Liver Glycogen Storage Diseases
Clinical and Management Updates
Metabolic Liver Disease
Jan 13-14, 2012
Priya S Kishnani, ...
The glycogen storage diseases (GSDs)
• Genetic deficiencies that result in the storage of
abnormal amounts and/or forms of...
Eat: Store energy
Fast: Release stored energy
Energy = glucose
Glycogen Storage Diseases
Brain Fuel Utilization

Fasting fuel system

Meal

Glycogenolysis Gluconeogenesis

1 Hour

4 Hours

Ketogenesis

10-12 Hou...
Portion of a glycogen molecule
Structure and degradation of
Glycogen
GSD TYPE

Deficient Enzyme

Tissue Involved

Clinical Findings

GSD 0

Glycogen Synthase

Liver

Hypoglycemia,
ketosis

GS...
GSD TYPE

Deficient Enzyme

Tissue Involved

Clinical Findings

GSD IV

Branching Enzyme

Liver

Hypoglycemia,
hepatomegal...
Glycogen Storage Disease
The Liver GSDs
GSD Ia
GSD Ib
GSD III
GSD IV
GSD VI
GSD IX (subtypes)
GSD XI(Fanconi-Bickel
syndro...
Glycogen Storage Disease type I
Von Gierke Disease

• Inherited autosomal recessive disease
• Estimated incidence is 1:150...
Metabolic sequele of GSD I
GSD-I
GSD I - Childhood
• Enlarged liver and kidneys (due to glycogen
and lipid storage)
• Retarded growth
• Low blood sugar
• H...
Goals of nutritional therapy for GSD
Type I
• Prevent hypoglycemia
• Correct metabolic derangements
• Provide optimal nutr...
Treatment Strategy:
Maintain Normoglycemia
• Methods
– Frequent feeding
– Continuous glucose infusion
• Total parenteral n...
Diet Guidelines for GSD I
Nutrition Composition
• Carbohydrates (60-70%)
– Complex sources – starches
– No sucrose or fruc...
Night time tube feeding
GSD Type I
• Formula – Sucrose, fructose, lactose free
• Primarily to provide glucose
– Infant:
8-...
Long-term Complications of GSD-I
• growth failure

• gout

• osteoporosis

• anemia

• renal calcification

• pulmonary hy...
GSD I - Hepatic Adenomas
• Some follow-up studies suggest prevalence of about 50%,
similar to that described in past
• Ret...
Medical Management of GSD I

• Allopurinol for gout
• Lipid lowering medications
• Citrate supplementation for low citrate...
GSD I diagnosis:
• Mutation analysis: For GSD Ia there are ~80 disease
causing mutations known in the G6PC gene, some
muta...
Hypovitaminosis D in GSD type I
• 16 of 26 (61.5 %) GSD I patients had 25-hydroxy
vitamin D levels <30 ng/ml despite suppl...
Use of Medium Chain Triglycerides in
GSD I

• 2 patients with GSD Ia and one with GSD Ib treated with
classical GSD diet a...
GSD III (Debranching enzyme
deficiency)
Debrancher enzyme
GSD-III subtypes:
a: Debrancher activity deficient in liver and
muscle (85% of cases)
b: Debrancher activity deficient onl...
Glycogen Storage Disease Type III
(GSD – III) Clinical Variability
•
•
•
•
•

Hepatomegaly
Growth retardation
Hypoglycemia...
Major phenotypic expression: GSD-III
• Hypoglycemia- improves with age

• Massive hepatomegaly- due to abnormal
glycogen a...
Complications associated with GSD III
Highly Variable
• Clinical signs: hepatomegaly short stature, +/skeletal myopathy, c...
Adult patient with GSD IIIa
• The neuromuscular manifestations of GSD III are not
well characterized.
• Medical records of 40 patients seen at Duke
Un...
Treatment of GSD III
• Less demanding than in Type I
• Frequent meals high in carbohydrates and
cornstarch as well as high...
GSD type III diagnosis:
• Large gene with 35 exons

•For GSD III b (no muscle disease) mutational analysis is
done for two...
GSD IV
Portion of a glycogen molecule

Lack of branching makes glycogen insoluble, glycogen
appears like fibers of amylopectin, b...
GSD IV (Amylopectinosis) common
clinical presentation:
Extremely heterogeneous in terms of tissue
involvement, age of onse...
GSD IV presentation variability:
• Progressive liver cirrhosis, failure to thrive
• Non-progressive milder hepatic form
• ...
Treatment of GSD-IV
• NONE
Supportive dietary measures
Liver transplant ---but some patients MAY
show no progression so wa...
GSD IV diagnosis:
•

