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Pathobiology: Genetic Diseases (Poulik)
GENERAL PRINCIPLES OF GENETIC DISEASES AND SINGLE GENE DISORDERS:

Genetic Mutations:
Definition: stable, heritable alteration in DNA
Different Types of Mutations:
o Chromosomal Level: result in cytogenic or karyotypic abnromalities

Genome mutation: loss or gain of a whole chromosome (ie. trisomy)

Chromosome mutation: structural changes in chromosome that gives rise to visible structure
changes in the chromosome (ie. translocations, deletions)

Trinucleotide repeats: although gene mutations, may be visible by karyotype when cells
cultured in different media (ie. Fragile X syndrome visible in foalte deficient media)
o Gene Level: most are NOT visible by karyotype (some trinucleotide repeats are the exception) and
therefore require molecular genetics techniques to define mutation (ie. DNA sequencing)

Point Mutations: single base substitution
 In exon: protein coding sequence of enzyme, structural or regulatory protein
 In intron: in non-protein coding sequences (promoter, enhancer etc.)
o May lead to reduction or loss of transcription

Frameshift Mutations: caused by deletions or insertions in coding sequence and alterations
in reading frame of DNA

Trinucleotide Repeats
Pathological Significance of Genetic Alterations: may do a number of things
o Directly cause disease (ie. Tay Sachs)
o Predispose to disease (ie. X-linked agammaglobulinemia)
o Alter response to another disease (sickle cell anemia protection against malaria)
Manifestations of Genetic Disease:
o Abnormal metabolism or physiology
o Abnormal development that may result in major or minor malformations
o Spontaneous abortion or stillbirth (with or without malformations)
o Asymptomatic or subclinical (ie. female carrier of X-linked trait)

Single Gene Disorders with Mendelian Inheritance:
Definition: diseases resulting from a mutation in a single gene of large effect, inherited according to Mendelian
patterns
Inheritance Patterns: most are recessive*
o Autosomal Dominant: clinical phenotyp occurs with single copy of mutant allele

Usually non-enzymatic proteins

1 parent affected (if not affected, de novo mutation)

Both males and females affected

1 in 2 chance of transmitting disorder

Clinical features modified by reduced penetrance and expressivity
o Autosomal Recessive: clinical phenotype occurs only when both alleles are defective (although defect
in both alleles does not have to be the same)

Usually enzymatic proteins

Trait usually does not affect parents

Both males and females affected

1 in 4 chance of transmitting disorder

More uniform expression of defect than AD disorders (complete penentrance common)

Onset usually early in life
o X-linked: more common in males (only 1 X cs)
Mechanisms of Pathogenesis of Single Gene Disorders:
o Mutations:

Enzymes or enzyme inhibitors

Receptors

Transport or structural proteins
o Enzyme Defects: result in reduce or absent enzyme leading to specific block in metabolism (usually of a
catabolic pathway) leading to

Abnormal accumulation of metabolites (substrates)

Decreased amount of end product that is necessary for normal function

Failure to inactivate a tissue damaging substance
ENZYME DEFECTS- LYSOSOMAL STORAGE DISEASES:

Lysosomal Storage Diseases- General:
Lysosomes: “intracellular digestive tract” involved in turnover of macromolecules within the cell
o Contain degradative enzymes called hydrolases
o Function in acid environment of the lysosome
o Made in the ER, sent to the Golgi, undergoes post-translational modification to target it to lysosomes
Lysosomal Storage Diseases: due to lack of any protein essential for normal function of lysosomes
o Distribution of non-degraded material (ie. organ affected) due to an LSD is determined by:

Tissue where most of the degraded material is found

Location where most of the degradation usually occurs
o Rare (1/8000 births)
o Most are autosomal recessive

Exceptions: both are X-linked recessive
 Fabry Disease
 Hunter Syndrome
o Grouped based on type of macromolecule undergoing degradation:

Mucopolysaccharides

Sphingolipids

Sulfatidoses

Cerebrosides

Mucopolysaccharidoses (MPS):
General:
o Mucopolysaccharides: group of macromolecules composed of glycosaminoglycans (GAGS), which are
long chain carbohydrates with disaccharide repeating units

GAG Examples:
 Dermatan sulfate (heart, blood vessels, skin)
 Heparan sulfate (lung, arteries, skin)
 Keratan sulfate (cartilage, cornea, intervertebral discs)
 Chondroitin sulfate
 Hyaluronic acid

Proteoglycans: GAG + protein (secreted by GAG synthesizing cells)

