Block 11 - L17- Flashcards
1
Q
What is the inheritance pattern of NFI?
A
AD
2
Q
How is NFI diagnosed?
A
2 of the following:
- Family history of NF1
- > 6 cafe’ au lait spots
- 2+ neurofibromas (soft, fleshy growths)
- Lisch nodules
- Optic gliomas
- Angiofibromas
- Axillary and/or inguinal freckling
3
Q
How do neurofibromas appear on H&E?
A
Spindle-shaped cells with collagen and nerves
4
Q
What is the most common CNS tumor?
A
Optic glioma
5
Q
What are the sequelae of optic glioma (in 1/3 of patients)?
A
Decreased visual acuity Proptosis Strabismus Headaches Nausea
6
Q
What are Lisch nodules?
A
Iris hamartomas, usually seen on slit lamp exam
7
Q
What is a rare orthopedic sign of NF?
A
Osseous defect of the fibula (one of the first signs in infancy, but rare)
8
Q
___ is common in patients with NF1.
A
Hypertension (can develop at any age, most cases are essential)
9
Q
How is NF1 managed?
A
- Yearly ophthalmologic exams (monitor for optic glioma)
- Close BP monitoring
- Removal of NF if they are in areas causing irritation or for cosmetic reasons
10
Q
What are the systemic features of Marfan syndrome (assign point values)?
A
- Chest wall deformities - pectus excavatum (1) and pectus carinatum (2)
- Spontaneous Pneumothorax
- Scoliosis (greater than 20 degrees) (2)
- Pes planus (1)
- Steinberg thumb sign and wrist sign (3)
- Either Steinberg thumb sign OR wrist sign (1)
- Lower body segment is greater than the upper body segment (1)
- Wing span is greater than the height (1)
- Striae (1)
- Myopia (1)
- Mitral valve prolapse (1)
11
Q
What are the ophthalmologic features of Marfan syndrome?
A
- Ectopia lentis (upward)
- Myopia
- Flat cornea
- Elongated globe
12
Q
What are the cardiovascular features of Marfan syndrome?
A
- Dilation of the ascending aorta (Z score >2)
- Aortic dissection
- MV prolapse
13
Q
What is the inheritance pattern of Marfan syndrome?
A
AD
14
Q
Marfan syndrome is caused by an abnormality in ___, due to a mutation in ___ gene.
A
Fibrillin (connective tissue); FBN1
15
Q
How is Marfan syndrome diagnosed without a family history?
A
- Ao (Z>2) + ectopis lentis
- Ao (Z>2) + FBN1
- Ao (Z>2) + systemic features (7+ points)
- Ectopia lentis + FBN1
16
Q
How is Marfan syndrome diagnosed with a family history?
A
Family history plus one of the following:
- Ectopic lentis
- Systemic features (7+ points)
- Ao (Z>2 over age 20 and >3 below 20)
- FBN1
17
Q
Patients with Marfan Syndrome have a ___% risk of passing it onto their children.
A
50
18
Q
How is Marfan syndrome managed?
A
- Annual eye exam
- Close cardiology follow-up
- Medications to lower BP (Beta-blockers + Losartan)
- Limitation of sports participation if aortic root is enlarged
- Avoidance of weight lifting and scuba diving
19
Q
What is the inheritance pattern of Duchenne’s Muscular Dystrophy (DMD)?
A
X-linked recessive
20
Q
What are the clinical features of DMD?
A
- Progressive muscle weakness
- Calf hypertrophy
- Toe walking
- Lordosis
- Gower sign
21
Q
What is often the cause of death in patients with DMD?
A
Heart failure (dilated cardiomyopathy)
22
Q
What protein is mutated in DMD?
A
Dystrophin (protein that connects the actin of a muscle fiber to the surround ECM)
23
Q
What is the largest known human gene? Where is it located?
A
Dystrophin gene (DMD); short arm of X chromosome (Xp22.1)
24
Q
Discuss the pathophysiology of DMD caused by mutated dystrophin.
A
When the membrane does not have structural support of the cytoskeleton, surface membrane rips occur in the cell membrane. CK migrates from the inside of the cell to the outside. Ca2+ migrates into the cell; when combined with proteases, Ca2+ is actiavted and breaks down muscle cells
25
Compare DMD and Becker Muscular dystrophy.
DMD - either deletion of a significant portion of the gene or a missense mutation (no dystrophin protein produced)
BMD - decreased protein, milder phenotype
26
How is DMD managed?
