The therapy of hyperammonemia due to ornithine transcarbamylase defiency in a male neonate.

Ornithine transcarbamylase deficiency in the male neonate has been considered to be invariably fatal because of the severity of the hyperammonemia. An extreme degree of hyperammonemia in a male neonate was brought under control by a series of exchange transfusions, prolonged peritoneal dialysis, adequate caloric intake, and a mixture of essential amino acids with an excess of aspartic acid and arginine. After the initial phase, it was possible to maintain the plasma ammonia level with dietary therapy alone, in spite of a number of complications that might be expected to cause tissue damage and increase the hyperammonemia.

Comparison of phenylketonuric and nonphenylketonuric sibs from untreated pregnancies in a mother with phenylketonuria.

Two children, one with phenylketonuria (PKU) and the other nonphenylketonuric, from untreated pregnancies in a mother with PKU provided the opportunity to compare the degree of damage from maternal PKU between these genotypically different fetuses. Both the phenylketonuric offspring and her nonphenylketonuric sib were microcephalic at birth and had congenital anomalies, esophageal atresia in the former and congenital dislocation of the hip in the latter. However, the phenylketonuric child also had intrauterine growth retardation while the nonphenylketonuric sib had normal weight and length at birth. Both children are mentally retarded with an IQ below 50 in the phenylketonuric child despite early dietary treatment for PKU and an IQ of 54 in the nonphenylketonuric sib. Both children also have hypoplasia of the corpus callosum and enlarged cerebral ventricles. This experience and review of the literature indicates that the residual liver phenylalanine hydroxylase activity of a nonphenylketonuric fetus offers little or no protection from damage in untreated maternal PKU. Consequently, the outcome in maternal PKU is likely to depend on control of the maternal biochemical abnormalities in the mother regardless of whether the fetus has or does not have PKU.

Nutrition in the management of inborn errors of metabolism.

The determination of specific nutrients is important in the diagnosis of several inborn errors of metabolism. Phenylketonuria (PKU) is a well-known example. In this case, the nutrient, phenylalanine, is assayed to confirm a diagnosis and is routinely measured to monitor therapy, which consists of a diet low in this particular amino acid. Although many of the described inborn errors of metabolism are uncommon, or even rare, in occurrence, the laboratory plays an essential role in the diagnosis and management of these diseases.

Baclofen in the treatment of polymyoclonus and ataxia in a patient with homocystinuria.

A patient with homocystinuria due to cystathionine beta-synthase deficiency developed severe progressive polymyoclonus and ataxia. To our knowledge, this is the first time polymyoclonus and ataxia have been reported in association with homocystinuria. Although cerebrovascular thrombosis is usually thought to be responsible for neurologic dysfunction in homocystinuric patients, no infarctions were demonstrated on magnetic resonance imaging scans in our case. We have previously reported that baclofen dramatically improved the polymyoclonus and ataxia in a patient with Unvericht-Lundborg disease. Baclofen given to our patient reversed the polymyoclonus and the ataxia as well. This suggests that patients with polymyoclonus and ataxia, no matter what the etiology, may benefit from the use of baclofen.

Newborn screening for homocystinuria.

It is becoming increasingly apparent that pyridoxine responsive homocystinuria patients are being missed by newborn screening programs. The possibility that screening for homocystine, rather than the methionine, might be more effective was investigated by comparing homocystine and methionine levels of non-responsive patients at diagnosis. The plasma methionine levels of 11 infants were much more abnormal than the homocystine levels. Urine homocystine was low or not detectable and always less than methionine. Therefore, methionine determination is much more effective than homocystine determination for newborn screening for homocystinuria. It seems that a second blood specimen at a later age may be required to find the pyridoxine responsive infants.

Familial congenital short small bowel with associated defects. A long-term survival.

In 1974, Royer et al. described a familial syndrome consisting of a short and sluggish small bowel, malrotation of the gut, and pyloric stenosis. These authors stressed the uniformly fatal outcome of their four cases, as well as other possibly unrecognized cases previously described in the literature. The present report deals with two more familial cases, of which one represents a long-term survivor of the syndrome. The intensive work of maintaining nutrition, controlling infection, and managing the complications of associated defects are described.

Biochemical and molecular diagnosis of lipoamide dehydrogenase deficiency in a North American Ashkenazi Jewish family.

A late-onset presentation of lipoamide dehydrogenase (E3) deficiency is described in a North American Ashkenazi Jewish (AJ) family. Diagnosis was made by urine organic acid and molecular analyses.

Cerebral glucose metabolism in adults with early treated classic phenylketonuria.

