Clinical Cases Description
Here we present several clinical cases involving one form or another of a defect in the metabolism of branched-chain amino acids.
Clinical Case #1
ID/CC: White male infant, born to a 30-year-old mother and a 32-year old father.
Family history of the disease: Both parents are of Mennonite origin from the Province of Quebec, Canada. Mother had 2 maternal aunts who died in the "first year" of life from unknown causes. Two of her paternal aunts also died in the first month of life. The father has 7 brothers and 3 sisters; all of them are living and well. He has a maternal aunt who died at 7 months of age from unknown causes. The maternal parents on the father’s side and the paternal parents on the mother’s side are related (the exact relationship is not known). The first child of this couple also suffered from an identical disease. The infant died at the age of 9 days. The second child is 51/2 years old with normal growth, development and intelligence.
PE: Poor feeding from 5th day, completely stopped on the 7th day. On the 9th day he was irritable and had arching of his back and rigidity on his limbs. Chest and skull x-ray were normal
SELECTED LABS
Lumbar puncture showed clear C. S. F., containing 4 WBC per high power field, no RBC, 45 mg% of protein, 46 mg% of sugar, and no bacteria in gram stain smears. CSF culture was negative. Blood glucose was 83 mg%. Urine contained no bile, protein or sugar, but had a "sweet smell", ketone bodies and a strong reaction with the 2,4-dinitrophenylhydrazine test for keto acids. Maple syrup urine disease was suspected and the infant milk feeding was replaced with 5 % dextrose.
Skin biopsies were obtained from the patient his sister and his parents for tissues cultures. The ability of the skin fibroblasts to metabolize 1-C14-valine/isoleucine/leucine was determined. The activity of the enzyme was at the normal level for the sister, almost twice less for the parents and 200 times less for the patient.
Treatment
Treatment with diet free of leucine, isoleucine and valine was given by naso-gastric tube.
At the age of 2 months, the patient weighed 4.6 kg, and was completely free of symptoms.
Questions for case #1
1. What is the significance of Mennonite origin of the parents?
2. How would you explain the fact that the first child of the family died and the second child is of normal development without any symptoms?
3. Explain the chemistry behind the dinitrophenylhydrazine test.
4. Which enzyme(s) is affected by this form of the disease?
5. Why were there ketone bodies present in patient’s urine?
6. Why was milk feeding replaced with 5% dextrose?
7. What is the cause of the "sweet smell" of the urine sample?
Clinical Case #2
ID/CC: Infant. Female.
Family history: The patient was the fourth child of parents who were unrelated. Her three siblings, all male, and both parents, were normal.
HPI: During the first year of life the girl had several immunizations and suffered mild illnesses without becoming acutely ill. She consumed large amounts of milk, eggs, and meats during infancy. Except for the increased body weight, the rest of physical examination was unremarkable. Her physical growth normal but her development was slowed overall.
PE: Skin and hair were fair. Mild hipertelorism was present. Reflexes were normal. Neurological development resembled that of a normal child approximately half her age.
SELECTED LABS
Results of the initial examination revealed anemia, hyperuricemia and mild systemic acidosis.
Patient’s blood contained increased amounts of leucine, isoleucine, and valine, as determined by paper chromatography.
The blood and urine contained abnormally large quantities of the branched chain keto and amino acids; the amount varying directly with the protein content of the diet.
The total serum ketoacid level was 44mg/100 ml and urinary acid excretion was 2,900 mg/twenty four hours; the normal excretion is 3 to 5 mg/day.
Ketoacid decarboxylase activity in vitro revealed deficiency of decarboxylase activities (15 to 25 percent of normal).
Treatment
During hospitalization the patient’s anemia responded fully to therapy with oral ferrous gluconate.
Combined diet consisting of carbohydrates, minerals and amino acids, reduced the levels of serum leucine and valine almost to normal range. Isoleucine levels remained three times normal, regardless of the diet.