1. Physical therapy
2. Steroid injections in the muscle
3. Cardiac medications to improve function
4. Exon skipping therapy in the future?
27
Approximately 80% of patients with DMD have involvement in exon ___.
51
28
Describe the concept of exon skipping.
Skip reading of mutated exons (which normally cause translation to stop) to restore the reading frame - leads to a functional (albeit shorter) protein
29
What are the symptoms of Beckwith-Wiedemann Syndrome (BWS)?
1. Increased birth weight
2. Neonatal hypoglycemia
3. Hypocalcemia
4. Anterior ear creases
5. Macroglossia
6. Wilms tumor (increased risk)
7. Hepatoblastoma (increased risk)
8. Omphalocele
9. Organomegaly
10. Hemihyperplasia
30
What is the most common cause of BWS?
Duplication of the insulin growth factor receptor (11p)
31
There is an increased incidence of BWS in infants conceived by ___.
IVF
32
What are the symptoms of FAS?
1. Prenatal alcohol exposure
2. Microcephaly
3. Low birth weight
4. FTT
5. Long smooth philtrum
6. Thin upper lip
7. Hearing loss
8. Congenital heart defects
33
What is fetal alcohol effects (FAE)?
Alcohol use during pregnancy, but not enough features to fulfill diagnosis of FAS
34
What four categories are used to diagnose FAS?
1. Prenatal alcohol exposure
2. Dysmorphic features
3. Growth deficiency
4. Cognitive delays
35
How is gestational exposure to alcohol scored?
1: Confirmed absence of exposure
2: Exposure not confirmed
3: Confirmed exposure, level unknown
4: Confirmed exposure to high levels of alcohol
36
How are dysmorphic features scored?
Short palpebral fissure length (hypertelorism), long philtrum, thin upper lip
1: no features
2: 1/3 features
3: 2/3 features
4: all 3 features
37
How is growth scored?
1: height and weight about the 10th percentile
2: height or weight below the 10th percentile
3: heigh and weight below the 10th percentile
4. height and weight below the 3rd percentile
38
How is CNS scored?
1: no neurologic impairment
2: some evidence of neurologic dysfunction
3: significant neurologic dysfunction
4: structural anomalies of the brain/microcephaly
39
How is FAS diagnosed clinically?
1. 4 for all 4 criteria OR
| 2. 3 level 4's and 1 level 3
40
How is FAE diagnosed clinically?
1. 1 criteria at level 4
| 2. Remaining criteria at level 3 or 2
41
Generally, how does metabolic disease present clinically?
Non-specific problems of lethargy, decreased feeding, vomiting - can progress to seizure/coma
*Similar symptoms can be seen with many etiologies, including congenital heart defects and sepsis
42
What is "newborn crash"?
Usually term infant with a well interval presenting with non-specific poor feeding, vomiting, lethargy progressing to seizures and coma; occasional abnormal urine odor
43
DDx - newborn crash
```
SEPSIS
Adrenal insufficiency
Congenital heart disease
Amino acid abnormality
Urea cycle abnormality
Organic aciduria (proprionic, methymalonic)
Mitochondrial disorder
```
44
Define metabolic acidosis.
1. Decreased blood pH (<7.4) caused by accumulation of H+
2. Decreased bicarbonate (HCO3<16)
3. Decreased PaCO2 (compensatory hyperventilation)
45
DDx - metabolic acidosis in a newborn
Diarrhea (loss of bicarbonate), renal tubular acidosis, diabetic ketoacidosis, inborn error of metabolism
46
Anion gap = ?
| Normal anion gap = ?
Na - Cl - HCO3 = AG
| Normal = 10-15
47
What causes a normal anion gap metabolic acidosis?
Diarrhea, renal tubular acidosis (abnormal losses of bicarbonate)
48
What causes an expanded anion gap metabolic acidosis?
Organic acidopathy, ketoacidosis, lactic acidosis (accumulation of fixed acid)
49
What are the clinical and laboratory features of organic acidurias?
Decompensation in the first 2 weeks of life (though glutaric acidemia can present later), acidosis, elevated AG, elevated lactic acid, hypoglycemia, bone marrow suppression, hyperammonemia (200-600)
50
List the 4 organic acidurias.
1. Methylmalonic
2. Isovaleric
3. Proprionic
4. Glutaric acidemia
51
Enzyme defects can result in the inability to convert one amino acid to another, leading to an ___. Give two examples.
Amino acidemia; PKU, homocystinuria
52
Describe the pathophysiology of phenylketonuria (PKU).
