Unit II Genetic Disorders Flashcards
Duchenne Muscular Dystrohpy: Inheritance
X- Linked Recessive
Duchenne Muscular Dystrohpy: Incidence
1/3000 males
Duchenne Muscular Dystrophy: clinical presentation
onset at 2 yrs, progressively lose motor function, wheelchair by 18 yrs. progressive myopathy, calf hypertrophy, + Gowers Maneuver, abnormal gait, high creatine kinase levels
Duchenne Muscular Dystrohpy: Mechanism
Deletion of multiple exons, Xp21.2 - dystrophin gene - loss-of-function
high mutation rate
in-frame deletion leads to Becker dystrophy
Hereditary Neuropathy with Liability to Pressure Palsies (HNPP): Inheritance
Autosomal Dominant
HNPP: Clinical Presentation
temporary (usually reversible) neuropathy when pressure applied to various nerves (i.e. “arm going to sleep” for days etc) Onset at 20-30 yrs
HNPP: Mechanism
deletion of PMP22 gene (PMP22 is integral to glycoprotein in nerurons)
Loss-of-Function mutation
(reciprocal mutation to CMT1A that is a duplication of PMP22)
Osteogenesis Imperfecta Type I: Inheritance
Autosomal Dominant
Osteogenesis Imperfecta Type I: Incidence
1/30,000-50,000
Osteogenesis Imperfecta Type I: Clinical Presentation
Brittle bones and increased fractures, blue sclerae, normal stature, progressive hearing loss in adults
Osteogenesis Imperfecta Type I: mechanism
nonsense/frameshift mutation in the COL1A1 gene that leads to premature termination (mRNA is unstable and degraded) - assembly of multimeric protein COL1A1 is disrupted, normal ratio of protein subunits is disrupted and protein not produced in sufficient quantities
Charcot-Marie-Tooth Type 1A: Inheritance
Autosomal Dominant
Charcot-Marie-Tooth Type 1A: Clinical Presentation
Demyelinating motor and sensory neuropathy; lower extremitiy weakness and muscle atrophy along with mild sensory loss, foot deformity known as hammertoes
Charcot-Marie-Tooth Type 1A: Mechanism
Duplication of PMP22 gene (17p11.2)
Gain-of-Function mutation (reciprocal mutation to HNPP that is a deletion of PMP22)
Osteogenesis Imperfecta Type II, III, IV: Inheritance
Autosomal Dominant
Osteogenesis Imperfecta Type II, III, IV: Clinical Presentation
Brittle bones, increased fractures, blue sclerae (usually a more sever phenotype than Type I)
Osteogenesis Imperfecta Type II, III, IV: Mechanism
Novel property mutation of the COL1A2 protein that results in different folding of COL1A2 protein that forms collagen trimer (1/2 collagen being abnormal is worse than 1/2 being produced but is normal)
Huntington Disease: Inheritance
Autosomal Dominant
Huntington Disease: Incidence
1/10,000
Huntington Disease: Clinical Presentation
Progressie neurodegenerative disorder with adult onset - fatal within 15 yrs of onset
Gene anticipation (earlier onset/more severe phenotype in subsequent generations)
parental origin helps determine onset
paternal origin = early onset, maternal origin = later onset
Huntington Disease: Mechanism
trinucleotide repeat disorder in an exon of the HTT gene on 4p16.3 leads to increased polyglutamine residues in huntington protein
Novel Property Mutation
Number of repeats - <27 = normal, >40 = 100% penetrant disease, >60 = Juvenile onset
Myotonic Dystrophy I: Inheritance
Autosomal Dominant
Myotonic Dystrophy I: Incidence
1/20,000
Myotonic Dystrophy I: Clinical Presentation
Adult-onset muscular dystophy (progressive muscle wasting and weakness), Droopy eyes, cataracts, intellectual disability, hypotonia, cardiac conduction defects
Myotonic Dystrophy I Mechanism
Tri-nucleotide repeat disorder: repeats in the 3’ UTR of the DMPK gene (19q13.3)
maternal expansion (leading to anticipation) more likely
Number of Repeats: 5-34 = normal, 34-49 = premutation range, >50 = 100% penetrance
Phenylketouria (PKU): Inheritance
Autosomal Recessive
PKU: Incidence (Northern Europeans) and degree of allelic heterogeneity
1/10,000 live births in Northern Europeans
High allelic heterogeneity - compound heterozygotes more likely = range of phenotypes observed
PKU: Clinical Presentation
Microcephaly, intellecutal disability if untreated in infancy. Seizures, tremor, gait disorders.
