Medical Genetics
11 单基因遗传病（ B）
Single Gene Disorder (B)
Medical Genetics
2,Inborn Errors of Metabolism
Inborn errors of metabolism are
rare genetic disorders in which the
body cannot turn food into energy
(metabolize food) normally,The
disorders are usually caused by
defects in the enzymes involved in
the biochemical pathways that break
down food components,
Medical Genetics
In 1904 the doctor Archibald E,Garrod
described alkaptonuria,a disease he classified as a
lifelong congenital chemical
alteration,Later on,in 1909,
he described other diseases,
albinism,cystinuria,
porphyria and pentosuria,
which he named "Inborn
Errors of Metabolism",Garrod's
conclusions were completely
correct in relation to the genetic
basis of metabolic disorders and
the gene-enzyme concept,
Medical Genetics
The gene defect can cause a
particular enzyme to be defective or
missing,And because the enzyme
isn't doing what it is supposed to do
for the body,poor health may result,
Medical Genetics
Simply put,enzymes help the body
by stimulating biological reactions inside
cells,Enzymes are proteins that help the
body use food,produce energy,and do
work,When a particular enzyme is
defective or missing,then the body isn't
able to do something that it should do to
maintain health,The enzyme involved
determines what the body can't do and
what the resulting physical features are,
Medical Genetics
Inborn errors of metabolism
affect about 1 in every 5,000 babies
born,Some of the more familiar
inborn errors of metabolism are
cystic fibrosis,hypothyroidism,,
phenylketonuria (PKU) and Tay-
Sachs disease,
Medical Genetics
The symptoms of inborn errors of
metabolism vary greatly,Each one must
be reviewed separately to know what the
physical features are,Often,an infant will
show signs of failure to thrive by failing to
gain weight,not eating well,and generally
showing developmental delay,Vomiting
and diarrhea are among other symptoms
that may signal the healthcare provider to
test for an inborn error of metabolism,
Medical Genetics
Metabolic
defect
Results in Onset Example
Energy
generation
?Energy deficit
?Hypoglycemia
?Confusion
?Acute LOC
?Coma
?Early
?First year of life when the baby need to generate his own
energy
?Under stress,when having other concurrent illness,
URTI
Fatty acid oxidation defect
(hypoketotic hypoglycemia)
Intoxication,
accumulatio
n of toxic
metabolites
Toxicitiy to
?Brain
?Liver
?Kidney
Depends on exposure to toxic substance (could be early or
late)
?Brain,seizure,confusion,coma,motor dysfunction,
mental retardation
?Liver,cirrhosis,jaundice
Glutaric aciduria Type I,
PKU
Tyrosinemia
Inability to
breakdown
metabolites
Storage diseases in,
?Liver
?Muscle
?Brain
?Leukocytes
Usually late onset
Storage takes times to accumulate and produce symptoms
Mucopolysarrcharidosis
Glycogen storage diseases
Urea cycle Unable to convert
ammonia to urea
Neurological,vomiting,coma
^^ NH3
OTC
Citrullinemia
Lactic
acidosis
Different disorders ^ Lactate (from mild to severe)
Clinical symptoms commonly specific for a particular
disorder
Kearn-Sayre
MELAS
Reye’s
syndrome
like
Acute intoxication ?
hepatic
encephalopathy
Depends on specific defect Various disorders
What are the symptoms in IMD
Medical Genetics
The enzyme defects that lead to
the inborn errors of metabolism are
caused by abnormal genes,In most
cases,the abnormal gene is
autosomal recessive in character,
Medical Genetics
Medical Genetics
2.1 Phenylketonuria,PKU
Phenylketonuria is one of the
commonest inherited disorders - occurring
in approximately 1 in 10,000 babies born
in the U,S,It occurs in babies who inherit
two mutant genes for the enzyme
phenylalanine hydroxylase (PAH),This
enzyme normally breaks down molecules
of the amino acid phenylalanine that are
in excess of the body's needs for protein
synthesis,
Medical Genetics
Medical Genetics
Because we inherit two copies of the
gene for the enzyme,both must be
defective to produce the disease,A
laboratory test that measures how quickly
an injection of phenylalanine is removed
from the blood can distinguish a person
who has one PKU gene from a person who
has none,but the person with one is
perfectly healthy because the unmutated
allele produces enough of the enzyme,
However,these heterozygous individuals
are "carriers" of the disease,
Medical Genetics
The phenylalanine tolerance
test,A short time after administering
a measured amount of phenylalanine
to the subject,the concentration of
phenylalanine in the blood plasma is
measured,
Medical Genetics
The level is usually substantially higher in people
who carry one PKU gene (even though they show no
