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breakdown by removing
1,4glucosyl residues from the outer branches of glycogen with
liberation of glucose-1-phosphate.
2.
GSDV is commonly caused by either a nonsense mutation which results in a
normal argi-
nine
→
nonsense
at position 49 (R49X) causing a premature STOP codon (90% of cases in
European and US populations) or a missense mutation which results in a
normal
glycine
→
serine
substitution at position 204 (G204S; 10% of cases in European and US
populations).
3. Prevalence.
The prevalence of GSDV is 1/100,000 births.
4. Clinical features include:
exercise-induced muscle cramps and pain, “second wind” phe-
nomenon with relief of myalgia and fatigue after a few minutes of rest, episodes of myo-
globinuria, increased resting basal serum creatine kinase (CK) activity, onset typically
occurs around 20 to 30 years of age; clumsiness, lethargy, slow movement, and laziness in
preadolescents.
G. Other Glycogen Storage Diseases.
These include: glycogen storage disease type II (GSDII;
Pompe); glycogen storage disease type IIIa (GSDIIIa; Cori); glycogen storage disease type IV
(GSDIV; Andersen); glycogen storage disease type VI (GSDVI; Hers); and glycogen storage
disease type VII (GSDVII; Tarui).
III. METABOLIC GENETIC DISORDERS INVOLVING AMINO
A. Phenylalanine Hydroxylase (PAH) Deficiency (or PKU).
1.
PAH deficiency is an autosomal recessive genetic disorder caused by a mutation in the
PAH gene
on
chromosome 12q23.2
for
phenylalanine hydroxylase
which catalyzes the reac-
tion phenylalanine
→
tyrosine.
2.
PAH deficiency is caused by missense (most common; 62% of cases); small deletion (13%
of cases); RNA splicing (11% of cases); silent (6% cases); nonsense (5% of cases); or inser-
tion (2% of cases) mutations.
3.
PAH deficiency results in an intolerance to the dietary intake of phenylalanine (an essen-
tial amino acid). This produces a variability in metabolic phenotypes including
classic
phenylketonuria (PKU), non-PKU hyperphenylalaninemia
,
and
variant PKU
.
This variability in
metabolic phenotypes is caused primarily by different mutations in the PAH gene that
result in variations in the kinetics of phenylalanine uptake, permeability of the
blood–brain barrier, and protein folding.
4.
Classic PKU is associated with the complete absence of PAH and is the most severe of the
three types of PAH deficiency.
5. Prevalence.
The prevalence of PAH deficiency is 1/10,000 births in the Caucasian popula-
tion and 1/200,000 in the Ashkenazi Jewish population. Since the advent of universal new-
born screening, symptomatic classic PKU is rarely seen.
6. Clinical features of classic PKU include:
no physical signs are apparent in neonates with
PAH deficiency; diagnosis is based on detection of elevated plasma phenylalanine con-
centration (
1,000 umol/L for classic PKU) and normal BH
4
cofactor metabolism; a
dietary phenylalanine tolerance of
500 mg/day; untreated children with classic PKU
show impaired brain development, microcephaly, epilepsy, severe mental retardation,
behavioral problems, depression, anxiety, musty body odor, and skin conditions like
eczema.
B. Hereditary Tyrosinemia Type I (TYRI).
1. TYRI
is an autosomal recessive genetic disorder caused by a mutation in the
FAH gene
on
chromosome 15q23-q25
for
fumarylacetoacetate hydrolase
,
which catalyzes the reaction
fumarylacetoacetic acid
→
fumarate
acetoacetate.
2. TYRI
is caused by either a missense mutation, which results in a
normal proline
S
S
leucine
substitution at position 261 (P261L) or RNA splicing mutations. The P261L mutation
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accounts for 100% of cases in the Ashkenazi Jewish population. The P261L and some RNA
splicing mutations account for 60% of cases in the US population.
