Inborn Errors of Metabolism Flashcards
1
Q
What should come to mind when a previously healthy infant develops poor feeding, hypoglycemia, lethargy, vomiting, tachypnea, apnea, irritability, seizures, coma, apnea?
A
Inborn errors of metabolsim
2
Q
What is often the crucial clue for answers regarding inborn errors of metabolism?
A
Antecedent events, even if they seem inconsequential (like feeding)
3
Q
What should you focus on with questions regarding inborn errors of metabolism?
A
Specific differences since many are quite similar
Use a logical approach
4
Q
If you are presented with a lethargic or comatose infant, what is appropriate to order?
A
CBC, electrolytes, serum ammonia level, and urine organic acids
5
Q
If you are given values for electrolytes, what should you do?
A
Measure the anion gap…
Serum Sodium - [Chloride + Bicarbonate]
6
Q
What is normal anion gap?
A
8-12 mEq/L
7
Q
What should an elevated anion gap in an infant who is lethargic or comatose make you think of?
A
Elevated ammonia
8
Q
What 2 symptoms do all of the metabolic disorders present with?
A
- Vomiting
- Lethargy
*So distinguishing the fine differences between them can be a challenge… key phrases and wording distinguish one from the other
9
Q
What does it mean if they emphasize that the infant is afebrile?
A
ID tree is the wrong tree…look for other clues in the question that this isn’t an infection (normal WBC count and platelet count)
10
Q
Metabolic acidosis, Elevated serum ammonia (NH4)…disorders?
A
- Propionic acidemia
- Methylamalonic acidemia
- Fatty acid oxidation defects
11
Q
ABG normal, Elevated serum ammonia (NH4)…disorders?
A
- Urea cycle defect
2. Transient hyperammonemia
12
Q
Metabolic acidosis, Normal serum ammonia (NH4)…disorders?
A
- MSUD
2. Some organic acidemias
13
Q
ABG normal, Normal serum ammonia (NH4)…disorders?
A
- Aminoacidopathy
- Galactosemia
- Non-ketotic hyperglycinemia
14
Q
What is a normal serum ammonia value in a newborn?
A
Below 110 mcmol/L
15
Q
In a kid with galactosemia, why might they have a metabolic acidosis?
A
From sepsis… pure galactosemia has a normal ABG
16
Q
What are 3 examples of organic acidemias?
A
- Methylmalonic acidemia
- Propionic acidemia
- Isovaleric acidemia
17
Q
Which organic acidemia has an odor of sweaty feet?
A
Isovaleric acidemia
18
Q
What common problem can present with a metabolic acidosis?
A
Sepsis
19
Q
How do organic acidemias typically present?
A
With a “drunk-like” intoxicated picture…but the disease is life threatening
20
Q
What are important lab findings in organic acidemias?
A
- Elevated serum ammonia levels (in many, but not all)
- Acidosis
- High anion gap
- Ketonuria
21
Q
When do organic acidemias often present?
A
First 2 days after the introduction of protein in the diet
22
Q
What is the most important initial step after diagnosing an organic acidemia?
A
HYDRATION…to maintain good urine output
23
Q
What is indicated after you hydrate your patient you have diagnosed with organic acidemia?
A
Appropriate diet
24
Q
What is the most important laboratory study for organic acidemia?
A
Urine organic acid levels
25
When they present you with an infant with a septic appearance with sepsis ruled out, what is likely cause?
Metabolic (generally)
26
What should be done next if they present you with an infant with a septic appearance with sepsis ruled out?
Obtain a serum ammonia level
Additional correct choices: Lactic acid level, serum pyruvate, total and free carnitine, acetylcarnitine
27
Why can granulocytopenia and thrombocytopenia occur with organic acidemias?
Because metabolic acidosis can suppress bone marrow
28
If you have a history consistent with organic acidemia and a low platelet and WBC count, is this normal?
Could be...metabolic acidosis (from organic acidemias) can suppress bone marrow leading to granulocytopenia and thrombocytopenia
29
How does a child with organic acidemias present?
Decreased appetite, falling down frequently, delayed developmental milestones, with no overt physical abnormalities or dysmorphology
*Think of someone who is drunk...think of organic acids as very powerful alcoholic drinks
30
Since brain tumors and organic acidemias can both present with balance problems and vomiting, what can help distinguish?
If it is a brain tumor they will hint that the symptoms have been progressively worse... might also mention morning headaches and visual disturbances
31
How are fatty acid oxidation defects inherited?