signs of disease) than in individuals who are
homozygous for the unmutated gene,Both parents
must be heterozygous (i.e.,must be "carriers" of the
trait) to produce a child with PKU,The chance of their
doing so is 1 in 4,
Medical Genetics
Inability to remove excess
phenylalanine from the blood during
infancy and early childhood produces a
variety of problems including mental
retardation,Fortunately,a simple test
(needing only a drop of blood) done
shortly after birth can identify the genetic
defect and,with close attention to the
amount of phenylalanine in their diet,the
children can develop normally,
Medical Genetics
Medical Genetics
Genetic
screening
for "a"
(NOTE,not
"the" -
many
different
mutations
in the PKU
gene have
been
identified)
PKU allele,
Medical Genetics
By treatment,her sister,who suffered
from PKU too,got married healthily,
Medical Genetics
2.2 albinism
Albinism is a defect of melanin
production,This defect results in the
partial or full absence of pigment
from the skin,hair,and eyes,
Medical Genetics
In Type 1 albinism defects in the
metabolism of tyrosine lead to failure
in converting this amino acid to
melanin,This is due to a genetic
defect in tyrosinase -- the enzyme
responsible for metabolizing tyrosine,
Medical Genetics
Medical Genetics
Type 2 albinism is due to a
defect in the "P" gene,Those with
this type have slight pigmentation at
birth,
Medical Genetics
In the most severe form of
albinism (called oculocutaneous
albinism),those affected appear to
have hair,skin,and iris color that
are white or pink as well as vision
defects,This is inherited via an
autosomal recessive process,
Medical Genetics
Medical Genetics
A patient with oculocutaneous albinism with white eyebrows and lashes,
Medical Genetics
Left fundus of a patient with albinism,Note the lack of
RPE pigment which allows the choroidal vessels to become
clearly visible,The patient also has macula hypoplasia,
the temporal arcade of the retinal vessels run almost
horizontally,
Medical Genetics
2.3 alkaptonuria
Alkaptonuria is a rare inherited
disorder of metabolism,
characterized by urine that turns
black when exposed to air,Another
characteristic is the development of
arthritis in adulthood,
Medical Genetics
Alkaptonuria is an autosomal
recessive inherited disorder,In
affected individuals,an amino acid
known as tyrosine is not properly
metabolized,due to a defect in an
enzyme called homogentisic acid
oxidase,
Medical Genetics
Medical Genetics
Because of the defect,
homogentisic acid is excreted in the
urine and turns a brown color upon
exposure to air,This is the result of a
dark pigment with an ochre color
(earthy red or yellow),which led to
the name ochronosis,The bones and
cartilage of the body may be brown-
colored,
Medical Genetics
Medical Genetics
2.4 Wilsons disease
Wilson's disease is an inherited
disorder where there is excessive
amounts of copper in the body,This
causes a variety of effects,including
liver disease and damage to the
nervous system,
Medical Genetics
Wilson's disease is a rare
inherited disorder,If both parents
carry an abnormal gene for Wilson's
disease,there is a 25% chance that
each of their children will develop the
disorder (i.e.,it is an autosomal
recessive disease),
Medical Genetics
Wilson's disease causes the body
to absorb and retain excessive
amounts of copper,The copper
deposits in the liver,brain,kidneys,
and the eyes,
Medical Genetics
Molecular mechanism,ATP7B (wilson
copper transporting ATPase)
Medical Genetics
Medical Genetics
The deposits of copper cause tissue
damage,death of the tissues,and scarring,
which causes the affected organs to stop
functioning properly,Liver failure and
damage to the central nervous system
(brain,spinal cord) are the most
predominant,and the most dangerous,
effects of the disorder,If not caught and
treated early,Wilson's disease is fatal,
Medical Genetics
A patient with Wilson's disease
Medical Genetics
Medical Genetics
Kayser-Fleischer rings
Medical Genetics
Lab findings may include,
? Serum ceruloplasmin - low (although
it is normal in 5% of cases)
? Serum copper - low in spite of the
copper deposits in tissues
? Urine copper - high
? CBC - may show hemolytic anemia
or decreased white blood cell count
? Serum uric acid levels - low
Medical Genetics
The following medications may be used,
? Zinc acetate (Galzin),which blocks the
absorption of copper in the intestinal tract,
? Trientine (Syprine),which binds or
chelates the copper and leads to increased
urinary excretion of the metal,
? Penicillamine (Cuprimine,Depen),which
also binds or chelates copper and leads to
increased urinary excretion,
