Dr. Mushtak Gherbawe
Lec. 1
METABOLIC
DISORDERS
Mon
15 / 12 / 2014
Published by : Ali Kareem
2014 – 2015
مكتب اشور لالستنساخ
Metabolism
A complex biochemical reactions usually catalyzed by an enzyme
(proteins) through certain metabolic pathways to yield both energy
molecules and essential buildingblocks.
Metabolic disorders
Any disease that negatively affects the biochemical reactions and blocks
the metabolic pathways that yield energy or essential building-blocks to
perform the functions
necessary to sustain life.
Leading to one of the following
1. Accumulation of substrates to toxic concentrations, Examples:
galactosemia,
Gaucher’s disease.
2. Production of toxic byproducts through a normally minor pathway.
Examples: tyrosinemia type I, adenosine deaminase deficiency.
3. Deficiency of an end product. Examples: albinism.
4. Loss of regulation resulting in overproduction of intermediates to toxic
levels. Examples: congenital adrenal hyperplasia, intermittent porphyria,
familial hypercholesterolemia.
Metabolic disorders are usually either:
� A genetic defect which are also known as inborn errors of metabolism,
� Or acquired as a result of diet, toxins, or infections…etc (environmental
causes).
Mode of Inheritance : Usually one of the following
� Autosomal recessive inheritance (most common)
� X-linked (or sex-linked) recessive inheritance
� Mitochondrial inheritance. (Mitochondrial DNA is inherited from the
mother )
� Autosomal Dominant (rare).
GALACTOSEMIA
Autosomal recessive trait caused by absent function of galactose 1-
phosphate uridyltransferase (GALT) which results in the accumulation of
galactose and galactose 1- phosphate in blood and excretion of excess
galactose and galactitol in urine.
Less severe forms
•uridine diphosphate (UDP) galactose 4- epimerase (GALE)
•galactokinase (GALK) deficiency
Clinical Manifestations
Begins within a few days of ingestion of milk,
Feeding intolerance
(
vomiting or diarrhea), neonatal jaundice, bleeding
diathesis, lethargy, Escherichia coil sepsis, hypotension, and death if
untreated.
Later in life: Due to chronic accumulation of galactose
-Verbal dyspraxia (56%),
-Reduced lQ (46%),
-Cataracts (10%),
-Ovarian failure (up to 85%),
-Ataxia and tremors (18%),
-And growth delay (before puberty).
Cataracts without hepatic, ovarian, or central nervous system pathologic
conditions are found in GALK deficiency
Diagnosis
- GALT enzyme is measured by enzyme-linked fluorometric methods
- Erythrocyte galactose 1-phosphate increased to above 1.5 mg/dL,
- Urinary galactitol above 78 mmol/mol creatinine,
- ¹³C02 in breath below 5% of administered ¹³C-d-galactose indicate
clinically significantly impaired GALT.
- GALK will not be detected by most public health screening programs and
should be suspected in any patient with congenital or early-onset
ocular cataracts
Treatment
Exclusion of galactose from the diet, which involves the elimination of
milk and its products. The mainstay of the diet for such an infant is
substitution of a soy preparation for all milk products.
Some fruits and vegetables, such as watermelon and tomatoes, contain
bioavailable galactosides and are avoided.
Education of the family.
Prevention
- primary prevention of galactosemia involving heterozygote detection and
prenatal counseling of high risk family members or parents of galactosemic
children.
- Prenatal monitoring is available in the early second trimester by combined
GALT enzyme analysis of cultured amniotic fluid cells or chorionic villous
cells.
Prognosis
� If a galactose-restricted diet is provided during the first 7 days and
continued throughout life, the prognosis is good.
� If the diagnosis of GALT-deficient galactosemia is not established within
days of life, complications such as mental and growth retardation are likely.
� Despite early and adequate therapy, the long-term complications in older
children
and adults with “very severe” galactosemia can occur.
Amyloidosis
Amyloidosis are group of disorders that are acquired or hereditary.
Characterized by the extracellular deposition of insoluble proteins
called Amyloid.
Amyloid diseases are classified by etiology and/or type of protein deposited to:
Etiology:
A) Systemic:
There are 3 major systemic forms of amyloidosis:
Primary
Secondary
Familial
As well as several miscellaneous forms
• B 2 - microglobulin associated with chronic hemodialysis or peritoneal
dialysis for long periods, usually> 8 yr.
•Senile systemic amyloidosis Normal proteins (transthyretin) are
deposited in tissues starting at age > 70 years (affects > 90%of 90-year-
olds) Usually asymptomatic, feature of normal ageing.
