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Copy of Amino Acid Metabolism Disorders

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soha osama

on 5 October 2017

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Transcript of Copy of Amino Acid Metabolism Disorders

Genetic diseases synthesis of a
particular protein
, or the synthesis of a
defective protein.
single gene mutations that results
the defective or absent protein is an
(Most of these inborn disorders)
The defective or absent protein is involved it
transport processes
as cystinuria and Hartnup diseases.
Clinical manifestation of inborn error
What is a metabolic disease?

any disease originating in our chemical individuality”
“Inborn errors of metabolism


Form a large class of genetic diseases involving congenital disorders of metabolism. The majority are due to defects of single genes mutation
Inborn errors of metabolism occur from a group of rare genetic disorders in which the body cannot metabolize food components normally. These disorders are usually caused by defects in the enzymes involved in the biochemical pathways that break down food components.
inborn error :
an inherited (i.e. genetic) disorder
metabolism :
chemical or physical changes undergone by substances in a biological system
Disorders of the amino acid metabolism
How do you recognize a metabolic disorder ??
Index of suspicion
Index of suspicion
Family History
Index of suspicion
Family History
Patient History
Physical examination
Some metabolic disorders of amino acids
Metabolism Disorders
Dr. Soha Osama Mahmoud

the accumulation of substrate.
reduction of the product
diversion of intermediates
failure of transport mechanisms.
Clinical manifestation
parents are cousins
neonatal deaths, fetal losses
maternal family history

Index of suspicion
How do you recognize a
metabolic disorder ??

Patient History
Timing of onset of symptoms
after feeds were started

Index of suspicion
Physical examination
– dysmorphisms (abnormality in shape or size)
Maple syrup
smell in
Maple syrup
urine disease
smell in

smell in
trimethyl aminuria

smell in
Index of suspicion
BUN (blood urea nitrogen),
The clinical presentation of inborn error
The clinical presentation of these disorders is often
In an infant
the symptoms may include
poor feeding,
which are seen in any illness

older children
, failure to thrive or developmental delay may be the only presentation
Many of these genetic disorders result in irreversible brain damage and early mortality.
Dietary Restriction
Supplement deficient product
Stimulate alternate pathway
Supply vitamin co-factor
Organ transplantation
Enzyme replacement therapy
Gene Therapy

1. Primary aminoaciduria -- It is further divided into two groups: -
- Overflow type
- Renal type
2. Secondary aminoaciduria

Glycine metabolic disorders
a - Glycinuria

It results from a defect in renal tubular reabsorption
Clinical features :
It is characterized by excessive urinary excretion of glycine and plasma glycine level is normal.
b – Primary hyperoxaluria:
It is characterized by excessive urinary excretion of oxalate that unrelated to dietary intake of oxalate in diet.
Clinical features :
Progressive bilateral urolithiasis
Recurrent infection of the urinary tract
Rrenal failure
Sulpher-containing amino acids metabolic disorders:
a – Cystinuria (Cystine-Lysinuria):
b – Cystinosos (Cystine storage disease):

c – Homocystinuria
Clinical features

mental retardation,
dislocated lenses.
Phenylalanine & Tyrosine metabolic disorders:
a – Phenylketonuria (PKU)
Phenylalanine accumulates in the blood and is excreted in the urine together with its derivatives such as phenyl pyruvate, phenyl lactate and phenyl acetate.
The disease acquires its name from the recognition of these derivatives in the urine.
The clinical features
irritability, feeding problems, vomiting in the first few weeks of life,
mental retardation,
generalized eczema and reduced melanine formation.
mousey odor urine
b – Alkaptonuria
An inherited deficiency of liver homogentisic acid oxidase with accumulation of homogentisic acid in blood, tissues and urine.
Oxidation and polymerization of this substance produces the alkapton pigment.

The clinical features
black urine or urine becomes dark on standing in air.
c – Albinism
An inherited deficiency of
tyrosinase enzyme
in melanocytes causes one form of albinism.

The clinical features
lacks melanin pigment in skin, hair and iris
acute photosensitivity.
IV – Natural amino metabolic disorders
Hartnup disease:
There a renal and intestinal transport defect involving neutral amino acids with increased urinary loss of tryptophan.
Tryptophan is normally partly converted to nicotinamide.
The clinical features
Resemble those of pellagra, namely: a red, scaly rash on exposed areas of skin
Mental confusion
Excessive amounts of indol compounds in the urine that arise from intestinal bacteria degradation of unabsorbed tryptophan.

