Metabolic Flashcards
1
Q
Inheritance of inborn error of metabolism (IEM)
- Most IEMs have _____ inheritance
- Next most common are those that are X-linked
- Only a few are autosomal dominant (AD) disorders
- Many of the described diseases are caused by mutations in the mitochondrial genome.
A
Inheritance of inborn error of metabolism (IEM)
- Most IEMs have autosomal recessive inheritance
- Next most common are those that are X-linked
- Only a few are autosomal dominant (AD) disorders
- Many of the described diseases are caused by mutations in the mitochondrial genome.
2
Q
Inborn error of metabolism (IEM)
- IEM intoxications are caused by upstream or accessory pathway buildup of toxic chemicals:
- 1) Disorders of amino acid metabolism
- 2) Urea cycle disorders
- 3) Organic acidemias
- 4) Sugar intolerance
- Pt:
- Brief symptom-free period after birth, followed by rapid decompensation, leading to lethargy, seizures, coma, and potentially death within the first week after birth
- _______ is a serious red flag
- Clinical presentations of IEM intoxications can be characterized as:
- Acute encephalopathy
- Suspect IEM intoxication if acute encephalopathy occurs without warning in previously normal neonates or young infants and progresses rapidly.
- Most are NORMAL AT BIRTH, following uneventful pregnancies.
- Symptoms: Unexplained seizures, coma, lethargy, hypertonia, hypotonia
- Because of the acute onset, focal neurologic deficits are usually NOT present
- Key strategy in acute phase:
- 1) Stop catabolism by providing adequate calories and
- 2) Dilute toxins and promote excretion with generous hydration
- Suspect IEM intoxication if acute encephalopathy occurs without warning in previously normal neonates or young infants and progresses rapidly.
- Chronic encephalopathy
- Pt: Slowly progressive manner as toxic metabolites build up. The symptoms are not immediately life-threatening; however, this usually changes over time as more and more damage occurs.
- Acid-base disturbances
- Due to either accumulation of fixed anions or loss of bicarbonate (almost always due to renal tubular dysfunction)
- Acute encephalopathy
A
Inborn error of metabolism (IEM)
- IEM intoxications are caused by upstream or accessory pathway buildup of toxic chemicals:
- 1) Disorders of amino acid metabolism
- 2) Urea cycle disorders
- 3) Organic acidemias
- 4) Sugar intolerance
- Pt:
- Brief symptom-free period after birth, followed by rapid decompensation, leading to lethargy, seizures, coma, and potentially death within the first week after birth
- Developmental regression is a serious red flag
- Clinical presentations of IEM intoxications can be characterized as:
- Acute encephalopathy
- Suspect IEM intoxication if acute encephalopathy occurs without warning in previously normal neonates or young infants and progresses rapidly.
- Most are NORMAL AT BIRTH, following uneventful pregnancies.
- Symptoms: Unexplained seizures, coma, lethargy, hypertonia, hypotonia
- Because of the acute onset, focal neurologic deficits are usually NOT present
- Key strategy in acute phase:
- 1) Stop catabolism by providing adequate calories and
- 2) Dilute toxins and promote excretion with generous hydration
- Suspect IEM intoxication if acute encephalopathy occurs without warning in previously normal neonates or young infants and progresses rapidly.
- Chronic encephalopathy
- Pt: Slowly progressive manner as toxic metabolites build up. The symptoms are not immediately life-threatening; however, this usually changes over time as more and more damage occurs.
- Acid-base disturbances
- Due to either accumulation of fixed anions or loss of bicarbonate (almost always due to renal tubular dysfunction)
- Acute encephalopathy
3
Q
When differentiating between patients, the first step is to obtain an ammonia level, blood gas, and BMP.
- If the pt has a high anion gap present, the pt has _____ (elevated ___ and elevated ____)
- If the anion gap is normal, look at the ____ level.
- If the ammonia is normal, the pt has ___ or one of the ___.
- If ammonia is high, they have ___ disorder (_____ is a clue).
A
When differentiating between patients, the first step is to obtain an ammonia level, blood gas, and BMP.
- If the pt has a high anion gap present, the pt has organic acidemia (elevated ammonia and elevated urine organic acids)
- If the anion gap is normal, look at the ammonia level.
- If the ammonia is normal, the pt has galactosemia or one of the aminoacidurias.
- If ammonia is high, they have urea cycle disorder (respiratory alkalosis is a clue).
4
Q
ORGANIC ACIDEMIA (aka organic acidurias)
- Group of rare inherited disorders caused by a defect in specific enzymes that process proteins
- For the most part are _____inheritance? disorders.
- Kidneys clear most organic acids, so it is easiest to examine the _____ for these disorders - which is why these disorders are also called organic acidurias.
- Dx: The diagnosis is strongly suggested by elevated serum ____ level and increased excretion of organic acids in the ____.
- If patient has a high anion gap present, the pt has one of the organic acidemias.
A
ORGANIC ACIDEMIA (aka organic acidurias)
- Group of rare inherited disorders caused by a defect in specific enzymes that process proteins
- For the most part are AR disorders.
- Kidneys clear most organic acids, so it is easiest to examine the URINE for these disorders - which is why these disorders are also called organic acidurias.
- Dx: The diagnosis is strongly suggested by elevated serum ammonia level and increased excretion of organic acids in the urine.
- If patient has a high anion gap present, the pt has one of the organic acidemias.
5
Q
Glutaric acidemia Type 1
- Path: ____inheritance? enzyme defect of riboflavin-dependent ____ in the catabolic pathway of lysine, hydroxylysine, tryptophan.
- Pt:
- _____ at birth but generally have normal development until they have a febrile illness or metabolic stressor, at which time they suddenly develop hypotonia and dystonia.
