Genetic Diseases 2

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1/13/12 11am

Mucopolysaccharidoses

Accumulation of GAG components of proteoglycans is the problem of MPSs. GAGs that tend to accumulate are dermatan sulfate, heparan sulfate, keratan sulfate, and chondroitin sulfate.
Mucopolysaccharide=polysaccharide containing hexosamine (an amino sugar)=glycosaminoglycan (GAG); HS=heparan sulfate.
Excretion of MPS in urine (diagnosis). Dermatan sulfate and heparan sulfate for our cases.
Hurler---autosomal recessive--alpha-L-iduronidase. Early clouding of cornea; death before 10
Hunter--X-linked--iduronate sulphatase. No clouding of cornea; milder; death by 15 (mild form at 30-50 with fair intelligence)
MPS IV (Maorquio's)--aortic regurgitation

Hurler Syndrome (garogoylism)

Clinical: valvular heart disease, corneal clouding. Deafness, joint stiffness; MPS in macrophages, fibroblasts, endothelium and smooth muscle cells of vessels (accumulate in spleen, liver, bone marrow, lymph nodes, vessels, heart). Coarse facial features, wide nasal bridge and flattened midface. Mental Retardation. Kyphoscoliosis
One of the most severe MPSs. Death by 6-10 with cardiovascular complications
Treatments: Laronidase (aldurazyme)--biosynthetic replacement of L-iduronidase--doesn't cross blood brain barrier. Bone marrow transplant. Cord blood transplant
Zebra bodies (like NPC)
Neuronal GM2 and GM3 ganglioside storage-- mechanism of ganglioside accumulation in MPS is not understood--inhibition of acid beta-galactosidase by acidic mucopolysaccharides.
Hepatosplenomegaly, skeletal deformities, valvular lesions, and subendothelial arterial deposits, particularly in the coronary arteries, and lesions in the brain, are common threads that run through all of the MPSs.

Hunter Syndrome

coarse facial features but no corneal clouding. X-linked.
Has later onset than Hurler syndrome. Absence of corneal clouding. Survival to the teens or twenties is common.
Diagnosis: specific MPS in urine.
Treatment: drug idursulfase--FDA approved enzyme replacement

Alkaptonuria

Lack of homogentisic oxidase blocks the catabolic metabolism of phenylalanine-tyrosine at the level of homogentisic acid--accumulate in body.
A large amount of homogentisic acid is excreted imparting a black color to urine if allowed to stand.
Blue-black pigmentation (ochronosis) most evident in the ars, nose, and cheeks. The most serious consequences of ochronosis, hoever, stem from deposits of the pigment in the articular cartilages of the joints. Has diabling arthropathy.

Glycogenoses

3 major groups: hepatic (von-Gierke--glucose 6 phosphatase), myopathic (McArdle--muscle phosphorylase), Other (generalized/Pompe--lysosomal glucoside/acid maltase).
Treat von Gierke: diet preventing hypoglycemia via continuous feeding or diet high in complex carbs; liver transplant
Treat McArdle: nothing. Oral surcrose before exercise may help
Heaptic form: hepatic enlargement and hypoglycemia dominate the clinical picture
Myopathic: present with muscle cramps after exercise and lactate levels in the blood fail to rise after exercise due to a block in glycolysis.
Pompe: Cardiomegaly is prominent!! Infantile form characterized by cardiomyopathy. Juvenile/Adult forms: skeletal myopathy with protracted course leading to respiratory failure. Children have delayed gross-motor development and progressive weakness in limb. Early involvement of the diaphragm is a common feature. This usually leads to respiratory failure and death in second or third decade. Usually no cardiomegaly

Glycogen

Synthesis: glucose to G6P to G1P then make glycogen and branch. Take apart with phosphorylases and debranching enzyme. Degraded in lysosomes with acid maltase.

Down Syndrome

Trisomy 21. (1/700)
Increase in beta-amyloid plaques, like Alzheimer disease. Abundant neck skin, epicanthic folds and flat facial profile, simian crease, predisposition to leukemia (lymphoblastic and acute myeloid leukemia), congenital heart defects (40%), intestinal stenosis, mental retardation, umbilical hernia, hypotonia. Abnormal immune response.
Virtually all patients with trisomy 21 older than age 40 develop neuropathologic changes characteristic of Alzheimers
Trisomy; robertsonian translocation (normal parent); mosaicism. Advanced maternal age strongly influences incidence.
Pathogenesis: several miRNA genes on chromosome 21 that can shut down translation of genes that map elsewhere in the genome (potential role for epigenetic mechanism). There is a loci on 21 associated with mental retardation and most of the facial features.

