The patient's diet was evaluated using a 3 days food record prior to KD initiation, and the evaluation was repeated 6 months after starting KD. Dietary intakes were calculated using the national food composition database of the National Institute for Health and Welfare, Finland The KD was guided by the same dietitian M.

throughout the study period. Nutrition and diet were assessed and counseled at clinic visits or by phone or email contacts several times during the initiation period and later at least yearly. Daily energy intake was planned to be at the same level as before the KD, the amount of carbohydrates was restricted to 10 g per day, and the consumption of fat and protein was encouraged, aiming at a ketogenic ratio of ~ Consumption of unsaturated fats was recommended to avoid unfavorable changes in serum lipids.

Multivitamin, additional vitamin D, and calcium supplementations were introduced. Temporal mitigation of carbohydrate restriction using small or moderate amounts of e. Laboratory parameters were followed up regularly; e.

The laboratory results from the time points of exercise testing are presented in Table 1. In addition, concentrations of some vitamins vitamins D and A , minerals such as selenium and zinc , carnitine total and free , prealbumin, and urine calcium and creatinine were measured discretionarily to optimize nutrient intakes.

Blood β-hydroxybutyrate was also measured by the patient at home to ensure ketosis target level 2. Table 1. Laboratory parameters before ketogenic diet KD and during the 5 years follow-up at the time points of cardiopulmonary exercise testing.

Cardiopulmonary exercise test with breath gas analysis spiroergometry was performed as described earlier before KD and at 3, 8 months, and 5 years after start of KD The venous blood specimens were taken via a vacuum technique, and the analysis of lactate and ammonia specimens as well as the venous blood gases and electrolytes have been reported earlier The results of four healthy men with a mean age of 48 range 35—60 years and BMI Younger men and women from the original controls were excluded.

Spearman's correlation test was performed between the baseline and diet phases for the patient as well as for the controls. The β-hydroxybutyrate concentrations measured in laboratory ranged between 0.

During periodical mitigation of carbohydrate restriction β-hydroxybutyrate concentration was lower. An increase was initially seen in cholesterol values, with the highest concentrations measured after 2 years on KD, total cholesterol 8.

Ezetimibe 10 mg Ezetimibe accord ® medication was started due to high cholesterol values. Finally, during medication, total cholesterol, and LDL-cholesterol were below baseline values and HDL-cholesterol was slightly increased at 5 years control.

Plasma glucose and insulin values were within normal limits before and during KD and both decreased after beginning of the diet Table 1. Already after 6 months' exposure to KD, the patient began to experience a subjective alleviation of muscle symptoms, manifesting as more rapid recovery and less muscle discomfort.

He was able to increase daily exercise and could gradually spend extended periods of time hiking and hunting in the forest. However, he still often suffered from stiffness.

At 5 years, his muscle strength MRC was within the normal range 5 of 5 except for ankle extension forces 4 of 5. Deep tendon reflexes were present excluding Achilles. He felt that exercise tolerance had improved during KD and experienced less cramping and nausea during exercise than before KD.

During KD he could participate in long hiking trips, moving at a similar speed as his peers, also not possible before KD. He felt that especially capability to walk on an incline was better than before KD.

The patient's weight had decreased from 71 to 58 kg height cm , with BMI falling from The main results of the cardiorespiratory exercise testing during the follow-up at the time points of 3, 8 months and 5 years are presented in Table 2. The maximal working capacity was moderately reduced before KD, increasing slightly during KD, but it remained lower than the values of age-matched controls.

Table 2. Results of cardiorespiratory exercise testing of the patient before and during KD. However, slight hyperventilation was found, as assessed in slightly increased minute ventilation vs.

The venous lactate level at rest remained at pre-KD level 1. Before KD, metabolic alkalosis was seen after exercise pH 7. Figure 1. Lactate levels associated with exercise tests of the patient before diet and during the follow-up.

The values of the control subjects without dietary intervention are also given for comparison. The baseline lactate data has been published earlier 10 , the controls matched to the age and gender of the patient were obtained from the forementioned publication.

A strong correlation existed between the patient's baseline lactate values and his diet curves at 3, 7 months, and 5 years, rho being 0.

Figure 2. Ammonia levels associated with exercise tests of the patient before the diet and during the follow-up. Values of the control subjects without dietary intervention are also given for comparison.

The baseline ammonia data has been published earlier 10 , and the controls matched to the age and gender of the patient were obtained from the aforementioned publication.

No correlations existed between the baseline curve of the patient and those of the controls or the diet curves of the patient. Figure 3. pH levels associated with exercise tests of the patient before the diet and during the follow-up.

The baseline ammonia curve has been published earlier 10 , and the controls matched to the age and gender of the patient were obtained from the aforementioned publication. During the 5 years follow-up of KD the patient remained clinically stable with subjective alleviation of muscle pain symptoms and better exercise tolerance.

In cardiopulmonary exercise testing, working capacity and mechanical efficiency had increased. In venous blood, lactate levels had decreased from the low pre-KD levels, and the very high ammonia levels associated with exercise testing detected in the measurements before KD had decreased to normal.

However, the end tidal CO 2 level FetCO 2 remained rather low, indicating permanent hyperventilation tendency. Increasing evidence is emerging for a benefit of dietary therapy, especially in metabolic muscle diseases 14 , but also in dystrophic disorders However, among GSDs specific enzyme replacement therapy exists only in Pompe's disease GSD II In McArdle's disease GSD V , some data suggest a benefit of KD in relieving symptoms In one child with PFKM deficiency presenting with congenital arthrogryposis and severe myopathy, KD starting at age 4 months alleviated clinical symptoms, enhanced motor skill development, and improved muscle strength The patient's original diet was evaluated for the first time before the initiation of KD, but had remained similar for years.

KD was fairly well-tolerated by the patient. About 7 months after adopting KD, high LDL-cholesterol level was measured 4. Since cardiovascular disease exists among the patient's immediate family, the disadvantage of the KD for the patient was reconsidered, and the restriction of carbohydrates was mitigated e.

Based on the patient's subjective experience of lowered exercise capability after the increase of carbohydrates, however, the KD was again tightened. With rising LDL-cholesterol values up to 6. The LDL-cholesterol level was at the 5 years control lower than before KD 2.

During follow-up, no abnormalities were detected in the liver or kidney functions. The patient's weight decreased by 13 kg during KD.

He was satisfied with the weight decrease, although it was not the original aim of the treatment. Interestingly, the reported energy intake during KD was greater than before KD. This may be due to the better working capacity, leading to increased physical activity during the diet. However, it is also possible that the difference between these calculated intakes is explained by normal day-to-day variation in food intake since the food record periods were short 3 days.