Medical Genetics
2.5 galactosemia
Galactosemia is the inability of
the body to use (metabolize) the
simple sugar galactose (causing the
accumulation of galactose 1-
phosphate),which then reaches high
levels in the body,causing damage
to the liver,central nervous system,
and various other body systems,
Medical Genetics
Galactosemia is an inherited
disorder (transmitted as an
autosomal recessive trait),It occurs
at a rate of approximately 1 out of
60,000 births,
Medical Genetics
There are 3 forms of the disease,
galactose-1 phosphate uridyl
transferase deficiency (classic
galactosemia,the most common and
most severe form),deficiency of
galactose kinase,and deficiency of
galactose-6-phosphate epimerase,
Medical Genetics
Medical Genetics
People with galactosemia are unable
to fully break down the simple sugar
galactose,Galactose makes up half of
lactose,the sugar found in milk,Lactose is
called a disaccharide (di meaning 2 and
saccharide meaning sugar) because it is
made up of two sugars,galactose and
glucose,bound together,
Medical Genetics
If an infant with galactosemia is
given milk,derivatives of galactose
build up in the infant's system,
causing damage to the liver,brain,
kidneys,and eyes,
Medical Genetics
Individuals with galactosemia
cannot tolerate any form of milk
(human or animal) and must
carefully watch intake of other
galactose-containing foods,Exposure
to milk products may result in liver
damage,mental retardation,cataract
formation,and kidney failure,
Medical Genetics
Medical Genetics
cataract
Medical Genetics
Treatment
Once the disease is recognized,
treatment consists of strictly avoiding all
milk and milk-containing products,The
infant can be fed with soy formula,meat-
base formula,or Nutramigen (a protein
hydrolysate formula),or other lactose-free
formula,The condition is lifelong and
requires abstinence from milk and milk
products for life,
Medical Genetics
Parents need to take care and
educate the child to avoid not only
milk and milk products,but also
those foods that contain dry milk
products,For this reason,it is
essential to read product labels and
be an informed consumer,
Medical Genetics
2.6 G-6-PD deficiency
G-6-PD deficiency is a hereditary,
sex-linked enzyme defect that
results in the breakdown of red blood
cells when the person is exposed to
the stress of infection or certain
drugs,
Medical Genetics
G-6-PD deficiency is an
inheritable,X-linked recessive
disorder whose primary effect is the
reduction of the enzyme G-6-PD in
red blood cells,causing destruction
of the cells,called hemolysis,
Ultimately,this hemolysis leads to
anemia -- either acute hemolytic or a
chronic spherocytic type,
Medical Genetics
Medical Genetics
Three classes of deficiency are
described,corresponding to three types of
enzymatic variants,This classification is
based on the enzyme residual activity,
class 1,very severe deficiency,activity
close to 0%
class 2,severe deficiency,activity <10%
class 3,moderate deficiency,activity
between 10 and 60%
class 4,variants with normal activity
Medical Genetics
Medical Genetics
Drugs that can bring on this reaction include,
? antimalarial agents
? sulfonamides (antibiotic)
? aspirin
? nonsteroidal anti-inflammatory drugs
(NSAIDs)
? nitrofurantoin
? quinidine
? quinine
? others
Medical Genetics
Medical Genetics
2.8 glycogen storage disease,GSD
Glucose is a large energy source
for the body,It is stored by the body
in the form of glycogen and later
released into the body with the help
of enzymes,
Medical Genetics
Glycogen storage disease (GSD) is a
group of inherited (born with) disorders
where an abnormal amount or type of
glycogen settles in the liver and causes
failure of the liver's ability to break down
glycogen to supply glucose to the rest of
the body,This happens when one or more
of the many enzymes (proteins produced
by the body) needed to convert sugar
(glucose) into its storage form (glycogen)
are missing,
Medical Genetics
types of GSD
diseases OMIM defected gene symptoms
GSD 0 240600 肝糖原合酶 AR,12p12.2
GSD Ⅰ a 232200 葡萄糖 -6-磷酸酶 AR,17q21 低血糖血症
GSD Ⅰ b 232220 微体葡萄糖 -6-磷酸转运 AR,11q23 巨舌，肌张力减退
GSD Ⅰ c 232240 微体磷酸吡咯转运 AR,11q23
GSD Ⅱ 232300 α-1,4-葡糖苷酶 AR,17q25.2
GSD Ⅱ b 300257 α-1,4-葡糖苷酶 XR,Xq24
GSD Ⅲ 232400 淀粉 -1,6-葡糖苷酶 AR,1p21 与 I型相似
GSD Ⅳ 232500 淀粉 -(1,4;1,6)转葡糖苷酶 AR,3p12 肝脾肿大，肝硬化
GSD Ⅴ 232600 肌磷酸化酶 AR,11q13 肌无力，肌痉挛
GSD Ⅵ 232700 肝磷酸化酶 AR,14q21 低血糖症生长迟缓
GSD Ⅶ 232800 肌磷酸果糖激酶 AR,12q13.3 肌痉挛肌无力肌痛
GSD Ⅷ 306000 磷酸化酶激酶 XR,Xp22.2 轻型低血糖症白内障
GSD Ⅸ c 604549 AR
Medical Genetics
2.9 Mucopolysaccharidosis
One of a series of inherited
metabolic disorders affecting a type
