Inborn errors of metabolism
Garrod’s hypothesis
Major categories of inherited metabolic diseases
Major categories of inherited metabolic diseases (1)
Disorders of carbohydrate metabolism
• E.g., glycogen storage disease
Disorders of amino acid metabolism
• E.g., phenylketonuria , maple syrup urine disease, glutaric
acidemia type 1
Disorders of organic acid metabolism (organic acidurias)
• E.g., alcaptonuria
Disorders of fatty acid oxidation and mitochondrial metabolism
• E.g., medium chain acyl dehydrogenase deficiency (glutaric
acidemia type 2)
Disorders of porphyrin metabolism
• E.g., acute intermittent porphyria
Major categories of inherited metabolic diseases (2)
Disorders of purine or pyrimidine metabolism
• E.g., Lesch-Nyhan syndrome
Disorders of steroid metabolism
• E.g., congenital adrenal hyperplasia
Disorders of mitochondrial function
• E.g., Kearns-Sayre syndrome
Disorders of peroxisomal function
• E.g., Zellweger syndrome
Lysosomal storage disorders
• E.g., Gaucher's disease
Disorders of carbohydrate metabolism, Glycogen storage disease
Glycogen storage disease
Glycogen storage disease (GSD, also glycogenosis and dextrinosis) is the
result of defects in the processing of glycogen synthesis or breakdown within
muscles, liver, and other cell types. GSD has two classes of cause: genetic and
acquired.
Genetic GSD is caused by any inborn error of metabolism (genetically
defective enzymes) involved in these processes.
In livestock(المواشي), acquired
GSD is caused by intoxication with the alkaloid castanospermine.
Glycolysis Fate
GSD Type I (Von Gierke’s disease)
Symptoms:
Hypoglycemia, Hyperlipidemia, Hepatomegaly,
Lactic
acidosis, and Hyperuricemia.
Progression: Growth failure
Enzyme deficiency: (glucose-6-phosphatase) which is an enzyme
that hydrolyzes glucose-6-phosphate resulting in the creation of a phosphate
group and free glucose. This deficiency impairs the ability of the liver to
produce free glucose from glycogen and from gluconeogenesis. Since these are
the two principal metabolic mechanisms by which the liver supplies glucose to
the rest of the body during periods of fasting, it causes severe hypoglycemia.
GSD Type I (Von Gierke’s disease)
Treatment:
The essential treatment goal is prevention of hypoglycemia and the
secondary metabolic derangements by frequent feedings of foods high in glucose
or starch (which is readily digested to glucose). To compensate for the
inability of the liver to provide sugar, the total amount of dietary
carbohydrate should approximate the 24-hour glucose production rate. The diet
should contain approximately 65-70% carbohydrate, 10-15% protein, and 20-25%
fat. At least a third of the carbohydrates should be supplied through the
night, so that a young child goes no more than 3–4 hours without carbohydrate
intake
Two methods have been used to achieve this goal in young children: (1)
continuous nocturnal gastric infusion of glucose or starch; and (2) night-time
feedings of uncooked cornstarch.
GSD Type II (Pompe’s disease)
Is an autosomal recessive metabolic disorder, which damages muscle and
nerve cells throughout the body. It is caused by an accumulation of glycogen in
the lysosome due to deficiency of the lysosomal acid alpha-glucosidase enzyme
that transforms glycogen into glucose in lysosomes.
The build-up of glycogen causes progressive muscle weakness (myopathy)
throughout the body and affects various body tissues, particularly in the
heart, skeletal muscles, and weakness facial and oral muscles. Pompe's disease
is one of the infiltrative causes of restrictive cardiomyopathy and
hepatomegaly.
caused by a mutation in a gene (acid alpha-glucosidase: also known as
acid maltase) on long arm of chromosome 17.
GSD Type II (Pompe’s disease)
Nutrition & Weight Maintenance
Because of weakened facial and oral muscles, patients of all ages, from
infants to adults, may experience difficulties eating. Trouble with sucking,
chewing, and/or swallowing can lead to insufficient caloric intake, problems
maintaining a healthy weight, and a general failure to thrive. Inadequate
nutrition may even lead to endogenous muscle protein breakdown.
Several approaches can address these issues:
• Physical therapy to help strengthen muscles and allow for
independent feeding.
• Modification of food texture to facilitate swallowing and reduce
the risk of aspiration.
