Genetics Chapter 7
Biochemical Genetics: Disorders of Metabolism
 Each metabolic process consists of sequence of catalytic steps mediated by enzymes encoded by genes
 Sir Archibald Garrod – recognized variants of metabolism and studied alkaptonuria (AKU)
 AKU – rare disorder in which homogentisic acid (HGA), an intermediate metabolite in phenylalanine and tyrosine
metabolism, is excreted in large quantities in urine, causing it to darken on standing (black urine disease)
o Oxidation of product of HGA directly deposited in connective tissues, resulting in abnormal
pigmentation and debilitating arthritis
o AKU produced by failure to synthesis homogentisate 1,2-dioxygenase (HGO) – mutations encode
proteins that show no HGO activity when expressed
Variants of Metabolism
 Most inborn errors are rare, but taken together, metabolic disorders account for substanstial percentrage of
morbidity and mortality directly attributable to genetic disease
 Reye syndrome – often fatal acute metabolic encephalopathy diagnosed in many children in the 1970s; some
patients with encephalopathy indistinguishable from Reye syndrome had urea cycle defect that produced
hyperammonemia and death; fatty infiltration of liver and cerebral edema
o Reye syndrome is phenocopy of urea cycle defect
 Supportive care – care that supports elementary functinos of body, such as maintenance of fluid balance,
oxygenation, and blood pressure, but not aimed at treating disease process directly
 Some children who have died from SIDS have been found to have defect of fatty acid metabolism
 Most metabolic disorders inherited in autosomal recessive pattern
 Carrier testing and prenatal diagnosis available for many metabolic disorders
 Testing samples of dried blood for elevated levels of metabolites in newborn period (for PKU and galactosemia)
remains most commonly used population-based screening test for metabolic disorders
o Expanded newborn screening that tests for dozens of different disorders by checking for presence of
abnormal metabolites in blood becoming increasingly more common
 Metabolic disorders classified based on pathological effects of pathway blocked (absence of end product,
accumulation of substrate), different functional classes of proteins (receptors, hormones), associated cofactors
(metals, vitamins), and pathways affected (glycolysis, citric acid cycle)
o Classification that most completely integrates knowledge of cell biology, physiology, and pathology with
metabolic disorders categorizes defects of metabolism by types of processes disturbed
Diagnosis of a Metabolic Disorder
 During gestation, maternal-placental unit usually provides essential nutrients and prevents accumulation of toxic
substrates, so fetus infrequently symptomatic
o After birth, people with metabolic disorders can present at ages ranging from first 24 hrs to adulthood
o Onset of symptoms can be gradual or rapid
 For most metabolic disorders, presymptomatic period and onset of symptoms lie somewhere between extremes
Defects of Metabolic Processes
 Biomolecules can be categorized into nucleic acids, proteins, carbohydrates, and lipids
o Major metabolic pathways that metabolize above are glycolysis, citric acid cycle, pentose phosphate
shunt, gluconeogenesis, glycogen and fatty acid synthesis and storage, degradative pathways, energy
production, and transport systems
Carbohydrate Metabolism Defects
 Carbohydrates are most abundant organic substance on earth; function as substrates for energy production and
storage, as intermediates of metabolic pathways, and as structural framework of DNA and RNA; galactose and
fructose converted to glucose before glycolysis; failure to effectively use galactose and fructose accounts for
majority of inborn errors in human carbohydrate metabolism
 Galactosemia – most common monogenic disorder of carbohydrate metabolism (transferase deficiency
galactosemia or classic galactosemia); most commonly caused by mutations in gene encoding GAL-1-P uridyl
transferase (about 70% of galactosemia-causing alleles in people of Western European origin have single
missense mutation in exon 6)
o


Patients cannot convert galactose to glucose, so galactose alternatively metabolized to galactitol and
galactonate
o Typically manifests in newborn period with poor sucking, failure to thrive, and jaundice
o If left untreated, sepsis, hyperammoneia, and shock leading to death usually follow
o Cataracts found in 10% of infants
o Newborn screening for galactosemia widespread, and patients now often identified before they begin to
develop symptoms
o Treatment is mostly eliminating dietary galactose
o Long-term disabilities include poor growth, developmental delay, mental retardation, and ovarian
failure – caused by endogenous production of galactose; patients treated early in life have less
prominent symptoms
o Can be caused by mutations in genes encoding galactokinase or uridine diphosphate galactose-4epimerase (UDP-galactose-4-epimerase)
 Deficiency of galactokinase associated with formation of cataracts but does not cause growth
failure, mental retardation, or hepatic disease; dietary restriction of galactose
 Deficiency of UDP-galactose-4-epimerase can be limited to RBCs and leukocytes, causing no ill
effects, or can be systemic and produce symptoms similar to those of classic galactosemia;
treatment aimed at reducing dietary galactose, but not as severely as in patients with classic
galactosemia, because some galactose must be provided to produce UDP-galactose for synthesis
of some complex carbohydrates
