GSD

1. GLYCOGEN STORAGE
DISORDERS

2. GSD
 Inherited disorders of glycogen metabolism.
 Any Enzyme can be involved.
 Can affect synthesis and degradation .
 glycogen in abnormal quantity or quality or both
.
 Categorized as numeric type in chronological
order they discovered.
 Frequency of all forms 1 in 20,000 live births.

5. TYPESOF GSD
 The glycogen storage diseases (GSDs) and related disorders are caused
by defects of glycogen degradation, glycolysis and, paradoxically,
glycogen synthesis.
 They are all called glycogenoses, although not all affect glycogen
breakdown.
 Glycogen, an important energy source, is found in most tissues, but is
especially abundant in liver and muscle.
 In the liver, glycogen serves as a glucose reserve for the maintenance of
normoglycemia.
 In muscle, glycogen provides energy for muscle contraction.
 Despite some overlap, the GSDs can be divided in three main groups:
those affecting liver, those affecting muscle, and those which are
generalized .
 GSDs are denoted by a Roman numeral that reflects the historical
sequence of their discovery, by the deficient enzyme, or by the name of
the author of the first description.

7. liver glycogen storage
disorders
 GSD I, the hepatic presentations of GSD III, GSD IV, GSD VI, the liver forms of GSD
IX, and GSD 0.
 GSD I, III, VI, and IX present with hypoglycemia, marked hepatomegaly,and growth
retardation.
 GSD I is the most severe affecting both glycogen breakdown and gluconeogenesis. In
GSD Ib there is additionally a disorder of neutrophil function.
 Most patients with GSD III have a syndrome that includes hepatopathy, myopathy, and
often cardiomyo pathy.
 GSD VI and GSD IX are the least severe: there is only a mild tendency to fasting
hypoglycemia, liver size normalises with age, and patients reach normal adult height.
 GSD IV manifests in most patients in infancy or childhood as hepatic failure with cirrhosis
leading to end-stage liver disease.
 GSD 0 presents in infancy or early childhood with fasting hypoglycemia and ketosis
and, in contrast, with postprandial hyperglycemia and hyperlactatemia.
 Treatment is primarily dietary and aims to prevent hypoglycemia and suppress
secondary metabolic decompensation. This usually requires frequent feeds by day, and
in GSD I and in some patients with GSD III, continuous nocturnal gastric feeding.

8. muscle glycogenoses
 two clinical groups.
 The first comprises GSD V, GSD VII, the muscle forms of
GSD IX, phosphoglycerate kinase deficiency , GSD X, GSD
XI, GSD XII and GSD XIII.
 Characterised by exercise intolerance with exercise-induced
myalgia and cramps, which are often followed by
rhabdomyolysis and myoglobinuria; all symptoms are
reversible with rest.
 Disorders in the second group, consisting of the myopathic
form of GSD III, and rare neuromuscular forms of GSD IV,
manifest as sub-acute or chronic myopathies, with
weakness of trunk, limb, and respiratory muscles.
 Involvement of other organs (erythrocytes, central or
peripheral nervous system, heart, liver) is possible, as most
of these enzymes defects are not confined to skeletal

9. Generalized glycogenoses
 GSD II, caused by the deficiency of a
lysosomal enzyme, and Danon disease
due to the deficiency of a lysosomal
membrane protein.
 Recent work on myoclonus epilepsy with
Lafora bodies ( Lafora disease) suggests
that this is a glycogenosis, probably due to
abnormal glycogen synthesis.
 GSD II can be treated by enzyme
replacement therapy, but there is no
specific treatment for Danon and Lafora
disease

10. THE LIVER
GLYCOGENOSES

11. The Liver Glycogenoses
 The liver GSDs comprise GSD I, the hepatic presentations of GSD III, GSD
IV, GSD VI, the liver forms of GSD IX, and GSD 0.
 GSD I, III, VI, and IX present with similar symptoms during infancy, with
hypoglycemia, marked hepatomegaly, and retarded growth.
 GSD I is the most severe of these four conditions because not only is
glycogen breakdown impaired, but also gluconeogenesis.
 Most patients with GSD III have a syndrome that includes hepatopathy,
myopathy, and often cardiomyopathy.
 GSD IV manifests in most patients in infancy or childhood as hepatic
failure with cirrhosis leading to end-stage liver disease.
 GSD VI and the hepatic forms of GSD IX are the mildest forms: there is
only a mild tendency to fasting hypoglycemia, liver size normalises with
age, and patients reach normal adult height.
 GSD 0 presents in infancy or early childhood with fasting hypoglycemia
and ketosis contrasting with postprandial hyperglycemia and
hyperlactatemia.

