Download Genetics Ch 7 128-148 [4-20

Genetics Ch. 7 128 – 148
Metabolic processes consist of a sequence of catalytic steps mediated by enzymes encoded by certain
genes.
Mutations can reduce the efficiency of enzymes to a point where normal metabolism won’t occur.
-AKU is a disorder where homogentisic acid (HGA), an intermediate metabolite in phenylalanine and
tyrosine metabolism, is secreted in large quantities in urine causing it to darken. (Black urine disease).
-HGA is abnormally deposited in connective tissues resulting in abnormal pigmentation and
debilitating arthritis
-HGA is caused by a mutant gene product if homogentisic acid oxidase
-Almost all biochemical processes of human metabolism are catalyzed by enzymes. Variations of
enzymatic activity among humans are common, and a minority of variants cause disease.
Other important metabolic disorders:
-Maple Syrup Urine Disease – Banched-chain α-ketoacid dehydrogenase mutation
-Phenylketonuria – Phenylalanine hydroxylase mutation
-Hemochromatosis – Human Hemochromatosis protein (HFE) Mutation
-Galactosemia – Galatose-1-phosphate uridyl transferase mutation
Variants of Metabolism
-Incidence of metabolic disorders is 1:2500 births (10% of all monogenic conditions)
-Reye Syndrome – acute metabolic encephalopathy in children, often confused with a urea cycle defect
that produced hyperammonemia (a lot of ammonia in blood) and death (Termed Phenocopy)
-Individual metabolic disorders are rare, their overall contribution to morbidity and mortality is
substantial
Inheritance of Metabolic Defects
-Most are inherited in an autosomal recessive pattern (only two mutant alleles show disease)
-Most common blood tests are for phenylketonuria and galactosemia
-The carrier state of disease is not associated with morbidity, can be tested readily
Types of Metabolic Processes
-Metabolic disorders are classified based on the pathological effects of the pathway blocked (absence of
end products, accumulation of substrate, different functional classes of proteins, associated cofactors,
and pathways affected.
Defects of Metabolic Processes
-Catalytic properties of enzymes increase the reaction rates by more than a million-fold
-Reactions mediate synthesis, transfer, use and degradation of biomolecules to maintain the cell
-Major metabolic pathways include glycolysis, citric acid cycle, pentose phosphate shunt,
gluconeogenesis, glycogen and fatty acid synthesis and storage, degradative pathways, energy
production, and transport systems.
Carbohydrate Metabolism
-Carbohydrates are the most abundant organic substance on earth: function as substrates for energy
production and storage, intermediates in pathways, and structural framework for DNA and RNA
-Major portion of human diet and are metabolized into glucose, galactose, and fructose
-galactose and fructose are converted to glucose before glycolysis
-Failure to effectively use these sugars produces majority of inborn errors of carbohydrate metabolism
Galactose Disorders
-the most common monogenic disorder is transferase deficiency galactosemia (classic galactosemia)
-1:30000 newborns
-Associated by mutations in the galactose-1-phosphate uridyl transferace (Gal-1-P uridyl
transferase) enzyme
-Causes 70% of all galactosemia in western european populations
-Affected people cannot convert galactose to glucose, and therefore galactose is metabolized to
galactitol and galactonate
-If untreated, can lead to sepsis, hyperammonemia, and shock leading to death
-Cataracts (opacification of lens) are found in 10% of infants
-Causes growth failure, mental retardation
-Galactosemia can also be caused by mutations in genes encoding galactokinase or uridine diphosphate
galactose-4-epimerase (UDP-galactose-4-epimerase)
-deficiency of galactokinase causes cataracts but not growth failure, mental retardation or
hepatic disease…
-treatment is dietary restriction of galactose
-deficiency of UDP-galactose-4-epimerase is limited to red blood cells and leukocytes, and can
cause no ill effects, however it can also cause systemic effects similar to classic galactosemia…
treatment is dietary restriction of galactose
Fructose Disorders
-Three autosomal recessive defects of fructose metabolism have been described
1.) Most common is in a gene encoding hepatic fructokinase – catalyzes first step in metabolism of
dietary fructose, conversion to fructose-1-phosphate.
-results in asymptomatic fructosuria (fructose in urine)
2.) -Hereditary Fructose Intolerance (HFI) – results in poor feeding, failure to thrive, hepatic and renal
insufficiency, and death.
-caused by deficiency of fructose 1,6-biphosphate aldolase in the liver, kidney cortex, and small
intestine
-infants are asymptomatic unless they ingest fructose or sucrose, asymptomatic during
breastfeeding until fruits and veggies are added to diet
3.) Deficiency in hepatic fructose 1,6-bisphosphatase (FPBase) causes impaired gluconeogenesis,
hypoglycemia, and severe metabolic academia (serum pH of <7.4)
-Asymptomatic deficiency of fructokinase is the most common defect of fructose metabolism.