- Rarely presents in newborn period. Affected children have metabolic decompensation with ketoacidosis, hyperammonemia, hypoglycemia, and encephalopathy during the 1st year or later, often accompanied by infection and fever. Typically have microencephalic macrocephaly (earliest sign of GA1).
- This is the 1 metabolic disease that can cause ___ and ____, which can be mistaken for ____.
- CT/MRI shows frontal and cortical atrophy at birth
- Dx: ____ organic acids test shows increased excretion of ___ and ___ acids.
- Tx:
- ______, riboflavin (cofactor of GCDH), and a special diet.
- Rapid implementation of IVFs containing glucose
A
Glutaric acidemia Type 1
- Path: AR enzyme defect of riboflavin-dependent glutaryl-CoA dehydrogenase (GCDH) in the catabolic pathway of lysine, hydroxylysine, tryptophan.
- Pt:
- Macrocephaly at birth but generally have normal development until they have a febrile illness or metabolic stressor, at which time they suddenly develop hypotonia and dystonia.
- Rarely presents in newborn period. Affected children have metabolic decompensation with ketoacidosis, hyperammonemia, hypoglycemia, and encephalopathy during the 1st year or later, often accompanied by infection and fever. Typically have microencephalic macrocephaly (earliest sign of GA1).
- This is the 1 metabolic disease that can cause subdural hematomas and retinal hemorrhages, which can be mistaken for child abuse.
- CT/MRI shows frontal and cortical atrophy at birth
- Dx: Urine organic acids test shows increased excretion of glutaric and 3-hydroxyglutaric acids.
- Tx:
- L-carnitine, riboflavin (cofactor of GCDH), and a special diet.
- Rapid implementation of IVFs containing glucose
6
Q
Propionic acidemia
- ___inheritance?
- Path: Deficiency in _____
- A mnemonic to remember these amino acids is ____ - which is what kids with PA do when they get sick
- Pt:
- Early neonatal period, present as severe ketoacidosis with or without hyperammonemia.
- A milder presentation is ketoacidosis precipitated by infection or vomiting.
- Labs
- Metabolic ketoacidosis with a high anion gap
- Hyperammonemia
- Ketonuria
- Cytopenias
- Hypoglycemia
- Newborn screen: Elevated _____
- Dx: Urine organic acids with large amounts of ___ and ____.
- Testing of urine organic acids is recommended in children who are either symptomatic or identified on NBS. An elevated 3-hydroxypropionate level and the presence of methylcitrate.
- Tx:
- Restricting ____ in the diet (usually <1g/kg/day) and giving formula devoid of isoleucine, valine, methionine, and threonine.
- ____ is usually required for supplementation to increase excretion of propionyl-CoA
A
Propionic acidemia
- AR
- Path: Deficiency in propionyl-CoA carboxylase
- A mnemonic to remember these amino acids is VoMIT - which is what kids with PA do when they get sick
- Pt:
- Early neonatal period, present as severe ketoacidosis with or without hyperammonemia.
- A milder presentation is ketoacidosis precipitated by infection or vomiting.
- Labs
- Metabolic ketoacidosis with a high anion gap
- Hyperammonemia
- Ketonuria
- Cytopenias
- Hypoglycemia
- Newborn screen: Elevated C3 acylcarnitine / propionylcarnitine
- Dx: Urine organic acids with large amounts of 3-hydroxypropionic and methylcitric acids.
- Testing of urine organic acids is recommended in children who are either symptomatic or identified on NBS. An elevated 3-hydroxypropionate level and the presence of methylcitrate.
- Tx:
- Restricting protein in the diet (usually <1g/kg/day) and giving formula devoid of isoleucine, valine, methionine, and threonine.
- Carnitine is usually required for supplementation to increase excretion of propionyl-CoA
7
Q
Methylmalonic acidemias
- Path: These either affect ____activity or interfere with the formation of ____
- Pt:
- Present early usually in first 2 weeks of life with hyperammonemia, ketoacidosis, and thrombocytopenia - or later with chronic ketotic hyperglycinemia, vomiting, and FTT.
- A late-onset complication is renal failure of uncertain origin, and cardiomyopathy can also occur.
- Dx: Organic acid analysis of urine, which shows increased methylmalonic acid and abnormal ketone bodies.
- ______ is also present if the pt has the enzyme deficit in the pathway that blocks the synthesis of methyl-B12, resulting in increased methylmalonic acid and increased levels of homocysteine.
- Tx:
- Restricting dietary ____.
- ____ is useful
- If the pt has both methylmalonic aciduria and homocystinuria, treat with ____ (which provides another methyl donor for the conversion of homocysteine to methionine) and IM ____
A
Methylmalonic acidemias
- Path: These either affect methylmalonyl-CoA mutase activity or interfere with the formation of cobalamin (vitamin B12).
- Pt:
- Present early usually in first 2 weeks of life with hyperammonemia, ketoacidosis, and thrombocytopenia - or later with chronic ketotic hyperglycinemia, vomiting, and FTT.
- A late-onset complication is renal failure of uncertain origin, and cardiomyopathy can also occur.
- Dx: Organic acid analysis of urine, which shows increased methylmalonic acid and abnormal ketone bodies.
- Homocystinuria is also present if the pt has the enzyme deficit in the pathway that blocks the synthesis of methyl-B12, resulting in increased methylmalonic acid and increased levels of homocysteine.
- Tx:
- Restricting dietary protein.
- Carnitine is useful
- If the pt has both methylmalonic aciduria and homocystinuria, treat with betaine (which provides another methyl donor for the conversion of homocysteine to methionine) and IM vitamin B12.
8
Q
Isovaleric Acidemia (IVA) - \_\_\_inheritance?
- Path: Defect in the 3rd step of _____ metabolism. Enzyme defect is in _____.