Fructose – 3 autosomal recessive defects described
o Most common caused by mutations in gene encoding hepatic fructokinase (catalyzes first step in
metabolism of dietary fructose, conversion to fructose-1-phosphate); inactivation of hepatic
fructokinase results in asymptomatic fructosuria (fructose in urine)
o Hereditary fructose intolerance (HFI) – results in poor feeding, failure to thrive, hepatic and renal
insufficiency, and death; caused by deficiency of fructose 1,6-bisphosphate aldolase in liver, kidney
cortex, and small intestine
 Patients asymptomatic unless they ingest fructose or sucrose (sugar composed of fructose and
glucose)
 Infants who are breast-fed become symptomatic after weaning, when fruits and vegetables
added to diet
 Affected infants may survive into childhood because they avoid foods they consider noxious and
thus self-limit intake of fructose
 Differences in geographic distribution of mutant alleles have been found
o Deficiency of hepatic fructose 1,6-bisphosphatase (FBPase) causes impaired gluconeogenesis,
hypoglycemia, and severe metabolic acidemia; affected infants commonly presented for treatment
shortly after birth, although cases diagnosed later in childhood have been reported
 If patients adequately supported beyond childhood, growth and development normal
 Handful of mutations found in gene encoding FBPase, some of which encode mutant proteins
that are inactive
Abnormalities of glucose metabolism most common errors of carbohydrate metabolism; causes are
heterogeneous and include both environmental and genetic factors
o Type 1 DM (T1DM) – associated with reduced or absent levels of plasma insulin and usually manifests in
childhood
o T2DM – characterized by insulin resistance and, most commonly, is adult onset
o Maturity-onset diabetes of the young (MODY)
o Mutations in insulin receptor associated with disorder characterized by insulin resistance and acanthosis
nigricans (hypertrophic skin with corrugated appearance); can decrease number of insulin receptors on
cell surface or can decrease insulin-binding activity level or insulin-stimulated tyrosine kinase activity
level
o Mutations in mitochondrial DNA and genes encoding insulin and glucokinase associated with
hyperglycemic disorders

Ability to metabolize lactose (sugar composed of glucose and galactose) depends in part on activity of intestinal
brush-border enzyme (lactase-phlorizin hydrolase or LPH); autosomal recessive trait to be able to digest lactose
o Lactase nonpersistence (lactose intolerance) common in most tropical and subtropical countries
o Can experience nausea, bloating, and diarrhea after ingesting lactose
o LPH encoded by lactase gene (LCT) on chromosome 2
o In European populations, adult LPH expression regulated by polymorphism located in upstream gene
(minichromosome maintenance 6 or MCM6) – not in African populations that drink milk
o African lactose tolerance is from polymorphisms that increase transcription of LCT
o Mutations that abolish lactase activity altogether cause congenital lactase deficiency and produce
severe diarrhea and malnutrition in infancy (very rare)
 Defects of each of proteins involved in glycogen metabolism have been identified, causing different forms of
glycogen storage disorders and are classified numerically according to chronological order in which enzymatic
basis was described
o 2 organs most severely affected by glycogen storage disorders are liver and skeletal muscle
o Glycogen storage disorders that affect liver typically cause hepatomegaly and hypoglycemia
o Glycogen storage disorders that affect skeletal muscle cause exercise intolerance, progressive weakness,
and cramping
o Pompe disease can also affect cardiac muscle, causing cardiomyopathy and early death
o Treatment of some glycogen storage disorders by enzyme replacement can improve, and in some cases
prevent, symptoms and therefore preserve function and prevent early death
Type
Defect in
Major Affected Tissues
Ia (Von Gierke)
Glucose-6-phosphate
Liver, kidney, intestine
Ib
Microsomal glucose-6-phosphate
Liver, kidney, intestine, neutrophils
transport
II (Pompe)
Lysosomal acid β-glucosidase
Muscle, heart
IIIa (Cori)
Glycogen debranching enzyme
Liver, muscle
IIIb
Glycogen debranching enzyme
Liver
IV (Anderson)
Branching enzyme
Liver, muscle
V (McArdle)
Muscle phosphorylase
Muscle
VI (Hers)
Liver phosphorylase
Liver
VII (Tarui)
Muscle phosphofructokinase
Muscle
Amino Acid Metabolism
 Phenylalanine – defects in metabolism cause hyperphenylalaninemias caused by mutations in genes that encode
components of phenylalanine hydroxylation pathway
o Elevated levels of plasma phenylalanine disrupt essential cellular processes in brain such as myelination
and protein synthesis, eventually producing severe mental retardation
o Most cases of hyperphenylalaninemia caused by mutations of gene that encodes phenylalanine
hydroxylase (PAH), resulting in classic phenylketonuria (PKU)
o Less commonly, hyperphenylalaninemia caused by defects in synthesis of tetrahydrobiopterin (cofactor
necessary for hydroxylation of phenylalanine) or by deficiency of dihydropteridine reductase
o Treatment of most hyperphenylalaninemias aimed at restoring normal blood phenylalanine levels by
restricting dietary intake of phenylalanine levels by restricting dietary intake of phenylalanine-containing
foods; phenylalanine is an essential amino acid, and adequate supplies necessary for normal growth and
development, so fine balance must be maintained between providing enough protein and phenylalanine