DNA sequencing of the GBE gene

• Muscle, skin fibroblasts or liver biopsy to
determine BE enzymatic ...
GSD VI (Hers)
• Liver specific phosphorylase deficiency
• Typically benign course, mild hypoglycemia,
hepatomegaly and gro...
GSD VI lab diagnosis:
•Liver biopsy measures the deficient
phosphorylase enzyme activity and also measures
elevated glycog...
GSD IX
• Accounts for about 25% of all GSDs
• Caused by deficiency of glycogen phosphorylase
kinase (PhK)
–
–
–
–

Activat...
Subunit

Gene(s) Chromosome
location

Tissue
Mutations found in
expression GSD IX?

alpha
(regulatory)

PHKA1

Xq12-q13

M...
GSD IX
•
•
•
•
•

Features often similar to GSD III
Elevations of AST and ALT
Patients can have a significant ketosis
CPK ...
GSD IX
• Treatment is symptomatic
– If hypoglycemia present, treat accordingly
– Improved growth with increased complex
ca...
(GSD XI)
Fanconi-Bickel syndrome
• Presentation in infancy typically from 3-10 months
with failure to thrive, hepatorenome...
Fanconi-Bickel syndrome (GSD XI)
• Fasting hypoglycemia; postprandial
hyperglycemia also observed
• Some patients diagnose...
(GSD XI) Fanconi-Bickel syndrome
• Autosomal recessive; caused by mutations in GLUT2
gene (SLC2A2)
• GLUT2, glucose-transp...
Fanconi-Bickel syndrome
Clinical management
• Avoid fasting hypoglycemia with small, frequent
meals, and uncooked cornstar...
Conclusions
•
•
•
•

Several liver GSDs (GSD I, III, IV, VI, IX, XI)
Based on features can differentiate largely
Molecular...
Modified Cornstarch Therapy
First trials with Glycosade in Europe were encouraging
•short-term double-blind cross-over pil...
Modified Cornstarch Therapy
• Median starch load
duration 9 hours for
WMHM20 and 7 hours for
uncooked cornstarch
• Glucose...
Modified Cornstarch Therapy

– Glycosade maintained
BG longer than Argo
– Argo demonstrated a
higher peak glucose
concentr...
Acknowledgements
• Our patients and their families
• Treating physicians and other health care
personnel world wide
• Coll...
Acknowledgements
• Duke University
•
•
•
•
•
•
•
•

Anne Boney
Jennifer Sullivan
Deeksha Bali
Dwight Koeberl
Don Frush
Lui...
Glycogen Storage Disease III
• Inherited Autosomal Recessive
• Cori’s Disease
• Amylo-1,6-glucosidase (debrancher)
deficie...
GSD IIIa
• GSD IIIa (liver and muscle) can mimic GSD I in
infancy/young child
– May present with hepatomegaly and
hypoglyc...
GSD IIIa - Treatment
• Infancy/Young child – may mimic GSD I
– Avoid fasting; frequent feedings to prevent hypoglycemia
(s...
GSD IIIa – Diet Treatment
• High protein; complex carbs, low sugar
• Dr. Slonim: 25 – 30% pro; 35 – 40% cho; 30 – 35% fat
...
GSD IIIa
• Adult – myopathy ~3rd or 4th decade
– Hypoglycemia improves; myopathy worsens;
cardiomyopathy
– Concern with he...
GSD IIIb
• GSD IIIb (liver only)
– Infancy: may mimic GSD I; frequent feedings;
avoid fasting/hypoglycemia
– Young child: ...
GSD IV
• Anderson’s disease
• Autosomal recessive
• Amylo-1,4-1,6transglucosidase deficiency
– Glycogen Brancher Enzyme
(G...
GSD IV
• Typically presents with liver disease, progresses to cirrhosis
and death (5 y)
– Liver transplant has been done f...
GSD VI, IX
• GSD VI – Hepatic Phosphorylase, Hers’ disease
– caused by mutations in PYGL gene
– Autosomal Recessive

• GSD...
GSD IX – variable inheritance; many
isoforms
•Phosphorylase kinase
deficiency - obstructs
glycogen breakdown
– Usually onl...
GSD IX
• Accounts for about 25% of all GSDs
• Caused by deficiency of glycogen phosphorylase
kinase (PhK)
–
–
–
–

Activat...
Subunit

Gene(s) Chromosome
location

Tissue
Mutations found in
expression GSD IX?

alpha
(regulatory)

PHKA1

Xq12-q13

M...
Subtypes of phosphorylase kinase deficient
GSDs (GSD IX)