The benefit of KD was more clearly seen in the mild increase in maximal working capacity, which rose from 56 to 68 W, with a simultaneous decrease in maximal heart rate. The mechanical efficiency, which is the maximal working power during the exercise test relative to the simultaneous maximal oxygen consumption uptake , also increased during KD, reflecting improved exercise performance.

However, at 5 years on KD, his exercise capacity remained at The decrease in the respiratory quotient RQ, relation of CO 2 production to O 2 consumption at 5 years may more be associated with decreased glucose oxidation and increased fat oxidation 20 than with submaximal effort.

This would be in line with former findings of inverse connection between free fatty acid concentration and oxidation with insulin concentration 21 since insulin adequately decreased after beginning of the KD. Before KD, a very low lactate level was found in the cardiopulmonary exercise test, with a delayed increase occurring 10—20 min after the exercise During KD the lactate curve associated with exercise testing had a similar shape as before the diet, but was situated lower, which is explained by less ingested carbohydrates.

The level of ammonia increased to very high levels in exercise testing before KD compared with control subjects Figure 2 as well as with earlier data on exercise tests in healthy subjects High levels of ammonia might cause the patient's exercise fatigue and short-term neurological discomfort, as reported also in sport medicine 23 , 24 , being one explanation for the increased ventilation, especially during exercise.

With KD, the level of ammonia during exercise was drastically decreased, attaining normal levels. In line with our finding, elevated ammonia has earlier been reported in Tarui disease during exercise testing 8. A common route to catabolize proteins and nucleotides is deamination of adenosine monophosphate AMP to inosine monophosphate IMP 23 — 25 which generates ammonia.

Hepatomegaly in GSD I attributable to fat and glycogen deposition is universal, resulting in a marked steatotic and enlarged liver. Given that the stored glycogen is normal in structure, liver enzymes are typically normal in GSD I.

An elevation of liver enzymes may sometimes be noted early in the disease course, typically around the time of diagnosis. Hepatocellular adenoma HCA , HCC, hepatoblastoma, focal fatty infiltration, focal fatty sparing, focal nodular hyperplasia, and peliosis hepatis are some of the liver lesions noted in GSD Ia patients.

The prevalence of HCAs increases with age in GSD I. Adenomas noted in patients with GSD I are different than those that are noted in the general population. GSD Ia patients seem to present with greater numbers of HCAs that are more likely to be in a bilobar distribution than those in the general population.

Furthermore, unlike in the general population, there is no gender predisposition in GSD I. One study noted that of 66 HCAs detected by magnetic resonance imaging in 14 patients, 44 lesions were found in 5 patients, with a mean of 5 lesions per GSD I patient.

A recent study demonstrated decreased adenoma formation in the setting of good metabolic control, and regression of adenomas has occurred in some patients after outstanding metabolic control was achieved.

Because patients with GSD I live longer, new long-term complications are being recognized. HCC has been noted in several patients with GSD I. There are several challenges concerning the diagnosis of HCC in GSD I. The cause for HCC is unclear, but there appears to be an adenoma-to-HCC transformation, rather than HCC arising in normal liver tissue.

Because of the abundance of adenomas, biopsy is not an option. There is no effective biomarker because α-fetoprotein and carcinoembryonic antigen levels are often normal even in the setting of HCC. No good imaging tool separates HCA from HCC. Until recently, the genetic makeup of the adenomas from patients with GSD I was not known.

However, Kishnani et al. Although loss of 6q without gain of 6p was identified in two non-GSD I HCA general population HCAs in this study, and simultaneous gain of 6p and loss of 6q has been reported in two general population HCAs in a previous report, the significance of loss of 6q for HCA development in the general population was inconclusive because the aberration was just one of multiple chromosomal aberrations in these cases.

It is speculated that GSD I HCA with simultaneous gain of 6p and loss of 6q could confer high risk for malignant transformation, implicating genes on chromosome 6 in the transformation of HCA to HCC.

Patients with these high-risk aberrations may be good candidates for LT until we have a better understanding of the pathogenesis and other therapeutic targets. These findings also suggest that good metabolic control alone may be insufficient to prevent the development of HCA in some patients with GSD I.

In the general population, HCAs regress in some patients after the cessation of oral contraceptives. In GSD I, there is some evidence that metabolic control may be a modifier of adenoma formation and progression, but there are cases in which adenomas occur despite good metabolic control.

Whereas most investigators agree that HCAs in GSD Ia patients should be observed for signs of malignancy, the management of concerning lesions is not established. Liver imaging is routinely performed in individuals with GSD I. With increasing age, computed tomography or magnetic resonance imaging scanning using i.

contrast should be considered to look for evidence of increasing lesion size, poorly defined margins, or spontaneous hemorrhage. contrast to minimize the number of missed lesions is recommended.

It is also known that α-fetoprotein and carcinoembryonic antigen levels do not predict the presence of HCAs or malignant transformation 24 , in patients with GSD I see next section.

Initially, the management of liver adenomas in the GSD I population should be conservative Box 3. An approach of watchful waiting may be used. There are reports of the use of percutaneous ethanol injection as the initial treatment of enlarging liver adenomas.

Resection of HCAs suspected of being malignant is an effective intermediate step in the prevention of HCC in GSD Ia patients. As such, adenoma resection may be used as the initial management of lesions suspicious for malignancy in GSD I.

A study by Reddy et al. In this study it was noted that GSD Ia patients present with a greater burden of adenomatous disease and shorter progression-free survival after resection than the general population. This experience of HCA resection in GSD Ia patients demonstrates that partial hepatectomy is feasible in these patients and is an effective intermediate step in the prevention of HCC until definitive treatment such as a LT.

Because of the low numbers, the true risks of partial hepatectomy particular to this population have not been explored. Liver replacement is the ultimate therapy for hepatic metabolic disease. It should be considered for patients with multifocal, growing lesions that do not regress with improved dietary regimens and who do not have evidence of distant metastatic disease.

The first reported LT for GSD I was performed in ref However, there are several obstacles to LT in GSD Ia patients. These include uncertainties regarding timing of transplantation, limited organ availability, prospects of worsening renal function with immunosuppression, and fears of poor patient compliance with immunosuppressive medication given a history of faulty adherence to a strict dietary regimen.

This score is calculated using a logarithmic assessment of three objective and reproducible variables, namely total serum bilirubin and creatinine concentrations, and the international normalized ratio.