3. Prevalence.
The prevalence of TYRI is 1/120,000 births.
4. Clinical features include:
diagnosis is based on detection of elevated plasma succinylace-
tone concentration; elevated plasma tyrosine, methionine, and phenylalanine concentra-
tions; elevated urinary tyrosine metabolite (e.g., hydroxyphenylpyruvate) concentration;
elevated urinary
-aminolevulinic acid; cabbage-like odor; untreated children with HTI
show severe liver dysfunction, renal tubular dysfunction, growth failure, and rickets.
C. Maple Syrup Urine Disease (MSUD).
1.
MSUD is an autosomal recessive genetic disorder cause by
60 different mutations in
either the
BCKDHA gene
on
chromosome 19q13.1-q13.2
for the
E1
subunit of the branched-
chain ketoacid dehydrogenase complex (BCKD),
the
BCKDHB gene
on
chromosome 6q14
for
the
E1ß subunit of BCKD,
or the
DBT gene
on
chromosome 1p31
for the
E2 subunit of BCKD
all
of which catalyze the second step in the degradation of branched-chain amino acids (e.g.,
leucine, isoleucine, and valine).
2.
The BCKD enzyme is an enzyme complex found in the mitochondria.
3. Prevalence.
The prevalence of MSUD is 1/185,000 births.
4. Clinical features include:
untreated children with MSUD show maple syrup odor in ceru-
men 12 to 24 hours after birth, elevated plasma branched-chain amino acid concentra-
tion, ketonuria, irritability, poor feeding by 2 to 3 days of age, deepening encephalopathy
including lethargy, intermittent apnea, opisthotonus, and stereotyped movements like
“fencing” and “bicycling” by 4 to 5 days of age; acute leucine intoxication (leucinosis)
associated with neurological deterioration due to the ability of leucine to interfere with
the transport of other large neutral amino acids across the blood–brain barrier, thereby
reducing the amino acid supply to the brain.
IV. METABOLIC GENETIC DISORDERS INVOLVING LIPID PATHWAYS
A. Medium-Chain Acyl-coenzyme A Dehydrogenase (MCAD) Deficiency.
1.
MCAD deficiency is an autosomal recessive genetic disorder caused by
45 different
mutations in the
ACADM gene
on
chromosome 1p31
for
medium-chain acyl-coenzyme A
dehydrogenase (MCAD)
which catalyzes the initial dehydrogenation of acyl-CoAs with a
fatty acid chain length of 4 to 12 carbon atoms.
2.
The ACADM gene is a nuclear gene that codes for MCAD enzyme, which is active in the
mitochondria and part of the mitochondrial fatty acid ß-oxidation pathway. A defect in
MCAD leads to an accumulation of medium-chain fatty acids, which are further metabo-
lized to glycine-esters, carnitine-esters, and dicarboxylic acids (all of which are detectable
in blood, urine, and bile).
3.
The mitochondrial fatty acid
-oxidation pathway normally fuels hepatic ketogenesis,
which is a major source of energy when hepatic glycogen stores are depleted during pro-
longed fasting or high energy demands.
4.
MCAD deficiency is caused by a missense mutation which results in a
normal lysine
S
S
glutamate
substitution at position 304 (K304E) prevalent in the Northern European popu-
lation.
5. Prevalence.
The prevalence of MCAD is 1/15,700 births in the US population. MCAD is
especially prevalent in Caucasians of Northern European descent.
6. Clinical features include:
hyperketotic hypoglycemia, vomiting, and lethargy triggered by
either a common illness (e.g., viral gastrointestinal or upper respiratory tract infections)
or prolonged fasting (e.g., weaning the infant from nighttime feedings) which may quickly
progress to coma and death; hepatomegaly and acute liver disease; children are normal at
birth and present between 3 and 24 months of age; later presentation into adulthood is
possible.
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B. Smith-Lemli-Opitz (SLO) Syndrome.
1.
