L-Carnitine Supplementation Improves Self-Rating Depression Scale Scores in Uremic Male Patients Undergoing Hemodialysis.

BACKGROUND: Depression is highly prevalent in uremic patients undergoing hemodialysis (HD). We previously found that low free-carnitine levels are associated with depression severity in male patients undergoing HD. However, whether L-carnitine supplementation improves the depression state in male patients undergoing HD remains unclear. METHODS: Sixteen male patients undergoing HD were orally administered 900 mg L-carnitine daily or intravenously administered 1000 mg L-carnitine immediately after undergoing HD for 3 months. The depression state and various types of carnitine levels were evaluated using the self-rating depression scale (SDS) and tandem mass spectrometry, respectively, at baseline and 3 months after treatment. RESULTS: L-carnitine supplementation significantly increased serum levels of free and other acylcarnitine types, associated with improved SDS scores in male patients undergoing HD. Univariate analysis revealed that low baseline butyryl- and isovaleryl-/2-methylbutyryl-carnitine levels were significantly correlated with SDS scores after treatment. Multiple regression analysis revealed that butyryl-carnitine levels were a sole independent predictor of SDS scores after treatment (r2 = 0.533). CONCLUSION: L-carnitine supplementation for 3 months improved the depression state in uremic male patients undergoing HD. Thus, low butyryl-carnitine levels may predict the clinical response to L-carnitine supplementation in male patients undergoing HD and who have mild depression.

Isovaleric acidemia: Therapeutic response to supplementation with glycine, l-carnitine, or both in combination and a 10-year follow-up case study.

Isovaleric acidemia (IVA) is an organic acid disease caused by a deficiency of isovaleryl-CoA dehydrogenase. Deficiency of this enzyme leads to accumulation of organic acids, such as isovalerylcarnitine and isovalerylglycine. The proposed IVA treatments include leucine restriction and l-carnitine and/or glycine supplementation, which convert isovaleric acid into non-toxic isovalerylcarnitine and isovalerylglycine, respectively. We examined the therapeutic response using the leucine load test and performed a 10-year follow-up in the patient. METHODS: We evaluated the patient with IVA beginning at 5 years of age, when he presented with a mild to intermediate metabolic phenotype. Ammonia, free carnitine, isovalerylcarnitine, and isovalerylglycine were analyzed in the urine and blood after a meal consisting of 1600 mg leucine with glycine alone (250 mg/kg/day), l-carnitine alone (100 mg/kg/day), or both glycine and l-carnitine for four days each. RESULTS: (Leucine load test) Three hours after the meal, serum ammonia levels increased most dramatically with glycine treatment alone, then with both in combination, and least with l-carnitine alone. Urinary isovalerylglycine levels increased 2-fold more with glycine supplementation than those following supplementation with both agents or with l-carnitine alone. Treatment with both agents resulted in a gradual increase in urinary acylcarnitine levels during the 6-h period following the leucine load, reaching concentrations comparable to those observed with l-carnitine alone. (Clinical course) After initiation of both glycine (200 mg/kg/day) and l-carnitine (100 mg/kg/day) supplementation at 5 years of age, doses were gradually reduced to 111.7 mg/kg/day and 55.8 mg/kg/day, respectively, at 15 years of age. His mind and body had developed without any sequelae. DISCUSSION: We concluded that l-carnitine conjugated isovaleric acid earlier than glycine. Additionally, during the 10-year follow-up period, the patient displayed no clinical deterioration.

An adult patient with mucolipidosis III alpha/beta presenting with parkinsonism.

A 36-year-old man with mucolipidosis type III alpha/beta presented with hypoactivity, mutism, muscle rigidity, and involuntary movement. The involuntary movement was interpreted to be tremor at rest on physical examination and surface electromyography, which revealed mostly asynchronous contractions at 3-4 Hz of the biceps and triceps brachii muscles. All these symptoms were consistent with abnormalities of parkinsonism, which is caused by an insult to the basal ganglia that permeates the entire basal ganglia-thalamocortical circuitry. This report is the first to present a case of mucolipidosis type III alpha/beta in association with parkinsonism.

Maternal and fetal circulation of unusual bile acids: a pilot study.

BACKGROUND: Large amounts of unusual bile acids are synthesized by the fetal liver in late gestation. These compounds are mostly transferred from fetus to mother, although some are excreted into the amniotic fluid. We investigated the role of placental transfer of bile acids in fetal bile acid metabolism, particularly with respect to the unusual bile acids (1ß-hydroxylated and ketonic bile acids). METHODS: We measured concentrations of bile acids in umbilical cord blood and urine of newborn infants, and in perinatal maternal serum and urine, using gas chromatography-mass spectrometry. Serum and urine specimens from healthy non-pregnant women were used as controls. RESULTS: In newborn infants at delivery, cord blood and urine contained mostly primary and 1ß-hydroxylated bile acids, respectively. We also detected large amounts of ketonic bile acids in their urine, and the urinary concentration of total bile acids was elevated. Main maternal bile acids at 30 and 35 weeks of gestation and at delivery were 1ß-hydroxylated bile acids. After delivery, main bile acids changed from 1ß-hydroxylated bile acids to primary bile acids (P < 0.03), which also predominated in healthy non-pregnant women. CONCLUSION: Fetally synthesized unusual bile acids were transported from fetus to mother. Pregnant women appear to excrete these bile acids into the urine, lowering both fetal and maternal serum bile acid concentrations.