PKU: Screening
Use Tandem Mass Spectrometry
Timing is important because PAH normal at birth due to mothers PAH in circulation, must wait a few days after birth, but screen before CNS damage occurs
PKU: Mechanism
partial or complete loss-of-function mutations in PAH gene (12q22-24) - many patients compound heterozygotes (two different mutant alleles)
Defect in PAH (phenylalanine hydroxylase enzyme) or BH4 cofactor - leads to high levels of phenylalanine that damges CNS (exact mechanism unclear)
PKU: Treatment
low-phenylalanine diet recommended early, and maintained throughout life.
BH4 deficient patients supplemented with oral BH4.
Important for pregnant mothers to maintain diet throughout pregnancy to avoid miscarriage or congenital malformations, intellectual disability, growth impairment (circulating phenylalanine damages fetus regardless of phenotype).
alpha1-Antitrypsin Deficiency (ATD): Inheritance
Autosomal Recessive
ATD: Incidence (Northern Europeans)
1/2500 - carrier frequency 1/25
ATD: Clincal Presentation
late onset. 20X increased risk of emphysema (more severe for smokers - ecogenetics). liver cirrhosis.
ATD: Mechanism
SERPINA1 gene on 14q32.13.
Z (15% of SERPINA1 level) and S (50-60% of SERPINA1 level) alleles most common mutations
ATD: Treatment
Recombinant AT1 therapy (intravenous infusion, aerosol inhalation) is often used, may not be as effective as once believed
Tay-Sachs Disease: Inheritance
Autosomal Recessive
Tay-Sachs Disease: Incidence (whole population and Ashkenzai Jew)
1/360,000 general pop 1/3,600 Ashkenazi Jew
Tay-Sachs Disease: Clinical Presentation
Progressive neurodegeneration of the CNS. Onset at 3-6 months, muscle weakness, decreased attentiveness. characteristic “cherry-red spot” in eye
Later - seizures, vision/hearing loss, diminished mental function, paralysis. Fatal 3-4 yrs
Tay-Sachs Disease: Mechanism
Mutation of the HEXA gene leads to defective hexosaminidase- lysosomal storage disorder (accumulation of Gm2 ganglioside - primarily in the brain)
100 mutations known for HEXA
Tay-Sachs Disease: Screening
Enzymatic activity for HEXA/HEXB enzymes. can screen carriers for lower levels of HEXA - or prenatal screening
DNA testing best for mutations known in Ashkenazi Jewish pop
AB - variant Tay-Sachs Disease
rare form when HEXA/B enzymes normal, but GM2 accumulates because of defect in GM2 activator protein that facilitates interaction with HEXA
Sandhoff Disease
Similar to Tay-Sachs, but there is a defect in both HEXA and HEXB due to defect in beta subunit that is used for both proteins
Cystic Fibrosis: Inheritance
Autosomal Recessive
Cystic Fibrosis: Clinical Presentation
Salty skin, poor growth and poor weight gain despite a normal food intake, accumulation of thick, sticky mucus, frequent chest infections, and coughing or shortness of breath
Cystic Fibrosis: Mechanism
Mutation of CFTR gene; CFTR protein needed to regulate components of sweat, digestive juices, and mucus by regulating movement of chloride and sodium ion across epithelial membranes
Achondroplasia: Inheritance
Autosomal Dominant
Achondroplasia: Incidence
1/40,000 newborns (80% new mutation rate, 100% penetrant)
Achondroplasia: Clinical Presentation
Short Stature, rhizomelic limb shortening (proximal limb shorter than distal), large head with frontal bossing, spinal cord compression, “trident” hand, brainstem compression - 3-7% die suddenly during 1st year of life
Achondroplasia: Mechanism
mutation in the FGFR3 (Fibroblast Growth Factor Receptor 3) gene - 98% due to a specific Gain of Function mutation.