Hereditary fructose intolerance is less prevalent but is associated with much more severe problems.
Glucose
-These are the most common of all carbohydrate metabolisms
-Associated with hight plasma glucose (hypercalcemia)
-Three categories:
1.) Type 1 diabetes mellitus – absent or reduced insulin at birth
2.) Type 2 diabetes mellitus – insulin resistance and adult onset
3.) Maturity-onset diabetes of the young
-Mutations in the insulin receptor gene have been associated with a disorder characterized by insulin
resistance and acanthosis nigricans (hypertrophic skin with corrugated appearance)
-These mutations decrease the number of insulin receptors on cell’s surface or lower the binding
of insulin to its receptor
Lactose – Lactose metabolism depends on an enzyme in the intestinal brush border called lactasephlorizin hydrolase (LPH).
-LPH activity diminishes in most mammals after weaning
-In humans, persistence of LPH is autosomal recessive with incidence ranging from 5-90%
-Dairy products as a source of vitamin D had selective advantage in these populations
-Lactase non-persistence is associated in tropical regions – people can experience nausea, bloating, and
diarrhea after ingesting lactose
-LPH encoded by the lactase gene (LCT) on chr. 2. Adult LPH is regulated by a polymorphism in an
upstream gene named minichromosome maintenance 6 (MCM6).
-in African and tropical countries where lactose persistence is prevalent, this mutation is found
at lower frequency.
-found to be as a result of mutations that acted to increase transcription of LCT
-Mutations that abolish lactose activity altogether cause congenital lactase deficiency and produce
severe diarrhea and malnutrition in infancy – very rare
Glycogen – carbs are stored as glycogen in humans
-glycogen degradation enzyme deficiencies are also considered carbohydrate metabolism disorders
Examples:
1.) Type Ia (Von Gierke) – defect in glucose-6-phosphatase
2.) Type Ib - defect in microsomal glucose-6-phosphate transport
3.) Type II (Pompe) – Lysosomal acid B-glucosidase
4.) Type IIIa (Cori) – Glycogen debranching enzyme
5.) Type IIIb – Glycogen debranching enzyme
-Two organs most severely affected by glycogen disorders are liver and skeletal muscle
- Liver - can cause hepatomegaly and hypoglycemia
- Muscle – can cause exercise intolerance, progressive weakness, and cramping… Pompe disease
can affect cardiac muscle causing cardiomyopathy and death
-Treatment is enzyme replacement
Amino Acid Metabolism – Some amino acids can be synthesized endogenously (nonessential), while
others need to be obtained from the environment (essential)
Phenylalanine – defects would cause hyperphenylalaninemias
-These disorders are caused by mutations in genes encoding components of phenylalanine
hydroxylation pathway
-hyperphenylalaninemias disrupt cellular processes such as brain myelination, protein synthesis, and can
cause severe mental retardation
-most disorders are caused by mutations in phenylalanine hydroxylase (PAH) which results in
phenylketonuria (PKU)
-mutations here range from substitutions, deletions and insertions
-Less common hyperphenylalaninemia is caused by defects in the synthesis of tetrahydrobiopterin,
cofactor necessary for the hydroxylation of phenylalanine
-Another cause is a deficiency of dihydropteridine reductase
-Treatment is dietary restriction of phenylalanine, but since it is an essential amino acid, must balance
restriction with intake so as to not raise serum levels too high
-hyperphenylalaninemia in pregnant women causes high phenylalanine in fetus – results in poor growth,
birth defects, microcephaly, and mental retardation regardless of genotype of fetus
Tyrosine – tyrosine is the starting point of synthetic pathways leading to catecholamines, thyroid
hormones, and melanin pigments. It is also incorporated into many proteins.
-High tyrosine can be acquired or as a result of congenital error of catabolism
1.) Hereditary tyrosinemia type 1 (HT1) is most common metabolic defect and is caused by a deficiency
of fumarylacetoacetate hydrolase (FAH), which catalyzes the last step in tyrosine metabolism
-accumulation of substrate fumarylacetoacetate and its precursor, maleylacetoacetate is
thought to be mutagenic and toxic to the liver
-characterized by dysfunction of renal tubules, acute episodes of peripheral neuropathy,
progressive liver disease (cirrhosis), and high risk of hepatocellular carcinoma
-management is dietary restriction of phenylalanine and tyrosine and administration of NTBC or
nitisinone, an inhibitor of an enzyme upstream of FAH.