of complex carbohydrate called a
mucopolysaccharide that is deposited
in body tissues because the person
lacks the specific enzyme needed to
metabolize it,
Medical Genetics
The deposition of
mucopolysaccharide in tissues
damages and distorts them,stunts
the child's growth and development,
limits their joint movement and in
some (but not all) types of MPS
causes mental retardation,
Medical Genetics
The condition usually becomes evident
in early childhood,That something is
wrong may be noticed by parents or
doctors,The diagnosis may be suspected
by the clinical features,Confirmation of
the diagnosis,however,requires
biochemical tests of blood,urine,or
tissues,Prenatal diagnosis is feasible in all
types of MPS,
Medical Genetics
The classification (as of 2001) is as follows,
? MPS type I -- Hurler syndrome,Scheie syndrome,
and Hurler-Scheie syndrome -- due to varying
degrees of deficiency of the enzyme alpha-L-
iduronidase
? MPS type II -- Hunter syndrome -- due to
deficiency of the enzyme iduronate sulfatase
? MPS type IIIA -- Sanfilippo syndrome -- due to
deficiency of the enzyme heparan N-sulfatase
? MPS type IIIB -- Sanfilippo syndrome -- due to
deficiency of the enzyme alpha-N-
acetylglucosaminidase
? MPS type IIIC -- Sanfilippo syndrome -- due to
deficiency of the enzyme acetyl CoA:alpha-
glucosaminide acetyltransferase
Medical Genetics
? MPS type IIID -- Sanfilippo syndrome -- due to
deficiency of the enzyme N-acetylglucosamine 6-
sulfatase
? MPS type IVA -- Morquio syndrome -- due to
deficiency of the enzyme N-acetylgalactosamine-
6-sulfate sulfatase
? MPS type IVB -- Morquio syndrome -- due to
deficiency of the enzyme beta-galactosidase
? MPS type VI -- Maroteaux-Lamy syndrome -- due
to deficiency of the enzyme N-
acetylgalactosamine-4-sulfatase
? MPS type VII -- Sly syndrome -- due to deficiency
of the enzyme beta-glucuronidase
? MPS type VIII -- DiFerrante syndrome -- due to
deficiency of the enzyme glucosamine-6-sulfate
Medical Genetics
All types of MPS are inherited as
recessive traits,With one exception,
they are autosomal (not sex-linked),
Boys and girls alike can have these
diseases if they receive two copies of
the relevant gene,one from each of
their parents,The risk for each
subsequent child is 1 in 4,
Medical Genetics
All types of MPS are lysosomal
storage diseases,They involve
enzymes found within the cell in
lysosomes,miniature structures that
are packets of degradative enzymes,
In this respect,MPS is like all the
other disorders of lysosomal storage
such as Gaucher disease,Fabry
disease,and Pompe disease,
Medical Genetics
Symptoms may include,
? Growth failure
? Muscle cramps
? Low blood sugar
? A greatly enlarged liver
? A swollen belly
Medical Genetics
Medical Genetics
MPS type I
MPS type II
Medical Genetics
2.10 Lesch-Nyhan syndrome
Lesch-Nyhan syndrome is a
condition characterized by the
overproduction of uric acid,a
nitrogen-containing compound found
in urine,Problems with the nervous
system and behavioral disturbances
are characteristic of this disorder,
Medical Genetics
The overproduction of uric acid can
cause gouty arthritis (arthritis caused by
uric acid in the joints),as well as kidney
and bladder stones,Abnormal involuntary
muscle movements such as flexing,
jerking,flinging,and flailing are often
displayed,Self-injury through biting and
head banging is the most common
behavioral problem in Lesch-Nyhan
patients,
Medical Genetics
Mutations in the HPRT1 gene cause Lesch-
Nyhan syndrome,
Mutations in the HPRT1 gene cause a shortage
(deficiency) of the enzyme hypoxanthine
phosphoribosyltransferase 1,This enzyme is
responsible for recycling purines,a type of
building material for DNA and its chemical cousin
RNA,When this enzyme is lacking,the
breakdown of purines results in abnormal levels
of uric acid buildup in the body,The mechanism
by which high uric acid levels cause neurological
and behavioral disturbances is currently not well
understood,
Medical Genetics
This condition is inherited in an X-
linked recessive pattern,A condition is
considered X-linked if the mutated gene
that causes the disorder is located on the
X chromosome (one of the two sex
chromosomes),In males,who have only
one X chromosome,one altered copy of
the gene is sufficient to cause the
condition,
Medical Genetics
In females,who have two X
chromosomes,a mutation must usually be
present in both copies of the gene to
cause the disorder,Males are affected by
X-linked recessive disorders much more
frequently than females,A striking
characteristic of X-linked inheritance is
that fathers cannot pass X-linked traits to
their sons,
Medical Genetics
?
