Abstract
We aimed to determine the clinical profile and outcome of Indian children with glycogen storage disorders. Ours was a retrospective study from 2005 to 2018 in 36 children diagnosed on the basis of a liver biopsy. Most (77.7%) presented with abdominal swelling but a quarter with convulsion, four of whom had documented hypoglycaemia associated, doll-like facies or developmental delay. Diarrhoea was found in four patients, ascites in two and portal hypertension in one. One child died, and over half were unfortunately lost to follow-up, though the rest had recurrent seizures, three more developed neutropenia, two recurrent infections, one portal hypertension with epistaxis, one nephrocalcinosis and liver adenoma. Liver function improved in six (37.5%) with normalisation of triglycerides, and four of serum transaminases.
Introduction
Glycogen storage disorders (GSDs) are inherited disorders of glycogen metabolism affecting primarily the liver, muscle, heart, kidneys, intestine and occasionally the central nervous system and leucocytes.1,2 They are classified based on enzyme deficiency and affected tissues. Some 12 types are described. 2 Their estimated incidence of GSD overall is approximately 1 in 20,000–43,000 live births. 2 According to a 2006 Indian study, 17 cases were reported, divided into type I in 12 and type III in 5, 3 while at our centre we had 18 cases clinically diagnosed with 5 suspected of having type I (2 being of type Ib with neutropenia), 3 patients type III and the remainder remained unclassified. 4 As GSD is a rare disease, world-wide follow-up data on outcome and management are limited. Our retrospective analysis aims to determine the clinical profile and outcome data of Indian patients seen with GSD.
Methods and materials
Ours is a retrospective descriptive analysis of data on GSD patients diagnosed at the BJ Wadia children’s hospital, Mumbai from 2005 to mid-2018. Data on clinical profile, biochemical parameters, radiological features, treatment at the time of presentation and last follow-up data on complications, biochemical and radiological parameter were collected retrospectively from the pre-structured case record forms. GSD was diagnosed on the basis of liver biopsy with features showing distension of liver cells by glycogen: specifically, PAS positive and diastase sensitive glycogen uniformly distributed within the cytoplasm, with a mosaic or plant cell pattern, and fatty changes with or without fibrosis. Siblings of a case proven on biopsy having biochemical features of GSD along with significant hepatomegaly were also considered as GSD diagnoses. Enzyme study or mutation analysis was not possible owing to unaffordability. Annual follow-up required at least one visit over the previous 12 months of the study period. Patients were monitored for various biochemical parameters such as fasting blood glucose, lipids, uric acid, serum lactate, WBC count, serum bicarbonate, blood pH, liver function test, serum albumin, coagulation profile and serum lactate dehydrogenase (LDH). a
Growth was monitored in all children; growth failure was defined as weight and/or height <3rd percentile according to the World Health Organization (WHO) standard growth chart up to five years of age and subsequently using the Indian Academy of Paediatrics (IAP) growth chart. 5 All patients were monitored with regular abdominal ultrasound scans monitoring of renal enlargement, formation of adenomas and portal hypertension. This was determined if the portal vein size was >1 cm or there were collaterals on colour Doppler or oesophagogastroscopy (OGD) showed varices.
Patients were followed up every three months for growth, dietary compliance and biochemical parameters including complete blood count, fasting blood sugar, fasting lipid profile, pH, bicarbonate levels and serum uric acid. Abdominal ultrasonography and α-fetoprotein (case based) were measured yearly.
Results
A total of 38 children were clinically diagnosed with GSD, out of whom 2 were excluded because the liver biopsy in one was normal and in the second showed cirrhosis of unspecified aetiology. Of the remaining 36, the male:female ratio was 5:4. Nine children (25%) were of a consanguineous parenthood and siblings were affected in seven (77.8%). The mean age of onset of symptoms was 2.17 ± 1.4 years, whereas the mean age of presentation to our clinic was 3.01 ± 1.8 years. All our patients had hepatomegaly, the diagnosis being confirmed on histopathology, which revealed liver fibrosis in 15 (41.6%). Five (13.8%) had neutropenia (two on presentation and three on follow-up) and hence were suspected to have type Ib GSD clinically. The main presenting features were protrusion of abdomen in 28 (77.7%), convulsion in 9 (25%) out of whom 4 (11.1%) had documented hypoglycaemia at the time, 4 (11.1%) had diarrhoea and 8 (22%) had developmental delay of whom 1 had proximal myopathy and the other had motor delay. One (2.7%) had portal hypertension seen on colour Doppler of the portal venous system and two (5.5%) had ascites. Nine (25%) were noted to have doll-like face, splenomegaly was found in 11 (30.5%). Short stature was documented in 23/34 (67.6%).
Biochemical parameters at the time of diagnosis.
LDH, Lactate dehydogenase; SGOT, serum glutamate oxaloacetate transaminase; SGPT, serum glutamate pyruvate transaminase.
Only one child had renal enlargement. Electroencephalography performed on the patients having convulsion showed abnormalities only in one.
On diagnosis, all patients were given dietary advice and compliance was monitored according to fasting serum glucose readings and other biochemical parameters. Oral bicarbonate supplementation was commenced on eight (22.2%), two (5.5%) on an uricosuric agent, one (2.7%) on a lipid lowering agent and two (5.5%) on anticonvulsants owing to euglycemic seizures.