- Pt:
- Suspect with newborn with the_____, esp if the infant has encephalopathy
- Can present in newborn period with acute episode of severe HAGMA and moderate ketosis with vomiting
- Dx: Urine organic acids.
- Tx:
- Acute setting is aimed at acidosis, which responds to IV glucose and bicarbonate.
- Center long-term tx of restricting ____ intake and prescribing ____ and/or glycine to increase conversion of isovaleryl-CoA to isovalerylglycine, which is excreted easily.
A
Isovaleric Acidemia (IVA) - AR disorder
- Path: Defect in the 3rd step of leucine metabolism. Enzyme defect is in isovaleryl-CoA dehydrogenase.
- Pt:
- Suspect with newborn with the odor of sweaty feet, esp if the infant has encephalopathy
- Can present in newborn period with acute episode of severe HAGMA and moderate ketosis with vomiting
- Dx: Urine organic acids.
- Tx:
- Acute setting is aimed at acidosis, which responds to IV glucose and bicarbonate.
- Center long-term tx of restricting leucine intake and prescribing carnitine and/or glycine to increase conversion of isovaleryl-CoA to isovalerylglycine, which is excreted easily.
9
Q
3-Methylcrotonyl-CoA Carboxylase Deficiency
- ____inheritance? disorder
- Path: Defect in the 4th step of ____ metabolism. The biotin-containing enzyme, 3_____, is missing
- Dx: Urine organic acid analysis, which shows increased excretion of ____ and _____
- Tx:
- Acute tx: IV ___, fluids, and electrolytes
- Long-term therapy: Oral ____ to correct carnitine deficiency
A
3-Methylcrotonyl-CoA Carboxylase Deficiency
- AR disorder
- Path: Defect in the 4th step of leucine metabolism. The biotin-containing enzyme, 3-methylcrotonyl-CoA carboxylase, is missing
- Dx: Urine organic acid analysis, which shows increased excretion of 3-methylcrotonylglycine and 3-hydroxyisovaleric acid
- Tx:
- Acute tx: IV glucose, fluids, and electrolytes
- Long-term therapy: Oral carnitine to correct carnitine deficiency
10
Q
Multiple Carboxylase Deficiency
- 2 disorders associated with ____ deficiency or inability to incorporate biotin:
- Biotinidase deficiency
- Holocarboxylase synthetase deficiency
- Pt: Classic triad of carboxylase deficiency: ____, ___, and ____.
- Dx: Analyzing urine organic acid and finding increased _____ and ____ with lactic acids.
- Tx: Free ___ 5-20mg/day
A
Multiple Carboxylase Deficiency
- 2 disorders associated with biotin deficiency or inability to incorporate biotin:
- Biotinidase deficiency
- Holocarboxylase synthetase deficiency
- Pt: Classic triad of carboxylase deficiency: Encephalopathy, alopecia, and skin rash.
- Dx: Analyzing urine organic acid and finding increased 3-methylcrotonylglycine and 3-hydroxyisovaleric acid with lactic acids.
- Tx: Free biotin 5-20mg/day
11
Q
Phenylketonuria/ Phenylalanine Hydroxylase (PAH) Deficiency
- ____inheritance?
- Most common cause: Mutation in ____, which helps convert ____ to ____, leading to elevated levels of amino acid ____, low ___ levels
- Pt:
- Most common presentation: ______ body odor (due to phenylacetic acid in the urine), eczematous rash, vomiting, irritability. ______ involving skin, hair (fair haired and fair skinned), eye, brain nuclei
- For those who remain untreated, severe _____ regression
- Dx:
- Most discovered through Newborn screening
- Additional testing is warranted to confirm suspected diagnosis of PKU, which should include Serum Quantitative amino acid analysis (increased plasma amino acid phenylalanine levels, typically >1000umol/L) (without increased tyrosine)
- Tx:
- Treatment involves implementation as soon as possible after birth.
- Indefinite dietary restriction of _____ (<500mg/day) and low-protein and supplemental intake of _____
- During infancy, breastmilk is encouraged along with low-protein diet with _____-free medical formula.
- Regular blood work for phenylalanine levels must be conducted indefinitely, regardless if normalize
- Treatment involves implementation as soon as possible after birth.
- Inadequate management at any point in life can lead to irreversible intellectual development / cognitive impairment.
- Maternal PKU During pregnancy
- Infants do not actually have PKU, but they can have growth deficiency, microcephaly, intellectual disability, and congenital heart defects (similar to fetal alcohol syndrome)
- Woman with PKU should maintain phenylalanine-restricted diet for several months prior to conception and continuing through the pregnancy, with preferred phenylalanine levels 120-360 umol/L (2-6mg/dL)
- If woman with PKU is planning to become pregnant, it is rec to maintain PHE levels <6mg/dl at least 3mo before attempting to conceive
- A woman with phenylketonuria that is poorly controlled (levels consistently >____umol/L) during pregnancy will be at highest risk for having a child with ________
A
Phenylketonuria/ Phenylalanine Hydroxylase (PAH) Deficiency
- AR
- Most common cause: Mutation in phenylalanine hydroxylase, which helps convert phenylalanine to tyrosine, leading to elevated levels of amino acid phenylalanine (Phe), low tyrosine levels
- Pt:
- Most common presentation: Musty “mousy” “wolflike” body odor (due to phenylacetic acid in the urine), eczematous rash, vomiting, irritability. Hypopigmentation involving skin, hair (fair haired and fair skinned), eye, brain nuclei
- For those who remain untreated, severe intellectual disability/developmental regression
- Dx:
- Most discovered through Newborn screening
- Additional testing is warranted to confirm suspected diagnosis of PKU, which should include Serum Quantitative amino acid analysis (increased plasma amino acid phenylalanine levels, typically >1000umol/L) (without increased tyrosine)
- Tx:
- Treatment involves implementation as soon as possible after birth.