Medical Genetics
Medical Genetics
2.11 xeroderma pigmentosum
Xeroderma pigmentosum (XP) was first
described in 1874 by Hebra and Kaposi,In 1882,
Kaposi coined the term xeroderma pigmentosum
for the condition,referring to its characteristic
dry,pigmented skin,XP is a rare disorder
transmitted in an autosomal recessive manner,It
is characterized by photosensitivity,pigmentary
changes,premature skin aging,and malignant
tumor development,These manifestations are
due to a cellular hypersensitivity to ultraviolet
(UV) radiation resulting from a defect in DNA
repair,
Medical Genetics
Medical Genetics
11 单基因遗传病（ B）
Single Gene Disorder (B)
Medical Genetics
2,Inborn Errors of Metabolism
Inborn errors of metabolism are
rare genetic disorders in which the
body cannot turn food into energy
(metabolize food) normally,The
disorders are usually caused by
defects in the enzymes involved in
the biochemical pathways that break
down food components,
Medical Genetics
In 1904 the doctor Archibald E,Garrod
described alkaptonuria,a disease he classified as a
lifelong congenital chemical
alteration,Later on,in 1909,
he described other diseases,
albinism,cystinuria,
porphyria and pentosuria,
which he named "Inborn
Errors of Metabolism",Garrod's
conclusions were completely
correct in relation to the genetic
basis of metabolic disorders and
the gene-enzyme concept,
Medical Genetics
The gene defect can cause a
particular enzyme to be defective or
missing,And because the enzyme
isn't doing what it is supposed to do
for the body,poor health may result,
Medical Genetics
Simply put,enzymes help the body
by stimulating biological reactions inside
cells,Enzymes are proteins that help the
body use food,produce energy,and do
work,When a particular enzyme is
defective or missing,then the body isn't
able to do something that it should do to
maintain health,The enzyme involved
determines what the body can't do and
what the resulting physical features are,
Medical Genetics
Inborn errors of metabolism
affect about 1 in every 5,000 babies
born,Some of the more familiar
inborn errors of metabolism are
cystic fibrosis,hypothyroidism,,
phenylketonuria (PKU) and Tay-
Sachs disease,
Medical Genetics
The symptoms of inborn errors of
metabolism vary greatly,Each one must
be reviewed separately to know what the
physical features are,Often,an infant will
show signs of failure to thrive by failing to
gain weight,not eating well,and generally
showing developmental delay,Vomiting
and diarrhea are among other symptoms
that may signal the healthcare provider to
test for an inborn error of metabolism,
Medical Genetics
Metabolic
defect
Results in Onset Example
Energy
generation
?Energy deficit
?Hypoglycemia
?Confusion
?Acute LOC
?Coma
?Early
?First year of life when the baby need to generate his own
energy
?Under stress,when having other concurrent illness,
URTI
Fatty acid oxidation defect
(hypoketotic hypoglycemia)
Intoxication,
accumulatio
n of toxic
metabolites
Toxicitiy to
?Brain
?Liver
?Kidney
Depends on exposure to toxic substance (could be early or
late)
?Brain,seizure,confusion,coma,motor dysfunction,
mental retardation
?Liver,cirrhosis,jaundice
Glutaric aciduria Type I,
PKU
Tyrosinemia
Inability to
breakdown
metabolites
Storage diseases in,
?Liver
?Muscle
?Brain
?Leukocytes
Usually late onset
Storage takes times to accumulate and produce symptoms
Mucopolysarrcharidosis
Glycogen storage diseases
Urea cycle Unable to convert
ammonia to urea
Neurological,vomiting,coma
^^ NH3
OTC
Citrullinemia
Lactic
acidosis
Different disorders ^ Lactate (from mild to severe)
Clinical symptoms commonly specific for a particular
disorder
Kearn-Sayre
MELAS
Reye’s
syndrome
like
Acute intoxication ?
hepatic
encephalopathy
Depends on specific defect Various disorders
What are the symptoms in IMD
Medical Genetics
The enzyme defects that lead to
the inborn errors of metabolism are
caused by abnormal genes,In most
cases,the abnormal gene is
autosomal recessive in character,
Medical Genetics
Medical Genetics
2.1 Phenylketonuria,PKU
Phenylketonuria is one of the
commonest inherited disorders - occurring
in approximately 1 in 10,000 babies born
in the U,S,It occurs in babies who inherit
two mutant genes for the enzyme
phenylalanine hydroxylase (PAH),This
enzyme normally breaks down molecules
of the amino acid phenylalanine that are
in excess of the body's needs for protein
synthesis,
Medical Genetics
Medical Genetics
Because we inherit two copies of the
gene for the enzyme,both must be
defective to produce the disease,A
laboratory test that measures how quickly
an injection of phenylalanine is removed
from the blood can distinguish a person
who has one PKU gene from a person who
has none,but the person with one is
perfectly healthy because the unmutated
allele produces enough of the enzyme,
However,these heterozygous individuals
are "carriers" of the disease,
Medical Genetics
The phenylalanine tolerance
