METABOLIC & ENDO Flashcards
Inborn errors of metabolism or inherited metabolic disorders
- single gene mutation
- ateration of primary proteni
- compromised or abolished
- disease states
is a common finding in a variety of inborn
errors of metabolism
Hepatomegaly
An inborn error of metabolism should be considered in any child with 1 or more of the following manifestations:
- Unexplained intellectual disability developmental delay or regression motor deficits or adventitious movements (e.g. dystonia, choreoathetosis) convulsions, unusual odor (particularly during an acute illness)
- Intermittent episodes of unexplained vomiting acidosis, mental deterioration, psychotic behavior or coma
- Hepatomegaly, renal stones, muscle weakness, cardiomyopathy
The majority of patients with genetic disorders of
metabolism respond to 1 or all of the following
treatments:
- Special diets: plays an important role
- Hemodialysis: removal of accumulated noxious compounds
- Catabolic states in patients at risk for metabolic crisis
- Administration of the deficient metabolite
- Administration of the cofactor or coenzyme
- Activation of alternate pathways to reduce the noxious compounds
- Administration of the deficient enzyme
- Bone marrow transplantation
- Liver transplantation
modalities have the potential to cure the metabolic abnormalities
The bone marrow and liver transplantation
- Has the most severe clinical manifestations
- Affected infants who are normal at birth develop
> poor feeding and vomiting in the 1%t week of life
> Lethargy and coma may ensue within a few days - Physical examination reveals:
> Hypertonicity
> Muscular rigidity
> Severe opisthotonus
> Hypoglycemia
> Cerebral edema may be present
> convulsions occur in most infants
> Death usually occurs in untreated patients in the first few weeks o months of life
Classic Maple Syrup Urine Disease
Classical Maple Syrup Urine Disease Diagnosis confirmed by
- marked elevations in plasma levels of leucine, isoleucine, valine, and alloisoleucine (a stereoisomer of isoleucine not normally found in blood) and depression of alanine
- Leucine levels are usually higher than those of the other 3 amino acids
- Urine contains high levels of leucine, isoleucine, and valine and their respective ketoacids
MSUD, The enzyme activity can be measured in
- leukocytes
- cultured fibroblasts
Treatment of the acute state MSUD
- hydration and rapid removal of the branched-chain amino acids
- Hemodialysis: most effective
- mannitol, diuretics: if cerebral edema (+)
- All forms are inherited as an autosomal recessive trait
- Mutations in genes for Ela (45%) and E18 (35%) account for approximately 80% of cases
- the infant may be quite sick by the time the results of the screening becomes available
MSUD
- Inherited as autosomal recessive traits
- Prenatal diagnosis
> Is possible using specific genetic probes in cells obtained from biopsy of the chorionic villi - Unpleasant odor of phenylacetic acid, which has been described as musty or mousey
Classic Phenylketonuria
- Very high plasma concentrations (>20 mg/dL or >1,200 pmole/L)
- Plasma concentrations >20 mg/dL, excess phenylalanine is metabolized to phenylketones (phenylpyruvate and phenylacetate) that are excreted in the urine
- Their presence in the body fluids simply signifies the severity of the condition
Classic phenylketonuria
Mildly elevated levels (2-10 mg/dL or 120-600 pmole/L)
Mild hyperphenylalaninemia
- (plasma phenylalanine levels >20 mg/dL)
- Affected infant is normal at birth
- Profound intellectual disability develops gradually if the infant remains untreated
- In untreated patients
> 50-70% will have an IQ below 35, and 88-90% will have an IQ below 65
> Only 2-5% of untreated patients will have normal intelligence
> Older untreated children become hyperactive
with autistic behaviors, including purposeless hand movements, rhythmic rocking, and athetosis
> Microcephaly, prominent maxillae with widely spaced teeth, enamel hypoplasia, and growth retardation
Severe hyperphenylalaninemia
blood for screening for PKU be obtained in the
first 24-48 hr of life after feeding protein
PKU is confirmed by measurement of
plasma phenylalanine concentration (may rise 4hr after birth)
Mainstay of treatment of PKU is
low-phenylalanine diet
- Maintenance of lower plasma phenylalanine levels (2-10 mg/dL) has been strongly encouraged even after 12 yrs of age.
- denotes the elevated level of galactose in the blood
- Two forms of the deficiency exist:
> infants with complete or near complete deficiency of the enzyme (classic)
> partial transferase deficiency
Galactosemia
- onset of symptoms typically by the second half of the 1st wk of life.