The score may range from as low as 6 to a high of A MELD score of 15—17 is significant in that this is the point at which the mortality risk associated with liver disease and its complications is equivalent to the 1-year mortality associated with complications arising from LT.

In GSD I, because the hepatic abnormalities are the result of a single-gene, cell-autonomous defect, there is no possibility of recurrence of primary liver disease within the transplanted allograft.

The most common indication for liver transplantation in GSD I has been hepatic adenomatous disease for removal of potentially premalignant lesions. Other indications have included growth failure and poor metabolic control. Transplantation should be reserved for patients who have not had success with medical management, have a history of recurrent adenomas despite liver resection, have a rapid increase in the size and number of liver adenomas, and are at high risk for liver cancer.

Although the survival rate after transplantation has improved over the past 20 years, complications in the postoperative course remain.

Chronic renal failure is a well-documented complication of liver transplantation in GSD Ia, and some patients with GSD Ia have progressed to renal failure within a few years of transplantation.

Alternatively, a primary GSD-related nephrotoxic effect may be present because of the untreated condition in the kidney. Postoperative pulmonary hypertension has also been documented in a small number of patients after transplantation.

Although hypoglycemia similarly abates when liver transplantation is performed in GSD Ib, the neutropenia, neutrophil dysfunction, and Crohn disease—like inflammatory bowel disease are variably affected by liver transplantation. G-CSF is still often needed to treat the neutropenia associated with GSD Ib despite normalization of the metabolic profile after liver transplantation because neutropenia is primarily attributable to an intrinsic defect in the neutrophils of GSD Ib patients and is not corrected by LT.

Renal manifestations of GSD I appear early in childhood and often go undetected without specific diagnostic evaluation. Glycogen deposition occurs in the kidneys, which typically are large on renal imaging; however, nephromegaly is not sufficient to be readily detected on physical examination.

As a result of both the metabolic perturbations that arise and the glycogen accumulation with GSD I, there can be not only proximal and distal renal tubular dysfunction but also progressive glomerular injury that can result in functional renal impairment and even end-stage renal disease requiring renal replacement therapy.

Specific interventions aimed at ameliorating or trying to prevent the progression of these renal consequences of GSD I are best commenced early after their presentation to have the best opportunity to alter the course of renal injury.

The proximal tubule is the site of a great deal of energy expenditure and G6Pase activity is normally highest. With proximal tubular dysfunction, wasting of bicarbonate, phosphate, glucose, and amino acids can be seen.

In GSD I, proximal tubular dysfunction has been ascribed to glycogen accumulation in proximal tubular cells or inability to produce glucose for metabolic needs. In children with poorly controlled GSD I, there tends to be more documentation of aminoaciduria and phosphaturia because these children have such low serum glucose and bicarbonate levels that little tubular reabsorption is required.

The other proximal tubular defects improve with effective therapy such as the provision of CS and, as a result, tend not to be seen in most patients receiving treatment to maintain glucose levels. Along the proximal tubule, there is also sodium-linked reabsorption of calcium and the organic acids such as citrate that can freely cross the glomerular filtration barrier.

The citrate that remains in the urine plays an important role in enhancing the ionic strength of the urine, essentially chelating urinary calcium and helping to prevent its precipitation and the development of nephrolithiasis or nephrocalcinosis. As a result, individuals with low urinary citrate levels are more predisposed to urinary tract calcifications, and such urinary tract calcifications can increase the chances of urinary tract infection or mediate renal parenchymal damage with loss of renal functional reserve.

With GSD I, instead of the usual increasing urinary excretion of citrate with ongoing maturity, there is an actual decrease in citrate excretion that accelerates during adolescence and early adulthood. Glycogen deposition in the proximal tubule does reduce proximal tubular calcium reabsorption and is the likely mechanism for altered urinary calcium levels in GSD I.

Hypercalciuria is widespread in prepubertal children with GSD I, and the likelihood for nephrolithiasis and nephrocalcinosis increases with ongoing significant elevation in urinary calcium levels.

Oral citrate supplementation will augment citrate excretion, favorably altering the urinary milieu to decrease the chances of urinary calcium precipitation and, as a result, is likely very beneficial in GSD I patients with low urinary citrate levels Box 4.

In individuals with normal renal function, potassium citrate is preferred over sodium citrate because higher sodium intake is linked to greater urinary calcium excretion.

It also can result in systemic hypertension. In older children and adults, potassium citrate tablets at a dose of 10 mEq three times per day can also be commenced and the dose adjusted as needed.

Because the effects of citrate supplementation wane over time, multiple daily doses spread over the waking hours are preferred to maximize the proportion of the day with improved urinary citrate levels. Citrate use should be monitored because it can cause hypertension and life-threatening hyperkalemia in the setting of renal impairment.

Patients should also be monitored for sodium levels. With hypercalciuria, thiazide diuretics can also be provided as a way to enhance renal reabsorption of filtered calcium and decrease urinary calcium excretion. Especially in GSD I individuals with known urinary tract calcification and ongoing hypercalciuria, thiazide diuretic therapy can be considered.

Chlorothiazide is used in young children who require liquid preparations; tablets of hydrochlorothiazide are recommended for older children and adults. The efficacy of therapy can be gauged by interval urinary calcium-to-creatinine ratios.

This ability to decrease urinary calcium excretion is unique to thiazide diuretics, unlike other classes of diuretics that tend to increase urinary calcium excretion. Other nonspecific measures to reduce urinary calcium deposition, such as optimizing hydration, maintaining a no-added salt diet, or supplementing magnesium intake, can also be considered on an individual basis as well.

GSD I mediates hemodynamic and structural changes in the kidney that can lead to the development of glomerular injury. The exact mechanisms by which these changes occur are not well understood, but activation of the renin—angiotensin system, prolonged oxidative stress, and profibrotic cytokines such as transforming growth factor-β have all been implicated, as well as alterations in renal tubular epithelial cell energy stores related to G6Pase defects.

These changes in GFR may not be readily detected because they result in serum creatinine levels that are often reported as normal. With hyperfiltration, enhanced glomerular blood flow and intraglomerular pressure occur. As glomeruli become obsolete, fibrosis replaces surface area that previously allowed filtration.

Histologically, this injury appears as focal and segmental sclerosis, with a subset of glomeruli demonstrating limited scarring. As more and more glomeruli are lost to scarring, the overall GFR decreases and there is then an accelerated rate of obsolescence in these remnant glomeruli, creating even more stimuli for further glomerular injury.

