Phenotype / Result of disease--(1. hyperammonemia, 2. High glutamine, no citrullene). Inheritance -- (X-chromosome, X-linked recessive).

 Inheritance -- (X-chromosome,  X-linked recessive).

Mutation--(Xp21.1. However, genotype is variable and no prevalent mutation exists).

Testing--(Labs to check levels of Citrulline and orate. DNA analysis. Biopsy from liver or lumen for OTC activity.)

Treatment--(Acutely: Dialysis/ Drugs to remove ammonia. Long term: Bone Marrow transplant, drugs, low protein diet).

Special Notes--(1. Mostly male, 2. X inactivation, 3. Jesse Geshund - died from gene therapy, 4. not on newborn screening panel)

Phenotype / Result of disease--(Ovarian dysgenesis, short stature (100%), lack of menses and secondary sexual characteristics, broad chest, widely spaced nipples, peculiar learning disabilities).

Inheritance -- (X chromosome ).

Mutation--(1. Non hereditary X chromosome monosomy (only 1 X chromosome), mosaicism, or defect. 2. Hugs and kisses (X and O) from Tina Turner).

Testing--(1.Karyotype for chromosome number, blood and urine test for hormone levels. 2. Cystic hygroma)

Treatment--(Recombinant growth hormone to added growth (usually about 6 cm), cycling of estrogen and progesterone for secondary sex characteristics).

Special Notes--(1. 57% are X chromosome monosomy, 29% have X chromosome mosaicism, and 14% have X chromosome defect (the last two have relative severity of symptoms depending on the severity of the defect). 2. Lymphedema problem at birth )

Phenotype / Result of disease--(1. developmental defect of the brain, caused by incomplete neuronal migration. 2. Lissencephaly (smooth brain), dysmorphic facial features).

Inheritance -- (1. Can inherit from parental balanced rearrangement. Usually de novo mutation. 2. Ch 17).

Mutation--1.Chromosomal deletion of LIS1 gene. 2. Microdeletion in LIS1 à syndromic (MDS). 3. Point mutation in LIS1à nonsyndromic (not MDS)).

Testing--(1. FISH for deletion of 17p13.3. 2. MRI to look for absence of gyri in brain. 3. Ultrasound not reliable because brain starts smooth in development)

Treatment--(None. Comfort measures and feeding tubes are used.).

Special Notes--(1. LIS1 codes for PAFAH--Platelet Activating Factor AcetylHydrolase. PAFAH is crucial to brain development and breaks down PAF (an inhibitor of neuronal migration). MDS is an example of de novo Microdeletion (syndromic, 80%), unbalanced translocation (20%), Contiguous Gene Disorder, and Haploinsufficiency )

Phenotype / Result of disease--(1. Muscle biopsy shows ragged red fibers and subsarcolemmal accumulation of mitochondria. 2. Epilepsy: decrease in neuronal and muscular tissue due to apoptosis, increase in lactic acid in the body due to a switch in ATP formation. 3. Myoclonus = twitching ).

Inheritance -- (mtDNA, no DNA repair in mt).

Mutation-- (1. Mutation of the tRNA(lys) gene. 2. Disrupts the production of complexes 1 and 4 of the electron transport chain.).

Testing--(muscle biopsy, PCR-RFLP, sequencing, RT-PCR to detect MEERF or the mutation.  muscle biopsy may be false negative since not all fibers affected due to heteroplasmy.)

Treatment--(antiepileptic drugs & vitamin supplementation.  Positive testing results does not indicate severity of the condition.  Negative results can be false, due to mitochondrial genetics. Do NOT use valproate to treat (affects mt)).

Special Notes-- (1. All children of carrier mother will inherit disease. 2. “Ragged red clumps” seen in staining are clumps of mt. 3. Abnormal mt proliferate faster than normal ones. 4. elevated lactate levels are often the best diagnostic test)

Phenotype / Result of disease--(1. Dwarfism. 2. Prominent forehead, large brain, rhizomelia (shortening of proximal segs of extremities)).

Inheritance -- (1. Autosomal Dominant. 2. Ch 4).

Mutation-- (1. FGFR3 gene (fibroblast GF) - negative regulatory effect on bone growth. 2. the mutated form of the receptor is constitutively active and this leads to severely shortened bones.).

Testing--(physical exam, x-rays, prenatal ultrasonography, Chorionic Villus Sampling/Amniocentesis, real-time PCRs, Fluorescent hybridization probes, DNA Sequencing )

Treatment--(surgery, obesity prevention, monitor other symptoms. NO CURE. ).

