Metabolism

Question 1

Name the 3 branched-chain amino acids

Answer 1

Valine, leucine, and isoleucine
Explanation
Difficulty metabolizing these 3 amino acids is known as maple syrup urine disease (MSUD). Accumulation of organic acid intermediates results in toxic effects. Look (smell, actually) for a syrup odor in the urine and ear wax. There is autosomal recessive inheritance, and it is more common in the Mennonite population

Question 2

Children with galactosemia are at greater risk of what infection?

Answer 2

E. coli sepsis
Explanation
Infants with galactose 1-phosphate uridyl transferase deficiency (galactosemia) are at increased risk of having E. coli sepsis, which commonly precedes the diagnosis of galactosemia!

Question 3

Menkes disease (a.k.a. kinky hair disease) is caused by impaired uptake of what mineral?

Answer 3

Answer
Copper
Explanation
Menkes disease is a rare X-linked recessive disease (boys only) due to a mutation in the Menkes (ATP7A) gene, which causes impaired uptake of copper. It occurs in about 1/50,000 to 1/250,000 births. Partial deficiency of the enzyme dopamine-β-hydroxylase is a hallmark of Menkes disease.

Question 4

Ptosis
Ophthalmoplegia
Ragged-red fiber myopathy
What does this triad indicate the presence of?

Answer 4

Kearns-Sayre syndrome and chronic progressive external ophthalmoplegia (CPEO) syndromes
Explanation
Kearns-Sayre is the most severe of these syndromes and can begin in infancy, childhood, or adolescence. In addition to the triad, multisystem disease is common, particularly:

Cardiomyopathies
Diabetes mellitus
Cerebellar ataxia
Deafness
The CPEO syndromes are less severe and present later in life.

Question 5

A patient presents with:

Marfanoid habitus
Developmental delay
Ocular lens dislocation, which is downward and medial
What is the most likely diagnosis?

Answer 5

Homocystinuria
Explanation
Homocystinuria is an autosomal recessive disorder that causes elevated levels of homocysteine. Do not get homocystinuria confused with Marfan syndrome. In Marfan, the patients have a normal IQ and the lens dislocation is upward (upward lens, normal IQ), as opposed to homocystinuria, where the IQ is low and the lens dislocation is downward (downward lens, low IQ).

Question 6

18-year-old presents with:

Exercise-induced muscle cramps
Increasing exercise intolerance
Burgundy-colored urine after exercise
CPK that is elevated at rest and increases after exercise
Elevated ammonia, instead of elevated lactate (as would normally be expected), after exercise
What is the most likely diagnosis?

Answer 6

Type 5 glycogen storage disease (GSD), a.k.a. McArdle disease
Explanation
The key with Type 5 GSD is the elevated CPK at rest and the elevated ammonia after exercise. Exercise will also increase uric acid in the blood. This is an autosomal recessive disorder. The muscle phosphorylase deficiency causes reduced ATP generation by glycogenolysis, resulting in glycogen accumulation

Question 7

An infant is normal at birth but, within several weeks, presents with:

Hypotonia and generalized muscle weakness
Macroglossia
Hepatomegaly
HF due to hypertrophic cardiomyopathy
Elevated CK, AST, and LDH
Muscle biopsy shows vacuoles that are full of glycogen on staining.
What is the most likely diagnosis?

Answer 7

Type 2 glycogen storage disease (GSD; a.k.a. Pompe disease)
Explanation
Type 2 GSD is caused by deficiency in the lysosomal acid α-1,4-glucosidase (a.k.a. acid maltase), which is responsible for breaking down glycogen in lysosomal vacuoles. It is an autosomal recessive disorder. This is the infantile-onset presentation, which is the most severe. There is also a juvenile/late childhood form and an adult form.

Question 8

A child presents with presumed mucopolysaccharidosis. His disease is X-linked recessive and there is no corneal clouding.

What type of mucopolysaccharidosis does he have?

Answer 8

Mucopolysaccharidosis (MPS) Type 2 (Hunter syndrome)
Explanation
MPS Type 2 is X-linked (only males display the trait [except for the rare affected female patient with Turner syndrome]) and does not have corneal clouding. Remember, you have to see well to be able to “hunt.” Hunter = no corneal clouding. Atlantoaxial instability is not as common in MPS Type 2 as in MPS Type 1.