Over time, microalbuminuria has a tendency to progress to frank proteinuria with urinary protein-to-creatinine ratios exceeding 0. Chronic proteinuria is thought to exacerbate glomerular injury through induction of chemokines and inflammatory pathways.

In GSD I, the development of pathologic proteinuria may be inevitable. In GSD I, this initial period of hyperfiltration that leads to microalbuminuria and frank proteinuria does seem to then progress to widespread glomerular scarring and eventual renal dysfunction.

Most renal biopsy samples from GSD I patients with frank proteinuria or any decrease in GFR demonstrate focal and segmental sclerosis as the histologic change that precedes the loss of renal function and progression to end-stage renal disease.

There have been some data to suggest that metabolic control in GSD I may affect the progression of renal injury. For many years, angiotensin blockade has been used to blunt proteinuria and slow loss of GFR in patients with renal diseases such as diabetes mellitus, in which there is similar hyperfiltration injury.

In cases in which there is a need for further angiotensin blockade, use of both an ACE and an ARB can prove synergistic to reduce proteinuria, with no increased rate of hyperkalemia or drug-related renal insufficiency. Although not yet tested in any systematic fashion in GSD I, the role of initiating angiotensin blockade with the early onset of persistent microalbuminuria seems to be a potential strategy to try to slow the factors that cause accelerated glomerular obsolescence and that ultimately lead to microalbuminuria, proteinuria, and renal insufficiency.

Typical measures to maintain GSD metabolic control are beneficial to general renal health because they help prevent acidosis and limit hyperuricemia and hyperlipidemia. Chronic acidosis can predispose to higher urinary calcium excretion and decreased urinary citrate, both problems that already exist in GSD I.

Hyperuricemia and hyperlipidemia by themselves have both been implicated in causing or accelerating renal injury. In patients receiving effective dietary therapy for their GSD I, it is unlikely that there will be diffuse proximal tubular dysfunction.

There should be periodic assessment of serum electrolytes, calcium, and phosphate as well as interval measurement of blood urea nitrogen and creatinine levels.

GFR should be estimated from the serum creatinine using a validated formula such as the Bedside Schwartz Equation in children or the Modification of Diet in Renal Disease Equation for adults.

Screening urinalysis should be performed at intervals on all GSD I patients. The presence of hematuria determined by dipstick should lead to assessment of urinary calcium excretion and ultrasound imaging of the urinary tract for calcifications.

Even in the absence of hematuria, renal ultrasound should be performed at intervals to assess kidney size and to assess for evolving nephrocalcinosis or nephrolithiasis. Especially for purposes of screening or for routine follow-up, ultrasound is preferred to other imaging techniques.

Despite good metabolic control, hypocitraturia and hypercalciuria may be common in GSD I and, as a result, urine should be assessed at regular intervals for calcium and citrate excretion even if urinalysis is benign.

Spot samples are adequate and easier and quicker to collect than are those of timed urine collection. With hypocitraturia, citrate supplementation should be considered, especially if there is concomitant hypercalciuria or a history of nephrolithiasis or nephrocalcinosis.

With hypercalciuria, there needs to be ongoing good hydration and consideration of thiazide therapy to reduce urinary calcium levels, especially in individuals with known or recurrent urinary tract calcifications. Urine should also be assessed for microalbuminuria and proteinuria. With a negative screening urinalysis for proteins, urine albuminuria should be quantified by spot albumin-to-creatinine ratio.

Dipstick-positive proteinuria should be quantified by urinary protein-to-creatinine ratio. Positive results should be confirmed using a first morning void sample to rule out any orthostatic component. Persistent microalbuminuria or frank proteinuria warrants initiation of angiotensin blockade despite patients being normotensive.

Medications should be adjusted to try to blunt the proteinuria to levels that are normal or as near normal as possible as tolerated without causing postural hypotension or hyperkalemia.

Attempts should be made to maintain angiotensin blockade chronically, and medication sequelae should be treated in some fashion so that the angiotensin blockade can be maintained or a different type of angiotensin blockade ACE vs.

ARB should be attempted. Because chronic hypertension accelerates renal injury, blood pressure should be maintained in a normal range for adults and at less than the 90th percentile for age, gender, and height for children.

If antihypertensive therapy needs to be started, angiotensin blockade with ACE or ARB should be considered as first-line therapy if not already instituted for other reasons. Loop diuretics should be avoided because of the risk of hypercalciuria.

With renal insufficiency, there is decreased production of erythropoietin EPO by the kidney and anemia may develop. Concomitant clinical factors in GSD patients such as chronic metabolic acidosis, iron deficiency, and bleeding diathesis may potentiate or exacerbate this anemia.

In children and adolescents with chronic kidney disease, anemia is linked to impairments in cognitive and developmental gains as well as increased hospitalization rates.

With adults, there are fewer data to support a specific hemoglobin level under which EPO should be started. As a result, EPO therapy is initiated if there is any evolving symptomatic anemia to prevent the need for blood transfusion.

Because iron deficiency anemia is common in GSD I, it is prudent to screen both children and adults with chronic renal failure for iron deficiency anemia and replace iron as needed before starting EPO therapy.

Long-term exposure to nephrotoxic medications should also be avoided. This includes use of nonsteroidal anti-inflammatory drugs such as ibuprofen and is especially important if there is any reduction in GFR or if patients have a bleeding diathesis.

Metabolic derangements from ongoing chronic renal insufficiency may exacerbate some of the issues that arise from GSD, making renal transplantation a more attractive therapy. In this case the option of both liver and kidney transplant may be considered. Hematologic aspects in GSD I include risk for anemia, bleeding diathesis, and neutropenia in GSD Ib.

Anemia is a significant long-term morbidity in individuals with GSD I. In , Talente et al. The report was based on an observational study of 32 subjects. Anemia in the pediatric population was recognized in ref. The cause of anemia in GSD I is multifactorial—the restricted nature of the diet, chronic lactic acidosis, renal involvement, bleeding diathesis, chronic nature of the illness, suboptimal metabolic control, 40 hepatic adenomas, 29 and irritable bowel disease in GSD Ib are all contributing factors.

In one study it was noted that patients with hemoglobin concentrations 2 SDs below the mean for their age had higher mean daily lactate concentrations as compared with the nonanemic population 3. An association between severe anemia and large hepatic adenomas was identified as well.

Many patients with GSD I have iron deficiency anemia. In some, it is an iron refractory anemia attributable to aberrant expression of hepcidin.

It is secreted in the bloodstream and is the key regulator of iron in the body, controlling iron absorption across the enterocyte, as well as macrophage recycling of iron. In the presence of hepatic adenomas, there are increased hepcidin levels.

