Genetic Disorders & Inborn Errors Of Metabolism Flashcards
What are the classic mendelian disorders?
- Autosomal dominant
- Autosomal recessive
- X-linked dominant
- X-linked recessive
Which mendelian disorder is more severe or lethal in males while affected females have a 50% risk of having an affected daughter?
X-linked dominant
What are unstable repeat sequences?
Occur when the number of specific nucleotide copies within a gene increases, resulting in increased disease severity
What is uniparental disomy?
Occurs when instead of inheriting one gene or chromosome from each parent, both members of a chromosome or gene pair are inherited from same parent
What is genomic imprinting?
Occurs when a gene defect is expressed solely based on the sex of the parent passing on the defective gene
If a mother passes on an abnormal 11q region on chromosome 15, the offspring will have…
Angelman Syndrome
If a father passes on an abnormal 11q region on chromosome 15, the offspring will have…
Prader Willi syndrome
What are the differences between malformation, deformation, or disruption?
- Malformation: Occurs when an intrinsically abnormal process forms abnormal tissue
- Deformation: Occurs when mechanical forces are exerted on normal tissues
- Disruption: Occurs when normal tissue becomes abnormal after being subjected to destructive forces
What is a syndrome?
Occurs when a collection of seemingly unrelated abnormal features occur in a familiar pattern
What causes increased maternal α-fetoprotein?
- Fetal neural tube defects
- Multiple gestation pregnancies
- Underestimated gestational age
- Ventral abdominal wall defects
- Fetal demise
What are the three markers in a triple screen?
What is indicated if there is low AFP, low unconjugated estriol, and high ß-HCG?
What if all three are low?
- AFP
- Unconjugated estriol
- ß-HCG
Down syndrome; trisomy 18
When is Chorionic villus sampling (CVS) done for genetic evaluation of a fetus?
When can amniocentesis be done?
10-13 weeks
16-18 weeks
Marfan syndrome is an autosomal ______ disorder
What gene defect is associated with Marfan syndrome?
Autosomal dominant
The gene defect has been mapped to a region on chromosome 15 that codes for fibrillin
What are the clinical features of Marfan syndrome?
Skeletal findings:
Occular findings:
Cardiovascular findings:
- Skeletal findings: tall stature with elongated extremities and long fingers
- Occular findings: upward lens subluxation
- Cardiovascular findings: Aortic route dilatation
What disorder has many of the same clinical features as Marfan’s syndrome and must be ruled out
Homocystinuria
What are some complications of marfan’s syndrome?
Endocarditis, retinal detachment, and sudden death as a result of aortic dissection
What are some clinical features of Prader-Willi syndrome?
- Craniofacial: Almond-shaped eyes; fishlike mouth
- Failure to thrive; obesity as a result of hyperphagia later in childhood
- Hypotonia, mental retardation
- Hypogonadism
What are the clinical features of angelman syndrome?
- Neurologic findings include jerky arm movements, ataxia, and paroxysms of inappropriate laughter
- Craniofacial findings include a small wide head, large mouth with widely spaced teeth, tongue protrusion, and prognathia
What is Noonan syndrome?
“male version of Turner syndrome”
What are the clinical features of Noonan syndrome?
- Short stature and a shield chest
- Short webbed neck and low hairline
- Right-sided heart lesions, most commonly pulmonary valve stenosis
- Mental retardation in 25%
What two distinct syndromes have a deletion at chromosome 22q11?
DiGeorge syndrome
Velocardiofacial syndrome
What is CATCH-22?
A name describing the features of 22q11 deletions
- Cardiac anomaly
- Abnormal facies
- Thymic hypoplasia
- Cleft palate
- Hypocalcemia
- Gene defect on chromosome 22
DiGeorge syndrome is caused by a defect in the structures derived from the ____ and _____ pharyngeal pouches
third and fourth
THymus and parathyroid hypoplasia in DiGeorge syndrome cause…
cell-mediated immunodeficiency and severe hypocalcemia
What is Ehler-Danlos syndrome?