Special Notes-- (1. Gain of Function (common w/ autosomal dominant). 2. New gene mutation associate w/ paternal age - occurs in older males spontaneously. 3. 80% mutations de novo. 4. Very common)

Phenotype / Result of disease--(1. Unusually tall, long, slender limbs. Arachnodactyly (long,slender fingers) Arched palate, crowded teeth, lax joints. Chest abnormailites (pectus excavatum or carinatum), scoliosis, dislocated ocular lens. 2. predisposition to cardiovascular abnormalities, specifically those affecting the heart valves and aorta.).

Inheritance -- (1. Autosomal dominant. 2. Ch 15).

Mutation-- (1. mutation in FBN1 coding for fibrillin 1 in ECM essential for proper formation of ECM: proper elastin formation. 2. This gene shares homolgy with TGF-B, and during inflammatory response, we see degradation of elastin fibers -> bad for heart valves, aorta… (lots of elastin)).

Testing--(A mutation in FBN1 gene does not automatically mean Marfan's And you can have marfan's without having a mutation in the FBN1 gene… so, we classify people as affected if they manifest symptoms in two or more systems (with a first degree relative) or three or more symptoms if a second degree relative is affected. )

Treatment--(Monitor/keep Marfan kids out of sports - they have cardiovascular abnormalities and are at risk for a dissected ascending aorta.. ).

Special Notes-- (1. Dominant negative pathogenesis - acts in opposition to normal gene activity. 2. haploinsufficiency - functional gene copy is insufficient to produce a wildtype phenotype. 3. Phenocopy – similar clinical findings, but different disease. Marfan’s phenocopy is homocystoneuria. 4. Often in athletes)

Phenotype / Result of disease--(1. deficiency in phenylalanine hydroxylase (PAH) necessary to metabolize phenylalanine to tyrosine. 2. mental retardation, decreased skin pigmentation).

Inheritance -- (1. Autosomal Recessive. 2. Ch 12).

Mutation-- (various mutations in PAH gene).

Testing--(Guthrie (Newborn Screening), HPLC for blood Phe levels, PCR/RFLP, PCR/ASO Hybridization Assay)

Treatment--(Low Phe "Diet for Life," progress being made with BH4 supplements to upregulate PAH expression in certain types of PKU).

Special Notes-- (1. Other notable phenotypes: musty smell, eczema (inflammation of the upper layers of the skin). 2. Three types of PKU: Type I most common (PAH deficiency), Type II, Type III. 3. This began all the mandatory neonatal screening done today.)

Phenotype / Result of disease--(1. harmful ganglioside (fatty acid) accumulation in the nerve cells of the brain.2. delayed phys, and neuro development. Cherry Red Spot on Retina. 3. Die by age of 4).

Inheritance -- (1. Autosomal Recessive. 2. Ch 15).

Mutation-- (mutation in the HEXA gene -> underproduction of Hexoamidase A -> accumulation of GM2, swollen lysosomes).

Testing--(genetic testing for carriers with inexpensive enzyme assay that detects serum HexA levels)

Treatment--(no cure so far, treatment only for the symptoms (i.e. for the seizures)).

Special Notes-- (1. opened up genetic medicine where they were able to warn those people (Ashkanazi Jews) that were at risk in having Tay Sach's children--->very rare now because of it. 2. Excessive startle reflexes. 3. Compound heterozygosity. 4. Pseudoalleles – essentially polymorphisms that make healthy pt appear diseased. 5. Lysosomal storage disease)

Phenotype / Result of disease--(Splenomegaly with Gaucher cells, hepatomegaly, low beta-glucocerebrosidase in blood, anemia).

Inheritance -- (1. Autosomal recessive. 2. Chr1).

Mutation-- (1. Individual lacks the enzyme glucocerebrosidase (acid beta-glucosidase). 2. 80 known mutations).

Testing--(Blood test (enzyme activity), spleen biopsy, MRI, CT, skeletal X-ray, genetic testing)

Treatment--(1. Enzyme replacement therapy. 2. First of its kind. 3. Bone marrow transplant in severe cases ).

Special Notes-- (1. Most common lysosomal storage disease. 2. Variable expressivity. 3. 3 types, type 1 most common. 4. Ashkenazi Jewish heritage = highest risk)

Phenotype / Result of disease--(Progressive muscle wasting, early childhood onset (5yrs). Gower’s sign: using hands to stand).