Edwards Syndrome

1/8000 47, XX +18, mosaic: 46, XX/47,XX +18
Low set ears, overlapping fingers, congenital heart defects, rocker-bottom feet, micrognathia, prominent occiput, mental retardation, short neck, renal malformation, limited hip abduction. omphalocele, diaphragmatic hernia, ventricular septal defect. 10% alive at 1 year.

Patau Syndrome

1/15000, 47, XX +13; 46, XX +der (13;14); 46, XX/47, XX +13
Microphthalmia, (postaxial) polydactyly, microcephaly and mental retardation, cleft lip and palate, rocker-bottom feet, renal defects (polycystic kindeys), cardiac defects, umbilical hernia, nervous system malformations, patent ductus arteriosus, VSD, ASD, dextrocardia
Survival beyond first year is uncommon

Velocardiofacial Syndrome

22q11 deletion--variation
Microcephaly, long face, prominent nasal bridge, broad tip of nose, flat maxilla, micrognathia, cleft palate, everted upper lip, prominent ears
Congenital heart defects, abnormal palate, facial dysmorphism, developmental delay, variable degrees of T-cell immunodeficiency and hypocalcemia
Previously 2 syndromes--DiGeorge and Velocardiofacial syndrome.
DiGeorge: thymic hypoplasia, parathyroid hypoplasia, cardiac malformation
Velocardiofacial: facial dysmorphism, cleft palate, Cardiovascular anomalies, learning disability. May have immunodeficiency
CNS involvement: high risk for psychotic illnesses such as schizophrenia and bipolar disorders
CATCH 22--cardiac, abnormal facies, T cell deficit, cleft palate, hypocalcemia, microdeletion of chromosome 22

Klinefelter

47, XXY, 48, XXXY; 49, XXXXY.
Taller, usually sterile, risk of breast cancer, male hypogonadism, sub-average intelligence (mental retardation uncommon), use testosterone and mastectomy.
Important genetic cause of reduced spermatogenesis and male infertility.
Maternal age may be increased in cases with errors in oogenesis.
All but one X undergoes inactivation--problem? CAG repeats worsen androgen receptor and the one with the least CAG repeats is selectively inactivated.
XYY--taller but no other problems (maybe learning difficulty)

Turner Syndrome

1/3000. 45,X (46,X i(Xq); 46,XXq-; 46, XXp-; 46, X, r(X); 45,X/46,XX)
Short stature, webbing of neck, coartation of aorta (preductal), peripheral lymphedema at birth, hypogonadism (streak ovaries--infertility), amenorrhea (primary), patent ductus arteriosus, preductal coartations of aorta and bicuspid aortic valve (congenital heart diseases). Low posterior hairline, broad chest and widely spaces nipples, pigmented nevi, cubitus valgus (elbow deviating away from midline of body). Cystic hygroma (swelling on back of neck)
No normal secondary sex characteristics.
50% have autoantibodies that react with the thyroid gland--hypothyroidism. Glucose intolerance, obesity and insulin resistance
Short stature--short stature homeobox (SHOX) gene (also on Y)--haploinsufficiency of SHOX gives rise to short stature.
Clearly several other genes on the X are involved in the other abnormalities.
15% of chromosomal abnormalities found in spontaneous abortions are 45, X

Define Sex (4 ways)

Genetic sex=presence or absence of Y chromosome (usually) or fragment of Y
Gonadal sex=histologic charactertistic of gonads
Ductal sex=presence of derivatives of mullerian (female) or wolffian (male) ducts
Phenotypic or genital sex=appearance of external genitalia
sexual ambiguity=disagreement among these four definitions of the sex of an individual

Hermaphrodite definitions

True hermaphrodite=presence of ovarian and testicular tissue (based on gonadal sex). Very rare. Karyotype is 46, XX in 50% others are usually 46,XX/46,XY mosaic
Pseudohermaphrodite=disagreement between phenotypic and gonadal sex
Female pseudohermaphrodite=ovaries with male external genitalia. genetic sex=XX. develop ovaries and internal genitalia is normal. External genitalia are virilized because of excessive exposure to androgenic steroids during early gestation. Most common cause (source of androgens) is congenital adrenal hyperplasia (autosomal recessive), which involves defects in cortisol synthesis leading to excessive androgen synthesis
Male pseudohermaphrodite=testicular tissue but female genitalia. Genetic sex is male; gonadal sex is male; genital ducts or external genitalia are incompletely differentiated along male phenotype; external genitalia are ambigusous or completely female.
Many causes with common feature of defective virilization, usually from defects in androgen synthesis and/or action (e.g., complete androgen insensitvity syndrome (testicular feminization) from mutated androgen receptor (X-linked recessive))