What type of inheritance is it?
Characterized by the production of defective type V collagn resulting in hyerextensible joints, fragile vessels, and loose skin
Autosomal dominant
What are the cardiovascular findings in Ehler-Danlos syndrome?
Mitral valve prolapse, Aortic root dilatation, and fragile blood vessels that result in ease of bruising
What is osteogenesis imperfecta?
Results from mutations that cause production of abnormal type I collagen
What are the clinical features of Type I Osteogenesis Imperfecta?
- Blue sclerae
- Skeletal findings such as fragile bones
- Yellow or gray-blue teeth
- Easy bruisability
What are some complications of Ehler Danlos syndrome?
Early conductive hearing loss
Skeletal deformities as a result of fractures
What are the VACTERL anomalies?
- Vertebral defects
- Anal atresia
- Cardiac anomalies (VSDs)
- TracehoEsophageal fistula
- Renal and genital defects
- Limb defects
What are the CHARGE associations?
- Colobomas (absence/defect of ocular tissue)
- Heart defects (Tetralogy of Fallot)
- Atresia of the nasal choanae
- Retardation of growth and cognition
- Genital anomalies
- Ear anomilies (hearing loss and cup shaped ears)
What is Williams syndrome?
Notable for a unique loquacious personality often described as a “cocktail party” personality; caused by deletion on chromosome 7
What are the clinical features of Williams syndrome?
- Elfin facies
- Mental retardation and loquacious personality
- Supravalvular aortic stenosis
- Idiopathic hypercalcemia in infancy
- Conncective tissue abnormalities
What is most notable about Cornelia de Lange (Brachmann-de Lange) syndrome?
Most notable for a single eyebrow and very short stature without skeletal abnormalities
What behavioral features are associated with Cornelia de Lange (Brachmann-de Lange) syndrome?
Autistic features, lack of facial expression, and self-destructive tendencies
What is classically seen in Russel-Silver syndrome?
Short stature and skeletal asymmetry with a normal head circumference
What skin findings are associated with Russell-Silver syndrome?
Cafe-au-lait spots and excessive sweating
Pierre Robin syndrome clinical features?
Micrognathia, cleft lip and palate, and a large protruding tongue
Cri du chat syndrome is caused by a partial deletion of the short arm of chromosome __
5
What is the most common trisomy syndrome?
Down syndrome (trisomy 21)
What is the second most common trisomy syndrome? It is three times more common in ________
Trisomy 18; females
What are the general clinical features of trisomy syndromes?
- Mental retardation and hypertonia with scissoring of the lower extremities
- Delicate, small facial features
- Clenched hands with overlapping digits, rocker bottom feet
- Trident shaped hands
________ is 20 times more common in Down Syndrome than in general population
Leukemia
How are trisomy syndromes diagnosed?
Chromosomal analysis
What are the clinical features of Turner syndrome?
- Short stature
- Webbed neck
- Shield chest
- Swelling of the dorsum of hands and feet
- Ovarian dysgenisis
What cardiac effects are associated with Turner syndrome?
- Left-sided heart lesions
- Coarcatation of the aorta
- Bicuspid aortic valve
- Hypoplastic left heart
Fragile X syndrome is an X-linked disorder caused by a site on the X chromosome that contains a variable number of ____ repeats
CGG
What type of inheritance pattern is associated with Fragile X syndrome?
Anticipation
What is the most common inherited cause of mental retardation?
Fragile X syndrome
What are some clinical features of Fragile X syndrome?
- Mild to severe mental retardation
- Large ears
- Large testes develop during puberty
- Emotional instability
What is the most common cause of male hypogonadism and infertility?
Klinefelter syndrome
What are the clinical features of Klinefelter syndrome?