for normal growth and preventing serum phenylalanine level from rising too high
o Hyperphenylalaninemia in pregnant women causes elevated phenylalanine levels in fetus, causing poor
growth, birth defects, microcephaly, and mental retardation in fetus (even if fetus normal genotype)
 Tyrosine – starting point of synthetic pathways leading to catecholamines, thyroid hormones, and melanin
pigments; incorporated into many proteins
o Hereditary tyrosinemia type 1 (HT1) – most common metabolic defect; caused by deficiency of
fumarylacetoacetate hydrolase (FAH), which catalyzes last step in tyrosine catabolism
 Accumulation of FAH’s substrate (fumarylacetoacetate) and its precursor (maleylacetoacetate)
mutagenic and toxic to liver

Characterized by dysfunction of renal tubules, acute episodes of peripheral neuropathy,
progressive liver disease leading to cirrhosis, and high risk for developing liver cancer
 Management includes supportive care, dietary restriction of phenylalanine and tyrosine, and
administration of NTBC or nitisinone (inhibitor of enzyme upstream of FAH
 Use of NTBC combined with low tyrosine diet has produced marked improvement in children
with HT1
 Liver transplantation can be curative but is typically reserved for people who fail to respond to
NTBC or who develop malignancy
o Tyrosemia type 2 (oculocutaneous tyrosinemia) – caused by deficiency of tyrosine aminotransferase;
characterized by corneal erosions, thickening of skin on palms and soles, and variable mental
retardation
o Tyrosinemia type 3 associated with reduced activity of 4-hydroxyphenylpyruvate dioxygenase and
neurological dysfunction
 Branched-chain amino acids (BCAAs) – valine, leucine, and isoleucine; can be used as source of energy through
oxidative pathway that uses α-ketoacid as an intermediate; decarboxylation of α-ketoacids mediated by enzyme
complex branched-chain α-ketoacid dehydrogenase (BCKAD)
o BCKAD complex composed of 4 catalytic components and 2 regulatory enzymes, coded by 6 genes
o Deficiency of any one of above components produces maple syrup urine disease (MSUD) (called that
because urine of affected persons has odor of maple syrup)
o Untreated patients with MSUD accumulate BCAAs and their associated ketoacids, leading to progressive
neurodegeneration and death in first few months of life
o Treatment consists of dietary restriction of BCAAs to minimum required for normal growth
o Despite treatment, episodic deterioration common and supportive care required during crises
o Therapy with thiamine (cofactor of BCKAD) used to treat patients
Dietary Management of Inborn Errors of Metabolism
 Most important component of therapy for many inborn errors of metabolism is manipulation of diet – includes
avoiding substrates they cannot metabolize (carbohydrates, fats, amino acids, etc.), avoidance of fasting,
replacement of deficient cofactors, or using alternative pathways of catabolism to eliminate toxic substances
 Imperative to provide infants with diets that provide adequate calories and nutrients for normal growth and
development
 Newborns with PKU cannot be breast fed because breast milk contains too much phenylalanine to be used as
only source of nutrients, so they are placed on expensive low-phenylalanine formula only available by
prescription; small quantities of breast milk can be mixed with formula, although breast milk must be pumped
and carefully titrated to avoid giving infant too much phenylalanine
o Serum phenylalanine levels measured frequently and adjustments made to diet to compensate
o As child with PKU grows older, low-protein food substitutes introduced to supplement formula
o Anything with aspartame must have warning for people with PKU
 Dietary restrictions can be difficult for socializing and being “normal”
Lipid Metabolism
 Elevated serum lipid levels (hyperlipidemia) common and result from defective lipid transport mechansims
 Errors in metabolism of fatty acids (hydrocarbon chains with terminal carboxylate group) much less common
 During fasting and prolonged aerobic exercise, fatty acids mobilized from adipose tissue and become major
substrate for energy production in liver, skeletal muscle, and cardiac muscle
o Major steps include uptake and activation of fatty acids by cells, transport across outer and inner
mitochondrial membranes, and entry into β-oxidation spiral in mitochondrial matrix
o Defects of fatty acid oxidation (FAO) most common
 Most common inborn error of fatty acid metabolism results from deficiency of medium-chain acyl-coenzyme A
dehydrogenase (MCAD); MCAD deficiency characterized by episodic hypoglycemia, often provoked by fasting
o Commonly, child with MCAD deficiency presents with vomiting and lethargy after period of diminished
oral intake due to minor illness
o Fasting results in accumulation of fatty acid intermediates, failure to produce ketones in sufficient
quantities to meet tissue demands, and exhaustion of glucose supplies
o Cerebral edema and encephalopathy result from effects of fatty acid intermediates in CNS
o
o
Death often follows unless usable energy source such as glucose provided promptly
Treatment consists of avoidance of fasting, ensuring adequate source of calories, and providing
supportive care during periods of nutritional stress
o Most cases are those of NW European origin and have an A-to-G missense mutation that results in
substation of glutamate for lysine (can be caused by substitution, insertion, and deletion mutations, but
far less common)
o Testing for MCAD has been added to some NBSs in U.S.