- Indefinite dietary restriction of phenylalanine (<500mg/day) and low-protein and supplemental intake of tyrosine
- During infancy, breastmilk is encouraged along with low-protein diet with phenylalanine(Phe)-free medical formula.
- Regular blood work for phenylalanine levels must be conducted indefinitely, regardless if normalize
- Treatment involves implementation as soon as possible after birth.
- Inadequate management at any point in life can lead to irreversible intellectual development / cognitive impairment.
- Maternal PKU During pregnancy
- Infants do not actually have PKU, but they can have growth deficiency, microcephaly, intellectual disability, and congenital heart defects (similar to fetal alcohol syndrome)
- Woman with PKU should maintain phenylalanine-restricted diet for several months prior to conception and continuing through the pregnancy, with preferred phenylalanine levels 120-360 umol/L (2-6mg/dL)
- If woman with PKU is planning to become pregnant, it is rec to maintain PHE levels <6mg/dl at least 3mo before attempting to conceive
- A woman with phenylketonuria that is poorly controlled (levels consistently >360umol/L) during pregnancy will be at highest risk for having a child with intellectual disability
12
Q
Hyperphenylalaninemia
- Are without classic PKU but have elevated levels of Phe in the blood.
- Path:
- Most have a milder deficiency of the PAH enzyme and can tolerate higher amounts of Phe
- A subset of pts has a defect in the synthesis or recycling of biopterin.
- Pt: Neurologic symptoms that progress despite dietary tx that maintain normal Phe levels.
- Pt: Severe _____ disease with marked hypotonia, spasticity, and posturing.
- Tx: ____ restriction and supplementation of ______ and biogenic amine precursor (ie 5-hydroxytryptophan and dopa)
A
Hyperphenylalaninemia
- Are without classic PKU but have elevated levels of Phe in the blood.
- Path:
- Most have a milder deficiency of the PAH enzyme and can tolerate higher amounts of Phe
- A subset of pts has a defect in the synthesis or recycling of biopterin.
- Pt: Neurologic symptoms that progress despite dietary tx that maintain normal Phe levels.
- Pt: Severe neurologic disease with marked hypotonia, spasticity, and posturing.
- Tx: Phe restriction and supplementation of biopterin and biogenic amine precursor (ie 5-hydroxytryptophan and dopa)
13
Q
Tyrosinemia
- Group of disorders in which blood tyrosine levels are elevated.
- Transient tyrosinemia - Most common form, particularly in premature infants.
- Hereditary tyrosinemia type 1 (Hepatorenal tyrosinemia)
- \_\_\_\_inheritance?
- Path: Due to deficiency of \_\_\_\_\_\_. Severe symptoms result from accumulation of succinylacetone
- Common in French-Canadian population
- Pt:
- FTT, hepatomegaly with\_\_\_\_\_\_\_\_ that progress to hepatoblastomas, and liver failure are the most common presentations. These infants are NOT \_\_\_\_\_. They have \_\_\_\_ resembling Fanconi syndrome as well as XR findings of rickets.
- Dx: Elevated plasma \_\_\_\_ levels, but the definitive diagnostic finding is \_\_\_\_ in the urine.
- Tx:
- Pts must be on a diet low in \_\_\_\_ and \_\_\_\_.
- \_\_\_\_\_ (NTBC), which blocks tyrosine metabolism before the fumarylacetoacetate hydrolase enzyme, which prevents the accumulation of toxic metabolites (ie succinylacetone).
- Tyrosinemia Type 2 (Richner-Hanhart syndrome; oculocutaneous tyrosinemia)
- AR
- Pt:
- Corneal ulcers or dendritic keratitis, along with red papular or keratotic lesions on their palms and soles.
- \_\_\_\_ and \_\_\_\_ lesions are from deposition of tyrosine itself.
- Do not have liver toxicity seen in Type I disease since they do not build up succinylacetone.
- Tx: Diet low in tyrosine, but even this is not always curative.
- Tyrosinemia Type 3
- AR
- Pt: Can have intellectual disability
- Tx: Respond well to a diet low in tyrosine.
A
Tyrosinemia
- Group of disorders in which blood tyrosine levels are elevated.
- Transient tyrosinemia - Most common form, particularly in premature infants.
- Hereditary tyrosinemia type 1 (Hepatorenal tyrosinemia)
- AR
- Path: Due to deficiency of fumarylacetoacetate hydroxylase. Severe symptoms result from accumulation of succinylacetone
- Common in French-Canadian population
- Pt:
- FTT, hepatomegaly with hepatic adenomas that progress to hepatoblastomas, and liver failure are the most common presentations. These infants are NOT intellectual disabled. They have renal tubular acidosis resembling Fanconi syndrome as well as XR findings of rickets.
- Dx: Elevated plasma tyrosine levels, but the definitive diagnostic finding is succinylacetone in the urine.
- Tx:
- Pts must be on a diet low in tyrosine and Phe.
- Nitisinone (NTBC), which blocks tyrosine metabolism before the fumarylacetoacetate hydrolase enzyme, which prevents the accumulation of toxic metabolites (ie succinylacetone).
- Tyrosinemia Type 2 (Richner-Hanhart syndrome; oculocutaneous tyrosinemia)
- AR
- Pt:
- Corneal ulcers or dendritic keratitis, along with red papular or keratotic lesions on their palms and soles.
- Eye and skin lesions are from deposition of tyrosine itself.
- Do not have liver toxicity seen in Type I disease since they do not build up succinylacetone.
- Tx: Diet low in tyrosine, but even this is not always curative.
- Tyrosinemia Type 3
- AR
- Pt: Can have intellectual disability
- Tx: Respond well to a diet low in tyrosine.
