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An 8-month-old boy with persistent watery diarrhoea and failure to thrive developed abdominal distension, hypokalaemia, and flushing of the face and trunk. A high concentration of vasoactive intestinal peptide-like immunoreactivity was found in the serum. Soon after resection of a suprarenal mass, the serum level of vasoactive intestinal peptide became normal and the diarrhoea stopped. Histologically the tumour was a ganglioneuroblastoma: the cells showed fluorescence by the indirect immunofluorescence technique with anti-vasoactive intestinal peptide serum. Electron microscopical examination showed abundant secretory granules in the tumour cells. Reports of chronic watery diarrhoea in children due to neural crest tumours are reviewed, with particular respect to the clinical features of the syndrome. [ABSTRACT FROM AUTHOR]

The breath hydrogen test (BHT) was adapted for use in young infants and children. The diagnostic criterion of sugar malabsorption in the BHT was determined by oral administration of 0.5 g/kg of unabsorbable sugar (lactulose) to 21 healthy infants and children. A maximum increase in breath hydrogen less than 0.05 ml/min per m2 was observed in all subjects. A good correlation between results by the BHT and by the ordinary lactose tolerance test was obtained after oral administration of 2 g/kg lactose to 21 healthy infants and children, 2 congenital lactase-deficient infants, and 7 adults. Using this test, 80 healthy Japanese infants and children (aged between one month and 15 years) and 18 adults were examined for lactose malabsorption after a dose of 1 g/kg lactose. All infants and children under 2-years old absorbed lactose completely. The incidence of lactose malabsorption was 30% in 3-year, 36% in 4-year, 58% in 5-year, and 86% in 6-year-old children, 85% in schoolchildren, and 89% in adults. Thus the incidence of lactase deficiency gradually increases with age from 3 years, and about 90% of all normal Japanese adults are lactase-deficient. [ABSTRACT FROM AUTHOR]

Sixteen cases of transient infantile hyperthyrotrophinaemia were followed up for two to seven years. Concentrations of serum triiodothyronine, thyroxine, and free thyroxine were maintained within the normal range in all cases. All but one child, who had a hearing disturbance, showed normal mental development with normal physical and skeletal maturation. Eleven children had normal concentrations of serum thyroid stimulating hormone and no signs or symptoms of thyroid dysfunction; in three children, diffuse small goitres developed and two further children showed relapse with slightly raised concentrations of thyroid stimulating hormone. It is concluded that 'transient infantile hyperthyrotrophinaemia' is a syndrome, which differs from typical transient neonatal hypothyroidism, and that careful follow up is necessary because some children show signs of mild pituitary-thyroid dysfunction in later childhood. [ABSTRACT FROM AUTHOR]

A case of transient hyperthyrotropinaemia was found by mass screening for neonatal hypothyroidism using the paired TSH assay method. The patient was a baby boy born at term after a normal pregnancy who grew without any abnormal signs or symptoms. For the first 7 months after birth, his serum TSH was abnormally high while his total serum T4, T3, and free T4, T3 were within normal limits, exept for slightly low free T4 level at 7 months. The raised serum TSH decreased spontaneously to within normal limits after he was 9 months old. [ABSTRACT FROM AUTHOR]

Background: About twice as many boys as girls undergo growth hormone (GH) therapy in GH deficiency (GHD). However, this sex difference may not correctly reflect a real incidence., Objectives: We analyzed the evidence of a selection bias whereby more boys seek treatment at short stature clinics., Subjects and Methods: The present study included 3,902 children who visited 17 short stature clinics with a height SD score of -2 SD or less. The percentage of children who underwent the GH stimulation test was compared between boys and girls, as was the percentage of children ultimately diagnosed with GHD., Results: The children comprised 2,390 boys (61.3%) and 1,512 girls (38.7%), with a boy:girl ratio of 1.58:1. The percentage of children who underwent the GH stimulation test did not differ between boys (45.7%) and girls (49.8%). Among the children who underwent the GH stimulation test, the percentage diagnosed with GHD did not differ significantly between boys (22.0%) and girls (20.1%). The boy:girl ratio of children diagnosed with GHD was 1.59:1., Conclusions: The boy:girl ratio of children with short stature (1.58:1) did not differ significantly from that of children diagnosed with GHD (1.59:1). These results indicate that the predominance of boys in GHD does not reflect a real incidence, but rather a selection bias whereby a higher proportion of boys with short stature seek treatment at clinics. This difference arises because parents are more concerned about boys' height, and because boys reach adult height at an older age., (© 2021 S. Karger AG, Basel.)