 Long-chain acyl-CoA fatty acid metabolism – first step controlled by long-chain acyl-CoA dehydrogenase (LCAD)
o Next step catalyzed by enzymes part of enzyme complex called mitochondrial trifunctional protein (TFP)
 One of enzymes of TFP is long-chain L-3-hydroxylacyl-CoA dehydrogenase (LCHAD)
 LCHAD deficiency one of most severe of FAO disorders – first cases reported manifested with severe liver
disease ranging from fulminant neonatal liver failure to disease ranging from fulminant neonatal liver failure to
chronic, progressive destruction of liver
o Over last 10 years, phenotype expanded to include cardiomyopathy, skeletal myopathy, retinal disease,
peripheral neuropathy, and sudden death
o Women pregnant with fetus with LCHAD deficiency developed severe liver disease (acute fatty liver of
pregnancy (AFLP)) and HELLP syndrome (hemolysis, elevated liver function tests, low platelets)
 Failure of fetus to metabolize free fatty acids results in accumulation of abnormal fatty acid
metabolites in maternal liver and placenta
 Accumulation in placenta might cause intrauterine growth retardation and increase probability
of preterm delivery, both common in children with LCHAD deficiency
 Elevated levels of plasma cholesterol associated with various conditions (atherosclerotic heart disease)
o Substantially reduced levels of cholesterol can adversely affect growth and development
o Final step of cholesterol biosynthesis catalyzed by Δ7-sterol reductase (DHCR7)
o Smith-Lemli-Opitz (SLO) syndrome have reduced levels of cholesterol and increased levels of 7dehydrocholesterol (precursor of DHCR7)
 Characterized by various congenital anomalies of brain, heart, genitalia, and hands
 Caused by mutations in DHCR7 gene; most of mutations are missense mutations that result in
substitutions of highly conserved residue of protein
 Carrier frequency is higher than would be expected of rate of SLO babies, so some SLO babies
might be miscarriages or might be undetected in some mildly affected patients
 Supplementing diet of SLO children with cholesterol can ameliorate growth and feeding
problems
Steroid Hormones
 Cholesterol is precursor for steroid hormones; actions of steroid hormones typically mediated by binding to
intracellular receptor
 Congenital adrenal hyperplasia (CAH) – group of autosomal recessive disorders of cortisol biosynthesis
o 95% of cases caused by mutations in CYP21A2 (gene that encodes 21-hydroxylase)
o Characterized by cortisol deficiency, variable deficiency of aldosterone, and excess of androgens
o Clinical severity depends on extent of residual 21-hydroxylase activity
o CAH most common cause of ambiguous genitalia in 46,XX infants
o Boys with CAH have normal genitalia, so age of diagnosis depends on severity of aldosterone deficiency
 Most boys have salt-losing form so present between 7-14 days in adrenal crisis manifested by
weight loss, lethargy, dehydration, hyponatremia (decreased Na+), and hyperkalemia
o If CAH left untreated, death soon follows
o Adrenal crisis less common in girls because ambiguous genitalia typically leads to early diagnosis
o Boys who do not have salt-losing form present at 2-4 years of age with premature virilization
o Less severe cases present later with premature pubertal development, hirsutism (women growing hair
in weird places for women), amenorrhea or oligomenorrhea, polycystic ovaries, or acne
o Treatment consists of replacing cortisol, suppressing adrenal androgen secretion, and providing
mineralocorticoids to return electrolyte concentrations to normal
o In pregnancies in which fetus at risk for classic CAH, steroids administered to mother to suppress fetal
overproduction of androgens and reduce incidence of ambiguous genitalia in affected female infants
o
o
CYP21A2 located on chromosome 6p21 in major histocompatibility complex (MHC)
About 90% of mutant CYP21A2 alleles caused by gene conversion (2 different DNA segments recombine
in such a way that one segment altered to become identical to other) in which deleterious mutations
transferred to CYP1A2
Steroid Hormone Receptors
 Defects of most steroid hormone receptors rare (defects of estrogen receptor found in people that failed
epiphyseal closure results in tall stature or mutations in gene that encodes glucocorticoid receptor can produce
hereditary resistance to actions of cortisol)
 Mutations in X-linked gene that encodes androgen receptor (AR) relatively common; mutations commonly result
in complete or partial androgen insensitivity syndromes (CAIS or PAIS) in 46, XY persons
o CAIS formerly called testicular feminization syndrome – characterized by typical female external
genitalia at birth, absent or rudimentary müllerian structures (fallopian tubes, uterus, etc.), short vaginal
vault, inguinal or labial testis, and reduced or absent secondary sexual characteristics
o PAIS – have ambiguous external genitalia, varied positioning of testes, absent or prestn secondary sexual