Function: involved in structural integrity of the ECM

GAG Synthesizing Cells: fibroblasts, endothelial cells, leukocytes
 Secrete proteoglycans
 GAGs that are not secreted are degraded by lysosomal hydrolases (enzyme
deficiency results in accumulation in lysosomes and free GAGs in urine)
o Mucopolysaccharidoses (MPS):

Usually progressive disorders

Classified numerically from MPSI-MPSIV

Share similar clinical features:
 Multi-system involvement
 Organomegaly
 Abnormal facies
 Joint stiffness and deformity
 Mental retardation

Diagnosis:
 Presence of GAGS:
o Urinary: age-dependent (present in normal infants up to a year old)

Look for larger than normal amounts of heparan and dermatan
sulfate (normal urine contains mostly chondroitin sulfate)
o Amniotic fluid
 Enzyme Assays:
o Prenatal:

Cultured cells from amniotic fluid

Chorionic villus biopsy less suitable (have low enzyme activity)
o Postnatal: measure enzyme activity in plasma, leukocytes or skin
fibroblasts
-
-

Hurler Syndrome (MPS I):
o Inheritance Pattern: autosomal recessive
o Deficiency: α-L-idurondase enzyme activity
o Onset: 6-8 months
o Common Features: severe mental and motor regression with death usually before 10 years of age

Respiratory disease
 Storage in airway epithelium and bone
 Small ribcage (oar-shaped ribs) and stiff joints
 Decreased expansion due to hepatomegaly
 Upper airway obstruction due to storage in tongue, lymphoid tissue, airway
epithelium, pharyngeal soft tissue

Coarse facial features

Ophthalmic disease with early corneal clouding (retinal disease, glaucoma)

CV disease (valve disease, CAD, congestive heart failure)
 Accumulation of GAGs in histiocytes, mycocardial cells, heart valves, coronary
arteries and aorta

Dwarfing
 Accumulates in bone (growth plates) and prevents linear growth

Stiff joints

Hepatosplenomegaly
 Storage in hepatocytes and Kupffer cells of lvier
 Storage in histiocytes in the spleen

CNS disease (mental retardation, hydrocephalus, spinal cord compression)
 Storage in neurons, macrophages and meninges

Deafness

Alder-Reilly anomaly (accumulation of MPS in PMNs- granular appearance)
o Diagnosis: urinary excretion of dermatan and heparan sulfate
Hunter Syndome (MPS II):
o Inheritance Pattern: X-linked recessive
o Deficiency: iduronate sulfatase
o Onset: in early infancy or childhood
o Common Features: similar clinical features to Hurler, but LESS severe (mental deterioration with
varying degrees of neurological involvement)

Coarse facial features

Dwarfing

Stiff joints

Progressive deafness

NO corneal clouding*
o Diagnosis: urinary excretion of dermatan and heparan sulfate
Sphingolipidoses:
General:
o Cause: defect in metabolism of sphingolipids
o Sphingolipids: long-chain amino alcohols (sphingosine) attached to a fatty acid to produce a complex
lipid (ceremide)

Membrane Lipids:
 Sphingomyelin
 Glycosphingolipids:
o Cerebrosides (add sugar to ceremide)
o Sulfatides
o Globosides
o Gangliosides (add polysaccharide + N-acetylnueramic acid to ceramide)
Niemann-Pick Disease:
o General:

Type I (A and B):
 Cause: deficiency of sphingomyelinase enzyme, leading to progressive
accumulation of sphingomyelin (ubiquitous component of cellular organellar
membranes)

o
Type I:


o
-
Type II (C and D):
 Cause: defect in cholesol esterification causing lysosomal accumulation of
unesterified cholesterol
Type A (Severe Infantile):
 Most common of type I: 70-80% of all cases (often in Eastern European Jews)
 Presentation: within the first weeks of life (death occurs by age 3 or 4)
o Severe neurologic impairment (hypotonia, progressive psychomotor
retardation)
o Failure to thrive
o Hepatosplenomegaly (marked)
o Macular cherry red spot (50% of patients)
o Accumulation of foamy lipid macrophages in many tissues (liver, lung,
spleen, LNs, kidneys, bone marrow, peripheral and central neurons)
o Atrophy of the brain
Type B (Chronic Visceral):
 Less common than Type A: also often seen in Eastern European Jews
 Presentation: infancy or childhood (typically survive into adulthood)
o Organomegaly (often present with splenomegaly and then develop
generalized visceral involvement)
o Generally NO CNS involvement
Type II:

Type C:
 Most common: more common than A and B combined
 Cause: defect in NPC-1 (95%) or NPC-2 gene that encodes for a protein involved in
cellular trafficking of exogenous cholesterol (normally brings free cholesterol from
the lysosome to the cytoplasm)
 Clinical Features: variable
o Classic Phenotype (Neurovisceral): presents in childhood (2-4 years) with
death typically occurring between 5-15 years of age

Variable hepatosplenomegaly

Vertical supranuclear opthamoplegia (supranuclear palsy)

Progressive ataxia

Seizures

Psychomotor regression (accumulation of cholesterol in
neurons is lethal to those cells)

Bone marrow contains Niemann-pick cells (foamy) and sea blue
histiocytes
o May present at birth with hydrops fetalis and still birth
o Fatal neonatal liver disease (giant cell hepatitis)
o If live into adulthood, may present with dementia and psychosis

Type D:
 Rare variant of type C: found in Nova Scotia (less severely affected)
Gangliosidoses:
o GM1 Gangliosidoses:

Deficiency: deficiency in β-galactosidase enzyme that results in accumulation of ganglioside
in neurons (clinical variability depends on amount of residual enzyme activity)
 Β-Galactosidase Enzyme: 3 isoenzymes (A,B,C)
o Transcription of this enzyme requires an activator that may cause similar
features if deficient

Type I (Generalized/Infantile):
 Deficiency: virtual absence of all 3 isoenzymes of B-galactosidase
 Onset: birth to 6 months (death often before age 2)
 Clinical Features:
o Progressive neurologic deterioration (seizures)
o Coarse facial features
o Hepatosplenomegaly (accumulation of gangliosides in liver, spleen, renal
tubular epithelium)
o
o
o

-
Macular cherry red spots (50% of patients)
Skeletal deformities (dystosis multiplex)
Has features of both neurolipidoses and MPS, leading to a “pseudoHurler phenotype”
Type II (Juvenille):
 Deficiency: absence of A and B isoenzymes only
 Onset: juvenile (1-2 years old) with death occurring by age 3-10
 Clinical Features:
o Slower psychomotor retardation
o Less visceromegaly
o Milder skeletal disease

Diagnosis:
 Measurement of B-galactosidase activity in peripheral blood leukocytes:
o Type I: virtually no activity
o Type II: 5-10% activity
 Peripheral Blood Smear: vacuolization of lymphocytes (crude method due to the
fact that many LSDs have this feature)
o GM2 Gangliosidoses:

Cause: inability to catabolize GM2 ganglioside (required 3 polypeptides encoded by 3
separate loci)
 Tay Sachs Disease: defect in α subunit of Heaminidase A
 Sandhoff’s Disease: defect in β subunit of Hexaminidase A
 GM2 Activator Deficiency Gangliosidosis: defect in GM2 activator

Clinical Features: similar because they all result in GM accumulation
 GM2 accumulates in many tissues, but CNS and retina are the dominant features of
the disease
o Neurons are swollen and contain cytoplasmic vacuoles
o Lysosomes contain whorled material by EM
o Brain first enlarges, and then becomes atrophic
 Infants appear normal at birth, followed by rapidly progressive neurodegenerative
disease with seizures, dementia and blindness
o Loss of motor skills at 3-6 months
o Death by 2-4 years of age
 Macular cherry red spot

Ethnic Risk: 1/30 carrier rate in the Askenazi Jewish population
Sulfatidoses:
o Metachromatic Leukodystrophy:

Cause: deficiency of arylsulfatase A enzyme, leading to the accumulation of non-degradeable
galactocerebroside sulfate in the white matter of the brain, peripheral nerves, liver and
kidney
 Results in breakdown of myelin sheath (demyelination and gliosis)
 As a result, predominantly a neurodegenerative disorder
 Arylsulfatase A also requires presence of saposin B (solubilizes hydrophobic lipid to
allow it to be accessible to the enzyme) and therefore, absence of SAP will cause
similar disease

3 Forms:
 Late Infantile: most common (diagnosed by age 2; death before age 5)
o Regression of motor skills (hypotonia, muscle weakness)
o Mental deterioration (loss of milestones)
o Rigidity and convulsions
o Unusual loss of white matter on CNS imaging
 Juvenile: diagnosed between 3-16 years of age; death 6-8 years after diagnosis
o Changes in gait and cognitive skills
o Progressive regression of all skills
 Adult Onset: diagnosed after 16 years of age
o Psychiatric or cognitive symptoms occur first
o Motor symptoms (neurologic) appear later