SLO syndrome is an autosomal recessive genetic disorder caused by
70 different
mutations in the
DHCR7 gene
on
chromosome 11q12-q13
for
7-dehydrocholesterol reduc-
tase
which catalyzes the last step in cholesterol biosynthesis 7-dehydrocholesterol
→
cholesterol.
2.
SLO syndrome is commonly caused either by a missense mutation which results in a
nor-
mal threonine
→
methionine
substitution at position 93 (T93M), a nonsense mutation
which results in a
normal tryptophan
S
S
nonsense
at position 151 (W151X) causing a pre-
mature STOP codon, or a intron 8 splice acceptor mutation, all of which account for
50%
of all cases.
3. Prevalence.
The prevalence of SLO is 1/20,000 to 40,000 births.
4. Clinical features include:
prenatal and postnatal growth retardation, microcephaly, mod-
erate to severe mental retardation, cleft palate, cardiac defects, underdeveloped external
genitalia and hypospadias in males, postaxial polydactyly, Y-shaped 2 to 3 toe syndactyly,
downslanting palpebral fissures, epicanthal folds, anteverted nares, and micrognathia.
C. Familial Hypercholesterolemia (FH).
1.
FH is an autosomal dominant genetic disorder caused by
400 different mutations in the
LDLR gene
on
chromosome 19p13.1-13.3
for the
low-density l ipoprotein receptor
which binds
LDL and delivers LDL into the cell cytoplasm.
2.
Mutations in the LDLR gene are grouped into 6 classes:
a. Class 1
mutations prevent LDLR synthesis.
b. Class 2
mutations prevent LDLR transport to the cell membrane.
c. Class 3
mutations prevent LDL binding to LDLR.
d. Class 4
mutations prevent LDL internalization into the cell cytoplasm by coated pits.
e. Class 5
mutations prevent LDLR recycling back to the cell membrane after LDL
LDLR
dissociation.
f. Class 6
mutations prevent LDLR targeting to the apical membrane adjacent to the
blood capillaries.
3.
Other genes associated with FH include:
a.
FH is also an autosomal dominant genetic disorder caused by a mutation in the
APOB
gene
on
chromosome 2p23-p24
for
apolipoprotein B-100
which is a component of LDL and
the ligand for LDLR. The prevalence of APOB gene homozygotes is 1/1,000,000 births.
The prevalence of APOB gene heterozygotes is 1/1,000 births in Caucasians of
European descent.
b.
FH is also an autosomal dominant genetic disorder caused by a missense, gain-of-
function mutations in the
PCSK9 gene
on
chromosome 1p32-p34.1
for
proprotein conver-
tase subtilisin/kexin type 9.
The increased PCSK9 protease activity degrades LDLR lead-
ing to hypercholesterolemia. This type of FH is very rare.
c.
The
Tyr142Stop
and
Cys679Stop
nonsense mutations in the
PCSK9 gene
are loss-of-func-
tion mutations. The decreased PCSK9 protease activity has been associated with a 40%
reduction in LDL cholesterol (i.e.,
hypocholesterolemia
) and a 90% reduced risk of coro-
nary artery disease in 2.6% of the African American population.
d.
The
Arg46Leu
mutation in the
PCSK9 gene
is a loss-of-function mutation. The decreased
PCSK9 protease activity has been associated with a 15% reduction in LDL cholesterol
(i.e.,
hypocholesterolemia
) and 50% reduced risk of coronary artery disease in 3.2% of
whites in the US population.
4. Prevalence.
The prevalence of LDLR gene homozygotes is 1/1,000,000 births. The preva-
lence of LDLR gene heterozygotes is 1/500 births. Most cases of hypercholesterolemia and
hyperlipoproteinemia in the general population are of multifactorial origin.