test,A short time after administering
a measured amount of phenylalanine
to the subject,the concentration of
phenylalanine in the blood plasma is
measured,
Medical Genetics
The level is usually substantially higher in people
who carry one PKU gene (even though they show no
signs of disease) than in individuals who are
homozygous for the unmutated gene,Both parents
must be heterozygous (i.e.,must be "carriers" of the
trait) to produce a child with PKU,The chance of their
doing so is 1 in 4,
Medical Genetics
Inability to remove excess
phenylalanine from the blood during
infancy and early childhood produces a
variety of problems including mental
retardation,Fortunately,a simple test
(needing only a drop of blood) done
shortly after birth can identify the genetic
defect and,with close attention to the
amount of phenylalanine in their diet,the
children can develop normally,
Medical Genetics
Medical Genetics
Genetic
screening
for "a"
(NOTE,not
"the" -
many
different
mutations
in the PKU
gene have
been
identified)
PKU allele,
Medical Genetics
By treatment,her sister,who suffered
from PKU too,got married healthily,
Medical Genetics
2.2 albinism
Albinism is a defect of melanin
production,This defect results in the
partial or full absence of pigment
from the skin,hair,and eyes,
Medical Genetics
In Type 1 albinism defects in the
metabolism of tyrosine lead to failure
in converting this amino acid to
melanin,This is due to a genetic
defect in tyrosinase -- the enzyme
responsible for metabolizing tyrosine,
Medical Genetics
Medical Genetics
Type 2 albinism is due to a
defect in the "P" gene,Those with
this type have slight pigmentation at
birth,
Medical Genetics
In the most severe form of
albinism (called oculocutaneous
albinism),those affected appear to
have hair,skin,and iris color that
are white or pink as well as vision
defects,This is inherited via an
autosomal recessive process,
Medical Genetics
Medical Genetics
A patient with oculocutaneous albinism with white eyebrows and lashes,
Medical Genetics
Left fundus of a patient with albinism,Note the lack of
RPE pigment which allows the choroidal vessels to become
clearly visible,The patient also has macula hypoplasia,
the temporal arcade of the retinal vessels run almost
horizontally,
Medical Genetics
2.3 alkaptonuria
Alkaptonuria is a rare inherited
disorder of metabolism,
characterized by urine that turns
black when exposed to air,Another
characteristic is the development of
arthritis in adulthood,
Medical Genetics
Alkaptonuria is an autosomal
recessive inherited disorder,In
affected individuals,an amino acid
known as tyrosine is not properly
metabolized,due to a defect in an
enzyme called homogentisic acid
oxidase,
Medical Genetics
Medical Genetics
Because of the defect,
homogentisic acid is excreted in the
urine and turns a brown color upon
exposure to air,This is the result of a
dark pigment with an ochre color
(earthy red or yellow),which led to
the name ochronosis,The bones and
cartilage of the body may be brown-
colored,
Medical Genetics
Medical Genetics
2.4 Wilsons disease
Wilson's disease is an inherited
disorder where there is excessive
amounts of copper in the body,This
causes a variety of effects,including
liver disease and damage to the
nervous system,
Medical Genetics
Wilson's disease is a rare
inherited disorder,If both parents
carry an abnormal gene for Wilson's
disease,there is a 25% chance that
each of their children will develop the
disorder (i.e.,it is an autosomal
recessive disease),
Medical Genetics
Wilson's disease causes the body
to absorb and retain excessive
amounts of copper,The copper
deposits in the liver,brain,kidneys,
and the eyes,
Medical Genetics
Molecular mechanism,ATP7B (wilson
copper transporting ATPase)
Medical Genetics
Medical Genetics
The deposits of copper cause tissue
damage,death of the tissues,and scarring,
which causes the affected organs to stop
functioning properly,Liver failure and
damage to the central nervous system
(brain,spinal cord) are the most
predominant,and the most dangerous,
effects of the disorder,If not caught and
treated early,Wilson's disease is fatal,
Medical Genetics
A patient with Wilson's disease
Medical Genetics
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Kayser-Fleischer rings
Medical Genetics
Lab findings may include,
? Serum ceruloplasmin - low (although
it is normal in 5% of cases)
? Serum copper - low in spite of the
copper deposits in tissues
? Urine copper - high
? CBC - may show hemolytic anemia
or decreased white blood cell count
? Serum uric acid levels - low
Medical Genetics
The following medications may be used,
? Zinc acetate (Galzin),which blocks the
absorption of copper in the intestinal tract,
? Trientine (Syprine),which binds or
chelates the copper and leads to increased
urinary excretion of the metal,
? Penicillamine (Cuprimine,Depen),which
also binds or chelates copper and leads to
increased urinary excretion,
Medical Genetics