• Carefully balanced diets to maximize nutrients and provide
protein to muscles.
• Tube feeding, most commonly in severely ill infants.
GSD Type II (Pompe’s disease)
Treatment:
In 2006, the European Medicines Agency (EMEA) and the U.S. Food and Drug
Administration (FDA) both granted marketing approval for the drug Myozyme (alglucosidase
alfa) for treatment of Pompe disease. Myozyme replaces the enzyme missing
in the disease, which helps break down glucose.
Early diagnosis and early treatment leads to much better outcomes.
Progression: Death by age ~2 years.
GSD Type V (McArdle Disease)
Is a metabolic disorder, caused by a deficiency of enzyme Myophosphorylase,
which is the muscle isoform of the enzyme glycogen phosphorylase.
This enzyme helps break down glycogen into glucose-1-phosphate, so that
it can be utilized within the muscle cell.
Symptoms: The onset of this disease is usually noticed in
childhood, but often not diagnosed until the third or fourth decade of life.
Symptoms include exercise intolerance with myalgia, early fatigue, painful
cramps, weakness of exercising muscles and myoglobinuria. Myoglobinuria, the
condition where myoglobin is present in urine, may result from serious damage
to the muscles, or rhabdomyolysis, where skeletal muscle cells breakdown
rapidly, sending their contents into the bloodstream.
GSD Type V (McArdle Disease)
Treatment/Therapy
Oral vitamin B6 appears to impart greater resistance
to fatigue. No specific therapy exists, but combined aerobic exercise programs
and high-protein diets may help. Some patients learn the limits of their
exercise and work within their restrictions, going on to live fairly normal
lives.
Supervised exercise programs have been recommended to lessen the risks
of extended inactivity.
Sucrose treatment is now being recommended prior to exercise.
Progression: Renal failure due to muoglobinuria.
GSD Type VII (Tarui’s Disease)
Is metabolic disorder with autosomal recessive inheritance Phosphofructokinase
deficiency.
Pathophysiology:
In this condition, a deficiency phosphofructokinase enzyme impairs the
ability of cells such as erythrocytes and skeletal muscles to use carbohydrates
for energy.
The mutation impairs the ability of phosphofructokinase to phosphorylate
fructose-6-phosphate prior to its cleavage into glyceraldehyde which enters the
Krebs cycle, effectively limiting energy production.
Unlike most other GSD, it directly affects glycolysis.
GSD Type VII (Tarui’s Disease)
Presentation
The disease presents with exercise-induced muscle cramps and weakness
(sometimes rhabdomyolysis), myoglobinuria, as well as with haemolytic anaemia causing
dark urine. Hyperuricemia is common. Phosphofructokinase deficiency also
presents in a rare infantile form, results in severe myopathy and leads to
death in the infancy or early childhood.
Treatment/interventions
There is no cure for Tarui disease, but various treatments may alleviate
symptoms and complications.
Individuals with Tarui disease should be observant to myoglobulinuria,
presenting as a dark discoloration of the urine. Owing to the risk of kidney
damage, medical help should be sought immediately if symptoms arise.
Dialysis is needed if toxic waste products accumulate owing to renal failure
(uraemia).
GSD Type VII (Tarui’s Disease)
Treatment/interventions
In Tarui’s disease, jaundice is mild and generally does not require
treatment.
High uric acid concentrations that may cause gout can be treated with
drugs which lower uric acid levels in the blood.
The effectiveness of dietary management remains unclear. It is possible
that food with a high fat content (notably fatty fish) has a beneficial effect,
as the glycerol in neutral fat can replace glucose as a source of energy. It
may be possible to "teach" the skeletal muscle cells to oxidise fatty
acids rather than glucose to produce energy.
Individuals with Tarui’s disease should avoid intensive muscle activity
that has many negative consequences for physical and mental health.
Other Types of Glycogen Storage Diseases
Disorders of amino acid metabolism
Phenylketonuria (PKU)
(PKU) is an autosomal
recessive metabolic genetic disorder characterized by a deficiency in the
hepatic enzyme phenylalanine hydroxylase (PAH). This enzyme is necessary to
metabolize the phenylalanine (Phe) to the tyrosine. When PAH is deficient,
phenylalanine accumulates and is converted into phenylpyruvate, which is
detected in the urine.
It can cause problems with brain development, leading to progressive
mental retardation, brain damage, and seizures.