-
Diagnosis:
 Urine: spot screening test (shows metachromasia due to presence of sulfatide)
 Imaging: usual loss of white matter due to demyelination
 Biopsy: usually of a sural nerve (demyelination, metachromatic granules and
unusual cytoplasmic inclusions)
o Stains: PAS +, Alcian blue, acidified Cresyl violet
 Arylsulfatase A activity levels
 Genetic testing: gene located on long arm of cs 22
o Multiple Sulfatase Deficiency:

Cause: reduction in activities of several sulfatidases (arylsulfatidase A,B,C) resulting in the
accumulation of sulfatides, sulfated GAGs, sphingolipids and steroid sulfates

Clinical Presentation: combines clinical features of metachromatic leukodystrophy and MPS
Cerebrosidoses:
o Gaucher Disease: most common lysosomal storage disease*

Defect: glucocerebrosidase enzyme (results in accumulation of glucocerebrosides and other
glycolipids)
 Glucocerebrosides: derived from breakdown of the membranes of senescent
leukocytes and RBCs
 Accumulation: incompletely metabolized substrate stored in monocytes and
macrophages (stains positively with PAS)
o Gaucher Cell: crumpled paper appearance to cytoplasm with
eccentrically displaced nucleus

Type 1 (Chronic Non-Neuronopathic Form):
 Cause: reduced levels of glucocerebrosidase
 Most common type: 99% of cases
 Population affected: children and adults (common in Ashkenazi Jews)
 Clinical features: accumulation of glucocerebrosidase limited to mononuclear
phagocytes throughout the body, WITHOUT brain involvement
o Hepatosplenomegaly
o Cytopenias secondary to (hypersplenism and bone involvement)
o Bone involvement:

Avascular necrosis (esp. of the hip)

Osteopenia with fractures (radioluscent bones due to
replacement by Gaucher cells)

Lytic lesion

Bone crises (collections of Gaucher cells interfere with
vascularization, causing SEVERE pain)

Erlenmeyer flask deformity (abnormality in new bone
formation resulting in flattened ends of femurs)

Type 2 (Acute Neuronopathic Form):
 Cause: absent glucocerebrosidase
 Population affected: infants, with death usually by age 2; no predilection for
Ashkenazi Jews (panethnic)
 Clinical features:
o Progressive CNS involvement
o Hepatosplenomegaly
o Cytopenias (secondary to hypersplenia)
o NO bone involvement

Type 3 (Sub-Acute, Intermediate Form):
 Cause: reduced glucosidase activity
 Population affected: rare, juvenile form
 Clinical features:
o Progressive CNS involvement (begins in teens and twenties)
o Hepatosplenomegaly
o Cytopenias (secondary to hypersplenism and bone involvement)
o Bone involvement

Diagnosis: measurement of glucocerbrocidase activity (peripheral blood leukocytes or
fibroblast culture)

-
Treatment:
 Replacement therapy with recombinant enzymes
 Bone marrow transplantation
 Future gene therapy
Other Sphingolipidoses:
o Fabry Disease
o Krabbe Disease
ENZYME DEFECTS- DISORDERS OF CARBOHYDRATE METABOLISM:

Galactosemia:
Cause: deficiency of galatose-1-phosphate uridyltransferase enzyme
Inheritance: autosomal recessive
Clinical Features:
o Symptoms: appear a few days after milk ingestion

Vomiting

Failure to thrive

Diarrhea

Liver dysfunction
o Accumulation of galactose-1-phosphate: causes damage to liver, CNS, and other body systems (eyes,
liver and brain most affected)

Renal failure

Hepatomegaly and cirrhosis

Cataracts

Brain damage

Increased frequency of E.coli septicemia
o Pathologic Findings:

Marked steatosis of hepatocytes (eventually leading to cirrhosis)

Brain shows edema, gliosis and neuronal necrosis
Lab Diagnosis:
o Galactosuria (clintest will be positive)
o Generalized aminoaciduria, proteinuria and hyperchloremic acidosis common
Newborn Screening: will likely never see a case because of this
Other causes of elevated levels of galactose:
o Galactokinase deficiency
o UDP-galactose-4-epimerase deficiency

Glycogen Storage Diseases:
General:
o Cause: defects in enzymes involved in degrading and in synthesizing glycogen

Note: glycogen also degraded by lysosomes by acid maltase; deficiency in this enzyme will
result in lysosomal accumulation of glycogen
o Glycogen:

Liver: maintains normal blood glucose during fasting
 Defects: storage of glycogen in the liver leading to reduced blood glucose