We report on fluorescence in situ hybridization (FISH) analysis in 30 mosaic or nonmosaic females diagnosed as having apparently simple terminal X deletions by standard G-banding analysis. FISH studies for DXZ1, the Xp and Xq telomere regions, and the whole X chromosome painting were carried out for the 30 females, indicating rearranged X chromosomes with signal patterns discordant with terminal deletions in 6 cases: one dic(X)(DXZ1++) chromosome, two der(X)(qtel++) chromosomes, one Xq- (qtel+) chromosome, and two der(X)(ptel++) chromosomes. Additional FISH studies were performed for the 6 cases using probes defining 12 loci on the X chromosome, showing large Xp deletion and small Xp duplication in the dic(X)(DXZ1++) chromosome, partial Xp deletions and partial Xq duplications in the two der(X)(qtel++) chromosomes, an interstitial Xq deletion in the Xq- (qtel+) chromosome, and partial Xq deletions and partial Xp duplications in the two der(X)(ptel++) chromosomes. Clinical assessment of the 6 cases revealed tall and normal stature in the two mosaic cases with the der(X)(ptel++) chromosomes that were shown to be associated with SHOX duplication. The results suggest that unusual X chromosome rearrangements are often misinterpreted as simple terminal X deletions, and that FISH analysis is useful for precise structural determination and better genotype-phenotype correlation of the X chromosome aberrations., (Copyright 2001 Wiley-Liss, Inc.)

Iodide transport defect results from the malfunction of iodide transporter (sodium iodide symporter [NIS]), and is characterized by low uptake of iodide into thyroid cells. Genetic analysis revealed that a T354P missense mutation causes iodide transport defect in the homozygous state and is a frequent mutation in the Japanese population. We recently reported three siblings with iodide transport defect harboring the T354P mutation in the heterozygous state. Here we report a novel V59E missense mutation associated with these siblings. The mutant protein showed low iodide transport activity.

We have previously reported a novel heterozygous donor splice site mutation in intron 9 of the GH receptor (GHR) gene in Japanese siblings who showed partial GH insensitivity and high serum GH-binding protein (GHBP) levels. This mutation caused the splicing abnormality and produced the truncated GHR consisting of 277 amino acids (GHR-277), which lacked most of the intracellular domain of GHR, including both boxes 1 and 2. In this study, we have characterized the function of GHR-277 expression in COS-7 and CHO cells in vitro. Scatchard analysis revealed that GHR-277 possessed approximately 1.5 times higher affinity to GH and twice the number of binding sites compared to wild-type full-length GHR (GHR-fl). The GHBP level in culture medium of GHR-277-expressing cells was approximately 3 times higher than that in GHR-fl-expressing cells. Interestingly, the ligand-induced internalization of GHR-277 was significantly reduced compared with that of GHR-fl. Moreover, in GH-induced tyrosine phosphorylation of signal transducer and activator of transcription-5 (STAT5), GHR-277 exerted a dominant negative effect when GHR-277 and GHR-fl were cotransfected. These in vitro data would well explain the clinical characteristics in our patients showing high serum GHBP levels and development of short stature despite a heterozygous mutation of the GHR gene.

Iodide transport defect (ITD) is a rare disorder causing congenital hypothyroidism. We previously reported that homozygous T354P mutation in the sodium/iodide symporter (NIS) gene caused ITD. To clarify the prevalence of this mutation, artificial substitution introducing PCR followed by restriction enzyme analysis was developed as a rapid screening method to detect the T354P mutation. Three apparently unrelated families with ITD, one patient with low thyroidal 99mTc pertechnetate (99mTcO4-) uptake and 52 healthy controls (104 alleles) were analyzed for this mutation. All families with ITD harbored the mutation, suggesting that T354P is a recurrent mutation and a major cause of ITD. This was not a widespread mutation, because it was not detected in the 52 unrelated normal controls. Because two cases with homozygous T354P mutation developed multinodular goiters within their second decade of life though they had been maintained in euthyroid state, homozygous T354P mutation alone and/or low intrathyroidal iodide and high serum TSH level in early life might account for tumorigenesis. The patient with low thyroidal 99mTcO4- uptake did not harbor the T354P mutation. Because familial hypocalciuric hypercalcemia was also present in this family, a possibility of the combined abnormality of TSH receptor and calcium functions, which includes an abnormality around the G protein, may be examined further.