Inheritance -- (X-linked recessive).

Mutation-- (1. Mutation in gene encoding dystrophin protein. Have no dystrophin. 30% of cases are de novo mutations. Largest gene in humans and most commonly involved with spontaneous mutations. 2. More commonly, big deletion. 3. Frameshift mutaton).

Testing--(CK test, muscle biopsy, immunoblotting, PCR/Southern Blotting, electromyography,prenatal testing is also available )

Treatment--(No cure. Treat symptoms with medications, PT, OT, passive stretching, surgeries, pacemakers, assisted ventilation).

Special Notes-- (1. Fatal. 2. Can have milder form called Becker Muscular Distrophy. 3. Allelic heterogeneity. 4. Ethical issues – dad leaving b/c he blames mom for son’s cond’n)

Phenotype / Result of disease--(1. inherited neuropathy -> loss of muscle tissue and touch sensation, predominantly in the feet and legs but also in the hands and arms. 2. Inverted bottle legs. Leg cramps, Decreased nerve conduction).

Inheritance -- (1. Autosomal Dominant. 2. Ch 17).

Mutation-- (Duplication of the PMP22 gene on chromosome 17 which causes an increase dosage of PMP22. Overproduction of PMP22 clog ER & Golgi and causes demyelination).

Testing--(1. Decreased nerve conduction (EMG). Nerve biopsy. Pulsed field gel electrophoresis,FISH or southern blotting. 2. Romberg test: Pt able to stand with eyes open, loses stability when closed. No proprioception, rely on sight)

Treatment--(1. No cure. Manage the symptoms. Physical therapy, surgeyr, etc. 2. Experimental treatment: Neurotrophin-3).

Special Notes-- (1. Normal life expextancy. Most commonly inherited neuropathy but NOT the most common cause of neuropathy! 2. Most commom causes of neuropathy: 1) Diabetes, 2) Alcoholism, 3) 1&2 together 3. Gene dosage principle: The more affected genes one has, the worst the condition)

Phenotype / Result of disease--(1. neurodevelopmental disorder 2. loss of language and motor skills between 6-24 months; microcephaly; loss of muscle tone; hand wringing; seizures; teeth grinding; abnormal sleep patterns).

Inheritance -- (X-linked dominant).

Mutation-- (Mutation in MECP2 gene; involved in repression of gene transcription; also establishes and maintains neuronal pathways).

Testing--(1st: Diagnostic - physical and neurological exam, patient/family history; 2nd: Genetic Testing - sequence/mutation scanning or PCR)

Treatment--(can only treat the symptoms; given many medications (anti-convulsants, serotonin, melatonin); support groups for families).

Special Notes-- (1. Predominantly in females 2. 99% of mutations are de novo, but 70% of the time the mutation is found on the paternal chromosome. 3. Loss of function. 4. methylation disorder, abnormal reg of lots of other genes 5. non-degenerative)

Phenotype / Result of disease--(mental retardation, large testicles (macroorchidism), prognathism, hypotonia and autism, gynecomastia, malocclusion.).

Inheritance -- (1. X-linked Dominant 2. Xq27.3 (fragile site) 3. normal = 6-50 repeats, premutation = 59-200 repeats, full mutation is > 200 repeats 4. mosaicism -> mixture of cell types ).

Mutation-- (1. FMR1 (fragile X mental retardation 1, polysomal mRNA binding protein) gene containing 6 – 55 CGG repeats 2. >200 CGG repeats -> gene methylation -> inactivates FMR1 gene & no FMRP protein is made).

Testing--(1. FMR-1 gene test via PCR 2. karyotype 3. methylation sensitive PCR 4. southern blot (less common))

Treatment--(1. educational interventions, therapy and medication. 2. NO CURE. 3. determine severity of disease 4. some medication for symptoms 5. physical/occupational therapy).

Special Notes-- (1. Disease is a triplet expansion disease 2. Sherman Paradox (the effects of Fragile X syndrome seemed to worsen with each passing generation = anticipation) 3. X inactivation; mosaicism 4. x-linked 5. developmental disorders (most common cause of autism) 6. female at risk for passing it on)

Phenotype / Result of disease--(1. Decrease in coordination and balance. 2. Choreiform (involuntary, rapid and jerky movement) and dysphagia 3. motor impairments (chorea is a big one) 4. common to see psychiatric disorders (depression, ocd, bipolar)).