Question 9

Homozygous children with this disorder develop planar xanthomas from birth to 5 years of age. Tendon and tuberous xanthomas occur between 5 and 15 years of age.

What is the disorder?

Answer 9

Familial hypercholesterolemia (FH)
Explanation
FH is autosomal dominant in its transmission. Achilles tendonitis or tenosynovitis may be the 1st clue in a teenager. Angina and symptomatic coronary disease also occur in the 2nd decade of life. Serum cholesterol is usually 600–1,000 mg/dL

Question 10

A 1-year-old presents with fasting-induced lethargy and documented hypoglycemia with a seizure. AST and ALT are elevated, as well as CK. He also has a history of arrhythmias.

What is the most likely diagnosis?

Answer 10

wer
Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency
Explanation
MCAD deficiency, the most common β-oxidation defect, typically presents in the first 2 years of life. Diagnose MCAD deficiency by finding elevated C6, C8, C8:1, and C10:1 esters.

Question 11

A n infant presents with:

Vomiting
Jaundice
Hepatosplenomegaly
Hypoglycemia
Seizures
Poor weight gain
Cataracts
Vitreous hemorrhage
Ascites
What is the most likely diagnosis?

Answer 11

Answer
Galactose 1-phosphate uridyl transferase (GALT) deficiency (galactosemia)
Explanation
Galactosemia classically presents in infancy with some combination of these findings. The infant cannot metabolize galactose 1-phosphate, and this accumulates in the kidney, liver, and brain. Removing galactose from the diet reverses growth failure and renal/hepatic problems. Even the cataracts will regress!

Question 12

An adolescent boy at the onset of puberty presents with:

Severe, episodic pain in the hands and feet
Fever
Heat exposure sets off pain crises.
He doesn’t sweat.
What is the most likely diagnosis?

Answer 12

Answer
Fabry disease
Explanation
Fabry disease is the only sphingolipidosis transmitted as an X-linked recessive disease; thus, it mainly affects boys. Confirm the diagnosis by finding deficiency of lysosomal α-galactosidase in plasma, leukocytes, or cultured skin fibroblasts.

Question 13

Name the metabolic disease that can cause subdural hematomas and retinal hemorrhages, which can be mistaken for child abuse.

Answer 13

Glutaric acidemia (a.k.a. glutaric aciduria) Type 1
Explanation
Glutaric acidemia Type 1 is an autosomal recessive enzyme defect (lack of glutaryl-CoA dehydrogenase) in the catabolic pathway of lysine, hydroxylysine, and tryptophan.

Question 14

What are some complications of propionic acidemia (PA)?

Answer 14

Cardiomyopathy, FTT, recurrent infections, pancreatitis
Explanation
PA presents in the early neonatal period as severe ketoacidosis with or without hyperammonemia. The infant will have encephalopathy, vomiting, and bone marrow depression. Long-term complications include cardiomyopathy, malnutrition with FTT, recurrent infections, and pancreatitis

Question 15

An infant is normal at birth, but by 3–5 days of life, she begins to have feeding difficulties, irregular respirations, and loss of the Moro reflex. She has a severe seizure, prompting the family to bring her in. You note a sweet smell from the child.

What is the most likely diagnosis?

Answer 15

Answer
Maple syrup urine disease
Explanation
Classic maple syrup urine disease presents with 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 by 3–5 days of life, with rapid progression to death in 2–4 weeks without treatment. They cannot catabolize the branched-chain amino acids. Thus, they have increased plasma and urine levels of valine, leucine, and isoleucine. Finding alloisoleucine, an abnormal amino acid, is diagnostic

Question 16

What skeletal defects are you most worried about in a child with mucopolysaccharidosis (MPS) Type 1 (Hurler syndrome)?

Answer 16

Atlantoaxial subluxation
Explanation
With MPS Type 1, skeletal growth is usually normal during the 1st year of life, but severe growth restriction soon develops. These children are at high risk for atlantoaxial subluxation

Question 17

An infant presents with encephalopathy and you notice the odor of “sweaty feet.”