Receptor that normally inhibits bone growth turns on, shortening of limbs.
new mutations common, most often in paternal germline (higher risk with increasing age)
displays incomplete dominance - homozygous form is fatal pre-/perinatally
Neurofibromatosis Type I: Inheritance
Autosomal Dominant
Neurofibromatosis Type I: Incidence
1/3,000 births 50% new mutation rate
Neurofibromatosis Type I: Clinical Presentation
Cafe au Lait spots, axillary and inguinal freckling, multiple neurofibromas, Lisch nodules (eye)
Neurofibromatosis Type I: Mechanism
Loss of Function mutation in the NF1 gene (17q11.2) - 1000 mutations have been described. 100% penetrance but variable expressivity
Marfan Syndrome: Inheritance
Autosomal Dominant
Marfan Syndrome: Incidence
1/5,000
Marfan Syndrome: Clinical Presentation
Conective tissue disorder; ocular, skeletal and cardiovascular manifestations. risk of aortic aneurysm, apear tall and skinny, hypermobile joints, pectus excavatum/carnatum
Variable Expressivity
Marfan Syndrome: Mechanism
Mutation in FBN1 (15q21.1) gene that effects Fibrillin
Tuberous Sclerosis: Inheritance
Autosomal Dominant
Tuberous Sclerosis: Incidence
1/6,000
Tuberous Sclerosis: Clinical Presentation
hypopigmentation, angiofibroma, shagreen patch, renal cysts, Cardiac rhabdomyoma (infants) Variable Expressivity
Tuberous Sclerosis: Mechanism
Variable Expressivity Loss of function mutation in the TSC1 or TSC2 gene that encodes hamartin and tuberin proteins that regulate cell growth and proliferation
Fragile X Syndrome: Inheritance
X - linked dominant
Fragile X Syndrome: Incidence (males and females)
1/2,500-4,000 males 1/7,000-8,000 females
Fragile X Syndrome: Clinical Presentation
Childhood onset. Mental deficiency, enlarged testicles (macroorchidism), speech/language delay, autistic behaviors, social anxiety
Fragile X Syndrome: Mechanism
Trinucleotide repeat expansion in the 5’UTR of the FMR1 gene - results in hypermethylation and silencing of the gene.
Number of repeats: 6-45 = normal, 55-200 = premutation, >200 = penetrant disease
Fragile X associated tremor/ataxia syndrome (FXTAS)
expressed when the 5’ UTR repeat number in the FMR1 gene (Fragile X) is in the premutation range.
Does not result in hypermethylation, but rather a gain of function mutation of the FMR1 gene.
Phenotype - adult onset with Ataxia, tremor, memory loss, peripheral neuropathy
Premature Ovarian Failure
Occurs in women when the 5’ UTR repeats in the FMR1 gene are in the premutation range. Leads to cessation of menses before the age of 40.
Hemophilia A: Inheritance
X-linked recessive
Hemophilia A: Incidence
1/4,000 male births
Hemophilia A: Clinical Presentation
blood clotting disorder. spontaneous bleeds into joints, muscle, intercranial. excessive bruising, prolonged bleeding after injury, delayed wound healing
Hemophilia A: Mechanism
Mutation in F8 gene (Xp28) that leads to a deficiency in Factor VIII
Hemophilia A: Treatment
Some success has been found introducing Factor VIII transgene into muscle tissue to secret transgeneic Factor VIII
Turner Syndrome: Inheritance and Incidence
Sex Chromosome Disorder (45, XO) effects 1/2,000-5,000 live births. Often the result of Meiotic nondisjunction
Turner Syndrome Presentation: Cardiovascular
bicuspid aortic valve, coarctation of aorta, systemic hypertension, prolonged QT syndrome, partial anomalous pulmonary venous connection, persistent left SVC
Turner Syndrome Presentation: Eye
Inner epicanthal folds, ptosis, blue sclera
Turner Syndrome Presentation: Skeletal
Cubitus valgus, short 4th metacarpal, short stature
Turner Syndrome Presentation: Neck
Web Neck, low hairline, Cystic Hygroma (fetal)
Turner Syndrome Presentation: Learning abnormalities
difficulty in math, visual spatial skills, and non-verbal scores
Turner Syndrome Presentation: Chest, head/face
prominent auricles, low-set ears, high narrow palate, small mandible, shield chest, broad nipples, pectus excavatum, sensironeural hearing loss
Turner Syndrome Presentation: Endocrine
Hypothyroidism, Gonadal dysgenesis
Turner Syndrome: Challenges across the lifespan
Infertility, stature, sexual Development, and concerns regarding health and aging.