B) Localized:
There are 2 major localized forms,
B-protein amyloidosis (associated with
Alzheimer’s disease)
� IAPP (Islet amyloid polypeptide amyloidosis) which occurs in the
pancreasof patients with type 2 diabetes.
Primary amyloidosis (AL)
Amyloid light chain (AL) is a plasma cell disorder in which the abnormal
protein is an immunoglobulin, usually a light chain fragment (Bence Jones
protein).
Common sites for deposition include the skin, nerves, heart, GI tract,
kidneys, liver, spleen, and blood vessels.
A mild plasmacytosis may occur in the bone marrow, which is suggestive of
multiple myeloma, but most patients do not have true multiple myeloma.
However, about 10 to 20% of patients with multiple myeloma also
develop amyloidosis.
Secondary amyloidosis (AA) Reactive
>This form can occur secondary to several infectious, inflammatory, and
malignant conditions due to degradation of the acute-phase reactant
serum amyloid
>Common causative infections include TB, bronchiectasis,
osteomyelitis, and leprosy.
>inflammatory conditions include Rheumatoid Arthritis, juvenile
idiopathic arthritis,
Crohn’s disease, and familial Mediterranean fever
.
>AA amyloidosis shows a predilection for the spleen, liver, kidneys,
adrenals, and lymph nodes.
>Involvement of the heart and peripheral or autonomic nerves is rare.
Familial amyloidosis (HEREDITARY SYSTEMIC AMYLOIDOSIS) ATTR
>lnherited in an autosomal dominant pattern.
>The familial form results from accumulation of a mutated plasma protein
(transthyretin [TTR], so called ATTR). Nearly all of the abnormal protein is
produced by the liver.
>Age at onset ranging from the teens to the 70s.
> ATTR causes peripheral sensory, and autonomic neuropathy. Carpal
tunnel syndrome is also common.
>Later in the illness, cardiovascular and renal involvement occurs.
Symptoms and Signs of Amyloidosis
Symptoms and signs are nonspecific and relate to the organ or system
affected.
Kidneys: nephrotic syndrome is early manifestation, ends with renal
failure.
Liver involvement: causes painless hepatomegaly, which may be massive
(liver weight > 7 kg). liver function tests remain normal. Jaundice is rare.
Portal hypertension may develops, with resulting esophageal varices and
ascites.
Cardiac involvement: causes a restrictive cardiomyopathy, leading to
heart failure. Cardiomegaly and various degrees of heart block or
arrhythmia may occur.
Peripheral neuropathy: with paresthesias of the fingers and toes, is a
common presenting manifestation in AL and ATTR amyloidoses.
Autonomic neuropathy: cause orthostatic hypotension, erectile
dysfunction, sweating abnormalities, and GI motility disturbances.
Gl amyloid: may cause motility abnormalities of the esophagus and small
and large intestines. Gastric atony, malabsorption, bleeding, perforation or
pseudo-obstruction may also occur. Macroglossia is common in AL
a amyloidoses.
Lung involvement (mostly in AL amyloidosis) can be characterized by
focal pulmonary nodules, tracheobronchial lesions, or diffuse alveolar
deposits.
Skin conditions, such as abnormal growths, color changes, purpura.
Diagnosis:
The diagnosis of amyloidosis should be considered in all cases of
unexplained nephrotic syndrome, cardiomyopathy and peripheral
neuropathy.
The diagnosis is established by biopsy of an affected organ.
The pathognomonic histological feature is apple-green birefringence of
amyloid deposits when stained with Congo red dye and viewed under
polarised light.
Immunohistochemical staining can then identify the type of amyloid fibril
present.
Prognosis
Prognosis depends on the type of amyloidosis and the organ involved.
AL amyloidosis with multiple myeloma has the poorest prognosis: death
within 1 yr is common. Untreated ATTR amyloidoses are fatal within 10 to
15 yr. ln general, renal or cardiac involvement in patients with any type of
amyloidosis is bad. Prognosis in AA amyloidosis depends on successful
treatment of the underlying disorder,.
Treatment
Management is generally symptomatic of involved organs.
Sometimes chemotherapy for AL amyloidosis with autologous stem cell
transplantation.
In 2ndry type, treatment of the underlying disorder can sometimes arrest
amyloidosis. ln patients with renal amyloid, kidney transplantation provides
long-term survival. But amyloid ultimately recurs in a donor kidney, survival
up to 10 yr.
Heart transplantation has been successful in carefully selected patients
with AL amyloidosis and severe cardiac involvement.
ln patients with ATTR amyloidosis, liver transplantation
—which removes
the site of synthesis of the mutant protein
—is very effective