Most of the GH receptor (GHR) gene abnormalities causing GH insensitivity syndrome (GHIS) are located in the region coding the extracellular domain, and serum GH-binding protein (GHBP) levels, determined by ligand-mediated immunofunctional assay, are low in most of the patients with GHIS. We present here a heterozygous point mutation of the donor splice site in intron 9 of the GHR gene in two Japanese siblings with GHIS, whose serum GHBP levels were high. The same mutation was found in their mother as well. The analysis of ribonucleic acid from the peripheral leukocytes revealed complete skipping of exon 9 from one allele, but not the other, in the GHR complementary DNA and appearance of a premature stop codon in exon 10. The translated protein was truncated with deletion of 98% of the intracellular domain of the GHR, including boxes 1 and 2, which are critical for GH signal transduction and GHR internalization, respectively. Recently, it was shown that the truncated GHR lacking the intracellular domain was physiologically present in a minute amount, served as a negative regulator for GH signaling, and possessed increased capacity to generate GHBP. Therefore, the mutation found in our patients caused the pathogenetic production of the truncated GHR with a dominant negative effect on GH signaling, which is probably responsible for their short stature and high serum GHBP levels.

A girl with severe growth retardation had the clinical features of Laron syndrome. Her serum insulin-like growth factor-I level was completely unresponsive to exogenous GH administration. The serum GH-binding protein (GHBP) level was below the detectable limit in the patient, but it was normal in her parents and brother. Her parents and brother were normal in their height. Amplification with PCR and direct sequencing of her GH receptor gene revealed compound heterozygous mutations. The allele from her mother contained a transversion of G to T in exon 7 that could introduce a stop codon in place of a glutamic acid at amino acid 224. Another mutation was found in the allele in her father and also identified in her brother. It was a C deletion at position 981 in exon 10 that could introduce a frame shift, thereby causing the production of 20 novel amino acids (310-329) instead of the wild-type sequence, the premature termination at codon 330, and the subsequent deletion of the C terminal portion of the intracellular domain. RT-PCR of her father's lymphocytes and sequencing of its complementary DNA revealed that only the wild-type GH receptor messenger RNA was expressed in his lymphocytes, though the mechanism remains unclear. These results suggest that neither of the mutant alleles could generate a functional GH receptor, which would be consistent with the patient's severe growth retardation and undetectable serum GHBP.

PIT1 abnormality is defined as a genetic abnormality in the PIT1 gene, which encodes a pituitary specific transcription factor Pit-1/GHF-1.PIT1 abnormality has been reported in several patients displaying either complete or incomplete deficiency of thyrotropin (TSH), growth hormone (GH), and prolactin (PRL) in either familial or sporadic cases. To see if there are abnormalities in the PIT1 gene in patients with incomplete TSH, GH, and PRL deficiency, we utilized a PCR direct sequencing method to determine the Pit-1/GHF-1 coding sequence. A total of 15 patients, 1 patient from a family with TSH and GH deficiency, 3 patients with TSH, GH, and PRL deficiency, and 11 patients treated with both human GH (hGH) and thyroid hormone were studied. In one patient of combined pituitary hormone deficiency, the Arg-271-Trp mutation was detected. Since both of the parents did not harbor this mutation, it is a de novo germ line mutation. No mutation was detected in the other patients, showing that PIT1 abnormality is not a frequent cause of GH deficiency.

We have shown previously that serum insulin-like growth factor binding protein-3 (IGFBP-3) levels have good predictive value for complete, but not partial, growth hormone deficiency (GHD). In this study, we compare IGFBP-3 levels in short children previously divided into groups on the basis of their post-stimulation GH levels. Complete GHD (N = 59) included those children with peak post-stimulation GH < 5 micrograms/l. The partial GHD group (N = 49) had post-stimulation GH peaks of > 5 micrograms/l but < 10 micrograms/l. The normal children with short stature (N = 103) had post-stimulation GH peaks > 10 micrograms/l. Partial GHD and normal children with short stature also were divided into either low IGF-I or normal IGF-I subgroups. The clinical sensitivity of IGFBP-3 for complete GHD was 92%, whereas its sensitivity for partial GHD was 39%. For partial GHD, among those with low IGF-I (N = 19) 68% were also low for IGFBP-3, while 80% of those with normal IGF-I (N = 30) were also normal for IGFBP-3. The clinical specificity of IGFBP-3 for normal children with short stature was 69%. For these groups, among those with low IGF-I (N = 22) 73% also were low for IGFBP-3, while 80% of those with normal IGF-I (N = 81) also were normal for IGFBP-3. In addition, we tested whether IGFBP-3 can predict the response to GH treatment in prepubertal children by comparing pretreatment IGFBP-3 with the height gain achieved by 1 year of GH treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