Turner Syndrome: Pitfalls in medical culture
Secret keeping, difficulty in communicating infertility diagnosis, perceived negative experiences with physicians. Practice culturally effective medicine!!
Kleinfelter Syndrome: Inheritance and Incidence
Sex Chromosome Disorder - occurs in 1/500-1,000 newborn boys (47, XXY)
Kleinfelter Syndrome: Clinical Presentation
Learning disabilities, delayed speech and language, tall stature, small testis, reduced facial/body hair, infertility, hypospadias, gynecomastia
Kleinfelter Syndrome: Mechanism
Meiotic nondisjunction - half of cases are due to pseudoautosomal recombination (15% of these mosaic)
Jacobs (XYY) syndrome
Sex Chromosome disorder - 1/1,000 newborn boys learning disabilities, speech delays, developmental delays, behavioral/emotional difficulties, autism spectrum, tall. Not associated with criminal behavior!
Androgen Insensitivity Syndrome (AIS)
X-linked recessive varies from mild under-virilization to full sex reversal mutation causes abnormality of androgen receptor, tissue cannot respond to androgen
Congenital Adrenal Hyperplasia
Autosomal Recessive, 1/25,000 births Ambiguous genetalia due to deficieny of 21-hydroxylase
5 - Alpha Reductase Deficiency
Autosomal Recessive disorder causing a failure to convert testosterone to dihydrotestosterone that leads to incomplete phallic development and under virilization that may be reversed naturally at the onset of puberty
(“Middlesex” example)
Nonsyndromic Deafness: Inheritance (progressive childhood and congenital varieties)
Progressive childhood type - Autosomal dominant
Congenital type - Autosomal recessive
Genetic causes account for 1/4 of congenital deafness, 3/4 of genetic causes are nonsyndromic
Nonsyndromic Deafness: Clincial Presentation
Deafness (duh)
Nonsyndromic Deafness: Mechanism
50% of nonsyndromic cases are due to a mutation in the GJB2 - typically a loss of function mutation
Syndromic deafness: Clinical Presentation and different types
Deafness along with generally intellectual disability, seizures, dysmorphic syndromes
Reinitis pigmentosa - Usher Syndrome (AR)
thyroid goiter - Pendred (AR)
arrythmia or sudden death - Jervell and Lange-Nielson syndrome (AR)
white forelock - Waardenburg syndrome (AD)
8th nerve schwannomas - Neurofibromatosis type II
Fabry Disease: Inheritance
X-linked recessive
Fabry Disease: Clinical Presentation
Microvascular disease, neuropathy, cardiomyopathy, reduced sweating, progressive renal failure
Fabry Disease: Mechanism
deficiency of alpha-galactosidase leads to accumulation of glycosphingolipids that causes widespread damage
Fabry Disease: Treatment
Chaperone-based therapy may help to fold the protein correctly and increase enzymatic activity. Recombinant enzyme therapy has also been used to mitigate progression of the disease
Downs Syndrome: Inheritance
Chromosomal Abnormality due to Trisomy 21 - most often associated with advnaced maternal age
Down Syndrome: Screening
1st trimester screening - ultrasound measurement of nuchal folds + beta-hCG + PAPP-A
2nd trimester - beta-hCG, AFP, unconjugated estriol, and inhibin Detection rate of 95% for 1st and 2nd trimester
Down Syndrome: Clinical Presentation
normal growth parameters, midfacial hypoplasia, upslanting palpebral fissures, epicanthal folds, small ears, large-appearing tongue, low muscle tone (hypotonia), increased joint mobility, short fingers, transverse palmar crease, Vth finger incurving, increased space between toes 1 and 2