14
Q
Alkaptonuria
- Path: Deficiency in _____, which is the 3rd step in _____ metabolism. Causes an accumulation of homogentisic acid; however, blood levels of tyrosine are ______!
- Pt:
- By the time in the 30s, adults start to have pigment deposition in the ears and sclerae (ochronosis). Later, ______ can occur, which is the major medical complication of the disorder.
- Excretion of_____ urine is the classic finding.
A
Alkaptonuria
- Path: Deficiency in homogentisate 1,2-dioxygenase, which is the 3rd step in tyrosine metabolism. Causes an accumulation of homogentisic acid; however, blood levels of tyrosine are not elevated!
- Pt:
- By the time in the 30s, adults start to have pigment deposition in the ears and sclerae (ochronosis). Later, ochronosis arthritis can occur, which is the major medical complication of the disorder.
- Excretion of dark-colored urine is the classic finding.
15
Q
Maple syrup urine disease - branched chain bc high valine, leucine, isoleucine
- AR
- Path: Deficiency in branched-chain _____ complex. Defect in the oxidative decarboxylation of keto-acids (ketoacids smell sweet), which are formed by catabolism of the branched-chain amino acids (BCAAs).
- Pt:
- Classic MSUD: _____ disease early in infancy, and the urine (or hair or skin) smells like _____. Infants are well at birth but start having symptoms 3-5 days with rapid progression to death in 2-4 weeks without treatment. Babies have feeding difficulties, irregular respirations, or loss of the Moro reflex.
- Labs:
- Elevated branched-chain amino acid BCAAs (___, ___, ___) in the plasma and urine
- Finding _____, an abnormal amino acid, is diagnostic for MSUD
- Tx: Dietary restriction of ___, __, and ___.
A
Maple syrup urine disease - branched chain bc high valine, leucine, isoleucine
- AR
- Path: Deficiency in branched-chain alpha-keto acid dehydrogenase complex. Defect in the oxidative decarboxylation of keto-acids (ketoacids smell sweet), which are formed by catabolism of the branched-chain amino acids (BCAAs).
- Pt:
- Classic MSUD: CNS disease early in infancy, and the urine (or hair or skin) smells like maple syrup. Infants are well at birth but start having symptoms 3-5 days with rapid progression to death in 2-4 weeks without treatment. Babies have feeding difficulties, irregular respirations, or loss of the Moro reflex.
- Labs:
- Elevated branched-chain amino acid BCAAs (isoleucine, leucine, valine) in the plasma and urine
- Finding alloisoleucine, an abnormal amino acid, is diagnostic for MSUD
- Tx: Dietary restriction of leucine, isoleucine, and valine.
16
Q
Homocystinuria (Cystathionine B-synthase (CBS) deficiency) - thromboses, marfanoid features, intellectual disability
- ____inheritance? disorder
- All diseases cause elevated levels of _____.
- Pts with ______ deficiency have _____ habitus (tall, long thin limbs, joint hyperlaxity, chest deformities), developmental delay, lens dislocation, and an increased risk of thromboembolism in both arteries and veins.
- Suspect homocystinuria in a child with subluxation/dislocation of the ocular lens. Lenticular subluxation is usually _____ and medial.
- Looks like Marfans but HC has stroke or MI and DOWNWARD subluxation of lens
- Only homocystinuria: ___, ___, ___
- Intellectual disability is _____ common. (DOWN = low IQ)
- Joints are limited in mobility (not hypermobile as in Marfan syndrome)
- Vascular events are the primary cause of morbidity and mortality in CBS deficiency
- Dx:
- Initial testing for dx: Amino acid screening of plasma and urine to check for excess homocysteine or methionine levels.
- Increased total plasma ___ level, in conjunction with an elevated ____ level on serum amino acid analysis
- Confirmatory testing with detection of biallelic pathogenic mutations demonstrates a decreased level of activity of _____ in fibroblasts.
- Initial testing for dx: Amino acid screening of plasma and urine to check for excess homocysteine or methionine levels.
- Tx:
- Large doses of ______ cause a decrease in the total plasma homocysteine levels (in the vitamin-responsive form).
- Affected individuals also require a diet low in ______ (which gets broken down into homocysteine).
A
Homocystinuria (Cystathionine B-synthase (CBS) deficiency) - thromboses, marfanoid features, intellectual disability
- AR disorder
- All diseases cause elevated levels of homocysteine.
- Pts with cystathionine B-synthase deficiency have marfanoid habitus (tall, long thin limbs, joint hyperlaxity, chest deformities), developmental delay, lens dislocation, and an increased risk of thromboembolism in both arteries and veins.
- Suspect homocystinuria in a child with subluxation/dislocation of the ocular lens. Lenticular subluxation is usually DOWNWARD and medial.
- Looks like Marfans but HC has stroke or MI and DOWNWARD subluxation of lens
- Only homocystinuria: fair hair and eyes, developmental delay, cerebrovascular accidentals
- Intellectual disability is fairly common. (DOWN = low IQ)
- Joints are limited in mobility (not hypermobile as in Marfan syndrome)
- Vascular events are the primary cause of morbidity and mortality in CBS deficiency
- Dx:
- Initial testing for dx: Amino acid screening of plasma and urine to check for excess homocysteine or methionine levels.
- Increased total plasma homocysteine level, in conjunction with an elevated methionine level on serum amino acid analysis
- Confirmatory testing with detection of biallelic pathogenic mutations demonstrates a decreased level of activity of cystathionine B-synthase in fibroblasts.
- Initial testing for dx: Amino acid screening of plasma and urine to check for excess homocysteine or methionine levels.
- Tx:
- Large doses of pyridoxine (vitamin B6) cause a decrease in the total plasma homocysteine levels (in the vitamin-responsive form).