-A splice-site mutation is common and results in an in-frame deletion of an exon, which removes
a series of critically important amino acids from FAH
-missense and nonsense mutations have also been found in HT1
2.) Tyrosinemia type 2 (oculocutaneous tyrosinemia) – is caused by a deficiency of tyrosine
aminotransferase
-characterized by corneal erosions, thick skin on palms and soles, and mental retardation
3.) Tyrosinemia type 3 - associated with reduced activity of 4-hydroxyphenylpyruvate dioxygenase and
neurological dysfunction
Branched-chain amino acids – such as valine, leucine, and isoleucine – and can be used as a source of
energy through an oxidative pathway that uses an alpha-ketoacid as an intermediate
-decarboxylation of alpha-ketoacids is mediated by a multimeric enzyme complex called branched-chain
alpha-ketoacid dehydrogenase (BCKAD) – which has 4 catalytic components and 2 regulatory enzymes (6
different genes)
-Deficiency of any one of these components results in Maple Syrup Urine Disease (MSUD),
where urine of patient smells like maple syrup
-All carriers of MSUD of the Mennonites in Pennsylvania have the same mutation of E,alpha, one of the
loci of a catalytic component of BCKAD
-Untreated patients accumulate BCAAs and ketoacids, leading to progressive neurodegeneration and
death
-Maple Syrup Urine Disease is caused by defects in branched-chain alpha-ketoacid dehydrogenase,
which cause accumulation of BCAAs to cause neurodegeneration and death.
-Treatment consists of dietary restriction
Lipid Metabolism – Lipipds are heterogeneous groups of biomolecules that are insoluble in water and
highly soluble in organic solvents, provide backbone for phospholipids and sphingolipids in membranes,
and can be steroid hormones such as cholesterol
-elevated serum lipid levels are common and result from defective lipid transport systems.
-metabolic errors of lipids are much less common
-During fasting, fatty acids are mobilized from adipose tissue to become major substrate for energy
production in the liver, skeletal muscle, and cardiac muscle
Fatty Acids – Most common inborn error of fatty-acid metabolism is a deficiency of medium-chain acylcoenzyme A dehydrogenase (MCAD).
-MCAD deficiency characterized by hypoglycemia, vomiting, lethargy
-fasting results in accumulation of fatty acid intermediates, a failure to produce ketones in sufficient
quantities to meet tissue demands, and exhaustion of glucose supplies
-results in cerebral edema and encephalopathy
-death follows unless another energy source like glucose is provided
-Majority of Europeans have a missense A-G mutation resulting in substitution of glutamate for lysine.
-addition substitution, insertion, and deletion mutations have also been identified
Long-chain Acyl-CoA Fatty Acids – metabolized first by long-chain acyl-CoA dehydrogenase (LCAD) and
the second step Is through a complex called mitrochondrial trifunctional protein (TFP). One enzyme in
TFP is long-chain-L-3-hydroxyacyl-CoA Dehydrogenase (LCHAD)
-LCHAD deficiency is the most severe of the fatty acid oxidation disorders
-neonatal liver failure, destruction of liver, cardiomyopathy, skeletal myopathy, retinal disease,
peripheral neuropathy, and sudden death
-pregnant women with fetus affected with LCHAD deficiency have developed a severe liver
disease called acute fatty liver of pregnancy (AFLP) and HELLP Synrome (Hemolysis, elevated
liver function, low platelets)
Cholesterol – Elevated plasma cholesterol has been associated with atherosclerotic heart disease, and
reduced cholesterol results in adverse growth and development
-final step in cholesterol biosynthesis is ∆7-sterol reductase (DHCR7)
-SLO syndrome patients showed reduced levels of cholesterol and increased levels of 7dehydrocholesterol (precursor to DHCR7)
-characterized by anomalies such as brain, heart, genitalia, and hands
-SLO is caused by mutations in the DHCR7 gene, most are missense mutations
-Clinical presentation of children with defects of lipid metabolism varies from slow deterioration to
sudden death. MCAD deficiency is the most common of these disorders. Most affected people can be
diagnosed by biochemical analysis of a drop of dried blood at birth
Steroid Hormones – Cholesterol is the precursor to several major steroid hormones including
glucocorticoids, mineralocorticoids, androgens, and estrogens.