Developmental pattern of urinary bile acid profile in preterm infants.

BACKGROUND: Bile acid metabolism in preterm infants is yet to be fully characterized. We compared the developmental pattern of urinary bile acid profiles in ten infants born at gestational ages from 25 to 33 weeks with previous data from full-term infants from birth to about 7 months of age. METHODS: Gas chromatography-mass spectrometry was performed on serial samples. RESULTS: Total urinary bile acid concentrations gradually increased until 1 to 2 months of age. After this peak of excretion (30 to 60 micromol/mmol creatinine), total urinary bile acid concentrations gradually decreased to less than 20 micromol/mmol creatinine. The percentage of usual bile acids (mainly cholic acid) relative to total urinary total bile acids gradually deceased from approximately 30% at birth to less than 15% at 7 months of age. On the other hand, 1beta-hydroxylated bile acids (mainly 1beta,3alpha,7alpha,12alpha-tetrahydroxy-5beta-cholan-24-oic acid) relative to total urinary bile acids were increased gradually from 60% at birth to reach 70% to 80% at 1 month of age. The percentage of 1beta-hydroxylated bile acids relative to total urinary bile acids then remained stable at a high percentage (70% to 90%) until the age of 7 months. CONCLUSION: Physiological cholestasis in preterm infants persists longer than in full-term infants. Moreover, as large amounts of cholic and 1beta,3alpha,7alpha,12alpha-tetrahydroxy-5beta-cholan-24-oic acids were detected in urine from preterm infants during this study, the 25-hydroxylation pathway may be particularly important for bile acid synthesis in early preterm infants.

Perinatal bile acid metabolism: bile acid analysis of meconium of preterm and full-term infants.

BACKGROUND: Our purpose was to evaluate the metabolism of bile acids in the fetus by analyzing the bile acid composition of meconium of preterm (less than 30 weeks' gestational age) and full-term infants and comparing the results with the bile acid composition of feces of preterm and full-term infants 6 days after delivery. METHODS: The concentrations of individual bile acids were determined by gas chromatography-mass spectrometry after solvolysis and hydrolysis of bile acid conjugates. RESULTS: In meconium, the main bile acids were chenodeoxycholic and hyocholic acids. The main bile acid of feces from preterm infants at 6 days of age was the same as that of meconium. We also detected large amounts of secondary bile acids, especially deoxycholic acid and ursodeoxycholic acid. The ratio of cholic acid relative to chenodeoxycholic acid in meconium of preterm and full-term infants and in feces of preterm infants was less than 1, 0.36, 0.55, and 0.55, respectively. The percentage of chenodeoxycholic acid relative to total bile acids in meconium of preterm (P < 0.05) and full-term (P < 0.01) infants was significantly higher than that in feces of 6-day-old full-term infants. CONCLUSIONS: More than half of the main pathway, at least, for bile acid synthesis in preterm infants may be the acidic pathway until the infants reach about 7 days of age.

Novel mutations in five Japanese patients with 3-methylcrotonyl-CoA carboxylase deficiency.

Isolated 3-methylcrotonyl-CoA carboxylase (MCC) deficiency appears to be the most frequent organic aciduria detected in tandem mass spectrometry (MS/MS) screening programs in the United States, Australia, and Europe. A pilot study of newborn screening using MS/MS has recently been commenced in Japan. Our group detected two asymptomatic MCC deficiency patients by the pilot screening and collected data on another three MCC deficiency patients to study the molecular bases of the MCC deficiency in Japan. Molecular analyses revealed novel mutations in one of the causative genes, MCCA or MCCB, in all five of the patients: nonsense and frameshift mutations in MCCA (c.1750C > T/c.901_902delAA) in patient 1, nonsense and frameshift mutations in MCCB (c.1054_1055delGG/c.592C > T) in patient 2, frameshift and missense mutations in MCCB (c.1625_1626insGG/c.653_654CA > TT) in patient 3, a homozygous missense mutation in MCCA (c.1380T > G/ 1380T > G) in patient 4, and compound heterozygous missense mutations in MCCB (c.569A > G/ c.838G > T) in patient 5. No obvious clinical symptoms were observed in patients 1, 2, and 3. Patient 4 had severe neurological impairment and patient 5 developed Reye-like syndrome. The increasing use of MS/MS newborn screening in Japan will further clarify the clinical and genetic heterogeneity among patients with MCC deficiency in the Japanese population.