Paul W.K. Wong

Homocysteinemia due to folate deficiency

We examined the relationship between serum folate and total homocyst(e)ine levels by determining protein-bound homocyst(e)ine in stored serum from 19 subjects with subnormal serum folate (less than 2 ng/mL), 137 subjects with low normal serum folate (between 2.0 and 3.9 ng/mL), 44 subjects with normal serum folate (between 4.0 and 17.9 ng/mL), and 38 subjects with high serum folate (above 18 ng/mL). Eighty-four percent of the subjects with subnormal serum folate and 56% of the subjects with low normal serum folate had more than 7.05 nmol/mL serum total homocyst(e)ine (ie, more than two standard deviations above the normal mean). Thirty-two percent of these subjects had more than a three-fold increase in serum total homocyst(e)ine. These observations support the hypothesis that depletion of tissue folate causes homocysteinemia in nonhomocystinuric subjects. Subnormal as well as low normal concentrations of serum folate appear to produce an accumulation of homocyst(e)ine. In addition, relatively normal levels of serum total homocyst(e)ine were observed in four pregnant women with low serum folate, supporting previous suggestions of an influence of female sex hormone(s) in homocysteine metabolism.

Genetic and nongenetic factors for moderate hyperhomocyst(e)inemia

To assess the risk for homocyst(e)ine-associated vascular disease, overt hyperhomocyst(e)inemia should be demonstrated. In nonhomocystinuric subjects, clinical vascular disease must have developed after 40 or more years of persistent hyperhomocyst(e)inemia which may not be present without a genetic defect(s). Nongenetic factors, however, may amplify or mask phenotypic expression of a genetic defect, causing difficulties for the evaluation of hyperhomocyst(e)inemia based on plasma homocyst(e)ine concentration alone. Therefore, the search for genetic defects seems as important as the determination of plasma homocyst(e)ine concentration in evaluating the relationship between hyperhomocyst(e)inemia and the development of vascular disease. If genetic defect, such as heterozygous cystathionine synthase deficiency or thermolabile methylenetetrahydrofolate reductase is not detected, post-methionine homocyst(e)ine determination is a suitable means to identify genetic susceptibility to hyperhomocyst(e)inemia when the environmental factors are similar in the control and study groups.

Protein-Bound Homocyst(e)ine in Normal Subjects and in Patients with Homocystinuria

Summary: A method was developed to quantitate protein-bound homocyst(e)ine using 2-mercaptoethanol. Protein-bound homocyst(e)ine was discovered in the plasma from normal individuals, ranging from 0.5–2.2 nmole/ml. In two obligatory heterozygotes for classical homocystinuria, plasma protein-bound homocyt(e)ine was 3.5 and 4.8 nmole/ml, respectively. Untreated homozygotes showed approximately a 40-fold increase of plasma protein-bound homocyst(e)ine. Furthermore, using conventional methods, no free homocystine was detectable in the supernatant of plasma precipitate from two classical homocystinuric patients treated with pyridoxine, but plasma protein-bound homocyst(e)ine showed a 10-fold increase. Protein-bound homocyst(e)ine was also demonstrated in the liver, kidney, and brain tissues from a patient with methylenetetrahydrofolate reductase deficiency.Speculation: The results in this study suggest that determination of proteinbound homocyst(e)ine using 2-mercaptoethanol may provide a more reliable assessment of treatment in patients with homocystinuria and a potentially useful tool for the definition of the carrier state.Demonstration of protein-bound homocyst(e)ine in various tissues of homocystinuric patients suggests the possibility that this compound may be directly associated with the development of some of the pathologic changes in the tissues

Total homocyst(e)ine in plasma and amniotic fluid of pregnant women

Total homocyst(e)ine was determined by the quantitation of protein-bound homocyst(e)ine in the stored plasma and amniotic fluid from 25 pregnant women and in the stored plasma from 17 nonpregnant women. The mean +/- SE of plasma total homocyst(e)ine was 29.8 +/- 2.4 nmol/g protein in pregnant women and 52.4 +/- 3.8 nmol/g protein in nonpregnant women. In contrast, the mean +/- SE of total homocyst(e)ine in amniotic fluid obtained at 16 weeks of gestation was 36.3 +/- 2.9 nmol/g protein. There was a statistically significant difference in the plasma total homocyst(e)ine concentrations from pregnant and nonpregnant women (P less than 0.01). Similarly, there was also a statistically significant difference between plasma total homocyst(e)ine from nonpregnant women and amniotic fluid total homocyst(e)ine (P less than 0.01). These observations suggested that the metabolism of homocysteine to cysteine was more efficient in pregnant women. In addition, the concentrations of total homocyst(e)ine in amniotic fluids were within narrow limits in normal pregnancies. Hence, total homocyst(e)ine concentration might be very valuable as a rapid assessment of fetuses for congenital defects of homocysteine metabolism.