-these bind to intracellular receptor, and elicit widespread effects physiologically
Congenital Renal Hyperplasia (CAH) – genetically heterogeneous autosomal recessive disorders of
cortisol biosynthesis
-95% of cases caused by mutations in CYP21A2 , gene that encodes 21-hydroxylase
-characterized by cortisol deficiency, aldosterone deficiency, and excess androgens
-severity depends on extent of residual 21-hydroxylase activity
-Severe form is typified by overproduction of cortisol precursors and excess adrenal
androgens – aldosterone deficiency results in loss of salt
-Female infants have ambiguous genitalia due to high levels of androgens
-Most boys have salt-losing form of CAH manifested as weight loss, lethargy, dehydration,
hyponatremia (decreased Na+ plasma concentration)
-if untreated, death soon follows
-treatment consists of replacing cortisol, suppressing adrenal androgen secretion, and providing
mineralocorticoids to return electrolyte concentrations to normal
-CYP21A2 is on chromosome 6p21 within MHC complex, mutations here result in protein that
lacks normal 21-hydroxylase activity
-Congenital renal hyperplasia is relatively common defect of cortisol synthesis that causes
masculinization of the genitalia in females and premature virilization in males. It is commonly caused by
diminished activity of 21-hydroxylase.
Steroid Hormone Receptors – Defects in steroid hormone receptors are rare
-Mutations in the X-linked gene that encodes the androgen receptor (AR) are common, and result in
complete or partial androgen insensitivity (CAIS or PAIS)
-CAIS is characterized by female genitalia at birth, absent or rudimentary mullerian structures
(fallopian tubes, uterus, and cervix), short vaginal vault, inguinal or labial testis
-PAIS people can have ambiguous genitalia, varied positioning of testis, absent secondary sexual
characteristics, nearly all are infertile
-both are transmitted in an X-linked manner and 95% of patients have AR mutations
Peroxisomal Enzymes – peroxisomes are organelles that contain more than 50 enzymes that catalyze
synthetic and degradative metabolic functions related to lipid metabolism. Divided into two groups:
peroxisome biogenesis disorders (PBDs) and single peroxisomal enzyme deficiencies (PEDs)
1.) Peroxisome biogenesis disorders (PBDs) – comprises 4 disorders
a. Zellweger Syndrome – most severe, includes hypotonia, progressive white matter
disease of brain, distinctive facial features, typical death at infancy
b. Neonatal Adrenoleukodystrophy – lighter symptoms than Zellweger, but with
seizures
c. Infantile Refsum – less severe than A and B, yet still have developmental delay,
learning abilities, hearing loss, and visual impairment
d. Chondrodysplasia Punctata Type 1
-PBDs are caused by mutations that encode peroxins, which are necessary for peroxisome
biogenesis and importing proteins into matrix.
2.) Peroxisomal Enzyme Deficiencies (PEDs) – nearly a dozen PEDs have been described
-most common is X-linked adrenoleukodystrophy (ALD) – involves faulty B-oxidation of
very long chain fatty acids (VLCFA)
-ALD is divided into two common disorders
1.) Childhood cerebral ALD – cognitive/behavioral deterioration
2.) Adrenomyeloneuropathy (AMN) – less severe symptoms but later
onset
-Peroxisomal defects cause a wide variety of neurological problems in children and adults, these range
from relatively mild and slowly progressive to severe and life threatening
Lysosomal Storage Disorders – prototypical inborn errors of metabolism, results from accumulation of
substrate
-enzymes within lysosomes catalyze degradation of sphingolipids, glycosaminoglycans, glycoproteins,
and glycolipids
Mucopolysaccharidoses – (MPS Disorders) – caused by reduced ability to degrade one or more
glycosaminoglycans
-10 different enzyme deficiencies cause six different MPS disorders which share clinical features
-All but one are autosomal recessive – Hunter Syndrome is X-linked recessive
-All MPS disorders characterized by chronic and progressive multisystem deterioration, hearing vision,
joint, and cardiovascular dysfunction
-Deficiency of iduronidase (MPS I) is the prototypic MPS disorder (Hurler, Scheie syndromes)
-Hunter Syndrome – (MPS II) – deficiency of iduronate sulfatase
-mild and severe phenotypes based on clinical assessment – coarse facial features, short stature,
skeletal deformities, joint stiffness, and mental retardation
-Treatment has involved bone marrow transplantation or enzyme replacement with recombinant
enzyme
-Defects of glycosaminoglycan degradation cause a heterogeneous group of disorders called
mucopolysaccharidoses (MPS Disorders). All MPS disorders are characterized by progressive
multisystem deterioration causing hearing, vision, joint, and cardiovascular dysfunction. These
disorders can be distringuished from each other by clinical, biochemical, and molecular studies.
