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The Bouquots and the Beggs
1973
General Pathology (DENF 2701)
Fall, 2005
Topic: Genetic and Developmental Disorders
Fall, 2005; Mondays & Wednesdays, 11:00-11:50 am; Room 132
Course Director: Dr. Jerry Bouquot
Room 3.094B; 713-500-4420; 713-745-2330 (cell)
Genetic Diseases
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30,000 genes in humans
– Many capable of affecting multiple characteristics (pleiotropy)
– Many characteristics have multiple genes controlling them
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Common cause of diseases
– 20% of pediatric in-patients have genetically related diseases
– 50% of spontaneous abortions have chromosomal aberrations
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Not all inherited genes present in infancy or childhood
– e.g. Huntington’s disease (Huntington’s chorea)
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Not all birth defects are inherited
-- e.g. congenital syphilis
Genetic Terminology
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Congenital: present at birth
-- Doesn’t have to be inherited, e.g. congenital syphilis
Familial: runs in families (genetics may be unknown)
Hereditary: derived from gametes of one’s own parents
Polygenic (multifactorial) inheritance: multiple genes involved,
multiple patterns of inheritance
Polymorphism: multiple allelic forms for one gene
Codominance: both alleles of a gene pair are fully expressed
Pleiotropy: one gene with multiple phenotypic effects
Phenotype: physical or biochemical characteristic controlled by
a gene or genes
Genotype: chromosomal/gene characteristics
Genetic Terminology
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Autosomal dominant (AD): only one gene is mutated
-- Only one is needed for disease
Autosomal recessive (AR): two genes are mutated
-- One from each parent, both are needed for disease
Consanguinity: child is a product of sex between close relatives
(common in AR disorders)
X-linked (sex-linked): mutation is only X chromosome
-- Only one is needed for disease, but only when there is no
additional X chromosome to counter it (i.e. girls are unaffected)
Reduced penetrance: gene does not create the clinical/biochemical
characteristic it is capable of creating
Variable expressivity: not all clinical/biochemical characteristics of
an inherited disorder are expressed in all affected individuals
Genetic Terminology
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Heterozygous: the child has only one disease allele of the gene, from
only one parent
Homozygous: the child has two disease alleles of the gene, one from
each parent
Normal Male Karyotype
Genetic Mutations
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Permanent DNA change
Only germ cell mutations can be passed on to progeny
Point mutation: single nucleotide base is altered
Four basic types:
– Missense mutation
– Nonsense mutation
-- Frameshift mutation
– Trinucleotide repeat mutation
Point Mutations: Missense Type
e.g. Sickle Cell Anemia/Disease
Point Mutations: Nonsense Type
e.g. Sickle Cell Anemia/Disease
Stop codon replaces regular nucleotide
Point Mutations: Frameshift Type
e.g. Cystic Fibrosis
-- Insert or delete 1 or 2 base pairs
-- If 3 pairs: protein is created with missing amino acid
Point Mutations: Trinucleotide Repeat Type
e.g. Fragile X Syndrome
Results in amplification
Basic Types of Genetic Disorders
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Single gene mutation
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Chromosomal aberration
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Single gene mutation
with nonclassical inheritance
Single Gene Disorders
Medelian Inheritance
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5,000+ disorders; 6-8% of pediatric hospital admissions
Three basic patterns: AD, AR, X-linked
Examples of codominance and polymorphism:
– Histocompatibility
– Blood group antigens
Pleiotropy occurs
-- e.g. Marfan disease (defective fibrillin production)
Mutations at different sites may produce the same phenotypic effect
-- Heterogeneity
When less than 50% of the normal gene is controlling:
-- Clinical change, -- e.g. retinitis pigmentosa
Cytogenetic (Chromosomal) Disorders
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Karyotype (photograph of metaphase spread of chromosomes)
– Look for altered number and structure of chromosomes
Chromosomal abnormalities occur in 1/200 newborns