Muscle: provides substrates for generation of ATP through glycolysis for muscle contraction
 Defects: storage of glycogen in the muscle leading to muscle weakness
o Presentation: with either liver or muscle involvement, or a more generalized picture
Hepatic Forms:
o General: cause hepatomegaly and hypoglycemia
o Von Gierke Disease (Type I):

Defect: glucose-6-phosphatase enzyme

Clinical Presentation:
 Hepatomegaly (leading to adenomas and eventually carcinomas)
 Renomegaly
 Short stature
 Excessive fat in the face and buttocks (doll-like appearance)
 Marked lipidemia (causing eruptive xanthomas)
 Severe fasting hypoglycemia

-
-
Pathologic Findings:
 Liver: uniform distribution of glycogen within hepatocytes (distended)
 Renal tubular cells: accumulation of glycogen
 Muscle: normal
Myopathic Forms:
o General: causes glycogen storage in muscles
o McArdle Disease (Type V):

Defect: deficiency in muscle phosphorylase enzyme (required to convert glycogen to G1P)

Clinical Presentation:
 Muscle weakness and painful cramps after exercise WITHOUT increased lactate
 Prolonged exercise can result in muscle fiber necrosis (rhabdomyolysis),
myoglobinuria and acute renal failure
 Marked decline in muscle function and wasting of individual muscle groups with
age (typically presents in 2nd/3rd decade of life)

Pathologic Findings:
 Skeletal Muscle:
o Subsarcolemmal accumulation of glycogen (forms vacuoles and blebs
seen by LM)
o Can also stain for muscle phosphorylase enzyme
Systemic Forms:
o General: do not fit in hepatic or myopathic categories
o Pompe Disease/Generalized Glycogenosis (Type II):

Defect: lysosomal enzyme acid maltase (alpha-1-4 glucosidase)

Clinical Features:
 Presentation: infantile (death by 1-2 years of age)
 Symptoms:
o Muscle weakness (hypotonia and wasting)
o Heart involvement (cardiomegaly leading to progressive heart failure)*
o Hepatomegaly
o Enlarged tongue

Pathologic Findings:
 Glycogen deposits in lysosomes: in myocardium, skeletal muscle, liver, smooth
muscle of vessels, neurons of CNS
o PAS: glycogen
o PAS diastase: shows empty space where glycogen was digested
o EM: glycogen in packets within lysosomes
o Anderson’s Disease/Brancher Glycogenosis (Type IV):

Defect: amylo-1,4-to 1,6-transglucosidase (brancher enzyme)

Clinical Features:
 Presentation: more generalized disease presenting in infancy with death within 2
years due to cirrhosis
 Symptoms:
o Hepatomegaly and failure to thrive in the first year of life
o Progresses to portal fibrosis, cirrhosis and death
o Cardiomyopathy
o Muscle atrophy

Pathologic Findings:
 Liver: diffuse fibrosis and remaining hepatocytes contain cytoplasmic
accumulations of chunky, hyaline or vacuolated material
o Abnormal deposits are PAS+ but diastase resistant
ENZYME DEFECTS- DISORDERS OF AMINO ACID METABOLISM:

Phenylketonuria (PKU):
Cause:
o Classic: deficiency of phenyalanine hydroxylase (PAH; 98% of cases)

Cannot convert Phe  Tyr
o Other: in these cases, the patients are also unable to metabolize tyrosine and tryptophan, and dietary
restriction will not prevent neurologic impairment
-
-
-
-

Abnormalities in BH4 (cofactor for PAH)

Abnormalities in dihydropteridine reductase (DHPR) enzyme that recycles BH4
Clinical Features:
o Mental retardation
o Fair hair and blue eyes
o Musty body odor
o Eczema
Laboratory Screening:
o Newborn screening
o Urinary excretion of minor pathways of phenylalanine metabolism

Phenylpyruvic acid, phenyllactic acid, phenylacetic acid
o Serum phenyalanine levels
Management:
o Infant strict dietary restriction (to prevent mental retardation)
o Children over 10 may be able to tolerate normal diet (more common thinking is diet for life)
o Pregnancy requires dietary restriction
Pathologic Findings:
o Gray and white matter changes

Demyelination and gliosis in white matter
DEFECTS IN MEMBRANE PROTEINS:

Familial Hypercholesterolemia:
Defect: in LDL receptor that transports cholesterol, leading to hypercholesterolemia
Pathologic Consequences:
o Accelerated atherosclerosis
o Skin xanthomas (focal accumulations of cholesterol in macrophages)
DEFECTS IN TRANSPORT PROTENS:

Cystic Fibrosis:
Inheritance: autosomal recessive
Cause: mutation in CFTR gene (can be severe or mild) that codes for a transporter necessary for chloride
transport
o Location: lungs, intestines, pancreas, sweat glands, reproductive tract
o Result: defective transport results in defective passage of chloride and water, resulting in production
of thick secretions
o Most common genotype: F508 (70% of all cases) mutation that results in loss of aa at 508 position

Result: little or no functional CFTR
Clinical Features: due to F508 mutation (most severe)
o Lungs: thick bronchial secretions, leading to obstruction and infections
o Pancreas: thick secretions block ducts, leading to backup of enzymes and autodigestion of pancreas

Results in fibrosis and loss of pancreatic parenchyma
o Intestines: thick secretions lead to blockage and in utero atresia
o Vas deferens: thick secretions lead to blockage and resultant sterility
DEFECTS IN STRUCTURAL PROTEINS:

Marfan Syndrome:
Cause: defect in FBN1 gene coding for fibrillin-1 (located on cs 15q21)
o Fibrillin-1: major component of microfibrils in the ECM (abundant in aorta, ligaments and ciliary
zonules supporting lens)

Mutant fibrillin-1 disrupts the assembly of normal microfibrils
Inheritance: autosomal dominant (7-85% of cases)
Clinical Features:
o CV:

Dilated ascending aorta, aneurysms, dissection due to cystic medionecrosis

Mitral valve prolapse
o Skeletal abnormalities:

Tall stature

Abnormal joint mobility
o

Scoliosis and pectus excavatum

Arachnodactyly (abnormally long fingers)
Ocular Abnormalities:

Ectopia lentis

Myopia
DEFECTS IN PROTEINS REGULATING CELL GROWTH:

Neurofibromatosis Type 1 (NF-1):
General:
o Inheritance: autosomal dominant
o Frequency: 1/3000
o Penetrance: 100%
o Expressivity: variable
Cause: defect in NF-1 gene located at cs 17q11.2, which codes for neurofibromin protein (normally down
regulates p21 and ras
NIH Diagnostic Criteria: must have 2 or more of the following
o 6 or more pigmented skin lesions (café au lait spots; found in over 90% of patients)
o Freckling in the axillary or inguinal regions
o Pigmented iris hamartomas (Lisch nodules; found in over 94% of patients)
o 2 or more neurofibromas of any type OR 1 plexiform neurofibroma

Neurofibromas: benign tumors involving peripheral nerves (but are at increased risk for
developing malignant transformation to malignant peripheral nerve sheath tumors/MPNST)

Plexiform neurofibromas: less common but can cause disfigurement and loss of function
o Optic glioma

Tumor that can lead to blindness
o 1st degree relative with NF1
Other Manifestations:
o Skeletal abnormalities (scoliosis)
o 2-4x increased risk of developing other tumors

Neurofibromatosis Type 2 (NF-2):
General:
o Inheritance: autosomal dominant
o Penetrance: 100% by age 60
o Less common than NF1: 1/40,000
Cause: defect in NF-2 gene located on cs 22, which codes for the protein merlin
o Merlin: may function to mediate communication between extracellular milieu and cytoskeleton
Clinical Features:
o Presents in 2nd and 3rd decades (with 100 % penetrance by age 60)
o Bilateral acoustic schwannomas
o Multiple menangiomas (can be deadly)
o Ependymomas of the spinal cord
MULTI-FACTORIAL AND CHROMOSOMAL DISORDERS:

Multifactorial Conditions: result from the interaction of 2 or more mutant genes and environmental influences
General Characteristics:
o Increased occurrence in families
o Aggregation shown to be genetic rather than environmental
o Familial pattern does not fit Mendelian patterns
More Specific Characteristics of Multifactorial Disorders:
o Risk of expressing a disorder is related to the number of deleterious genes inherited
o Environmental risk factors modify the risk of expressing the disease
o Rate of recurrence is the same for all first degree relatives (2-7%)
o Risk of recurrence depends on the outcome in previous pregnancies

One child affected, 7% chance

Two children affected, 9% chance
Examples of Multifactorial Conditions:
o Coronary Heart Disease, HTN, Type I Diabetes Mellitus, Colorectal cancer, Cleft lip/palate

Chromosomal/Cytogenic Disorders:
Cause: abnormal number of cs or a structural abnormality of a cs (sex chromosomes or autosomes)
o Constitutional/Congenital: involving all cells in the body
o Acquired post-natally: involving a limited cell population
KARYOTYPIC DISORDERS- NUMERIC DISORDERS:

Trisomy 21 (Down’s Syndrome):
Incidence: 1/700
o Affected by maternal age:

<20: 1/1500

>45: 1/25
Cause:
o 47 XX, +21: most common (95%); due to MEIOTIC non-disjunction
o Translocation: 4%
o Mosaicism- 46 XX/47XX +21: 1%; due to MITOTIC non-disjunction
Clinical Features:
o Intrauterine growth retardation (reduced growth rate and stature)
o Neurologic findings

Mental retardation

Hypotonia at birth

Alzheimer’s Disease
o Minor dysmorphisms:

Characteristic facial features (epicanthic folds, flat facial profile, low set ears)

Hand anomalies (Simian crease)

Hyperextensibility of the joints
o GI abnormalities

Duodenal atresias (double bubble sign)

Hirschsprung Disease
o Congenital heart defects
o Predisposition to leukemia
o Immunologic defects leading to infections (leading cause of death)
Detection: karyotype, FISH

Trisomy 18 (Edward’s Syndrome):
Incidence: 1/8000
Genotype: most are 47XX, +18 (95%); mosaicism also possible
Outcome: only 5-10% live beyond first year of life
Clinical Features:
o Craniofacial dysmorphisms

Prominent occiput

Microcephaly

Micrognathia

Low set ears (flat pinna with pointed upper portions)

Clenched fists with overlapping fingers
o Neurologic abnormalities:

Mental retardation

Feeding difficulties and apnea
o Malformations:

Congenital heart defects

Renal malformations (horseshoe kidneys)

Rocker bottom feet
o Visceral abnormalities:

Tracheoesophageal fistula

Esophageal atresia

Trisomy 13 (Patau’s Syndrome):
Incidence: 1/15000
Cause: most result from non-dysjunction
-
Clinical Features:
o Dysmorphisms:

Microcephaly

Microopthalmia

Midline facial defects (bilateral cleft lip, proboscis- nose defect)

Umbilical hernia
o Neurologic abnormalities:

Mental retardation
o Malformations:

Polydactyly

Aplasia cutis congenital (hole in the scalp)

Congenital heart defects

Renal malformations

Rocker bottom feet

Klinefelter Syndrome (47XXY):
General: one of the most common causes of hypogonadism in men
Incidence: 1/500 live male births
Karyotypes: XXY most common
o Others: XY/XXY and XXY/XXXY mosaics, XXYY (rare, severe phenotype)
Clinical Features:
o Elongated body (increased length between sole and pubic bone)
o Small atrophic testes and small penis
o Lack of secondary male characteristics
o Gynecomastia
o Renal and ureteral abnormalities

Renal cysts

Hydronephrosis

Hyroureter

Ureterocele

Turner Syndrome (45 X):
Incidence: 1/2500
Fetal Mortality: very high (99% of conceptuses spontaneously aborted)
Karyotypes:
o Monosomy (45 X): 57%
o Mosaics: 29%
o Structural abnormalities of X cs: 14%
Clinical Features:
o Short stature
o Webbed neck
o Broad chest with wide spaced nipples
o Ovarian dysgenesis (streak gonads)
o Many pigmented nevi (birthmarks)
o Cardiac defects (coarctation of the aorta)
o Congenital lympedema (with residual puffiness in hands/feet)
KARYOTYPIC DISORDERS- STRUCTURAL ABNORMALITIES:

Deletion 22q11 Syndrome (DiGeorge and Velocardial Facial Syndromes):
Cause: deletion of band 11 on long arm of cs 22 (at least 30 genes in this segment, and therefore, patients have
significant clinical heterogeneity)
Clinical Features:
o Congenital heart defects
o Cleft palate (NOT cleft LIP)
o Facial dysmorphism

Prominent nose with hypoplastic nares

Upslanted palpebral fishers

Small mouth with everted lip

Small abnormal ears
Developmental delay (with possible psychotic illness)
Variable degrees of T cell immunodeficiency

Thymic hypoplasia or dysgenesis
o Hypocalcemia (if PT glands absent)
Diagnosis:
o FISH
o Prenatal testing available for fetuses with congenital heart defects or cleft palate detected by
ultrasound
o
o
-

Fragile X Disease:
General: common genetic cause of mental retardation
Incidence: 1/1500 for males; 1/8000 for females
FMR 1 Gene: located on X cs (q27.3)
o Encodes FXMR protein found in the cytoplasm of many cells (esp. abundant in neurons and gonads)
Cause: CGG repeats in the FMR1 gene
o Normal: 10-55 repeats
o Premutation: 55-200 repeats (transmitting males, carrier females)

