|Year : 2019 | Volume
| Issue : 3 | Page : 136-144
A cross-sectional study of complications in children with glycogen storage disease: a single-center study
Mohammed M Abd El-Razzak1, Khadiga M Ali2, Mohammad S Al-Haggar3, Mona A.L Alsayed4
1 Resident at Mansoura University Children’s Hospital, Faculty of Medicine, Mansoura University, Mansoura, Egypt
2 Department of Pathology, Faculty of Medicine, Mansoura University, Mansoura, Egypt
3 Department of Pediatrics, Unit of Genetics, Faculty of Medicine, Mansoura University, Mansoura, Egypt
4 Department of Pediatrics, Pediatric Gastroenterology and Hepatology Unit, Mansoura University Children’s Hospital, Faculty of Medicine, Mansoura University, Mansoura, Egypt
|Date of Submission||14-Jun-2019|
|Date of Decision||23-Jun-2019|
|Date of Acceptance||23-Jun-2019|
|Date of Web Publication||27-Apr-2020|
PhD Khadiga M Ali
Department of Pathology, Faculty of Medicine, Mansoura University, Elgomhoria Street, Mansoura, Eldakahliya 35516
Source of Support: None, Conflict of Interest: None
Background Glycogen storage diseases (GSDs) are a heterogeneous group of metabolic disorders that result from the deficiency of particular enzymes implicated in glycogen metabolism. Identification of the exact diagnosis is essential, as there are different treatments, complications, and natural histories for the various kinds of this disorder. However, with the lack of molecular and enzymatic assay owing to unaffordable cost, we aimed to investigate children diagnosed with GSD for detection of disease-related complications.
Patients and methods This cross-sectional observational study included 43 children diagnosed as having GSD based on liver biopsy, with emphasis on the possible associated complications despite the lack of molecular subtyping. Patients were selected from the outpatient clinic of Hepatology Unit of Mansoura University Children’s Hospital during the period from February 2016 to December 2018.
Results A total of 27 (62.8%) patients were males. Their age ranged from 1 to 18 years and median value was 7 years. Positive consanguinity was present in 26 (60.5%) cases. Overall, 46% showed delayed puberty. Thirty-five children developed complications in the form of type I diabetes mellitus in one (2.3%), chronic kidney disease in two (4.7%), osteopenia in 24 (68.5%), delayed motor development in 21 (49%), and cardiomyopathy in five (11.6%).
Conclusion Development of complications in pediatric patient with GSD can occur even with the strict diet control. Anticipation of complications and regular checkup of their occurrence is mandatory to prevent their progression and allow prompt management.
Keywords: children, complications, Egyptian, glycogen storage disease, liver biopsy
|How to cite this article:|
Abd El-Razzak MM, Ali KM, Al-Haggar MS, Alsayed MA. A cross-sectional study of complications in children with glycogen storage disease: a single-center study. Alex J Pediatr 2019;32:136-44
|How to cite this URL:|
Abd El-Razzak MM, Ali KM, Al-Haggar MS, Alsayed MA. A cross-sectional study of complications in children with glycogen storage disease: a single-center study. Alex J Pediatr [serial online] 2019 [cited 2020 Jun 2];32:136-44. Available from: http://www.ajp.eg.net/text.asp?2019/32/3/136/283321
| Introduction|| |
Glycogen storage diseases (GSDs) are a heterogeneous group of autosomal recessive metabolic disorders that affect primarily the liver, muscles, and heart . They are caused by the deficiency of particular enzymes implicated in the synthesis/degradation of glycogen, which serves as a main source to deliver glucose needed by all cell types for energy expenditure . Twelve forms of GSD have been described in humans with identification of their precise genetic defects .
