S
SYNDROMES
O S EVERY
GENETICIST SHOULD
KNOW
Amy E.
E Roberts,
Roberts M.D.
MD
ACMG Genetic Review Course June 25-28, 2009
ACMG Genetics Review Course June 25-29, 2009
, ACUTE INTERMITTENT PORPHYRIA
Responsible gene: HMBS Protein: Porphobilinogen deaminase
Cytogenetic locus: 11q23.3 Inheritance: AD
Cli i l F
Clinical Features
t and
d Diagnostic
Di ti Criteria:
C it i Onset
O t after
ft puberty,
b t
GIC DISORDERS
acute attacks, abdominal pain, muscle weakness, neuropathy,
hysteria, anxiety, hepatocellular carcinoma, NO CUTANEOUS
FINDINGS
Clinical Tests: inc urine delta-amonolevulinic acid (ALA) and
porphobilinogen (PBG) during acute attack
Molecular Tests: HMBS gene sequencing (>98%) ( 98%)
MATOLOG
Disease Mechanism: ?direct neurotoxicity of PBG, ?generation of
reactive oxygen species or inhibition of GABA release at central
synapses by ALA, ?loss of heme in the CNS
HEM
Treatment: Stop or treat precipitant (medication, infection, EtOH,
dehydration, smoking, poor caloric intake); intubate if bulbar
paralysis; IV dextrose; IV hemin (repress ALAS-N enzyme activity);
pain control
ACMG 2
, ALPHA THALASSEMIA
Responsible genes: HBA1, HBA2 Protein names: Hemoglobin subunit alpha 1
and 2 Cytogenetic locus (loci): 16pter-p13.3
Inheritance: AR; if parents Alpha Thal trait, risk for HbH disease if one parent’s
parent s
mutations are in cis, at risk for HB Bart if both parents in cis
GIC DISORDERS
Clinical Features and Diagnostic Criteria: HB Bart: loss or dysfunction of all 4
alpha thal alleles, hydrops fetalis, severe hypochromic anemia, death in neonatal
period; HbH: loss or dysfunction of 3 of 4 alpha thal alleles
alleles, microcytic hypochromic
hemolytic anemia, HSM, jaundice Alpha Trait:loss or dysfunction of 2 alpha thal
alleles, low MCV, low MCH, nl levels Hgb A2 and F; Alpha “silent” carrier: loss or
dysfunction of one alpha thal allele, none or mild thalassemia-like effect
Clinical Tests: MCV,
MCV MCHMCH, peripheral smear
smear, reticulocyte count
count, hemoglobin
MATOLOG
electrophoresis. Prenatal screen at risk populations!
Molecular Tests: Targeted mutation analysis for common deletions (90%); gene
sequencing (10%)
HEM
Disease Mechanism: Inability to form normal Hb A (normally composed of two
alpha and two beta chains)
Treatment/Prognosis: No tx for HB Bart, rec termination due to maternal
complications with hydrops. Hb H: prbc transfusions during hemolytic crisis,
anemia causing cardiac sx, sx or severe bony changes; splenectomy with abx
prophylaxis (if <5y) for splenomegaly
ACMG 3
, GIC DISORDERS
MATOLOG
HEM
ALPHA THALASSEMIA
http://sickle.bwh.harvard.edu/alpha two.gif
http://sickle.bwh.harvard.edu/alpha_two.gif
ACMG 4
SYNDROMES
O S EVERY
GENETICIST SHOULD
KNOW
Amy E.
E Roberts,
Roberts M.D.
MD
ACMG Genetic Review Course June 25-28, 2009
ACMG Genetics Review Course June 25-29, 2009
, ACUTE INTERMITTENT PORPHYRIA
Responsible gene: HMBS Protein: Porphobilinogen deaminase
Cytogenetic locus: 11q23.3 Inheritance: AD
Cli i l F
Clinical Features
t and
d Diagnostic
Di ti Criteria:
C it i Onset
O t after
ft puberty,
b t
GIC DISORDERS
acute attacks, abdominal pain, muscle weakness, neuropathy,
hysteria, anxiety, hepatocellular carcinoma, NO CUTANEOUS
FINDINGS
Clinical Tests: inc urine delta-amonolevulinic acid (ALA) and
porphobilinogen (PBG) during acute attack
Molecular Tests: HMBS gene sequencing (>98%) ( 98%)
MATOLOG
Disease Mechanism: ?direct neurotoxicity of PBG, ?generation of
reactive oxygen species or inhibition of GABA release at central
synapses by ALA, ?loss of heme in the CNS
HEM
Treatment: Stop or treat precipitant (medication, infection, EtOH,
dehydration, smoking, poor caloric intake); intubate if bulbar
paralysis; IV dextrose; IV hemin (repress ALAS-N enzyme activity);
pain control
ACMG 2
, ALPHA THALASSEMIA
Responsible genes: HBA1, HBA2 Protein names: Hemoglobin subunit alpha 1
and 2 Cytogenetic locus (loci): 16pter-p13.3
Inheritance: AR; if parents Alpha Thal trait, risk for HbH disease if one parent’s
parent s
mutations are in cis, at risk for HB Bart if both parents in cis
GIC DISORDERS
Clinical Features and Diagnostic Criteria: HB Bart: loss or dysfunction of all 4
alpha thal alleles, hydrops fetalis, severe hypochromic anemia, death in neonatal
period; HbH: loss or dysfunction of 3 of 4 alpha thal alleles
alleles, microcytic hypochromic
hemolytic anemia, HSM, jaundice Alpha Trait:loss or dysfunction of 2 alpha thal
alleles, low MCV, low MCH, nl levels Hgb A2 and F; Alpha “silent” carrier: loss or
dysfunction of one alpha thal allele, none or mild thalassemia-like effect
Clinical Tests: MCV,
MCV MCHMCH, peripheral smear
smear, reticulocyte count
count, hemoglobin
MATOLOG
electrophoresis. Prenatal screen at risk populations!
Molecular Tests: Targeted mutation analysis for common deletions (90%); gene
sequencing (10%)
HEM
Disease Mechanism: Inability to form normal Hb A (normally composed of two
alpha and two beta chains)
Treatment/Prognosis: No tx for HB Bart, rec termination due to maternal
complications with hydrops. Hb H: prbc transfusions during hemolytic crisis,
anemia causing cardiac sx, sx or severe bony changes; splenectomy with abx
prophylaxis (if <5y) for splenomegaly
ACMG 3
, GIC DISORDERS
MATOLOG
HEM
ALPHA THALASSEMIA
http://sickle.bwh.harvard.edu/alpha two.gif
http://sickle.bwh.harvard.edu/alpha_two.gif
ACMG 4
