GENETIC DISORDERS
Disease Category Pathogenesis / Heredity
Cystic Fibrosis Autosomal Recessive. CFTR
gene defect on Chrom 7 ------>
No Cl- transport and failure to
hydrate mucous secretions (no
NaCl transport) ------>
excessively viscous mucoid
exocrine secretions
Fanconi Anemia Autosomal Recessive
congenital pancytopenia.
Hartnup's Disease Autosomal Recessive. Defect in
GI uptake of neutral amino
acids ------> malabsorption of
tryptophan (niacin precursor) -
-----> niacin deficiency among
other things.
Kartagener's Autosomal Recessive. Defect in
Syndrome dynein arms ------> lost
motility of cilia
Pathology, Cardinal
Symptoms
Meconium ileus (caused
by thick, mucoid
meconium), respiratory
bronchiectasis,
Pseudomonas
pneumonia, pancreatic
insufficiency, hypertonic
(high Cl- concentration)
sweat.
Normocytic anemia with
neutropenia.
Short stature,
microcephaly,
hypogenitalism,
strabismus, anomalies of
the thumbs, radii, and
kidneys, mental
retardation, and
microphthalmia.
Pellagra-like syndrome
(diarrhea, dementia,
dermatitis), light-sensitive
skin rash, temporary
cerebellar ataxia.
Recurrent
sinopulmonary
infections (due to
impaired ciliary tract).
Situs inversus, due to
impaired ciliary motion
during embryogenesis:
lateral transposition of
lungs, abdominal and
thoracic viscera are on
opposite sides of the
 body as normal. Possible
dextrocardia, male
sterility.

Pyruvate Autosomal Recessive. Neurologic defects.

Dehydrogenase Pyruvate Dehydrogenase
Deficiency deficiency ------> buildup of
lactate and pyruvate ------>
lactic acidosis.
Treatment: Increase
intake of ketogenic
nutrients (leucine,
lysine) ------> increase
formation of Acetyl-CoA
from other sources.

Xeroderma Autosomal Recessive. Defect in Dry skin, melanomas, pre-

Pigmentosum DNA repair, inability to repair
thymine dimers resulting from
UV-light exposure ------>
excessive skin damage and skin
cancer.
malignant lesions, other
cancers. Ophthalmic and
neurologic abnormalities.

Familial Autosomal A group of inherited diseases Heterozygous:

Hypercholesterolemia Dominant associated with accelerated
Disorders hypercholestrolemia. atherosclerosis.
Homozygous: accelerated
atherosclerosis, MI by age
35, xanthomas.

Hereditary Autosomal Autosomal Dominant. Telangiectasias of skin

Hemorrhagic Dominant and mucous membranes.
Telangiectasia (Osler- Disorders
Weber-Rendu
Syndrome)

Hereditary Autosomal Autosomal Dominant. Band-3 Sequestration of

Spherocytosis Dominant deficiency in RBC membrane --- spherocytes in spleen -----
Disorders ---> spherical shape to cells. -> hemolytic anemia.
Other RBC structural enzyme
deficiencies can cause it, too.

Huntington's Disease Autosomal Autosomal Dominant, 100% Progressive dementia

Dominant penetrance.
Disorders
Genetic defect on Chrom 4 -----
-> atrophy of caudate nuclei,
putamen, frontal cortex.
with onset in adulthood,
choreiform movements,
athetosis.
Marfan's Syndrome Autosomal Autosomal Dominant. Fibrillin Arachnodactyly,
Dominant deficiency ------> faulty dissecting aortic
Disorders scaffolding in connective tissue aneurysms, ectopia
(elastin has no anchor). lentis (subluxation of
lens), mitral valve
prolapse.

Neurofibromatosis Autosomal Autosomal Dominant. NF1 Multiple neurofibromas

(Von Recklinghausen Dominant gene defect (no GTPase (Caf au Lait spots) which
Disease) Disorders protein) ------> dysregulation of may become malignant,
Ras tumor-suppressor protein. Lisch nodules
(pigmented hamartomas
of the iris).

Increased risk for tumors:

pheochromocytoma,
Wilms tumor,
Rhabdomyosarcoma,
leukemias.

Tuberous Sclerosis Autosomal Autosomal Dominant. Tubers (glial nodules),

Dominant seizures, mental
Disorders retardation. Associated
with adenoma sebaceum
(facial lesion), myocardial
rhabdomyomas, renal
angiomyolipomas.