12. Glycogen Storage Disease Type I
(Glucose-6-Phosphatase of Translocase
Deficiency)
 GSD I, first described by von Gierke.
 GSD Ia caused by deficiency of the catalytic subunit
of glucose-6- phosphatase (G6Pase).
 GSD Ib, due to deficiency of the endoplasmic
reticulum (ER) glucose-6-phosphate (G6P)
translocase.
 There is controversy about the existence of ER
phosphate translocase deficiency (GSD Ic) and ER
glucose transporter deficiency (GSD Id) as distinct
entities.
 The term GSD Ib includes all GSD I non-a forms.

13. Clinical Presentation
 Neonate-hypoglycemia , lactic acidosis.
 Infancy- hepatomegaly , hypoglycemic seizures .
 Doll like features-obesity , prominent cheeks , thin extremities ,protuberent abdomen, hypotrophic
muscles, and growth delay .
 Profound hypoglycemia and lactic acidosis elicited by trivial events.
 Liver changes.
 Renomegaly.
 Spleen normal.
 Bleeding tendency.
 Skin xanthomas.
 Gouty arthritis.
 patients with GSD Ib develop neutropenia .
 GSD Ib patients show symptoms of inflammatory bowel disease (IBD).

14. Metabolic Derangement
 Hypoglycemia occurs during fasting as soon as exogenous
sources of glucose are exhausted.
 Hyperlactatemia is a consequence of excess G6P that cannot be
hydrolysed to glucose and is further metabolised in the glycolytic
pathway, ultimately generating pyruvate and lactate.
 Substrates such as galactose, fructose and glycerol need liver
G6Pase to be metabolised to glucose. Consequently ingestion of
sucrose and lactose results in hyperlactatemia, with only a small
rise in blood glucose .
 serum of untreated patients has a milky appearance due to
hyperlipidemia.
 Hyperuricemia is a result of both increased production and
decreased renal clearance.
 Halmarks of disease are hypoglycemia,lactic
acidosis,hyperlipidemia,hyperurecemia.

15. Genetics&Diagnosis
 GSD Ia and Ib are autosomal recessive disorders.
 gene encoding G6Pase (G6PC) was identified on
chromosome 17q21.
 the gene encoding the G6P transporter (G6PT) was
identified on chromosome 11q23.
 enzyme studies in liver tissue obtained by biopsy are now
usually un-necessary since the diagnosis can be based on
clinical and biochemical findings combined with DNA
investigations in leukocytes.
 Identification of mutations in either G6PC or G6PT alleles
of a GSD I index case allows reliable prenatal DNAbased
diagnosis in chorionic villus samples.

16. Dietary Treatment
 The goal of treatment is, as far as possible, to prevent hypoglycemia, thus limiting
secondary metabolic derangements.
 Initially, treatment consisted of frequent carbohydrate- enriched meals during day and
night.
 In 1974, continuous nocturnal gastric drip feeding (CNGDF) via a nasogastric tube
was introduced, allowing both patients and parents to sleep during the night .
 In 1984 uncooked cornstarch (UCCS), from which glucose is more slowly released
than from cooked starch, was introduced .
 stringent maintenance of normolactatemia by complete avoidance of lactose and
fructose ingestion.
 Special attention should be directed to calcium (limited milk intake) and vitamin D.
 Increased carbohydrate metabolism needs an adequate supply of vitamin B1.
 During surgery,-iv fluids.

17. Pharmacological Treatment
 Until recently, (sodium)bicarbonate was recommended to reduce hyperlactatemia.
Bicarbonate also induces alkalisation of the urine, thereby diminishing the risk of
urolithiasis and nephrocalcinosis.
 However, it was found that a progressive worsening of hypocitraturia occurs so that
alkalisation with citrate may be even more beneficial in preventing or ameliorating
urolithiasis and nephrocalcinosis.
 Uric acid is a potent radical scavenger and it may be a protective factor against the
development of atherosclerosis . Consequently, it is recommended to accept a serum
uric acid concentration within the high normal range. To prevent gout and urate
nephropathy, however, a xanthine-oxidase inhibitor (allopurinol) should be started if it
exceeds this.
 If persistent microalbuminuria is present, a (long-acting) angiotensin converting
enzyme (ACE) inhibitor should be started to reduce or prevent further deterioration of
renal function. Additional blood pressure lowering drugs should be used if blood
pressure remains above the 95th percentile for age.
 triglyceride- lowering drugs (nicotinic acid, fibrates) are indicated only if severe
hypertriglyceridemia persists.
 prophylaxis with cotrimoxazol may be of benefit in symptomatic patients or in those
with a neutrophil count < 500 .
 granulocyte colony-stimulating factor GCSF

19. Follow-up, Complications, Prognosis,
 Proximal and distal renal tubular as well as glomerular
functions are at risk.
 Single or multiple liver adenomas may develop in the
second or third decade.
 Osteopenia.
 Anemia.
 Polycystic ovaries (PCOs).
 Despite severe hyperlipidemia, cardiovascular morbidity
and mortality is infrequent.
 Depressive illness.