To analyze the utility of insulin-like growth factor-I (IGF-I) and insulin-like growth factor binding protein-3 (IGFBP-3) radioimmunoassay in the diagnosis of growth hormone deficiency (GHD) we measured IGF-I and IGFBP-3 in sera from normal children (n = 309), short children (n = 99) and patients with GHD (n = 73). In 80% and 93% of classical GHD (cGHD), IGF-I and IGFBP-3 levels, respectively, were below the age-related cutoff levels (lower limit). In 81% and 88% of normal short children (NS), IGF-I and IGFBP-3 levels, respectively, were above the age-related cutoff levels. Thus, both IGF-I and IGFBP-3 were good parameters for screening GHD. In contrast, in more than half of partial GHD (pGHD), either IGF-I or IGFBP-3 was above the age-related cutoff levels. The poor discrimination between patients with pGHD and NS by using these two parameters may be the result of their relatively similar GH levels, as compared to cGHD, or due to the limitations of GH stimulation tests. In about 80-90% of NS, IGF-I and IGFBP-3 were above the age-related cutoff levels at all ages. A hundred percent of cGHD under 10 years old had IGFBP-3 below the age-related cutoff levels, whereas 79% of cGHD under 10 years old had IGF-I below the age-related cutoff levels. Thus in the younger age groups, IGFBP-3 may be more sensitive than IGF-I. It may be because IGFBP-3 levels are relatively higher than those of IGF-I in younger subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

To analyze the utility of insulin-like growth factor binding protein-3 (IGFBP-3) radioimmunoassay for diagnosis of growth hormone deficiency (GHD) we measured IGFBP-3 in sera from normal children, short children and patients with GHD. The sensitivity (true positive ratio) of IGFBP-3 for complete GHD (cGHD) was 93%, while the specificity (true negative ratio) for normal short children (NS) was 88%. In contrast, the sensitivity of IGFBP-3 for partial GHD (pGHD) was only 43%. The poor discrimination between patients with pGHD and NS may be the result of their relatively similar GH level, as compared to cGHD, or due to the limitations of GH stimulation tests. The specificity of IGFBP-3 for NS was excellent in children of all ages: less than 10 years old (87%) and older than 10 (88%). However, sensitivity for GHD was good for children less than 10 years old (84%) but poor for children older than 10 (64%). IGFBP-3 may be less sensitive for diagnosing GHD in older children because IGFBP-3 levels may also increase during puberty due to mechanisms independent of the GH-IGF-I axis.

Massive intestinal protein loss was demonstrated and the site of loss determined by abdominal scintigraphy with 99mTc-labeled human serum albumin in a 9-year-old girl following the Fontan operation for pulmonary atresia with intact ventricular septum. Significant activity accumulating in the lower small intestine and moving with its contents into the colon were shown. Her condition may have resulted from intestinal lymphangiectasia, caused by increased central venous pressure. Abdominal scintigraphy with 99mTc-human serum albumin is useful in the diagnosis of protein-losing enteropathy.

A vertical banded gastroplasty was performed in an adult female patient with Prader-Willi syndrome in an attempt to prevent the metabolic deterioration caused by polyphagia. After her operation, the patient felt satiated with the scheduled amount of food and one month later, her fasting blood sugar concentration (FBS) decreased from 521 to 125 mg/dl, and her urinary sugar excretion (US) from 257 to 9 g/day. Both glucose tolerance and insulin secretion were also improved. However, these parameters subsequently became worse after dietary control was lost since the surgical procedure alone was unable to continue to suppress the insatiable desire to eat food. Both her glucose tolerance and insulin secretion by the 31st postoperative month were better than before the surgery, but worse than at one month after the surgery. At the end of the surgery, but worse than at one month after the surgery. At the end of the 34th postoperative month, even under the temporary administration of 0.625 mg/day of glibenclamide, her FBS was 158 mg/dl and US, 38.1 g/day. Her body weight had also increased to over her preoperative value. Based on these results, we conclude that the effect of gastroplasty to prevent metabolic deterioration in our patient with Prader-Willi syndrome gradually diminishes.