2.5 galactosemia
Galactosemia is the inability of
the body to use (metabolize) the
simple sugar galactose (causing the
accumulation of galactose 1-
phosphate),which then reaches high
levels in the body,causing damage
to the liver,central nervous system,
and various other body systems,
Medical Genetics
Galactosemia is an inherited
disorder (transmitted as an
autosomal recessive trait),It occurs
at a rate of approximately 1 out of
60,000 births,
Medical Genetics
There are 3 forms of the disease,
galactose-1 phosphate uridyl
transferase deficiency (classic
galactosemia,the most common and
most severe form),deficiency of
galactose kinase,and deficiency of
galactose-6-phosphate epimerase,
Medical Genetics
Medical Genetics
People with galactosemia are unable
to fully break down the simple sugar
galactose,Galactose makes up half of
lactose,the sugar found in milk,Lactose is
called a disaccharide (di meaning 2 and
saccharide meaning sugar) because it is
made up of two sugars,galactose and
glucose,bound together,
Medical Genetics
If an infant with galactosemia is
given milk,derivatives of galactose
build up in the infant's system,
causing damage to the liver,brain,
kidneys,and eyes,
Medical Genetics
Individuals with galactosemia
cannot tolerate any form of milk
(human or animal) and must
carefully watch intake of other
galactose-containing foods,Exposure
to milk products may result in liver
damage,mental retardation,cataract
formation,and kidney failure,
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Medical Genetics
cataract
Medical Genetics
Treatment
Once the disease is recognized,
treatment consists of strictly avoiding all
milk and milk-containing products,The
infant can be fed with soy formula,meat-
base formula,or Nutramigen (a protein
hydrolysate formula),or other lactose-free
formula,The condition is lifelong and
requires abstinence from milk and milk
products for life,
Medical Genetics
Parents need to take care and
educate the child to avoid not only
milk and milk products,but also
those foods that contain dry milk
products,For this reason,it is
essential to read product labels and
be an informed consumer,
Medical Genetics
2.6 G-6-PD deficiency
G-6-PD deficiency is a hereditary,
sex-linked enzyme defect that
results in the breakdown of red blood
cells when the person is exposed to
the stress of infection or certain
drugs,
Medical Genetics
G-6-PD deficiency is an
inheritable,X-linked recessive
disorder whose primary effect is the
reduction of the enzyme G-6-PD in
red blood cells,causing destruction
of the cells,called hemolysis,
Ultimately,this hemolysis leads to
anemia -- either acute hemolytic or a
chronic spherocytic type,
Medical Genetics
Medical Genetics
Three classes of deficiency are
described,corresponding to three types of
enzymatic variants,This classification is
based on the enzyme residual activity,
class 1,very severe deficiency,activity
close to 0%
class 2,severe deficiency,activity <10%
class 3,moderate deficiency,activity
between 10 and 60%
class 4,variants with normal activity
Medical Genetics
Medical Genetics
Drugs that can bring on this reaction include,
? antimalarial agents
? sulfonamides (antibiotic)
? aspirin
? nonsteroidal anti-inflammatory drugs
(NSAIDs)
? nitrofurantoin
? quinidine
? quinine
? others
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Medical Genetics
2.8 glycogen storage disease,GSD
Glucose is a large energy source
for the body,It is stored by the body
in the form of glycogen and later
released into the body with the help
of enzymes,
Medical Genetics
Glycogen storage disease (GSD) is a
group of inherited (born with) disorders
where an abnormal amount or type of
glycogen settles in the liver and causes
failure of the liver's ability to break down
glycogen to supply glucose to the rest of
the body,This happens when one or more
of the many enzymes (proteins produced
by the body) needed to convert sugar
(glucose) into its storage form (glycogen)
are missing,
Medical Genetics
types of GSD
diseases OMIM defected gene symptoms
GSD 0 240600 肝糖原合酶 AR,12p12.2
GSD Ⅰ a 232200 葡萄糖 -6-磷酸酶 AR,17q21 低血糖血症
GSD Ⅰ b 232220 微体葡萄糖 -6-磷酸转运 AR,11q23 巨舌，肌张力减退
GSD Ⅰ c 232240 微体磷酸吡咯转运 AR,11q23
GSD Ⅱ 232300 α-1,4-葡糖苷酶 AR,17q25.2
GSD Ⅱ b 300257 α-1,4-葡糖苷酶 XR,Xq24
GSD Ⅲ 232400 淀粉 -1,6-葡糖苷酶 AR,1p21 与 I型相似
GSD Ⅳ 232500 淀粉 -(1,4;1,6)转葡糖苷酶 AR,3p12 肝脾肿大，肝硬化
GSD Ⅴ 232600 肌磷酸化酶 AR,11q13 肌无力，肌痉挛
GSD Ⅵ 232700 肝磷酸化酶 AR,14q21 低血糖症生长迟缓
GSD Ⅶ 232800 肌磷酸果糖激酶 AR,12q13.3 肌痉挛肌无力肌痛
GSD Ⅷ 306000 磷酸化酶激酶 XR,Xp22.2 轻型低血糖症白内障
GSD Ⅸ c 604549 AR
Medical Genetics
2.9 Mucopolysaccharidosis
One of a series of inherited
metabolic disorders affecting a type
of complex carbohydrate called a
mucopolysaccharide that is deposited
in body tissues because the person
lacks the specific enzyme needed to
metabolize it,
Medical Genetics
The deposition of
mucopolysaccharide in tissues
damages and distorts them,stunts
the child's growth and development,