Maple syrup urine disease
There is a
deficient Oxidative decarboxylation of branched-chain α-keto acid dehydrogenase
resulting from deamination of the three branched-chain amino acids,
leucine, isoleucine and valine.
Plasma and urinary levels of these amino acids and their
-ketoacids are elevated.
Increased ketoacids -> ketosis, metabolic acidosis
Increased glucose utilization -> ketosis
Increased leucine -> brain toxicity
The clinical features
maple syrup or burnt sugar odour of the urine
the disease presents in the first week of life and if untreated, severe neurological lesions develop with death in a few months.

Metabolic disorders of branched-chain amino acids metabolism:
Intestinal Lumen
= Symptoms:

Skin lesions
Pigmentation changes
Mental Retardation
Visual Distubances
Clinical features :

Stone formation renal tract
Clinical features :
• Ocular Features
• Systemic Features
• Patients die from acute renal failure.

what is metabolic disease?
Small molecule disease
Nucleic Acids
Organelle disease

Three Types
Type 1: Silent Disorders
Type 2: Acute Metabolic Crises
Type 3: Neurological Deterioration
Categories of IEMs are as follows:
Disorders of protein metabolism (eg, amino acidopathies, organic acidopathies, and urea cycle defects)
Disorders of carbohydrate metabolism (eg, carbohydrate intolerance disorders, glycogen storage disorders, disorders of gluconeogenesis and glycogenolysis)
Lysosomal storage disorders
Fatty acid oxidation defects
Mitochondrial disorders
Peroxisomal disorders

a) Cholestyramine (Questran), anion exchange resin; binds bile acids; enhances cholesterol excretion.
b) Colestipol (Colestid), same as cholestyramine.
c) Lovastatin, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor; decreases cholesterol synthesis in the liver.
d) Nicotinic acid (niacin), decreases release of free fatty acids from adipose tissue; increases lipogenesis in liver; decreases glucagon release; most effective for type V disorder.
e) Neomycin, experimental medication; questionable mode of action; decreases LDLs.
f) Clofibrate (Atromid-S), decreases release of free fatty acids from adipose tissue; decreases hepatic secretion of VLDL and increases catabolism of VLDL.
g) Gemfibrozil (Lopid), similar to clofibrate but increases HDLs more.

Deficient β-oxidation of fatty acids can be produced by carnitine deficiency or genetic defects in the translocase or other enzymes involved in the transfer of long-chain fatty acids into the mitochondria.
This causes cardiomyopathy.
In addition, it causes hypoketonemic hypoglycemia with coma, a serious and often fatal condition triggered by fasting, in which glucose stores are used up because of the lack of fatty acid oxidation to provide energy, and ketone bodies are not formed in normal amounts because of the lack of adequate CoA in the liver.

Classes of sphingolipids and their hydrophilic groups include:
Sphingomyelin: phosphorylcholine
Cerebrosides: galactose or glucose
Gangliosides: branched oligosaccharide chains terminating in the 9-carbon sugar, sialic acid (N-acetylneuraminic acid, NANA)
Sphingolipids released when membrane is degraded are digested in endosomes after fusion with lysosomes. Lysosomes contain many enzymes, each of which removes specific groups from individual sphingolipids. Genetic deficiencies of many of these enzymes are known, and the diseases share some of the characteristics of I-cell disease.


Apolipoprotein B deficiency (abetalipoproteinemia)
a. Autosomal recessive
b. Deficiency of apolipoprotein B-48 and B-100
(1) Deficiency of chylomicrons, VLDL and LDL
(2) Decrease in serum CH and TG
c. Clinical findings
1) Malabsorption
a) Chylomicrons accumulate in villi and prevent reabsorption of micelles.
b) Marked decrease in vitamin E
2) Ataxia (spinocerebellar degeneration), hemolytic anemia with thorny RBCs (acanthocytes) related to vitamin E deficiency.
d. Treatment - vitamin E

a. Pathogenesis
1) Increase in chylomicrons and VLDL
2) Due to decreased activation and release of CPL
b. Familial hypercholesterolemia (type IV) + exacerbating disorder
• Exacerbating disorders — diabetic ketoacidosis (DKA: most common), alcohol
c. Increased serum TG > 1000 mg/dL; normal CH and LDL.
d. Turbid plasma
1) Supranate after refrigeration, due to increased chylomicrons
2) Infranate after refrigeration, due to increased VLDL.
e. Hyperchylomicronemia syndrome
1) Eruptive xanthomas
2) Increased incidence of acute pancreatitis
3) Lipemia retinalis - retinal vessels look like milk: blurry vision
4) Dyspnea and hypoxemia - impaired gas exchange in pulmonary capillaries
5) Hepatosplenomegaly
6) Increase in serum TG (usually >1000 mg/dL)
7) Normal serum CH and LDL
8) Turbid supranate and infranate after refrigeration
f. Treatment
(1) Treat exacerbating disorder (e.g.. DKA)
(2) Nicotinic acid or fibric acid derivatives