Inheritance

Tissue affected

Mutant gene

X-Linked recessive

M...
GSD IX
• Treatment is symptomatic
– If hypoglycemia present, treat accordingly
– Improved growth with increased complex
ca...
GSD IX
•

For a GSD IX child presenting with hypoglycemia and growth delay…
– Keep Food and Blood Glucose Record (how long...
GSD 0
• Glycogen Synthase Deficiency
– Autosomal recessive disease
– Few reported cases, several mutations
– Symptoms incl...
GSD 0
• Treatment – Prevent hypoglycemia
– Small frequent meals with complex carbohydrates
and protein through out the day...
Modified Cornstarch Therapy
First trials with Glycosade in Europe were encouraging
•short-term double-blind cross-over pil...
Modified Cornstarch Therapy
• Median starch load
duration 9 hours for
WMHM20 and 7 hours for
uncooked cornstarch
• Glucose...
Modified Cornstarch Therapy
• Pilot Study done in the US was also
encouraging:
– Randomized, 2-d, double blinded, crossove...
Modified Cornstarch Therapy

– Glycosade maintained
BG longer than Argo
– Argo demonstrated a
higher peak glucose
concentr...
Glycogen storage diseases  talk priya kishnani 1
Glycogen storage diseases  talk priya kishnani 1
Glycogen storage diseases  talk priya kishnani 1
Glycogen storage diseases  talk priya kishnani 1
Glycogen storage diseases  talk priya kishnani 1
Glycogen storage diseases  talk priya kishnani 1
Glycogen storage diseases  talk priya kishnani 1
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Glycogen storage diseases talk priya kishnani 1