-- Higher in stillborns
-- ½ of first trimester abortions
Normal: 46 chromosomes, i.e.2n = 46
Exact multiple = euploid (3n or 4n = polyploid)
Aneuploid (not an exact multiple of the normal set of
chromosomes)
Trisomy (2n+1): extra chromosome after meiosis
Monosomy (2n-1); one less chromosome after meiosis
-- Not compatible with life
Mosaicism: two or more populations of cells in the same individual
(from postzygotic mitotic disjunction)
Multifactorial Inheritance
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Risk of expressing the disease is dependent on number of mutations
inherited
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Risk of new baby with the disease (2-7%) is same for all first-degree
relatives (parents, siblings)
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Risk of new baby with the disease depends on how many previous
babies were affected
– 7% risk with one affected sibling; 9% risk with two affected siblings
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Concordance with identical twins is 20-40%; less for nonidentical
twins
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This is probably the inheritance for many common disease, e.g.
diabetes mellitus, hypertension, gout, schizophrenia, bipolar
disorder, certain congenital heart defects.
Karyotype
Metaphase Chromosomes
Nomenclature and notation
of karyotype translocation between
long arms of chromosomes 9 and 22
p (petit) = short arm of chromosome
q = long arm of chromosome
t = translocation
Photo: Stevens A, Lowe J. Slide atlas of pathology. Mosby, London, 1995.
Extra Credit Question
Aneuploidy is defined as:
A.
Duplication of chromosomes
B.
Abnormal number of chromosomes in
daughter cell
C. Exact number of chromosomes in daughter
cell
D. Loss of a chromosome in the daughter cell
E.
An extra chromosome in the daughter cell
General Pathology (DENF 2701)
Fall, 2005
Topic: Genetic and Developmental Disorders
Fall, 2005; Mondays & Wednesdays, 11:00-11:50 am; Room 132
Course Director: Dr. Jerry Bouquot
Room 3.094B; 713-500-4420; 713-745-2330 (cell)
Structural Changes in Chromosomes
Chromosomal Breakage; Loss or Rearranged Material
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Usually from chromosomal breakage, with loss or rearrangement of
material
Each arm is numbered from centromere outward
– e.g. 2q34 = region 3, band 4 on long arm of chromosome 2
Translocations: chromosome fragments are exchanged between
chromosomes
Deletion: loss of a portion of a chromosome
– If not at terminal of an arm: chromosome is lost
Inversion: two breaks with reunion after pieces turn around
Ring chromosome: after loss of segments from each end of
chromosome, the arms unite to form ring
– Variant of deletion
Main Structural Changes of Chromosomes
Photo:s Stevens A, Lowe J. Slide atlas of pathology. Mosby, London, 1995.
Types of Chromosomal Rearrangements
Chromosomal Translocation
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t = translocation (transfer of part of one chromosome to another)
Usually reciprocal
-- e.g. 46,XX,t(2;5)(q31;p14) = reciprocal translocation between the
long arm of chromosome 2 at region 5, band 1 and the short arm
of chromosome 5, region 1, band 4
If balanced: not harmful to the carrier
Centric (Robertsonian) Translocation
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Break is close to centromere, short arms affected
Result: one huge and one very small chromosome (which is lost)
Carrier has only 45 chromosomes
Compatible with survival because short arms have many redundant
genes
Isochromosome Translocation
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Centromere divides horizontally instead of vertically
One arm is lost, remaining arm is duplicated
Most common: long arm of X chromosome: i(Xq)
Trisomy Disorders
 Trisomy 21
 Trisomy 13
 Trisomy 18
Down Syndrome
Trisomy 21; Mongolism
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Extra chromosome 21 (47,XX,+21)
– Chromosome 21 has 225 genes
Most common of the chromosomal disorders
– 1/700 births
– Increased risk with increased mother’s age
(1/25 births for mothers over 45 years of age)
– Age of father does not affect risk
4% are from translocation: 46,XX,der(14;21)(q10;q10),+21
– Usually these are familial, with one parent a
carrier for robertsonian translocation
1% are mosaic: 46,XX/47,XX,+21
– From nondisjunction later in embryogenesis
– Usually milder case
Trisomy 21
Down’s Syndrome, Mongolism
 Facies: flat, oblique