characteristics – nearly all affected persons are infertile
o CAIS and PAIS transmitted in X-linked recessive pattern
o More than 95% of persons with CAIS have mutations in AR gene, most of which impair androgen binding
or binding of androgen receptor to DNA
 Expansion of polyglutamine tract in androgen receptor causes spinal bulbar muscular atrophy
Peroxisomal Enzymes
 Disorders of peroxisomes divided into peroxisome biogenesis disorders (PBDs) and single peroxisomal enzyme
deficiencies (PEDs)
 PBDs – Zellweger syndrome, neonatal adrenoleukodystrophy, infantile Refsum disease, and rhizomelic
chondrodysplasia punctata type 1; caused by mutations in genes that encode peroxins (proteins necessary for
peroxisome biogenesis and for importing proteins of perosixomal matrix and membrane
o Zellweger syndrome – manifests in newborns as severe hypotonia, progressive disease of white matter
of brain, distinctive facial appearance, and typically death in infancy
o Neonatal adrenoleukodystrophy – similar to Zellweger but less severe symptoms along with seizures
o Infantile Refsum disease – less severe than Zellweger and neonatal adrenoleukodystrophy, but affected
children have developmental delay, learning disabilities, hearing loss, and visual impairment
 PEDs – persons with enzyme defects have widely disparate clinical characteristics depending on which
peroxisomal function primarily impaired
o Adrenoleukodystrophy (ALD) – X-linked; involves faulty β-oxidation of very long chain fatty acids
(VLCFAs); subdivided into several disorders depending in part on age of onset
 Childhood cerebral ALD (CCALD) and adrenomyeloneuropathy (AMN) – most common subsets
of ALD
 CCALD typically manifests between age3-10 years with progressive cognitive and behavioral
deterioration that leads to profound disability
o AMN causes similar but less-severe neurological symptoms than CCALD but has much later age of onset
and slower rate of progression; 40-50% of women who are heterozygous for ALD develop AMN-like
symptoms
Degradative Pathways
 Byproducts of energy production, substrate converstions, and anabolism need to be processed and eliminated
 Errors in degradative pathways result in accumulation of metabolites that would otherwise have been recycled
or eliminated
Lysosomal Storage Disorders
 Prototypical inborn errors of metabolism; disease results from accumulation of substrate
 Accumulation (storage) of undegraded molecules results in cell, tissue, and organ dysfunction
 Most caused by enzyme deficiencies, although some caused by inability to activate enzyme or transport enzyme
to subcellular compartment where it can function properly
 Mucopolysaccharidoses (MPS disorders) heterogeneous group of conditions caused by reduced ability to
degrade one or more GAGs
o GAGs are degradation products of proteoglycans found in ECM
o
o
o
o

10 different enzyme deficiencies cause 6 different MPS disorders, which share clinical features
Prenatal testing after amniocentesis or chorionic villus sampling possible
Except for X-linked recessive Hunter syndrome, all MPS disorders inherited autosomal recessive
All MPS disorders characterized by chronic and progressive multisystem deterioration, which causes
hearing, vision, joint, and cardiovascular dysfunction
o Hurler, severe Hunter, and Sanfilippo syndromes characterized by mental retardation
o MPS I – deficiency of iduronidase; produces Hurler (severe), Hurler-Scheie (moderate), and Scheie (mild)
syndromes; cannot be distinguished from each other by measuring enzyme activity, so MPS I phenotype
assigned on basis of clinical criteria
o Hunter syndrome (MPS II) – caused by deficiency of iduronate sulfatase; categorized into mild and
severe phenotypes based on clinical assessment; onset of disease occurs between 2-4 years of age
 Affected children develop coarse facial features, short stature, skeletal deformities, joint
stiffness, and mental retardation
 20% of all identified mutations are large deletions, and most of remainder are missense and
nonsense mutations
o Symptomatic treatment has been standard care for MPS diseases
 Restoration of endogenous enzyme activity accomplished by either bone marrow
transplantation (BMT) or enzyme replacement with recombinant enzyme
 BMT mainstay of treatment for persons with Hurler syndrome and has shown to improve coarse
facial features, upper airway obstruction, and cardiac disease; mitigates neurological
deterioration
 BMT less successful for other MPS disorders (BMT itself can be associated with morbidity and
mortality)
 Enzyme replacement for Hurler syndrome improves hepatosplenomegaly and respiratory
disease
Defects in degradation of sphingolipids (sphingolipidoses) result in gradual accumulation, which leads to
multiorgan dysfunction – lipid storage diseases
o Gaucher disease – deficiency of lysosomal enzyme glucosylceramidase (glucocerebrosidase or βglucosidase); causes accumulation of glucosylceramide