5. Clinical features include:
premature heart disease as a result of atheromas (deposits of
LDL-derived cholesterol in the coronary arteries); xanthomas (cholesterol deposits in the
skin and tendons); arcus lipoides (deposits of cholesterol around the cornea of the eye);
homozygote and heterozygote phenotypes are known; homozygotes develop severe
symptoms early in life and rarely live past 30 years of age; heterozygotes have plasma cho-
lesterol level twice that of normal.
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BRS Genetics
V. METABOLIC GENETIC DISORDERS INVOLVING THE UREA
A.
The urea cycle produces the amino acid arginine (this is the only source of endogenous argi-
nine) and clears waste nitrogen resulting from the metabolism of proteins and dietary intake
(this is the only pathway for waste nitrogen clearance). The waste nitrogen is converted to
ammonia (NH
4
) and transported to the liver.
B.
The severity of these disorders is influenced by the position of the defective enzyme in the
urea cycle pathway and the severity of the enzyme defect (partial activity vs. absent activity).
C.
Because the urea cycle is the only pathway for waste nitrogen clearance, clinical symptoms
develop very rapidly.
D. Prevalence.
The prevalence of urea cycle disorders is 1/30,000 births.
E. Clinical features include:
infants initially appear normal but then rapidly develop hyperam-
monemia, cerebral edema, lethargy, anorexia, hyperventilation or hypoventilation,
hypothermia, seizures, neurologic posturing, and coma; in infants with partial enzyme defi-
ciencies, the symptoms may be delayed for months or years, the symptoms are more subtle,
the hyperammonemia is less severe, and ammonia accumulation can be triggered by illness
or stress throughout life.
F.
Metabolic genetic disorders involving the urea cycle pathway include:
1. Ornithine transcarbamylase (OTC) deficiency.
a.
OTC deficiency is an X-linked recessive genetic disorder caused by a mutation in the
OTC gene
on
chromosome Xp21.1
for
ornithine transcarbamylase
.
b.
OTC deficiency along with CPSI deficiency and NAGS deficiency are the most severe
types of urea cycle disorders. Newborns with OTC deficiency rapidly develop hyperam-
monemia and these children are always at risk for repeated bouts of hyperammone-
mia.
c.
OTC can be distinguished from carbamoylphosphate synthetase (CPSI) deficiency by
elevated levels of
orotic acid
in OTC individuals.
d.
15% of female carriers develop hyperammonemia during their lifetime and many
require chronic medical management.
2. Other urea cycle disorders.
These include: carbamoylphosphate synthetase I (CPSI) defi-
ciency; argininosuccinic acid synthetase (ASS) deficiency (or citrullinemia type I); argini-
nosuccinic acid lyase (ASL) deficiency (or argininosuccinic aciduria); arginase (ARG) defi-
ciency (or hyperargininemia); and N-acetyl glutamate synthetase (NAGS) deficiency.
VI. METABOLIC GENETIC DISORDERS INVOLVING
A. Menkes Disease (MND).
1.
MND is an X-linked recessive genetic disorder caused by various mutations in the
ATP7A
gene
on
chromosome Xq12-q13
for
Copper-Transporting ATPase 1,
which is a P-type ATPase
that transports copper across cell membranes thereby controlling copper homeostasis.
2.
MND is commonly caused by small insertion and deletion mutations (35%), nonsense
mutations (20%); RNA splicing mutations (15%), and missense mutations (8%).
3.
These mutations result in low serum concentration of copper (0 to 60
g/dL vs. 70 to 150
g/dL normal), low serum concentration of ceruloplasmin (30 to 150 mg/dL vs. 200 to 450
mg/dL normal), a decreased intestinal absorption of copper, an accumulation of copper
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in some tissues, and a decreased activity of copper-dependent enzymes (e.g., dopamine
ß-hydroxylase critical for catecholamine synthesis or lysyl oxidase).
4. Prevalence.
The prevalence of MND is 1/1,000,000 births.