Von Hippel-Lindau Autosomal Autosomal Dominant, short (1) Hemangioblastomas

Syndrome Dominant arm of chromosome 3. Same of cerebellum, medulla,
Disorders genetic region is associated or retina, (2) adenomas,
with incidence of renal cell (3) cysts in visceral
carcinoma. organs. High risk for renal
cell carcinoma.

Congenital Fructose Carbohydr Autosomal Recessive. Aldolase Severe hypoglycemia.

Intolerance ate B deficiency ------> buildup of Treatment: Remove
Metabolis Fructose-1-Phosphate in fructose from diet.
m Defect tissues ------> inhibit
glycogenolysis and
gluconeogenesis.

Galactosemia Carbohydr Autosomal Recessive. Inability Failure to thrive, infantile

ate to convert galactose to glucose cataracts, mental
Metabolis ------> accumulation of retardation. Progressive
m Defect galactose in many tissues. hepatic failure, cirrhosis,

(1) Classic form: Galactose-1-
phosphate Uridyltransferase
deficiency.
(2) Rarer form: Galactokinase
deficiency.
death.
Galactokinase-deficiency:
infantile cataracts are
prominent.
Treatment: in either case,
remove galactose from
diet.

Angelman Syndrome Chromoso Deletion of part of short arm of Mental retardation, ataxic
mal chromosome 15, maternal gait, seizures.
copy. An example of genomic Inappropriate laughter.
imprinting.

Cri du Chat Syndrome Chromoso 5p-, deletion of the long arm of "Cry of the cat." Severe
mal chromosome 5. mental retardation,
microcephaly, cat-like cry.
Low birth-weight, round-
face, hypertelorism (wide-
set eyes), low-set ears,
epicanthal folds.

Down Syndrome Chromoso Trisomy 21, with risk
mal increasing with maternal age.
(Trisomy 21) Familial form (no age-
associated risk) is translocation
t(21,x) in a minority of cases.
Most common cause of
mental retardation. Will
see epicanthal folds,
simian crease,
brushfield spots in eyes.
Associated syndromes:
congenital heart
disease, leukemia,
premature Alzheimer's
disease (same
morphological changes).

Edward's Syndrome Chromoso Trisomy 18 Mental retardation,

mal micrognathia, rocker-
(Trisomy 18) bottom feet, congenital
heart disease, flexion
deformities of fingers.
Death by 1 year old.

Patau's Syndrome Chromoso Trisomy 13 Mental retardation,

mal microphthalmia, cleft lip
(Trisomy 13) and palate, polydactyly,
 rocker-bottom feet,
congenital heart disease.
Similar to and more
severe than Edward's
Syndrome. Death by 1
year old.

Prader-Willi Chromoso Deletion of part of short arm of Mental retardation, short

Syndrome mal chromosome 15, paternal stature, hypotonia,
copy. An example of genomic obesity and huge
imprinting. appetite after infancy.
Small hands and feet,
hypogonadism.

Fragile-X Syndrome Chromoso Progressively longer tandem Second most common

mal repeats on the long arm of the
X-chromosome. The longer the
Sex number of repeats, the worse
chromoso the syndrome. Tandem repeats
me tend to accumulate through
generations.
cause of mental
retardation next to
Down Syndrome. Macro-
orchidism (enlarged
testes) in males.

Klinefelter's Chromoso Non-disjunction of the sex Hypogonadism, tall

Syndrome (XXY) mal chromosome during Anaphase stature, gynecomastia.
I of meiosis ------> Trisomy Mild mental retardation.
Sex (47,XXY) Usually not diagnosed
chromoso until after puberty. One
me Barr body seen on buccal
smear.

Turner's Syndrome Chromoso Non-disjunction of the sex Streak gonads, primary

(XO) mal chromosome during Anaphase amenorrhea, webbed
I of meiosis ------> Monosomy neck, short stature,
Sex (45,X) coarctation of Aorta,
chromoso infantile genitalia. No
me mental retardation. No
Barr bodies visible on
buccal smear.