The Effect of D-Penicillamine on Protein-Bound Homocyst(e)ine in Homocystinurics

Summary: There is considerable evidence that homocystine has a direct damaging effect on vascular endothelium and other tissues. The demonstration of the existance of protein-bound homocyst(e)ine has strengthened this hypothesis. In an attempt to remove bound homocyst(e)ine, D-penicillamine was given to three patients with pyridoxine-nonresponsive homocystinuria. Before the clinical trial, it had been demonstrated that 0.1 μmole per ml concentration of D-penicillamine or cysteamine released approximately 50% of the homocyst(e)ine bound to plasma proteins in vitro. Oral D-penicillamine effectively reduced both free and plasma protein-bound homocyst(e)ine in homocystinurics from the second day of treatment. The homocystine excreted in the urine was mainly in the form of homocysteine-penicillamine disulfide. No mixed disulfide was detectable in the plasma, indicating an extremely high renal clearance. These observations suggested that oral D-penicillamine removed a considerable quantity of the bound homocyst(e)ine accumulated in the tissue proteins.Speculation: D-Penicillamine treatment may be used on an experimental basis in pyridoxine-nonresponsive homocystinuric patients when dietary treatment is not practical. It may also be used in pyridoxine-responsive patients when control with pyridoxine is unsatisfactory. In addition, determination of protein-bound homocyst(e)ine should be used for the assessment of the effectiveness of therapy.

Intravenous supplementation of l-amino acids and dextrose in low-birth-weight infants

The effect of intravenous 3.4 per cent l -amino acid and 10 per cent dextrose supplementation on mortality rate, weight gain, and biochemical blood values was examined in 54 low-birth-weight newborn infants. At 24 to 48 hours of age, the infants were assigned according to birth weight to Group I (701 to 1,000 Gm.), Group II (1,001 to 1,250 Gm.), or Group III (1,251 to 1,500 Gm.). Each group was subdivided randomly into amino acid-treated infants (A) and control subjects (C). There was no significant difference in the case fatality rates between infants in Subgroups A and C. Serial determinations of serum electrolytes, CO 2 combining power, and hematocrit were similar in Groups A and C. Serial blood urea nitrogen concentrations in Group A infants were significantly higher than those in Group C infants. Plasma amino acids showed undue elevations in methionine and glycine concentrations in some of the infants who received supplemental amino acids. At 21 days, a significantly greater increase in weight was observed in Group IIA (178±26 Gm.) compared to Group IIC (54±51 Gm.). Similarly, weight increase in Group IIIA (206±27 Gm.) was significantly greater than that in Group IIIC (58±24 Gm.). Infants in Groups IIA and IIC reached a discharge weight of 2,041 Gm. at 45±11 days and 55±9 days, respectively. Infants in Group IIIA reached the discharge weight significantly earlier than those in Group IIIC (41±1 and 49±2 days, respectively).

Protein‐Bound Homocyst(e)ine in Patients With Rheumatoid Arthritis Undergoing D‐Penicillamine Treatment

Protein‐bound homocyst(e)ine was measured in the plasma of 38 nonhomocystinuric patients with rheumatoid arthritis. Nineteen of them were treated orally with d‐penicillamine 100‐1,500 mg/d for a period of one month to 15 years. For these patients, the mean ± standard deviation level of plasma protein‐bound homocyst(e)ine was 1.95 ± 1.07 nmol/mL. In contrast, the mean plasma level of protein‐bound homocyst(e)ine was 4.72 ± 1.11 nmol/mL in the 19 patients who had not been treated with oral d‐penicillamine. There was a statistically significant difference (P < .0001) in the plasma protein‐bound homocyst(e)ine concentrations between patients with and without oral d‐penicillamine therapy. Thus, it may be speculated that oral d‐penicillamine may be beneficial in protecting patients from the development of thromboembolism and arteriosclerosis.

Trisomy 22 Mosaicism with Normal Blood Chromosomes Case Report with Literature Review

A female infant with growth failure, microcephaly, hypertelorism, epicanthal folds, preauricular pit, congenital heart defect, hypotonia, and delayed development is reported. Trisomy 22 mosaicism (46,XX/47,XX,+22) was found in cultured skin fibroblasts but not in blood lymphocytes. Trisomy restricted to skin fibroblasts is uncommon. Cytogenetic evaluation of a second tissue (preferably skin) is suggested in patients with physical and mental abnormalities who have normal blood chromosome studies.

Family with Pelizaeus-Merzbacher disease/X-linked spastic paraplegia and a nonsense mutation in exon 6 of the proteolipid protein gene

We report on a C-to-T transition in exon 6 of the PLP gene in a male with Pelizaeus-Merzbacher disease/X-linked spastic paraplegia. The transition changes a glutamine at amino acid residue 233 to a termination codon. This premature stop codon probably results in a truncated protein that is not functional. Six other relatives were analyzed for the mutation and two female carriers were identified. Autopsy data on one male are presented.

Ocular findings in partial trisomy 10q syndrome.

We examined three siblings with partial trisomy 10q born to a mother carrying a balanced translocation between chromosomes 4 and 10. Our patients had many of the phenotypic abnormalities characteristic of this syndrome, and their chromosomal abnormality was confirmed by karyotypes of peripheral blood lymphocytes. Two ophthalmoscopic abnormalities not previously reported in this syndrome were noted in our patients. One child had bilateral enlarged, gray optic disks with elevated, blurred margins and distended retinal vessels. Another child had bilateral punctate yellow deposits scattered around the macula and optic disk.