palpebral fissures,
depressed nasal bridge,
epicanthal folds, open
mouth, macroglossia
 Short stature
 Short middle phalanx of
little finger
 Horizontal palmar crease,
-- Simian crease
 Short, broad hand
 Hyperflexibility of joints
 Poor muscle tone
 Pelvic abnormalities
 Congenital heart disease
 Mental retardation
Photo: Stevens A, Lowe J. Slide atlas of pathology. Mosby, London, 1995.
Down Syndrome
Trisomy 21; Mongolism
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Epicanthic folds and antimongolian obliquity
Increased risk of acute leukemia
Cardiac malformations
-- Causes most childhood deaths
Live to be about 30
-- Presuming no serious cardiac malformation
Susceptible to infections
-- Causes many deaths
If live into middle age:
Alzheimer disease or dementia
Trisomy 13
Patau Syndrome
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Extra chromosome 13 (47,XX,+13)
1/15,000 births
Mental retardation
Polydactyly
Microcephaly
Rocker-bottom feet
Renal and hear defects
Umbilical hernia
Cleft lip and palate
Microphthalmia
Trisomy 18
Edwards Syndrome
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Extra chromosome 18 (47,XX,+18)
1/8,000 births
Mental retardation
Renal and heart malformations
Rocker-bottom feet
Overlapping fingers
Short neck, low-set ears
Micrognathia
Sex Chromosome Disorders
 Klinefelter syndrome (47,XXY)
 Turner syndrome (45,XO)
 XYY syndrome (47,XYY)
 Usually compatible with life
 There is little genetic information on the Y chromosome
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-- Genes for male attributes are on short arm
 Phenotypically normal males have had 2 or 4 Y chromosomes
Lyonization of X Chromosome
 Lyonization of X chromosomes: females are actually mosaics
 Barr body = genetically inactive X chromosome, stuck to
nuclear membrane
 Inactivation occurs about 16 days after conception
 Once inactivated, all daughter cells have same kind of X
chromosome
 Only 1 X chromosome is ever active in a cell
Photos: N. Vigneswaran, University of Texas at Houston, Houston, Texas
Klinefelter’s Syndrome
XXY Male
 15% are mosaic >> mild cases
 ↑ maternal age >> ↑ risk
 ↑ maternal age >> ↑ risk
 Low serum testosterone
 Tall stature
 Long arms and legs
 Hypogonadism (small testes)
 Sterile (testicular atrophy)
 Small penis
 Mental retardation
More Xs >> More MR
 Gynecomastia *
 Female pubic hair profile *
 High pitched voice *
 Reduced facial & body hair *
*feminization feature
Photo: Stevens A, Lowe J. Slide atlas of pathology. Mosby, London, 1995.
Turner’s Syndrome
Non-dysfunction in meiotic division of
gamete formation = 45,XO
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50% = mosaic
Infantile genitalia (even when adult)
No secondary sex features
Widely spaced nipples
Micrognathia
Prominent ears
Short stature
Neck webbing (distended lymphatics)
Primary amenorrhea
Cubitus valgus (wide carrying angle)
Short fourth metacarpal bone
Congenital renal anomalies
Congenital aortic anomalies
Photo: Stevens A, Lowe J. Slide atlas of pathology. Mosby, London, 1995.
Autosomal Dominant Inheritance
Rules of Inheritance
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Gender of child is not a factor
Gender of parent is not a factor; usually inherit from one parent
Each child has 50% risk of inheriting disease gene
Only affected children can pass on the disease gene
Usually anatomic/physical anomalies
Homozygous inheritance may be lethal
Osteogenesis Imperfecta
AD Inheritance
Autosomal Dominant Inheritance
Punnett (Genetic) Square
Paternal Gametes
Maternal
Gametes
A
a
a
Aa
(affected)
a
Aa
(affected)
aa
(normal)
aa
(normal)
A = disease gene
a = normal gene
Therefore, 50% of children will be affected.
Autosomal Dominant Disorders
Disease
Inherited Problem
Achondroplasia
Dwarfism due to short limb bones
Neurofibromatosis I & II
Multiple nerve sheath tumors; acoustic
neuromas
Adult polycystic disease
Enlarging cysts replacing kidney
Huntington’s disease
Progressive neural degeneration
Myotonic dystrophy
Muscle weakness and wasting
Familial hypercholesterolemia
Increased cholesterol blood levels
Osteogenesis imperfecta
Brittle bones, fractures with minimal
trauma
Marfan’s syndrome
Abnormal elastic tissues, skeletal,
cardiovascular and ocular disease
Ehlers Danlos syndrome (some types)
Abnormal collagen – skin, joints and
vascular effects
Retinoblastoma
Malignant retinal tumor
Autosomal Dominant Disorders
Mendelian Inheritance with Organ Systems Involved
System
Disorder
Nervous
Huntington disease
