Download Examples of genetic disorders

Overview of monogenic genetic disorders
Doc. MUDr. Marie Černá, CSc.
Autosomal dominant diseases (where frequencies are not marked, there are ≤ 1/ 10 000)
The frequent diseases (frequency > 1/ 2 000):
Lactose intolerance (10% of adult Caucasian population)
the mutation of lactase-phlorizin hydrolase
Dominant otosclerosis (frequency 1/ 300)
progressive lose of hearing, late onset, surgery treatment
Monogenic forms of type 2 diabetes: MODY + neonatal diabetes (frequency 1/ 400)
Monogenic form of hyperlipoproteinemia: familial hypercholesterolemia (frequency 1/ 500)
Adult polycystic kidney disease (frequency 1/ 1 000)
the mutation of PKD1 gene – polycystin-1 (85%) or PKD2 gene – polycystin-2 (15%) → two-hit
hypothesis in tissue for development of renal cysts and hepatic, pancreatic, ovarian, splenic cysts →
progressive renal failure. Treatment: dialysis and transplantation
Nervous defects:
Neurofibromatosis 1 - von Recklinghausen (NF1) (frequency 1/ 3 000)
the mutation of tumor suppressor gene (accumulation of ras-GTP) → risk of malignancy, 50% of
patients have new mutations, variable expressivity within families, café-au-lait spots on skin,
prominent benign neurofibromas of the peripheral nerves and malignant tumors of the CNS
Tuberous sclerosis
heterogeneity: the mutation of TSC1 gene – hamartin (on chromosome 9) or TSC2 gene – tuberin (on
chromosome 16), cortical brain tubers (hamartomas of the blood vessels), depigmantation (ash leaf)
spots and raised lesions on skin, lung lesions, severe mental handicap, epilepsy
Huntington disease (HD)
belongs to dynamic mutations – non-Mendelian type of inheritance, the mutation of huntingtin gene,
neurodegenerative disease, progressive dementia with chorea movements, late onset (5th decade),
early onset is typical for paternal transmission, familial - no new mutations were described
Red blood cell defects: Hereditary spherocytosis (frequency 1/ 5 000)
the mutation of ankrin-1 gene, hemolytic anemia
Skeletal defects:
Osteogenesis imperfecta, type I-IV (frequency 1/ 5 000)
the mutation of collagen genes, multiple fractures and lens deformity
Ehlers-Danlos syndrome, many types
the mutation of collagen genes, skin fragility and elasticity, joint hypermobility
Marfan syndrome
the mutation of fibrillin-1 gene, pleiotropy - defects of three systems: the skeleton (tail stature,
elongated limbs and fingers, scoliosis), the heart (aneurysm of aorta), the eyes (ectopia lentis)
Achondroplasia
the mutation of the fibroblast growth factor receptor 3 (FGFR3) gene, a few hypermutation regions
(major and minor mutation), 80% of patients have the new mutation, much more severe phenotype
in homozygotes, dwarfism with the short proximal segments of the limbs, macrocephaly, lordosis
Risk of malignancy (mutations of tumor suppressor genes):
Familial adenomatous polyposis coli (FAPC)
the mutation of tumor suppressor gene (FAP) → risk of malignancy in adulthood → progression
toward an adenocarcinoma: 1) deletion of the second normal FAP gene, 2) hypomethylation of DNA,
3) activation of K-ras oncogene, 4) deletion of DCC (deleted in colorectal carcinoma) gene, 5) deletion
of P53 gene. Prevention: removal of affected part of intestine
Retinoblastoma
the mutation of tumor suppressor gene (retinoblastoma - Rb) → risk of malignancy in childhood →
Knudson’s two-hit hypothesis: 1) in familial cases one lesion is inherited, 2) only one further mutation
in any retinal cell is necessary. Hereditary retinoblastoma occurs early, tumors are multiple and
bilateral (one somatic mutation during life is needed). Sporadic retinoblastoma occurs later, tumor is
single and unilateral (two somatic mutations during life are needed).
Neurofibromatosis 1 (peripheral) and 2 (central)
Overview of monogenic genetic disorders
Doc. MUDr. Marie Černá, CSc.