Down Syndrome Common Medical Issues: GI
10-15% have structural abnormalities esophageal atresia, duodenal atresia, Hirschsprung’s
Feeding problems, constipation, GERD, Celiac Disease
Down Syndrome Common Medical Issues: Cardiac
50% of patients all types of anomalies, atrioventricular canal is common
Down Syndrome Common Medical Issues: Ophthalmologic
blocked tear ducts, myopia, lazy eye, Nystagmus, Cataracts
Down Syndrome Common Medical Issues: ENT
chronic ear infections, deafness, chronic nasal congestion, enlarged tonsils and adenoids (obstructive apnea)
Down Syndrome Common Medical Issues: Orthopedic
hips, joint sublexation - especially of the atlantoaxial subluxation
Down Syndrome Common Medical Issues: Endocrine
Thyroid disease, Insulin Dependent Diabetes, Alopecia areata, reduced fertility
Down Syndrome Common Medical Issues: Hematologic issues
increased risk of leukemia, iron deficiency anemia
Down Syndrome Common Medical Issues: Developmental
hypotonia effects gross motor development.
spectrum of intellectual disability, average is mild-moderate disability
speech delay (sign language taught early on)
Down Syndrome Common Medical Issues: Psychiatric
depression, early Alzheimer’s, Autism (10% of patients)
Down Syndrome Common Medical Issues: Neurologic
Hypotonia, seizures
Down Syndrome: Mechanism
95% of cases are due to nondisjunction error associated with advanced maternal age 3-4% of patients due to unbalnced translocation of chromosome 21 and another acrocentric chromosomes (13, 14, 15, 22) 1-2 % of patients are mosaic Down Syndrome - loss of 3rd chromosome early in fetal development leads to different karyotype in different cells - milder phenotype
Trisomy 13 (Patau’s): Inheritance
Chromosomal abnormality
Trisomy 13 (Patau’s): Clinical Presentation
facial dysmorphism, severe intellectual disability, holoprosencephaly, facial celfts, polydactyly, renal anomalies Often fatal by 1st year of life
Trisomy 13 (Patau’s): Mechanism
Due to nondisjunction error. 20% of cases due to a Robertsonian translocation (chromosome 14 has and extra 13 tacked onto the end of it)
Trisomy 18 (Edward’s): Inheritance
Chromosomal Abnormality
Trisomy 18 (Edward’s): Clinical Presentation
Intrauterine growth retardation, characteristic face, severe intellectual disability, clenched fingers, rocker-bottom feet Congential malformations: heart, NS, renal) Often fatal by 1st year of life
Trisomy 18 (Edward’s): Mechanism
Often due to translocation der(14, 18)
Cri-du-Chat
microdeletion of 5p15.2 (microcephaly, characteristic cry, seizures, disability)
Prader-Willi Syndrome: Inheritance
Autosomal contiguous gene syndrome
Prader-Willi Syndrome: Clinical Presentation
Hypotonia, hypopigmentation, hypogenitalism, obesity, excessive eating, short stature, small hands and feet, hypogonadism, intellectual disability
Prader-Willi Syndrome: Mechanism
70% due to deletion of 15q11-13 region on paternal gene (imprinting does not allow for expression of this gene on the maternal chromosome) 28% due to Uniparental Disomy (maternal) 2% due to imprinting center mutation (paternal copy imprinting same as maternal copy)
Angelman Syndrome: Inheritance
Autosomal contiguous gene syndrome
Angelman Syndrome: Clinical Presentation
mildly dysmorphic facial features, hypotonia in infancy, intellectual disability, seizures, autism
Angelman Syndrome: Mechanism