20. Glycogen Storage Disease Type III
(Debranching Enzyme Deficiency)
 The release of glucose from glycogen
requires the activity of both
phosphorylase and glycogen
debranching enzyme (GDE).
 known as Cori or Forbes disease.
 Autosomal recessive disorder due to
deficiency of GDE which causes storage
of glycogen with an abnormally compact
structure, known as phosphorylase limit
dextrin.

21. Clinical Presentation
 Hepatic Presentation
 Hepatomegaly, short stature, hypoglycemia, and
hyperlipidemia predominate in children, may be
indistinguishable from GSD I.
 Splenomegaly can be present.
 kidneys are not enlarged and renal function is
normal.
 With increasing age, these symptoms improve
in most GSD III patients and may disappear
around puberty.

22. Myopathic Presentation
 Clinical myopathy may not be apparent in infants or
children, although some show hypotonia and
delayed motor milestones.
 Myopathy often appears in adult life, long after liver
symptoms have subsided.
 Adult-onset myopathies may be distal or
generalised.
 Patients with distal myopathy develop atrophy of
leg and intrinsic hand muscles, often leading to the
diagnosis of motor neurone disease or peripheral
neuropathy .
 The course is slowly progressive and the myopathy
is rarely crippling.

23. Contd,
 Muscle biopsy typically shows a vacuolar
myopathy.
 The vacuoles contain PAS-positive
material and corresponds to large pools of
glycogen, most of which is free in the
cytoplasm.
 However, some of the glycogen is present
within lysosomes.
 Biochemical analysis shows greatly
increased concentration of phosphorylase-
limit dextrin, as expected.

24. Metabolic Derangement
 GDE is a bifunctional enzyme, with two
catalytic activities, oligo1,4-
glucantransferase and amylo-1,6-
glucosidase.
 After phosphorylase has shortened the
peripheral chains of glycogen to about four
glycosyl units, these residual stubs are
removed by GDE in two steps.
 A maltotriosyl unit is transferred from a
donor to an acceptor chain (transferase
activity), leaving behind a single glucosyl
unit, which is hydrolysed.

25. Metabolic Derangement
 During infancy and childhood patients suffer from
fasting hypoglycemia, associated with ketosis
and hyperlipidemia.
 Serum transaminases are also increased in
childhood but decrease to (almost) normal values
with increasing age.
 In contrast to GSD I, blood lactate concentration
is normal.
 Elevated levels of serum creatine kinase (CK)
and aldolase suggest muscle involvement, but
normal values do not exclude the future
development of myopathy.

26. Genetics& Diagnosis
 The gene for GDE (GDE) is located on
chromosome 1p21.
 Diagnosis is based on enzyme studies in
leukocytes, erythrocytes and/or fibroblasts,
combined with DNA investigations in
leukocytes.
 Prenatal diagnosis is possible by
identifying mutations in the GDE gene if
these are already known.

27. Treatment
 The main goal of dietary treatment is prevention of
hypoglycemia and correction of hyperlipidemia.
 Dietary management is similar to GSD Ia but, since the
tendency to develop hypoglycemia is less marked, only
some younger patients will need continued nocturnal gastric
drip feeding, and a late evening meal and/or uncooked corn
starch will be sufficient to maintain normoglycemia during
the night.
 In GSD III (as opposed to GSD I), restriction in fructose and
galactose is unnecessary .
 Dietary protein intake can be increased since no renal
dysfunction exists. This would not only have a beneficial
effect on glucose homeostasis, but also on atrophic
myopathic muscles.

28. Complications, Prognosis
 With increasing age, both clinical and biochemical
abnormalities gradually disappear in most patients;
parameters of growth normalise, and hepatomegaly
usually disappears after puberty.
 In older patients, however, liver fibrosis may develop
into cirrhosis.
 In about 25% of these patients, liver adenoma may
occur, and transformation into hepatocellular
carcinoma has been described, although this risk is
apparently small.
 Liver transplantation has been performed in patients
with end-stage cirrhosis and/or hepatocellular
carcinoma .