Inheritance -- (1. Autosomal dominant 2. Ch 4 3. normal = 6-35 CAG repeats, Huntington = > 36 CAG repeats).

Mutation-- (1. CAG Triplet Expansion in the exon 1 of HD gene. 2. Function of gene product, huntingtin is unknown. 3. Inclusions of protein cause the problems. 4. Number of repeats affects penetrance, age of onset, and severity).

Testing--(1. Pedigree (family history), Cognitive Impairment Exams (WAIS, Mini-Mental Status), MRI, CT, PCR and Southern Blot 2. genetic testing (PCR))

Treatment--(1. Pharmacologic therapies for symptomatic treatment and supportive care 2. interdisciplinary care 3. some drugs can be given (depression is one symptom treated)).

Special Notes-- (1. Mutant: >36 CAG repeats. The number of CAG repeats affects the age of onset but not the severity of the disease. 2. Genetic anticipation (more likely if paternally transmitted). 3. Morphology: "Boxed Car Ventricles" 4. Nancy Wexler’s mother had this, she made Congress fund cure studies 5. chorea, impaired gait, cognitive impairment/speech changes, depression (motor before cognitive impairments) 6. buzzwords (anticipation, premutation [more likely from father], threshold))

Phenotype / Result of disease--(1. Cancer of the retina. 2. Strabismus (misalignment), leukocoria ("white pupil"), esotropia (medial deviation) , often seen with pineoblastoma).

Inheritance -- (1. Autosomal Dominant 2. Ch 13 3. high penetrance 4. loss of heterozygosity ).

Mutation-- (1. Two-hit hypothesis (inactivation of both RB1 alleles) is required for tumor formation. 2. Can be by deletion, somatic recombination, nondisjunction. 3. mutation in RB1 4. can be inherited or random mutation).

Testing--(1. Cytogenetic Analysis (FISH, MLPA, multiplex PCR) using blood sample can determine location, type of mutation. 2. Red reflex test 3. prenatal testing (CVS and amniocentesis 4. scans 5. no biopsy)

Treatment--(1. Photocoagulation (fry the tumor's blood supply) for small tumors, enucleation (eye removal) for large tumors 2. focal therapy (minor and isolated tumors….cryotherapy, thermotherapy, brachytherapy, photocoagulation) 3. beam radiotherapy 4. chemotherapy 5. follow up is important).

Special Notes-- (1. Individuals with hereditary version are at extremely high risk for tumors in other organs later in life. 2. loss of function of tumor suppressor gene (RB1). 3. 2-hit hypothesis came from this disorder 4. Retina undergoes rapid proliferative cycle – see inc mutations here. 5. leukocoria 6. highest curable rate of any genetic disease 7. early detection key)

Phenotype / Result of disease--(1. Loss of DNA mismatch repair -> microsatellite instability 2. Colon cancer).

Inheritance -- (1. Autosomal dominant (many types of mutations) 2. Ch 3 (MLH1, MSH1 and others) -> help in mismatch repair 4. loss of heterozygosity 5. Penetrance of ~80%).

Mutation-- (1. All cells thave one inherited mutation (DNA MMR) 2. In colon second copy of DNA MMR mutated. 3. Loss of DNA MMR increases mutations. 4. Mutations occur in protoonco or tumor supressor genes = Cancer ).

Testing--(1. Microstatellite instability screening (PCR) or immunohistochemistry 2. PCR and sanger sequencing 3. Amsterdam criteria (3 relative with histologically veridfied colorectal cancer))

Treatment--(1. Screening. 2. Removal of polyps. 3. Sugical resection of colon. 4. Chemotherapy 5. anti-VEGF treatment 6. heathy lifestyle and diet 7. colonoscopy (VERY impt) 8. Prophylactic surgery).

Special Notes-- (Known as Lynch syndrome. The inherited mutation does not directly lead to cancer. It is the loss of DNA MMR and the subsequent loss of protoonco or tumor supressor genes that leads to cancer. 2. Two-hit hypothesis 3. FAP is key disease you need to rule out before thinking about HNPCC 4. autosomal dominant 5. mutations in one of six genes (MSH2 on chr. 2 and MLH1 on chr. 3) 6. DNA mismatch repair problem 7. colonoscopies early for this disease and annually 8. microsatellite instability 9. accelerated carcinogenesis in CRC 10. endometrial cancer is second most common in US)

Phenotype / Result of disease--(1. Café au lait spots (brown pigments), Lisch nodules (benign iris tumor), bilateral axillary freckling, blindness, neurofibromas (tumors), pain, convulsions 2. hypertension, short stature, macrocephalies, skeletal abnormalities (hydrocephalus, scoliosis, kyphosis, meningocele) 3. behavioral development issues (ADHD, speech and language delays, spatial cognition) 4. increased risk of cancer).