Classic phenylketonuria (PKU) is characterized by severe mental retardation in untreated individuals and mild neurocognitive abnormalities in some early treated adults. The exact biochemical mechanisms underlying this neurotoxicity remain undetermined. Several theories implicate abnormal cerebral energy utilization and alterations in biochemical pathways that involve glucose metabolism. This pilot study was undertaken to investigate whether 18F-deoxyglucose positron emission tomography (PET) is an effective tool to study cerebral glucose metabolism in early treated PKU. After PET coregistration with SPGR MRI, relative glucose metabolic rates (rGMR) at the center of standard atlas positions was determined. Repeated measures MANOVA was used to assess regional metabolic differences, which were then correlated with age-specific and day-of-scan plasma phenylalanine and age. Patients with PKU in comparison to controls had decreased rGMR in cortical regions including the prefrontal, somatosensory, and visual cortices, and increased activity in subcortical regions including the striatum and limbic system. Day-of-scan phenylalanine correlated with abnormal activity in subcortical structures, and older age was associated with decreased activity in the prefrontal and visual cortices. The clinical significance of these abnormalities of glucose metabolism in specific areas of the brain remains unknown.

The value of plasma citrulline to predict mucosal injury in intestinal allografts.

Diagnosis of intestinal transplant rejection depends on clinical assessment, endoscopy and most importantly, histology of intestinal biopsies. Plasma citrulline levels (P-Cit) reflect functional enterocyte mass in nontransplant patients and have been evaluated in two small series after transplant. This study was designed to determine the sensitivity and specificity of P-Cit as diagnostic tool for allograft injury, especially to distinguish between viral enteritis and rejection. We prospectively collected 403 P-Cit samples within 24 h of intestinal biopsy in 49 patients. P-Cit levels were correlated with the mucosal damage and histopathological diagnoses. P-Cit levels in bowels with significant mucosal damage (i.e. moderate or severe rejection, viral enteritis, PTLD, ischemia reperfusion injury, allergic enteritis) were significantly lower than in intestines with no or mild injury (i.e. indeterminate or mild rejection, nonspecific enteritis): 22.9 +/- 15.4 versus 38 +/- 23.2 nmol/mL (p < 0.0001). Sensitivity and specificity of the test were 80% and 58.1% for rejection, and 56.5% and 66% for viral enteritis, thereby unable to distinguish between both entities. In conclusion, P-Cit reflects the extent of mucosal injury regardless of the etiology, but does not seem to be a predictive marker for rejection or viral enteritis, as its values may decline only when diffuse mucosal damage has occurred.

Successful long term therapy of biopterin deficiency.

A hyperphenylalaninaemic infant, started on dietary therapy at 14 days of age, had severe developmental retardation and neurological abnormalities despite excellent biochemical control. A diagnosis of a deficit in biopterin synthesis was made at five months of age as a result of the following: high neopterin and low biopterin levels in both blood and urine, normal dihydropteridine reductase in the liver and a sharp drop in the plasma phenylalanine level 4 h after the administration of a test dose of tetrahydrobiopterin. Treatment with levodopa, carbidopa and 5-hydroxytryptophan resulted in prompt neurological improvement. This was followed by gradual and sustained development. At present, at the age of 7 years, the child is mentally and physically normal.

Influence of metabolic control on growth in homocystinuria due to cystathionine B-synthase deficiency.

The etiology of the tall stature almost invariably seen in homocystinuric patients is not known. The effect of metabolic control and the role of the GH-IGF system on growth were investigated in 10 patients with homocystinuria. There was a direct correlation between the plasma free homocyst(e)ine and growth velocity SD scores in 18 patient years (r, 0.46; p < 0.05). Plasma 2-y cumulative free homocyst(e)ine and height SD scores were directly correlated (r, 0.82; p < 0.01). Growth velocity SD scores were lower in patients with optimal metabolic control than in those with poorer control (-0.10 +/- 0.65 versus 0.95 +/- 0.68, p < 0.01). Height SD scores were also lower in the optimally controlled group (-0.01 +/- 0.81 versus 1.73 +/- 0.88, p < 0.05). GH and GH-related peptides did not deviate significantly from the reference ranges. These findings suggest that overgrowth is directly mediated by homocysteine, that the GH-IGF axis is not involved, and that it may be prevented by optimal metabolic control.

Argininemia.