Out of 36 children, 1 (2.7%) died briefly after the diagnosis had been made at another hospital at the age of 2 years; only 16 (44.4%) continued for regular follow-up. Their mean duration was 2.9 ± 3.0 years and mean age at follow-up was 5.5 ± 3.3 years. Clinical events noted were 3 (15.7%) with recurrent seizures, 3 (15.7%) developed acidosis, 3 (15.7%) developed neutropenia, 2 (10.5%) had recurrent infections, of whom one child had acute serous otitis media, recurrent diarrhoea and the other had a recurrent cough with hypereosinophilia. The child who developed portal hypertension had epistaxis. One (5.26%) child developed nephrocalcinosis and liver adenoma which was diagnosed at 10 years of age. Renal enlargement was seen in another child on follow-up. Of those whose height was documented 6/10 were stunted and two had developmental delay. Normalisation of triglyceride level <2.3 mmol/L was seen in 6/16 with mean of 2.9 ± 2.1, and of serum transaminases in 4/14, while the mean SGOT was 178.6 ± 51.3 and SGPT of 148.3 ± 154. Ten (71.4%) out of 14 patients had fasting blood sugar >3.3 mmol/L on follow-up. Bicarbonate supplementation was given to 2/6 to correct acidosis (Table 1).
Discussion
Although our retrospective analysis covers 13 years, the rarity of the GSD, its natural history, the efficacy of treatment and evidently the small sample size are significant hinderances. 6 As there are no previous studies with follow-up in India, we endeavour to close the gap. The mean age of presentation was found to be 15 months in a previous Indian study, 3 but shorter in a Brazilian study on 21 patients (17 Type Ia and 4 Type Ib) at seven months. 6 As regards the age of onset of symptoms noted in this study, the authors believe it to be subjected to recall bias.
From a case series by Tamhankar et al., 7 GSDIa accounted for 20% (2/10 cases) of liver glycogenosis. Among various types of GSDs, types I, III, IV, VI, IX predominantly have liver involvement. GSD type I manifests with hepatomegaly, failure to thrive, hypoglycaemia, hyperlactataemia, hyperuricaemia and hyperlipidaemia. Type IIIa has both liver and muscle involvement, whereas Type IIIb has only liver involvement. Type IV presents with hepatomegaly and growth retardation with progression to cirrhosis. Type VI manifests with asymptomatic hepatomegaly, growth retardation, usually having a benign course. In Types VI and IX, no hyperuricaemia or hyperlactataemia is found. Type XI is characterised by hepatic and renal involvement. Types II, V, VII have predominant muscle involvement.1,2
We were unable to perform mutational analysis, and so could not definitively sub-classify cases. However, the five children with neutropenia were clinically diagnosed as Type Ib. The finding of periportal or reticular fibrosis does not differentiate between Types I, III, IV and VI. 1 Though fibrosis was present in 15 (41.6%) of our patients, Turkish investigators found 75.6%. 8 However, mutational analysis and/or liver enzyme activity must be correlated with histopathology to type the GSD effectively, for otherwise isolated histological findings are not useful for typing the GSD. Mutational analysis is replacing more invasive diagnostic modality such as liver biopsy, 6 and will prove to be a significant advance.
Consanguineous parentage is an obvious area suggesting counselling. The pathophysiology of the short stature in GSD, which is relatively frequent, is not clear, but it appears to be secondary to metabolic acidosis, renal tubular dysfunction, inadequate metabolic control leading to recurrent infection and inflammatory bowel disease.6,9
On presentation, elevated transaminases (97.1%), acidosis (85%) and hypertriglyceridaemia (68%) were common findings like other studies. 8 Documented hypoglycaemia was seen in just 39% patients. As lactic acid is used alternatively for cerebral metabolism, symptomatic hypoglycaemia may be missed. Absence of hypoglycaemia does not rule out diagnosis of GSD but may result in delayed diagnosis or indicate milder form of the disease. 6 Treatment for GSD is primarily dietary intervention with frequent meals, uncooked corn starch, continuous nocturnal nasogastric drip feeding 9 which aims at maintaining normoglycaemia, suppress metabolic derangements and thus prevention or delaying of complications.
The criteria for adequacy of metabolic control as per European study on glycogen storage disease type 1(ESGD 1) are: Pre-prandial blood glucose >63 mg/dl, serum triglyceride <530 mg/dl, serum uric acid <7 mg/dl, venous blood bicarbonate >20 mmol/L, urine lactate/creatinine ratio <0.06 mmol/mmol, BMI between 0 and +2.0 SD. 9 Not included in ESGD 1, absence of hepatic adenoma and adequate height for age are important markers for metabolic control. 6 However, in the present study, serum triglyceride level <200 mg/dl was considered to have adequate control. On follow-up, 37.5% had normalisation of triglyceride level, 28.5% had normalisation of serum transaminases, 71.4% had fasting blood sugar >60 mg/dl, 33.3% had normalisation of acidosis who were on treatment. In one patient with serum triglyceride of 821 mg/dl was started on lipid-lowering agents. Patients with liver adenoma had inadequate metabolic control with hypertriglyceridaemia, hyperuricaemia, nephrocalcinosis, neutropenia, acidosis. Incidence of hepatocellular adenomas is 22–75% of adults with GSDIa and risk of malignant transformation is approximately 10%. 6
Conclusion
A high index of suspicion is needed to diagnose GSD and to consider in differentials of hypoglycaemia, altered lipid profile, growth failure to facilitate early diagnosis and treatment. Proper dietary management is the cornerstone of the treatment of GSD irrespective of type. Histopathology of the liver remains the preferred diagnostic means in India. However, mutational analysis might replace this invasive technique subsequently. Long-term data on metabolic control, dietary interventions, liver adenoma, renal complication, haematological manifestations, growth, bone metabolism, puberty, pregnancy and quality of life (developmental milestones, scholastic performance, employment) are needed.
Footnotes
Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.
