Genetic Disorders & Inborn Errors Of Metabolism Flashcards
1
Q
What are the classic mendelian disorders?
A
- Autosomal dominant
- Autosomal recessive
- X-linked dominant
- X-linked recessive
2
Q
Which mendelian disorder is more severe or lethal in males while affected females have a 50% risk of having an affected daughter?
A
X-linked dominant
3
Q
What are unstable repeat sequences?
A
Occur when the number of specific nucleotide copies within a gene increases, resulting in increased disease severity
4
Q
What is uniparental disomy?
A
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
5
Q
What is genomic imprinting?
A
Occurs when a gene defect is expressed solely based on the sex of the parent passing on the defective gene
6
Q
If a mother passes on an abnormal 11q region on chromosome 15, the offspring will have…
A
Angelman Syndrome
7
Q
If a father passes on an abnormal 11q region on chromosome 15, the offspring will have…
A
Prader Willi syndrome
8
Q
What are the differences between malformation, deformation, or disruption?
A
- 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
9
Q
What is a syndrome?
A
Occurs when a collection of seemingly unrelated abnormal features occur in a familiar pattern
10
Q
What causes increased maternal α-fetoprotein?
A
- Fetal neural tube defects
- Multiple gestation pregnancies
- Underestimated gestational age
- Ventral abdominal wall defects
- Fetal demise
11
Q
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?
A
- AFP
- Unconjugated estriol
- ß-HCG
Down syndrome; trisomy 18
12
Q
When is Chorionic villus sampling (CVS) done for genetic evaluation of a fetus?
When can amniocentesis be done?
A
10-13 weeks
16-18 weeks
13
Q
Marfan syndrome is an autosomal ______ disorder
What gene defect is associated with Marfan syndrome?
A
Autosomal dominant
The gene defect has been mapped to a region on chromosome 15 that codes for fibrillin
14
Q
What are the clinical features of Marfan syndrome?
Skeletal findings:
Occular findings:
Cardiovascular findings:
A
- Skeletal findings: tall stature with elongated extremities and long fingers
- Occular findings: upward lens subluxation
- Cardiovascular findings: Aortic route dilatation
15
Q
What disorder has many of the same clinical features as Marfan’s syndrome and must be ruled out
A
Homocystinuria
16
Q
What are some complications of marfan’s syndrome?
A
Endocarditis, retinal detachment, and sudden death as a result of aortic dissection
17
Q
What are some clinical features of Prader-Willi syndrome?
A
- Craniofacial: Almond-shaped eyes; fishlike mouth
- Failure to thrive; obesity as a result of hyperphagia later in childhood
- Hypotonia, mental retardation
- Hypogonadism
18
Q
What are the clinical features of angelman syndrome?
A
- 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
19
Q
What is Noonan syndrome?
A
“male version of Turner syndrome”
20
Q
What are the clinical features of Noonan syndrome?
A
- 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%
21
Q
What two distinct syndromes have a deletion at chromosome 22q11?
A
DiGeorge syndrome
Velocardiofacial syndrome
22
Q
What is CATCH-22?
A
A name describing the features of 22q11 deletions
- Cardiac anomaly
- Abnormal facies
- Thymic hypoplasia
- Cleft palate
- Hypocalcemia
- Gene defect on chromosome 22
23
Q
DiGeorge syndrome is caused by a defect in the structures derived from the ____ and _____ pharyngeal pouches
A
third and fourth
24
Q
THymus and parathyroid hypoplasia in DiGeorge syndrome cause…
A
cell-mediated immunodeficiency and severe hypocalcemia
25
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
26
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
27
What is osteogenesis imperfecta?
Results from mutations that cause production of abnormal type I collagen
28
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
29
What are some complications of Ehler Danlos syndrome?
Early conductive hearing loss
Skeletal deformities as a result of fractures
30
What are the VACTERL anomalies?
* Vertebral defects
* Anal atresia
* Cardiac anomalies (VSDs)
* TracehoEsophageal fistula
* Renal and genital defects
* Limb defects
31
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)
32
What is Williams syndrome?
Notable for a unique loquacious personality often described as a "cocktail party" personality; caused by deletion on chromosome 7
33
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
34
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
35
What behavioral features are associated with Cornelia de Lange (Brachmann-de Lange) syndrome?
Autistic features, lack of facial expression, and self-destructive tendencies
36
What is classically seen in Russel-Silver syndrome?