Discussion of Case 2
The patient described represents an intermediate form of MSUD. The constant presence of increased levels of branched-chain amino acids and corresponding keto acids in blood and urine is prominent. These findings, together with significant mental retardation, distinguish her from the intermittent form of MSUD. Her clinical state was altered only to a mild extent by feeding her with the branched chain amino acids or a high protein diet, in contrast to the very toxic effects of those factors on patients with classical MSUD. Absence of seizures or neurological deficit and rather long survival without therapy also set her apart from typical patients with MSUD.
The intermediate nature of the patient’s condition is consistent with her incomplete deficiency of decarboxylase activity for all the three-branched-chain amino acids. Typically, the complete deficiency occurs in the patients suffering from classic form of MSUD.
Questions for Case 2
1. How many forms of MSUD have been described?
2. What are the main features of each of them?
3. What is a general treatment for MSUD?
4. Does the thiamine therapy always work? Why?
5. What connection is there between MSUD and abnormally high levels of branched amino acids in the urine?
6. How is hyperuricemia related to MSUD?
Clinical Case #3
Two families with two children in each family suffering from transient episodes of neurological signs accompanied by elevated levels of BCAA/BCKA, are described.
ID/CC
15 months old female, second child of the family. Norwegian family.
HPI: Medical history includes several acute infections, without neurological signs.
Several days prior to admission she had a series of brief tonic convulsions and become progressively lethargic.
On occasion the urine has had a slight odor.
The amino acid levels in serum and urine have been examined several times and always have been normal.
Family history: Her eight years old brother was admitted to the hospital few months after this case, and was diagnosed with meningitis. There was a "curry" odor of the urine. Serum valine and leucine/isoleucine levels were detected and corresponding keto acids were found in urine. In spite of infusion, he lapsed into coma and died. Degenerative changes in the cortex and necrosis of the granule-cell layer of the cerebellum were discovered on autopsy. He was considered physically and mentally fit.
PE: Weight, height and intelligence is normal for her age. Admitted to the hospital for ear infection (bilateral purulent otitis media). On admission she was semicomatose and had a strong "curry" odor.
Labs: Chromatography of the urine sample revealed increased levels of leucine and valine.
TREATMENT
Intravenous infusions of electrolyte solutions, after which she was discharged from the hospital.
Case Discussion: A prominent difference from the classical picture of MSUD was the late onset of symptoms and normal appearance of the children in between the attacks. However, one child died during an attack, suggesting the lethal nature of the disease. The enzyme activities of BKCDH in the surviving members of the family were determined. The results showed there was a marked reduction in the decarboxylase activity, but it was not as severe as in the classic form of MSUD.
Questions for clinical case #3
1. What is the difference between the intermittent and classical forms of MSUD?
2. How would you explain the periodic episodes of the disease?
3. Is this form of MSUD detectable before the symptoms occur?
Young woman, two months pregnant.
The patient's records showed that at eleven days after birth, she had been semicomatose and acidotic. She was diagnosed with MSUD; at the time of diagnosis the plasma Leu concentration was 2878 micromolar (normal is 120); Ile and Val were similarly much higher than normal. Cultured fibroblasts confirmed the diagnosis of MSUD.
Two older male siblings had died, undiagnosed, each before their first birthday. The patient had since been on a highly restricted diet, of limited whole protein with an amino acid supplement free of BCAA. She had experienced frequent childhood episodes of acidosis, generally following respiratory infections. Her IQ was above 100.
She had a noticeable deficit in visual-motor skills; two months pregnant; otherwise unremarkable.
Current BCAA were within normal range.
Treatment
The patient was treated with a diet that restricted whole-protein intake, supplemented with a BCAA-deficient amino acid formula, along with carnitine at 50 mg/g, prenatal vitamins, and calcium.
Questions for Case #4
1. Why the special diet that restricts intake of whole protein?
2. Why the carnitine supplement?
3. Explain the death of the older siblings.
4. How could respiratory infection lead to acidosis in this case?
5. Some cases of MSUD are treatable by thiamine supplements alone. Suggest a possible biochemical basis for this. (Hint: consider the effects of a mutation in the alpha-E1 subunit.)
6. Predict the effect of a mutation in the E2 subunit, that causes a block in attachment of lipoamide.
7. What special precautions in diet and supplements might be necessary in order to conclude this pregnancy successfully?