The inability of hepcidin to be downregulated in the setting of anemia causes abnormal iron absorption and iron deficiency.

Intravenous iron infusions can partially overcome the resistance to iron therapy, but, because of an inhibition of macrophage recycling of iron, a good response is typically not seen. The restricted nature of the diet, with a focus on maintaining normoglycemia, often results in nutritional deficiencies see Nutrition section including poor intake of iron, vitamin B12, and folic acid.

Progression of kidney disease is another risk factor for anemia, and some patients require supplementation with EPO to maintain hemoglobin levels. The causes of anemia in GSD Ib are similar to those of anemia in GSD Ia, as was noted in five subjects studied by Talente et al.

Numerous case reports documented the presence of anemia in this population, but studies of the pathophysiology of this complication were lacking. Interleukin 6—a marker of inflammation known to upregulate hepcidin expression, which is increased during inflammatory bowel disease exacerbations—is the likely cause of low hemoglobin concentrations and another cause for the anemia observed in patients with GSD Ib.

A larger study involving subjects with GSD I at two large GSD centers has shed more light on the causes of anemia in GSD I. Mild anemia is common in the pediatric population because of iron deficiency and dietary restrictions. As previously stated, overall, pediatric patients with anemia have worse metabolic control, but the anemia is responsive to improved therapy and iron supplementation.

By contrast, anemia in adulthood is associated with hepatic adenoma formation, particularly in people with more severe anemia. The finding that all subjects who had resection of the dominant hepatic adenoma experienced resolution of their anemia supports the proposed pathophysiology of hepcidin-induced anemia.

In contrast to the GSD Ia population, there was no association between anemia and metabolic control or hepatic adenomas in either children or adults with GSD Ib; however, a strong association with systemic inflammation was documented.

In GSD I, a coagulation defect attributed to acquired platelet dysfunction with prolonged bleeding times, decreased platelet adhesiveness, and abnormal aggregation has been described Box 5. Bleeding manifestations include epistaxis, easy bruising, menorrhagia, 45 and excessive bleeding during surgical procedures.

Although dietary intervention can ameliorate the bleeding diathesis, the exact etiology of the bleeding diathesis remains unclear.

More than one study, with limited numbers of patients, showed that infusions of glucose and total parenteral nutrition corrected the bleeding time and in vitro platelet function in patients with GSD I, suggesting that coagulation defects were secondary to metabolic abnormalities.

These agents could be utilized in patients with GSD I when clinically indicated, but use of deamino d -arginine vasopressin in GSD I must be performed with caution because of the risk of fluid overload and hyponatremia in the setting of i.

glucose administration. In addition, the use of a fibrinolytic inhibitor, such as ɛ-aminocaproic acid Amicar , can be used as an adjunctive medication if there is mucosal-associated bleeding. For more severe mucosal-associated bleeding, an i. If the i.

The use of Amicar is contraindicated in individuals with disseminated intravascular coagulation and if activated prothrombin complex concentrate FEIBA has been used. Caution must be taken to ensure that there is no genitourinary tract bleeding, because inhibition of fibrinolysis can lead to an obstructive nephropathy.

Neutropenia and recurrent infections are common manifestations of GSD Ib. Neutropenia persists throughout childhood with little change in the neutrophil levels. It is unclear if neutrophil function is normal in this setting. Adult patients also have severe neutropenia and recurrent infections.

The patterns of infections vary from patient to patient, but there is no clear genotype—phenotype relationship. Neutropenia and the susceptibility to infections are now attributed to specific abnormalities in neutrophil production and function.

Mutations in glucose 6-phosphate transporter G6PT cause apoptosis of developing neutrophils, ineffective neutrophil production, and neutropenia.

Monocyte functions are also abnormal, probably contributing to the formation of granulomas and chronic inflammatory responses. It is also important to note that some patients with GSD Ia have also been known to develop neutropenia.

Individuals with GSD Ia who are homozygous for the mutation p. GlyArg were reported to have a GSD Ib—like phenotype with neutropenia.

G-CSF has been used for treating neutropenia and preventing infections in patients with GSD Ib since refs. This cytokine stimulates and accelerates neutrophil production by the bone marrow, releases neutrophils from the bone marrow, prolongs the survival of the cells, and enhances their metabolic burst.

Administration of G-CSF increases blood neutrophil counts to normal or above normal levels, usually within a few hours. In a review of 18 European patients given either glycosylated or nonglycosylated G-CSF median age: 8 years; treated for up to 7 years , there was a positive clinical response both in the severity of infections and in the manifestations of inflammatory bowel disease in all patients.

Almost all reports on GSD Ib indicate that G-CSF increases blood neutrophil levels, decreases the occurrence of fevers and infections, and improves enterocolitis. Before G-CSF treatment, median ANC for this group was 0.

Treatment can be performed daily, on alternate days, or on a Monday—Wednesday—Friday schedule with similar benefits DC Dale, personal communication , but some children require daily therapy to avoid infections.

G-CSF should be administered subcutaneously starting at 1. The G-CSF dose should be increased in a stepwise manner at approximately 2-week intervals until the target ANC of more than to up to 1. The ANC for these patients is not pushed to higher levels because G-CSF appears to increase the spleen size in GSD Ib patients.

Blood count should be monitored several times per year. The lowest effective G-CSF dose should be used to avoid splenomegaly, hypersplenism, hepatomegaly, and bone pain. With use of G-CSF, occurrences of infections were greatly reduced and inflammatory bowel disease also improved in most, but not all, patients.

In more than patient-years of observations, the Severe Chronic Neutropenia International Registry has recorded three deaths in GSD Ib patients, sepsis, 1; after liver and hematopoietic transplant, 1; hepatomegaly and neutropenia, 1.

Side effects of treatment with G-CSF in the GSD Ib population were reported by the European Study on Glycogen Storage Disease Type I. This complication did regress with reduced treatment.

There are known cases in which the splenomegaly did not improve with reduction of the dose and splenectomy was required. Increase in spleen size and the need to reduce G-CSF dose can usually be determined by physical examination and confirmed by ultrasound when necessary.

In addition, this group reported two patients that have been on G-CSF and developed acute myelogenous leukemia. Based on available data, the risk of acute myelogenous leukemia is very low.

However, all patients should be observed, with serial blood counts monitored approximately quarterly for development of loss of response to G-CSF, presence of myeloblasts in the blood, evidence of hypersplenism, new patterns of bone pain, or any other changes that might suggest a change in hematological disease or development of a myeloid malignancy.