Autosomal recessive pattern
32
Name 4 fatty acid oxidation defects?
1. Medium chain acyl-CoA dehydrogenase deficiency
2. Long chain acyl-CoA dehydrogenase deficiency
3. Very long chain acyl-CoA dehydrogenase deficiency
4. Glutaric aciduria
33
How do infants with a defect in fatty acid metabolism present?
Hypoglycemia and hepatomegaly
*Fatty acid oxidation defects may or may not present with hepatomegaly...it may be part of the presentation on boards however
34
What preceding signs should you watch for with fatty acid oxidation defect?
Preceding benign illness during which oral intake was decreased (this could occur in a toddler)
35
When do many of the signs of fatty acid oxidation defects present?
With fasting (why you have to watch for illness with associated oral intake)
36
True or false: In between episodes of fasting, a child with a defect in fatty acid metabolism is fine?
True
37
What is seen in urine and serum with defects in fatty acid metabolism?
Absence of reducing substances and ketones in urine
| Normal serum amino acids
38
How is definitive diagnosis of a defect in fatty acid metabolism made?
Via plasma acylcarnitine profile
39
How do urea cycle defects present?
With hyperammonemia in the absence of acidosis and ketosis. Also look for a symptom-free period, followed by hypotonia and coma.
40
What acid-base issues can be present with urea cycle defects?
Respiratory alkalosis as well as lactic acidosis
41
What causes symptoms consistent with encephalopathy (vomiting, lethargy, coma) in urea cycle defects?
Hyperammonemia
42
What is treatment for urea cycle defects?
Reduce serum ammonia (NH4) by reducing protein intake and increasing glucose intake by IV... dialysis might be needed on a PRN, usually acute, basis
43
What does a neonate with hyperammonemia, acidosis, and ketosis have?
Organic aciduria
44
What does a neonate with no acidosis and ketosis, but hyperammonemia have?
Urea cycle defects
45
Infant with hypoglycemia, seizures, hepatomgealy, failure to thrive...most helpful measure to determine etiology?
Most important measurements to determine the etiology of hypoglycemia in infants is urine measurement of ketones and reducing substances
*Don't fall for cortisol and growth hormone (if macrosomic) or insulin level measurement
46
When do infants with galatosemia present?
After their first meal containing lactose (breast milk or formula)...infants with galactosemia will appear normal at birth
47
After consuming lactose, how do babies with galactosemia present?
Non-specific findings...poor feeding and failure to thrive
48
Which states test for galactosemia?
All of them...but symptoms may develop before the newborn screen results are recieved
49
What should be done for a newborn with symptoms of galactosemia or a positive screen for galactosemia?
Changed immediately to a soy-based formula and repeat NBS
50
Name more specific findings of galactosemia
1. Abdominal distension with hepatomegaly
2. Hypoglycemia
3. Non-glucose reducing substances in the urine
4. Lethargy and hypotonia
51
What should you think with a history of prolonged jaundice and/or infection with gram negative organisms including E. Coli?
Galactosemia
52
What is galactosemia due to?
Deficiency of galactose-1-phosphate uridyltransferase (GALT)
53
How is definitive diagnosis of galactosemia made?
Measuring GALT in RBCs
54
What is treatment of galactosemia?
Soy formula...galactose-free diet
55
Failure to treat galactosemia can result in what?
Cataracts, intellectual disability, and/or liver disease
56
True or False: Cataracts due to galactosemia are reversible with diet change?
True
57
Since several glycogen storage diseases presents with hepatosplenomegaly, what buzz word should make you think galactosemia?
Positive reducing substances in urine
58
What are 3 other diseases that should be in your differential diagnosis for galactosemia?
1. Lactose intolerance
2. Maple Syrup Urine Disease
3. Urea Cycle Defects
59
How is lactose intolerance different from galactosemia?
Presents later in childhood...much more benign
60
How is maple syrup urine disease different from galactosemia?
MSUD presents with hypoglycemia, but also presents with acidosis, increased tone, odor of maple syrup in the urine, seizures
61
How are urea cycle defects different from galactosemia?
In addition to lethargy and poor feeding, urea cycle defects present with coma and hyperammonemia
62
How can infants of diabetic mothers present?
Hypoglycemia, jitteriness, seizures....Because of exposure to higher than normal serum glucose in utero, these babies have their insulin production going strong... once born and decreased glucose, but still high insulin...hypoglycemic...checking serum glucose is crucial
63
What can be the cause of tremors, apnea, cyanosis, lethargy, and tachypnea in infants?