5. Clinical features include:
infants initially appear normal up to 2 to 3 months of age but
then develop hypotonia; seizures; failure to thrive; loss of developmental milestones;
changes in hair (short, coarse, twisted, lightly pigmented, “steel wool” appearance); jowly
facial appearance with sagging cheeks; temperature instability; hypoglycemia; urinary
bladder diverticulae; and gastric polyps. Without early treatment with parenteral copper,
MND progresses to severe neurodegeneration and death by 7 months
→
3 years of age.
B. Wilson Disease (WND).
1.
WND is an autosomal recessive genetic disorder caused by
260 mutations in the
ATP7B
gene
on chromosome
13q14.3-q21.1
for
Copper-Transporting ATPase 2,
which is a P type
ATPase expressed mainly in the kidney and liver that plays a key role in incorporating cop-
per into ceruloplasmin and in the release of copper into bile.
2.
WND is commonly caused by either a missense mutation which results in a
normal histi-
dine
S
S
glutamine
substitution at position 1069 (H1069Q), a missense mutation which
results in a
normal arginine
S
S
leucine
substitution at position 778 (R778L), or a
15 base pair
deletion
in the promoter region.
3.
The H1069Q mutation accounts for 45% of cases in the European population. The R778L
mutation accounts for 60% of cases in the Asian population. The 15 base pair deletion
mutation is common in the Sardinian population.
4.
These mutations result in
high hepatic concentration of copper
(
250 g/g dry weight vs.
55 g/g dry weight normal); high urinary excretion of copper (0.6 umol/24 hours); and
damage of various tissues due to excessive accumulation of copper
.
5. Prevalence.
The prevalence of WND is 1/30,000 in most populations. The prevalence is
1/10,000 in Chinese and Japanese populations.
6. Clinical features include:
symptoms occur in individuals from 3 to 50 years of age; recurrent
jaundice; hepatitislike illness; fulminant hepatic failure; tremors; poor coordination; loss
of fine motor control; chorea; masklike facies; rigidity; gait disturbance; depression; neu-
rotic behaviors;
Kayser-Fleischer rings
(deposition of copper in Descemet’s membrane of
the cornea); blue lunulae of the fingernails; and high degree of copper storage in the body.
C. HFE-Associated Hereditary Hemochromatosis (HHH).
1.
HHH is an autosomal recessive genetic disorder caused by
28 different mutations in
the
HFE gene
on
chromosome 6p21.3
for
hereditary hemochromatosis protein
,
which is a cell
surface protein, expressed as a heterodimer with ß
2
-microglobulin, binds the transfer-
rin receptor 1, and reduces cellular iron uptake although the exact mechanism is
unknown.
2.
HHH is most commonly caused by two missense mutations that result in a
normal cys-
teine
S
S
tyrosine
substitution at position 282 (C282Y), resulting in decreased cell surface
expression or that result in a
normal histidine
S
S
asparagine
substitution at position 63
(H63D), resulting in pH changes that affects binding to the transferrin receptor 1.
3.
≈
87% of HHH affected individuals in the European population are homozygous for the
C282Y mutation or are
compound heterozygous
(i.e., two different mutations at the same
gene locus) for the C282Y and H63D mutations.
4.
These mutations result in elevated transferrin-iron saturation, elevated serum ferritin con-
centration, and hepatic iron overload assessed by
Prussian blue
staining of a liver biopsy.
5.
If a person has HHH decides to have a child, then the carrier risk factor becomes impor-
tant. The risk that a partner of European descent is a heterozygote (Hh) is 11% (1 out of 9
individuals), due the high carrier rate in the general European population for HHH.
6. Prevalence.
The prevalence of HHH is 1/200 to 500 births.
7. Clinical features include:
excessive storage of iron in the liver, heart, skin, pancreas, joints,
and testes; abdominal pain, weakness, lethargy, weight loss, and hepatic fibrosis; without
therapy, symptoms appear in males at 40 to 60 years of age and in females after menopause.
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