complement to Prader-Willi - deletion of 15q region on maternal chromosome of UBE3A which is turned off by imprinting on the paternal copy of chromosome 15 Can also be caused by (paternal) uniparental disomy or imprinting center mutations
IDIC 15
Inverted duplicated isodicentric 15q Due to a supernumerary marker chromosome 15 Phenotype - Autism, not dysmorphic, often hypotonic, seizures
15q interstitial duplication
Only results in a phenotype if the duplication is inherited from the mother, not the father Phenotype - autism, not dysmorphic, seizures common, hypotonia common (similar to IDIC 15) related to GABA protein
WAGR Syndrome
Autosomal contiguous gene syndrome Phenotype - WIlms Tumor, Aniridia, Genitourinary anomalies, (retardation) intellectual disability interstitial del 11p13 - large enough to see on karyotype
DiGeorge Syndrome
Autosomal contiguous gene syndrome Phenotype - absent or hypoplastic thymus and parathyroid, congenital heart disease deletion of 22q11.2
Acute Lymphoblastic Leukemia (ALL)
chromosome or FISH analysis of bone marrow can reveal prognosis
hyperdiploidy (55 chromosomes) is a favorable prognosis, hypodiploidy (<38 chromosomes) is unfavorable
Chronic Myelogenous Leukemia (CML)
Presentation: night seats, fatigue, weight loss, anemia (enlarged spleen, anemia, thrombocytopenia)
Due to a translocation t(9;22) of BCR/ABL genes that cause a fusion protein product - evaluated via FISH
Treatment with Gleevac (Imantinib) that inhibits tyrosine kinase activity of fusion protein (competitive inhibitor of ATP)
Acute Promyeloid Leukemia (PML)
due to a translocation of PML/RARA genes t(15;17) that causes fusion protein product that represses gene expression, Can be diagnosed via FISH probe, or visualizaton of AUER rods Treated with retinoic acid (change confirmation of protein so that it recruites coactivator machinery - transcribes gene)
Gaucher Disease: Inheritance and Incidence
Autosomal Recessive 1/50,000 in general pop 1/450 in Ashkenazi Jew
Gaucher Disease: Clinical Presentation
Hepatosplenomegaly, thrombocytopenia, anemia, joint pain, may have neurological involvement, osteopenia, fatigue
Type I - most common, least severe phenotype (no neurologic symptoms
Type II - rare, severe and fatal in infants
Type III - intermediate, presents after infancy, nerological component present
Gaucher Disease: Mechanism
Many mutations identified for the GBA gene (allelic heterogenetiy) deficiency in the glucocerbrosidase enzyme that breaks down glucocerebroside (membrane protein). Ends up accumulating in the macrophage lysosomes in liver and spleen leading to enlargement (Gaucher cells)
Gaucher Disease: Treatment
Enzyme Replacement Therapy has been found to alleviate symptoms, but is costly (infusions 2X per month for life). Can be supplemented with substrate reduction therapy (SRT).
Pompe Disease
Shit is expensive yo
Pompe Disease
Autosomal Recessive progressive muscle failure, respiratory distress caused by accumulation of glycogen in lysosome due to deficiency in alpha-glucodidase enzyme
ERT treatment IV every 2 weeks for life
Progeria
de novo dominant trait premature aging syndrome caused by a point mutation in the LMNA/C gene yielding abnormal progerin protein Treatment with farnesyl transferse inhibitors to help reduce progerin sequestration at the nuclear membrane
Hb Kempsey
qualitative hemoglobinopathy altered Hb that results from a gain of function missense mutation. Causes hemoglobin to bind O2 at a higher rate - results in increased erthropoeitin production and polycythemia.