Sphingolipidoses (Lipid Storage Diseases) – defects in degradation of sphingolipids result in their
gradual accumulation, which leads to multiorgan dysfunction
-Gaucher Disease – Deficiency of lysosomal enzyme glucosylceramidase or B-glucosidase, which
causes an accumulation of glucosylceramide
-spleno- and hepatomegaly, multiorgan failure, and skeletal disease
Type I – Most common and does not involve CNS
Type II – Most severe, often leading to death within 2 years of life
Type III – intermediate between the two forms
-Gaucher’s disease caused by more than 200 different mutations in the GBA gene, which codes
for glucosylceramidase
-Frequency is higher in Ashkenazi jews
-Persons with N370S allele is most common, do not develop neuro disease and are mild
Urea Cycle Disorders – Primary role for the urea cycle is to prevent accumulation of nitrogenous wastes
by incorporating nitrogen into urea, which is excreted by the kidney
-Also responsible for de novo synthesis of arginine
-Deficiencies of Carbamyl Phosphate Synthetase (CPS), Ornithine Transcarbamylase (OTC),
argininosuccinic acid synthetase (ASA), and argininiosuccinase (AS) result in accumulation of urea
precursors such as ammonium and glutamine.
-Patients present with lethargy, coma, and closely resemble Reye Syndrome
-All are autosomal recessive except for OTC, which is X-linked recessive disorder
-OTC is the most prevalent of the urea cycle disorders
Energy Production – energy can be produced from glucose, ketones, amino acids, and fatty acids.
Catabolism requires cleavage to smaller molecules (citric acid cycle or B-oxidation) followed by oxidative
phosphorylation. OXPHOS has 5 multiprotein complexes that transfer electrons to O2. 13 out of the
100 polypeptides in the complexes are encoded by mitochondrial DNA.
-More than 20 disorders are characterized by OXPHOS defects, substitutions, deletions, insertions in the
mitochondrial genome are maternally inherited
-inherited in an autosomal recessive manner
Electron Transfer Flavoprotein (ETF) and ETF-ubiquinone reductase (ETF-QO) are nuclear
encoded proteins through which electrons enter OXPHOS
-defects can cause glutaric academia type II – hypotonia, hepatomegaly, hypoketotic or
nonketotic hypoglycemia, and metabolic academia, often die within months
-Tissues that mainly utilize glycolysis with no OXPHOS result in high pyruvate and lactic acid. Lactate is
absorbed by the liver and converted to glucose, defects in this can produce lactic acidemia
-Deficiency in Pyruvate Dehydrogenase (PDH) Enzyme – may be caused by mutations in any
one of five genes in complex – lactic acidemia, CNS abnormalities, resemble fetal alcohol
syndrome.
Transport Systems – movement of molecules between compartments and across a barrier
requires a macromolecule that connects the two compartments, and can have abnormalities
Cystine - disulfide derivative of amino acid cysteine, abnormal Cystine transport can produce
two disorders:
1.) Cystinuria – most common inherited disorders of metabolism, substantial morbidity
and death, caused by defect of dibasic amino acid transport affecting epithelial cells
of the GI tract and renal tubules
a. Cystine, lysine, arginine, and ornithine are secreted in urine. Since Cystine is
insoluble, can cause renal calculi (kidney stones)
b. Treatment includes dilution of Cystine
i. Type I Cystinuria –missense, nonsense, and deletion of SLC2A1
ii. Type II and III – mutations in SLC7A9
2.) Cystinosis – rare disorder caused by diminished ability to transport cystine across
lysosomal membrane
a. –causes accumulation of cystine crystals in lysosomes, requiring dialysis
and/or kidney transplantation
Heavy Metals – Many enzymes use cofactors to function properly, such as heavy metals can have
defects (Zinc, copper, and iron.)
Copper – absorbed by epithelial cells of small intestine and used by various proteins
Menkes Disease – X-linked recessive disorder characterized by mental retardation, seizures,
hypothermia, twisted and hypopigmented hair, loose skin, arterial rupture, and death.
-copper can be absorbed by the GI epithelium but cannot be exported from these cells
into the blood stream
-gene responsible is ATP7A, encodes adenosine triphosphatase
Wilson Disease – results from excess copper caused by defective excretion of copper into the
biliary tract
-Causes liver disease, cirrhosis, cardiomyopathy
-Autosomal recessive
-Caused by ATP7B, in contrast to ATP7A, expressed predominantly in liver and kidney
Zinc – Acrodermatitis Enteropathica (AE) is caused by defect in absorption of zinc from intestinal tract.
-Experience growth retardation, diarrhea, dysfunction of immune system, and severe dermatitis
(skin inflammation)
-Caused by mutations in SLC39A4, encoding a putative zinc transporter protein expressed on
apical membrane of epithelial cells of small intestine.