- incidence is predicted to be 1 in 60,000 live births
- newborn infant receives high amounts of lactose (up to 40% in breast milk and certain formulas), which consists of equal parts of glucose and galactose
Classic galactosemia
- unable to metabolize galactose-1-phosphate
- the accumulation of which results in injury to kidney, liver, and brain
- diagnosis considered in newborn or young infants with any of the following features:
> Jaundice, hepatomegaly, vomiting, hypoglycemia, seizures, lethargy, irritability, feeding difficulties, poor weight gain or failure to regain birth weight, aminoaciduria, nuclear cataracts, vitreous hemorrhage, hepatic failure, liver cirrhosis, ascites, splenomegaly, or intellectual disability - Symptoms are milder and improve when milk is temporarily withdrawn and replaced by intravenous or lactose-free nutrition
- Increased risk for Escherichia coli neonatal sepsis
-Pseudotumor cerebri can occur and cause a bulging fontanel - Death from liver and kidney failure and sepsis may follow within days
- When the diagnosis is not made at birth
> damage to the liver (cirrhosis) and brain (intellectual disability) becomes increasingly severe and irreversible
Galactose-1-phosphate uridyl transferase deficiency galactosemia
- generally asymptomatic
- diagnosed in newborn screening because of moderately elevated blood galactose and/or low transferase activity
- considered for the newborn or young infant who is not thriving or who has any of the preceding findings
- Light and electron microscopy of hepatic tissue
> reveals fatty infiltration, the formation of pseudoacini, and eventual macronodular cirrhosis
Partial transferase deficiency G1PUTDG
made by demonstrating a reducing substance in several urine specimens collected while the patient is receiving human milk, cow’s milk, or any other formula containing lactose
preliminary diagnosis of galactosemia
- Are usually negative
- test materials rely on the action of glucose oxidase, which is specific for glucose and is nonreactive with galactose
Clinistix urine test results
- establishes the diagnosis
- confirm that the patient did not receive a blood transfusion before the collection of the blood sample, as a diagnosis could be missed
Direct enzyme assay using erythrocytes
accurately detect levels of galactose-1-phosphate uridyl transferase in erythrocytes
Nonradioactive UV and high-performance liquid
chromatography
Tx for Galactosemia
Elimination of galactose from the diet along with adequate calcium supplementation
is reported in 80% to more than 90% of female patients with classic galactosemia
Hypergonadotrophic hypogonadism
- principal metabolites accumulated are
galactose and galactitol - Cataracts are usually the sole manifestation
- pseudotumor cerebri is a rare complication
- otherwise asymptomatic
- Heterozygote carriers may be at risk for presenile cataracts
- diagnosis is made by demonstrating an absence of galactokinase activity in erythrocytes or fibroblasts
- Transferase activity is normal
- Treatment is dietary restriction of galactose
Galactokinase Deficiency Galactosemia
- the most frequent disease involving enzymes of the hexose monophosphate pathway
- responsible for 2 clinical syndromes:
1. episodic hemolytic anemia
2. chronic nonspherocytic hemolytic anemia - Most common manifestations
- neonatal jaundice and episodic acute hemolytic anemia
- induced by infections, certain drugs, and, rarely, fava beans
- X-linked deficiency
G6PD Deficiency
- provides protection against oxidant threats from certain drugs and infections
- otherwise cause precipitation of hemoglobin (Heinz bodies) or damage the RBC membrane
Reduced GSH
- Most cases of are not hereditary and result from thyroid dysgenesis
- Most infants are detected by newborn screening
programs in the 1st few wk after birth - before obvious clinical symptoms and signs develop
Congenital HYpothyroidism
- (aplasia, hypoplasia, or an ectopic gland) is the most common cause of permanent congenital hypothyroidism
- accounting for 80-85% of cases
- approximately 33% of cases of dysgenesis, even sensitive radionuclide scans can find no remnants of thyroid tissue (aplasia)
- other 66% of infants, rudiments of thyroid tissue are found in an ectopic location, anywhere from the base of the tongue (lingual thyroid) to the normal position in the neck (hypoplasia)
- 2:1female: male ratio
- cause is unknown in most cases
- occurs sporadically, but familial cases occasionally have been reporte
Thyroid Dysgenesis: Primary
- most common of the thyroxine (T4) synthetic defects
- marked “discharge” of thyroid radioactivity when perchlorate or thiocyanate is administered 2 hr after administration of a test dose of radioiodine
Thyroid Peroxidase Defects of Organification and
Coupling
- autosomal recessive disorder
- caused by a mutation in the chloride—iodide transport protein common to the thyroid gland and the cochlea
- comprised of sensorineural deafness and goiter most common cause of syndromic deafness
- mutation in the pendrin gene have impaired iodide
organification and a positive perchlorate discharge
Pendred syndrome
- a family of autosomal recessive disorders of cortisol biosynthesis
- Cortisol deficiency increases secretion of corticotropin (adrenocorticotropic hormone [ACTH]), which, in turn, leads to adrenocortical hyperplasia and overproduction of intermediate metabolites
COngenital Adrenal Hyperplasia
affected fetuses by 8-10 wk of gestation and leads to
abnormal genital development | in females
Prenatal Androgen Excess (CAH)
Blood levels of CAH
17-hydroxyprogesterone are markedly elevated
- Diagnosis is most reliably established by measuring 17- hydroxyprogesterone before and 30 or 60 min after an intravenous bolus of 0.125-0.25 mg of cosyntropin (ACTH 1-24)
Mothers with pregnancies at risk for CAH are given
dexamethasone, in an amount of 20 ug/kg
prepregnancy maternal weight daily in 2 or 3 divided doses