Neurofibromatosis
Myotonic dystrophy
Tuberous sclerosis
Urinary
Polycystic kidney disease
Gastrointestinal
Familial polyposis coli
Hematopoietic
Hereditary spherocytosis
Von Willebrand disease
Skeletal
Marfan Syndrome
Ehlers-Danlos syndrome
Osteogenesis imperfecta
Achondroplasia
Metabolic
Familial hypercholesterolemia
Acute intermittent porphyria
Extra Credit Question
47, XXY refers to what genetic disease?
A.
B.
C.
D.
E.
Down syndrome
Turner syndrome
Klinefelter syndrome
Marfan syndrome
Trisomy 13
Autosomal Recessive Disorders
Mendelian Inheritance
 Largest group of mendelian disorders
 Both alleles are mutated
-- One defective gene from each parent
 Most persons with mutation are unaffected
-- Because they are heterozygous
 Parents of AR child are normal in appearance
-- But have the disease gene
 Disease is not manifested unless child has both genes
-- Homozygous
 With only one gene: child is a carrier
-- Can pass on the gene
-- Does not have the disease
Autosomal Recessive Disorders
Mendelian Inheritance
 Each child has a 25% chance of being affected
-- Regardless of gender
 Consanguinity is common
-- Similar genes in both parents
 New mutations are rare (or are rarely discovered)
 Usually a biochemical problem
-- e.g. missing enzyme
Results:
-- Less end product
-- Accumulation of garbage
Autosomal Recessive Inheritance
Family pedigree (expression is in homozygotes)
Rules of inheritance:
 Gender of child is not a factor
 Gender of parent is not a factor; must inherit from both parents to be
affected
 Risk of inheriting disease gene varies (50-100%)
 Affected children are homozygotes
 Usually enzymatic/chemical anomalies
 Unaffected children can pass on the disease gene
Photo: Stevens A, Lowe J. Slide atlas of pathology. Mosby, London, 1995.
Autosomal Recessive Inheritance
Punnett (Genetic) Square – Single Parent with Gene
Paternal Gametes
Maternal
Gametes
a
A
a
Aa
aa
(heterozygote
carrier)
(normal)
Aa
a
(heterozygote
carrier)
aa
(normal)
Therefore, 50% of children will be carriers.
A = disease gene
a = normal gene
Autosomal Recessive Inheritance
Punnett (Genetic) Square – Both Parents with Gene
Paternal Gametes
Maternal
Gametes
A
A
a
AA
Aa
(homozygote
affected)
(heterozygote
carrier)
Aa
a
(heterozygote
carrier)
aa
(normal)
Therefore, 50% of children will be carriers and 25% will have the disease.
A = disease gene
a = normal gene
Autosomal Recessive Inheritance
Punnett (Genetic) Square – Single Parent with Disease
Paternal Gametes
Maternal
Gametes
a
a
A
A
Aa
Aa
(heterozygote
carrier)
(heterozygote
carrier)
Aa
Aa
(heterozygote
carrier)
(heterozygote
carrier)
Therefore, all children are carriers
A = disease gene
a = normal gene
Autosomal Recessive Inheritance
Punnett (Genetic) Square – Both Parent with Disease
Paternal Gametes
Maternal
Gametes
A
A
A
A
AA
AA
(heterozygote
carrier)
(heterozygote
carrier)
AA
AA
(heterozygote
carrier)
(heterozygote
carrier)
Therefore, all children are affected
A = disease gene
a = normal gene
Autosomal Recessive Disorders
Disease
Inherited Problem
Cystic fibrosis
Abnormal ion-transport protein
Sickle-cell anemia
Abnormal hemoglobin
Thalassemia
Abnormal hemoglobin
Glycogenosis
Enzyme deficiency
Mucopolysaccharidosis
Enzyme deficiency
Lipidosis
Enzyme deficiency
Phenylketonuria
Enzyme deficiency
Albinism
Enzyme deficiency
Wilson’s disease
Copper accumulation
Autosomal Recessive Disorders
Mendelian Inheritance with Organ Systems
System
Disorder
Metabolic
Cystic fibrosis
Phenylketonuria
Galactosemia
Lysosomal storage disease
α1-antitrypsin deficiency
Wilson disease
Hemochromatosis
Glycogen storage disease
Hematopoietic
Sickle cell anemia
Thalassemia
Endocrine
Congenital adrenal hyperplasia
Skeletal
Ehlers-Danlos syndrome
Alkaptonuria
Nervous
Neurogenic muscular atrophies
Friedreich ataxia
Spinal muscular atrophy
X-Linked (Sex-Linked) Disorders
Mendelian Inheritance
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Very few X-linked disorders
– e.g. Vitamin D resistant rickets
All mutated genes are on the X-chromosome
– Only 1 Y-chromosome characteristic/disease is know: hairy ears
Usually recessive
-- Rarely dominant
X-Linked (Sex-Linked) Disorders
Mendelian Inheritance
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In males only one gene is needed to produce disease
– Females are protected by their second X chromosome
-- Must have more than 50% of bad gene before a disease is expressed
Affected males cannot pass gene to sons
-- Only to daughters (50% chance)
