be reasonably attributed to the fact that many HLA haplotypes significantly associated with these disorders are also common in the general population.
PMCID: PMC166147  PMID: 12803653
common variable immunodeficiency; haplotype; HFE; hemochromatosis; HLA; IgG subclass deficiency; population genetics
19.  Loss-of-Function Mutations in PTPN11 Cause Metachondromatosis, but Not Ollier Disease or Maffucci Syndrome 
PLoS Genetics  2011;7(4):e1002050.
Metachondromatosis (MC) is a rare, autosomal dominant, incompletely penetrant combined exostosis and enchondromatosis tumor syndrome. MC is clinically distinct from other multiple exostosis or multiple enchondromatosis syndromes and is unlinked to EXT1 and EXT2, the genes responsible for autosomal dominant multiple osteochondromas (MO). To identify a gene for MC, we performed linkage analysis with high-density SNP arrays in a single family, used a targeted array to capture exons and promoter sequences from the linked interval in 16 participants from 11 MC families, and sequenced the captured DNA using high-throughput parallel sequencing technologies. DNA capture and parallel sequencing identified heterozygous putative loss-of-function mutations in PTPN11 in 4 of the 11 families. Sanger sequence analysis of PTPN11 coding regions in a total of 17 MC families identified mutations in 10 of them (5 frameshift, 2 nonsense, and 3 splice-site mutations). Copy number analysis of sequencing reads from a second targeted capture that included the entire PTPN11 gene identified an additional family with a 15 kb deletion spanning exon 7 of PTPN11. Microdissected MC lesions from two patients with PTPN11 mutations demonstrated loss-of-heterozygosity for the wild-type allele. We next sequenced PTPN11 in DNA samples from 54 patients with the multiple enchondromatosis disorders Ollier disease or Maffucci syndrome, but found no coding sequence PTPN11 mutations. We conclude that heterozygous loss-of-function mutations in PTPN11 are a frequent cause of MC, that lesions in patients with MC appear to arise following a “second hit,” that MC may be locus heterogeneous since 1 familial and 5 sporadically occurring cases lacked obvious disease-causing PTPN11 mutations, and that PTPN11 mutations are not a common cause of Ollier disease or Maffucci syndrome.
Author Summary
Children with cartilage tumor syndromes form multiple tumors of cartilage next to joints. These tumors can occur inside the bones, as with Ollier disease and Maffuci syndrome, or on the surface of bones, as in the Multiple Osteochondroma syndrome (MO). In a hybrid syndrome, called metachondromatosis (MC), patients develop tumors both on and within bones. Only the genes causing MO are known. Since MC is inherited, we studied genetic markers in an affected family and found a region of the genome, encompassing 100 genes, always passed on to affected members. Using a recently developed method, we captured and sequenced all 100 genes in multiple families and found mutations in one gene, PTPN11, in 11 of 17 families. Patients with MC have one mutant copy of PTPN11 from their affected parent and one normal copy from their unaffected parent in all cells. We found that the normal copy is additionally lost in cartilage cells that form tumors, giving rise to cells without PTPN11. Mutations in PTPN11 were not found in other cartilage tumor syndromes, including Ollier disease and Maffucci syndrome. We are currently working to understand how loss of PTPN11 in cartilage cells causes tumors to form.
PMCID: PMC3077396  PMID: 21533187
20.  The Significance of Clinical and Laboratory Features in the Diagnosis of Glycogen Storage Disease Type V: A Case Report 
Journal of Korean Medical Science  2014;29(7):1021-1024.
Glycogen storage disease type V (GSD-V) is the most common disorder of muscle glycogenosis with characteristic clinical and laboratory findings. A 32-yr-old woman complained of exercise intolerance and myoglobulinuria since early adolescence. She reported several episodes of second-wind phenomenon. Physical examination did not show any neurological abnormality, including fixed muscle weakness or atrophy. Serum creatine kinase level was 1,161 IU/L at rest. The result of the non-ischemic forearm exercise test was compatible with GSD-V. Mutation analysis identified the compound heterozygous mutations of the PYGM, p.D510fs and p.F710del, which has not yet been reported in Korea. The present case recognizes that detail clinical and laboratory analysis is the first step in the diagnosis of GSD-V.
Graphical Abstract
PMCID: PMC4101771  PMID: 25045239
Glycogen Storage Disease Type V; McArdle's Disease; Phosphorylase, Glycogen, Muscle (PYGM)
21.  Progress and problems in muscle glycogenoses 
Acta Myologica  2011;30(2):96-102.