 Most common metabolic storage disorder; characterized by visceromegaly (enlarged visceral
organs), multiorgan failure, and debilitating skeletal disease
 Type 1 – most common and does not involve CNS
 Type 2 – most severe, often leading to death in first 2 years of life
 Type 3 – intermediate between types 1 and 2
 Extent to which specific organs affected by Gaucher disease determines person’s clinical course
 Splenomegaly, hepatomegaly, and pulmonary disease shared among all three types
 Splenomegaly associated with anemia, leukopenia, and thrombocytopenia
 Splenic infarction can cause abdominal pain
 Hepatomegaly can cause liver dysfunction (usually not cirrhosis or hepatic failure)
 Caused by more than 200 different mutations in GBA (gene that encodes glucosylceramidase)
 Frequency of type 1 high in Ashkenazi Jews
 Persons with at least one N370S allele (one of most common alleles) do not develop
primary neurological disease and tend to have milder outcome in general
 Enzyme replacement can reverse symtpoms resulting from spleen and liver involvement
 Some persons with severe involvement, particularly chronic neurological symptoms, benefit
from BMT
o Enzymes that function in lysosomes targeted and transported into lysosomal space by specific pathways
 Targeting mediated by receptors that bind mannose-6-phosphate recognition markers attached
to enzyme (posttranslational modification)
o I-cell disease (mucolipidosis II) – deficiency in mannose-6-phosphate recognition markers; cytoplasm of
fibroblasts from affected persons contains inclusions of partially degraded oligosaccharides, lipids, and
GAGs; newly synthesized lysosomal enzymes secreted into extracellular space instead of being correctly
targeted to lysosomes

Patients have coarse facial features, skeletal abnormalities, hepatomegaly, corneal opacities,
mental retardation, and early death
No specific treatment

Urea Cycle Disorders
 Primary role of urea cycle is to prevent accumulation of nitrogenous wastes by incorporating nitrogen into urea
o Responsible for de novo synthesis of arginine
 Deficiencies of carbamyl phosphate synthetase (CPS), ornithine transcarbamylase (OTC), argininosuccinic acid
synthetase (ASA), and argininosuccinase (AS) result in accumulation of urea precursors such as ammonium and
glutamine
o Clinical presentations of persons with above diseases similar, producing progressive lethargy and coma
and closely resembling clinical presentation of Reye syndrome
o Affected persons present in neonatal period (or later); wide interfamilial variability in severity
o Differential diagnoses made by biochemical testing
o All of above (except OTC deficiency) inherited by autosomal recessive
o OTC deficiency is X-linked recessive; women can be symptomatic carriers depending in part on fraction
of hepatocytes in which normal allele is inactivated
o Goal of therapy is to provide sufficient calories and protein for normal growth and development while
preventing hyperammonemia
 Arginase deficiency – causes progressive spastic quadriplegia and mental retardation
 OTC deficiency – most prevalent of urea cycle disorders; variety of exon deletions and missense mutations
(some mutations that affect RNA processing)
Energy Production
 Catabolism of glucose, ketones, amino acids, and fatty acids requires stepwise cleavage into smaller molecules
(via processes such as citric acid cycle or β-oxidation), followed by passage of H+ through oxidative
phosphorylation (OXPHOS) system
 OXPHOS system consists of 5 multiprotein complexes that transfer electrons to O2; complexes located in inner
mitochondrial membrane
o 13 of 100 polypeptides needed encoded by mitochondrial genome, and rest encoded by nuclear genes
o Assembly and function of OXPHOS system requires ongoing signaling and transport between nucleus
and mitochondrion
o OXPHOS regulated by O2 supply, hormone levels, and metabolite-induced transcription control
o 20 disorders of OXPHOS defects in mitochondrial genome (maternally inherited)
o Nuclear genes can cause mtDNA deletions or depletion of mtDNA (inherited in autosomal recessive)
o Electron transfer flavoprotein (ETF) and ETF-ubiquinone oxidoreductase (ETF-QO) – nuclear-encoded
proteins through which electrons can enter OXPHOS system
 Inherited defects in either proteins cause glutaric acidemia type II, characterized by hypotonia,
hepatomegaly, hypoketotic or nonketotic hypoglycemia, and metabolic acidemia
 Most affected persons present in neonatal period or shortly thereafter
 Despite aggressive therapy, affected children often die within months
 In most tissues, metabolism of pyruvate proceeds through pyruvate dehydrogenase, citric acid cycle, and
OXPHOS system; but in tissues with high glycolytic activity and reduced or absent OXPHOS capacity, end
products of metabolism are pyruvate and lactic acid
o Lactate produced by reduction of pyruvate, and bulk of circulating lactate usually absorbed by liver and