In contrast to the hypertrophic cardiomyopathy of GSD II Pompe disease or GSD III, the heart itself is not primarily affected by GSD I. The most common cardiovascular abnormality in patients with GSD I is systemic hypertension Box 6.

This is reviewed in the Nephrology section of this article. There are conflicting data about this question, and two small series examining clinical surrogates of early atherosclerosis found no evidence to suggest early atherosclerosis. One of the most ominous, yet rare, potential complications of GSD I is the occurrence of pulmonary arterial hypertension PAH.

PAH may coexist with numerous systemic illnesses such as rheumatologic diseases, portal hypertension, infections such as HIV , and exposure to toxins anorexigens.

PAH is also known to be a complication of several other conditions, such as hypoxic lung disease, thromboembolic disease, pulmonary venous hypertension secondary to left-sided heart disease, and congenital heart disease with left-to-right shunting through the lungs. Finally, it may occur in isolation as primary PAH.

To date, nine GSD I patients with PAH have been reported. This suggests that the GSD I patient with a coexisting condition that may also predispose a patient to development of PAH is at the highest risk for this complication. In all the cases of GSD I with PAH described in the literature, the diagnosis of PAH was not made until it was quite advanced, and in seven of nine patients PAH led to their deaths.

Recently, oral medications for PAH, such as sildenafil, have been shown to be effective treatments. GSD I patients with this serious complication have a better chance of longer survival if PAH is diagnosed at an earlier stage and medical treatment is initiated promptly.

Management recommendations for cardiovascular manifestations of GSD I include screening to detect systemic or pulmonary hypertension at early stages when these conditions are most amenable to treatment. Because systemic hypertension in children is only rarely associated with clinical symptoms such as headaches or vision changes beginning in infancy, accurate measurements of systemic blood pressure should be obtained at all clinic visits.

Any elevated blood pressure measurements should be carefully followed up to confirm the diagnosis of hypertension. It is important to note that age-appropriate and gender-appropriate norms for blood pressure should be applied when reporting it.

Good metabolic control is the best management option for maintaining serum lipid levels as close to normal as possible, thereby reducing the risk of acute pancreatitis and long-term development of atherosclerosis.

Management of hyperlipidemia with medications usually does not begin until the patient is at least 10 years old. Screening for pulmonary hypertension by periodic echocardiography with attention to estimating right-ventricular pressure by tricuspid regurgitation jet is indicated because PAH is unlikely to have clinical features that would be apparent on physical examination or with simple testing such as electrocardiogram until the PAH is well advanced.

Obtaining the tricuspid regurgitation jet by echocardiogram is the best method to periodically screen for elevated right-side heart pressures. Because most of the patients with PAH also had poor metabolic control, achieving good metabolic control may prevent PAH.

If PAH is detected, pursuing effective treatment methods such as treatment with Bosentan and Sildenafil in consultation with a physician experienced in managing PAH is recommended.

The primary-care physician should take care of the regular physical examinations and immunizations, as well as any intercurrent medical problem not related to the GSD. Other available immunizations, such as those for seasonal influenza, hepatitis B, and pneumococcal infections polyvalent after 2 years of age , should be offered because they can prevent the hypoglycemia caused by the gastrointestinal manifestations associated with the disease processes.

Hepatitis C status should be monitored in patients at risk. Because patients with GSD I may receive several medications, it is always recommended to check for potential interactions with the physician or pharmacy when a new medication is prescribed.

Drugs that can potentially cause hypoglycemia should be avoided. These include β-blockers, quinidine, sulfonamides Bactrim , pentamidine, and haloperidol, as well as some over-the-counter medications. Antidepressant agents should be used with caution because they can affect glucose regulation hypoglycemia or hyperglycemia.

Insulin and insulin secretagogues sulfonylureas should be used with caution. The use of growth hormone should clearly be limited to only those who are proven to have a growth hormone deficiency and, in this situation, close monitoring for liver adenomas and metabolic disturbances is critical.

The use of aspirin, nonsteroidal anti-inflammatory drugs, and other medications that reduce or affect platelet function should be avoided. Hypoglycemia risks should be checked before starting medications. Due consideration should be given to medications that have a high sodium or potassium content; the latter is especially important in the setting of renal failure.

All patients should be encouraged to participate in age-appropriate physical activities. However, contact or competitive sports should be avoided because of the risk of liver injury, unless proper protection is used.

Patients should avoid alcohol intake as it may predispose them to hypoglycemia. Good hygiene and frequent hand-washing precautions are advised, especially for patients with neutropenia. As a general rule, patients should avoid unnecessary contact with sick people, especially during the winter season.

Good dental hygiene and frequent monitoring of dental health are advised for all patients, but it is particularly important in patients with GSD Ib, who have a tendency to develop chronic gingivitis. During intercurrent illnesses, early evaluation and treatment are encouraged to prevent complications, especially when infectious processes are suspected in patients with neutropenia.

In such cases more frequent monitoring of BG and additional doses of CS may be indicated. glucose treatment. The emergency letter should be reviewed annually and updated as needed.

Patients should wear a medical alert identification. A variety of types are offered by pharmacies and websites:. Necklaces and bracelets with engraved patient name, diagnosis, and emergency contact information. org offers a sponsored membership program that provides bracelets with an engraved toll-free telephone number and patient ID number.

Metabolic derangement caused by fasting and infections are a common cause of morbidity in patients with GSD I, even with current treatments. In addition, some illnesses causing anorexia and vomiting interrupt oral or nasogastric feedings. Patients and their parents should be educated regarding the symptoms of hypoglycemia and metabolic decompensation.

They should be taught to respond to minor ailments by giving frequent oral or NG glucose-containing fluids, and they should be educated regarding the need for emergency care if oral feeds are not tolerated. Of course, due consideration of fluid volume is given in the setting of renal failure.

Intravenous solutions containing lactate are contraindicated and should be avoided. Patients with GSD I cannot tolerate typical periods of fasting before procedures.

Progressive metabolic acidosis and cardiac dysrhythmia leading to cardiac arrest during surgery have been reported. Recommendations have been published as a guide for perioperative management.

supply of glucose can be provided. The i. BG, electrolyte, and lactic acid levels should be monitored. Although administration of dextrose-containing fluids at lower rates can result in normalization of BG, higher doses of glucose are needed to keep the patient anabolic and prevent lactic acidosis.

fluids should continue until oral feeding is re-established. Once the patient is taking oral feedings, the dextrose infusion should be slowly weaned over several hours. Caution should be used when prescribing hormonal birth control; estrogen is known to contribute to development of both benign and malignant hepatocellular tumors Box 9.