Heterozygous females almost never express phenotypical changes
Mothers are typically carriers and give disease to sons (50% chance)
Give disease gene, not disease, to daughters (50% chance)
X-Linked (Sex-Linked) Recessive Inheritance
Rules of inheritance:
 Abnormal gene is on the X chromosome
 Gender of child is important: only males are usually affected
 Transmitted from heterozygous, unaffected females
 Unaffected males do not carry the gene
 50% of males of female carrier will be affected
 Both affected males and carrier females can transmit to produce
unaffected heterozygous female
Photo: Stevens A, Lowe J. Slide atlas of pathology. Mosby, London, 1995.
X-Linked (Sex-Linked) Recessive Inheritance
Punnett (Genetic) Square – Carrier Mother
Paternal Gametes
Maternal
Gametes
XN
Y
XD
XDXN
XDY
(carrier female)
(affected male)
XNXN
XNY
(normal female)
(normal male)
XN
Therefore, 50% of females will be carriers.
XD = disease gene
XN = normal gene
X-Linked (Sex-Linked) Recessive Inheritance
Punnett (Genetic) Square – Affected Father
Paternal Gametes
Maternal
Gametes
XD
Y
XN
XNXD
XNY
(carrier female)
(normal male)
XNXD
XNY
(carrier female)
(normal male)
XN
Therefore, all females are carriers & all males are normal.
XD = disease gene
XN = normal gene
X-Linked (Sex-Linked) Recessive Inheritance
Punnett (Genetic) Square – Carrier Mother & Affected Father
Paternal Gametes
Maternal
Gametes
XD
Y
XD
XDXD
XDY
(affected female)
(affected male)
XNXD
XNY
(carrier female)
(normal male)
XN
Therefore, 50% of males and females will be affected,
50% of females will be carriers, 50% of males will be normal.
XD = disease gene
XN = normal gene
X-Linked Recessive Disorders
Disease
Inherited Problem
Hemophilia A
Bleeding tendency due to deficiency of clotting
factor VIII
Hemophilia B
Bleeding tendency due to deficiency of clotting
factor X
G-6-PD deficiency
Attacks of hemolytic anemia after certain drugs
Duchenne’s muscular
dystrophy
Progressive muscle weakness due to dystrophin
deficiency
Becker’s muscular
dystrophy
Relative dystrophin deficiency
X-linked (Bruton’s)
agammaglobulinemia
Decreased gamma globulins due to B-cell
maturation failure
X-linked ichthyosis
Permanently thick, scaly skin due to deficiency of
steroid sulphatase
X-Linked Recessive Disorders
Mendelian Inheritance
System
Disorder
Musculoskeletal
Duchenne muscular dystrophy
Blood
Hemophilias A & B
Chronic granulomatous disease
Glucose-6-phosphate dehydrogenase
deficiency
Immune
Aggamaglobulinemia
Wiskott-Aldrich syndrome
Metabolic
Diabetes insipidus
Lesch-Nyhan syndrome
Nervous
Fragile X syndrome
Mitochondrial Inheritance
Rules of inheritance:
 Inheritance is only through maternal line
 All children of affected mother receive a dose of abnormal
mitochondria in the ovum
 Progeny of affected male are normal
 Disease severity varies with dose of abnormal mitochondria
-- Heteroplasmy = mixture of normal & abnormal mitochondria
Photo: Stevens A, Lowe J. Slide atlas of pathology. Mosby, London, 1995.
Examples of
Autosomal Dominant
Disorders
Neurofibromatosis
NF-1; von Recklinghausen Disease
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Autosomal dominant inheritance
100,000 affected persons in US
2 types:
-- NF -1 (von Recklinghausen disease) = 90% of all cases
-- NF-2 (bilateral acoustic or central neurofibromatosis)
NF-1: mutation on chromosome 17
-- Poor neurofibromin (negative regulator of the RAS oncoprotein)
Multiple neurofibromas, usually on skin
-- Nodular v. plexiform neurofibromas
Skin pigmentation (café-au-lait spots)
-- May only have the skin spots, i.e. no neural tumors
Pigmented iris hamartomas (Lisch nodules)
Neurofibromatosis
NF-1; von Recklinghausen Disease
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30-50% with skeletal deformities
-- Scoliosis
-- Erosive bone defects, bone “cysts”
-- Others
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3% of neurofibromas become malignant
-- Neurofibrosarcoma
-- Usually from plexiform types
Bilateral Acoustic or Central Neurofibromatosis
NF-2
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Mutation on 22q12
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Poor merlin (a tumor suppressor protein)
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Cafe-au-lait spots
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Bilateral acoustic schwannomas and multiple meningiomas
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No Lisch nodules
Marfan Syndrome (Marfan Disease)
AD Inheritance