Short stature and skeletal asymmetry with a normal head circumference
37
What skin findings are associated with Russell-Silver syndrome?
Cafe-au-lait spots and excessive sweating
38
Pierre Robin syndrome clinical features?
Micrognathia, cleft lip and palate, and a large protruding tongue
39
Cri du chat syndrome is caused by a partial deletion of the short arm of chromosome \_\_
5
40
What is the most common trisomy syndrome?
Down syndrome (trisomy 21)
41
What is the second most common trisomy syndrome? It is three times more common in \_\_\_\_\_\_\_\_
Trisomy 18; females
42
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
43
\_\_\_\_\_\_\_\_ is 20 times more common in Down Syndrome than in general population
Leukemia
44
How are trisomy syndromes diagnosed?
Chromosomal analysis
45
What are the clinical features of Turner syndrome?
* Short stature
* Webbed neck
* Shield chest
* Swelling of the dorsum of hands and feet
* Ovarian dysgenisis
46
What cardiac effects are associated with Turner syndrome?
* Left-sided heart lesions
* Coarcatation of the aorta
* Bicuspid aortic valve
* Hypoplastic left heart
47
Fragile X syndrome is an X-linked disorder caused by a site on the X chromosome that contains a variable number of ____ repeats
CGG
48
What type of inheritance pattern is associated with Fragile X syndrome?
Anticipation
49
What is the most common inherited cause of mental retardation?
Fragile X syndrome
50
What are some clinical features of Fragile X syndrome?
* Mild to severe mental retardation
* Large ears
* Large testes develop during puberty
* Emotional instability
51
What is the most common cause of male hypogonadism and infertility?
Klinefelter syndrome
52
What are the clinical features of Klinefelter syndrome?
* Tall stature with long extremities
* Hypogonadism
* Gynecomastia
* Variable intelligence
* Antisocial behavior; excessive shyness or agression
53
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
54
What is the most common skeletal dysplasia; what classification does it fall under?
Achondroplasia; rhizomelia
55
What mutation is associated with achondroplasia?
Caused by mutation in the fibroblast growth factor receptor 3 gene; incidence increases with advancing paternal age
56
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
57
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
58
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
59
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
60
What is the most common teratogen?
Alcohol
61
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
62
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
63
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
64
In inborn errors of metabolism (IEM), chronic and progressive symptoms are suggestive of _________ disorders
mitochondrial
65
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
66
In IEM, serum NH3 \> 200mM is suggestive of _____ \_\_\_\_\_ defects
urea cycle
67
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
68
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
69
What are the management steps of IEM?
* Provide a source of energy (IV glucose)
* Prevent exposure to the offending substance
* Correct acidosis or hyperammonemia
70
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
71
What deficiency leads to homocystinuria?
What is the inheritance pattern?
Cystathionine synthase deficiency; autosomal recessive
72
What are the clincal features of homocystinuria?
* Marfanoid body habitus without arachnodactyly
* Downward lens subluxation
* Hypercoagulable state
* Cardiovascular abnormalities
* Scoliosis
* Developmental delay
73
How is homocysinuria diagnosed?
Increased methionine in urine and plasma or by positive urinary cyanide nitroprusside test
74
What is the management of homocystinuria?
A methionine-restricted diet, aspirin to decrease risk of thromboembolism, and folic acid and vitamin B6 supplementation
75
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
76
How do you manage transient tyrosinemia of the newborn?
Managment includes decreasing protein intake during the acute episode
Vitamin C may help eliminate tyrosine
77
Cystinuria is an autosomal _______ disorder caused by...
recessive; defect in renal reabsorption of cystine, lysine, arginine, and ornithine
78
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
79
Ammonia is toxic to the ____ and \_\_\_\_\_
brain and liver
80
What is the most common urea cycle defect?
Ornithine transcarbamylase deficiency
81
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
82
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
83
What type of transplant may be required in ornithine transcarbamylase deficiency?
Liver transplant
84
What type of inheritance is associated with galactosemia? What enzyme is deficient?
Autosomal recessive
Galactose-1-phosphate uridyltransferase deficiency
85
Galactosemia should be suspected in any newborn with ________ and \_\_\_\_\_\_\_
hepatomegaly and hypoglycemia
86
What are some clinical features of galactosemia?
* Vomiting, diarrhea, and FTT
* Hepatic dysfunction with hepatomegaly
* Cataracts with oil-droplet appearance
* Renal tubular acidosis
87
How is galactokinase diagnosed?
