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DISORDERS OF CHO METABOLISM

Disorder
GALACTOSEMIA

Deficiency
GALT
(Galactose-1-Phosphate
Uridyltransferase)
GALK (Galactokinase)
GALE
(UDP-Galactose-4epimerase)

Description

Pathophysiology

Abnormal accumulation of
galactose and gal-1-p in
brain, liver, kidneys
Galactitol (lens of eyes)
AUTOSOMAL RECESSIVE
1:10,000 to 1:30,000

Clinical Features

Diagnosis

Management

Develop soon after intake of


rd
lactose on 3 -rth day of life
Vomiting, Diarrhea, Failure to
thrive, Hepatomegaly,
Neonatal jaundice. Cataracts
Liver failure
Kidney Failure
E. coli Sepsis

Presence of reducing
substances in urine
Enzyme Assay in RBC, cord
blood and cultured
fibroblast
Measurement of
erythrocyte GALT activity
Molecular genetic testing

Cataracts if secondary to
galactitol accumulation is
reversible if lactose is
st
removed from diet within 1
3 months of life

First milk feeding provokes:


Failure to thrive
Vomiting & Diarrhea
Jaundice and
Hepatomegaly
Mental Retardation
Renal Fanconi Syndrome
GLYCOGEN STORAGE
DISEASES

Von Gierkes Disease

Result from enzymatic


deficiencies involved in
either the breakdown or
synthesis of glycogen
Glycogen accumulation or
formation of abnormal
glycogen structures
Glucose-6-Phosphate
Alpha System
AUTOSOMAL RECESSIVE

Liver:
GSD 1, 3, 4, 6
Muscles:
GSD 5, 7, 10, 11, 12, 13
Both:
GSD 0 and 9
Generalized
Glycogenolysis: GSD 2

1:20,000 to 1:25,00 birth

Newborn:
Vomiting, Hepatomegaly,
Cataracts

Exclusion of galactose from


diet
Substitution of lactose
containing milk and food
with casein hydrolates and
soy milk
Cataracts, Hepatic and Renal
manifestations are reversible
if therapy started within 3
months of life

Biochemical Abnormalities:
Elevated blood
lactate
Pyruvate
Uric Acid
Cholesterol
TGC
Classical GAL (GALT Deficiency)
o Untreated
o Neonatal onset: multiple
systems
o Liver dysfunction,
coagulopathy, feeding and
weight loss, vomiting, lethargy
and hypotonia, renal
dysfunction,encephalopathy,
hemorrhage, E. coli sepsis
o Cataracts
o Ovarian failure (90%)
o Chronic brain effects (global
deficits, disability, etc.)
GALK deficiency:
o Cataracts and galactosemia
in otherwise healthy

Massive Hepatomegaly
Fasting Hypoglycemia
Lactic Acidosis
Physical features:
Short stature
Doll-like facies
Protuberant
abdomen
Lumbar lordosis
Complications: Renal Disease
and Liver Adenomas
Detection
- Detection of increased
Gal-1-P metabolites
- Enzyme studies (in serum,

- Soya infant formula


- Lactose-free, galactose
free diet, throughout life
- Ca supplements- because
they have a tendency not
to drink milk in their
lifetime
- Avoid casein hydrolyze;
medicines with lactulose
- Evaluation of affected
systems
- Monitoring

Pompe Disease

Lysosomal Acid Maltase


1,4 glucosidase (GAA)enzyme responsible for
glycogenolysis in
liposomes

AUTOSOMAL RECESSIVE

Epimerase deficiency:
o Partial deficiency
o Rarely, presents similarly
with GALT but with increase
or normal GALT enzyme
accumulation of excess glycogen
in nearly all cells
heart, muscles and nervous
tissue are predominantly
affected
profound hypotonia with
progressive muscle weakness
but with normal mentation
hypoglycemia and ketosis are
absent
cardiomyopathy and respiratory
difficulties are common in
infantile form
walking difficulties in late and
juvenile forms
individuals are not mentally
retarded

RBC)
- DNA mutation analysis
(research basis at
present)

Clinical Phenotypes:
Infantile-onset PD (IOPD)
severe hypotonia,
hepatomegaly,
hypertrophic
cardiomyopathy
barely survive beyond
toddler age
GAA activity: typically
<1% of normal
Later-onset PD (LOPD)
includes childhood onset
and adult onset
heterogenous clinical
manifestations
symmetric or asymmetric,
limb girdle, axial tongue,
facial
respiratory insufficiency
could occur early
Cardiac involvement rare
GAA activity: between 140% of normal mean
Reason seen by neurologist
is because of myopathy