Hypoglycemia
64
Besides hypoglycemia, what 3 things are infants of diabetic mothers at risk for?
1. Hypocalcemia
2. Hyperbilirubinemia
3. Polycythemia
65
Icteric 4 day old newborn with lethargy and hepatomegaly. LP is positive for gram negative organisms...what is the best additional study to obtain?
Galactose-1-phosphate activity in RBCs (erythrocytes)
Don't fall for idea of sepsis and positive gram stain of CSF and jump to culture of CSF...hepatomegaly is the give-away
66
What is hepatomegaly and risk for gram-negative sepsis hallmark of?
Galactosemia
67
How is galactosemia diagnosed?
By measuring galactose-1-phosphate activity in erythrocytes
68
Presented with an infant with a sepsis-like picture, hepatomegaly, and positive culture for gram-negative organisms?
Galactosemia lurking in the erythrocyte
69
What is the treatment for galactosemia?
Antibiotics and diet restriction
70
What is an associated finding of galactosemia in the urine?
Reducing substances in the urine
71
Afebrile infant presenting with generalized seizures. They are hypoglycemic and it is fixed with injection of glucagon?
Hyperinsulinism
72
What size (length, weight, head circumference) are babies with hyperinsulinism?
Height, weight, and head circumference will all be in the upper limits of normal...typically in the 95th percentile for all parameters
73
Macrosomia, microcephaly, macroglossia, visceromegaly, omphalocele?
Beckwith-Wiedemann Syndrome
Don't confuse with hyperinsulinism...this has macrosomia too, but macrocephaly instead of microcephaly
74
What presents with hypoglycemia and ketonuria?
Adrenal insufficiency
- If they note absence of ketones in urine, they are ruling out adrenal insufficiency for you
- Don't confuse with hyperinsulinism..this also has hypoglycemia, but no ketones in urine
75
Hypoglycemia, vomiting, failure to thrive, hepatomegaly, non-glucose reducing substances in the urine?
Galactosemia
76
What is hypoglycemia due to in Beckwith-Wiedemann syndrome?
Islet cell hyperplasia
77
Full term infant who is hypoglycemic. Serum insulin levels are elevated. Despite glucose IV, still hypoglycemia. What next? Which medication most appropriate?
Diazoxide: Decreases insulin secretion and stimulates cortisol release...this is DOC in refractory hypoglycemia in infants
Don't pick glucagon (this is refractory hypoglycemia)
Don't pick CCB (even though Ca is needed to squeeze out insulin from pancreas, this rarely helps with refractory hypoglycemia)
78
Features of Glycogen Storage Disease Type I (Von Gierke Disease)?
1. Hypoglycemia
2. Distended abdomen
3. Doll-like or cherubic face
4. Poor growth
5. Large liver
6. Seizures (secondary to hypoglycemia)
7. Elevated triglycerides and cholesterol
79
What are 3 lab findings with Glycogen Storage Disease Type I?
1. Hypoglycemia
2. Lactic acidosis with fasting (elevated lactic acid)
3. Elevated uric acid levels
80
What is a common feature in the history of Von Gierke Disease?
Consanguinity
81
What is Glycogen Storage Disease Type I caused by?
A deficiency of hepatic glucose-6-phosphatase
This is the final step in the liver to produce glucose
82
When do glycogen storage diseases often present?
When an infant begins sleeping through the night...aka, "prolonged fasting"
83
What is the treatment for Glycogen Storage Disease Type I?
1. Frequent snacks and meals
2. Sometimes continuous tube feedings
3. Sometimes infusion of glucose continuously, especially at night until age of 2 (after 2, cornstarch is often used, since it releases glucose slowly)
84
What are some diversions for wrong treatment or inappropriate initial treatment of Glycogen Storage Disease Type I?
* It is only the continuous feeding of glucose that is helpful
1. Feeding of formula high in fructose or galactose
2. Glucagon injections
3. Liver transplant (might be appropriate down the road in the event of liver failure, but not the appropriate initial treatment of choice)
85
What disease results from a deficiency in lysosomal breakdown of glycogen?
Glycogen Storage Disease Type II (Pompe Disease)
86
Infant who is one month of age or younger, normal at birth. Becomes floppy, fails to thrive, develops a large liver with macroglossia, cardiomegaly, hypotonia with muscles that are "hard" on examination?
Glycogen Storage Disease Type II (Pompe Disease)
87
What causes death in Pompe Disease?