Inheritance -- (1. autosomal dominant. 2. Ch17 3. get truncated protein 4. Two hit hypothesis 5. 100% penetrance 6. familial inheritance (50% of cases) 7. de novo mutations (50% of cases)).

Mutation-- (NF1(neurofibromin) gene (negative regulator of the Ras oncogene -> acts as GAP for Ras) -> without NF1 you can't inactivate Ras and get cell growth/proliferation).

Testing--(1. Clinical diagnosis (6 of 7 signs) 2. Genetic - protein truncation (NF1 gene….southern blotting) 3. FISH)

Treatment--(1. Surgery to remove tumors, 2. Counselling, group therapy 3. no cure 4. manage symptoms (monitor -> tumors, vision, BP…) 5. radiotherapy 6. managing learning disabilities).

Special Notes-- (1. Loss of function mutation. Tumor suppressor gene 2. Elephant man incorrectly labeled to have neurofibromatosis 3. Germline mosaicism 4. lisch nodules and café au lait spots 4. auto dom 5. two hit hypothesis 6. no cure 7. related disease of NF2)

Phenotype / Result of disease--(1. A rare overgrowth syndromeassociated with an elevated risk of embryonic tumor formation. 2. Omphalocele, hemihyperplasia, macroglossia, large birth weight, wilms tumors, "strawberry patch").

Inheritance -- (1. Autosomal Dominant 2. Ch 11 ).

Mutation-- (1. Genomic Imprinting - assess methylation of KCNQOT1 & H19 2. H19 & CKDN1C -maternal 3. KCNQOT1 & IGF2 – paternal 4. uniparental disomy 5. H19 is maternal and IGF2 is paternal 6. CDKN1C is maternal and KCNQOT1 (LIT1) is paternal 7. 4 mutations (spontaneous in 85% of the cases due to abnornal imprinting -> loss of maternal CDKN1C)).

Testing--(1. Mainly use clinical findings to diagnose, use cytogenetics only if interested in type of chromosome anomaly 2. Genetic testings (methylations studies - see hyper or hypo methylation -> LIT1 hypo? and H19 hyper) 3. Sequencing)

Treatment--(1. Treat symptoms (repair omphalocele, monitor tumors, etc.) 2. support groups 3. screening (wilms tumor and hepatoblastoma)).

Special Notes-- (1. IVF increases risk of mutation (Iatrogenic effects – doctor induced) 2. Most mutations are sporadic w/ no inheritance pattern (85%) 3. Paternal uniparental disomy (10-15%, paternal isodisomy) 4. genomic imprinting)

Phenotype / Result of disease--(1. Asymptomatic unless given thiopurine drugs 2. Can result in leukopenia, upset stomach. Problem with metabolizing thiopurine drugs).

Inheritance -- (1. Autosomal Semidom. (Het = pink) 2. Ch 6).

Mutation-- (TPMT mutations are polymorphic TPMT*2 Ala80Pro, TPMT*3A Tyr240Cys and Ala154Thr, TPMT*3C Tyr240Cys).

Testing--(Blood test for TPMT in erythrocytes; PCR for TPMT mutation if about to start a thiopurine regimen or is reacting poorly to thiopurine drug.)

Treatment--( Personalize the thiopurine drug if pt. needs to take one. Adjust dosage with respect to mutation type.).

Special Notes-- (1. Aspect of individualized medicine and adapting drugs like prednisone and thiopurines (like Azathioprine and 6-thioguanine and 6-mercaptopurine to pt. (Pharmacogenetics!) 2. TMPT is autosomal semidominant 3. Ethics – should pts be tested for this before being placed on meds? )

Phenotype / Result of disease--(1. reduced amounts of normal collagen ->Type 1 -> General connective tissue disorders, bone fragility and distinctly blue sclera throughout life 2. Lack of functional collagen -> Type II -> Perinatal effects leading to early death).

Inheritance -- (1. autosomal dominant 2. Chr. 7q21.3).

Mutation-- (1. COL1A1 or COL1A2 genes that encode α1 and α2 chains of collagen. ).