The clinical features of argininemia in two cousins included hyperactivity, spasticity, ataxia, retardation, and repeated attacks of hyperammonemia. Study of a large kindred suggests that arginase-deficiency is transmitted as a Mendelian recessive. Treatment with an essential amino acid mixture with the total nitrogen intake limited to the requirement, controlled the hyperammonemia, reduced the plasma arginine level, and permitted a marked clinical improvement. There has been a significant increase in intelligence levels; the previously retarded children are now approaching the normal range of function.

The nutritional therapy of histidinemia.

Control of the plasma histidine level in histidinemia is possible with the use of an amino acid mixture free of histidine and a carefully monitored intake of histidine. This regimen is compatible with good physical growth and normal mental development. If further clinical experience demonstrates that widespread nutritional intervention in this disease is warranted, it should be possible to obtain good biochemical control.

Maple syrup urine disease: clinical, EEG, and plasma amino acid correlations with a theoretical mechanism of acute neurotoxicity.

Classical Maple Syrup Urine Disease (MSUD) is a disease of infancy which is an inherited disorder of metabolism of branched-chain amino acids (BCAA). The BCAA are normally transaminated to branched-chain keto acids (BCKA). However, the enzyme required to metabolize the BCKA is deficient, resulting in elevation of both, the BCAA and the BCKA. One of the BCAA (isoleucine) produces a metabolite that causes the urine to smell like maple syrup. The elevations of the BCAA and BCKA are associated with an acute, critical neurotoxic condition often prior to the age of two weeks. The clinical state, the electroencephalogram-(EEG), and plasma BCAA levels were evaluated in 26 patients with classical and variant MSUD. Patients were seen from the time of diagnosis, often within a week after birth, and some were followed clinically for more than 20 years while on specific diet therapy. They were monitored by plasma BCAA (leucine, isoleucine and valine) levels and a total of 101 EEGs were performed during different phases of their illness. During periods of acute metabolic decompensation, there were marked clinical symptoms of neurotoxicity including opisthotonos, seizures, and coma with elevated BCAA plasma levels. The EEGs revealed spikes, polyspikes, spike-wave complexes, triphasic waves, severe slowing and bursts of periodic suppression. Occasionally paradoxical EEG arousal was noted while the patient was lethargic. During asymptomatic periods when the plasma BCAA were at low or normal levels, EEG abnormalities occurred in patients with and without residual neurological deficit. These observations included rolandic sharp waves (comb-like rhythm) which were observed in 7 of 15 patients less than two months of age. Additionally, paroxysmal spike and spike-wave response to photic stimuli were observed in 9 of 17 patients. Loading tests were performed on three patients. Clinical and EEG changes were most marked after leucine. Less dramatic EEG changes also occurred with the other two BCAA loads but without clinical manifestations. Elevation of the appropriate BCAA plasma level occurred after each load. These studies and a review of the literature suggest that one component of the pathophysiological mechanism for the acute neurotoxic effects in this disorder is related to a defect in glutamate, glutamine and gamma-aminobutyric acid (GABA) production. The BCAAs are transaminated to BCKAs. Further metabolism of the BCKAs are blocked because of enzyme deficiency required for decarboxylation.(ABSTRACT TRUNCATED AT 400 WORDS)

Biochemical basis of type IB (E1beta ) mutations in maple syrup urine disease. A prevalent allele in patients from the Druze kindred in Israel.

Maple syrup urine disease (MSUD) is a metabolic disorder associated with often-fatal ketoacidosis, neurological derangement, and mental retardation. In this study, we identify and characterize two novel type IB MSUD mutations in Israeli patients, which affect the E1beta subunit in the decarboxylase (E1) component of the branched-chain alpha-ketoacid dehydrogenase complex. The recombinant mutant E1 carrying the prevalent S289L-beta (TCG --> TTG) mutation in the Druze kindred exists as a stable inactive alphabeta heterodimer. Based on the human E1 structure, the S289L-beta mutation disrupts the interactions between Ser-289-beta and Glu-290-beta', and between Arg-309-beta and Glu-290-beta', which are essential for native alpha(2)beta(2) heterotetrameric assembly. The R133P-beta (CGG --> CCG) mutation, on the other hand, is inefficiently expressed in Escherichia coli as heterotetramers in a temperature-dependent manner. The R133P-beta mutant E1 exhibits significant residual activity but is markedly less stable than the wild-type, as measured by thermal inactivation and free energy change of denaturation. The R133P-beta substitution abrogates the coordination of Arg-133-beta to Ala-95-beta, Glu-96-beta, and Ile-97-beta, which is important for strand-strand interactions and K(+) ion binding in the beta subunit. These findings provide new insights into folding and assembly of human E1 and will facilitate DNA-based diagnosis for MSUD in the Israeli population.