30. Glycogen Storage Disease Type IV
(Branching Enzyme Deficiency)
 GSD IV, or Andersen Disease, is an autosomal recessive
disorder due to a deficiency of glycogen branching enzyme
(GBE).
 Deficiency of GBE results in the formation of an
amylopectin-like compact glycogen molecule with fewer
branching points and longer outer chains.
 Patients with the classical form of GSD IV develop
progressive liver disease early in life.
 The non-progressive hepatic variant of GSD IV is less
frequent and these patients usually survive into adulthood.
 Besides these liver related presentations, there are rare
neuro muscular forms of GSD IV.

31. Clinical Presentation
Hepatic Forms
 Patients are normal at birth and present generally in early childhood with hepatomegaly,
failure to thrive, and liver cirrhosis.
 The cirrhosis is progressive and causes portal hypertension, ascites, and oesophageal
varices.
 Some patients may also develop hepatocellular carcinoma .
 Life expectancy is limited due to severe progressive liver failure and – without liver
transplantation – death generally occurs when patients are 4 to 5 years of age .
 Patients with the non-progressive form present with hepatomegaly and sometimes
elevated transaminases.
 Although fibrosis can be detected in liver biopsies, this is apparently non-progressive.
 No cardiac or skeletal muscle involvement is seen.
 These patients have normal parameters for growth.

32. Neuromuscular Forms
 four clinical presentations according to the age of onset.
 A neonatal form, which is extremely rare, presents as fetal akinesia deformation
sequence (FADS), consisting of arthrogryposis multiplex congenita, hydrops fetalis, and
perinatal death.
 A congenital form presents with hypotonia, cardiomyopathy, and death in early infancy.
 A third form manifests in childhood with either myopathy or cardiomyopathy.
 Adult form may present as a myopathy or as a multisystemic disease also called adult
polyglucosan body disease (APBD) .
 APBD is characterised by progressive upper and lower motor neurone dysfunction
(sometimes simulating amyotrophic lateral sclerosis), sensory loss, sphincter problems
and, inconsistently, dementia.
 In APBD, polyglucosan bodies have been described in processes of neurones and
astrocytes in both grey and white matter.
 Muscle biopsy in the neuromuscular forms shows the typical foci of polyglucosan
accumulation, intensely PASpositive and diastase-resistant.
 Similar deposits are seen in the cardiomyocytes of children with cardiomyopathy and in
motor neurones of infants with Werdnig-Hoffmann-like presentation

33. Metabolic Derangement
 Hypoglycemia is rarely seen, and only in the classical hepatic
form, when liver cirrhosis is advanced, and detoxification and
synthesis functions become impaired.
 The clinical and biochemical findings under these circumstances
are identical to those typical of other causes of cirrhosis, with
elevated liver transaminases and abnormal values for blood
clotting factors, including prothrombin and thromboplastin
generation time.
 The GBE gene has been mapped to chromosome 3p14.
 The diagnosis is usually only suspected at the histological
examination of a liver or muscle biopsy which shows large
deposits that are periodic-acid-Schiff-staining but partially resistant
to diastase digestion.
 The enzymatic diagnosis is based on the demonstration of GBE
deficiency in liver, muscle, fibroblasts, or leukocytes.

34. Treatment
 There is no specific dietary treatment for
GSD IV.
 Dietary treatment focuses on the
maintenance of normoglycemia by
frequent feedings and a late evening meal.
 Liver transplantation is the only effective
therapeutic approach at present for GSD
IV patients with the classic progressive
liver disease.

35. Glycogen Storage Disease Type VI
( Glycogen Phosphorylase Deficiency)
 GSD VI or Hers disease is an autosomal recessive disorder due to a
deficiency of the liver isoform of glycogen phosphorylase. Phosphorylase
breaks the straight chains of glycogen down to glucose-1-phosphate in a
concerted action with debranching enzyme. Glucose-1-phosphate in turn
is converted into glucose-6-phosphate and then into free glucose.
 Rare disorder with a generally benign course.
 Present with hepatomegaly and growth retardation in early childhood.
Cardiac and skeletal muscles are not involved. Hepatomegaly decreases
with age and usually disappears around puberty. Growth usually
normalises after puberty.
 The tendency towards hypoglycemia is not as severe as seen in GSD I or
GSD III and usually appears only after prolonged fasting in infancy.
Hyperlipidemia and hyperketosis are usually mild. Lactic acid and uric acid
are within normal limits.
 The gene encoding the liver isoform, PYGL, is on chromosome 14q21-
q22.
 Deficient phosphorylase activity can be documented in liver tissue.