* Nonglucose-reducing substance in urine (tested by Clinitest)
* Confirmation of enzyme deficiency in RBCs
* Prenatal and newborn screening are available
88
What affects nearly all females with galactosemia?
Death in early infancy is typically caused by ______ \_\_\_\_\_\_ sepsis
Ovarian failure
Escheria Coli
89
Hereditary fructose intolerance is caused by a deficiency in what enzyme?
Fructose-1-phosphate aldolase B
90
What are the symptoms of hereditary fructose intolerance?
Symptoms include hypoglycemia, vomiting, diarrhea, FTT, and seizures
91
Glycogen storage diseases are characterized by ________ and ______ \_\_\_\_\_\_\_\_
organomegaly; metabolic acidosis
92
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**
93
Pompes disease is due to an ________ deficiency
α-glucosidase deficiency
94
What are the presenting features of Von-Gierke's disease?
Presenting features may include persistent hypoglycemia, hepatomegaly, metabolic acidosis, hypertriglyceridemia, and enlarged kidneys
95
Pompe's disease shoudl be suspected in any infant with ______ \_\_\_\_\_\_\_ and \_\_\_\_\_\_\_\_
Muscular weakness and cardiomegaly
96
When do fatty acid oxidation defects occur?
Present during an acute illness or fasting when fatty acids are normally used as an energy source
97
What is the most common fatty acid oxidation disorder?
Medium-chain acyl-CoA dehydrogenase deficiency
98
Fatty acid oxidation is managed with...
Frequent feedings with a high-carbohydrate, low fat diet and carnitine supplementation during acute episodes
99
Mitochondrial disorders should be suspected if a common disease has ______ presentation or if a disease involves ______ or more organ systems
atypical; three
100
How are mitochondrial disorders diagnosed?
Based on tissue biopsy revealing abnormal mitochondria
101
What are the components of the mitochondrial disorder, MELAS?
* **M**itochondrial **E**ncephalopathy
* **L**actic **A**cidosis
* **S**troke-like episodes
102
Tay-Sachs disorder is an autosomal ______ disorder caused by ____________ deficiency
Recessive; hexosaminidase A
103
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
104
Juvenile or adult-onset Tay sachs disease has the same clinical features as the infantile form except for...
cherry red macula
105
Infantile Tay-Sachs disease is untreatable and death occurs by ___ years
4
106
Gaucher's disease is cause by ___________ deficiency and has autosomal _____ inheritance
glucocerebrosidase; recessive
107
What are the clinical features of Gaucher's disease?
Hepatosplenomegaly, thrombocytopenia, Erlenmeyer flask-shaped distal femur, and early mortality (4 years)
108
What is the management of Gaucher's disease?
Enzyme replacement therapy
109
Niemann Pick disease is caused by a ________ deficiency and presents by __ months of age
sphingomyelinase; 6 months
110
What is the presentation of Niemann-Pick disease?
* Progressive neurodegeneration
* Ataxia
* Seizures
* Hepatosplenomegaly
* Cherry-red macula
111
Metachromatic leukodystrophy is a neurodegenerative disorder caused by _______ deficiency
Arylsulfatase A
112
What are the presenting features of Metachromatic leukodystrophy?
Ataxia, Seizures, progressive mental retardation
113
What accumulates in mucopolysaccharidoses?
Glucosaminoglycans accumulate in multiple organs
114
What is the most common gangliosidosis?
Gaucher disease
115
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
116
Hurler syndrome is caused by a deficiency in...
α-L-iduronidase deficiency
117
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
118
What is the inheritance pattern for Hunter syndrome?
X-linked recessive
119
What are the clinical features of Hurler syndrome?
* Hepatosplenomegaly
* Developmental delay
* Kyphosis
* Progressively coarsened facial features
* Corneal clouding
120
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
121
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**
122
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
123
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
124
What disease is an autosomal recessive defect in copper excretion that leads to copper deposition in the liver?
Wilson's disease
125
What is the occular finding in Wilson's disease?
Kayser-Fleischer rings in the peripheral cornea (copper deposition in Descemet's membrane)
126
What is the most commonly used screening test for Wilson's disease?
Decreased serum ceruloplasmin
127
What is Menkes kinky-hair disease?
An X-linked recessive disorder caused by abnormal copper transport
128
What are the clinical features of Menke's disease?
Pale kinky friable hair, optic nerve atrophy, severe mental retardation, and early death