- Affected individuals also require a diet low in methionine (which gets broken down into homocysteine).
17
Q
Glycine and Oxalate Abnormalities - Nonketotic Hyperglycemia
- ____inheritance? inborn error of metabolism in which large amounts of glycine build up
- Pt: Classic form - Intractable _____ in the neonatal period requiring intubation or as hiccups in utero
- Dx: Increased ratio of CSF ___ to serum __.
- Tx: _____ seems to reduce CSF glycine levels and decrease seizures.
A
Glycine and Oxalate Abnormalities - Nonketotic Hyperglycemia
- AR inborn error of metabolism in which large amounts of glycine build up
- Pt: Classic form - Intractable seizures in the neonatal period requiring intubation or as hiccups in utero
- Dx: Increased ratio of CSF glycine to serum glycine.
- Tx: Sodium benzoate seems to reduce CSF glycine levels and decrease seizures.
18
Q
UREA CYCLE DISORDERS = high ammonia + normal anion gap + resp alkalosis
- a) N-acetylglutamate synthetase (NAGS) deficiency
- b) Carbamoyl phosphate synthetase 1 (CPS1) deficiency - Severe disorder
- c) Ornithine transcarbamylase (OTC) deficiency: High levels of urinary orotic acid - most common; X-linked; Severe disorder
- d) Argininosuccinate synthetase (AS) deficiency (Citrullinemia)
- e) Argininosuccinate lyase (AL) deficiency - accumulation of argininosuccinic acid with argininosuccinic aciduria
- f) Arginase deficiency (Argininemia)
- All of the urea cycle disorders have ____ inheritance, except for ____ deficiency, which is _____ inheritance (and is also the most common!)
- Path:
- Deficiencies of 1 of 4 enzymes within urea cycle which is responsible for the breakdown of nitrogen.
- Bad effects of not breaking down NH4 are increases in ammonia (NH3) and glycine, both of which easily pass the blood-brain barrier and have a very toxic effect on the brain.
- Pt:
- Within 48-72 hours, neonates will develop ____ alkalosis, ____ammonemia, and cerebral edema, which presents initially with fatigue and poor feeding but can progress to seizures, hypothermia, posturing, and coma
- With either CPS1 or OTC deficiency, plasma ammonia levels can be >1000umol/L (normal <35umol/L). In addition to elevated ammonia levels, a key diagnostic clue is that these infants usually have a ______, not a metabolic acidosis, as would be expected with sepsis or other metabolic disorders.
- Dx:
- Once clinically suspect, order ammonia level, quantitative plasma amino acid analysis, and urinary organic acids to establish the specific defect in urea synthesis.
- Glutamine, alanine, and asparagine are elevated - bc they are storage forms for nitrogen, which cannot be excreted.
- Citrulline is absent or very low in proximal disorders such as OTC and CPS1 defects - bc citrulline is the direct product of these reactions.
- Orotic acid is a byproduct of the OTC-catalyzed reaction and is a very sensitive indicator of OTC deficiency. It helps differentiate between OTC and CPS1 deficiency (low-undetectable levels)
- Plasma arginine concentration is low in all urea cycle defects except for argininemia (ie arginase deficiency). Without replacement, affected individuals have hair fragility and rash.
- Once clinically suspect, order ammonia level, quantitative plasma amino acid analysis, and urinary organic acids to establish the specific defect in urea synthesis.
- Tx: Acute treatment centers on volume replacement with D10W, restricting dietary protein, minimizing catabolism and enhancing anabolism, replacing deficient amino acids, and pushing alternative pathways to eliminate nitrogen waste.
- Medical emergency needs immediate recognition and tx to avoid irreversible brain damage
- Immediate administration of IV ________ is indicated, as this will promote nitrogen excretion via alternative pathways.
- Pushing alternative pathways is done with IV solution of sodium benzoate-sodium phenylacetate.
- Any neonate with severe hyperammonemia requires emergent _____.
- Long-term management:
- High-caloric, _____ restriction
- Medical emergency needs immediate recognition and tx to avoid irreversible brain damage
A
UREA CYCLE DISORDERS = high ammonia + normal anion gap + resp alkalosis
- a) N-acetylglutamate synthetase (NAGS) deficiency
- b) Carbamoyl phosphate synthetase 1 (CPS1) deficiency - Severe disorder
- c) Ornithine transcarbamylase (OTC) deficiency: High levels of urinary orotic acid - most common; X-linked; Severe disorder
- d) Argininosuccinate synthetase (AS) deficiency (Citrullinemia)
- e) Argininosuccinate lyase (AL) deficiency - accumulation of argininosuccinic acid with argininosuccinic aciduria
- f) Arginase deficiency (Argininemia)
- All of the urea cycle disorders have AR inheritance, except for OTC deficiency, which is X-linked inheritance (and is also the most common!)
- Path:
- Deficiencies of 1 of 4 enzymes within urea cycle which is responsible for the breakdown of nitrogen.
- Bad effects of not breaking down NH4 are increases in ammonia (NH3) and glycine, both of which easily pass the blood-brain barrier and have a very toxic effect on the brain.
- Pt:
- Within 48-72 hours, neonates will develop respiratory alkalosis, hyperammonemia, and cerebral edema, which presents initially with fatigue and poor feeding but can progress to seizures, hypothermia, posturing, and coma
- With either CPS1 or OTC deficiency, plasma ammonia levels can be >1000umol/L (normal <35umol/L). In addition to elevated ammonia levels, a key diagnostic clue is that these infants usually have a respiratory alkalosis, not a metabolic acidosis, as would be expected with sepsis or other metabolic disorders.
- Dx:
- Once clinically suspect, order ammonia level, quantitative plasma amino acid analysis, and urinary organic acids to establish the specific defect in urea synthesis.