The universal predictive criteria for neonatal overt thyrotoxicosis requiring treatment were examined in 108 neonates (including a pair of twins) born to mothers with Graves' disease (36 patients under treatment with antithyroid drugs [group A] and 71 in remission [group B]). Anti-thyroid-stimulating hormone (TSH) receptor antibody activity was measured by both radioreceptor assay (TSH-binding inhibitor immunoglobulin [TBII]) and biologic stimulation assay (thyroid stimulating antibody [TSAb]). For generalization of the predictive criteria, the expression of TBII activity was standardized using standard serum made taking units of Medical Research Council long-acting thyroid stimulator, standard B as a reference, and expression of TSAb activity was standardized using bovine TSH as a standard. TBII activity was positive in 22 mothers at delivery, and TSAb activity was positive in 18. In 12 cases, both activities were positive. Both the TBII and the TSAb activity of maternal serum at delivery correlated well with that of the cord serum. Neonatal thyrotoxicosis occurred in 9 of 108 neonates (8%), of whom five (5%) had clinical overt symptoms requiring antithyroid drug treatment. In all nine cases the TBII and TSAb activities were both positive, but no neonate without TBII or TSAb activity developed thyrotoxicosis. The prediction rate (42%) of neonatal overt thyrotoxicosis was higher when both TBII and TSAb were measured than when only TBII (23%) or TSAb (28%) was measured. Clinical overt thyrotoxicosis could be predicted in five of six neonates (83%) of mothers when the cutoff levels of antibody activities were increased to a TBII activity of above 8 U/ml and TSAb activity of above 1.0 TSH microUEq.(ABSTRACT TRUNCATED AT 250 WORDS)

We investigated levels of the glycine cleavage system in livers of spf-fur mutant mice with ornithine transcarbamylase (OTC) deficiency treated with sodium benzoate. The activities of the glycine cleavage system in benzoate-treated spf/Y males and the control mice livers are not significantly different. We examined plasma folate level and Vit. B6 status in a patient with OTC deficiency during the therapy with benzoate. Plasma folate level and vitamin B6 status during the therapy period and during control period are not different and these data were within normal ranges. The observation suggests that the glycine cleavage system is not the candidate for the increase of the de novo synthesis of glycine in hyperammonemic patients treated with benzoate.

DNA samples from five unrelated Japanese patients with 21-hydroxylase (21-OHase) deficiency were studied by Southern analysis using human 21-OHase cDNA. Patterns seen after digestion with not only TaqI but also KpnI showed that two out of the five patients were homozygous for a deletion of the 21-OHase B gene. This result supports the report that the 21-OHase B gene is functional. In the other three, smaller mutations might be responsible for the disorder. The parents of one of the two patients with the deletion had a common ancestor. Hybridization patterns of DNA from members of the family of the patient were consistent with an autosomal recessive mode of inheritance of the deletion that correlates with the clinical phenotype. The deletion segregated with HLA-Aw 24; Bw 61; Cw 3. Heterozygous carriers of 21-OHase deficiency could be detected by comparing the patterns as well as the HLA haplotypes in this family. The application of the family study to the prenatal diagnosis is also discussed.

The seasonal distribution of birth dates of 31 patients with sporadic cretinism due to thyroid dysgenesis was analyzed in Osaka area for 14 years. The incidence was statistically high in the summer months. A hypothesis that some environmental factors such as viral infection may cause the disease is proposed.

Various assay methods for detection of thyroid hormones in human milk were evaluated in recovery and dilution experiments after which the concentrations of thyroxine (T4) and 3,5,3'-triiodothyronine (T3) were measured and compared with those in serum. The effect of breast feeding on pituitary thyroid function of normal babies also was studied. Competitive protein-binding analysis (CPBA) was found to be unsuitable for measurement of T4 in milk. T4 was not detected in samples of human milk by four radioimmunoassays (RIA), although more than 100% of T4 was recovered in the assays. RIA (double antibody-ANS system) seemed to be reliable for detection of T3 in milk, judging from recovery and dilution experiments. T3 was detectable in all samples obtained 1-4 months postpartum. The T3 concentration in milk was not correlated with protein concentration or daily volume. The concentration of T3 in milk was lower than that in serum and the mean ratio of serum T3 to milk T3 was 2.8 +/- 1.7 (mean +/- S.D.). No correlation was observed between the T3 concentration or daily T3 excretion in milk and the T3 concentration in serum. The total amount of T3 excreted in milk was estimated as only 5-1000 ng/day. The serum levels of thyrotropin, T4, free T4 and T3 were not significantly different between breast-fed and bottle-fed babies. These results indicate that T3 excretion in milk cannot be explained by simple diffusion from the blood into the mother's milk and that breast feeding has no influence on the pituitary thyroid axis of normal babies.