  1. 1. Liver Glycogen Storage Diseases Clinical and Management Updates Metabolic Liver Disease Jan 13-14, 2012 Priya S Kishnani, MD Division Chief, Medical Genetics Duke University Medical Center
  2. 2. The glycogen storage diseases (GSDs) • Genetic deficiencies that result in the storage of abnormal amounts and/or forms of glycogen • Some deficiencies affect only one tissue, others several, and even individuals with the same disease class can have heterogeneous manifestations. • Focus today: Liver GSDs
  3. 3. Eat: Store energy Fast: Release stored energy Energy = glucose
  4. 4. Glycogen Storage Diseases
  5. 5. Brain Fuel Utilization Fasting fuel system Meal Glycogenolysis Gluconeogenesis 1 Hour 4 Hours Ketogenesis 10-12 Hours
  6. 6. Portion of a glycogen molecule
  7. 7. Structure and degradation of Glycogen
  8. 8. GSD TYPE Deficient Enzyme Tissue Involved Clinical Findings GSD 0 Glycogen Synthase Liver Hypoglycemia, ketosis GSD Ia Glucose-6phosphatase Liver, Kidney Hypoglycemia, hepatomegaly, lactic acidosis, hyperlipidemia GSD Ib Glucose-6phosphatase translocase Liver, Kidney GSD Ia plus neutropenia and infections GSD II Acid alphaglucosidase (lysosomal) Cardiomyopathy, myopathy Infants: cardiorespiratory failure Later onset: myopathy GSD IIIa Debranching enzyme Liver, muscle, heart Hypoglycemia, hepatomegaly, myopathy GSD IIIb Debranching enzyme Liver Hypoglycemia, hepatomegaly
  9. 9. GSD TYPE Deficient Enzyme Tissue Involved Clinical Findings GSD IV Branching Enzyme Liver Hypoglycemia, hepatomegaly GSD V Phosphorylase Muscle Exercise intolerance, myoglobinuria GSD VI Phosphorylase Liver Hepatomegaly GSD VII Phosphofructokinase Phosphoglycerate kinase Phosphoglycerate mutase Muscle Exercise intolerance GSD IX Phosphorylase b kinase Liver Hepatomegaly
  10. 10. Glycogen Storage Disease The Liver GSDs GSD Ia GSD Ib GSD III GSD IV GSD VI GSD IX (subtypes) GSD XI(Fanconi-Bickel syndrome) GSD 0 Liver
  11. 11. Glycogen Storage Disease type I Von Gierke Disease • Inherited autosomal recessive disease • Estimated incidence is 1:150,000 births • Often picked up due to hypoglycemia or hepatomegaly • GSD Ia – glucose-6-phosphatase deficiency • GSD Ib – lack of transporter protein for glucose-6phosphatase • Genes known to be associated with GSDI are G6PC (GSDIa)- accounts for ~ 80% of GSDI cases, SLC37A4 (GSDIb)- accounts for ~ 20% of GSDI cases
  12. 12. Metabolic sequele of GSD I GSD-I
  13. 13. GSD I - Childhood • Enlarged liver and kidneys (due to glycogen and lipid storage) • Retarded growth • Low blood sugar • High blood lactate, lipid and uric acid
  14. 14. Goals of nutritional therapy for GSD Type I • Prevent hypoglycemia • Correct metabolic derangements • Provide optimal nutrition to support growth and development
  15. 15. Treatment Strategy: Maintain Normoglycemia • Methods – Frequent feeding – Continuous glucose infusion • Total parenteral nutrition • Intragastric feeding – Uncooked cornstarch • 1.75-2.5 g/kg q 6 hours
  16. 16. Diet Guidelines for GSD I Nutrition Composition • Carbohydrates (60-70%) – Complex sources – starches – No sucrose or fructose – Limit lactose/galactose (1 serving dairy/day) – Cornstarch • Protein (10-15%) – High biological value – Lean sources
  17. 17. Night time tube feeding GSD Type I • Formula – Sucrose, fructose, lactose free • Primarily to provide glucose – Infant: 8-10 mg glucose/kg/min – Young child: 8 mg glucose/kg/min – Older child: 6 mg glucose/kg/min – Adult: 4-5 mg glucose/kg/min • Alarm in case of failure • Eat or take CS within 30 minutes of discontinuing tube feeding
  18. 18. Long-term Complications of GSD-I • growth failure • gout • osteoporosis • anemia • renal calcification • pulmonary hypertension • renal dysfunction • Pancreatitis • hepatic tumours • Diabetes Mellitus, type II – Adenoma, HCC • hyperlipidemia • polycystic ovaries • (inflammatory bowel disease) • (bacterial sepsis)
  19. 19. GSD I - Hepatic Adenomas • Some follow-up studies suggest prevalence of about 50%, similar to that described in past • Retrospective data (European registry) shows ~50% prevalence in patients >age 20 • Other reports suggest lower incidence, and even regression, of adenomas in adequately treated patients • Complications of HCA include – bleeding – malignant transformation, poor prognosis with HCC • Metastasis to lung and bone • GI bleeds and liver failure most common causes of death
  20. 20. Medical Management of GSD I • Allopurinol for gout • Lipid lowering medications • Citrate supplementation for low citrate (prevent kidney stones) • ACE inhibitor for microalbuminuria • Kidney transplantation for kidney failure • Liver transplantation if other medical interventions fail (adenomas) • GCSF for Type lb