36. Glycogen Storage Disease Type IX
(Phosphorylase Kinase Deficiency)
 GSD IX, or phosphorylase kinase (PHK) deficiency, is the most
frequent glycogen storage disease.
 According to the mode of inheritance and clinical presentation six
different subtypes are distinguished.
(1) X-linked liver glycogenosis (XLG or GSD IXa), by far the most
frequent subtype.
(2) combined liver and muscle PHK deficiency (GSD IXb).
(3) autosomal liver PHK deficiency (GSD IXc).
(4) X-linked muscle glycogenosis (GSD IXd).
(5) autosomal muscle PHK deficiency (GSD IXe).
(6) heart PHK deficiency (GSD IXf) probably due to AMP kinase
mutations.

37. Clinical Presentation
 Hepatic Presentation
 hepatomegaly due to glycogen storage, growth retardation,
elevated liver transaminases, and hypercholesterolemia
and hypertriglyceridemia.
 Symptomatic hypoglycemia and hyperketosis are only
seen after long periods of fasting in young patients. The
clinical course is generally benign.
 Clinical and biochemical abnormalities disappear with
increasing age and after puberty most patients are
asymptomatic.
 Myopathic Presentation
 The myopathic variants present clinically similar to a mild
form of McArdle disease , with exercise intolerance,
cramps, and recurrent myoglobinuria in young adults.
 Less frequent presentations include infantile weakness
and respiratory insufficiency or late-onset weakness.
 Muscle morphology shows subsarcolemmal deposits of
normal-looking glycogen.

38. Treatment and Prognosis
 Treatment of the hepatic form is symptomatic, and
consists of preventing hypoglycemia using a high-
carbohydrate diet and frequent feedings; a late
evening meal is unnecessary except for young
patients.
 Growth improves without specific treatment with
age.
 XLG patients have a specific growth pattern
characterised by initial growth retardation, a late
growth spurt, and complete catch-up in final height
occurring after puberty .
 Prognosis is generally favourable for the hepatic
types, and more uncertain for the myopathic
variants.

39. Glycogen Storage Disease Type 0
( Glycogen Synthase Deficiency)
 The first symptom of GSD 0 is fasting hypoglycemia which appears in infancy or early
childhood.
 Patients can remain asymptomatic. Recurrent hypoglycemia often leads to neurological
symptoms.
 Developmental delay is seen in a number of GSD 0 patients and is probably associated
with these periods of hypoglycemia typically occurring in the morning before breakfast.
 The size of the liver is normal, although steatosis is frequent. Some patients display
stunted growth, which improves after dietary measures to protect them from hypoglycemia.
 The small number of patients reported in the literature may reflect underdiagnosis, since
the symptomatology is usually mild and the altered metabolic profile is not always
interpreted correctly.
 GSD 0 is caused by a deficiency of glycogen synthase (GS), a key-enzyme of glycogen
synthesis.
 Consequently, patients with GS deficiency have decreased liver glycogen concentration,
resulting in fasting hypoglycemia.
 This is associated with ketonemia, low blood lactate concentrations, and mild
hyperlipidemia.
 Post-prandially, there is often a characteristic reversed metabolic profile, with
hyperglycemia and elevated blood lactate.
 The gene that encodes GS, GYS2, is located on chromosome 12p12.2, and several
mutations are known.
 Patients with GSD 0 may be misdiagnosed as having diabetes mellitus, especially when
glucosuria and ketonuria are also present.
 Diagnosis of GSD 0 is based on the demonstration of decreased hepatic glycogen content
and deficiency of the GS enzyme in a liver biopsy or by DNA analysis.
 Treatment is symptomatic, and consists of preventing hypoglycemia with a high-
carbohydrate diet, frequent feedings and, in young patients, late evening meals.

40. FANCONI-BICKEL SYNDROME
 Hepatic glycogenesis with renal fanconi syndrome.
 Rare AR disorder.
 Deficiency of GLUT-2 in hepatocytes , pancreatic beta cells, intestinal
and renal epithelial cells.
 Proximal renal tubular dysfunction.
 Presents in 1st year of life as FTT , rickets , hepatomegaly ,
renomegaly.
 Glycosuria,phosphaturia , amino aciduria , bicarbonate
wasting,hypophosphatemia , ricketic radiological findings.
 Fasting hypoglycemia , hyperlipidaemia may be seen.
 No specific treatment.
 Symptomatic treatment with fluids , electrolytes , vit D, frequent small

41. MUSCLE
GLYCOGENOSES

42. Muscle Glycogenoses
 At rest, muscle utilizes predominantly fatty acids.
 During submaximal exercise, it additionally uses
energy from blood glucose, mostly derived from
liver glycogen.
 In contrast, during very intense exercise, the main
source of energy is anaerobic glycolysis following
breakdown of muscle glycogen.
 When the latter is exhausted, fatigue ensues.
 Enzyme defects within the pathway affect muscle
function.

