| A | B |
|---|
| 210 HPRT1 mutations assoc with L-N syndrome lesion indicates severity of disease | Normal at birth, symptomatic 3-6mo. Orange colored crystals in diaper hypotonic/hyperreflexia. Atheosis-chorea |
| Somatic mosaicism | Segmented NF1/NF2 |
| 22q12.2 | vestibular/cochlear issues via CN VIII – tinnitus/vertigo |
| 17q11.2, Neurofibromin | AD, variable expression, complete penetrance (by 5) -child |
| Lesch-Nyhan Syndrome | X-linked; Block forces conversion to uric acid crystals which accumulate in joints, tissues and CNS. kidney stones, hematuria, arthritis |
| Deficiency of Hexosaminidase A, enzyme needs α+β units+ activator, GM2 | Tay-Sachs Disease |
| Sandhoff Disease | Similar Presentation as Tay Sachs but with hepatosplenomegaly |
| Fabry Disease | X-linked; α-galactosidase A encoded by GLA (over 300 mutations characterized) |
| dark red to blue-black angiectases | Angiokeratomas (Fabry Disease) |
| pins and needles, numbness from sphingolipid deposition in small vessels supplying peripheral nerves | Acroparesthesia-(Fabry Disease) |
| Gaucher Disease | A.J. 4 mutations, 98% population – founder effect |
| Niemann-Pick Disease A and B | Type A and B – A.J. population |
| Niemann Pick Type C | membrane bound protein sterol-sensing domain prevent lipid movement out of cell |
| Niemann Pick Type C | more likely to occur in Hispanic Americans in southern New Mexico and Colorado |
| MPS - I | accumulation of heparan and dermatan sulfate |
| Scheie syndrome | milder form of MPS (MPI-IS) |
| Intermediate to Hurler and Scheie | MPS-IH/S |
| MPS-IH and MPS-IS | allelic |
| MPS-IH/S | cmpd heterozygote |
| MPS - I Hurley phenotype | coarse facies, enlarged skull, corneal clouding, hepatospleno, thickened skin, hernias, contractures evident by age 1. Accumulate in coronary artery leading to ischemia and cardiac insufficiency , respiratory infections, thickening of meninges, dec. in CSF circulation and inc. cranial pressure |
| MPS - I | Autosomal Recessive IDUA gene alpha-iduronidase |
| MPS – II –Hunter Syndrome | Clinical Severity correlate with the amount of iduronate X-linked |
| MPS – III –Sanfilippo Syndromes | LE 20yrs; degradation of heparan sulfate (not dermatan sulfate), heparan sulfate accumulates, in urine; infants are normal at brith, first changes child age 2-6 |
| MPS – III –Sanfilippo Syndromes | Autosomal Recessive; developmental delay, speech, behavioral changes, short attention span , impulsiveness, coarse facies, thickened eyebrows that meet (synophrys), skeletal changes similar to MPS-I, coarse thick blond or brown hair |
| (Heparan-N-sulfatase) | MPS IIIA |
| MPS IIIB | (α-N-acetylglucosaminidase) |
| Maternal triplet repeat | CpG islands that are amplified are methylated and downregulates production of FMR1 |
| Fragile X Syndrome; loss of FMR is associated with | methylation |
| Females –mental impairment, heterozygous carriers symptomatic due to x inactivation | Fragile X Syndrome |
| Huntington Disease | Later onset significant as allele may have already been passed to offspring; anticipation – larger expansion is associated with earlier onset and more severe symptoms (de novo not observed) |
| Paternal triplet repeat/inherited as autosomal dominant disease with complete pentrance | CAG repeats inhibits normal huntingtin movement between cytoplasm and nucleus, decreasing transport of BDNF via clathrin interaction, resulting in neuronal toxicity and progressive death of GABAergic neurons |
| Triplet repeats due to | faulty mismatch repair or unequal recombination |
| Loss of function | fragile X |
| gain of function | Huntington’s /other neurologic disorders i.e. CAG repeats (poly glutamate) |
| DNA slippage | DNA polymerase moves along expansions that bind to each other knocking the polymerase off |
| Unequal crossing over can | amplify duplicatons |
| Permutation phenotype | different clinical image than expected (as compared to other X-linked/recessive disorders) |
| Male carriers of permutation allele | FXTAS – ataxia, tremor, memory loss, atypical Parkinson’s, loss of vibration and tactile sensation and reflexes, lower limb weakness (penetration increases with age) |
| Females with FXTAS | also have premature ovarian failure <40 and increased incidence of dizygotic twins |
| Genetic anticipation | a molecular based explanation through amplification to explain the increase in disease severity in successive generation |
| Allelic vs. Locus Heterogeneity | Cystic Fibrosis – there are many alleles (versions) of the same gene leading to different expressions of functional activity, meaning different severities of the disease. Someone with an allele coding for an 80% functional enzyme will be better off than someone coding for a 10% functional enzyme. |
| Founder effect | high frequency of particular mutations in a population where the population is consistent with a small group of founders |