Optimal treatment involves lowering blood (Phe) levels to a safe range
and monitoring diet and cognitive development.
PKU is normally detected using the HPLC test after birth.
Phenylketonuria (PKU)
Signs and Symptoms:
the disease may present clinically with seizures, albinism (excessively
fair hair and skin), and a "musty odor" to the baby's sweat and urine
(due to phenylacetate, one of the ketones produced).
Treatment: by managing and controlling (Phe) levels through diet,
or a combination of diet and medication.
All PKU patients must adhere to a special diet low in phenylalanine for
at least the first 16 years of their lives. This requires severely restricting
or eliminating foods high in phenylalanine, such as meat, chicken, fish, eggs,
nuts, cheese, legumes, cow milk and other dairy products. Starchy foods such as
potatoes, bread, pasta, and corn must be monitored.
Infants require a commercial formula of milk that free from (Phe).
Phenylketonuria (PKU)
Tyrosine, which is normally derived from phenylalanine, must be
supplemented.
The sweetener of aspartame must be avoided, as aspartame consists
of two amino acids: phenylalanine and aspartic acid.
The oral administration of tetrahydrobiopterin (or BH4) (a cofactor for
the oxidation of phenylalanine) can reduce blood levels of this amino acid in
certain patients.
For childhood, we can add some
fruits and vegetables the low in (Phe) which provide essential vitamins and
minerals.
Maple syrup urine disease (MSUD)
Also called branched-chain ketoaciduria, is an autosomal
recessive metabolic disorder affecting branched-chain amino acids. It is one
type of organic acidemia.
MSUD is caused by a deficiency of the branched-chain alpha-keto acid
dehydrogenase complex (BCKDH), leading to a buildup of the branched-chain amino
acids (leucine, isoleucine, and valine) and their toxic by-products in the
blood and urine.
The disease is characterized in an infant by the presence of
sweet-smelling urine, with an odor similar to that of maple syrup. Infants with
this disease seem healthy at birth but if left untreated suffer severe brain
damage and eventually die.
From early infancy, symptoms of the condition include poor feeding,
vomiting, dehydration, lethargy, seizures, hypoglycaemia, ketoacidosis,
pancreatitis, coma and neurological decline.
Maple syrup urine disease (MSUD)
Management:
Keeping MSUD under control requires careful monitoring of blood
chemistry and involves both a special diet and frequent testing.
A diet with minimal levels of the amino acids leucine, isoleucine, and
valine must be maintained in order to prevent neurological damage. As these
three amino acids are required for proper metabolic function in all people,
specialized protein preparations containing substitutes and adjusted levels of
the amino acids have been synthesized and tested, allowing MSUD patients to
meet normal nutritional requirements without causing harm.
Glutaric aciduria type 1
Glutaric acidemia type 1 (or "Glutaric Aciduria",
"GA1", or "GAT1") is an inherited disorder in which the
body is unable to break down completely the amino acids lysine, hydroxylysine and
tryptophan. Excessive levels of their intermediate breakdown products (glutaric
acid, glutaryl-CoA, 3-hydroxyglutaric acid, glutaconic acid) can accumulate and
cause damage to the brain (and also other organs), but particularly the basal
ganglia, which are regions that help regulate movement. GA1 causes secondary
carnitine deficiency, as glutaric acid, like other organic acids, is detoxified
by carnitine. Mental retardation may also occur.
Treatment of: Glutaric aciduria type 1
Correction of secondary carnitine depletion by oral
supplementation.
Precursor restriction: Dietary control may help limit progression
of the neurological damage.
The entry of tryptophan to the brain is crucial in the proper synthesis
of the neurotransmitter serotonin in the brain …..….. 5-hydroxytryptophan, the
precursor of serotonin that is not metabolized to glutaryl-CoA, glutaric acid
and secondary metabolites, could be used as an adjunct to selective tryptophan
restriction.
Enhancement of precursor's anabolic pathway.
Disorders of organic acid metabolism (organic acidurias)
Alkaptonuria
Alkaptonuria (black urine disease) is a rare inherited
genetic disorder of phenylalanine and tyrosine metabolism. This is an autosomal
recessive condition that is due to a defect in the enzyme homogentisate
1,2-dioxygenase, which participates in the degradation of tyrosine.
As a result, a toxic tyrosine byproduct called homogentisic acid (or
alkapton) accumulates in the blood and is excreted in urine in large amounts.