Respiratory failure
88
Memory aid for Glycogen Storage Disease Type II?
Instead of Pompe Disease, change it to Pope disease...one feature is cardiomegaly (Pope has a big heart). He isn't afraid to speak out when necessary, so he has a large tongue (macroglossia)
89
True or False: Hypoglycemia and acidosis are often seen in Pompe Disease?
False... hypoglycemia and acidosis aren't part of Pompe Disease
90
Newborn presenting after being fed protein-containing formula for the first time. Become lethargic and eventually comatose.
Nonketotic hyperglycinemia
91
If an infant survives nonketonic hyperglycinemia, what will they often have?
Spastic Cerebral Palsy
92
Infant with tachypnea, shallow breathing pattern, profound lethargy, hypertonicity, burnt smell to urine
Maple Syrup Urine Disease
93
When is the classic onset of Maple Syrup Urine Disease?
First week of life
94
Which amino acids have elevated plasma levels in Maple Syrup Urine Disease?
```
VIAL (picture maple syrup in a vial)
Valine
Isoleucine
Alloisoleucine (never found in normal infants)
Leucine
```
95
What causes Maple Syrup Urine Disease?
Inability to break down the branched chain amino acids (Valine, isoleucine, alloisoleucine, leucine)
96
What is the problem in homocustinuria?
Error in methionine metabolism where a cystathionine synthase deficiency results in elevated blood methionine levels and elevated urine homocystine levels
97
Dislocated lenses, skeletal abnormalities, cognitive deficits, unpleasant odor, lighter-colored skin, hair, and eyes than other family members?
Homocystinuria
98
How is homocystinuria diagnosed?
By confirming homocysteine in the urine
99
What drug can a patient with homocystinuria who has residual enzyme activity respond to?
Pyridoxine
100
What is the correct treatment for homocystinuria?
Diet high in cysteine and low in methionine
101
What are common features of Marfan Syndrome and Homocystinuria and how do you tell them apart?
Both can have dislocated lenses, skeletal abnormalities, tall, thin, pectus excavatum
Marfan: Anterior lens displacement, no cognitive deficits
Homocystinuria: Posterior lens displacement, possible cognitive deficits
102
What causes phenylketonuria (PKU)?
Deficiency of enzyme that converts phenylalanine to tyrosine...leads to the accumulation of phenylalanine
103
Why isn't symptomatic PKU seen in the real world?
Due to mandatory newborn screening (it can still be on boards)
104
Blond hair, blue eyes. Asymptomatic for a few months. Then severe vomiting, irritability, eczema, musty/mousy odor of urine.
PKU
105
What are 3 later signs of untreated PKU?
1. Microcephaly
2. Congenital heart disease
3. Low birthweight
106
What does PKU ultimately lead to?
Profound intellectual disability and other neurological impairments
107
If an infant has a positive PKU screen, do they have PKU?
Not necessarily... the positive screen only indicates elevated phenylalanine levels
108
What can elevated phenylalanine levels (and a positive PKU screen) be caused by besides PKU?
1. Delayed enzyme maturation
2. Hyperphenylalaninemia
3. Biopterin deficiency
109
Why is it important for any Mom with PKU to be treated before conception (if contemplating pregnancy)?
Increased risk for miscarriage, SGA, microcephaly, cardiac defects, and intellectual disability
110
Why does a newborn screening have to be done at 48-72 hours?
PKU screening is only valid after a "protein" feeding
111
How is PKU treated?
With a low phenylalanine formula (Lofenalac)
112
What can be seen in overtreatment of PKU?
Increased lethargy, rash, diarrhea. Caused by low phenylalanine levels...because phenylalanine isn't synthesized in the body, overzealous treatment, especially in rapidly growing infants, can result in phenylalanine deficiency
113
Which amino acid becomes essential in PKU?
Tyrosine...adequate intake must be ensured
114
What disorders all present with coarse facies?
Mucopolysaccharidoses
115
What are 3 differences between the mucopolysaccharidoses that can help you distinguish between them?
1. Presence/Absence of corneal clouding
2. Intellectual disability
3. Modes of inheritance
116
When does Hurler Syndrome present?
Before age 2
117
Progressive facial coarsening, hirsutism, hepatosplenomegaly, thick skulls, corneal clouding, severe intellectual disability (along with other neurological deficits)
Hurler Syndrome (MPS Type I)
118
What is the significant lab finding in Hurler Syndrome?