  21. 21. GSD I diagnosis: • Mutation analysis: For GSD Ia there are ~80 disease causing mutations known in the G6PC gene, some mutations are specific for different ethnic group (90% pick up). • For GSD Ib there are ~70 disease causing mutations reported in G6PT gene so far. Mutations in exon 8 are more prevalent (60% pick up) • Mutational diagnosis is useful for prenatal and carrier testing. • Enzyme analysis on liver biopsy, proving actual enzyme deficiency is the final genetic test.
  22. 22. Hypovitaminosis D in GSD type I • 16 of 26 (61.5 %) GSD I patients had 25-hydroxy vitamin D levels <30 ng/ml despite supplementation. • Restrictive diet, metabolic derangements and intestinal malabsorption possible reasons for hypovitaminosis D • Suggest 25(OH)D considered in routine evaluation of GSD I Banugaria SG, Austin SL, Boney A, Weber TJ, Kishnani PS. Hypovitaminosis D in glycogen storage disease type I. Mol Genet Metab. 2010 Apr;99(4):4347.
  23. 23. Use of Medium Chain Triglycerides in GSD I • 2 patients with GSD Ia and one with GSD Ib treated with classical GSD diet and supplemented with MCT fats. • Improved metabolic control: MCT diet led to decreased uric acid levels in all three and decreased triglycerides in youngest patient. • MCT diet reduced calories needed to maintain blood glucose and led to improved growth Das AM, et al. GSD type 1: impact of MCTs on metabolic control and growth. Ann Nutr Metab. 2010;56(3):225-32 • 13 year old and two infants with GSD Ia received MCT milk • Lactate levels and triglyceride levels decreased in the 3 patients Nagasaka H, et al. Improvements of hypertriglyceridemia and hyperlacticemia in Japanese children with GSD type 1a by MCT milk. Eur J Pediatr. 2007 Oct;166(10):1009-16
  24. 24. GSD III (Debranching enzyme deficiency)
  25. 25. Debrancher enzyme
  26. 26. GSD-III subtypes: a: Debrancher activity deficient in liver and muscle (85% of cases) b: Debrancher activity deficient only in liver (15% of cases)
  27. 27. Glycogen Storage Disease Type III (GSD – III) Clinical Variability • • • • • Hepatomegaly Growth retardation Hypoglycemia Hyperlipidemia Elevated liver transaminases • Myopathy ± • Cardiomyopathy
  28. 28. Major phenotypic expression: GSD-III • Hypoglycemia- improves with age • Massive hepatomegaly- due to abnormal glycogen accumulation • Progressive cirrhosis can occur • Skeletal myopathy in Type IIIa • Hyperlipidemia • Hepatic adenomas not Lack of : Lactic acidemia as common as GSD I Hyperuricemia glucagon response • Elevation of AST and ALT And a normalcarbohydrate meal two hours after a distinguishes GSD-III from GSD-I
  29. 29. Complications associated with GSD III Highly Variable • Clinical signs: hepatomegaly short stature, +/skeletal myopathy, cardiomyopathy • Liver cirrhosis in some, HCC also noted in long term survivors • Biochemical Consequences: hypoglycemia (improves with age), hyperlipidemia, elevated liver enzymes (transaminases)
  30. 30. Adult patient with GSD IIIa
  31. 31. • The neuromuscular manifestations of GSD III are not well characterized. • Medical records of 40 patients seen at Duke University during 1990-2009 were reviewed. • The neuromuscular manifestations of GSD III include myopathy and neuropathy and are more likely to occur with increasing age • Intrinsic hand muscle weakness is likely due to a combination of nerve and muscle dysfunction • Implications for treatment
  32. 32. Treatment of GSD III • Less demanding than in Type I • Frequent meals high in carbohydrates and cornstarch as well as high protein diet. • Physical therapy for the progressive myopathy • Liver transplant if end stage cirrhosis
  33. 33. GSD type III diagnosis: • Large gene with 35 exons •For GSD III b (no muscle disease) mutational analysis is done for two common mutations (picks up 90% of mutant alleles) • GSD III linkage analysis offered only to families with known family history of GSD III and where intra-genic markers are informative • Liver and or muscle biopsy- Enzymatic analysis of DE deficiency - Glycogen content and structure
  34. 34. GSD IV
  35. 35. Portion of a glycogen molecule Lack of branching makes glycogen insoluble, glycogen appears like fibers of amylopectin, bad for the liver
  36. 36. GSD IV (Amylopectinosis) common clinical presentation: Extremely heterogeneous in terms of tissue involvement, age of onset and clinical manifestations • • Hepato-splenomegaly due to accumulation of amylopectin-like structures in affected tissues • Elevated liver enzymes (transaminases)
  37. 37. GSD IV presentation variability: • Progressive liver cirrhosis, failure to thrive • Non-progressive milder hepatic form • Multisystem disease including cardiac and skeletal muscle, nerve and liver (normal BE activity) • Fatal neonatal neuromuscular form (cardiomyopathy, arthrogryposis, even hydrops fetalis) •Adult polyglycosan disease