43. Glycogen Storage Disease Type V
(Myophosphorylase Deficiency)
 Clinical Presentation
 GSD V, decribed in 1951 by McArdle is characterised by exercise intolerance, with
myalgia and stiffness or weakness of exercising muscles, which is relieved by rest.
 Two types of exertion are more likely to cause symptoms: brief intense isometric
exercise, such as pushing a stalled car, or less intense but sustained dynamic
exercise, such as walking in the snow. Moderate exercise, for example walking on
level ground, is usually well tolerated.
 Strenuous exercise often results in painful cramps, which are true contractures as
the shortened muscles are electrically silent.
 An interesting constant phenomenon is the second wind that affected individuals
experience when they rest briefly at the first appearance of exercise-induced
myalgia.
 Myoglobinuria (with the attendant risk of acute renal failure) occurs in about half of
the patients. Electromyography (EMG) can be normal or show non-specific
myopathic features at rest, but documents electrical silence in contracted muscles.
 As in most muscle glycogenoses, resting serum CK is consistently elevated in
McArdle patients.
 After carnitine palmitoyl transferase II (CPT II) deficiency, McArdle disease is the
second most common cause of recurrent myoglobinuria in adults .
 Clinical variants of McArdle disease include the fatal infantile myopathy described in
a few cases, and fixed weakness in older patients .
 However, some degree of fixed weakness does develop in patients with typical
McArdle disease as they grow older and is associated with chronically elevated
serum CK level
 There are three isoforms of glycogen phosphorylase: brain/heart, liver, and muscle,
all encoded by different genes. GSD V is caused by deficient myophosphorylase
activity.

44. Genetics&Diagnosis
 GSD V is an autosomal recessive disorder. The gene for the muscle
isoform (PYGM) has been mapped to chromosome 11q13.
 The forearm ischemic exercise (FIE) test is informative but is being
abandoned as it is neither reliable, reproducible, nor specific, and is
painful.
 Alternative diagnostic tests include a non-ischemic version of the FIE , and
a cycle test based on the unique decrease in heart rate shown by McArdle
patients between the 7th and the 15th minute of moderate exercise, a
reflection of the second wind phenomenon .
 Muscle histochemistry shows subsarcolemmal accumulation of glycogen
that is normally digested by diastase.
 A specific histochemical stain for phosphorylase can be diagnostic except
when the muscle specimen is taken too soon after an episode of
myoglobinuria.
 Myophosphorylase analysis of muscle provides the definitive answer, but
muscle biopsy may be avoided altogether in Caucasian patients by looking
for the common mutation (R49X) in genomic DNA.

45. Treatment
 There is no specific therapy.
 Probably, the most important therapy is
aerobic exercise .
 Oral sucrose improved exercise tolerance,
and may have a prophylactic effect when
taken before planned activity.
 This effect is explained by the fact that
sucrose is rapidly split into glucose and
fructose; both bypass the metabolic block
in GSD V and hence contribute to
glycolysis

46. Glycogen Storage Disease Type VII
(Phosphofructokinase Deficiency)
 Clinical Presentation
 Clinically, GSD VII, first described by Tarui, is indistinguishable from McArdle disease,
except for the absence of the second wind phenomenon.
 Some laboratory results are useful in the differential diagnosis, including an increased
bilirubin concentration and reticulocyte count, reflecting a compensated hemolysis.
 The diagnosis of PFK deficiency is based on the combination of muscle symptoms and
compensated hemolytic anemia: the only other muscle glycogenosis with these features
is phosphoglycerate kinase deficiency .
 There are two clinical variants, one manifesting as fixed weakness in adult life (although
most patients recognise having suffered from exercise intolerance in their youth), the
other affecting infants or young children, who have both generalised weakness and
symptoms of multisystem involvement (seizures, cortical blindness, corneal
opacifications, or cardiomyopathy) .
 The infantile variant, in which no mutation in the PFK-M gene has been documented is
probably genetically different from the typical adult myopathy.
 PFK is a tetrameric enzyme under the control of three autosomal genes. A gene (PFK-
M) on chromosome 12 encodes the muscle subunit; a gene (PFK-L) on chromosome 21
encodes the liver subunit; and a gene (PFK-P) on chromosome 10 encodes the platelet
subunit.

