Genetic Disorders

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5p- (deletion)
-Severe MR, microceph, cat-like cry, wide-set eyes

DiGeorge Syndrome

-Microdeletion of 22q11
"CATCH 22"
-Cardiac abnormalities
-Abnl faces
-T-cell deficit d/t thymic hypoplasia
-Cleft palate
-Hypocalcemia
Also may be assoc. with behavioral disorders and psychosis
-From bad development of 3rd and 4th pouches

Edwards Syndrome (Trisomy 18)

-Usu from nondisjunction
-MR, prominent occiput, micrognathia, rocker-bottom feet, congenital heart disease

Patau Syndrome (Trisomy 13)

MR, microceph, microphthalmia, brain abnl, cleft lip, polydactyly, congenital heart disease, etc.

Klinefelter Syndrome

-47, XXY (also XXXY)
-Male phenotype with atrophic testes
-Tall stature, gynecomastia
-Decreased T production and increased pituitary GNs d/t loss of feedback inhibition
-Infertility
-No MR usually
-Maternal meiotic nondisjunction
-Incidence increases wit

Name 3 Trinucleotide repeat disorders

1. Fragile X
2. Huntington's
3. Myotonic dystrophy

Fragile X

-Males and females can be asymptomatic carriers
-Increased number of CGG repeats in FMR-1 gene
-Sons with full mutations have MR and macroorchidism
-Daughters have ~ 50% chance of having MR

Prader-Willi

-Due to paternal transmission
-Hypogonadism, hypotonia, MR, uncontrolled appetite

Angelman syndrom

-Due to maternal transmission (imprinting).
-ataxia, seizures, inappropriate laughter

Marfan syndrome

AD
-Defect of CT; faulty scaffolding
-Deficiency in fibrillin
-Tall, thin, spidery fingers
-Dislocation of ocular lens is frequent
-aneurysm of proximal aorta and/or mitral valve prolapse

Neurofibromatosis
AD

-Multiple neurofibromas in skin, etc
-Schwannomas of CN VIII, cafe au lait spots
-pigmented iris hamartomas
-Skeletal disorders such as scoliosis and bone cysts, and increased incidence of other tumors such as pheo and Wilms tumor
-Mutation in NF1 gene (t

Tuberous sclerosis

AD
-Glial nodules and distorted neurons in cerebral cortex
-Seizures, MR
-Rhabdomyomas of heart, renal angiomyolipomas

von Hippel-Lindau disease

AD
-Hemangioblastoma or cavernous hemagioma of the cerebellum, brain stem, or retina
-Adenomas
-Cysts of liver, kidney, pancreas
-Marked increase in renal cell CA

What is a lysosomal storage disease?

Characterized by deficiency of a specific single lysosomal enzyme, resulting in accumulation of abnl metabolic products

Tay-Sachs

-Lysosomal storage disease, AR
-Deficiency in hexosaminidase A with accumulation of GM2 ganglioside
-CNS degeneration, severe mental and motor deterioration
-Blindness, cherry-red spot on macula
-Death before age 4

Gaucher disease

AR, LSD
-Defic. of glucocerebrosidase, results in an accum. of glucocerebroside in mono. cells
-Presence of Gaucher cells on histo with "wrinkled tissue paper appearance"
-HSmegaly, aseptic necrosis of femur, bone crises

Niemann-Pick disease

AR
-Deficiency of sphingomyelinase with accum. of sphingomyelin in phagocytes (A,B) or defective cholesterol transport and subs. accum. of chol. (C)
-"foamy histiocytes" which proliferate in organs
-HSMegaly, anemia, fever
-Death by age 3

Hurler Syndrome

AR
-Defic. in a-L-iduronidase, with accum. of heparan sulfate and dermatan sulfate in heart, brain, liver
-Clinical: hsmegaly, dwarfism, stubby fingers, corneal clouding, MR
-Death by 10
-Very similar to Hunter syndrome, which is X-linked

von Gierke disease

AR
-Glycogen storage disease type I
-Deficiency in Glucose-6-phosphatase enzyme with accumulation of glycogen in liver, kidney
-hepatomegaly, hypoglycemia, inc. blood lactate

Pompe disease

AR
-Type II glycogen storage
-Defic. in a-1,4 glucosidase with accum. of glycogen in liver, heart, muscle
-Cardiomegaly, muscle hypotonia, splenomegaly
-Death before 3
-intractable hypoglycemia

Cori disease

AR
Type III glycogen storage
-Defic. of the debranching enzyme, amylo-1,6-glucosidase
-Leads to accum. of glyocen in liver, heart, muscle
-Stunted growth, hepatomeg, hypoglycemia

McArdle Syndrome

AR
-Glycogen storage type V
-Defic. of muscle phosphorylase with accum. of glycogen in muscle
-Painful cramps and muscle weakness following exercise

Classic galactosemia

-AR
-Defic. of galactose-1-phosphate uridyl transferase
-Accum. of galactose-1-phosphate
-FTT, infant cataracts, MR, progressive liver failure
-Can be prevented with early removal of galactose from diet
-Disease from accumulation of toxic substances