  38. 38. Treatment of GSD-IV • NONE Supportive dietary measures Liver transplant ---but some patients MAY show no progression so wait and see, before referral to surgeons
  39. 39. GSD IV diagnosis: • DNA sequencing of the GBE gene • Muscle, skin fibroblasts or liver biopsy to determine BE enzymatic deficiency and/or histology are the norms
  40. 40. GSD VI (Hers) • Liver specific phosphorylase deficiency • Typically benign course, mild hypoglycemia, hepatomegaly and growth retardation • Severe forms with significant ketosis being recognized • Treatment- avoid fasting, cornstarch for hypoglycemia
  41. 41. GSD VI lab diagnosis: •Liver biopsy measures the deficient phosphorylase enzyme activity and also measures elevated glycogen content (rare, benign). •Mutation analysis available
  42. 42. GSD IX • Accounts for about 25% of all GSDs • Caused by deficiency of glycogen phosphorylase kinase (PhK) – – – – Activates glycogen phosphorylase Key regulatory enzyme in glycogen metabolism Complex, multi-subunit enzyme 4 copies each of 4 different subunits, each with tissuespecific expression/isoforms
  43. 43. Subunit Gene(s) Chromosome location Tissue Mutations found in expression GSD IX? alpha (regulatory) PHKA1 Xq12-q13 Muscle PHKA2 Xp22.2.p22.1 Liver beta (regulatory) PHKB 16q12-q13 Liver & muscle Yes – autosomal recessive GSD IX (mild) gamma (catalytic) PHKG1 PHKG2 7p11.2 Muscle 16p12.1-p11.2 Liver No Yes – autosomal recessive GSD IX; can be severe delta CALM1 (calmodulin, CALM2 regulatory) CALM3 Yes – rare, muscle form of GSD IX Yes - most common form of GSD IX (75% of cases) 14q24-q31 Ubiquitous No 2p21 Ubiquitous No 19q13.2-q13.3 Ubiquitous No
  44. 44. GSD IX • • • • • Features often similar to GSD III Elevations of AST and ALT Patients can have a significant ketosis CPK rarely elevated Enzymology /mutation analysis often needed to confirm diagnosis
  45. 45. GSD IX • Treatment is symptomatic – If hypoglycemia present, treat accordingly – Improved growth with increased complex carbohydrates presumably by reducing demand for gluconeogenesis – Increased protein may also be beneficial (alternative source of energy)
  46. 46. (GSD XI) Fanconi-Bickel syndrome • Presentation in infancy typically from 3-10 months with failure to thrive, hepatorenomegaly, proximal renal tubular dysfunction, and rickets. • At early stage, patients may also present with fever, vomiting, and diarrhea • Hepatomegaly- Liver size typically normal at birth and increases in infancy; Hepatomegaly typically recedes after puberty. • Liver biopsy- glycogen accumulation present
  47. 47. Fanconi-Bickel syndrome (GSD XI) • Fasting hypoglycemia; postprandial hyperglycemia also observed • Some patients diagnosed with diabetes mellitus and treated with insulin • Later stage clinical features: growth delay, moon-shaped face, fat deposition in shoulders and abdomen, delayed dentition and delayed puberty, increased fracture risk, and pancreatitis
  48. 48. (GSD XI) Fanconi-Bickel syndrome • Autosomal recessive; caused by mutations in GLUT2 gene (SLC2A2) • GLUT2, glucose-transporter-2, a monosaccharide transporter • GLUT2- mediates transport of D-glucose, to lesser extent mediates transport of D-galactose, Dmannose, and D-fructose • Expressed in hepatocytes, pancreatic beta-cells, and basolateral membrances of intestinal and renal epithelial cells • Clinical molecular testing available • Clear genotype/phenotype correlation not reported
  49. 49. Fanconi-Bickel syndrome Clinical management • Avoid fasting hypoglycemia with small, frequent meals, and uncooked cornstarch overnight; • Can follow ketogenic diet • Improved growth and decreased liver size observed in patients in good metabolic control • For treatment of effects of renal tubulopathysupplement electrolytes and water • Supplement vitamin D and phosphate for hypophosphatemic rickets
  50. 50. Conclusions • • • • Several liver GSDs (GSD I, III, IV, VI, IX, XI) Based on features can differentiate largely Molecular diagnosis now available Liver biopsy for enzyme testing in most cases useful • Liver GSDs fairly common in Indian population • Treatment simple ( cornstarch, diet, and replacement of missing elements) • Can be life threatening if not diagnosed early
  51. 51. Modified Cornstarch Therapy First trials with Glycosade in Europe were encouraging •short-term double-blind cross-over pilot study comparing uncooked physically modified cornstarch (WMHM20) with uncooked cornstarch in patients •21 patients with GSD types Ia, Ib and III; ages 3-47, 9 female Bhattacharya K, et al. A novel starch for the treatment of glycogen storage disease. J Inherit Metab Dis (2007)30:350-357