- Tall stature with long extremities
- Hypogonadism
- Gynecomastia
- Variable intelligence
- Antisocial behavior; excessive shyness or agression
Describe the following classifications of skeletal dysplasias:
- Rhizomelia:
- Mesomelia:
- Acromelia:
- Spondylodysplasia:
- Rhizomelia: Proximal long bone abnormalities
- Mesomelia: Medial long bone abnormalities
- Acromelia: Distal abnormalities
- Spondylodysplasia: Involve abnormalities of the spine, with or without limb abnormalities
What is the most common skeletal dysplasia; what classification does it fall under?
Achondroplasia; rhizomelia
What mutation is associated with achondroplasia?
Caused by mutation in the fibroblast growth factor receptor 3 gene; incidence increases with advancing paternal age
What are the clinical features of achondroplasia?
- Megalencephaly (large brain); foramen magnum stenosis
- Lumbar kyphosis in infancy evolving into lumbar lordosis in later childhood
- Rhizomelic limb shortening
What are some complications of achondroplasia due to the foramen magnum stenosis?
May lead to hydrocephalus or cord compression
Sudden infant death may occur as a result of cord compression
What is Potter syndrome?
What can cause it?
Caused by severe oligohydramnios, which causes lung hypoplasia and fetal compression with limb abnormalities and facial features termed potter facies
May occur as the result of chronic amniotic fluid leak or intrauterine renal failure caused by bilateral renal agenesis, polycystic kidneys, or obstructive uropathy
What is amniotic band syndrome?
Occurs as a result of rupture of the amniotic sac; fluid leads to intrauterine constraint, and small strands from the amnion may wrap around the fetus, causing limb scarring and amputations
What is the most common teratogen?
Alcohol
What are some features of fetal alcohol syndrome?
- Small-for-gestational age at birth
- FTT
- Microcephaly
- Long smooth philtrum with a thin, smooth upper lip
- Mental retardation, ADHD, and cardiac defects
What risk is associated with pregnant women who have seizure disorders?
These women face the dilemna of exposing their unborn fetus to anticonvulsants or risk having a seizure
Fetal phenytoin syndrome causes a spectrum of defects with mild to moderate mental retardation
When should inborn errors in metabolism (IEM) be suspected in a child?
- When they are acutely ill and fail to respond to usual therapy
- Have unexplained seizures, developmental delay, or progressive neurologic deterioration
- Laboratory values inconsistent with clincal presenatation
In inborn errors of metabolism (IEM), chronic and progressive symptoms are suggestive of _________ disorders
mitochondrial
Pick the IEM that goes with the following odors:
- Mousey/musty:
- Sweet maple syrup:
- Sweaty feet:
- Rotten cabbage:
- Mousey/musty: Phenylketonuria
- Sweet maple syrup: Maple syrup disease
- Sweaty feet: Isovaleric or glutaric acidemia
- Rotten cabbage: Hereditary tyrosinemia
In IEM, serum NH3 > 200mM is suggestive of _____ _____ defects
urea cycle
Family history suspicious for IEM includes:
- Neonatal deaths in siblings or affected males on maternal side
- Parental consanguinity
- Mental retardation
- Unusual dietary preferences in relatives
What is the initial laboratory evaluation for IEM?
Assessment for metabolic acidosis and elevated serum ammonia; further evaluation depends on whtether metabolic acidosis or hyperammonemia are present
What are the management steps of IEM?
- Provide a source of energy (IV glucose)
- Prevent exposure to the offending substance
- Correct acidosis or hyperammonemia
How do you correct acidosis or hyperammonemia in IEM?
- Sodium bicarbonate corrects acidosis
- Sodium benzoate and sodium phenylacetate increase ammonia excretion
- Oral neosporin and lactulose prevent bacterial production of ammonia in the colon
- Dialysis may be necessary
What deficiency leads to homocystinuria?
What is the inheritance pattern?
Cystathionine synthase deficiency; autosomal recessive
What are the clincal features of homocystinuria?
- Marfanoid body habitus without arachnodactyly
- Downward lens subluxation
- Hypercoagulable state
- Cardiovascular abnormalities
- Scoliosis
- Developmental delay
How is homocysinuria diagnosed?