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Prevalence: 2 per 10,000 population
Main problem: the glycoprotein fibrillin is defective
Mutation: on FBN1 gene at 15q12, in 100% of cases
– FBN1 gene has 100+ different mutations!
25% are sporadic (spontaneous) mutations
Clinical features are primarily from poor connective tissue:
– Tall, slender body and thin face (like Abraham Lincoln)
– Ocular problems (dislocation, subluxation)
– Cardiovascular problems (aneurysm)
– Skin: “stretch marks” in areas of recurring stress
– Other: hypotonia (weak muscles), spontaneous pneumothorax
(air in lungs)
Ehlers-Danlos Syndromes (EDSs)
Mendelian Inheritance
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Main problem: defective collagen synthesis
-- There are 18+ types of collagen, all can be affected
Can be AD, AR, or X-linked: 10+ different types
Clinical features are primarily from poor connective tissues:
– Skin: hyperextensibility of skin, fragility
– Joints: hypermobility (“double jointed’), as seen in “rubber men”
in circus side shows
– Other: ruptured colon, blood vessels; detached retina
Familial Hypercholesterolemia
AD Inheritance
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Prevalence: 1 per 500 population; one of the most common
mendelian disorders
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Main problem: mutation of receptor protein
for low-density lipoprotein (LDL)
– LDL transports 70% of the cholesterol
in the blood
– 75% of LDL receptors are on hepatocytes
liver makes endogenous cholesterol
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Mutation impairs intracellular transport
and catabolism of LDL >>
LDL cholesterol accumulates in serum
IDL = intermediate-density lipoprotein
VLDL = very-low-density-lipoprotein
Familial Hypercholesterolemia
AD Inheritance
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With fewer liver LDL receptors:
-- Elevated serum cholesterol levels
– Macrophages must work harder to break it down >>
xanthomas of skin and tendon sheaths
– Endothelial cells must work harder to break it down >>
atherosclerosis
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Heterozygotes: 3x elevation of serum cholesterol levels
– Homozygotes: 5x elevation of serum cholesterol levels
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Treatment: statin drugs
-- Promote synthesis of LDL receptors
Examples of
Autosomal Recessive
Disorders
Phenylketonuria (PKU)
AR Inheritance
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Classic form is common in persons of Scandinavian descent,
-- Uncommon in blacks and Jews
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Homozygotes: severe deficiency of phenylalanine hydroxylase >>
hyperphenylalaninemia & PKU
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Inability to convert phenylalanine into tyrosine
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Normal at birth, but in a few weeks phenylalanine levels rise >>
severe mental retardation (by 6 mo.) & seizures
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Intermediate metabolites excreted into urine & sweat >> strong
musty or mousy odor
Phenylketonuria (PKU)
AR Inheritance
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100+ mutant alleles have been identified
– With some mutations: minimal problem
(benign hyperphenylalaninemia), but will test positive
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Some variants: disease cannot be corrected with diet
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1/3 cannot walk; 2/3 cannot talk
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Decreased pigmentation of hair and skin (less tyrosine to create
melanin); eczema
Phenylketonuria (PKU)
AR Inheritance
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If diet-controlled mother stops controlling her diet, then has baby >>
baby is severely mentally retarded
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Most states test new babies for this (e.g. Guthrie test)
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Treatment: avoid intake of phenylalanine from infancy (check food
labels, e.g. aspartame)
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Also: mothers with PKU tendencies must lower phenylalanine levels
before having a baby
Lysosomal Storage Diseases
AR Inheritance
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Inherited lack of lysosomal enzymes >> intracellular buildup of
improperly degraded cell products