Testing--(1. Biochemical testing is the analysis of structure and quantity of type 1 collagen synthesized in vitro 2. Sequence analysis of complementary DNA (cDNA) of COL1A1 and COL1A2 genes 3. Genomic DNA sequencing of COL1A1 and COL1A2 4. Bone biopsies 5. Bone mineral density (BMD) testing)

Treatment--(1. Supportive & Palliative measures 2. New focus on medical treatments aimed at increasing bone mass & strength (bisphosphonates and GH)).

Special Notes-- (1. non-accidental injury vs. OI 2. biochemical tests vs. genetic testing 3. Most common inherited disorder of connective tissue)

Phenotype / Result of disease--(Skin hyperextensibility, Atrophic scarring, Joint hypermobility, generalized and gross loose-jointedness fragile, bruisable skin that heals with peculiar 'cigarette-paper' scars, musculoskeletal deformity and diverse orthopedic complications. Prematurity occurs in approximately 50% of cases. Internal complications such as aortic and bowel rupture may occasionally occur. ).

Inheritance -- (1. Autosomal Dominant Types: Classical (I/II), Hypermobility (III), Vascular (IV) & Arthrochalasia (VIIa,b) 2. Autosomal Recessive Types: Kyphoscoliosis (VI) & Dermatosparaxsis (VIIc)).

Mutation-- (1. Type I -> Autosomal Dominant 2. 52% of patients have an abnormal Type 5 Collagen 17 mutations leading to a premature stop codon and 5 structural mutations were identified in the alpha-1 gene on chromosome 9q34 (COL5A1) and alpha-2 gene on chromosome 2q31 (COL5A2)).

Testing--(1. Clinical Evaluation (Skin hyperextensibility, Atrophic scarring, Joint hypermobility) 2. Family History (Autosomal dominant inheritance therefore usually familial association) 3. Genetic Testing (biochemical and molecular testing))

Treatment--(1. Reduce Chronic Pain (physical therapy and pain killers) 2. prevent complications (avoid joint injury and protect skin) 3. reduce morbidity).

Special Notes-- (1. auto dominant)

Phenotype / Result of disease--(exaggerated reflexes, spasticity/hypertonia, uric acid crystals in diaper, cognitive impairment/behavior, self-mutilating behavoior).

Inheritance -- (1. X-linked recessive 2. X chromosome (long arm) 3. 30% are de novo mutation).

Mutation-- 1. Mutation of HPRT1 gene 2. over 200 diff. mutations).

Testing--(1. physical exam 2. clinical tests (urate to creatinine ratio, HPRT enzyme activity, genetic testing for HPRT1 gene))

Treatment--(1. allopurinol 2. anti-anxiety, anti-psychotics 3. restraints 4. dental extraction 5. environment 6. diet 7. support group).

Special Notes-- (1. rare disease 2. most common in males 3. unusualy in females 4. X-linked recessive 5. build-up of uric acid 6. neuro deficits 7. aggression 8. self-mutilation)

Phenotype / Result of disease--(1. renal colic 2. kidney stones).

Inheritance -- (1. autosomal recessive 2. Chr. 19 (SLC7A9)).

Mutation-- (1. Defective transepithelial transporters for dibasic amino acids -> cystine crystal formation 2. SLC7A9, S379R mutations).

Testing--1. urine AA analysis 2. ultrasound 3. intravenous pyelography 4. stone analysis)

Treatment--(1. diet change (low protein intake, high liquid, low sodium intake) -> more alkaline foods 2. drug therapy (cystine binding thiol meds) 3. surgery 4. extracorporeal shock wave lithotripsy (ESWL) 5. long term management).

Special Notes--

Phenotype / Result of disease--(1. intrauterine growth retardation 2. psychomotor retardation 3. progressive pancytopenia 4. cerebellar hypoplasia 5. immunologocal abnormalities 6. demyelination of white matter).

Inheritance -- (X-linked recessive (1 in 1 million) 2. Xq28 locus).

Mutation-- (1. DKC1 mutation (codes for dyskerin, telomerase stabilization) 2. de novo or from mother 3. most frequent is 1150 C ->T).

Testing--(1. single strand conformation polymorphism technique (SSCP) )

Treatment--(1. no cure 2. treat symptoms and provide supportive care 3. primary concerns [bone marrow failure and immunodeficiency] 4. blood transfusions [short-term] and bone marrow transplants [long-term]).

Special Notes-- (1. less severe form called dyskeratosis congenita (bone marrow failure common to both))

Phenotype / Result of disease--(1. reduced rate of synthesis of one of the globin chains that make up hemoglobin  2. microcytic anemia,  3. Skeletal deformity).