- Glutamine, alanine, and asparagine are elevated - bc they are storage forms for nitrogen, which cannot be excreted.
- Citrulline is absent or very low in proximal disorders such as OTC and CPS1 defects - bc citrulline is the direct product of these reactions.
- Orotic acid is a byproduct of the OTC-catalyzed reaction and is a very sensitive indicator of OTC deficiency. It helps differentiate between OTC and CPS1 deficiency (low-undetectable levels)
- Plasma arginine concentration is low in all urea cycle defects except for argininemia (ie arginase deficiency). Without replacement, affected individuals have hair fragility and rash.
- Once clinically suspect, order ammonia level, quantitative plasma amino acid analysis, and urinary organic acids to establish the specific defect in urea synthesis.
- Tx: Acute treatment centers on volume replacement with D10W, restricting dietary protein, minimizing catabolism and enhancing anabolism, replacing deficient amino acids, and pushing alternative pathways to eliminate nitrogen waste.
- Medical emergency needs immediate recognition and tx to avoid irreversible brain damage
- Immediate administration of IV arginine hydrochloride is indicated, as this will promote nitrogen excretion via alternative pathways.
- Pushing alternative pathways is done with IV solution of sodium benzoate-sodium phenylacetate.
- Any neonate with severe hyperammonemia requires emergent hemodialysis.
- Long-term management:
- High-caloric, Protein restriction
- Medical emergency needs immediate recognition and tx to avoid irreversible brain damage
19
Q
Galactosemia / Galactose-1-Phosphate Uridyltransferase (GALT) Deficiency
- ____inheritance??
- Path: Deficiency of enzyme ____, causing ____ to be metabolized poorly or not at all. Galactose and its molecules then build up in cells and tissues, esp the liver, kidneys, and brain.
- Pt:
- Combination of:
- Jaundice
- Hepatosplenomegaly
- C______. May resolve if lactose-free formula is initiated shortly after birth
- Irritability
- Hypoglycemia
- Cirrhosis
- Intellectual disability
- Vomiting
- Seizures
- Lethargy
- Poor weight gain
- Vitreous hemorrhage
- Ascites
- ____ failure, feeding problems, FTT/poor weight gain, bilateral ____, ____glycemia, bleeding, jaundice, and _____ sepsis.
- Combination of:
- Abnormal lab tests: Liver dysfunction (hyperbilirubinemia, abnormal liver function test results, coagulopathy), metabolic acidosis, galactosuria (indicated by presence of reducing substances in the urine), and hemolytic anemia
- Suspect disorder in pts with galactosemia symptoms or when you discover a reducing substance in urine while the pt is drinking breast milk, cow’s milk, or formula containing lactose.
- Dx:
- Nearly 100% infants are detected by newborn screening.
- Definitive diagnosis requires deficient activity of ___ in RBCs or other tissues while also showing an increased concentration of ____.
- Detection of elevated erythrocyte_____ concentration, reduced erythrocyte galactose-1-phosphate uridylyltransferase (GALT) enzyme activity, and biallelic gene mutations in the GALT gene
- Tx
- _____ formula and discontinue breastfeeding. Imperative within the first ____ days after birth to abate the symptoms and reduce the risk of long-term complications
- All ______ foods should be removed from the diet, which includes breastfeeding and formula.
- Symptoms will quickly resolve with lactose-restricted diet in the first 2 weeks after birth.
- Elimination of lactose and galactose from the diet reverses growth failure and renal/hepatic problems. Even cataracts regress
- _____ formula and discontinue breastfeeding. Imperative within the first ____ days after birth to abate the symptoms and reduce the risk of long-term complications
A
Galactosemia / Galactose-1-Phosphate Uridyltransferase (GALT) Deficiency
- AR
- Path: Deficiency of enzyme GALT, causing galactose to be metabolized poorly or not at all. Galactose and its molecules then build up in cells and tissues, esp the liver, kidneys, and brain.
- Pt:
- Combination of:
- Jaundice
- Hepatosplenomegaly
- Cataracts- Cataracts, a lens opacity. May resolve if lactose-free formula is initiated shortly after birth
- Irritability
- Hypoglycemia
- Cirrhosis
- Intellectual disability
- Vomiting
- Seizures
- Lethargy
- Poor weight gain
- Vitreous hemorrhage
- Ascites
- Liver failure, feeding problems, FTT/poor weight gain, bilateral cataracts, hypoglycemia, bleeding, jaundice, and E coli sepsis.
- Combination of:
- Abnormal lab tests: Liver dysfunction (hyperbilirubinemia, abnormal liver function test results, coagulopathy), metabolic acidosis, galactosuria (indicated by presence of reducing substances in the urine), and hemolytic anemia
- Suspect disorder in pts with galactosemia symptoms or when you discover a reducing substance in urine while the pt is drinking breast milk, cow’s milk, or formula containing lactose.
- Dx:
- Nearly 100% infants are detected by newborn screening.
- Definitive diagnosis requires deficient activity of GALT in RBCs or other tissues while also showing an increased concentration of galactose-1-phosphate.
- Detection of elevated erythrocyte galactose-1-phosphate concentration, reduced erythrocyte galactose-1-phosphate uridylyltransferase (GALT) enzyme activity, and biallelic gene mutations in the GALT gene
- Tx
- Lactose-free formula, soy-based formula and discontinue breastfeeding. Imperative within the first 10 days after birth to abate the symptoms and reduce the risk of long-term complications
- All galactose-containing foods should be removed from the diet, which includes breastfeeding and formula.
- Symptoms will quickly resolve with lactose-restricted diet in the first 2 weeks after birth.
