100 Genetic Syndromes

Front 1

ACUTE INTERMITTENT PORPHYRIA

Back 1

Responsible gene: HMBS Protein: Porphobilinogen deaminase
Cytogenetic locus: 11q23.3 Inheritance: AD
Clinical Features and Diagnostic Criteria: Onset after puberty,
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%)
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
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

Front 2

ALPHA THALASSEMIA

Back 2

Responsible genes: HBA1, HBA2 Protein names: Hemoglobin subunit alpha 1
and 2
Inheritance: AR; if parents Alpha Thal trait, risk for HbH disease if one parent’s
mutations are in cis, at risk for HB Bart if both parents in cis
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, 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, MCH, peripheral smear, reticulocyte count, hemoglobin
electrophoresis. Prenatal screen at risk populations!
Molecular Tests: Targeted mutation analysis for common deletions (90%); gene
sequencing (10%)
Disease Mechanism: Inability to form normal HbA

Front 3

BETA-THALASSEMIA

Back 3

Responsible gene: HBB Protein:
Inheritance: AR
Clinical Features and Diagnostic Criteria: severe anemia and HSM. Without Tx:
severe FTT and shortened life expectancy. Thal. intermedia: present later, milder anemia,
only rarely requires transfusion; at risk for iron overload due to inc intestinal absorption of
iron. The clinical severity of the beta-thal syndromes depends on the extent of globin
alpha chain/non-globin alpha chain imbalance.
Clinical Tests: microcytic hypochromic anemia, an abnl peripheral blood smear with
nucleated RBCs, and reduced amounts of hemoglobin A (HbA) on hemoglobin analysis.
Carriers: reduced MCV, MCH, and RBC morphologic changes that are less severe than in
affected individuals.
Molecular Tests: Mutation scanning/sequencing. In each at-risk population, 4-10
mutations account for the large majority of HBB disease.