Abnormal storage: primarily in mononuclear phagocyte system

35 different diseases, each related to a specific enzyme deficiency

Very rare

Tay-Sachs disease

Niemann-Pick disease

Gaucher disease
Tay-Sachs Disease (GM2 Gangliosidosis)
AR Inheritance


Lysosomal storage disease; hexosaminidase α-subunit deficiency
Gangliosides accumulate in the brain and peripheral nerves
-- Usually within neurons and axons
Tay-Sachs Disease (GM2 Gangliosidosis)
AR Inheritance

85+ mutations identified
-- Most affect protein folding or intracellular transport

Most common among Ashkenazi Jews (1 of every 30)

Carriers can be detected via DNA analysis or checking
level of hexosaminidase in serum

Mental retardation, blindness, severe neurologic
dysfunction

Death by 3 years of age
Niemann-Pick Disease
AR inheritance

Lysosomal storage disease; sphingomyelinase deficiency

Sphingomyelin accumulates in phagocytic cells (liver, spleen,
marrow, lungs, lymph nodes), neurons

Massive visceromegaly and severe neurologic deterioration

Death within 3 years

Detection: evaluate sphingomyelinase
activity in leukocytes or fibroblasts
-- DNA-probe analysis
Foamy Hepatocytes
Gaucher Disease
AR Inheritance



Mutation of gene encoding glucocerebrosidase
Accumulation of glucocerebrosides in mononuclear phagocytic cells
-- From RBC breakdown
Chronic non-neuropathic form: 99% of all cases,
-- Hepatosplenomegaly
-- Gaucher cells in spleen, liver, lymph nodes, bone marrow >>
internal bone resorption, fewer blood elements, anemia,
leukopenia >> compatible with long life
Gaucher Disease
AR Inheritance




Most common in Ashkenazi Jews
Two of the three variants are lethal in childhood
--Severe CNS damage
Diagnosis for carriers: evaluated level of
glucocerebrosidase in leukocytes
Treatment: enzyme replacement via infusion of purified
glucocerebrosidase
Mucopolysaccharidoses (MPSs)
AR Inheritance (Usually)

Seven variants (MPS I - MPS VII), each with specific enzyme
deficiency

Mucopolysaccharides progressively accumulate in all tissues

Course facial features, corneal clouding, joint stiffness, mental
retardation

Urinary excretion of mucopolysaccharides is increased

Hurler syndrome (MPS 1 H)
Hunter syndrome (MPS II)

Hurler Syndrome
MPS 1 H; AR Inheritance

Deficiency of L-iduronidase >> accumulation of mucopolysaccharides

Ground substance is a mess >> joint stiffness

Course facial features + deformed bones of face >> gargoylism

Severe mental retardation
-- Lysosomal inclusions in neurons

Death within 6-10 years from cardiac problems
-- Mucopolysaccharides in coronary arteries
Examples of
X-Linked
Disorders
Hunter Syndrome
MPS II; AR Inheritance



X-linked recessive inheritance
Deficiency of L-iduronosulfate sulfatase >> accumulation of
mucopolysaccharides
No corneal clouding
Developmental Anomalies
Pattern
Definition &/or Mechanism
Example(s)
Agenesis
Complete failure to develop. Early failure
of development
Renal agenesis
Hypoplasia
Incomplete development; probably due
to teratogen during growth phase.
Microcephaly (alcohol)
Phocomelia (thalidomide)
Dysplasia
Abnormal tissue organization; failure of
differentiation and maturation
Renal dysplasia
Dysraphism
Failure of embryologic fusion
Myelomeningocele
Ectopia vesicae
Failure of
involution
Temporary embryological structure
remains indefinitely
Persistent urachus
Thyroglossal duct
Syndactyly
Atresia
Failure of lumen formation (no
programmed cell death in solid cylinder
of cells
Esophageal atresia
Biliary atresia
Ectopia
Organ or tissue displacement; failure of
cell migration during embryological
development
Maldescent of testes
Fordyce granules