Medical brain notes 15

  DISORDERS INVOLVING AN EXTRA AUTOSOME Down syndrome  (trisomy 21). The most common  karyotype  is 47, XX, +21. Down syndrome is the  most com-mon of the chromosomal disorders . The risk increases with maternal age to anincidence of 1 in 25 live births in women age ≥45. The pathogenesis involves meiotic nondisjunction (95%), Robertsonian translocation (4%), or mosaicism due to mitotic nondisjunction during embryogenesis (1%). Clinical findings  can include intellectual disability; mongoloid facial features (flatface, low-bridged nose, and epicanthal folds); Brushfield spots (speckled appearance of the iris); muscular hypotonia; broad short neck; palmar (simian) crease; and congenital heart defects. Endocardial cushion defect, if present, leads to the forma-tion of an atrioventricular canal (a common connection between all 4 chambers of the heart). Additional clinical problems that can develop include duodenal atresia (“double-bubble” sign); Hirschsprung di...

  DISORDERS INVOLVING CHROMOSOMAL DELETIONS Cri du chat syndrome  is due to deletion of the short arm of chromosome 5. Clini-cal findings include a characteristic high-pitched catlike cry; intellectual disability; congenital heart disease; and microcephaly.  Microdeletions  include 13q14 (retino-blastoma gene) and 11p13 (WAGR complex [Wilms tumor, aniridia, genitourinary anomalies, and intellectual disability [previously known as mental retardation]). Microdeletions are too small to be detected by karyotyping and require molecular techniques for detection.

  DISORDERS INVOLVING SEX CHROMOSOMES Klinefelter syndrome  is caused by meiotic nondisjunction and is a common causeof male hypogonadism. The most common karyotype is 47,XXY. Lab studies show elevated FSH and LH with low levels of testosterone. Clinical findings include testic-ular atrophy, infertility due to azoospermia, eunuchoid body habitus, high-pitched voice; female distribution of hair; and gynecomastia. Turner syndrome  is a common cause of female hypogonadism. The most commonkaryotype is 45,X. The second X chromosome is necessary for oogenesis and normal development of the ovary. Clinically, patients fail to develop secondary sex charac-teristics and have short stature with widely spaced nipples. Other features include gonadal dysgenesis with atrophic streak ovaries; primary amenorrhea; and infertility. Clinical features involving other organ systems include cystic hygroma and web-bing of the neck; hypothyroidism; congenital heart disease (preductal coarctation ...

  DISORDERS OF SEXUAL DEVELOPMENT (DSD) Determination of sex  can be established by a variety of methods that do not neces-sarily completely agree. ·              Karyotypic  (genetic) sex refers to which sex chromosomes an individual has;the presence of a Y chromosome results in testicular development.   ·              Gonadal  sex refers to the presence of ovarian or testicular tissue.   ·              Ductal sex  refers to the presence of Müllerian (female – Fallopian tube, uterus,cervix, and upper portion of vagina) or Wolffian (male – epididymis, vas def-erens, seminal vesicles, and ejaculatory ducts) duct adult derivatives.   ·              Phenotypic  (genital) sex refers to the external appearance o...

  MENDELIAN DISORDERS Mendelian disorders  are characterized by single gene mutations. Common types ofmutations include point mutations and frameshift mutations. ·              Point mutations  occur with a single nucleotide base substitution, which mayproduce a variety of effects. The form of point mutation called synonymous mutation (silent mutation) occurs when a base substitution results in a codon that codes for the same amino acid. The form of point mutation called mis-sense mutation occurs when a base substitution results in a new codon and a change in amino acids. The form of point mutation called a nonsense mutation occurs when a base substitution produces a stop codon and therefore produces a truncated protein.   ·              Frameshift mutations  occur when insertion or deletion of bases leads to ashift in the reading frame of the ...

  AUTOSOMAL RECESSIVE DISORDERS (This material is included here for reinforcement. It is also covered in the Physiol-ogy Lecture Notes.) Cystic fibrosis (CF)  is the most common lethal genetic disorder in Caucasians. Itis due to mutation of the chloride channel protein, cystic fibrosis transmembrane conductance regulator (CFTR), whose  CFTR  gene is located on chromosome 7 and most commonly has been damaged by a deletion of the amino acid phenylalanine at position 508 ( F508). The defective chloride channel protein leads to abnormally thick viscous mucus, which obstructs the ducts of exocrine organs. The  distribution of disease  reflects the distribution of eccrine sweat glands and exocrine glands. ·              In the lungs, CF may cause recurrent pulmonary infections; chronic bronchi-tis; and bronchiectasis.   ·              In th...

  AUTOSOMAL DOMINANT DISORDERS Familial hypercholesterolemia  is the most common inherited disorder (incidence1 in 500) and is due to a mutation in the low density lipoprotein (LDL) receptor gene (LDLR) on chromosome 19. The mutations in the LDL receptor cause increased levels of circulating cholesterol, loss of feedback inhibition of HMG-coenzyme A (HMG-CoA) reductase, and increased phagocytosis of LDL by macrophages. There are 5 major  classes of mutation . ·              Class I:  no LDL receptor synthesis   ·              Class II:  defect in transport out of the endoplasmic reticulum   ·              Class III:  defect in LDL receptor binding   ·              Class IV:  defect in ability to intern...

  X-LINKED RECESSIVE CONDITIONS In  X-linked recessive conditions , males with a mutant recessive gene on the X chro-mosome have the condition, while daughters of affected males are obligate carriers, who in many situations are asymptomatic. ·              Sons of affected males do not carry the mutation.   ·              Daughters of carrier females may be either normal or carriers.   ·              Sons of carrier females may be affected or normal (because males are hemi-zygous for the X chromosome).   Lesch-Nyhan syndrome  results from deficiency of hypoxanthine-guanine phophori-bosyltransferase (HGPRT), which impairs salvaging of the purines hypoxanthine and guanine. Clinical features include intellectual disability, hyperuricemia, and self-mutilation. Testicular feminization...