 Inheritance -- (Autosomal, recessive, ch. 11).

Mutation--(HBB gene).

Testing--(1. CBC (MCV low, MCH low).  2. Electrophoresis ( HbA2 High, HbF somewhat high).  3. PCR (for mutation analysis)  4. serum iron level (to rule out iron deficiency anema)  5. peripheral blood smear (bull's eye target cell, hypochromic, nucleated RBCs)

Treatment--(Transfusion, Iron Chelation, Splenectomy, Bone Marrow Transplant).

Special Notes--(1. Deficient synthesis of Hb β-chain.  2. Prevalence varies w/ ethnicity.  3. Selective advantage for malaria resistance. (Heterozygote, sickle cell being the other big Hb defect)  4. HbF may be future therapy.  5. microcytic anemia in  6. Zinedine Zidane Thalassemia Minor Man)

Phenotype / Result of disease--(1. Abnormality in clotting.  Hematomas especially in joints (hemarthrosis), prolonged prothrombin times, easy bruising, intracranial bleeding.   2. Age of onset associated with severity  3. susceptability to bleeding).

 Inheritance -- (1. X-linked recessive.   2.  Xq28, F8 gene for Hem. A     3. Xq27, F9 gene mutation for Hem. B).

Mutation--(Over 2100 known mutations. Hemophilia A: inversions, deletions, point mutations in clotting factor VIII gene. Hemophilia B: point mutations, deletions, etc. in clotting factor IX gene.  30% of mutations are de novo. ).

Testing--(1. Pedigree analysis, Blood assays testing levels and function of factor VIII and factor IX. Differential testing of von Willebrand factor, platelets, fibrinogen, etc.   2. Test to determine if blood is clotting properly or to determine levels of clotting factors in the blood)

Treatment--(Replacement of deficient clotting factor with recombinant or plasma derived clotting factors VIII or IX. Adjunct therapy such as physical therapy also important.).

Special Notes--(1. Males at greater risk than females.  2. Genetic heterogeneity  3. Ethics – Huge numbers of kids were given transfusions with factor VIII that were AIDS-contaminated  4. Ryan White infected with HIV from transfusion   5. Problems with normal clotting (types a and b similar)  6. A = inversion, B = point mutation...distinguish with specfic test))

Phenotype / Result of disease--

1. After age 4 months (Attacks of abdominal pain and bone pain, Delayed growth and delayed puberty, Dyspnea, Excessive thirst and frequent urination, Fatigue, Fever, Jaundice, Pallor, Tachycardia)

2. Painful episodes (crises), lasting hours to days, involving spine, long bones, ribs, and digits

3. Red blood cells sickle with low oxygen tension

4. splenomegaly

5. Sickled cells sludge, occluding small vessels, resulting in infarcts

(Dactylitis, Stroke, Renal papillary necrosis, Priapism, Skin ulcers, Retinal damage, Bone necrosis, Autosplenectomy)

Inheritance --

1. autosomal recessive 

2. chromsome 11 and 16

Mutation-- 

1. sickle cell disease -> alpha chain normal, beta chain mutated

2. GAG → GTG mutation   Glu 6 Val 

Testing--

1. Diagnosis (Family history, Anemia, Sickle cells on peripheral blood smear, Specific hemoglobin pattern by protein electrophoresis)

2. Real time PCR

Treatment--

1. Manage and control symptoms, and limit frequency of crises.

2. Supplements of folic acid (essential for producing red blood cells) because red blood cells are turned over so quickly.

3. Painful episodes treated with pain medicines (non-narcotic medications may be effective, but some patients will need narcotics) and copious fluids. 

4. Increasing levels of fetal hemoglobin with hydroxyurea (Hydrea)

5. Antibiotics and vaccines to prevent bacterial infections

6. Blood transfusions to treat a sickle cell crisis

7. Regular use to help prevent strokes.

8. Dialysis or kidney transplant for kidney disease

9. Gallbladder removal

10. Hip replacement for avascular necrosis of the hip

11. Irrigation or surgery for priapism

12. Bone marrow transplantation

Special Notes-- 

1. Novel Property Mutation

2. Heterozygote Advantage

3. Genetic Compound

4. Ethnic Variation in Allele Frequencies

5. Known protein change since 1959 and gene since 1978, but cure “just 10 years away”

Phenotype / Result of disease--

1. decreased AFP, increased beta hCG,  increased nuchal translucency

2. Dysmorphic features

3. Mental retardation, duodenal atresia, increased risk leukemia

4. Septum primum type atrial septal defect

5. Alzheimer’s >35yo

Genetics

1. Trisomy 21 (95%)

2. Robertsonian translocation (4%)

3. 21q21q translocation (2%)