Females with GSD I are known to have polycystic ovaries from a young age. Menorrhagia appears to be a problem in females of reproductive age with GSD I. Management of females with GSD I should include a multidisciplinary approach including the expertise of a gynecologist familiar with GSD I.

With significant strides in management of GSD I, patients are surviving into adulthood and pregnancies are now becoming common.

Successful pregnancies have been documented in women with GSD types Ia and Ib. Ideally, it is prudent to plan the pregnancy ahead of time so that metabolic parameters may be monitored and normalized in preparation for pregnancy.

A prepregnancy consultation should be conducted during which adherence to a safe diet routine to avoid low BG, accompanied by frequent BG monitoring, should be emphasized. Medications such as ACE inhibitors, allopurinol, and lipid-lowering drugs must be discontinued because they are known to cause fetal anomalies.

A baseline ultrasound of the kidneys and liver to monitor for hepatic adenomas should be performed before the patient becomes pregnant. Laboratory tests such as a lipid profile, serum uric acid test, liver function test, complete blood count, and urine protein test should be performed.

Good metabolic control will help normalize most of these parameters if abnormal. In addition, in patients with GSD Ib, conception at a time when inflammatory bowel disease is quiescent may make flare-ups during pregnancy less likely.

The high estrogenic state in pregnancy has been reported to cause an increase in adenoma formation. Increased proteinuria may be noted. Risk of stone formation is typically higher in GSD Ia than in GSD Ib, 40 but renal calcification was noted in two of three pregnant patients with GSD Ib in one case series.

Neutropenia and Crohn disease—like enterocolitis are problems unique to GSD Ib. Low neutrophil counts can lead to infectious complications. G-CSF is classified by the US Food and Drug Administration as a pregnancy class C drug. There are no recommendations for G-CSF use during pregnancy.

There are published reports in the literature of normal pregnancy outcomes after G-CSF use. Management of Crohn disease—like enterocolitis can be problematic in pregnancy because most medications used for treatment are not approved for use during pregnancy.

The risk to the fetus from active enterocolitis has to be considered in comparison with the risk from the medications themselves during decision making regarding management. BG levels should be monitored throughout the process to maintain euglycemia. Transient hypoglycemia has been observed in some neonates.

Neonates have been noted to have normal growth and development. There is no contraindication to breastfeeding. Increased metabolic demands will occur while breastfeeding. It has been observed that not all mothers may be successful at breastfeeding. The website provides descriptions of the various types of GSD and a listserv, a mechanism for people with all forms of GSD to connect via the Internet.

The association also holds a medical conference each year for individuals with GSD and their families. Similar to that for other inborn errors of metabolism, genetic counseling should be offered to all parents of children with GSD I and to adults affected with the condition Box GSD I is an autosomal recessive condition.

De novo mutation rates are expected to be infrequent, and parents of an affected individual are assumed to be carriers. DNA mutation analysis is necessary for the identification of additional family members in the extended family who may be carriers.

Targeted mutation analysis based on ethnic background is available for both the G6PC and SLC37A4 genes. Generally, full sequence analysis is recommended, starting with GSD Ia and then GSD Ib, if clinical suspicion is present.

Large deletions and duplications cannot be detected by sequence analysis. Identification of carrier status in the general population is limited and not routinely offered; however, mutation analysis to further refine the risk of having a child with GSD I can be offered to those at risk e.

Prenatal diagnostic testing is typically performed by mutation analysis either on cultured chorionic villus samples or on amniocytes, ideally of the probands of previously identified mutations. When the mutations segregating in the family are known, molecular testing is the gold standard.

Prenatal genetic diagnosis is also an option for families with GSD I if the mutations have been identified. Acute and chronic complications occur in GSD Ia despite adherence to dietary therapy, including growth retardation, hepatomegaly, intermittent hypoglycemia, lactic acidemia, hyperlipidemia, gout related to hyperuricemia, proteinuria, nephrolithiasis, and progressive nephropathy.

Modified CS shows promise for improving dietary therapy because a single dose at bedtime prevented hypoglycemia more effectively throughout the night in comparison with uncooked CS. Perhaps one of the most concerning complications of GSD I is the frequent occurrence of hepatic adenomas in adult patients, which are accompanied by a significant risk for malignant transformation to HCC.

The mechanism for tumorigenesis remains to be elucidated in GSD Ia, although it could include chronic inflammation. Progressive nephropathy is associated with proteinuria in adult patients. The overexpression of angiotensinogen suggests that suppression of the renin—angiotensin system might be effective in GSD Ia.

Microalbuminuria has been effectively treated with low doses of ACE inhibitors such as captopril and lisinopril.

In a study of 95 patients with GSD I, a significant and progressive decrease of glomerular hyperfiltration was noted in patients treated with ACE inhibitors. Hyperlipidemia in GSD Ia can be managed with lipid-lowering drugs such as 3-hydroxymethyl-glutaryl-CoA reductase inhibitors and fibrates.

The potential benefit of 3-hydroxymethyl-glutaryl-CoA reductase inhibitors was emphasized by a study that showed increased triglyceride synthesis in GSD Ia patients compared with normal controls. Hyperuricemia in GSD I can improve with good metabolic control; however, in some situations, hyperuricemia persists and can result in gouty attacks, gouty tophi, and kidney stones.

Use of agents, such as Allopurinol and Febuxostat, have been used to lower uric acid levels. Newer agents, such as pegloticase, have been used in situations where the use of other agents has failed. Colchicine has been used with success in the acute setting of gouty attacks.

At this time, there is no consensus as when to treat hyperuricemia with medications. The development of new therapy for GSD Ia, such as gene therapy or cell therapy, might prevent long-term complications that arise due to recurrent hypoglycemia and related biochemical abnormalities.

Pilot studies of hepatocyte transplantation have demonstrated persistence of donor cells, although the long-term efficacy of this approach remains to be demonstrated , Efficacy from liver-targeted gene therapy in GSD Ia might be expected, given the experience with human patients after liver transplantation.

Furthermore, complications of GSD Ib were incompletely reversed in experiments with an AAV vector encoding G6PT, and longer-term surviving mice developed hepatocellular carcinoma related to inadequate correction.

The duration of efficacy from AAV vectors has been limited, because the AAV vector genomes remain largely episomal and are lost after cell division.