Familial dysbetalipoproteinemia ("remnant disease")
1) AD inheritance
2) Deficiency of apo E
3) Decreased liver uptake of chylomicron remnants and IDL
Clinical findings
1) Palmar xanthomas in flexor creases
2) Increased risk for coronary artery disease
3) Increased risk for peripheral vascular
disease (unlike type II disorders)
Laboratorv findings
1) Serum CH and TG > 300 mg/dL
2) Serum CH 250 to 500 mg/dL
3) LDL< 190 mg/dL
4) Confirm diagnosis with ultracentrifugation to identify remnants
• Lipoprotein electrophoresis and identification of apo E gene defect are other studies that can be used.
• Fibric acid derivatives

(h) Estrogens, decrease IDL levels in type III disorders; experimental.
(i) Progesterone, decreases plasma triglycerides in type V disorders; experimental.

or dyslipoproteinemia refers to abnormal concentrations of serum lipoproteins

It is estimated that nearly half of the U.S. population has some form of dyslipidemia, especially among white and Asian populations. These abnormalities are the result of a combination of genetic and dietary factors.
Primary or familial dyslipoproteinemias result from genetic defects that cause abnormalities in lipid-metabolizing enzymes and abnormal cellular lipid receptors.
Secondary causes of dyslipidemia include several common systemic disorders, such as diabetes, hypothyroidism, pancreatitis, and renal nephrosis, as well as the use of certain medications such as certain diuretics, beta-blockers, glucocorticoids, interferons, and antiretrovirals.

Adult onset Niemann-Pick disease type C presenting with psychosis

The bright light at right enters through the pupil of the eye; at left, the “red spot” in diagnosis of Tay-Sachs disease

Tubero-eruptive xanthoma

Laboratory findings
1) Serum TG > 300 mg/dL; 2) Serum CH 250 to 500 mg/dL; 3) Serum LDL < 190 mg/dL;
4) Turbid infranate after refrigeration
Increase in VLDL - due to increase in synthesis or decrease in catabolism
Acquired causes of hypertriglyceridemia
1) Excess alcohol intake
2) Oral contraceptives - estrogen increases synthesis of VLDL
3) Diabetes mellitus - decreased muscle and adipose CLP
4) Chronic renal failure - increased synthesis of VLDL
5) Thiazides, β-blockers - possible inhibition of CPL
Familial hypertriglyceridemia
1) Autosomal dominant disorder
2) Clinical findings
a) Eruptive xanthomas - yellow, papular lesions
(b) Increased risk for coronary artery- and peripheral
vascular disease

a) Premature coronary- artery- disease and stroke
b) Tendon xanthomas
Cholesterol deposit located over tendons (e.g. Achilles) and extensor surfaces of joints
c) Xanthelasma
Yellow, raised plaque on the eyelid
e. Polygenic hypercholesterolemia (type Ila)
1) Most common hereditary cause (85% of cases)
2) Multifactorial (polygenic) inheritance
3) Alteration in regulation of LDL levels
4) Normal serum TG
f. Familial combined hypercholesterolemia (type lIb)
1) AD inheritance.
2) Serum CH and TG begin to increase around puberty.
3) Associated with metabolic syndrome.
4) Increase in CH and TG and decrease in HDL.

a. Laboratory findings
1) Serum LDL > 190 mg/dL
2) Serum CH > 260 mg/dL
a) Serum TG < 300 mg/dL (called type IIa)
b) Serum TG > 300 mg/dL (called type lIb)
b. Pathogenesis
• Decreased synthesis of LDL receptors.
c. Acquired causes of hypercholesterolemia
1) Primary hypothyroidism
• Decrease in LDL receptor synthesis or function
2) Nephrotic syndrome
• Increase in LDL correlates with the degree of hypoalbuminemia
3) Extrahepatic cholestasis (obstruction of bile)
Bile contains CH for excretion
d. Familial hypercholesterolemia
1) Autosomal dominant (AD) disorder
2) Deficiency of LDL receptors
3) Clinical findings