Autosomal recessive diseases
Primary hemochromatosis (frequency 1/ 400)
iron accumulation in tissues: the liver → cirrhosis, the heart → cardiomyopathy, the pancreas →
diabetes mellitus, and the skin → brownish color = bronze diabetes)
(Another heavy metal transport defect: Wilson disease – copper accumulation in tissues - rare)
Recessive mental retardation (frequency 1/ 2 000), deafness, blindness (frequency 1/ 10 000)
heterogeneity of deafness: deaf parents can have offspring with normal hearing
(Dominant deafness, blindness - frequency 1/ 10 000)
Cystic fibrosis (CF) (frequency 1/ 2 500)
the most frequent lethal AR disease in Caucasians (one in 25 are unaffected heterozygous carriers),
the mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, more than
1300 mutant alleles, but ∆F508 accounts for 70% of all mutations - defective chloride ion transport →
salt imbalance and water depletion out of cells – hyperviscosity of secretas → obstruction of ducts,
allelic heterogeneity = clinical heterogeneity (variable expressivity), among newborns 10-20% have
meconium ileus, lately patients suffer from chronic pulmonary disease (obstructive disease
accompanied by bacterial infection → death by 30 years of age), pancreatic insufficiency (blockage
of pancreatic and liver ducts → malabsorption), male sterility (bilateral absence of the vas deferens)
Alpha1-antitrypsin deficiency
the same frequency as cystic fibrosis in Caucasian population, the mutation of elastase inhibitor gene
(lung destruction), emphysema in middle age, especially in tobacco smokers
Steroid metabolism defects: Congenital adrenal hyperplasia (CAH) (frequency 1/ 10 000)
the enzyme deficiency of 21-hydroxylase, insufficiency of hormone production in adrenal glands,
defects in the biosynthesis of aldosterone and cortisol (salt deficiency), overproduction of androgenic
steroids proximal to the block (masculinization of female genitalia, precocious puberty in males)
Amino acid metabolism disorders: Phenylketonuria (PKU) (frequency 1/ 10 000)
the enzyme deficiency of phenylalanine hydroxylase (necessary for conversion of phenylalanine into
tyrosine), phenylalanine accumulates in the blood and related metabolites are excreted in the urine,
children are fair-haired with blue eyes (tyrosine deficiency), have muscular hypertonicity, convulsions
and become severely mentally retarded (phenylalanine intoxication), have a “mousy” smell due to
phenylacetic acid in the sweat and urine. Treatment: dietary reduction of phenylalanine
Lipid metabolism disorders: Smith-Lemli-Opitz syndrome (frequency 1/ 10 000)
the enzyme deficiency of δ-7-dehydrocholesterol reductase (the enzyme catalyzing the final step in
cholesterol biosynthesis) → abnormalities of the brain, heart, kidneys, genitalia and polydactyly
Sphingolipidoses
inability to degrade glycosylated membrane phospholipid in the lysosomes, with its accumulation
primarily in the brain, liver and spleen, death in early childhood
Tay-Sachs disease - frequent in Ashkenazi Jews, the enzyme deficiency of hexosaminidase-A,
accumulation of GM2 ganglioside in neurons → progressive neurological dysfunction
Gaucher disease - frequent in Ashkenazi Jews, the enzyme deficiency of β-glucosidase
Niemann-Pick disease - the enzyme deficiency of sphingomyelinase
Mucopolysaccharidoses
accumulation of sulphated polysaccharides (glycosaminoglycans), chronic and progressive multisystem physical and mental deterioration (hearing, vision, joint and cardiovascular function)
Carbohydrate metabolism disorders: Classical galactosemia + Hereditary fructose intolerance
the failure to utilize monosaccharides, physical and mental deterioration
Glycogen storage disorders: hepatic (Von Gierke disease) + muscular (Pompe disease)
accumulation of glycogen → hypoglycemia
Red blood cell defects: Sickle cell disease + Thalassemia, alpha and beta
the mutation of globin genes, hemolytic anemia
sickle cell disease
– point mutation of β-globin (qualitative defect)
alpha-thalassemia
– gene deletion of α-globin (quantitative defect)
beta-thalassemia
– protein absence of β-globin (quantitative defect)
Overview of monogenic genetic disorders
Doc. MUDr. Marie Černá, CSc.
X-linked recessive diseases
Red and green colour blindness (daltonism) (8% of Caucasian males)
the mutation of rhodopsin genes (hybrid red-green sensitive rhodopsin gene)
Non-specific X-linked mental retardation (frequency 1/ 2 000 males)
Fragile X syndrome (frequency 1/ 4 000 males)
belongs to dynamic mutations – non-Mendelian type of inheritance, mental retardation
X-linked muscular dystrophies:
progressive muscle weakness, the mutation of dystrophin gene
Duchenne muscular dystrophy (DMD) (frequency 1/ 3 500 males)
severe disorder, onset in early childhood (2 years), death by 20 years of age
1/3 of patients = new mutations
2/3 of patients = mother is a carrier of mutation
Becker muscular dystrophy (BMD) (frequency 1/ 20 000 males)
milder disorder, onset in late childhood (11 years)
(Autosomal dominant muscular dystrophy: myotonic dystrophy, MD, - frequency 1/ 8 000,
belongs to dynamic mutations – non-Mendelian type of inheritance, the mutation of DMPK gene,
tonic muscle spasm with prolonged relaxation, DMPK = dystrophia myotonica protein kinase
Autosomal recessive muscular dystrophy: spinal muscular atrophy, SMA, - frequency 1/ 10 000,
the mutation on the base of inverted duplication and additional deletion in several genes,
degeneration of the anterior horn cells of the spinal cord – survival and apoptosis changes)
X-linked coagulation disorders:
prolonged bleeding, hemorrhage into the joints (hemarthrosis)
Hemophilia A (frequency 1/ 5 000 males)
the deficiency of antihemophilic factor VIII
Hemophilia B (frequency 1/ 35 000 males)
the deficiency of antihemophilic factor IX
(Autosomal recessive coagulation disorder: hemophilia C - rare,
the deficiency of antihemophilic factor XI)
X-linked dominant diseases
Vitamin D-resistant rickets (hypophosphatemic rickets)
the kidneys have impaired ability to reabsorb phosphate, resulting in abnormal ossification