A double-stranded AAV vector transduced the liver and kidneys with higher efficiency when pseudotyped as AAV9 rather than the AAV8 vector used for initial experiments; however, G6Pase expression from these vectors gradually waned between 7 and 12 months of age.

The loss of G6Pase could be countered by readministration of an AAV vector of a new serotype to avoid antibodies formed in response to the initial AAV vector treatment. Despite these apparent limitations of gene therapy in GSD I, the development of AAV vector—mediated gene therapy will continue based on the success of early-stage clinical trials of gene therapy in hemophilia.

In patient 1 uncooked cornstarch at night could be slowly reduced over a period of 5 months and was then discontinued, patient 2 received uncooked cornstarch for two months only. Both patients were followed in our outpatient clinics patient 1: 32 months, patient 2: 26 months after start of MAD and were seen every 3—6 months.

To assess the metabolic status and therapy compliance the following parameters were recorded every 3 to 6 months: ketone bodies in plasma and urine, CK-levels in serum, liver function, acylcarnitine profile, amino acids in plasma, lipids and glucose in serum.

Cardiac investigations via echocardiography and electrocardiography were performed every 3—6 months. At home, parents monitored ketone bodies in urine via dip stick testing. While the family of patient 1 had no problems sticking to MAD, the family of patient 2 decided to stop MAD after 3 months and switched to traditional cooking.

Patient 2 and his family were noncompliant due to language difficulties and lack of comprehension of the disease. There were many psycho- social problems as the family had refugee status.

In the following months we were able to convince the family to resume MAD. Dietary treatment with MAD was well tolerated apart from transient hypoglycaemia. In patient 2 carbohydrate intake under MAD was 0.

No dietary assessment was done in this patient prior to MAD introduction. In both patients dietary recommendations according to DACH German-Austrian-Swiss association for nutrition were met as judged by dietary protocols during MAD.

Essential laboratory and echocardiographic parameters are summarized in Table 1. Plasma concentrations of ketone bodies ranged from 1.

The CK activity in blood fell significantly under MAD. Cardiac function improved as judged by echocardiography and ECG. Left ventricular outflow tract LVOT obstruction significantly improved; the gradient decreased from 20 mm Hg before initiation of MAD to 5 mm Hg after 32 months of MAD, ventricular septum thickness was reduced from 1.

This improvement is reflected in NT-Pro BNP N-terminal fragment pro brain natriuretic peptide -levels which were very high and normalized under MAD. Before MAD, the ECG revealed biventricular hypertrophy and abnormalities in repolarisation with a ST-elevation of 0. After 32 months of MAD, repolarisation normalized, ST-elevation disappeared, while signs for left ventricular hypertrophy were still observed.

The patient showed an increase of stamina and is able to walk metres without interruption. Weight gain and growth are commensurate with age. Apart from transient asymptomatic hypoglycaemia no side effects were observed. LDL-cholesterol levels were in the reference range, triglycerides were slightly increased Table 1.

MAD resulted in elevated ketone bodies in plasma with a maximum of 7. Chest pain after physical exercise and nausea disappeared. The boy gained more stamina.

Subsequently, under dietary noncompliance and complete withdrawal of MAD, ketosis was lost. Chest pain after physical exercise reappeared and a reduction of physical capacity was observed.

No cardiac follow-up could be performed due to incompliance. Chest pain and muscular weakness disappeared. No serious side-effects resulting from MAD were observed, LDL-cholesterol and triglyceride levels remained normal results not shown. Weight gain and growth were appropriate for age. GSD III has classically been treated with frequent carbohydrate-rich meals.

While this therapeutic option prevents hypoglycaemia it does not improve muscle [ 17 ] and cardiac dysfunction [ 18 ],[ 19 ] including arrythmias [ 20 ]. We hypothesized that reactive hyperinsulinism resulting from high carbohydrate feeding is responsible for the depletion of energy substrates fatty acids and ketone bodies in skeletal and cardiac muscles followed by muscle dysfunction.

Furthermore, elevated levels of insulin activate glycogen synthase and promote glycogen storage in myocytes [ 15 ]. This may exacerbate subtle energy deficiency which has been discussed to play a pathophysiological role in glycogenoses [ 21 ],[ 22 ].

CK-levels in plasma as an objective quantitative parameter for muscle dysfunction dropped under MAD. Quantitative tests of muscle strength were not performed. A involuntary cross-over study took place in patient 2. Heart function improved as judged by echocardiography and ECG in patient 1.

Pro BNP as a marker for compromised heart function impressively improved under MAD. Detailed studies of heart function were not performed in patient 2 as heart function was not severely compromised before MAD was initiated.

Most likely, the underlying pathophysiological mechanism is prevention of hyperinsulinism and its consequences. Daily carbohydrate allowance was low in both patients at 0. Adequate supply of energy substrates under MAD has a positive effect on muscle function.

Furthermore, ketosis is known to activate mitochondrial succinate dehydrogenase in heart thus improving the energetic balance [ 23 ]. Reduction of the glycogen synthase activity with consecutive reduction of stored glycogen may be another beneficial factor.

We observed transient hypoglycaemia at the start of MAD when ketone bodies were not yet elevated. Potential side effects of MAD as gastrointestinal symptoms, fatigue and dyslipidaemia [ 24 ] were not observed in our patients.

So far, it is not clear what is necessary in terms of plasma ketone body concentrations to secure adequate energy supply for heart and skeletal muscles.

It is not clear why the response to MAD in patient 2 was less pronounced as judged by CK-levels. Response may depend on the specific mutation underlying GSD IIIa, alternatively dietary compliance may have been incomplete between visits in our outpatient clinics. A similar stabilization and reversal of GSD IIIa-related cardiomyopathy and myopathy of respiratory muscles has been reported in patients on a high-protein diet [ 10 ]—[ 12 ] which is also suggested in a recent guideline [ 14 ].

We speculate that the underlying mechanism of this observation may be the prevention of reactive hyperinsulinism as well. Valayannopoulos et al. reported a case with improvement of cardiomyopathy under high-protein diet combined with administration of D, LHydroxybutyrate.

The supply of exogeneous ketone bodies is unphysiological and requires compliance of the patient. Sticking to a ketogenic diet is more demanding than following MAD. Thus, MAD may be more efficient and comfortable for the daily routine of the patient.

In summary, we report 2 boys with GSD IIIa who benefited from MAD. CK-levels fell, cardiac function improved and exercise tolerance increased. Apart from transient asymptomatic hypoglycaemia at the initiation of MAD no serious adverse effects were observed. Written informed consent was obtained from the parents of patient 1 and the mother of patient 2 for the publication of this report.

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