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Tyrosine (Tyr) is an essential amino acid in phenylketonuria (PKU) because of the limited hydroxylation of phenylalanine (Phe) to Tyr. The recommended intakes for Tyr in PKU are at least five times the recommended phenylalanine intakes. This suggests that Phe and Tyr contribute ∼20 and 80%, respectively, of the aromatic amino acid (AAA) requirement (REQ). In animals and normal humans, dietary Tyr was shown to spare 40–50% of the Phe requirement, proportions that reflect dietary and tissue protein composition. We tested the hypothesis that the Tyr REQ in PKU would account for 45% of the total AAA REQ by indicator amino acid oxidation (IAAO). Tyr REQ was determined in five children with PKU by examining the effect of varying dietary Tyr intake on lysine oxidation and the appearance of13CO2in breath (F13CO2) under dietary conditions of adequate energy, protein (1.5 g ⋅ kg−1⋅ day−1), and phenylalanine (25 mg ⋅ kg−1⋅ day−1). Lysine oxidation and F13CO2were determined using a primed 4-h oral equal-dose infusion ofl-[1-13C]lysine. Lysine oxidation and F13CO2decreased linearly as Tyr intake increased, to a break point that was interpreted as the mean dietary Tyr requirement (16.3 and 19.2 mg ⋅ kg−1⋅ day−1, respectively). At Tyr intakes of >16.3 and 19.2 mg ⋅ kg−1⋅ day−1, lysine oxidation and F13CO2, respectively, were low and constant. This represents 40.4 and 44.4%, respectively, of the total AAA intake. The current recommendations for Tyr intake in PKU patients appear to be overestimated by a factor of ∼5. This study is the first application of the IAAO technique in a pediatric population and in humans with an inborn error of metabolism.

Whether specific cognitive deficits related to frontal-lobe dysfunction that have been reported in individuals with phenylketonuria (PKU) are also characteristic of mild hyperphenylalaninemia (MHP) was investigated. Tests of executive function and control tasks not assessing executive function were administered to a group of individuals with MHP and a group without MHP, similar in age, gender, and IQ. Tests of academic skills and behavior-rating questionnaires were also administered to the group with MHP. No group differences were found for any measure, suggesting that the mild elevations of phenylalanine in individuals with MHP are not sufficient to produce behavioral and cognitive impairments characteristic of PKU.

Summary A previously unreported complication of minitracheotomy is described. The minitracheotomy introducer was lost into the pleural cavity and a thoracotomy was required to remove it.

Fabry's disease is a rare cause of cardiomyopathy. There are no previous reported cases of cardiac transplantation for end-stage cardiomyopathy secondary to Fabry's disease. Recurrence of disease in allografts following renal transplantation has been documented, but the course following heart transplantation is not known. A 53-year-old female presented with congestive heart failure and was found to have end-stage restrictive cardiomyopathy secondary to Fabry's disease, as diagnosed by endomyocardial biopsy. She underwent cardiac transplantation. Eight weeks post-transplantation, electron microscopy of an endomyocardial biopsy specimen showed concentric lamellar inclusions within myocytes similar to inclusions seen in the preoperative biopsy and the explanted heart. However, subsequent biopsies up to one year after heart transplantation did not show any such inclusions. There has been no clinical evidence of Fabry's cardiomyopathy. Heart transplantation is a viable option for end-stage Fabry's cardiomyopathy. However, long term follow-up is required to determine clinical outcome.

Central nervous system malformations have been reported in a number of inherited enzyme defects. Ethylmalonic encephalopathy, an organic aciduria of unknown pathogenesis, has not been reported previously in association with brain or spinal cord malformations. We report on 2 sibs with confirmed ethylmalonic encephalopathy and malformations of the central nervous system; one with tethered cord, the other with cerebellar tonsillar ectopia (Chiari I malformation).

We report on 2 patients with de novo proximal interstitial deletions of the long arm of chromosomes 4: in one the deletion resulted in monosomy (4)(q21.3q23), in the other it produced monosomy (4)(q13.2q23). Review of 9 cases of deletions involving the 4q21/4q22 region reported previously detected a characteristic phenotype in 8 patients. This phenotype was present in our patients. We conclude that the deletion in the 4q21/4q22 region results in a specific clinical syndrome associated with central nervous system overgrowth that may be a result of anomalous imprinting in the 4q21/4q22 region.