Our study of insulin-dependent diabetic teenagers proved that a multiple insulin injection regimen (MIR) can be an acceptable and effective method of glycemic control. Further, the artificial beta cell can be used to determine insulin requirements for MIR. And finally, continuous indirect calorimetry can be used to assess metabolic control in diabetes.

A case of mucolipidosis II was studied biochemically, nutritionally and immunologically. A possible functional deficiency of T cells was observed, but discrepancy between B cells and immunoglobulin content was not reasonably explained at this moment. There was no basic nutritional problem in this case and it is more likely that his growth retardation was due to frequent episodes of severe respiratory infection because he received adequate calorie intake with low normal basal metabolic rate. Results of enzymatic assays were also presented.

Serum and urinary organic acids in a 9-year-old girl with ornithine transcarbamylase deficiency were investigated. The urinary excretion of alpha-ketoglutarate (alpha-KG) and citrate were abnormally high. An inverse linear correlation was found between the plasma ammonium and alpha-KG levels when the plasma ammonium level was less than 200 micrograms/dl, but not at higher levels, suggesting that on overloading with ammonium, its route of metabolism and compensating mechanism are not functionally normal. After administration of NH4Cl, plasma and urinary levels of alpha-KG, pyruvate and citrate increased, but the urinary succinate level decreased slightly. After oral administration of citrate the plasma alpha-KG level increased and the ammonium level decreased transiently. Our results suggest that administration of citrate or alpha-KG is not effective for reducing hyperammonemia in ornithine transcarbamylase deficiency.

The effects of three isocaloric intravenous nutritional regimens were studied in seven infants and children, ages 2 months to 9 yr, with congenital gastrointestinal anomalies (four patients) or with prior history of malignant disease admitted in remission for bone marrow transplantation (three patients). Energy metabolism, as measured by the basal metabolic rate (BMR), and substrate utilization, as measured by the respiratory quotient (RQ), were studied to determine the effect of different levels of carbohydrate and fat on nitrogen retention in each patient. Solution A provided 8% of energy as amino acids, 87% as carbohydrate, and 5% as fat. Solution B provided 8% of energy as amino acids, 60% as carbohydrate, and 32% as fat. Solution C provided 8% of energy as amino acids, 34% as carbohydrate, and 58% as fat. Administration of solution A (high carbohydrate, low fat) was associated with moderately increased mean (+/- SD) BMR and RQ and with low nitrogen retention (19.1 +/- 12.7%, 1.06 +/- 0.14, and 98 +/- 28 mg N/kg/day). Both the BMR and the RQ decreased when less carbohydrate and more lipid was given: BMR 4.3 +/- 11.6% (p less than 0.005), RQ 0.92 +/- 0.09 (p less than 0.001) for solution B; BMR 3.94 +/- 10.6% (p less than 0.005), RQ 0.86 +/- 0.09 (p less than 0.001) for solution C. Among the solutions tested, optimal nitrogen retention [163 +/- 60 mg N/kg/day (p less than 0.01)] was noted with solution B. Our data support the conclusion that a physiologic balance of fat and carbohydrate results in optimal nitrogen retention.

The levels of copper and ceruloplasmin in the cerebrospinal fluid (CSF) of patients with Wilson disease were investigated. Ceruloplasmin concentrations in the CSF of all patients were almost the same but were lower than those of the controls. CSF copper concentrations in patients without neurologic signs were within the normal range, 22 +/- 6 ng/ml. In contrast, CSF copper concentrations in patients with neurologic signs (69-98 ng/ml) were significantly higher than the normal levels before and at the beginning of the treatment with D-penicillamine; it gradually decreased in response to treatment. These results suggest that the appearance of neurologic manifestations in Wilson disease is not related to the CSF ceruloplasmin concentration. The CSF copper concentration in this disease appears to reflect copper accumulation in the brain and may be useful as a marker for monitoring therapy.