Increased methionine in urine and plasma or by positive urinary cyanide nitroprusside test
What is the management of homocystinuria?
A methionine-restricted diet, aspirin to decrease risk of thromboembolism, and folic acid and vitamin B6 supplementation
What are the clinical features of transient tyrosinemia of the newborn? How is it diagnosed?
Clinical features begin during the first 2 weeks of life and may include poor feeding and lethargy
Diagnosis based on elevated serum tyrosine and phenylalanine levels
How do you manage transient tyrosinemia of the newborn?
Managment includes decreasing protein intake during the acute episode
Vitamin C may help eliminate tyrosine
Cystinuria is an autosomal _______ disorder caused by…
recessive; defect in renal reabsorption of cystine, lysine, arginine, and ornithine
What is hartnup disease?
What are some presenting symptoms?
An autosomal recessive disorder caused by a defect in the transport of neutral amino acids
Some may present with intermittent ataxia, photosensitive rash, mental retardation, and emotional lability
Ammonia is toxic to the ____ and _____
brain and liver
What is the most common urea cycle defect?
Ornithine transcarbamylase deficiency
What are the clinical features of ornithine transcarbamylase deficiency?
When do they begin?
- Vomiting and lethargy leading to coma
- Some females with mild disease may present in childhood with cyclic vomiting and intermittent ataxia
Clinical features begin at the onset of protein ingestion
How is ornithine transcarbamylase deficiency diagnosed?
Diagnosed based on elevated urine orotic acid, decreased serum citrulline, and increased ornithine, as well as by liver biopsy
What type of transplant may be required in ornithine transcarbamylase deficiency?
Liver transplant
What type of inheritance is associated with galactosemia? What enzyme is deficient?
Autosomal recessive
Galactose-1-phosphate uridyltransferase deficiency
Galactosemia should be suspected in any newborn with ________ and _______
hepatomegaly and hypoglycemia
What are some clinical features of galactosemia?
- Vomiting, diarrhea, and FTT
- Hepatic dysfunction with hepatomegaly
- Cataracts with oil-droplet appearance
- Renal tubular acidosis
How is galactokinase diagnosed?
- Nonglucose-reducing substance in urine (tested by Clinitest)
- Confirmation of enzyme deficiency in RBCs
- Prenatal and newborn screening are available
What affects nearly all females with galactosemia?
Death in early infancy is typically caused by ______ ______ sepsis
Ovarian failure
Escheria Coli
Hereditary fructose intolerance is caused by a deficiency in what enzyme?
Fructose-1-phosphate aldolase B
What are the symptoms of hereditary fructose intolerance?
Symptoms include hypoglycemia, vomiting, diarrhea, FTT, and seizures
Glycogen storage diseases are characterized by ________ and ______ ________
organomegaly; metabolic acidosis
What is the deficiency in Von Gierke’s disease? What are patients at risk for?
Glucose-6-phosphatase deficiency; Patients are at high risk for hepatocellular carcinoma
Pompes disease is due to an ________ deficiency
α-glucosidase deficiency
What are the presenting features of Von-Gierke’s disease?
Presenting features may include persistent hypoglycemia, hepatomegaly, metabolic acidosis, hypertriglyceridemia, and enlarged kidneys
Pompe’s disease shoudl be suspected in any infant with ______ _______ and ________
Muscular weakness and cardiomegaly
When do fatty acid oxidation defects occur?
Present during an acute illness or fasting when fatty acids are normally used as an energy source
What is the most common fatty acid oxidation disorder?
Medium-chain acyl-CoA dehydrogenase deficiency
Fatty acid oxidation is managed with…
Frequent feedings with a high-carbohydrate, low fat diet and carnitine supplementation during acute episodes
Mitochondrial disorders should be suspected if a common disease has ______ presentation or if a disease involves ______ or more organ systems
atypical; three
How are mitochondrial disorders diagnosed?
Based on tissue biopsy revealing abnormal mitochondria
What are the components of the mitochondrial disorder, MELAS?