converted to glucose
o Defects in pathway of pyruvate metabolism produce lactic acidemia
o Pyruvate dehydrogenase (PDH) complex deficiency – most common of lactic acidemia disorders
 May be caused by mutations in genes encoding one of five components of PDH complex (E1, E2,
E3, X-lipoate, or PDH phosphatase)
 Disorders – varying degrees of lactic acidemia, developmental delay, and abnormalities of CNS
 Could be alcohol related
Transport Systems
 Abnormalities of macromolecule transport systems have multiple effects, depending on whether altered barrier
integrity or accumulation of substrate has greater impact on normal physiology



Cystine – disulfide derivative of amino acid cysteine; abnormal cystine transport produces cystinuria and
cystinosis; both inherited in autosomal recessive fashion
o Cystinuria – abnormal cystine transport between cells and extracellular environment; one of most
common inherited disorders of metabolism
 Produces substantial morbidity, but early death uncommon
 Caused by defect of dibasic amino acid transport affecting epithelial cells of GI tract and renal
tubules, so cystine, lysine, arginine, and ornithine excreted in urine in quantities high quantities
 Cystine is most insoluble of amino acids, so elevated urinary cystine predisposes to formation of
renal calculi (kidney stones)
 Complications of chronic nephrolithiasis (presence of kidney stones) include infection,
hypertension, and renal failure
 Treatment consists of rendering cystine more soluble by administering pharmacological
amounts of water (4-6 L/day), alkalinizing urine, and using chelating agents such as penicillamine
 Type I cystinuria – associated with missense, nonsense, and deletion mutations in soluble carrier
family 3, member 1 amino acid transporter (SLC3A1) gene
 Types II and III caused by mutations in SLC7A9 gene
 Both SLC3A1 and SLC7A9 encode heavy and light subunits of amino acid transporter b0,+ located
on brush-border PM of epithelial cells in proximal tubules of kidney
o Cystinosis – rare disorder caused by diminished ability to transport cystine across lysosomal membrane,
producing accumulation of cystine crystals in lysosomes of most tissues
 Affected persons normal at birth but develop electrolyte disturbances, corneal crystals, rickets,
and poor growth by age 1 year
 Renal glomerular damage severe enough to necessitate dialysis or transplantation in first
decade of life
 Transplanted kidneys function normally, but chronic complications such as DM, pancreatic
insufficiency, hypogonadism, myopathy (muscle weakness), and blindness occur
 Cysteine-depleting agents such as cysteamine successful in slowing renal deterioration and
improving growth
 Gene encoding integral lysosomal membrane protein mutated in patients with cystinosis
Cofactors commonly trace elements such as ions of heavy metals
o Zinc ion acts as cofactor in carbonic anhydrase, placing OH- next to CO2 to facilitate formation of HCO3o Abnormalities in proteins that transport and store heavy metals cause progressive dysfunction of
various organs, often leading to premature death if untreated
Copper – absorbed by epithelial cells of small intestine and subsequently distributed by various chaperone
proteins that shuttle it to different places in cell; som transported to liver to be incorporated into proteins that
distribute it to other parts of body; excess copper in hepatocytes secreted in bile and excreted from body
o Menkes disease (MND) – X-linked recessive disorder; characterized by mental retardation, seizures,
hypothermia, twisted and hypopigmented hair (pili torti), loose skin, arterial rupture, and death in early
childhood
 Copper can be absorbed by GI epithelium but can’t be exported effectively from these cells into
blood stream, so when intestinal cells slough, trapped copper is excreted
 Treatment includes restoring copper levels in body to normal (subcutaneous injections)
 None of abnormalities completely corrected or prevented, even with Cu injection
 Gene responsible for MND (ATP7A) encodes ATP with 6 tandem copies of heavy-metal-binding
sequence
 ATP7A expressed in variety of tissues, but not liver; usually localized to Golgi network in
cell, where it supplies copper to various enzymes
 When Cu levels in epithelial cell of small intestine exceed certain concentration, ATP7A
redistributes to PM and pumps Cu into blood stream (mediates efflux of Cu into blood)
 ATP7A important transporter of Cu across blood-brain barrier
 15-20% of mutations are large deletions (in MND patients)
o Copper required cofactor in tyrosinase, lysyl oxidase, superoxide dismutase, cytochrome c oxidase, and
dopamine β-hydroxylase – explains clinical features of MND

Lysyl oxidase required for cross-linking collagen and elastin, so ineffectual cross-linking leads to
weakened vascular walls and laxity of skin
o Wilson disease (WND) – results from excess copper caused by defective excretion of copper into biliary