- Elimination of lactose and galactose from the diet reverses growth failure and renal/hepatic problems. Even cataracts regress
- Lactose-free formula, soy-based formula and discontinue breastfeeding. Imperative within the first 10 days after birth to abate the symptoms and reduce the risk of long-term complications
20
Q
Galactokinase Deficiency
- Asymptomatic except for ___
A
Galactokinase Deficiency
- Asymptomatic except for cataracts
21
Q
Uridine Diphosphate Galactose 4-Epimerase (UDP-Galactose 4-Epimerase) Deficiency
- Generalized form: Clinically resembles galactosemia, with the additional symptoms of ____ and ____. The GALT activity is ____, unlike in classic galactosemia.
- Tx with dietary restriction of ___ is effective.
A
Uridine Diphosphate Galactose 4-Epimerase (UDP-Galactose 4-Epimerase) Deficiency
- Generalized form: Clinically resembles galactosemia, with the additional symptoms of hypotonia and nerve deafness. The GALT activity is normal, unlike in classic galactosemia.
- Tx with dietary restriction of galactose is effective.
22
Q
Fructokinase Deficiency / Benign Fructosuria
- Benign. NO clinical manifestations.
- Incidental finding when discover fructose during a urine screen for reducing substances.
A
Fructokinase Deficiency / Benign Fructosuria
- Benign. NO clinical manifestations.
- Incidental finding when discover fructose during a urine screen for reducing substances.
23
Q
Hereditary Fructose Intolerance (_____ Deficiency)
- Enzyme deficiency leads to accumulation of _____
- Pt:
- Jaundice, hepatomegaly, vomiting, lethargy, seizures, irritability.
- Hypoglycemia, liver disease/liver failure, and poor growth
- Suspect if you find fructose as a ______ during a symptomatic episode.
- If fructose intake continues, severe hypoglycemia occurs, followed by liver and kidney failure and death. Sugar ingestion causes ______!
- Dx: Definitive depends on assaying fructose 1,6-bisphosphate aldolase B activity in the liver.
- Tx: Complete dietary elimination of all sources of fructose and its progenitors, sucrose and sorbitol.
A
Hereditary Fructose Intolerance (Aldolase B Deficiency)
- Enzyme deficiency leads to accumulation of fructose 1-phosphate
- Pt:
- Jaundice, hepatomegaly, vomiting, lethargy, seizures, irritability.
- Hypoglycemia, liver disease/liver failure, and poor growth
- Suspect if you find fructose as a urinary reducing substance during a symptomatic episode.
- If fructose intake continues, severe hypoglycemia occurs, followed by liver and kidney failure and death. Sugar ingestion causes hypoglycemia!
- Dx: Definitive depends on assaying fructose 1,6-bisphosphate aldolase B activity in the liver.
- Tx: Complete dietary elimination of all sources of fructose and its progenitors, sucrose and sorbitol.
24
Q
Fatty acid (beta-) oxidation defects - Hypo\_\_\_\_ hypo\_\_\_
Glycogen storage diseases
- Hepatomegaly
- Hypoglycemia
- Lactic acidosis
- FTT
A
Fatty acid (beta-) oxidation defects - Hypo\_\_\_\_ hypo\_\_\_
Glycogen storage diseases
- Hepatomegaly
- Hypoglycemia
- Lactic acidosis
- FTT
25
Q
FATTY ACID OXIDATION DISORDERS - WITHOUT KETOSIS
- Nearly all _____inheritance? disorders
- Common presentation
- Hypoketotic hypoglycemia with prolonged fasting
- Hepatomegaly
- Hypotonia
- AMS
- Seizures and sudden death if severe
- Labs may show metabolic acidosis.
- Labs: Analysis of plasma acylcarnitine
- Dx: Definitive requires measurement of specific enzyme activity or mutation analysis.
- Tx:
- IV D10 1/2NS or D10NS and possibly ____.
A
FATTY ACID OXIDATION DISORDERS - WITHOUT KETOSIS
- Nearly all AR disorders
- Common presentation
- Hypoketotic hypoglycemia with prolonged fasting
- Hepatomegaly
- Hypotonia
- AMS
- Seizures and sudden death if severe
- Labs may show metabolic acidosis.
- Labs: Analysis of plasma acylcarnitine
- Dx: Definitive requires measurement of specific enzyme activity or mutation analysis.
- Tx:
- IV D10 1/2NS or D10NS and possibly L-carnitine.
26
Q
Primary Carnitine Deficiency (Carnitine Uptake Defect)
- ____inheritance? defect in the plasma membrane of the cell.
- Path: Defect in carnitine transport protein in the kidneys. Result in low levels of free carnitine in the serum.
- Pt:
- In early infancy or later childhood with cardiomyopathy or recurrent episodes of encephalopathy and hypoketotic hypoglycemia.
- Labs:
- This can result in ____ ____ in affected patients. (this may differentiate this disorder from others with similar presentation, such as reye’s syndrome, in which ketoacids are present)
- Elevated ammonia levels in blood
- Dx: Very low levels of ___ in tissues. In serum, it may be undetectable or <1umol/L.
- Tx: Oral ___, which results in dramatic improvement.
A
Primary Carnitine Deficiency (Carnitine Uptake Defect)
- AR defect in the plasma membrane of the cell.
- Path: Defect in carnitine transport protein in the kidneys. Result in low levels of free carnitine in the serum.
- Pt:
- In early infancy or later childhood with cardiomyopathy or recurrent episodes of encephalopathy and hypoketotic hypoglycemia.
- Labs:
- This can result in hypoketotic hypoglycemia in affected patients. (this may differentiate this disorder from others with similar presentation, such as reye’s syndrome, in which ketoacids are present)
- Elevated ammonia levels in blood
- Dx: Very low levels of carnitine in tissues. In serum, it may be undetectable or <1umol/L.
- Tx: Oral L-carnitine, which results in dramatic improvement.