The overall GSD incidence is approximately one case in 20 000–43 000 live births . Generally, GSDs have a great phenotypic heterogeneity even with a specific enzyme deficiency. The early presenting forms of the disease during neonatal and infantile periods usually have unfavorable outcome . As the liver is an essential depot site for glycogen, liver affection in GSD represents mainly by hypoglycemia and hepatomegaly. Skeletal muscle affection manifests usually with muscle cramps, exercise intolerance, muscle weakness, and hypotonia .
The GSDs have generally been diagnosed using a blend of clinical symptoms, biochemical results, and pathological findings. Standard investigations performed by the pathologist incorporate muscle or liver histology findings in addition to electron microscopy and enzyme studies ,. Assay of enzymatic activity in the tissue biopsy is complicated and needs specific preservation requirements. Molecular testing has widely replaced the more invasive techniques for definitive diagnosis of GSD such as obtaining liver biopsy for pathologic assessment in addition to fresh liver or muscle tissue snips for enzymatic assay .
Regardless of the best dietary treatment, patients with GSD are inclined to complications, as the secondary features might be difficult to control. There are additionally a few difficulties that happen autonomously of treatment . For GSD III, myopathy is a specific issue. Cardiomyopathy and cirrhosis have been reported in GSD III, VI, and IX. The basis of these morbidities has not been identified . For GSD I, renal tubular dysfunction seems to be an inherent part of the disease . The monitoring of the diet has been proposed by the European Study of GSD I just as a more recent American group. Comprehensively, clinical parameters of growth and indices of biochemical control ought to be observed as often as possible in the under 5-year group, typically at 3 monthly intervals . We aimed in the present study to examine children diagnosed with GSD based on liver biopsy for the development of disease-related complications.
| Patients and methods|| |
This cross-sectional observational study included 43 children diagnosed as having GSD based on liver biopsy. Patients were selected from the Outpatient Clinic of Hepatology Unit of Mansoura University Children’s Hospital during the period from February 2016 to December 2018. Informed consent forms were signed by the parents/caregivers of all participants before enrollment in the study. The study was approved by the Institutional Research Board of Faculty of Medicine, Mansoura University, and it strictly followed the principles included in the Declaration of Helsinki.
History taking was directed specially to symptoms suggestive of hypoglycemia, muscular affection, convulsions, and family history of consanguinity and other sibling affected by the disease. Physical examination focused on examination of the characteristic facies (doll-like), muscle status (atrophy, muscle tone, and deep reflexes), stigmata of chronic liver disease, and Tanner staging of puberty. Anthropometric measurements were plotted against the Egyptian growth curves for both weight and height . Lastly, abdominal examination was done for abdominal distension and liver and splenic enlargement.
All patients had the following investigations: complete blood picture, liver functions (alanine aminotransferase, aspartate aminotransferase, total and direct serum bilirubin, alkaline phosphatase, prothrombin time, and international normalized ratio), serum creatinine kinase (CPK), serum uric acid, fasting blood sugar, complete lipid profile including serum triglyceride, and total serum cholesterol.
Phenotypic classification by enzymatic analysis was done using quantitative colorimetric/fluorimetric method for enzymatic activity in isolated peripheral leukocytes . Enzymatic analysis was carried out in only six (14%) patients owing to unaffordable cost.
All children were prescribed uncooked cornstarch at a dose of 2 g/kg every 6 h to prevent hypoglycemia. The cornstarch was mixed with water or milk at room temperature with emphasis that it should be raw or uncooked. Supplemental iron, calcium, and vitamin D were given to all children.
Abdominal ultrasound was done by a single operator to detect the liver echogenicity and span and to confirm the absence of focal lesions. Dual-energy radiography absorptiometry (DPX IQ-USA, software version 4.5; DEXA Lunar, DPX IQ-USA, software version 4.5, DPX Series YZB/USA 2099) was performed to assess the bone mineral density (BMD) at the postero-anterior lumbar spine (L2–L4). The DEXA results were interpreted as follow: ‘at risk for low BMD for chronologic age’ when BMD Z score is between −1.0 and −1.9, and ‘low BMD for chronologic age’ when BMD Z score is less than or equal to −2.0 .
