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36 Cards in this Set
- Front
- Back
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ACMG recommends AJ carrier screening for what?
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CF
Tay-Sachs Canavan Familial Dysautonomia |
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ACOG recommends AJ carrier screening for what?
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CF
Tay-Sachs Canavan Familial Dysautonomia MAY INQUIRE ABOUT Mucolipidosis IV Niemann-Pick disease type A Fanconi anemia group C Bloom syndrome Gaucher disease |
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Who should be screened for Tay-Sachs?
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AJ (1/30)
French Canadian (1/30) Cajun (1/30) |
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Tay-Sachs testing sensitivity:
1) Enzyme analysis 2) Common mutation panels |
Enzyme analysis in serum
Hexosaminidase A levels Not accurate in pregnant women Not accurate if on birth control pills (do leukocyte analysis) Are 2 pseudodeficiency alleles Mutation analysis 94-99% detection in AJ |
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Familial dysautonomia
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1/31
IKBKAP gene 1 mutation found in 99% carriers 2nd mutation also tested for 99% detection Disorder of sensory and autonomic nervous system (decreased neuron survival) Abnormal suck, feeding difficulties Episodic vomiting Abnormal sweating NO TEARS Pain and temperature insensitivity Labile blood pressure Scoliosis Hypotonia, lack of balance Normal intelligence |
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Fanconi anemia type C
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1/90 FANCA, FANCG
99% detection with 1 AJ mutation 13 complementation groups Recessive [FANCB by contrast is X-linked] Life expectancy 8-12 years Bone marrow failure/malformation syndrome Increased chromosome breakage Risk for malignancy Severe anemia Progresses to pancytopenia MALFORMED/ABSENT THUMBS and forearms Short stature, Failure to thrive Developmental delay Hearing loss Abnormal skin pigmentation Congenital anomalies: Limb, cardiac, genital-urinary, kidney Microcephaly MR Increased risk for leukemia in children (AML in 1/3) Acute Myeloid Leukemia Solid tumors in 1/3 (head, neck, female repro tract, liver) Bone marrow transplant been successful in some Chemo and radiation not a good idea |
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Niemann-Pick type A
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1/90
97% detection with 3 mutations Lysosomal storage disease Rapid neurodegeneration Similar to Tay-Sachs Diagnosed in infancy Die by 3-5 years Deficiency of sphingomyelinase enzyme No treatment |
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Bloom syndrome
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BLM gene
AUTOSOMAL RECESSIVE 1/100 AJ carrier risk 99% detection with 1 mutation (6 del/7 ins) DNA Helicase--helps maintain genomic stability during replication Increased sister chromatid exchange Chromosome breakage syndrome Predisposition to infections, malignancies Immunodeficiency Skin findings: facial telangiectasias, abnormal pigmentation Butterfly distribution after sun exposure Growth deficiency (pre- and post-natal) Learning difficulties, MR in some Mean age of death 27 (cancer) Female early menopause, male infertility No treatment Avoid radiation 25% cancer: Carcinoma (breast, colon, esophagus, liver) Lymphoma, leukemia Sarcoma Germ cell tumors Glioma Wilms tumor |
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Mucolipidosis IV
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1/127
95% detection with 2 mutations Lysosomal storage disease Neurodegenerative Growth retardation Psychomotor retardation Corneal clouding Retinal degeneration (progressive) Strabismus Most never speak, walk or develop beyond level of 1-2 year old Life expectancy may be normal No treatment |
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What is the most common AR disorder in Ashkenazi Jews?