4. Mosaic Down syndrome (2%)

Trisomy 21 (95%)

1. Meiotic non-dysjunction

–90% maternal, meiosis I

–10% paternal, meiosis II

2. Increased risk with maternal age

3. Recurrence risk 1%

4. Family history of trisomy 21 does not increase risk

Robertsonian Down Syndrome (4%)

1. 46 chromosomes, but one is Robertsonian translocation between 21q and long arm of an acrocentric chromosome, usually 14 or 22.

2. Essentially, 3 copies of 21q.

3. No relation to maternal age.

4. High recurrence risk

5. Carriers have 45 chromosomes

Trisomy 13 

1.Bilateral cleft lip and polydactyly

2. Growth retardation and severe mental retardation

3. Open sutures

4. Clenched hand, microcephaly, congenital heart defects, microphthalmia

5. Arhinencephaly or holoprosencephaly

6. 1:20,000 live births

7. 50% die within 1 month of birth

8. Increased risk with maternal age

9. Recurrence risk is low

**cyclopia

Trisomy 18

1. Mental retardation, failure to thrive

2. HYPERtonia

3. Prominent occiput

4. Clenched fist, rocker-bottom feet, micrognathia, congential heart defects

5. 1:7500 live births

6. 95% abort spontaneously

7. Usually only survive a few months

8. Increased risk with maternal age

Cri du Chat Syndrome

1. Terminal or interstitial deletion of 5p; critical region = 5p15

2. Microencephaly, mental retardation, hypertelorism, epicanthal folds, low set ears, micrognathia, congenital heart defects

3. CAT LIKE CRY

4. Mostly sporadic, but some due to translocation carrier parent

22q11 syndromes

1. Mnemonic: CaTCH-22

2. Cleft palate

3. Thymic aplasia -> T-cell deficiency

4. Cardiac defects (truncus arteriosis, tetralogy of Fallot)

5. Hypocalcemia due to parathyroid hypoplasia

•Variable presentation as DiGeorge syndrome (thymic, parathyroid, and cardiac defects) or velocardiofacial syndrome (palate, facial, and cardiac defects)

1. 47,XXY

2. Common cause of infertility

3. Learning difficulties and body image issues

4. Testicular atrophy, eunuchoid body shape, tall, long extremities, gynecomastia, female hair distribution

5. Presence of inactivated X (Barr body)

1. Hugs and kisses (XO) from Tina TURNER (female)

2. Short stature, ovarian dysgenesis (streak ovary), web neck, coarctation of aorta, most common cause of primary amenorrhea

3. No Barr body

4. hydrops fetalis

•Prader-Willi Syndrome (PWS)

–70% due to deletion of segment of Paternal chr 15q

–25% due to maternal UPD chr 15

–Defect is in the region of the SNRPN gene, but not clear if SNRPN is the PWS gene (thus can’t comment on point mutations)

–5% mutations in imprinting control element

-Microdeletion, genomic imprinting. Hyperphagia, obesity, mental retardation, hypogonadism, short, small hands and feet

•AngelMan Syndrome (AS)

–70% due to deletion of segment of Maternal chr 15q

–5% due to paternal UPD chr 15

–10% due to point mutation of UBE3A gene

–5% mutations in imprinting control element

-- Angelman syndrome (happy puppet syndrome) is usually due to a microdeletion on chromosome 15 that was derived from her mother. Severe mental retardation, no speech, characteristic gait, wide stance. Can also be due to paternal uniparental disomy (the UBE3A gene in inactivated on paternal chromosomes).

PWS vs AS

-Normal (Step 1):

1. UBE3A is inactivated on paternal chromosome 15; active on maternal chromosome

2. SNRPN region (PWS gene) is inactivated on maternal chromosome 15; active on paternal

-Deletion or UPD of 15q (Step 2):

1. Deletion on chr15 from Mom = no UBE3A expression = AngelMan.

2. Deletion of Paternal chr15 = no SNRPN expression = Prader-Willi.

OR 

3. Maternal UPD = no SNRPN expression = PWS (see image to the left).

4. Paternal UPD = no UBE3A expression = AS.