47. Diagnosis&Treatment
 Muscle histochemistry shows predominantly subsarcolemmal
deposits of normal glycogen, most of which stains normally with the
PAS and is normally digested by diastase.
 Patients with PFK deficiency also accumulate increasing amounts
of polyglucosan, which stains intensely with the PAS reaction but is
resistant to diastase digestion and – in the electron microscope –
appears composed of finely granular and filamentous
material, similar to the storage material in branching enzyme
deficiency and in Lafora disease.
 There is no specific therapy.
 Contrary to McArdle disease, sucrose should be avoided, but
aerobic exercise might be useful.
 The astute observation that patients with PFK deficiency noticed
worsening of their exercise intolerance after high-carbohydrate
meals was explained by the fact that glucose lowers the blood
concentration of free fatty acids and ketone bodies, alternative
muscle fuels.

48. Phosphoglycerate Kinase Deficiency
 Phosphoglycerate kinase (PGK) is a single polypeptide encoded by a gene
(PGK1) on Xq13 for all tissues except spermatogenic cells.
 Although this enzyme is virtually ubiquitous, clinical presentations depend
on the isolated or associated involvement of three tissues, erythrocytes
(hemolytic anemia), central nervous system (CNS, with seizures, mental
retardation, stroke), and skeletal muscle (exercise intolerance, cramps,
myoglobinuria).
 The most common association, seen in 8 of 27 reported patients, is
nonspherocytic hemolytic anemia and CNS dysfunction, followed by
isolated myopathy (7 patients), isolated blood dyscrasia (6 patients), and
myopathy plus CNS dysfunction (3 patients) .
 There was only one patient with myopathy and hemolytic anemia, while
two patients showed involvement of all three tissues.
 The seven myopathic cases were clinically indistinguishable from McArdle
disease, but muscle biopsies showed less severe glycogen accumulation .
 Mutations in PGK1 were identified in 4 of the 7 myopathic patients.
 The different involvement of single or multiple tissues remains unexplained
but it may have to do with leaky mutations allowing for some residual PGK
activity in some tissues.

49. Glycogen Storage Disease Type X
(Phosphoglycerate Mutase Deficiency)
 GSD X or phosphoglycerate mutase (PGAM) deficiency is an autosomal
recessive disorder.
 Phosphoglycerate mutase is a dimeric enzyme: different tissues contain
various proportions of a muscle (MM) isozyme, a brain (BB) isozyme, and
the hybrid (MB) isoform.
 Normal adult human muscle has a marked predominance of the MM
isozyme, whereas in most other tissues PGAM-BB is the only isozyme
demonstrable by electrophoresis .
 A gene (PGAMM) on chromosome 7 encodes the M subunit.
 The clinical picture is stereotypical: exercise intolerance and cramps after
vigorous exercise, often followed by myoglobinuria.
 Manifesting heterozygotes have been identified in several families.
 The muscle biopsy shows inconsistent and mild glycogen accumulation,
accompanied in one case by tubular aggregates . Four different mutations
in the PGAMM gene have been identified .

50. Glycogen Storage Disease Type XII
(Aldolase A Deficiency)
 GSD XII or aldolase A deficiency is an autosomal
recessive disorder.
 Aldolase exists in three isoforms (A, B, and C).
 skeletal muscle and erythrocytes contain
predominantly the A isoform, which is encoded
by a gene (ALDOA) on chromosome 16.
 The only reported patient with aldolase A
deficiency was a 4 1/2-year-old boy, who had
episodes of exercise intolerance and weakness
following febrile illnesses.

51. Glycogen Storage Disease Type XIII
(β-Enolase Deficiency)
 GSD XIII or-β enolase deficiency is an autosomal
recessive disorder.
 β -Enolase is a dimeric enzyme and exists in
different isoforms resulting from various
combinations of three subunits,ALFA,BETA, and
GAMMA.
 The β subunit is encoded by a gene (ENO3) on
chromosome 17.
 GSD XIII is still represented by a single patient, a
47-year-old Italian man with adult onset but rapidly
progressive exercise intolerance and myalgia, and
chronically elevated serum CK

52. Glycogen Storage Disease Type XI
(Lactate Dehydrogenase Deficiency)
 autosomal recessive disorder. Lactate
dehydrogenase is a tetrameric enzyme
composed of two subunits, M (or A) and H (or
B.
 The gene for LDH-M (LDHM) is on
chromosome 11.
 The first case was identified on the basis of an
apparently paradoxical laboratory finding:
during an episode of myoglobinuria, the patient
had the expected high levels of serum CK, but
extremely low level of LDH.
 All have exercise intolerance, cramps, with or
without myoglobinuria.

53. THE GENERALIZED
GLYCOGENOSES
AND RELATED DISORDERS

54. Glycogen Storage Disease Type II (Acid
Maltase Deficiency)
 GSD II is a lysosomal storage disorder, caused
by the generalized deficiency of the lysosomal
enzyme, acid maltase .
 The enzyme defect results in the accumulation
of glycogen within the lysosomes of all tissues,
but particularly in muscle and heart, resulting in
muscle weakness. Serum levels of
transaminases , CK and CK-myocardial band (in
the infantile form) are elevated.
 Acid maltase is encoded by a gene (GAA) on
chromosome 17q25.
 Frequency 1 in 40,000 live births.