XXX Syndrome Chromoso Trisomy (47,XXX) and other Usually phenotypically

mal multiple X-chromosome normal. May see
abnormalities. menstrual abnormalities
Sex or mild mental
chromoso retardation in some
me cases.
Ehlers-Danlos Connective Various defects in collagen Laxity of joints,
Syndrome Tissue synthesis. hyperextensibility of skin,
disease poor wound healing,
Type-I: Autosomal aneurysms.
dominant, mildest
form. Type-I:
Type-IV: autosomal Diaphragmatic
dominant. Defect in hernia. Common,
reticular collagen (type- normal life-
III) expectancy.
Type-VI: autosomal- Type-IV:
recessive. Ecchymoses,
Type-VII: Defect in arterial rupture.
collagen type I Dangerous due to
Type-IX: X-linked rupture
recessive aneurysms.
Type-VI: Retinal
detachment,
corneal rupture

Osteogenesis Connective Defects in Collagen Type I Multiple fractures after

Imperfecta tissue formation. birth, blue sclerae, thin
disease skin, progressive deafness
in some types (due to
abnormal middle ear
ossicles).

Type-I is most common;

Type-II is most severe;
Type-IV is mildest form.

Cori's Disease Glycogen Autosomal Recessive. Stunted growth,

Storage Debranching enzyme hepatomegaly,
(Glycogen Storage Disease deficiency (can only break hypoglycemia.
Disease Type III) down linear chains of
glycogen, not at branch points)
------> accumulate glycogen in
liver, heart, skeletal muscle.

McArdle's Disease Glycogen Autosomal Recessive. muscle Muscle cramps, muscle

Storage phosphorylase deficiency weakness, easy
(Glycogen Storage Disease (cannot utilize glycogen in fatigability.
Disease Type V) skeletal muscle) ------> Myoglobinuria with
accumulation of glycogen in strenuous exercise.
 skeletal muscle.

Pompe's Disease Glycogen Autosomal Recessive. alpha- Cardiomegaly,

Storage 1,4-Glucosidase deficiency hepatomegaly, and
(Glycogen Storage Disease (cannot break down glycogen) systemic findings, leading
Disease Type II) ------> accumulate glycogen in to early death.
liver, heart, skeletal muscle.

Von Gierke's Disease Glycogen Autosomal Recessive. Glucose- Severe fasting

Storage 6-Phosphatase deficiency hypoglycemia,
(Glycogen Storage Disease (cannot break down glycogen) hepatomegaly from lots
Disease Type I) ------> accumulate glycogen in of glycogen in liver.
liver and kidney.

Hemophilia A (Factor Hemophili X-Linked Recessive. Factor VIII Hemorrhage, hematuria,

VIII Deficiency) a deficiency hemarthroses. Prolonged
PTT.

Hemophilia B (Factor Hemophili X-Linked Recessive. Factor IX Milder than Hemophilia

IX Deficiency) a deficiency. A. Hemorrhage,
hematuria, hemarthroses.
Prolonged PTT.

Von Willebrand Hemophili Autosomal dominant and Hemorrhage, similar to

Disease a recessive varieties. Von
Willebrand Factor deficiency -
-----> defect in initial formation
of platelet plugs, and shorter
half-life of Factor VIII in blood.
hemophilia.
Type-I: Most mild. Type-
II: Intermediate. Type-III:
most severe, with
recessive inheritance
(complete absence).

Ataxia-Telangiectasia Immune Autosomal Recessive. Cerebellar ataxia,

deficiency Unknown. Numerous telangiectasia (enlarged
chromosomal breaks and capillaries of face and
Combined elevated AFP is found. skin), B and T-Cell
Deficiency Symptomatic by age 2 years. deficiencies, IgA
deficiency.

Chdiak-Higashi Immune Defect in polymerization of Recurrent pyogenic

Syndrome deficiency microtubules in neutrophils ---- infections,
--> failure in neutrophil Staphylococcus,
Phagocyte migration and phagocytosis. Streptococcus.
Deficiency Also results in failure in
lysosomal function in
neutrophils.
Chronic Immune X-Linked (usually) NADPH Failure of phagocytes
Granulomatous deficiency Oxidase deficiency ------> no leads to susceptibility to
Disease formation of peroxides and infections, especially
Phagocyte superoxides ------> no oxidative Staph Aureus and
Deficiency burst in phagocytes. Aspergillus spp. B and T
cells usually remain
normal.

Chronic Immune T-Cell deficiency specific to Selective recurrent

Mucocutaneous deficiency Candida. Candida infections. Treat
Candidiasis with anti-fungal drugs.
T-Cell
Deficiency

Job's Syndrome Immune A failure to produce gamma- High histamine levels,

deficiency Interferon by T-Helper cells,
leading to an increase in TH2
Phagocyte cells (no negative feedback) ----
Deficiency --> excessively high levels of
IgE.
eosinophilia. Recurrent
cold (non-inflammatory)
Staphylococcal
abscesses (resulting from
high histamine), eczema.