Reduced alpha-L-iduronidase activity in WBCs
119
Coarse facial features, organomegaly, joint contractures, skin that appears pebbly (especially over the upper back)
Hunter Syndrome (MPS Type II)
120
What is the significant lab finding for Hunter Syndrome (MPS Type II)?
Reduced iduronate sulfatase enzyme activity in WBCs
121
What are the similarities and differences between Hunter and Hurler syndrome?
Same: Hepatosplenomegaly, progressive deafness
Hunter: Short and have skeletal abnormalities, X-linked recessive
Hurler: Corneal clouding
122
Memory aid for Hunter Syndrome?
Picture a hunter with a bow and arrow (X-linked)...tips of arrows have giant X's. Short stature and skeletal abnormalities help then get around while hunting without being seen. No corneal clouding because you have to see in order to hunt.
123
Memory aid for similarities between Hunter and Hurler Syndrome?
H pattern...Hunter and Hurler are associated with Hepatosplenomegaly and Hearing deficits
124
What is infantile Gaucher disease due to?
Decreased beta glucosidase activity
125
Child in the 1st or 2nd year of life with progressive hepatosplenomegaly and CNS deterioration?
Infantile Gaucher disease
126
Splenomegaly with chronic problems including thrombocytopenia or pancytopenia?
Chronic juvenile Gaucher Disease (this form isn't as severe and there usually isn't any CNS involvement)
127
What child should Gaucher disease be considered in?
Any child presenting with hepatosplenomegaly, bone pain, and easy bruisability. Also short stature.
128
What are the symptoms due to in Gaucher disease?
Thrombocytopenia (large part)
129
What can be seen on XR in Gaucher disease?
Osteosclerosis and lytic lesions
130
Memory aid for Gaucher disease?
Picture a Gaucho cowboy falling off of his horse resulting in bone pain, nose bleeds, and lots of bruises
131
How does Tay Sachs Disease present?
With progressive neurologic degeneration of the first year of life, with death occurring by age 4 or 5
132
What causes Tay Sachs Disease?
Deficiency of activity in the hexosaminidase A enzyme (this is a lysosomal enzyme)
133
How is Tay Sachs Disease inherited?
Autosomal recessive
134
Normal development through first 9 months. Then non specific signs like lethargy and hypotonia. Also get exaggerated startle reflex, cherry red spot on the retina, and macrocephaly.
Tay Sachs Disease
135
What is the progression of Tay Sachs Disease?
Continued deterioration, including blindness and seizures. Death occurs by age 5.
136
Which ethnic groups does Tay Sachs Disease occur in?
Ashkenazi Jews, French Canadians
Screening is recommended even when only one parent is at risk based on ethnicity
137
Cherry red spot on the retina, CNS deterioration, hepatosplenomegaly...
Niemann-Pick Disease
138
Memory aid for Niemann-Pick?
Pick Axe attacking the liver and spleen causing inflammation
139
What are 2 ways you can do prenatal screening for many conditions?
Amniocentesis or CVS sampling
140
When should prenatal screening for specific non-NBS conditions take place?
Family history of deaths due to metabolic disorders, ethic background, and geographical origin. Ethic and racial profiling is appropriate and helpful. Parents' carrier status doesn't need to be known...don't pick a choice based on parents' carrier status.
141
Name the 3 lysosomal/lipid storage diseases (spingolipidoses)?
1. Gaucher Disease
2. Tay Sachs Disease
3. Niemann-Pick Disease
142
Previously healthy infant with new onset of lethargy, vomiting, tachypnea, apnea, irritability, or seizures?
Inborn errors of metabolism
143
Late infancy or early childhood, slowly progressive symptoms?
Lipid storage disease
144
When meals are more spread out (when the infant is sleeping more) is when this group of disorders presents.
Glycogen storage disease
145
1. Presents when meals are more spread out (infant sleeping more)
2. Illness or stress increases metabolic demands, leading to hypoglycemia, metabolic acidosis, and hyperammonemia
3. Nonketotic
Fatty acid oxidation disorders
146
Metabolic acidosis, increased anion gap, hyperammonemia, hypoglycemia
Organic acidemias
Remember that neutropenia and thrombocytopenia can be a part of the picture with organic acidemias
147
Hyperammonemia without acidosis, respiratory alkalosis
Urea cycle defects
148
Acidosis and hypoglycemia
Amino acid disorder
149
Acute encephalopathy, no metabolic acidosis, no hyperammonemia
Non-ketotic hyperglycinemia