Although liver biopsies are no longer required for diagnosing this condition, it was the cornerstone in diagnosis of GSD in our study owing to unaffordable cost of enzyme studies and molecular analysis. Liver biopsy was done in all patients after a period of 6 h fast using the percussion technique . Liver biopsy specimens were fixed in 10% buffered formalin and embedded in paraffin. Overall, 4-µm-thick sections were prepared for hematoxylin and eosin. Other sections were prepared for special stains such as periodic acid-Schiff (PAS), before and after diastase (PAS/D) digestion, and Masson-Trichrome. All samples were reviewed by a single histopathologist (K.M.A). Diagnostic features of glycogenesis include enlarged hepatocytes with rarefied cytoplasm, and thick cell membranes owing to peripheral relocation of organelles by the stored glycogen. Nuclei of liver cells are centrally placed with occasional glycogenated ones in the periportal zone . Assessment of fibrosis and the presence of steatosis are done in each case.
Definition of disease-related complications
We searched for the disease-related complications in the study group that can be detected by the clinical, laboratory, and radiologic evaluation. They were delayed puberty, growth failure, gross motor developmental delay detected by clinical neurological examination based on Denver Developmental screening test II, anemia, cardiac affection, nephropathy, osteopenia, and diabetes mellitus (DM). Renal biopsy was done in two patients with nephropathy to assess the glycogen-related complication.
Data were analyzed with SPSS, version 21 (IBM Corp., Armonk, New York, USA). The normality of data was first tested with Shapiro–Wilk test. Qualitative data were described using number and percent. Continuous variables were presented as mean±SD for parametric data and median and interquartile range (IQR) for nonparametric data. Spearman correlation was used to correlate between continuous nonparametric data. Statistical significance is considered when the probability of error is less than 5% (P<0.05).
| Results|| |
Clinical and demographic data:
The present work included 43 children diagnosed as having GSD based on liver biopsy. The median age of our patients was 7 years (range, 1–18 years; IQR, 7 years), and the median age at the time of initial presentation was 8 months ([Table 1]). A total of 27 (62.8%) patients were males, with a male to female ratio of 1.7 : 1.
|Table 1 Clinical and demographic data among the studied group of patients with glycogen storage disease|
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Mean±SD for height was 111.09±26.20 cm. Median and IQR for weight were 23.00 and 20 kg, respectively. Diffuse abdominal distention and soft hepatomegaly were present in all patients.
Regarding the laboratory results, median and IQR for alanine aminotransferase and aspartate aminotransferase were 145.5 (319.5) and 127 (349.75), respectively. Other parameters of liver functions were normal. Only one patient showed persistent neutropenia. Serum uric acid, triglyceride, cholesterol, and CPK are illustrated in [Table 2]. There was a significant negative correlation of serum triglyceride level and age (r=0.46, P=0.007). Enzymatic assessment that was carried out in six patients revealed GSD type III.
|Table 2 Serum uric acid, creatinine kinase, cholesterol, and triglyceride in the studied group of patients with glycogen storage disease|
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The abdominal ultrasound showed abnormal liver echogenicity in 76.7% of the patients and described as fatty infiltration or heterogeneous echo pattern. No focal liver lesions were detected by ultrasound ([Table 3]).
|Table 3 Liver biopsy and ultrasound findings among the studied group of patients with glycogen storage disease|
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Liver biopsy evaluation
The classical and uniform finding as described were present in 97.7% of patients ([Figure 1]), with one case showing features consistent with GSD IV described as hepatocellular PAS-positive, diastase-resistant inclusions of the abnormal glycogen deposits ([Figure 2]). Evidence of fibrosis was present in 21 (48.8%) patients ([Table 3]).