Canavan disease is inherited as an autosomal recessive trait that is caused by the deficiency of aspartoacylase (ASPA). The majority of patients with Canavan disease are from an Ashkenazi Jewish background. Mutations in ASPA that lead to loss of enzymatic activity have been identified, and E285A and Y231X are the two predominant mutations that account for 97% of the mutant chromosomes in Ashkenazi Jewish patients. The current study was aimed at finding the molecular basis of Canavan disease in 25 independent patients of non-Jewish background. Eight novel and three previously characterized mutations accounted for 80% (40/50) of mutant chromosomes. The A305E missense mutation accounted for 48% (24/50) of mutant chromosomes in patients of western European descent, while the two predominant Jewish mutations each accounted for a single mutant chromosome. The eight novel mutations identified included 1- and 4-bp deletions (32 deltaT and 876 deltaAGAA, respectively) and I16T, G27R, D114E, G123E, C152Y, and R168C missense mutations. The homozygous 32 deltaT deletion was identified in the only known patient of African-American origin with Canavan disease. The heterozygosity for 876 deltaAGAA mutation was identified in three independent patients from England. Six single-base changes leading to missense mutations were identified in patients from Turkey (D114E, R168C), The Netherlands (I16T), Germany (G27R), Ireland (C152Y), and Canada (G123E). A PCR-based protocol is described that was used to introduce mutations in wild-type cDNA. In vitro expression of mutant cDNA clones demonstrated that all of these mutations led to a deficiency of ASPA and should therefore result in Canavan disease.

Familial hypercholesterolemia (FH), an inherited autosomal dominant disorder of lipoprotein metabolism, is associated with premature atherosclerosis. The recommended pediatric therapy consists of dietary intervention and, when necessary, treatment with bile acid-binding resins. However, compliance has been poor in many children. Therefore, our objectives were to determine the efficacy, safety, and tolerance of the short-term use of lovastatin, a 3-hydroxy 3-methylglutaryl coenzyme A reductase inhibitor, in the control of severe FH in a male pediatric population and to evaluate the dose-response relationship.Sixty-nine male patients with FH 12.9 +/- 2.4 years of age (mean +/- SD) participated in this multicenter, randomized, double-blind trial. After a 4-week placebo period, the patients were allocated to four treatment groups (lovastatin 10, 20, 30, 40 mg/d) for 8 weeks. Plasma lipid and apolipoprotein (Apo) concentrations were measured every 2 weeks. Clinical and laboratory evidence of adverse events was monitored periodically throughout the study.All lovastatin doses reduced total cholesterol (-17% to -29%), low density lipoprotein cholesterol (-21% to -36%), and ApoB (-19% to -28%) concentrations. A dose-response relationship was seen, and between-group comparisons showed that results were significantly improved up to a dose of 30 mg/d. We observed a 7% increase in high-density lipoprotein cholesterol and a 4% increase in ApoA1 concentrations. The medication was well tolerated by all patients. No serious clinical adverse experience was reported. Lovastatin increased aspartate aminotransferase concentrations, but there was no evidence of a dose-response relationship, and no value exceeded two times the upper limit of normal. No significant change in alanine aminotransferase was observed. Three patients had marked (more than three times the upper limit of normal) asymptomatic elevations in their creatine kinase values, which returned spontaneously to normal, and no action was required regarding the drug.

It is not commonly appreciated that patients with hexosaminidase A deficiency (Tay-Sachs disease) can first present in adulthood with psychiatric illness.A 17-year-old non-Jewish male patient was referred with a history of treatment-resistant catatonic schizophrenia. We uncovered coexistent neurologic abnormalities and evidence of cognitive decline. Metabolic screening revealed a severe deficiency of beta-hexosaminidase A. We reviewed the literature on late-onset gangliosidosis with attention to (1) the nature of the associated psychiatric and neurologic abnormalities and (2) the treatment of psychosis in these patients.The patient's catatonia responded promptly to benzodiazepine therapy. Treatment with neuroleptic medication resulted in the rapid development of neuroleptic malignant syndrome. The patient was thereafter maintained on lorazepam with resolution of his acute psychiatric disturbances and unexpected improvement in his neurologic status.Patients with hexosaminidase deficiency may first present in adolescence or adulthood with psychiatric illness, particularly schizophrenic-like psychosis. The presence of speech disturbance, gait abnormalities, movement disorders, and cognitive decline may indicate an underlying metabolic disorder. The use of traditional neuroleptics to treat the psychosis in such individuals may produce an unacceptably high risk/benefit ratio. Benzodiazepines may ameliorate the psychiatric and neurologic abnormalities in these patients.