Fragile X--clinical

Common cause of familial mental retardation
Second most common genetic cause of mental retardation (after down syndrome)
broad forehead, elongated face, large prominent ears, strabismus, highly arches palate, hyperextensible joints, hand calluses, pectus excavatum, mitral valve prolapse, ENLARGED TESTICLES, hypotonia, soft, fleshy skin, flat feet, seizures
Macro-orchidism is the only notable physical abnormality in 90% of postpubertal males
Approximately 30% of females carrying the premutation have premature ovarian failure (before the age of 40 years), and about one third of premutation-carrying males exhibit a progressive neurodegenerative syndrome starting in their sixth decade.
Behavior characteristics: ADHD, short attention span, impulsivity, hand flapping, poor eye contact, poor adaptation to changes in routine, anxiety, resistance to veing touched or held, pervasive developmental disorder (like autism)

Fragile X--pathogenesis

Triplet repeat mutation in FMR1 gene
hallmark cytogenic characteristic is discontinuity of staining or constriction in the long arm of X
Repeat region is hypermethylated; methylation extends up stream into promoter, silencing transcription of FMR1 gene.--the 5' region of the gene becomes abnormally methylated. Transcriptional suppression of FMR1
FMRP might regulate translation of specific mRNAs
Expansion of triplet repeat over generations (only during oogenesis).--Anticipation
Carrier male will have affected grandsons. 30-50% of carrier females are affected (more than expected).
Premutations 55-200; full mutation >200
General trinucleotide: proclibity to expand depends strongly on sex of transmitting parent, repeat mutations in coding regions have toxic gain of function (via polyglutamine diseases). Those in noncoding regions have loss-of-function mutation (b/c decreased protein synthesis)

Mitochondrial DNA genome

All maternal inheritance.
LHON (Leber's hereditary optic neuropathy): bilateral loss of central vision leading to blindness.
mtDNA mainly encodes enzymes in oxidative phosphorylation--so affects organs dependent on it--like CNS, skeletal muscle, cardiac muscle, liver and kidneys.
Heteroplasmy--Can have both mutant and normal mitochondria in one cell.
The expression of disorders resulting from mutations in quite variable due to proportion or normal and mutant in a cell.

Genomic Imprinting

Genes are differentially inactivated during paternal and materal gametogenesis. One mechanism of inactivation in methylation of DNA at CpG sequences.
Maternal imprint: silence of maternal allele and v.v.
Mechanism: DNA methylation at CG nucleotides or histone H4 deacetylation and methylation
The importance of imprinint is not restricted to rare disorders. Parent-of-origin effects have been identified in a variety of inherited diseases, such as Huntington disease and myotonic dystrophy and in tumorigenesis.
Prader-Willi and Angelman--due to chromosome 15q12 imprinting--deletions of uniparental disomy causes syndrome

Prader-Willi Syndrome

Deletion of paternal region or maternal disomy
No single gene has been implicated in Prader-Willi
Mental retardation, short stature, hypotonia, profound hyperphagia, obesity, small hands and feet, hypogonadism.
2 phases: first with hypotonia, sleepiness and feeding difficulty (under 6 months). Then, over eating begins (2-4 years).
Cryptorchidism, strabismus, almond-shaped eyes, skin picking, scoliosis, diabetes, sleepiness, sleep apnea
HYPERPHAGIA--excessive appetite/food foraging/obsession with food
V shaped upper lip. small hands. truncal obesity

Angelman Syndrome

Deletion of maternal region or paternal disomy
The affected gene is a ubiquitin ligase that is involved in catalyzing the transfer of activated ubiquitin to target protein substrate. UBE3A mutations
posture and inappropriate laughter="happy puppet"
Mentally retarded, ataxic gait, seizures, inappropriate laughter. flat occiput, occipital groove, protruding tongue, feeding problems in infancy, wide mouth, wide-spaced teeth, frequent drooling, excessive chewing, strabismus, hypopigmented skin, hyperactive lower limb deep tendon reflexes, increased sensitivity to heat, sleep disturbance, attraction to/fascination with water

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