Excessive homogentisic acid causes damage to cartilage (leading to
osteoarthritis) and heart valves as well as precipitating as kidney stones.
Alkaptonuria
No treatment modality has been demonstrated to reduce the complications
of alkaptonuria.
Commonly recommended treatments include dietary restriction of
phenylalanine and tyrosine and large doses of ascorbic acid (vitamin C).
Dietary restriction may be effective in children, but benefits in adults
have not been demonstrated.
Disorders of fatty acid oxidation and mitochondrial metabolism
Medium chain acyl dehydrogenase deficiency (glutaric acidemia type 2)
Medium-chain acyl-coenzyme A dehydrogenase deficiency (MCADD) is
a fatty acid oxidation disorder associated with inborn errors of metabolism. It
is due to defects in the enzyme complex known as medium-chain acyl
dehydrogenase (MCAD) and reduced activity of this complex. This
complex oxidizes medium chain fatty acids (Fatty acids having 6-12 carbons)
while reducing FAD to FADH2
It is recognized as one of the more rare causes of sudden infant death
syndrome (SIDS).
Medium chain acyl dehydrogenase deficiency (glutaric acidemia type 2)
Treatment:
There is no cure for MCADD, but once diagnosed, adverse effects can be
prevented by proper management.
The most important part of treatment is to ensure that patients never go
without food for longer than 10–12 hours (overnight fast).
Patients with an illness causing loss of appetite or severe vomiting may
need IV glucose to make sure that the body is not dependent on fatty acids for
energy. Patients also usually adhere to a low-fat diet.
Patients may also take daily doses of carnitine, which helps reduce
toxic accumulation of fatty acids by forming acyl carnitines, which are
excreted in the urine.
Severity of symptoms seems to decrease after puberty.
Disorders of porphyrin metabolism
Acute intermittent porphyria
Acute intermittent porphyria (AIP) is a rare autosomal
dominant metabolic disorder affecting the production of heme, the
oxygen-binding prosthetic group of hemoglobin. It is characterized by a
deficiency of the enzyme porphobilinogen deaminase.
Symptoms of AIP include abdominal pain, constipation, muscle weakness,
and also tend to develop various psychiatric illnesses.
Treatment: A high-carbohydrate a glucose 10% infusion is
recommended, which may aid in recovery.
Iron intake should be adequate to avoid iron deficiency.
Disorders of purine or pyrimidine metabolism
Lesch-Nyhan Syndrome (Hyperuricemias)
Is inherited (X-linked recessive) disorder caused by a deficiency of the
hypoxanthine-guanine phosphoribosyltransferase enzyme (HGPRT),
produced by mutations in the HPRT gene.
The HGPRT deficiency causes a build-up of uric acid in all body fluids.
This results in both hyperuricemia and hyperuricosuria, associated with:
1- Severe gout and kidney
problems,
2- Neurological signs include
poor muscle control,
3- Moderate mental retardation.
These complications usually appear in the first year of life.
Lesch-Nyhan Syndrome (LNS)
In the second year of life, a particularly striking feature of LNS is
self-mutilating behaviors, characterized by lip and finger biting.
The LNS should associated with teeth extraction and restrains to avoid
self-mutilating behaviors.
Treatment:
The elevated level of uric acid in blood and urine doesn’t relate to
high purine diet, but due to physiological error.
Because a lack of HGPRT causes the body to poorly utilize vitamin B12,
some boys may develop megaloblastic anemia and neurological symptoms.
Disorders of steroid metabolism
Congenital adrenal hyperplasia
Congenital adrenal hyperplasia (CAH) refers to any of
several autosomal recessive diseases resulting from mutations of genes for
enzymes mediating the biochemical steps of production of cortisol from
cholesterol by the adrenal glands (steroidogenesis).
Most of these conditions involve excessive or deficient production of
sex steroids and can alter development of primary or secondary sex
characteristics in some affected infants, children, or adults. Approximately
95% of cases of CAH are due to 21-hydroxylase deficiency.
Steroid 21-hydroxylase is one of a cytochrome P450 enzymes that
is involved with the biosynthesis of the steroid hormones aldosterone and
cortisol.
Congenital adrenal hyperplasia
Treatment:
Supplying enough glucocorticoid to reduce hyperplasia and overproduction
of androgens or mineralocorticoids.
Providing replacement mineralocorticoid and extra salt.
