Charles R. Scriver

Phenylalanine hydroxylase deficiency

Phenylalanine hydroxylase deficiency is an autosomal recessive disorder that results in intolerance to the dietary intake of the essential amino acid phenylalanine. It occurs in approximately 1:15,000 individuals. Deficiency of this enzyme produces a spectrum of disorders including classic phenylketonuria, mild phenylketonuria, and mild hyperphenylalaninemia. Classic phenylketonuria is caused by a complete or near-complete deficiency of phenylalanine hydroxylase activity and without dietary restriction of phenylalanine most children will develop profound and irreversible intellectual disability. Mild phenylketonuria and mild hyperphenylalaninemia are associated with lower risk of impaired cognitive development in the absence of treatment. Phenylalanine hydroxylase deficiency can be diagnosed by newborn screening based on detection of the presence of hyperphenylalaninemia using the Guthrie microbial inhibition assay or other assays on a blood spot obtained from a heel prick. Since the introduction of newborn screening, the major neurologic consequences of hyperphenylalaninemia have been largely eradicated. Affected individuals can lead normal lives. However, recent data suggest that homeostasis is not fully restored with current therapy. Treated individuals have a higher incidence of neuropsychological problems. The mainstay of treatment for hyperphenylalaninemia involves a low-protein diet and use of a phenylalanine-free medical formula. This treatment must commence as soon as possible after birth and should continue for life. Regular monitoring of plasma phenylalanine and tyrosine concentrations is necessary. Targets of plasma phenylalanine of 120–360 μmol/L (2–6 mg/dL) in the first decade of life are essential for optimal outcome. Phenylalanine targets in adolescence and adulthood are less clear. A significant proportion of patients with phenylketonuria may benefit from adjuvant therapy with 6R-tetrahydrobiopterin stereoisomer. Special consideration must be given to adult women with hyperphenylalaninemia because of the teratogenic effects of phenylalanine. Women with phenylalanine hydroxylase deficiency considering pregnancy should follow special guidelines and assure adequate energy intake with the proper proportion of protein, fat, and carbohydrates to minimize risks to the developing fetus. Molecular genetic testing of the phenylalanine hydroxylase gene is available for genetic counseling purposes to determine carrier status of at-risk relatives and for prenatal testing.

Serum 1,25-Dihydroxyvitamin D Levels in Normal Subjects and in Patients with Hereditary Rickets or Bone Disease

The serum concentration of 1,25-dihydroxylvitamin D (1,25-[OH]2D) in normal children and in children with inherited diseases of bone was compared by use of a competitive binding assay. Observed values were: in 12 normal children and adolescents, 37.1 +/- 1.9 pg per milliliter (mean +/- S.D.); in 14 patients with X-linked hypophosphatemic rickets treated with vitamin D2 and phosphate supplements, 15.6 +/- 7.8 (P less than 0.01 versus control); in six patients with autosomal recessive vitamin D dependency treated with vitamin D2, 9.5 +/- 2.9 (P less than 0.01 versus control); and in four untreated patients with autosomal dominant hypophosphatemic (non-rachitic) bone disease, 30.2 +/- 6.3 (not significantly different from the controls). The difference in bone disease between X-linked hypophosphatemia (severe) and hypophosphatemic bone disease (mild) at comparable low serum levels of phosphate implies that 1,25-(OH)2D and phosphate may have independent roles in the pathogenesis of defective bone mineralization.

Labile methyl group balances in the human: the role of sarcosine.

Abstract Estimates of the daily rate of methionine utilization by adult humans, published previously, were under-estimated because available data did not permit quantitative assessment of the rate at which the methyl moiety of methionine is oxidized. 1 The present paper reports efforts to measure the rate of oxidation of methionine methyl by the two pathways that proceed through the intermediate N -methylglycine (sarcosine). Two sarcosinemic, sarcosinuric patients, proven or presumed to have specific genetic defects in the sarcosine-oxidizing system, were studied while maintained on constant diets containing differing amounts of methionine, choline (or choline derivatives), and glycine. The steadystate excretions of sarcosine, creatinine, creatine, and a number of other materials were determined. The results obtained suggest that sarcosine is formed in 2 ways: (1) In an amount equivalent to the dietary intake of choline (or choline derivative)—this pathway would make a net positive contribution to the methionine-methyl pool due to the transfer of a methyl group from betaine to homocysteine; and (2) By processes requiring net consumption of methionine methyl. For the single patient for whom reasonably complete data were attained, it appears that 2 such processes may be occurring. One proceeds at a rate (approximately 2 mmole/24 hr) that changed little as total intake of labile methyl groups ∗ was altered. The second became prominent (and accounted for the bulk of the incremental intake of labile methyl groups) when this intake exceeded the combined amounts required for the synthesis of creatine (10.2 mmole/24 hr), other transmethylation reactions (1.4 mmole/24 hr), polyamine synthesis (0.5 mmole/24 hr), and the “basal” process of sarcosine formation just mentioned (2 mmole/24 hr). It is possible that such “basal” sarcosine formation is due chiefly to endogenous choline synthesis, balanced by degradation, whereas the more responsive process of sarcosine formation may be due chiefly to methylation of glycine. Together with available data, these new data on methionine consumption due to sarcosine formation permit calculation of a turnover time for S-adenosylmethionine in human liver (no more than 3.5–7 min), as well as upward revision of previous minimal estimates 1 of the rate of methylneogenesis, the number of times that the average homocysteinyl moiety cycles between methionine and homocysteine during its passage through the body, and the partitioning of homocysteine between the remethylation and the transsulfuration pathways.