At risk for developing the following issues:
 Mild cognitive/behavioral deficits
 Premature ovarian failure
o Occurs in FEMALES with premutation (~20%)
o Menopause before age 40
 Fragile X associated tremor/ataxia syndrome (neurodegenerative disorder)
o Occurs in MALES with premutation
o Late onset cerebellar ataxia and intention tremor
o White matter lesions in the middle cerebellar peduncles and/or brain
stem (on MRI)

Transmitting males: transmit repeats with small changes in repeat numbers (no amplification
during spermatogenesis)

Carrier females: high probability of significant amplification of these repeats (during
oogenesis) and thus transmission of disease causing full mutation
o Full mutation: >200 repeats

Abnormal DNA methylation also present with full mutation

Results in transcriptional suppression of the gene
Clinical Features of Full Mutation:
o Mental impairment (learning disabilities progressing to mental retardation)
o Abnormal facies

Elongated face

Prominent forehead and jaw

Large protruding ears
o Other abnormalities:

Hyperextensible joints

Mitral valve prolapse
o Macro-orchidism
GENOMIC IMPRINTING:

General:
Functional differences between paternal and maternal genes result from selective inactivation of either the
maternal or paternal allele by nucleotide specific methylation or inactivation by another method
o Non-expressed allele is termed IMPRINTED

Maternal imprinting: inactivation of maternal allele

Paternal imprinting: inactivation of paternal allele
o Imprinting occurs in the ovum or sperm, and is transmitted to all somatic cells

Prader Will Syndrome:
Normal: maternal imprinting (genes on 15q11-13 on maternal cs imprinted/silenced, and functional allele
provided by the paternal cs)
PW Syndrome: develops when you lose the paternal cs, and all that is left is silenced maternal cs

o Paternal allele deleted (only silenced maternal allele remains)
o Uniparental disomy, resulting in both copies of alleles from the mother (both silenced/imprinted)
Clinical Features:
o Poor muscle tone at birth
o Mental retardation
o Short stature, with small hands and feet
o Hypogonadism
o Obesity (progresses with age)
o Face with narrow bifrontal diameter, almond eyes, and full cheeks
Angelman Syndrome:
Normal: paternal imprinting (set of genes on 15q of paternal cs imprinted/silenced, and functional allele
provided by the maternal cs)
Angelman Syndrome: develops when you lose the maternal cs, and all that is left is silenced paternal cs
o Deletion of maternal allele (only silenced paternal allele remains)
o Uniparental disomy, resulting in both copies of alleles from the father (both silenced/imprinted)
Clinical Features:
o Mental retardation
o Large mouth and prominent chin
o Ataxic gait
o Seizures
o Inappropriate laughter (happy puppets)
GONADAL MOSAICISM:

Cause: mutation that occurs postzygotically during early embryonic development
Only affects cells destined for gonads
Gametes carry the mutation; somatic cells are normal

Significance: explains how 2 “normal” parents will have 2 or more children with an autosomal dominant defect
SINGLE GENE DISORDERS WITH NONCLASSIC INHERITANCE (MITOCHONDRIAL GENE MUTATIONS):

General:
Mitochondrial Diseases: can be caused by one of 2 issues
o Defects in mtDNA: maternally inherited (passes on to ALL children); FOCUS ON THESE*
o Defects in nuclear genes: that encode proteins that function in the mitochondria

Inheritance: most are autosomal recessive

Two Groups:
 Abnormalities with altered number and structure of mitochondria
 Secondary degenerative and destructive changes due to impaired function of
mitochondria
Mitochondria DNA: mitochondria contain their own DNA
o Inheritance: inherited MATERNALLY (inherit mtDNA to all children, male and female)
o Heteroplasmy: coexistence of normal mtDNA and abnormal mtDNA in the same cell

Proportion of each is variable in daughter cells (due to mitotic segregation)
o Threshold: different cell types have different minimal oxidative requirements (ie. higher energy
requiring organs will have greater defects)
Mutations in Mitochondrial DNA:
o Encode for enzymes involved in production of ATP through oxidative phosphorylation
o Mutations lead to:

Abnormal function of cells (ATP not made efficiently)

Accumulation of free radicals and excess metabolites (ie. lactate) that are harmful
o Defects most noticeable in organs with high energy requirements:

Eyes

Skeletal and cardiac muscle

Liver

Kidneys

MERRF (Myoclonal Epilepsy and Ragged Red Fiber Disease):
Myoclonus, ataxia, lactic acidosis, weakness, seizures, progressive dementia, hearing loss

MELAS (Mitochondrial Encephalomyopathy Lactic Acidosis and Stroke-Like Episodes)