|Figure 1 Representative example of glycogen storage disease. Hepatocytes are swollen with pyknotic nuclei. The cytoplasm is rarefied (hematoxylin and eosin stain, a; ×4, b; ×40). A large quantity of glycogen in liver cells (c; periodic acid-Schiff before and d; after diastase ×10).|
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|Figure 2 An example of glycogen storage disease type IV. Lightly eosinophilic (ground glass-like) inclusions are present in many hepatocytes (hematoxylin and eosin stain, a; ×20, b; ×40). Cytoplasmic inclusions, intensely stained with periodic acid-Schiff (c; ×10), have not been digested by diastase (d; ×10).|
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Development of disease-related complications was evident. Height below the fifth percentile for age was noticed in 24 (55.8%) patients, whereas 12 (27.9%) patients had weight below the fifth percentile for age ([Table 1]). A statistically significant effect of GSD on height more than weight was observed (P=0.005). Delayed puberty was observed in 46% of our cohort. Five (11.6%) patients experienced hypertrophic cardiomyopathy documented by echocardiography. Type I DM developed in one (2.3%) patient, whereas chronic kidney disease (CKD) stages 4 and 5 developed in two patients owing to renal glycogen infiltration and tubulointerstitial disease confirmed by renal biopsy ([Table 1]). One patient was maintained on regular hemodialysis. ‘Low BMD for chronologic age,’ defined as BMD Z score less than or equal to −2.0, was present in 24 (68.5%) of 35 patients who performed DEXA study ([Table 1]). No significant correlation was found between DEXA and age (r=−0.2, P=0.3) or glycemic state of the patients (r=0.1, P=0.8).
Delayed gross motor development was observed in 21 (48.8%) patients. Clinical indicators of muscle affection were muscle wasting in 13 patients and variable degree of muscle power affection in nine patients. Serum CPK was elevated in seven patients with motor developmental delay. Significant difference was shown between children with and without developmental delay regarding muscle wasting and diminished muscle power (P=0.022 and 0.012, respectively). Mean blood glucose was statistically lower in those with developmental delay (mean±SD, 65.52±20.41 mg/dl) compared with those with normal development (mean±SD, 83.42±18.65, P=0.005). Serum CPK and triglycerides were significantly higher in patients with developmental delay ([Figure 3], [Figure 4]) ([Table 4]).
|Figure 3 Box plot for median serum creatinine kinase (CPK) among delayed and normal development.|
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|Figure 4 Box plot for median triglycerides among delayed and normal development.|
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|Table 4 Differences between the two groups with delayed and normal development|
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| Discussion|| |
For the past 3 decades, survival of children who are placed under intensive nutritional management with uncooked corn starch has improved; however, long-term complications persist including renal failure, nephrolithiasis, hepatic adenomas, and a high risk for hepatocellular carcinoma . The current study provides description of the long-term complications in Egyptian children diagnosed with GSD.
GSDs with the liver primarily affected usually present with recurrent hypoglycemia. Hypoglycemia, if not promptly recognized and treated, can lead to major neurological complications. Recurrent convulsions were the chief complaint in 25.6% of patients, and seven of them were labeled as hypoglycemic fits. Convulsions were present in 30% of the patients in the study by Saleem et al. , whereas they occurred in 38.7% in another study . Normal intelligence is expected in children with GSD, but recurrent significant hypoglycemia may lead to brain damage, and the results of tests of performance ability are significantly correlated with frequency of hypoglycemia . We reported gross motor delay in 21 of 43 patients. Moreover, serum CPK and triglyceride were significantly higher in patients with delayed development (P=0.036 and 0.031, respectively). In a previous study, it was found that CPK is higher in patients with GSD who had evidence of myopathic changes on electromyography study and showed symptoms of delayed development or exercise intolerance . However, elevated CPK was only noticed in seven patients with gross motor delay. Therefore, gross motor delay in our study may be attributed to other confounding factors such as repeated hypoglycemia, nutritional deficiencies, and the protuberant abdomen secondary to hepatomegaly.