Normally, phenylalanine is converted to tyrosine via the enzyme phenylalanine hydroxylase (PAH). In PKU, the enzyme does not function, leading to shunting of phenylalanine to phenylpyruvate, which is then converted to toxic acids (phenyl lactate, phenylacetate, phenylethylamine, phenylacetyl glutamine).
53
What is the inheritance pattern of PKU?
AR
54
How does PKU present?
Poor weight gain, microcephaly, "mousy" odor, loss of IQ points (acid is toxic to the brain)
55
How is PKU managed?
Diet low in protein (only enough PHE to allow for growth); kuvan - medication which can increase the conversion of phenylalanine to tyrosine
56
Describe the pathophysiology of homocystinuria.
Homocysteine is normally converted to cysteine by cystathionine synthase; when this enzyme is non-functional, homocysteine is converted to homocystINE and excreted in the urine. Elevated homocysteine results in a prothrombic state that increases the risk of blood clots.
57
What is the inheritance pattern of homocystinuria?
AR
58
How does hmocystinuria present?
Marfanoid habitus (long fingers, joint hypermobility, tall stature), cognitive delays, downward lens dislocation (different from Marfan's)
59
Describe the pathophysiology of maple syrup urine disease.
A nonfunctional enzyme in the BCKD complex fails to catalyze the decarboxylation of the alpha-keto acids of leucine, isoleucine, and valine to their respective branched-chain acyl-CoA; as a result, these amino acids increase.
60
How does maple syrup urine disease present?
1. Baby deteriorates in the first 1-2 weeks of life (lethargy, damage to neurons)
2. NH3 is normal or elevated
3. Lactate is normal
4. Glucose is normal/mild hypoglycemia
5. Maple syrup odor to urine
6. Serum amino acids have an elevation of leucine, isoleucine, valine, and alloisoleucine
61
How is maple syrup urine disease inherited?
AR
62
What causes the sweet smell, lethargy, and brain damage in maple syrup urine disease?
Elevated isoleucine - sweet smell
Elevated leucine - transported to the brain, converted to glutamate and glutamine, which cause lethargy and neuron damage
63
How is maple syrup urine disease managed?
Diet low in protein with limited branch chain amino acids
64
What is the purpose of the urea cycle?
To dispose of nitrogen waste and to syntheisze arginine
65
What is the most common urea cycle disorder?
Ornithine transcarbamylase deficiency
66
List the urea cycle disorders.
1. Ornithine transcarbamylase deficiency (OTC)
2. Citrullinemia
3. Argininosuccinate lyase deficiency
4. Arginase deficiency
67
Why are many patients with urea cycle defects often alkalotic?
Because of the accumulation of NH3
68
Explain the urea cycle, beginning with ammonia's conversion to carbamoyl phosphate (via carbamoyl phosphate synthetase I).
Note - this is not part of the urea cycle.
1. Carbamoyl phosphate is converted to citrulline via ornithine transcarbamoylase.
2. Citrulline is converted to argininosuccinate via argininosuccinate synthetase.
3. Argininosuccinate is converted to arginine and fumarate via argininosuccinase.
4. Arginine is converted to urea and ornithine via arginase.
Ornithine is transported back to the mitochondria to begin the urea cycle again.
69
What are the clinical features of glutaric acidemia?
1. Megalencephaly
2. Normal development until the first episode
3. Profuse sweating or unexplained fevers, irritability
4. Basal ganglia lesions and subdural hematomas
70
How is glutaric acidemia diagnosed?
1. Elevation of glutaric acid in urine organic acids
| 2. MRI abnormalities - lesions to the basal ganglia and subdural hematomas
71
What is the pathophysiology of the basal ganglion lesions and subdural hematomas in glutaric acidemia?
Glutaric acid is toxic to the brain, resulting in atrophy and additional fluid around the brain (microcephalic macrocephaly); subdural hematomas result from inflammation of the toxins and tearing of vessels
72
What is the most common cause of subdural hematomas in children?
Abuse
73
What is the inheritance pattern of medium-chain acyl-coenzyme A dehydrogenase deficiency (MCAD)?
Autosomal recessive
74
What are the symptoms of MCAD?
Episodic illness with hypoglycemia usually occurring between 3 months and 2 years of age, usually follows fasting for 12 hours or more, or with intercurrent infectious disease, acute episode often starts with vomiting, lethargy, seizures, can progress to coma rapidly
Can cause SIDS (2-3% are due to this)
75
What is the role of the deficient enzyme in MCAD?