Selective IgA Immune IgA deficiency may be due to a The most common
Deficiency deficiency failure of heavy-chain gene congenital immune
switching. deficiency. There also
B-Cell exists selective IgM and
Deficiency IgG deficiencies, but they
are less common.

Severe Combined Immune Autosomal Recessive. Severe deficiency in both

Immunodeficiency deficiency Adenosine Deaminase humoral and cellular
(SCID) deficiency ------> accumulation immunity, due to
Combined of dATP ------> inhibit impaired DNA synthesis.
Deficiency ribonucleotide reductase ------> Bone marrow transplant
decrease in DNA precursors may be helpful in
treatment.

Thymic Aplasia Immune Failure of development of the T-Cell deficiency from

(DiGeorge Syndrome) deficiency 3rd and 4th Pharyngeal no thymus.
Pouches ------> agenesis of the Hypocalcemic tetany
T-Cell thymus and parathyroid from primary parathyroid
Deficiency glands. deficiency.

Wiskott-Aldrich Immune Inability to mount initial IgM In infancy, recurrent

Syndrome deficiency response to the capsular pyogenic infections,
polysaccharides of pyogenic eczema,
Combined bacteria. thrombocytopenia,
 Deficiency excessive bleeding. IgG
levels remain normal.

X-Linked Immune X-Linked. Mutation in gene Recurrent pyogenic

Agammaglobulinemi deficiency coding for tyrosine kinase infections after 6 months
a (Bruton's Disease) causes failure of Pre-B cells to (when maternal
B-Cell differentiate into B-Cells. antibodies wear off). Can
Deficiency treat with polyspecific
gamma globulin
preparations.

Fabry's Disease Lysosomal X-Linked Recessive. alpha- Angiokeratomas (skin

Storage Galactosidase A deficiency ----
Disease --> buildup of ceramide
trihexoside in body tissues.
lesions) over lower trunk,
fever, severe burning
pain in extremities,
cardiovascular and
cerebrovascular
involvement.

Gaucher's Disease Lysosomal Autosomal Recessive. Type-I: Adult

Storage Glucocerebrosidase form. 80% of
Disease deficiency ------> accumulation cases, retain
of glucocerebrosides partial activity.
(gangliosides, sphingolipids) in Hepatosplenome
lysosomes throughout the galy, erosion of
body. femoral head,
mild anemia.
Normal lifespan
with treatment.
Type-II: Infantile
form. Severe CNS
involvement.
Death before age
1.
Type-III: Juvenile
form. Onset in
early childhood,
involving both
CNS and viscera,
but less severe
than Type II.

Niemann-Pick Lysosomal Autosomal Recessive. Sphingomyelin-

Lipidosis Storage Sphingomyelinase deficiency containing foamy
Disease ------> accumulation of histiocytes in
 sphingomyelin in phagocytes.
Hunter's Syndrome Lysosomal X-Linked Recessive. L-
Storage iduronosulfate sulfatase
Disease deficiency ------> buildup of
mucopolysaccharides
(heparan sulfate and dermatan
sulfate)
Hurler's Syndrome Lysosomal Autosomal Recessive. alpha-L-
Storage iduronidase deficiency ------>
Disease accumulation of
mucopolysaccharides
(heparan sulfate, dermatan
sulfate) in heart, brain, liver,
other organs.
Tay-Sachs Disease Lysosomal Autosomal Recessive.
Storage Hexosaminidase A deficiency
Disease ------> accumulation of GM2
ganglioside in neurons.
Albinism Nitrogen Autosomal Recessive.
Metabolis Tyrosinase deficiency ------>
m Defect inability to synthesize melanin
from tyrosine. Can result from a
lack of migration of neural crest
cells.
Alkaptonuria Nitrogen Autosomal Recessive.
Metabolis Homogentisic Oxidase
m Defect deficiency (inability to
metabolize Phe and Tyr) ------>
buildup and urinary excretion
of homogentisic acid.
reticuloendo-thelial
system and spleen.
Hepatosplenomegaly,
anemia, fever, sometimes
CNS deterioration. Death
by age 3.
Similar to but less severe
than Hurler Syndrome.
Hepatosplenomegaly,
micrognathia, retinal
degeneration, joint
stiffness, mild retardation,
cardiac lesions.
Gargoyle-like facies,
progressive mental
deterioration, stubby
fingers, death by age 10.
Similar to Hunter's
Syndrome.
CNS degeneration,
retardation, cherry red-
spot of macula, blindness
(amaurosis). Death before
age 4.
Depigmentation, pink
eyes, increased risk of
skin cancer.
Urine turns dark and
black on standing,
ochronosis (dark
pigmentation of fibrous
and cartilage tissues),
ochronotic arthritis,
cardiac valve
involvement. Disease is
generally benign.
Homocystinuria Nitrogen Autosomal Recessive. Mental retardation,
Metabolis Cystathionine synthase ectopia lentis, sparse
m Defect defect (either deficiency, or lost blond hair, genu valgum,
affinity for pyridoxine, Vit. B6) -- failure to thrive,
----> buildup of homocystine thromboembolic
and deficiency of cysteine. episodes, fatty changes of
liver.