In this selective review, we consider a number of unsolved questions regarding the glycogen storage diseases (GSD). Thus, the pathogenesis of Pompe disease (GSD II) is not simply explained by excessive intralysosomal glycogen storage and may relate to a more general dysfunction of autophagy. It is not clear why debrancher deficiency (GSD III) causes fixed myopathy rather than exercise intolerance, unless this is due to the frequent accompanying neuropathy. The infantile neuromuscular presentation of branching enzyme deficiency (GSD IV) is underdiagnosed and is finally getting the attention it deserves. On the other hand, the late-onset variant of GSD IV (adult polyglucosan body disease APBD) is one of several polyglucosan disorders (including Lafora disease) due to different etiologies. We still do not understand the clinical heterogeneity of McArdle disease (GSD V) or the molecular basis of the rare fatal infantile form. Similarly, the multisystemic infantile presentation of phosphofructokinase deficiency (GSD VII) is a conundrum. We observed an interesting association between phosphoglycerate kinase deficiency (GSD IX) and juvenile Parkinsonism, which is probably causal rather than casual. Also unexplained is the frequent and apparently specific association of phosphoglycerate mutase deficiency (GSD X) and tubular aggregates. By paying more attention to problems than to progress, we aimed to look to the future rather than to the past.
PMCID: PMC3235878  PMID: 22106711
glycogen storage diseases; GSD; polyglucosan disorders
22.  Glycogen storage disease type I and G6Pase-β deficiency: etiology and therapy 
Nature reviews. Endocrinology  2010;6(12):676-688.
Glycogen storage disease type I (GSD-I) consists of two subtypes: GSD-Ia, a deficiency in glucose-6- phosphatase-α (G6Pase-α) and GSD-Ib, which is characterized by an absence of a glucose-6-phosphate (G6P) transporter (G6PT). A third disorder, G6Pase-β deficiency, shares similarities with this group of diseases. G6Pase-α and G6Pase-β are G6P hydrolases in the membrane of the endoplasmic reticulum, which depend on G6PT to transport G6P from the cytoplasm into the lumen. A functional complex of G6PT and G6Pase-α maintains interprandial glucose homeostasis, whereas G6PT and G6Pase-β act in conjunction to maintain neutrophil function and homeostasis. Patients with GSD-Ia and those with GSD-Ib exhibit a common metabolic phenotype of disturbed glucose homeostasis that is not evident in patients with G6Pase-β deficiency. Patients with a deficiency in G6PT and those lacking G6Pase-β display a common myeloid phenotype that is not shared by patients with GSD-Ia. Previous studies have shown that neutrophils express the complex of G6PT and G6Pase-β to produce endogenous glucose. Inactivation of either G6PT or G6Pase-β increases neutrophil apoptosis, which underlies, at least in part, neutrophil loss (neutropenia) and dysfunction in GSD-Ib and G6Pase-β deficiency. Dietary and/or granulocyte colony-stimulating factor therapies are available; however, many aspects of the diseases are still poorly understood. This Review will address the etiology of GSD-Ia, GSD-Ib and G6Pase-β deficiency and highlight advances in diagnosis and new treatment approaches, including gene therapy.
PMCID: PMC4178929  PMID: 20975743
23.  The reporting quality, scientific rigor, and ethics of randomized placebo-controlled trials of traditional Chinese medicine compound formulations and the differences between Chinese and non-Chinese trials 
Background: An increasing number of randomized placebo-controlled trials involving traditional Chinese medicine (TCM) compound formulations have been implemented worldwide.
Objective: The aim of this study was to assess the reporting quality, scientific rigor, and ethics of randomized placebo-controlled trials of TCM compound formulations and compare these differences between Chinese and non-Chinese trials.
Methods: English-language databases included the following: PubMed, OVID, EMBASE, and Science Citation Index Expanded. Chinese-language databases included the following: Chinese Biomedical Literature Database, Wanfang Database, Chinese Scientific and Technological Periodical Database, and the China National Knowledge Infrastructure. All were searched from respective inception to March 2009 to identify randomized placebo-controlled trials involving TCM compound prescriptions. Two reviewers independently assessed the retrieved trials via a modified Consolidated Standard of Reporting Trials (CONSORT) checklist and some evaluation indices that embodied the TCM characteristics or the scientific rigor and ethics of placebo-controlled trials. Trial publishing time was divided into 3 intervals: phase 1 (≤1999); phase 2 (2000–2004); and phase 3 (2005–2009). The number and percentage of trials reporting each item and the corresponding differences between Chinese (mainland China, Hong Kong, and Taiwan) and non-Chinese (eg, Japan, United States, Australia, Korea, and United Kingdom) trials were calculated. Moreover, the influence of trial publishing time on the reporting of CONSORT items and the differences in the number of items reported for each time interval between Chinese and non-Chinese trials were assessed.