Involved in mitochondrial fatty acid beta-oxidation
76
What lab results are seen in MCAD?
1. Hypoglycemia
2. Urine dip negative for ketones despite fasting state
3. Hyperammonemia
4. High uric acid
5. High CPK
6. Organic acids and acylcarnitine studies show an increased C6-C10 dicarboxylics
77
As a group, fatty acid oxidation disorders occur when fat cannot be converted to energy. Where does this process occur?
Mitochondria
78
What are the steps of beta oxidation?
Acyl-CoA
79
What is the most common disorder of fatty acid oxidation?
MCAD
80
How is MCAD treated?
Carnitine supplementation, low fat diet, prevent fasting state
81
Galactosemia is a metabolic disorder resulting from the inability to utilize ___ as an energy source (to convert it to glucose). One of the most common sources of galactose is ___.
Galactose; lactose
82
Galactosemia usually results from the absence of what enzyme?
GALT (Galactose-1-P-uridyl transferase)
| Could also be due to GALK or GALE
83
When galactose cannot be converted to glucose, what happens?
It is converted to galactitol, which is toxic to the liver. It can accumulate in the lens of the eye, resulting in cataracts. Urine will show reducing substances (unmetabolized sugars).
84
What is the inheritance pattern of galactosemia?
AR
85
How does classical galactosemia present?
Jaundice, hepatomegaly, vomiting, feeding intolerance, E. coli sepsis (E. coli loves galactose), cataracts; progress rapidly to hepatic toxicity and death from sepsis or bleeding
86
How is galactosemia treated?
1. Lactose free diet
| 2. Soy formula during infancy (breast milk has lactose)
87
___ are a group of disorders resulting from the inability to properly break down glycogen.
Glycogen storage diseases
88
Glycogen stores sugars in long ___ with ___.
Chains; branches
89
What are the 4 glycogen storage diseases in the hepatic group?
1. Type I (Von Gierke)
2. Type III (DeBrancher defects)
3. Type IV (Branching Enzyme Defect)
4. Type VI: Liver Phosphorylase
90
What is deficient in Type I (Von Gierke)?
Glucose 6 phosphatase
91
How does Type 1 (Von Gierke) present?
3-4 months old, hepatomegaly, FTT, fat cheeks with thin extremities, hypoglycemia with seizures
92
What are the labs seen in Type I (Von Gierke)?
Hypoglycemia
Lactic acidosis
Hyperuricemia
Hyperlipidemia
93
How is Type I (Von Gierke) treated?
1. Preventing hypoglycemia with continuous feeds or cornstarch
2. Restricting galactose and fructose in diet
94
Discuss the pathophysiology of Type I (Von Gierke).
When blood glucose is low, the body breaks down glycogen. It is converted to Glucose-1-phosphate, and then to G6P, and then to glucose (via G6 phosphatase). When this is deficiency, excess G6P is converted to pyruvate, which leads to lactic acidosis and hyperuricemia.
95
What is deficiency in Type III (Cori)?
Glycogen debranching enzymes
96
What are the symptoms of Type III (Cori) disease?
Hepatomegaly, hypoglycemia, short stature, skeletal myopathy, cardiomyopathy
97
What are the 3 glycogen storage diseases in the muscle group?
1. Type II (Pompe)
2. Type V (McArdle)
3. Type VII (phosphofructokinase deficiency)
98
What is deficient in Type V (McArdle)?
Muscle phosphrylase
99
What is the inheritance pattern of Type V (McArdle)?
AR
100
What are the symptoms of Type V (McArdle)?
Begin in the early 20's
Exercise induced muscle cramps and exercise intolerance
Burgundy colored urine
CPK elevated and rest + increases significantly with exercise
101
How is Type V (McArdle) diagnosed?
Muscle biopsy identifying glycogen in muscle OR PYGM gene test (100% have mutation)
102
How is Type V (McArdle) treated?
Avoid strenuous exercise, IVF with glucose during rhabdomyolysis
103
What is deficient in Type VII?
Fructose-6-phosphatase
104
How does Type VII present?
Presents in childhood, hemolysis, increased uric acid levels, exercise intolerance much worse after carbohydrate meal, early onset of fatigue and pain with exercise
105
Urine smell - maple syrup
Maple syrup urin disease
106
Urine smell - weaty feet
Isovaleric acidemia
107
Urine smell - rotten cabbage
Tyrosinemia