Providing replacement testosterone or estrogen at puberty.
Diet:
Patients with congenital adrenal hyperplasia should be on an
unrestricted diet.
Patients should have ample access to salt because salt wasting.
Infants who have salt wasting generally benefit from supplementation
with NaCl (2-4 g/d) added to their formula.
Caloric intake may need to be monitored and restricted if excess weight
gain occurs because glucocorticoids stimulate appetite.
Activity: restriction is not necessary if appropriate
glucocorticoid.
Disorders of mitochondrial function
Kearns-Sayre Syndrome
(KSS) is a
mitochondrial myopathy with a typical onset before 20 years of age.
KSS is a more severe syndromic variant of chronic progressive external
ophthalmoplegia (CPEO), a syndrome that is characterized by isolated
involvement of the muscles controlling eyelid movement and those controlling
eye movement (extra-ocular muscles). This results in ptosis (dropping upper
eyelid) and ophthalmoplegia respectively.
KSS involves cardiac conduction abnormalities.
Other areas of involvement can include cerebellar ataxia, deafness,
diabetes mellitus, growth hormone deficiency, hypoparathyroidism, or other
endocrinopathies.
Demonstrated images of KSS
Kearns-Sayre Syndrome
Treatment: Currently there is no curative treatment for KSS.
One study described a patient with KSS who had reduced serum levels of
coenzyme Q10. Administration of 60–120 mg of Coenzyme Q10 for 3 months
resulted in normalization of lactate and pyruvate levels, improvement of
previously diagnosed first degree AV block, and improvement of ocular movements**.
Screening for endocrinologic disorders should be performed, including
measuring serum glucose levels, thyroid function tests, calcium and magnesium
levels, and serum electrolyte levels.
** Ogasahara, S et al. (1985)
"Improvement of abnormal pyruvate metabolism and cardiac conduction defect
with
coenzyme Q(10) in Kearns-Sayre
syndrome." Neurology 35: 372-377. PubMed ID : 3974895
Disorders of peroxisomal function
Zellweger Syndrome
Zellweger syndrome, also called cerebrohepatorenal syndrome
is a rare, congenital disorder (present at birth), characterized by the
reduction or absence of peroxisomes in the cells of the liver, kidneys, and brain.
Peroxisomes contain oxidative enzymes, such as catalase, D-amino acid
oxidase, and uric acid oxidase.
It is characterized by an individual's inability to beta-oxidize very-long
chain fatty acids in the peroxisomes of the cell.
The most features include
1- An enlarged liver, high
levels of iron and copper in the blood stream,
and vision disturbances.
2- Symptoms at birth may
include a lack of muscle tone, and glaucoma.
3- Mental retardation, and an
inability to suck and/or swallow.
4- Jaundice and
gastrointestinal bleeding may also occur.
Zellweger Syndrome
Treatment:
Treatment of Zellweger syndrome is primarily symptomatic and supportive.
Vitamin K may be needed to avoid abnormal bleeding.
DHA is an essential fatty acid, which is deficient in patients with
Zellweger syndrome. Improvement has been reported in some patients.
Actually; there is no cure for Zellweger syndrome and patient will die
at first year of life.
Lysosomal storage disorders
Gaucher's disease
Gaucher's disease is a genetic disease in which a fatty substance
accumulates in cells and certain organs.
It is caused by a hereditary deficiency of the enzyme glucocerebrosidase.
The enzyme acts on a fatty substance glucocerebroside (also known as glucosylceramide).
When the enzyme is defective, glucocerebroside accumulates, particularly
in white blood cells (mono & lymphocyte).
Glucocerebroside can collect in the spleen, liver, kidneys, lungs, brain
and bone marrow.
Sign and Symptoms:
Painless hepatomegaly, splenomegaly, mental retardation, and rapid and
premature destruction of blood cells, leading to anemia.
Gaucher's disease
Treatment:
The enzyme replacement therapy is essential for the treatment.
Osteoporosis can be reduced by Vit D.
Gaucher patients have increased caloric requirements because they have
higher-than-normal metabolism.
Despite the need for more food, patients with pronounced liver and/or
spleen enlargement can frequently have a suppressed appetite. The enlarged
organs leave little room in the body cavity for a full stomach, so patients
often report a sensation of feeling full, even after having only a few bites of
food.
Minerals or vitamins specially B12 are recommended..
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