Hb Kansas
Qualitative hemoglobinopathy altered Hb binding that leads to decreased function of hemoglobin (binds oxygen worse)
Sickle Cell Anemia: Classification and inheritance
Qualitative hemoglobinopathy Autosomal recessive (more frequent in African populations due to association with heterozygote malaria resistance)
Sickle Cell Anemia: Mechanism and Treatment
Due to a single base mutation in beta-globin gene (allelic homozygosity) Hbs is 80% less soluble when in relaxed state, polymerizes and forms sickle shaped cells - lodge into micro-capillaries to cause issue treatment with butyrate which increasing expression of fetal hemoglobin, can reduce polymerization of HbS
Hemoglobin C: Classification and inheritance
Qualitative hemoglobinopathy Autosomal recessive
Hemoglobin C: Presentation and Mechanism
milder form of hemolytic anemia - HbC is less soluble then HbA and tends to form crystals caused by single base mutation of beta globin gene
Hemoglobin SC
Presence of multiple common mutant alleles on the same gene can lead to a compound heterozygote that has a more severe phenotype than a normal heterozygote. Example is HbC and HbS mutations in same individual
Hemoglobin E
Qualitative Hemoglobinopathy Most common in Southeast Asia, results from single mutation in beta chain. mild hemolytic anemia and splenomegaly.
Hydrops Fetalis: Genotype
Homozygous for α-thal-1 allele mutation (–/–)
Hydrops Fetalis: Mechanism / Presentation
4 gene deletion - most severe form, results in still born no alpha subunit is produced, fetal hemoglobin Hb Barts is not sufficient for life after development
Hemoglobin H disease: Genotype
compound heterozygote ( α-/–)
Hemoglobin H disease: Mechanism / Presentation
moderate to severe anemia - only produce enough α subunit to make 25% of normal hemoglobin, 5-30% of hemoglobin is β4 (HbH) which precipitates . Sometimes transfusion dependent
α-thalassemia 1 trait: Genotype
heterozygote for α-thal-1 allele (αα/–)
α-thalassemia 2 trait: Genotype
homozygous for α-thal-2 allele (α-/α-)
α-thalassemia trait: Mechanism / Presentation
none to mild anemia
Distribution of α-thalassemia alleles
α-thal-1 (–) allele is more common in Southeast Asia, whereas α-thal-2 (α-) is more common in Africa, Mediterranean, Asia. α-thal-1 can lead to more potent forms of the disease (HbH, Hydrops Fetalis)
β-thalassemia: Inheritance
Autosomal recessive Many different possible mutations of the β-globin gene - high allelic heterogeneity means many patients with disease are compound heterozygotes
β-thalassemia molecular classifications: Simple β-thalassemia
caused by mutations or deletions that impair the production of β-globin chain alone, no other gene involvement.
β-thalassemia molecular classifications: Complex β-thalassemia
caused by large deletions that remove the β-globin gene plus other genes in the β-cluster on the locus control region. Ex - Hispanic (episilon gamma delta beta) thalassemia
clinical classifications: β-thalassemia major (Cooley’s anemia)
2 severly abnormal or absent genes leads to severe anemia, most RBCs are destroyed before being released into circulation. Thinning of bone cortex, enlarged liver/spleen. MCV low. Need to treat with blood transfusions and iron chelation therapy to avoid iron overload
clinical classifications: β-thalssemia intermediate
homozygous for 2 mildly mutated genes - mild to moderate anemia, low MCV. Sometimes need transfusion
clinical classifications: β-thalssemia minor
heterozygous for β-globin gene mutation - little to no clinical presentation
β+ thalassemia
most common form (90%) - some β-globin is made, so some HbA present.
β0 thalassemia
zero β-globin synthesis so no HbA present - deletion of β-globin gene, or nonsense/frameshift mutation. fatal.
δβ0 thalassemia
milder than β0 thalassemia. remaining γ gene is active and can therefore form HbF (α2,γ2)
Hereditary Persistence of Fetal Hemoglobin
symptom free - adequate levels of γ mean that despite lack of β-globin deficieincy HbF is the main hemoglobin, present at 17-35% the normal level of hemoglobin.
Rec(8)
pericentric inversion of chromosome 8 carriers are at risk for recombination errors that lead to a trisomy of 8q22.1 and monosomy for 8p23.1 presents as VSD, Hypertelorism, thin upper lip, wide face concentrated in Hispanic populati in SW USA