- Mitochondrial Encephalopathy
- Lactic Acidosis
- Stroke-like episodes
Tay-Sachs disorder is an autosomal ______ disorder caused by ____________ deficiency
Recessive; hexosaminidase A
What are the clinical features of Tay Sach’s disease?
- Infantile onset
- Hyperacusis (increases sensitivity to sound)
- Macrocephaly
- Cherry red macula
- Progressive blindness, seizures
- Severe developmental delay
Juvenile or adult-onset Tay sachs disease has the same clinical features as the infantile form except for…
cherry red macula
Infantile Tay-Sachs disease is untreatable and death occurs by ___ years
4
Gaucher’s disease is cause by ___________ deficiency and has autosomal _____ inheritance
glucocerebrosidase; recessive
What are the clinical features of Gaucher’s disease?
Hepatosplenomegaly, thrombocytopenia, Erlenmeyer flask-shaped distal femur, and early mortality (4 years)
What is the management of Gaucher’s disease?
Enzyme replacement therapy
Niemann Pick disease is caused by a ________ deficiency and presents by __ months of age
sphingomyelinase; 6 months
What is the presentation of Niemann-Pick disease?
- Progressive neurodegeneration
- Ataxia
- Seizures
- Hepatosplenomegaly
- Cherry-red macula
Metachromatic leukodystrophy is a neurodegenerative disorder caused by _______ deficiency
Arylsulfatase A
What are the presenting features of Metachromatic leukodystrophy?
Ataxia, Seizures, progressive mental retardation
What accumulates in mucopolysaccharidoses?
Glucosaminoglycans accumulate in multiple organs
What is the most common gangliosidosis?
Gaucher disease
Describe dystosis multiplex in the context of mucopolysaccharidoses
A constellation of bony abnormalities that include thickened cranium, J-shaped sella turcica, malformed ovoid or beak-like vertebrae, short and thickened clavicles, and oar shaped ribs
Hurler syndrome is caused by a deficiency in…
α-L-iduronidase deficiency
How is Hurler’s syndrome diagnosed? What is the management?
Diagnosis is by finding dermatan and heparan sulfates in the urine and decreased enzyme activity
Management may include early bone marrow transplant to prevent neurodegeneration
What is the inheritance pattern for Hunter syndrome?
X-linked recessive
What are the clinical features of Hurler syndrome?
- Hepatosplenomegaly
- Developmental delay
- Kyphosis
- Progressively coarsened facial features
- Corneal clouding
What is the difference between Hurler syndrome and hunter syndrome? (mnemonic: “a hunter needs sharp eyes; therefore, no corneal clouding occurs”)
Corneal clouding is only in hurler syndrome
What is Sanfilippo syndrome?
What is Morquio syndrome?
Sanfilippo is an autosomal recessive disorder that is characterized by rapid and severe mental and motor retardation
Morquio syndrome includes severe scoliosis leading to cor pulmonale which results in death by 40 years of age; Mental reatardation is absent
What are the clinical features of the acute intermittent porphyria?
- Neurologic:
- GI:
- Autonomic:
- Neurologic: Personality changes, emotional lability, paresthesias, and weakness
- GI: Colicky abdominal pain, vomiting, and constipation
- Autonomic: Tachycardia, hypertension, sweating, fever
Diagnosis of acute intermittent porphyria is based on…
What is the management?
Increased serum and urine porphobilinogen
Intravenous glucose, correction of electrolyte abnormalities, avoidance of fasting
What disease is an autosomal recessive defect in copper excretion that leads to copper deposition in the liver?
Wilson’s disease
What is the occular finding in Wilson’s disease?
Kayser-Fleischer rings in the peripheral cornea (copper deposition in Descemet’s membrane)
What is the most commonly used screening test for Wilson’s disease?
Decreased serum ceruloplasmin
What is Menkes kinky-hair disease?
An X-linked recessive disorder caused by abnormal copper transport
What are the clinical features of Menke’s disease?
Pale kinky friable hair, optic nerve atrophy, severe mental retardation, and early death
