CHEM-643 INTERMEDIARY METABOLISM

Problem Set 7, In class October 20, 1994

Sick Kids with an Unusual Organic Aciduria

Consider your group to be an expert consulting team that takes pride in diagnosing metabolic diseases based on the abnormal organic acids excreted in a patient's urine. Over the years, for good reason, doctors from far and wide have come to rely on your team to solve their difficult cases. Typically they want to know what enzyme is defective and what therapies might ameliorate or eliminate the pathological consequence of various inborn errors of metabolism. Your team sees each new case as an intellectual challenge, but the greatest satisfaction comes from being able to save lives or improve the quality of life often through simple changes in a patient's diet.

One day a pediatrician presents your team with an especially puzzling pair of similar cases which she has never seen described in the literature. Although she respects your group's talents and certainly wants to help her patients, privately she is entertained by the idea that these cases will finally stump you. How, she asks, can a single enzyme defect cause the accumulation of the organic acids she observes?

Description of the First Patient

The patient was a white female two years and nine months old, the product of a full-term pregnancy and delivery. At three months of age she began to have generalized seizures that occurred approximately 10 times per day and were unresponsive to phenobarbital. The seizures persisted and at 14 months an eczematoid rash and alopecia developed, progressing to involve the entire head, including eyebrows and eyelashes. At 16 months of age the patient was first noted to have metabolic acidosis with a serum bicarbonate less than 15 mmol per liter. By 21 months she had ataxia, severe enough to interfere with her ability to walk. At 22 months she was first noted to have an elevated concentration of lactic acid in plasma. At 31 months she had severe keratoconjunctivitis requiring hospitalization. The patient's developmental progress was normal until seven months of age, when her development was delayed. From seven to 37 months her developmental age progressed by only 22 months. Throughout this period she received a normal diet and at no time was fed raw eggs. Her physical appearance at 31 months of age is shown in Figure 1. (See original reference.) She was profoundly acidotic, with plasma lactic acid concentration of 41 mg per deciliter (4.6 mmol per liter) and pyruvate concentration of 2.7 mg per deciliter (0.31 mmol per liter). She was irritable, somnolent, and in moderate distress, with marked alopecia, keratoconjunctivitis, and perioral stomatitis.

[Reprinted from the New England Journal of Medicine 304:817--820 (1981).]

Description of the Second Patient

The second patient was a two-year old boy whose profile of urinary organic acids (Table 1) was similar to those of patient 1.

Table 1. Urinary Excretion of Organic Acids (micromol/mg creatinine) by Patient 2.

	21 Months		23 Months
Organic Acids:	0--24 Hrs	24--48 Hrs	0--24 Hrs	24--48 Hrs	Normal
3-Methylcrotonylglycine	1.79	2.86	1.06	2.52	<0.01
3-Hydroxyisovaleric acid	8.85	9.59	5.62	5.82	<0.16
3-Hydroxypropionic acid	0.27	0.36	0.42	0.26	<0.01
Methylcitric acid	0.28	0.31	0.27	0.20	<0.01
24 Hour Urine Volume (ml)	182	102	110	253
Creatinine (mg/ml)	0.35	0.60	0.95	0.48

Assignment:

Postulate a single enzymatic defect that could explain the presence of the various organic acids in the above table.
Suggest a therapy that might reduce or eliminate the symptoms.

643prob7.doc HBW 10/3/94

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