Slow growth velocity and delayed puberty are usually present in children with GSD, particularly if untreated ,. In our study, 24 (55.8%) patients had height below the fifth percentile for age, whereas 12 (27.9%) patients had weight below the fifth percentile for age. A statistically significant effect of GSD on height more than weight was observed (P=0.005). This finding is similar to previous reports of a cohort of children with GSD ,. Delayed puberty was observed in 46% of our cohort. The delayed puberty is related mainly to erratic metabolic control. A recent report documented hypogonadotrophic hypogonadism in males with GSD I who experienced bouts of hypoglycemia. The recurrent rises in cortisol because of hypoglycemia may be the underlying pathology prompting concealment of gonadotropin-releasing hormone release .
Cardiac involvement is an intrinsic feature in several GSDs . Despite the fact that hypertrophic cardiomyopathy has been reported in GSD III, there is no solid strategy to expect which patient will progress to cardiomyopathy . Mostly, patients are asymptomatic even in the presence of cardiac hypertrophy. We reported hypertrophic cardiomyopathy in five (11.6%) patients who had no cardiac symptoms and were diagnosed by echocardiography. This comes in agreement with Mogahed et al. , who documented hypertrophic cardiomyopathy in nine of 28 pediatric patients with GSD III. With the lack of molecular and enzymatic identification of GSD subtypes in the current work, cardiac affection could be considered as a complication of the disease, especially as it has been shown to be regressive in nature with adequate metabolic control of the disease.
Renal complications are will described in GSD mainly type I. The pathogenesis of renal affection may be related to proximal renal tubular dysfunction, glomerular injury mediated by activation of renin–angiotensin system or prolonged oxidative stress, glomerular hyperfilteration, and nephrolithiasis ,,. In the current study, we reported CKD in two patients. One patient with CKD stage 4 and is maintained on conservative therapy. This patient has clinical and biochemical evidence of GSD type IIb with persistent neutropenia, but no confirmatory molecular diagnosis was done. The other patient has end-stage renal disease and is maintained on regular hemodialysis.
The development of DM in GSD has been reported as a late complication of types Ia, Ib, and III ,,,,. The pathogenesis is mainly related to the associated metabolic syndrome and insulin resistance (type II DM), and pancreatitis related to hypertriglyceridemia (type I DM). We reported one patient who developed type I DM and presented with diabetic ketoacidosis and had low serum insulin/C-peptide. Insulin therapy was initiated and the patient showed good glycemic control.
Anemia is a significant long-term morbidity in patients with GSD and has a multifactorial pathogenesis such as iron deficiency secondary to dietary limitations, altered iron absorption from cornstarch therapy, and anemia of chronic disease ,. In our study, anemia was detected in 53.5% of the patients and 7% had severe anemia. In one study of a cohort of GSD type I, anemia was found in 41.7% of patients with GSD Ia, and a higher prevalence (71.8%) was detected in GSD Ib .
Bone-related complications seem to be clinical manifestations of GSD types I and III. The pathogenesis might be identified with deficient calcium consumption, vitamin D insufficiency because of dairy products restriction, raised cortisol from frequent hypoglycemia, and hyperlactatemia . Several reports have elucidated the low BMD in GDS in both pediatric and adult population ,,. We found low BMD in 24 (68.5%) of 35 patients who performed DEXA study, but no significant correlation was found between DEXA and age or glycemic state of the patients.
The current study has some limitations including the relatively small sample size, and the absence of enzymatic and molecular confirmation of the disease subtypes owing the unaffordable cost and partial unavailability of diagnostic tests.
| Conclusions|| |
GSDs are complex and can be distinguished via cautious biochemical and clinical surveillance. Development of complications in pediatric patient with GSD can occur even with the strict diet control. Anticipation of complications and regular checkup of their occurrence is mandatory to prevent their progression and allow prompt management.There are no conflicts of interest
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3], [Table 4]