55. Clinical Presentation
 Manifests as three different clinical phenotypes: infantile,
juvenile, and adult.
 The infantile form is generalised, and usually fatal by 1 year of
age.
 The diagnosis is suggested by the association of profound
hypotonia from muscle weakness, (floppy infant syndrome),
hyporeflexia and an enlarged tongue.
 The heart is extremely enlarged, and the electrocardiogram is
characterised by huge QRS complexes and shortened PR
intervals.
 The liver has a normal size unless enlarged by cardiac
decompensation.
 The cerebral development is normal.
 The clinical course is rapidly downward, and the child dies from

56. juvenile form,& adult form
 The juvenile form starts either in infancy or in childhood,
presents with retarded motor milestones and causes severe
proximal, truncal, and respiratory muscle weakness
(sometimes with calf hypertrophy, which, in boys, can raise the
suspicion of Duchenne muscular dystrophy), but shows no
overt cardiac disease.
 Myopathy deteriorates gradually leading to death from
respiratory failure in the second or third decade.
 The adult form is also confined to muscle and mimics other
myopathies with a long latency.
 Decreased muscle strength and weakness develop in the third
or fourth decade of life.
 Cardiac involvement is minimal or absent.
 The slow, progressive weakness of the pelvic girdle, paraspinal
muscles and diaphragm simulates limb-girdle muscular
dystrophy or polymyositis and results in walking difficulty and
respiratory insufficiency, but old age can be attained.
 The early and preferential involvement of truncal and
respiratory muscles is an important clinical characteristic

57. Diagnosis
 In the infantile form, a tentative diagnosis can be based
on the typical abnormalities in the electrocardiogram.
 Muscle biopsy shows a severe vacuolar myopathy with
accumulation of both intralysosomal and free glycogen
in both the infantile and childhood variants.
 Another clue to the correct diagnosis in myopathic
Pompe disease is the EMG, which shows, – besides
myopathic features – fibrillation potentials, positive
waves, and myotonic discharges, more easily seen in
paraspinal muscles.
 For confirmation, acid maltase should be determined in
tissues containing lysosomes. The preferred tissues are
fibroblasts or muscle, but lymphocytes may be usable.

58. Treatment
 Palliative therapy includes respiratory support, dietary
regimens (e.g. high-protein diet), and aerobic exercise.
 Enzyme replacement therapy using recombinant human
alfa-glucosidase, obtained in large quantities from rabbit
milk has been used successfully.
 Alglucosidase alfa (Myozyme), a recombinant analog of
human alfa-glucosidase manufactured in CHO cell
lines, has now available for use in both the infantile and
later onset forms.
 It appears to be important to start enzyme replacement
therapy as early as possible.

59. Danon Disease
 Danon Disease or GSD IIb, or pseudo-Pompe disease, is an X-linked
dominant lysosomal storage disease due to deficiency of LAMP-2
(lysosomal-associated membrane protein 2).
 The disease starts after the first decade, is extremely rare and affects
cardiac and skeletal muscle. Acid maltase activity is normal, muscle
biopsy shows vacuolar myopathy with vacuoles containing glycogen
and cytoplasmatic degradation products .
 Some patients are mentally retarded.
 As expected, hemizygous females are also affected, but generally
show the first symptoms at a later age.
 No specific therapy is available, but cardiac transplantation should be
considered .
 The gene encoding LAMP2 was mapped to Xq28

60. Lafora Disease
 Lafora disease (myoclonus epilepsy with Lafora bodies) is characterised
by seizures, myoclonus, and dementia. Onset is in adolescence and the
course is rapidly progressive, with death occurring almost always before
25 years of age.
 The pathologic hallmark of the disease are the Lafora bodies, round,
basophilic, strongly PAS-positive intracellular inclusions seen only in
neuronal perikarya, especially in the cerebral cortex, substantia nigra,
thalamus, globus pallidus, and dentate nucleus.
 Polyglucosan bodies are also seen in muscle, liver, heart, skin, and
retina, showing that Lafora disease is a generalised glycogenosis.
 However, the obvious biochemical suspect, branching enzyme, is
normal.
 Linkage analysis localised the gene responsible for Lafora disease
(EPM2A) to chromosome 6q24 and about 30 pathogenic mutation have
been identified .
 The protein encoded by EPM2A, dubbed laforin, may play a role in the
cascade of phosphorylation/dephosphorylation reactions controlling