What is the most likely diagnosis?

Answer 17

Isovaleric acidemia (IVA)
Explanation
IVA is an autosomal recessive disorder localized to chromosome 15 and is due to a defect in isovaleryl-CoA dehydrogenase. This is the “sweaty feet odor” intoxication. IVA can present in the newborn period with an acute episode of severe metabolic acidosis and moderate ketosis with vomiting, which can lead to coma and death. More typically, it presents in infancy or childhood and is precipitated by an infection or increased protein intake.

Question 18

What defect has cataracts as the only finding (with the infant otherwise completely asymptomatic)?

Answer 18

Galactokinase deficiency
Explanation
Galactokinase deficiency presents only as cataracts, and the infant is otherwise asymptomatic. The defect is on chromosome 17. Treat with dietary restriction of galactose.

Question 19

An infant presents at 6 weeks of age with:

Enhanced startle reflex to noise or light, with resulting quick extension of the arms and legs with clonic movement (does not diminish with repeated stimuli)
Motor skills are progressively lost.
Axial hypotonia
Extremity hypertonia
Hyperreflexia
Macrocephaly
Auditory stimuli cause the child to seize.
Visceral organs are normal.
A macular cherry-red spot
What is the most likely diagnosis?

Answer 19

Tay-Sachs disease
Explanation
Tay-Sachs disease can present in an infantile form (as here) or in the juvenile/adult form, with the latter being more common in individuals of Ashkenazi Jewish ancestry. The adult/juvenile form of the disease progresses slowly. Early in childhood, children with this form are labeled “clumsy and awkward.”

Question 20

What is the most common lysosomal storage disease?

Answer 20

Gaucher disease Type 1
Explanation
Gaucher disease Type 1 is due to a deficiency of lysosomal glucocerebrosidase. This is a non-CNS disease with splenomegaly as the most common presentation. Individuals of Ashkenazi Jewish ancestry have a carrier rate of 1/15.

Question 21

Lack of the phenylalanine hydroxylase enzyme in phenylketonuria prevents the conversion process of what amino acid?

Answer 21

Answer
Phenylalanine to tyrosine
Explanation
Without phenylalanine hydroxylase, phenylalanine cannot be converted into tyrosine. This results in a large, toxic buildup of phenylalanine in both the blood and CNS.

Question 22

A 3½-month-old presents with:

“Doll-like face with fat cheeks”
Thin extremities, short stature, and large protuberant abdomen
Hepatomegaly
Hypoglycemia with seizures
Lactic acidosis
Hyperuricemia
Hyperlipidemia—increased VLDL, LDL, and apolipoproteins B, C, and E
Normal AST and ALT
Plasma that appears milky
What is the most likely diagnosis?

Answer 22

Type 1 glycogen storage disease (GSD; a.k.a. von Gierke disease)
Explanation
Type 1 GSD is due to a defect in glucose-6-phosphatase in the liver, kidney, and intestinal mucosa. There are 2 subtypes: Type 1a is due to a defect in the enzyme, and Type 1b is due to a defect in the translocase that transports the enzyme across the cell membrane. Affected individuals suffer from severe and rapid fasting hypoglycemia; therefore, the babies present when they start to skip a feeding during the night.

Question 23

You are following a male patient with the following progression:

He is normal at birth.
By 3–6 months of age, he has FTT, emesis, and irritability.
By 2–3 years of age, he displays a tendency to self-mutilate, with biting of his lips and fingers.
What is the most likely diagnosis?

Answer 23

Lesch-Nyhan syndrome (hypoxanthine guanine phosphoribosyltransferase [HGPRT] deficiency)
Explanation
Lesch-Nyhan syndrome (HGPRT deficiency) is an X-linked recessive (boys only) disorder. The HGPRT enzyme preserves hypoxanthine and guanine, and then converts them to nucleotides. Absence of the enzyme results in the neurologic defects, and there is a huge increase in uric acid production, resulting in gout and renal stones

Question 24

A child is normal at birth. By 2 years of age, he presents with:

Coarsened facial features, midface hypoplasia, and large tongue
Frequent URIs
History of inguinal and umbilical hernias
Head circumference > 95th percentile
Obstructive sleep apnea
Hepatosplenomegaly
Corneal clouding
Deafness
What is the most likely diagnosis?