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Gaucher disease
Affects 1/900 |
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Canavan disease
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Least common of the first-line AJ diseases
1/41 ASPA gene (aspartoacylase) 97% detection with 2 mutations Lysosomal storage disease High NAA (N-acetyl aspartic acid) in the urine CNS disorder, demyelination Developmental delay Hypotonia LARGE HEAD, macrocephaly, head lag Can't sit, stand, talk Seizures Blindness Gastrointestingal reflux Die within first several years of life (<10) Deficiency of aspartoacylase enzyme No treatment |
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Gaucher disease Type I
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1/18
90% detection with 4 mutations Beta-glucosidase enzyme deficiency Enzyme therapy improves QOL Affects spleen, liver, bones Sometimes lungs, kidneys, brain May develop at any age Can be so mild don't know have it Chronic fatigue, anemia Easy bruising Nosebleeds, bleeding gums Prolonged, heavy menstruation Enlarged liver and spleen Osteoporosis Bone and joint pain |
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Tay-Sachs disease
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Hexosaminidase A (alpha subunit) enzyme deficiency
No treatment 1/31 AJ 92-99% detection with 3 mutations Lysosomal storage disease: GM2 gangliosidosis Severe, progressive CNS disorder Death in first few years of life (<6) Appear normal at birth By 6 months, poor muscle tone (hypotonia) Startle response to sound Cherry red spot on macula Delayed development Loss of developmental milestones Seizures MR Blind at 12-18 months Late-onset: Progressive muscle wasting Dystonia Psychosis |
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Prevalence of these disorders in non-Jewish populations?
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Unknown
(except for Tay-Sachs and CF) If only one partner Jewish, difficult to assess risk of affected offspring |
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When only one partner is AJ?
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They should be screened first
If both, may do simultaneously due to time pressure of pregancy |
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What if are carriers?
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Offer prenatal diagnosis
(CVS, amnio) |
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What proportion of AJ carry a mutation for any one of these disorders?
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1:4 to 1:5
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Founder effect results in what?
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For Jewish Genetic Diseases, 1-3 mutations account for the vast majuority of disease
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Considerations for AJ carrier screening (criteria)
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Natural history well understood
Test predicts severity of disease Clearly defined target population for the test Significant morbidity or mortality >90% detection rate (simple, accurate, inexpensive) Allele frequency >1/100 Cost effective for society |
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Risidual risk remains after carrier testing
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Larger in non-AJ population by far
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What degree of AJ heritage is enough for testing?
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One partner with one Jewish grandparent
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Which ones are deadly in childhood?
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Tay-Sachs
Canavan Familial dysautonomia Niemann-Pick type A |
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2 indications for carrier screening?
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AJ heritage
Family history of condition |
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Most common fatal autosomal recessive disorder in Caucasians?
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Cystic fibrosis
1/3000 pop frequency |
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Cystic Fibrosis
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CFTR gene (chloride channel)
Dehydrated secretions Newborn screening implemented in all but one state Panel of 23 mutations recommended by ACOG/ACMG All prospective parents |
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Reasons to test for CF
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Positive neonatal screening test
Fetal echogenic bowel To assist a clinical evaluation Carrier identification Prenatal genetic testing for carrier couples |
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Alpha thalassemia
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4 alpha globin genes (chrom 16p)
Large deletions predominate (85%) Imbalance of alpha, beta chains |
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Which deletion in alpha-thal gives you a fusion of the two alpha globin genes that is functional?
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3.7 kb deletion
African, Mediterranean, Chinese 4.2 kb deletion only affects alpha-2 gene Chinese |
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Most severe alpha-thalassemia deletion?
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SEA
China, South East Asia |
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African-American alpha-thalassemia deletions?
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Most often in trans
SE Asian in cis |
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Difference between alpha-2 and alpha-1 genes?
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Alpha-2 produces 3x more protein
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What is Hb constant spring?
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A read-through deletion that ignores the stop codon of alpha-2
Acts like a deletion |
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3 copies of alpha-globin?
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Silent alpha-thal trait
(or 3 plus constant spring) |
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2 copies of alpha-globin?
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Alpha-thal trait (mild anemia)
MCV<80 (or 2 plus constant spring) |
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1 copy of alpha-globin?
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Hemoglobin H disease
Alpha thalassemia (or 1 plus constant spring) Transfusion dependent |
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0 copies of alpha-globin?
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Hb Bart's
Hydrops Incompatible with life |