Supportive
Enzyme Replacement
Therapy
recombinant human GAA
20 mg/kg/2 weeks IV
IOPD - prolongs survival
and ventilator-free period;
rescue the
cardiomyopathy
LOPD - improved
weakness and lung
function
more effective at
addressing
cardiomyopathy
Newborn Screening
enables early identification
and treatment
newborn with
lymphocyte/fibroblast
activity <5% of the normal
mean plus 2 identified
GAA gene mutations
without cardiac
involvement -LOPD
Regular follow-up
every 3-6 months
check for motor
development and serum
creatine kinase (CK)
start treatment if with
significant CK or motor
delay

Forbes Disease

Amylo-1,6 glucosidase

resulting in accumulation
of abnormally structured
glycogen having very short
outer chains in muscle and
liver

GSD IIIa: patients with both liver and muscle


involvement have
GSDIIIb: liver involvement

AUTOSOMAL RECESSIVE

Andersen Disease

McArdles Disease

Amylo-(1,4 to 1,6)
transglycosylase
(Debranching enzyme
deficiency)
o
death common
<3 years old

Muscle Phosphorylase

causing accumulation of
abnormal glycogen
Amylopectinosis
X-LINKED

resulting in a block of the


normal glycogen
breakdown in muscles
AUTOSOMAL RECESSIVE

Hers Disease

Liver Phosphorylase

AUTOSOMAL RECESSIVE

Tarui Disease

Muscle
phosphofructokinase

AUTOSOMAL RECESSIVE

Inability to catabolise glycosphingolipids


causes progressive accumulation of
globotriaosylceramide (CTH, Gb3, or GL-3) in
endothelial cells, vascular smooth muscle,
erector pilori muscles in the skin,
myocardium, corneal epithelial cells and in
organs such as the kidney, pancreas, bowel
and lung

children in 2nd and 3rd decade of life


present with muscle cramps or temporary
muscle weakness after strenuous exercise
exercise intolerance and muscle cramps
following slight exercise.
3 different genetic defects:
1. x-linked phosphorylase b kinase
deficiency (liver)
2. autosomal phosphorylase b kinase
deficiency (muscle and liver)
3. deficiency of liver phosphorylate itself
Deficiency of enzyme that catalyzes the
reaction fructose-6-phosphate -fructose 1,6
biphosphate of the glycolytic pathway

Hepatomegaly, ketotic
hypoglycemia, hyperlipidemia,
variable skeletal myopathy,
cardiomyopathy and results in
short stature
The hepatic symptoms of GSDIII
usually resolve after puberty.
However, liver failure due to
cirrhosis may occur.
patients are well during the first
few months of life, later
nonspecific GI symptoms and
hepatosplenomegaly occurs
cirrhosis and portal
hypertension
Death will usually ensue by 5
years
Other manifestations:
o hypotonia
o muscle atrophy
o developmental delay
Attacks of myoglobinuria
frequently accompany the
muscle symptoms of GSDV
Exhibit burgundy colored urine
after exercise
S/Sx similar to GSD I & III but
milder

S/Sx similar to GSD V but:


- The muscle in Type VII is unable to
breakdown glucose, hence the
administration of glucose or glucagon
does not help.
- The RBC in Type VII have a hemolytic
tendency resulting in increased
reticulocyte count and serum bilirubin.
- Hyperuricemia is present with
exercise

Definitive diagnosis is only


made by examining the
structure of the glycogen in
patients as well as assaying
for the level of activity of the
debranching enzyme. This
diagnosis is best
accomplished from liver
and/or muscle biopsy.

High CHO meals with


cornstarch supplementshypoglycemia
High protein diet - drives
gluconeogenesis.

Liver biopsy
assay for branching enzyme
deficiency in muscle,
leukocytes, erythrocytes, or
fibroblasts can be carried out
to determine the exact
defect resulting in the
hepatomegaly

Maintenance of normal
blood glucose along with
adequate nutrient intake
both of which will improve
liver function and muscle
strength.

blood lactate = normal


even after exercise
myoglobinuria is present
in >50% of patients
associated large increase
in blood ammonia levels.
Blood lactate = normal
Uric acid = normal

There is currently no
effective treatment for the
progressive cardiomyopathy

In cases of progressive liver


failure, transplant may be
the only effective option.

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