Summary One hundred unpremedicated fit adult patients having elective minor day-stay surgery and general anaesthesia were randomly allocated to one of two groups. During 30 s of intravenous propofol administration (2.5 mg.kg-1), study group patients (n = 50) were instructed to take three vital capacity breaths of room air, whilst control group patients (n = 50) were given no specific instructions. Pulse oximetry was continuously recorded over the next 5 min and the lowest oxygen saturation was noted. Pre-induction oxygen saturation was the same for both groups, but the lowest median oxygen saturation in the study group patients was 94% versus 88% in the control group patients (p < 0.001). Oxygen saturation returned to the pre-induction value significantly earlier in the study group patients compared with controls (97 s vs 135 s, p < 0.01). These results demonstrate that significant desaturation occurs in patients following intravenous induction of anaesthesia with propofol. This desaturation may be attenuated by asking patients to take three vital capacity breaths of room air during induction of anaesthesia.

The role of neuroimaging in the lysosomal disorders has previously been limited to the initial evaluation and diagnosis of these disease processes and to the detection of treatable disease-related complications, such as hydrocephalus. Localization of changes to the gray or the white matter was useful in guiding the metabolic evaluation when clinical findings were indeterminate or unclear. Imaging features such as dilated VR spaces in MPS storage disease or focal calcifications in Krabbe's disease were occasionally pathognomonic for or highly suggestive of a specific disorder. Now that treatment options, including enzyme replacement therapy and bone marrow transplantation, are available for some of the neurometabolic disorders, staging before the initiation of therapy and evaluation throughout therapy are additional important roles. Even in those disease processes that are currently untreatable, imaging is useful in defining the radiographic appearance of the natural course of a given disorder, to aid in staging and treatment evaluation of future patients with that same disorder when treatment becomes available.

Two female siblings, offspring of consanguinous parents, died at 10 and 12 wk of age following short illnesses characterized clinically by hypoxia and severe metabolic acidosis. Cardiac catheterization confirmed severe pulmonary hypertension in the second infant, who survived 6 wk after onset of symptoms and 4 wk after admission to hospital; extensive investigations failed to identify any inborn metabolic error. At autopsy, small pulmonary arteries/arterioles in both cases showed marked medial thickening due to smooth muscle hyperplasia; concentric intimal fibrosis was present focally in the older infant. Compared morphometrically with small pulmonary arteries in 20 infantile controls who died of Reye's syndrome (n = 8), a Reye's-like illness (n = 5) or an identified metabolic error associated with metabolic acidosis (n = 7), intraacinar pulmonary arteries in both cases, were significantly more numerous and had a significantly greater relative medial thickness. We suggest that an autosomal recessive gene caused or potentiated the pulmonary medial hyperplasia. The latter finding, compared with medial hypertrophy, is rarely described as the morphologic basis of pulmonary hypertension, and its occurrence may be restricted to early infancy. In this family, the relationship between hypertensive pulmonary arteriopathy and severe metabolic acidosis remains speculative.

Tay-Sachs disease (TSD, GM2 gangliosidosis, Type I) is an autosomal recessive lysosomal storage disease caused by deficiency of beta-hexosaminidase A (Hex A) resulting from mutations in the gene (HEXA) encoding the alpha-subunit of the enzyme. Three mutations, in exons 7 and 11 and at the exon 12-intron 12 junction, account for90% of alleles identified in obligate Ashkenazi Jewish carriers. Mutation analysis requires amplification of available DNA by separate polymerase chain reactions (PCRs) and either restriction digestion and gel electrophoresis or 32P-labeled allele-specific oligonucleotide (ASO) probes. We developed a simple, nonradioisotopic method for rapidly identifying TSD carriers by a triplex PCR reaction followed by dot-blot analysis, using three wild-type and three mutant ASOs end-labeled with digoxigenin-dUTP (dig-ASO). Hybridization was demonstrated immunologically by reaction with an anti-digoxigenin-alkaline phosphatase conjugate followed by colorimetric demonstration of phosphatase activity. The results of analyses by the dig-ASO method of 65 carriers identified by serum enzyme activity and of 6 high-risk fetuses in prenatal testing were the same as those obtained by more conventional restriction analysis. Dig-ASO testing correctly reclassified 10 individuals who had tested inconclusively on analysis for leukocyte beta-hexosaminidase A activity; 3 were identified as carriers and 7 as noncarriers. The simplicity of the assay and the avoidance of the radioisotopes make this a potentially useful method for TSD carrier detection by mutation analysis in Ashkenazi Jews from populations in whom the identity and frequencies of the common TSD mutations are known.