limits their joint movement and in
some (but not all) types of MPS
causes mental retardation,
Medical Genetics
The condition usually becomes evident
in early childhood,That something is
wrong may be noticed by parents or
doctors,The diagnosis may be suspected
by the clinical features,Confirmation of
the diagnosis,however,requires
biochemical tests of blood,urine,or
tissues,Prenatal diagnosis is feasible in all
types of MPS,
Medical Genetics
The classification (as of 2001) is as follows,
? MPS type I -- Hurler syndrome,Scheie syndrome,
and Hurler-Scheie syndrome -- due to varying
degrees of deficiency of the enzyme alpha-L-
iduronidase
? MPS type II -- Hunter syndrome -- due to
deficiency of the enzyme iduronate sulfatase
? MPS type IIIA -- Sanfilippo syndrome -- due to
deficiency of the enzyme heparan N-sulfatase
? MPS type IIIB -- Sanfilippo syndrome -- due to
deficiency of the enzyme alpha-N-
acetylglucosaminidase
? MPS type IIIC -- Sanfilippo syndrome -- due to
deficiency of the enzyme acetyl CoA:alpha-
glucosaminide acetyltransferase
Medical Genetics
? MPS type IIID -- Sanfilippo syndrome -- due to
deficiency of the enzyme N-acetylglucosamine 6-
sulfatase
? MPS type IVA -- Morquio syndrome -- due to
deficiency of the enzyme N-acetylgalactosamine-
6-sulfate sulfatase
? MPS type IVB -- Morquio syndrome -- due to
deficiency of the enzyme beta-galactosidase
? MPS type VI -- Maroteaux-Lamy syndrome -- due
to deficiency of the enzyme N-
acetylgalactosamine-4-sulfatase
? MPS type VII -- Sly syndrome -- due to deficiency
of the enzyme beta-glucuronidase
? MPS type VIII -- DiFerrante syndrome -- due to
deficiency of the enzyme glucosamine-6-sulfate
Medical Genetics
All types of MPS are inherited as
recessive traits,With one exception,
they are autosomal (not sex-linked),
Boys and girls alike can have these
diseases if they receive two copies of
the relevant gene,one from each of
their parents,The risk for each
subsequent child is 1 in 4,
Medical Genetics
All types of MPS are lysosomal
storage diseases,They involve
enzymes found within the cell in
lysosomes,miniature structures that
are packets of degradative enzymes,
In this respect,MPS is like all the
other disorders of lysosomal storage
such as Gaucher disease,Fabry
disease,and Pompe disease,
Medical Genetics
Symptoms may include,
? Growth failure
? Muscle cramps
? Low blood sugar
? A greatly enlarged liver
? A swollen belly
Medical Genetics
Medical Genetics
MPS type I
MPS type II
Medical Genetics
2.10 Lesch-Nyhan syndrome
Lesch-Nyhan syndrome is a
condition characterized by the
overproduction of uric acid,a
nitrogen-containing compound found
in urine,Problems with the nervous
system and behavioral disturbances
are characteristic of this disorder,
Medical Genetics
The overproduction of uric acid can
cause gouty arthritis (arthritis caused by
uric acid in the joints),as well as kidney
and bladder stones,Abnormal involuntary
muscle movements such as flexing,
jerking,flinging,and flailing are often
displayed,Self-injury through biting and
head banging is the most common
behavioral problem in Lesch-Nyhan
patients,
Medical Genetics
Mutations in the HPRT1 gene cause Lesch-
Nyhan syndrome,
Mutations in the HPRT1 gene cause a shortage
(deficiency) of the enzyme hypoxanthine
phosphoribosyltransferase 1,This enzyme is
responsible for recycling purines,a type of
building material for DNA and its chemical cousin
RNA,When this enzyme is lacking,the
breakdown of purines results in abnormal levels
of uric acid buildup in the body,The mechanism
by which high uric acid levels cause neurological
and behavioral disturbances is currently not well
understood,
Medical Genetics
This condition is inherited in an X-
linked recessive pattern,A condition is
considered X-linked if the mutated gene
that causes the disorder is located on the
X chromosome (one of the two sex
chromosomes),In males,who have only
one X chromosome,one altered copy of
the gene is sufficient to cause the
condition,
Medical Genetics
In females,who have two X
chromosomes,a mutation must usually be
present in both copies of the gene to
cause the disorder,Males are affected by
X-linked recessive disorders much more
frequently than females,A striking
characteristic of X-linked inheritance is
that fathers cannot pass X-linked traits to
their sons,
Medical Genetics
?
Medical Genetics
Medical Genetics
2.11 xeroderma pigmentosum
Xeroderma pigmentosum (XP) was first
described in 1874 by Hebra and Kaposi,In 1882,
Kaposi coined the term xeroderma pigmentosum
for the condition,referring to its characteristic
dry,pigmented skin,XP is a rare disorder
transmitted in an autosomal recessive manner,It
is characterized by photosensitivity,pigmentary
changes,premature skin aging,and malignant
tumor development,These manifestations are
due to a cellular hypersensitivity to ultraviolet
(UV) radiation resulting from a defect in DNA
repair,
Medical Genetics
Medical Genetics