Results: A total of 324 trials from China and 51 trials from other countries were included. A mean of 39.7% of the CONSORT items across all Chinese trials and 50.2% of the items across all non-Chinese trials were reported. The number of the reported CONSORT items all increased over time in both groups and the gap between Chinese articles and non-Chinese articles gradually decreased. Additionally, of the 324 Chinese articles, 137 (42.28%) reported TCM syndrome type, 113 (34.88%) reported the diagnostic criteria of diseases for TCM, and 69 (21.30%) reported efficacy evaluation indices of TCM. Of the non-Chinese articles, 3 (5.88%) reported TCM syndrome type and 1 (1.96%) reported the diagnostic criteria of diseases and evaluation indices of efficacy for TCM. It was found that 45.37% and 6.17% of Chinese articles reported the standard intervention for the diseases being treated and the emergency plan, respectively, compared with 23.53% and 9.80% for the non-Chinese articles; 33.02% and 10.49% of Chinese articles reported informed consent and ethics committee approval, respectively, compared with 92.16% and 82.35% for the non-Chinese articles. With regard to placebo ethics, 38.89% of the Chinese trials and 23.53% of the non-Chinese trials found it would not be ethically acceptable to use placebo alone in the control group.
Conclusions: The data indicate that the reporting quality of the included trials on TCM compounds has improved over time, but still remains poor regardless of Chinese or non-Chinese trials. Across all trials, particularly Chinese trials, the reporting of the CONSORT items was inadequate (39.7%). The difference in the mean number of the reported CONSORT items between Chinese trials and non-Chinese trials narrowed from phase 1 (10.0 vs 13.8) to phase 3 (14.4 vs 17.4). Moreover, a large number of trials, especially non-Chinese trials (94.1%), were lacking syndrome differentiation of TCM. More importantly, in many placebo-controlled trials, especially Chinese trials, the use of placebo was not justified and was ethically contradictory.
PMCID: PMC3967323  PMID: 24683249
reporting quality; scientific rigor; ethics; traditional Chinese medicine compound formulation; placebo; randomized controlled trial; CONSORT statement
24.  Acroform type of enchondromatosis associated with severe vertebral involvement and facial dysmorphism in a boy with a new variant of enchondromatosis type I1 of Spranger: case report and a review of the literature 
Cases Journal  2008;1:324.
Enchondromatosis represent a heterogenous group of disorders. Spranger et al attempted a classification into 6 types: Ollier disease, Maffuci syndrome, metachondromatosis, spondyloenchondrodysplasia, enchondromatosis with irregular vertebral lesions, and generalized enchondromatosis. Halal and Azouz added 3 tentative categories to the 6 in the classification of Spranger et al.
Case presentation
We report on a 15-year-old boy with acrofrom upper limbs and mixed appearance of radiolucency, cysts and striae of fibro-chondromatosis. Lower limbs (femoral, tibial and fibular dysplasia showed enlarged metaphyses near the knees bilaterally) were present. Additional features of short stature, macrocephaly, facial dysmorphism, and generalised platyspondyly have been encountered. These bone shortenings were associated with bone bending, curving and rhizomelia of the upper limbs with significant macrodactyly. Limitations in articular movements were present. The forearm deformities were similar to those observed in hereditary multiple exostosis.
The acrofrom upper limbs with mixed appearances of radiolucencies, cysts and striae of fibro-chondromatosis are the basic features of type I1Spranger. The constellation of facial dysmorphic features and significant vertebral abnormalities in our present patient were not compatible with the above-mentioned type of enchondromatosis. Our report widens the knowledge of disorders characterised by enchondromatosis. Ascertainment of the mode of inheritance in our present patient was difficult because of insufficient family history and parents declined clinical/radiographic documentation.
PMCID: PMC2600790  PMID: 19017386
25.  Hepatocellular carcinoma and focal nodular hyperplasia of the liver in a glycogen storage disease patient 
World Journal of Hepatology  2012;4(6):191-195.
Glycogen storage disease type Ia (GSD-Ia; also called von Gierke disease) is an autosomal recessive disorder of carbohydrate metabolism caused by glucose-6-phosphatase deficiency. There have been many reports describing hepatic tumors in GSD patients; however, most of these reports were of hepatocellular adenomas, whereas there are only few reports describing focal nodular hyperplasia (FNH) or hepatocellular carcinoma (HCC). We report a case with GSD-Ia who had undergone a partial resection of the liver for FNH at 18 years of age and in whom moderately differentiated HCC had developed. Preoperative imaging studies, including ultrasonography, dynamic computer tomography (CT) and magnetic resonance imaging, revealed benign and malignant features. In particular, fluorodeoxyglucose-positron emission tomography (FDG-PET)/CT revealed the atypical findings that FDG accumulated at high levels in the non-tumorous hepatic parenchyma and low levels in the tumor. Right hemihepatectomy was performed. During the perioperative period, high-dose glucose and sodium bicarbonate were administered to control metabolic acidosis. He had multiple recurrences of HCC at 10 mo after surgery and was followed-up with transcatheter arterial chemoembolization. The tumor was already highly advanced when it was found by chance; therefore, a careful follow-up should be mandatory for GSD-I patients as they are at a high risk for HCC, similar to hepatitis patients.
PMCID: PMC3388117  PMID: 22761970
Glycogen storage disease type Ia; Hepatocellular carcinoma; Focal nodular hyperplasia; Hepatectomy; Metachronous

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