tract; causes progressive liver disease and neurological abnormalities
 Autosomal recessive disorder
 Patients usually present with acute or chronic liver disease in childhood; if left untreated, liver
disease progressive, resulting in liver insufficiency, cirrhosis, and failure
 Adults commonly develop neurological symptoms such as dysarthria (inability to correctly
articular words) and diminished coordination
 Accumulation of copper can cause arthropathy (inflammation of joints), cardiomyopathy, kidney
damage, and hypoparathyroidism
 Deposition of copper in Descemet’s membrane (at limbus of cornea) produces characteristic
finding in eye (Kayser-Fleischer ring), which is observed in 95% of all WND patients and 100% of
WND patients with neurological symptoms
 Decreased serum ceruloplasmin, increased serum nonceruloplasmin copper, increased urinary
copper excretion, and increased deposition of copper in liver
 Most sensitive indicator is reduced incorporation of isotopes of Cu into cells cultured in vitro
 Treatment consists of reducing load of accumulated copper through use of chelating agents
such as penicillamine and ammonium tetrathiomolybdate
 Gene responsible located on chromosome 13 (ATP7B); expressed predominantly in liver and
kidney; ATP7B moves between Golgi network and either endosomes or PM of hepatocytes and
controls excretion of Cu into biliary tree
 Aids in incorporation of Cu into ceruloplasmin
 Single missense mutation accounts for about 40% of disease-causing alleles in N
Europeans
o Ehler-Danlos syndrome type IX (X-linked cutis laxa or occipital horn syndrome) – caused by mutations of
splice sites in ATP7A; characterized by mild mental retardation, bladder and ureteric diverticula (cul-desac hermiations through wall), skin and joint laxity, and ossified occipital bone horns
 Mutations permit production of small amount of normal protein and prevent development of
severe neurological symptoms
 Zinc – acrodermatitis enteropathica (AE) caused by defect in absorption of zinc from intestinal tract
o Patients experience growth retardation, diarrhea, dysfunction of immune system, and severe dermatitis
around mouth, genitals, buttocks, and on limbs
o Children usually present after weaning, and AE can be fatal if not treated with high doses of
supplemental zinc (curative)
o Caused by mutations in SLC39A4, which encodes putative zinc-transporter protein expressed on apical
membrane of epithelial cell of small intestine
Hereditary Hemochromatosis
 Hemochromatosis – all disorders characterized by excessive iron storage
 Most common form of hereditary hemochromatosis (HH) is autosomal recessive disorder of iron metabolism in
which excessive iron absorbed in small intestine and accumulates in variety of organs such as liver, kidney,
heart, joints, and pancreas; one of most common genetic disorders observed in people of European ancestry (1
in 8 is carrier of N Europeans)
o Most common symptom is fatigue, but other symtpoms can include joint pain, diminished libido,
diabetes, increased skin pigmentation, cardiomyopathy, liver enlargement, and cirrhosis
o Abnormal serum iron parameters can identify most men at risk for iron overload, but HH not detected in
many premenopausal women
o Most sensitive diagnostic test is liver biopsy accompanied by histochemical staining for hemosiderin
o Increased frequency of human leukocyte antigen HLA-A3 allele in HH patients indicates HH gene might
be near MHC on chromosome 6p
o HH gene is widely expressed HLA class I-like gene (HFE); gene product is cell-surface protein that binds
to transferrin receptor, overlapping binding site for transferrin and inhibiting transferrin-mediated iron
uptake (does not directly affect iron transport from small intestine, but involved in cell’s ability to sense
o
o
o
o
o
o
iron levels) – function disrupted in HFE mutations, resulting in excessive iron absorption from small
intestine and iron overload
Single missense mutation that results in substitution of tyrosine for cysteine in β2-microglubulin-binding
domain accounts for 85% of all HH-causing mutations
Treatment consists of reducing accumulated iron in body by serial phlebotomy or use of iron-chelating
agent (deferoxamine)
Return to normal level of iron may take a few years depending on iron storage amounts
Iron reduction prevents further liver damage, cures cardiomyopathy, returns skin pigmentation to
normal, and might improve diabetes
Penetrance of HH depends on person’s age, sex, and whether presence of disease measured by
histological findings such as hepatic fibrosis or clinical symptoms
Most men homozygous for HH-causing mutation do not develop clinical symptoms, and those that do
seldom do before age 40; even smaller fraction of homozygous women develop clinical symptoms (if
they do show up, usually don’t before age 60 because menstruation, gestation, and lactation temper
iron overload)