A: Lateral borders of thickened Achilles' tendons are shown with arrows.
B: Tendinous xanthomas can also occur in the extensor tendons of the hands (shown), feet, elbows and knees.
C: Xanthelasmas are cholesterol deposits in the eyelids.
D: Arcus cornealis results from cholesterol infiltration around the corneal rim (arrow).

a. Epidemiology
1) Autosomal recessive
2) Rare childhood disease
b. Pathogenesis
1) Deficiency of CPL or
2) Deficiency of apo C-ll
c. Clinical findings
1) Chylomicrons are primarily increased in early childhood.
2) VLDL increases later in life.
3) Presents with acute pancreatitis
• Pancreatic vessels filled with chylomicrons rupture.
d. Laboratory findings
1) Increase in serum TG > 1000 mg/dL (primarily chylomicrons)
2) Turbid supranate (chylomicrons) and clear infranate (early childhood)
3) Normal (usual case) to moderately increased serum CH

Are osmotic!


 pH - Acidosis

KB in the blood

KB in urine

 Acetone breath

In many tissues, acetyl-CoA units condense to form acetoacetyl-CoA.
In the liver, which (unlike other tissues) contains a deacylase, free aceto-acetate is formed.
This β-keto acid is converted to β-hydroxybutyrate and acetone, and because these compounds are metabolized with difficulty in the liver, they diffuse into the circulation.
Acetoacetate is also formed in the liver via the formation of 3-hydroxy-3-methylglutaryl-CoA, and this pathway is quantitatively more important than deacylation.
Acetoacetate, β-hydroxybutyrate, and acetone are called ketone bodies (KB).
Tissues other than liver transfer CoA from succinyl-CoA to acetoacetate and metabolize the "active" acetoacetate to CO2 and H2O via the citric acid cycle. There are also other pathways whereby ketone bodies are metabolized.
Acetone is discharged in the urine and expired air.
The normal blood ketone level in humans is low (about 1 mg/dL) and less than 1 mg is excreted per 24 hours, because the ketones are normally metabolized as rapidly as they are formed. However, if the entry of acetyl-CoA into the citric acid cycle is depressed because of a decreased supply of the products of glucose metabolism, or if the entry does not increase when the supply of acetyl-CoA increases, acetyl-CoA accumulates, the rate of condensation to acetoacetyl-CoA increases, and more acetoacetate is formed in the liver.
The ability of the tissues to oxidize the ketones is soon exceeded, and they accumulate in the bloodstream (ketosis).

• Growth failure, failure to thrive, weight loss
• Ambiguous genitalia, delayed puberty, precocious puberty
• Developmental delay, seizures, dementia, encephalopathy, stroke
• Deafness, blindness, pain agnosia
• Skin rash, abnormal pigmentation, lack of pigmentation, excessive hair growth, lumps and bumps
• Dental abnormalities
• Immunodeficiency, low platelet count, low red blood cell count, enlarged spleen, enlarged lymph nodes
• Many forms of cancer
• Recurrent vomiting, diarrhea, abdominal pain
• Excessive urination, kidney failure, dehydration, edema
• Low blood pressure, heart failure, enlarged heart, hypertension, myocardial infarction
• Liver enlargement, jaundice, liver failure
• Unusual facial features, congenital malformations
• Excessive breathing (hyperventilation), respiratory failure
• Abnormal behavior, depression, psychosis
• Joint pain, muscle weakness, cramps
• Hypothyroidism, adrenal insufficiency, hypogonadism, diabetes mellitus

Diagnosis by
1. The DNA abnormality
2. The enzyme defect
3. Metabolic abnormality that is due to the defect.

direct enzyme assay of extracts of leucocytes, erythrocytes or cultured fibroblasts.
DNA based testing is possible for several disorders like PKU
Amniotic fluid may be used for prenatal diagnosis; however it is a high-risk procedure to obtain the specimen. Amniocentesis is done at 12-18 weeks of gestation, fetal cells are cultured and the cells are examined for enzyme activity.
Another test done is chorionic villus sampling, which allows direct gene analysis of tissue obtained by biopsy.

Types of phenyleketonuria (PKU):
1) Classical PKU
2) PKU Variants
3) Transient neonatal
4) Maternal hyperphenylalaninemia
5) Hyperphenylalaninemia due to tetrahydrobiopterin deficiency

colour is observed after addition of
ferric chloride
reagent yields a
brown colour
colour is observed on addition of saturated
silver nitrate
screening tests can be confirmed
chromatographic, enzymatic or spectrophotometric determinations of homogentisic acid.
X-rays of lumbar spine show degeneration and dense calcification of intervertebral discs and a bamboo like appearance
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