  52. 52. Modified Cornstarch Therapy • Median starch load duration 9 hours for WMHM20 and 7 hours for uncooked cornstarch • Glucose decreased more slowly and lactate suppressed faster for WMHM20 Bhattacharya K, et al. A novel starch for the treatment of glycogen storage disease. J Inherit Metab Dis (2007)30:350-357
  53. 53. Modified Cornstarch Therapy – Glycosade maintained BG longer than Argo – Argo demonstrated a higher peak glucose concentration and a more rapid rate of fall Correia, et al. Use of modified cornstarch therapy to extend fasting in glycogen storage disease types Ia and Ib. Am J Clin Nutr (2008) 88:1272-6
  54. 54. Acknowledgements • Our patients and their families • Treating physicians and other health care personnel world wide • Collaborations with Dr Nagral at Jaslok • NIH, NCRR • AGSD
  55. 55. Acknowledgements • Duke University • • • • • • • • Anne Boney Jennifer Sullivan Deeksha Bali Dwight Koeberl Don Frush Luis Franco Vidya Krishnamurthy YT Chen • Boston Children’s – David Weinstein • Nemours Children Hospital – Pamela Arn • Indian Team – – – – Madhulika Kabra Sheela Nampoothri Sujatha Jagadeesh Aabha Nagral
  56. 56. Glycogen Storage Disease III • Inherited Autosomal Recessive • Cori’s Disease • Amylo-1,6-glucosidase (debrancher) deficiency, AGL is associated gene – Glycogen breakdown is incomplete (abnormal glycogen w/ short outer chains accumulates) • Gluconeogenesis intact • GSD IIIa - Liver and Muscle (75-85%) • GSD IIIb - Liver only (15-25%)
  57. 57. GSD IIIa • GSD IIIa (liver and muscle) can mimic GSD I in infancy/young child – May present with hepatomegaly and hypoglycemia (with ketosis) • May have hyperlipidemia, but uric acid and lactic acid normal • Confirmed by absence of enzyme activity in liver and muscle in cultured fibroblasts.
  58. 58. GSD IIIa - Treatment • Infancy/Young child – may mimic GSD I – Avoid fasting; frequent feedings to prevent hypoglycemia (standard formula) – Small frequent meals with complex carbs and increased protein • alternative source of energy and to prevent muscle protein turnover) • Milk, protein powder (can be mixed with cornstarch) – Low sugar, but NO “diet restrictions” – May require cornstarch and/or night time tube feeding • CS dose may be same as GSD I or can be less • Rates of TF may be same as GSD I or can be less
  59. 59. GSD IIIa – Diet Treatment • High protein; complex carbs, low sugar • Dr. Slonim: 25 – 30% pro; 35 – 40% cho; 30 – 35% fat • 25% pro; 45% cho; 30% fat – Goldberg T, Slonim AE. Nutrition therapy for hepatic glycogen storage diseases. J Am Diet Assoc 1993;93:1423-1430
  60. 60. GSD IIIa • Adult – myopathy ~3rd or 4th decade – Hypoglycemia improves; myopathy worsens; cardiomyopathy – Concern with hepatic cirrhosis and carcinoma • Demo, E, et al, Glycogen storage disease type IIIhepatocellular carcinoma a long-term complication? Journal of Hepatology. 2007;46:492-498 – Bone Mineral Density should be monitored
  61. 61. GSD IIIb • GSD IIIb (liver only) – Infancy: may mimic GSD I; frequent feedings; avoid fasting/hypoglycemia – Young child: may need CS and/or night time tube feeding – May encourage protein as alternative source of energy, but not as important as in IIIa – Adults: require little treatment; monitor during illness/stress
  62. 62. GSD IV • Anderson’s disease • Autosomal recessive • Amylo-1,4-1,6transglucosidase deficiency – Glycogen Brancher Enzyme (GBE) deficiency; GBE1 gene • Accumulation of an amylopectin-like polysaccharide
  63. 63. GSD IV • Typically presents with liver disease, progresses to cirrhosis and death (5 y) – Liver transplant has been done for those with progressive hepatic failure • Also a non-progressive liver presentation – McConkie-Rosell A, et al. Clinical and laboratory findings in four patients with the non-progressive hepatic form of type IV glycogen storage disease. J Inher Metab dis. 1996:19;51-58 • No specific treatment – If hypoglycemia; treat accordingly • Frequent feedings; high in complex carbs – Dietary management of liver failure – Monitor for hepatic carcinoma
  64. 64. GSD VI, IX • GSD VI – Hepatic Phosphorylase, Hers’ disease – caused by mutations in PYGL gene – Autosomal Recessive • GSD IX – Phosphorylase B kinase – More common of the 2 Clinically similar • Short stature (eventually achieve normal height), variable hepatomegaly, variable hypoglycemia
  65. 65. GSD IX – variable inheritance; many isoforms •Phosphorylase kinase deficiency - obstructs glycogen breakdown – Usually only partially deficient; so some glucose available – Gluconeogenesis intact – May not have severe hypoglycemia