The rapid identification of mutations causing Tay-Sachs disease requires the capacity to readily screen the regions of the HEXA gene most likely to be affected by mutation. We have sequenced the portions of the introns flanking each of the 14 HEXA exons in order to specify oligonucleotide primers for the PCR-dependent amplification of each exon and splice-junction sequence. The amplified products were analyzed, by electrophoresis in nondenaturing polyacrylamide gels, for the presence of either heteroduplexes, derived from the annealing of normal and mutant DNA strands, or single-strand conformational polymorphisms (SSCP), derived from the renaturation of single-stranded DNA. Five novel mutations from Tay-Sachs disease patients were detected: a 5-bp deletion of TCTCC in IVS-9; a 2-bp deletion of TG in exon 5; G78 to A, giving a stop codon in exon 1; G533 to T in exon 5, producing the third amino acid substitution detected at this site; and G to C at position 1 of IVS-2, expected to produce abnormal splicing. In addition, two mutations, (G1496 to A in exon 13 and a 4-bp insertion in exon 11) that have previously been reported were identified.

The mucopolysaccharidoses are rare, genetically transmitted metabolic disorders that affect children early in life. These potentially life-threatening diseases almost invariably involve the auditory apparatus and the upper respiratory tract. Thus, the otolaryngologist is frequently involved in the care of these patients. This paper presents a 10-year retrospective review of the management of these patients at the Hospital for Sick Children. Data concerning auditory and upper respiratory pathology are presented. Results indicate that persistent serous otitis, sensorineural hearing loss, and upper respiratory obstruction leading to sleep apnea, are frequent findings in these patients. Specific recommendations are made with regard to appropriate otolaryngologic intervention in children affected with these diseases.

Eighteen males, 17 of whom were members of a single family, affected with angiokeratoma corporis diffusum were examined in detail to determine the extent of clinical variation of the expression of what was almost certainly the same X-linked mutation in each. The commonest symptom was episodic bouts of severe, painful dysaesthesia in hands and feet. This was a major complaint of 12, a minor complaint of 5, and absent in 1. In over half the subjects, the skin rash that is considered a characteristic sign of the disease was absent or inconspicuous. All exhibited mild clubbing of fingers and toes, and 15 showed variable limitation of active and passive extension of the 5th fingers bilaterally. Only 2 (age 36 and 47) had evidence of significant renal disease. Electrocardiograms showed abnormally short PR intervals in 4, and right ventricular conduction disturbances in 5. Echocardiograms on 9 showed no evidence of myocardial dysfunction. The marked variation of the expression of some features of the disease indicates that the clinical expression of the mutation is likely to be subject to considerable genetic or environmental modification in each individual.

An 8-week-old boy presented with a history of irritability, progressive feeding difficulty, generalised weakness, tachypnoea, and minor motor seizures. The clinical course was characterised by rapidly progressive respiratory failure, and neurological deterioration culminating in death at age 15 weeks. Electron microscopical examination and histological studies of the lung showed the presence of numerous intra-alveolar and a few interstitial macrophages. Enzyme studies and subsequent histopathological studies on brain confirmed the diagnosis of an unusual variant of Krabbe globoid cell leucodystrophy.

Since at present chromatographic methods for the separation of the glycosylated haemoglobins and determination of haemoglobin A1c are time-consuming and require continuous monitoring, a new micro-column method is reported that is cheap, rapid, easy to perform and permits anything up to 30 columns to be run simultaneously. The haemoglobin A1c leve in fifty normal subjects was measured and found to have a mean of 5.3 +/- 0.5% (m +/- S.D.).

The transition from a fee-for-service model to a prepaid health care system creates new challenges for both physicians and patients. Occasionally both can feel trapped in the new setting and must rely on new or different strategies to reach sometimes divergent objectives. This may alter the physician-patient relationship in ways that neither likes. Based on our experience in a large multispecialty academic group practice, we have developed management strategies to mitigate such stresses on both parties. These include review of marketing efforts; education of new patients to foster realistic expectations; a physician-generated, prospective internal policy for dealing with dissatisfied patients and physicians; a strong central administrative physician to serve as a "lightning rod" and counselor; and continuing physician orientation and education to improve judgment and attitudes. These strategies promote the physician's role as expert consultant-educator with the best interests of the patient as the first priority.