Treatment: Cysteine
supplementation, give
excess pyridoxine to
compensate for lost
pyridoxine affinity.

Lesch-Nyhan Nitrogen X-Linked Recessive. Hyperuricemia (gout),

Syndrome Metabolis Hypoxanthine-Guanine mental retardation, self-
m Defect Phosphoribosyltransferase mutilation (autistic
(HGPRT) deficiency ------> no behavior),
salvage pathway for purine re- choreoathetosis,
synthesis ------> buildup of spasticity.
purine metabolites

Maple Syrup Urine Nitrogen Autosomal Recessive. Severe CNS defects,

Disease Metabolis Deficiency of branched chain
m Defect keto-acid decarboxylase ------
> no degradation of branched-
chain amino acids ------>
buildup of isoleucine, valine,
leucine.
mental retardation,
death. Person smells like
maple syrup or burnt
sugar. Treatment: remove
the amino acids from diet.

Phenylketonuria Nitrogen Autosomal Recessive. Symptoms result from

(PKU) Metabolis Phenylalanine hydroxylase
m Defect deficiency (cannot break down
Phe nor make Tyr) ------>
buildup of phenylalanine,
phenyl ketones (phenylacetate,
phenyl lactate,
phenylpyruvate) in body
tissues and CNS.
accumulation of
phenylalanine itself.
Mental deterioration,
hypopigmentation
(blond hair and blue
eyes), mousy body odor
(from phenylacetic acid in
urine and sweat).

Treatment: remove
phenylalanine from diet.

Glucose-6-Phosphate RBC X-Linked Recessive. Glucose-6- Susceptibility to oxidative

Dehydrogenase Disease Phosphate Dehydrogenase damage to RBC's, leading
(G6PD) Deficiency (G6PD) deficiency ------> no
hexose monophosphate shunt
------> deficiency in NADPH -----
-> inability to maintain
glutathione in reduced form,
in RBC's
to hemolytic anemia.
Can be elicited by drugs
(primaquine,
sulfonamides, aspirin),
fava beans (favism). More
prevalent in blacks.

Glycolytic enzyme RBC Autosomal Recessive. Defect in Hemolytic anemia

deficiencies Disease hexokinase, glucose-
phosphate isomerase, aldolase,
triose-phosphate isomerase,
phosphate-glycerate kinase, or
enolase. Any enzyme in
glycolysis pathway.
results from any defect in
the glycolysis pathway, as
RBC's depend on
glycolysis for energy.

Autosomal Recessive Renal Autosomal Recessive. Numerous, diffuse

Polycystic Kidney bilateral cysts formed in
Disease (ARPKD) the collecting ducts.
Associated with hepatic
fibrosis.

Bartter's Syndrome Renal Juxtaglomerular Cell Elevated renin and

Hyperplasia, leading to aldosterone, hypokalemic
primary hyper-reninemia. alkalosis. No hypertension.

Fanconi's Syndrome Renal Autosomal Recessive. Deficient (1) Cystine deposition

Type I resorption in proximal tubules. throughout body,
cystinuria. (2) Defective
(Child-onset tubular resorption leads
cystinosis) to amino-aciduria,
polyuria, glycosuria,
chronic acidosis;
Hypophosphatemia and
Vitamin-D-resistant
Rickets.

Fanconi's Syndrome II Renal Autosomal Recessive. Defective Similar to Fanconi

resorption in proximal tubules. Syndrome Type I, but
(Adult-onset) without the cystinosis.
Adult onset
osteomalacia, amino-
aciduria, polyuria,
glycosuria.

Autosomal Dominant Renal Autosomal Dominant. Numerous, disparate,

Polycystic Kidney heterogenous renal cysts
Disease (ADPKD) occurring bilaterally.
Autosomal Onset in adult life.
Dominant Associated with liver
Disorders cysts.