  66. 66. GSD IX • Accounts for about 25% of all GSDs • Caused by deficiency of glycogen phosphorylase kinase (PhK) – – – – Activates glycogen phosphorylase Key regulatory enzyme in glycogen metabolism Complex, multi-subunit enzyme 4 copies each of 4 different subunits, each with tissuespecific expression/isoforms
  67. 67. Subunit Gene(s) Chromosome location Tissue Mutations found in expression GSD IX? alpha (regulatory) PHKA1 Xq12-q13 Muscle PHKA2 Xp22.2.p22.1 Liver beta (regulatory) PHKB 16q12-q13 Liver & muscle Yes – autosomal recessive GSD IX (mild) gamma (catalytic) PHKG1 PHKG2 7p11.2 Muscle 16p12.1-p11.2 Liver No Yes – autosomal recessive GSD IX; can be severe delta CALM1 (calmodulin, CALM2 regulatory) CALM3 Yes – rare, muscle form of GSD IX Yes - most common form of GSD IX (75% of cases) 14q24-q31 Ubiquitous No 2p21 Ubiquitous No 19q13.2-q13.3 Ubiquitous No
  68. 68. Subtypes of phosphorylase kinase deficient GSDs (GSD IX) Inheritance Tissue affected Mutant gene X-Linked recessive Muscle Liver (XLG1, detectable on RBCs) Liver (XLG2, blood cells normal) PHKA1 (Xq12) PHKA2 (Xp22) PHKA2 (Xp22) (most common) Autosomal Recessive Liver & Muscle (detectable on RBC), mildest PHKB (16q) Liver (detectable on RBC), Severe phenotype PHKG2 (16p) Muscle Heart PHKG1 (7p12) PHKG1 (7p12) XLG1 patients - Blood and liver PHK deficiency. ~20 disease causing mutations known in the structural part of the gene PHKA2. XLG2 patients - PHK activity deficient in Liver but can not be proven in vitro, have mutations in the regulatory part of same gene PHKA2 ~ 4 mutations known so far.
  69. 69. GSD IX • Treatment is symptomatic – If hypoglycemia present, treat accordingly – Improved growth with increased complex carbohydrates presumably by reducing demand for gluconeogenesis – Presumably increased protein may also be beneficial (alternative source of energy)
  70. 70. GSD IX • For a GSD IX child presenting with hypoglycemia and growth delay… – Keep Food and Blood Glucose Record (how long can they fast?) – DIET ORDER: High Protein, High Complex Carbohydrates, Avoid Simple Sugars, Low Fat – Prescribe Cornstarch at bedtime if needed • If needed can use similar diet for GSD VI Schippers HM, Smit PA, Rake JP, Visser G. Characteristic growth pattern in male X-linked phosphorylase-b kinase deficiency. J Inherit metab Dis 2003;26:43-47. Adamenko RS, Brandes B, Karpen SJ: A 5-year-old boy with hepatomegaly and linear growth delay. Current Opinion in Pediatrics 1998, 10:523-526. Goldberg T, Slonim AE. Nutrition therapy for hepatic glycogen storage diseases. J Am Diet Assoc 1993;93:14231430.
  71. 71. GSD 0 • Glycogen Synthase Deficiency – Autosomal recessive disease – Few reported cases, several mutations – Symptoms include ketotic hypoglycemia with fasting, no hepatomegaly, and postprandial hyperglycemia, hyperlactatemia and hyperlipidemia – Glycogen Synthase is absent in the liver, but present in muscle
  72. 72. GSD 0 • Treatment – Prevent hypoglycemia – Small frequent meals with complex carbohydrates and protein through out the day – Cornstarch may be used at bed time to prevent hypoglycemia Weinstein DA, et al. Hepatic glycogen synthase deficiency: An infrequently recognized cause of ketotic hypoglycemia. Molecular Genetics and metabolism. 2006;87:284-288 .
  73. 73. Modified Cornstarch Therapy First trials with Glycosade in Europe were encouraging •short-term double-blind cross-over pilot study comparing uncooked physically modified cornstarch (WMHM20) with uncooked cornstarch in patients •21 patients with GSD types Ia, Ib and III; ages 3-47, 9 female Bhattacharya K, et al. A novel starch for the treatment of glycogen storage disease. J Inherit Metab Dis (2007)30:350-357
  74. 74. Modified Cornstarch Therapy • Median starch load duration 9 hours for WMHM20 and 7 hours for uncooked cornstarch • Glucose decreased more slowly and lactate suppressed faster for WMHM20 Bhattacharya K, et al. A novel starch for the treatment of glycogen storage disease. J Inherit Metab Dis (2007)30:350-357
  75. 75. Modified Cornstarch Therapy • Pilot Study done in the US was also encouraging: – Randomized, 2-d, double blinded, crossover pilot study (12 subjects: 6 with GSD Ia and 6 with GSD Ib, >13 years) – Heat-moisture processed cornstarch Glycosade (Vitaflo) compared to Argo brand CS Correia, et al. Use of modified cornstarch therapy to extend fasting in glycogen storage disease types Ia and Ib. Am J Clin Nutr (2008) 88:1272-6 • A Larger Trial is planned in the near future
  76. 76. Modified Cornstarch Therapy – Glycosade maintained BG longer than Argo – Argo demonstrated a higher peak glucose concentration and a more rapid rate of fall Correia, et al. Use of modified cornstarch therapy to extend fasting in glycogen storage disease types Ia and Ib. Am J Clin Nutr (2008) 88:1272-6

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