In order to test the feasibility of returning older children with classical phenylketonuria (PKU) to therapeutically and nutritionally adequate phenylalanine-restricted diets after 8 to 13 years of unrestricted diets, 7 adolescents (13 to 19 years old) of normal or near-normal intelligence with classical PKU were returned to phenylalanine-limited diets for periods of 8 to 10 weeks. During a 4- to 5-week period when the phenylalanine-restricted diet was supplemented with added L-phenylalanine to mimic pretreatment conditions, plasma phenylalanine levels were 1,327 +/- 282 microM on total phenylalanine intakes of 2,794 +/- 248 mg/day (55.3 +/- 11.5 mg/kg/day). During a similar period of dietary phenylalanine restriction, plasma phenylalanine levels were successfully maintained at 713 +/- 266 microM on dietary intakes of 655 +/- 210 mg/day (12.6 +/- 4.3 mg/kg/day). On the basis of 3-day diet records, the intakes of total protein, energy, calcium, phosphorus, iron, vitamins D, E, and A, ascorbic acid, thiamin, riboflavin, niacin, folacin, and vitamin B-12 over the entire 8- to 10-week study period were adequate by the standards of the Recommended Nutrient Intakes (RNI) for Canada, where the study was undertaken. Intakes of magnesium and zinc were significantly lower than the RNI. Although the return to nutritionally and therapeutically adequate dietary phenylalanine restriction was judged to be successful in each case, the amount and intensity of re-education and reinforcement required to maintain compliance was much greater than anticipated.

Human serum was exposed to various amounts of [6-3H] galactosyl-(alpha1 goes to 4)-galactosyl-(beta1 goes to 4)-glucosylceramide under standardized conditions in vitro, and the uptake of the lipid by serum lipoproteins was determined. Of the bound glycolipid, 2% was isolated with very low density, 24% with low density-, 47% with high density lipoproteins and 27% with the ultracentrifugal residue. The distribution was different from the distribution of endogenous galactosyl-galactosylglucosylceramide, indicating that the glycolipid is probably an integral part of the lipoprotein complexes in vivo.

The metabolism of endogenous sphingomyelin labeled with 32P or [methyl-3H]choline and of exogenous [choline-methyl-3H], [32P]-, or [N-acyl-1-14C]sphingomyelin was studied in normal and Niemann-Pick Type A (NP-A) cultured fibroblasts. Despite a greater than 96% decrease in lysosomal sphingomyelinase activity in the NP-A cells, they were able to degrade endogenously produced [32P]- or [methyl-3H]sphingomyelin at normal or near normal rates. Exogenous [methyl-3H]-, [methyl-3H, 32P]-, and [methyl-3H, N-acyl-1-14C] sphingomyelin was taken up intact by normal and NP-A cells, with NP-A cells accumulating 4-8 times more lipid. By 20 h, 50% of the control cell-associated 3H and 32P was recovered in lecithin, and the ratio of activities (3H/32P) indicated most of the phosphorylcholine derived from sphingomyelin had been transferred intact. By comparison in NP-A cells, after a 40-h incubation only 20% of the labeled phosphorylcholine derived from sphingomyelin was recovered in lecithin. With both cell lines, 20 to 50 times more sphingomyelin was hydrolyzed than was taken up by the cells; the reaction products in the medium were ceramide and a mixture of water-soluble compounds such as phosphorylcholine and choline. These results indicate that there are at least two metabolic pathways for sphingomyelin modification in cultured fibroblasts in addition to degradation by the lysosomal acid sphingomyelinase. One route is hydrolysis by a cellular sphingomyelinase. The second is the hydrolysis and/or transfer of phosphorylcholine from sphingomyelin and results in the synthesis of lecithin.

Nine adolescents with phenylketonuria (PKU), who had been on unrestricted diets for 2 to 11 years, underwent serial neuropsychological testing over two consecutive 4- to 5-week periods during which each was maintained on a low-phe diet supplemented in a triple-blind fashion either with L-phe (high phe) or L-alanine (low phe). Assignment to the initial condition was done randomly, and the alternate condition was substituted at the end of the first 4- to 5-week period. In 6 of 7 subjects with PKU, baseline median choice reaction times (RTs) were slower than those of controls matched for age, sex, handedness, and Full-Scale IQ (WISC-R). A highly significant improvement occurred during the low-phe phases of the study. Results suggest that adolescents with PKU on unrestricted diets have a neuropsychological deficit that is out of proportion to their overall intellectual handicap. Moreover, this deficit appears to be at least partly reversible by return to dietary phe restriction despite years of hyperphenylalaninemia.