Phenylketonuria PKU

AR
-Caused by mutation of phenylalanine hydroxylase gene, which results in inability to convert Phenyalanine to Tyr
-high blood conc. of phe, which is neurotoxic
-Progressive mental deterioration, musty odor
-Screened at birth
-Tx with phe free diet

Alkaptonuria

-AR
-Incomplete metab. of phe and tyr d/t deficiency of homogentisic oxidase, leading to accum. of homogentisic acid
-Urine turns dark when standing
-Ochronosis - pigment of cartilage
-Arthritis

Maple syrup urine disease

-AR inborn error of metabolism
-caused by defects to a-ketoacid dehydrogenase which means less degradation of branched AAs
-Ile, Leu, Val build up (esp Leu)
-MR, feeding problem, high urine levels of keto acids
-Untreated leads to death

Hunter syndrome

X-linked; similar to Hurler's but not as severe
-lysosomal storage disease
-Def. in L-iduronosulfate resulting in accum. of heparan sulfate and dermatan sulfate
-hsmegaly, micrognathia, retinal degeneration, joint stiffness, mild MR, cardiac lesions

Fabry disease

X-linked
-Lysosomal storage disease
-Defic. in a-galactosidase A with accum. of ceramide trihexoside
-Characteristic skin lesions (angiokeratomas) on lower trunk, fever, burning pain in extremities
-Death in early adulthood d/t renal failure

Classic hemophilia

X-linked
-mutation in Factor VIII gene
-recurrent hemorrhage

Lesch-Nyhan syndrome

X-linked
-Deficiency in HGPRT
-Impaired purine metab. and excess production of uric acid
-Gout, MR, spasticity, self-mutilation, aggression

Xeroderma pigmentosum

AR
-Increased risk of skin cancers caused by hypersensitivity to UV light
- Involves defect in genes that function in nucleotide excision repair.

Osler-Weber-Rendu aka
Hereditary hemorrhagic telangectasia

-AD
-Localized dilation and convolution of venules/capillaries of the skin and mucous membranes
-Often with epistaxis and GI bleeding

Werdnig-Hoffman disease
aka infantile spinal muscular atrophy

AR
Presents at birth with "floppy baby", tongue fasciculations
Median age of death 7 months
LMN only; degeneration of anterior horns

Hereditary Hemochromatosis

AR
Hfe gene on chromo 6
-Triad of cirrhosis, DM, and increased skin pigmentation
-Increase in serum iron, reduction in TIBC, transferrin with resultant increased transferrin iron saturation

Wilson's disease

AR
-Disorder of copper metabolism-
-Decreased serum ceruloplasmin
-Liver disease varies from chronic hepatitis to cirrhosis
-Kayser-Fleischer ring in eye
-Involvement of basal ganglia (Extra-pyramidal signs)
-Tx with penicillamine

Familial Adenomatous Polyposis

AD mutation of APC gene on 5q
-Two hit hypothesis
-Thousands of polyps, pancolonic, always involves rectum
-Gardner's syndrome = FAP with osseous and soft tissue tumors, retinal hyperplasia
-Turcot's syndrome - FAP with possible brain inv. (glioblastoma)

HNPCC or Lynch syndrome

-Mutations of DNA mismatch repair genes
~80% get CRC
-Proximal colon always involved.

Adult Polycystic Kidney Disease

AD
-Manifests clinically b/w 15-30
-Partial replacement of renal parenchyma by cysts
-Associated with berry aneurysm
-Freq. assoc. with cystic disease of other organs (liver)
-HTN, Hematuria, Palpable renal masses, prog. to RF

Infantile polycystic kidney disease

AR
-Multiple cysts evident at birth
-Closed cysts not in continuity with collecting system
-Death results shortly after birth

Beckwith-Wiedeman

-congenital anomalies + Wilm's tumor
-Deletion of WT-2 gene
-Imprinting. Abnormal alleles of maternal origin

Krabbe's disease

AR LSD
-Deficiency in galactocerebrosidase with accum. of galactocerebroside
-Peripheral neuropathy, MRDD, optic atrophy, globoid cells

Metachromatic leukodystrophy

AR LSD
-Deficiency in arylsulfatase A with accum. of cerebroside sulfate
-Central/peripheral demyelination with ataxia, dementia

Becker muscular dystrophy

Clinically similar but less severe than Duchenne
-Truncated and less funcitonal dystrophin

Fascioscapulohumeral MD

AD
-Slow progressive, nondisabling course with almost nl life expect.
-Sequentially involves face, scapular area, humerus

Limb-Girdle dystrophy

AR
Involves proximal muscles of shoulder, pelvic girdle, both

Myotonic dystrophy

AD
CTG repeat disorder
-Weakness with myotonia, cataracts, testicular atrophy, baldness in men

Wiskott-Aldrich syndrome

X-linked
Defect in ability to mount an IgM response to capsular polysacch. of bacteria.
Associated with high IgA levels
Triad of symptoms: Infections, purpura, eczema (WIPE)

Bruton's agammaglobulinemia

X-linked recessive
low levels of all classes of Abs
Decreased # of B cells
Recurrent bacterial infections after 6 months of age