Answer 24

Mucopolysaccharidosis (MPS) Type 1 (Hurler syndrome)
Explanation
MPS Type 1 is due to a defect in the gene coding for α-L-iduronidase. There is a wide variation in disease presentations. Those severely affected are diagnosed in the first 2 years of life. Those less severely affected are often not diagnosed until early adulthood. They present with bone abnormalities (spondylolisthesis of L5/S1, degenerative bone loss) or eye problems (corneal clouding and retinal disease).

Question 25

What is the classic triad of holocarboxylase synthetase or biotinidase deficiency?

Answer 25

Alopecia, skin rash, encephalopathy
Explanation
Seizures, hearing loss, and blindness can also be complications of untreated disease. Multiple carboxylase deficiency is due to either lack of holocarboxylase synthetase or biotinidase. Biotinidase deficiency usually presents later, and has a rash that looks like acrodermatitis enteropathica

Question 26

Mitochondrial inheritance comes from which parent

Answer 26

The mother
Explanation
Mitochondrial DNA (mtDNA), and therefore all disorders of mtDNA, are maternally inherited.

Question 27

A 2-week-old, with noticeably fair hair and skin compared to the parents, was completely normal at birth. The child had a home delivery with no postnatal testing for inborn errors.

Now she has developed these findings:

Vomiting
Irritability
Eczematoid rash
“Mousy” or musty odor
What is the most likely diagnosis?

Answer 27

Phenylketonuria
Explanation
Phenylketonuria (PKU) is an autosomal recessive disorder in which phenylalanine cannot be converted into tyrosine. The enzyme defect is in phenylalanine hydroxylase (PAH). Those who remain untreated have severe intellectual disability (IQ < 30), with irreversible damage by 8 weeks of age. PKU was the first metabolic condition on newborn screening, beginning 50 years ago. Hopefully you will never see this in clinic, but be suspicious if the symptoms fit, especially if the baby was born outside of the U.S

Question 28

Which mucopolysaccharidosis has disproportionate involvement of the CNS compared to the rest of the body?

Answer 28

Mucopolysaccharidosis (MPS) Type 3 (Sanfilippo syndrome)
Explanation
MPS Type 3 is usually diagnosed at ~ 4–5 years of age, with severe CNS involvement. This disproportionate CNS involvement is unique among the MPSs. Type 3 results from the inability to catabolize heparan sulfate

Question 29

Most cases of this disorder occur in children 3–5 years of age with:

Ataxia
Dysphagia
Supranuclear, vertical-gaze palsy (downward, upward, or both)—i.e., voluntary, vertical eye movement is lost.
Involuntary, reflex “doll’s eye” movements are preserved.
Hepatosplenomegaly
With an emotional scare, cataplexy (sudden loss of motor movement) can occur.
Narcolepsy is common.
Older children (6–12 years of age) present with poor school performance and impaired fine motor skills.

What is the most likely diagnosis?

Answer 29

Niemann-Pick disease (NPD) Type C
Explanation
NPD Type C is the most common form of NPD and occurs in 250–500 children (1/150,000) each year in the U.S. It occurs when cholesterol accumulates within the lysosomes of the reticuloendothelial system, resulting in a secondary buildup of GM2 ganglioside molecules (a.k.a. gangliosidosis

Question 30

A patient presents with:

Elevated plasma ammonia
Low BUN
Respiratory alkalosis
What general class of metabolic disorders is the most likely diagnosis?

Answer 30

Urea cycle defect
Explanation
The key with urea cycle defects is the finding of elevated ammonia with a respiratory alkalosis (not a metabolic acidosis, as would be expected with sepsis or other metabolic disorders). The most common defect is ornithine transcarbamylase (OTC) deficiency, which is also one of the few X-linked recessive metabolic conditions. (All other urea cycle defects have autosomal recessive inheritance