Use of Phosphate and Vitamin D to Prevent Dwarfism and Rickets in X-Linked Hypophosphatemia

Abstract Eight children with X-linked hypophosphatemia (three girls and five boys between three and 15 years of age) were treated for a total of 11,297 patient days with an inorganic phosphate salt...

Hyperparathyroidism as the Cause of Hyperaminoaciduia and Phosphaturia in Human Vitamin D Deficiency

Extract: Thirty-nine infants with simple vitamin D deficiency were studied; three stages of deficiency were recognized. Stage I comprised hypocalcemia, usually as the sole important biochemical finding, while convulsions were a common clinical sign. Stage II revealed normocalcemia with hyperaminoaciduria, hypophosphatemia, and hyperphosphaturia; rickets was also in evidence. Stage III was comparable to stage II, but with recurrence of hypocalcemia and convulsions, the rickets was more severe. Patients progressed spontaneously from the early to the later stages of the deficiency syndrome; administration of parathyroid extract appeared to accelerate the rate of progression. Calcium infusion and vitamin D therapy each initially raised the serum calcium level in hypocalcemic patients; thereafter, aminoaciduria and hyperphosphaturia were suppressed.These diverse observations were interpreted in accordance with current knowledge of vitamin D and parathyroid hormone interrelations. The acquired excretory abnormality involving amino acid and phosphorus is the result of impaired tubular absorption; this defect is considered to be dependent on the development of endogenous reactive hyperparathyroidism, and not dependent on cellular deficiency of vitamin D per se. The stimulus for the hyperparathyroidism is hypocalcemia induced by deficiency of vitamin D. Normocalcemia is restored if sufficient vitamin D is present in cellular membranes to amplify the stimulative action of parathyroid hormone on intestinal transport of calcium and its release from bone. Severe deficiency of vitamin D blocks this regulatory effect upon calcium, but does not block the inhibitory effect of parathyroid hormone on renal tubular transport of amino acids and phosphorus.Speculation: An excess of parathyroid hormone rather than a simple deficiency of vitamin D at the renal tubular epithelial cell appears to cause the disturbance of transport affecting the absorption phosphorus, amino acids and other solutes. This impairment of function is the price paid in renal cellular economy for the conservation of calcium. The cellular mechanisms underlying this coexistent inhibitory effect of parathyroid hormone constitutes an important and fascinating subject for further investigation.

Age at onset and causes of disease.

We know a good deal about the origins and pathogenesis of monogenic diseases, but we still know too little of how and what the genes contribute to multifactorial diseases. We seldom know which loci are involved, or which alleles inhabit them. Nor can we say how the effects of each gene modify those of others in the deranged homeostasis that constitutes the phenotype. And we can seldom specify the elements of the environment that interact with the effects of the genes.

Familial Hyperprolinemia, Cerebral Dysfunction and Renal Anomalies Occurring in a Family with Hereditary Nephropathy and Deafness

This report presents clinical, genetic and biochemical studies of a family with cerebral dysfunction, congenital renal anomalies and a defect in the metabolism of the amino acid L-proline. In addit...

Serum Parathyroid Hormone in X-Linked Hypophosphatemia

Serum immunoreactive parathyroid hormone(IPTH) is normal in patients with X-linked hypophosphatemic rickets who are not treated with phosphate salts. Phosphate raises IPTH in these patients. Endogenous IPTH does not influence the existing defect in tubular reabsorption of phosphate in male patients.

An inherited disorder of isoleucine catabolism causing accumulation of alpha-methylacetoacetate and alpha-methyl-beta -hydroxybutyrate, and intermittent metabolic acidosis.

Extract: At least 15 apparently inherited disorders of branched chain amino acid catabolism are now known; the 12th in chronological order of discovery is described in this report. It is a partial defect of the pathway of isoleucine oxidation beyond the level of oxidative decarboxylation and prior to the oxidation of propionate. The impairment of isoleucine catabolism appears to be situated at the “thiolase” reaction which converts α-methylacetoacetyl coenzyme A (CoA) to propionyl-CoA and acetyl-CoA.Two pedigrees (B and M) were investigated in detail. A third (S pedigree) has been brought to our attention for analysis of metabolites in urine but we have not performed additional studies in the latter. Each propositus was ascertained because of intermittent, odorless metabolic acidosis usually precipitated by intercurrent infection. Lethargy and coma occurred frequently during the periods of acidosis. One M sib, also presumably affected, died abroad in such an episode. Symptoms can be ameliorated by a low protein diet and careful attention to the management of intercurrent illness.A large excess of α-methyl-β-hydroxybutyrate and a seemingly smaller excess of α-methylacetoacetate is present at all times in the urine of the three propositions. The M and S propositi also excrete N-tiglylglycine. The amounts of these unusual metabolites increase severalfold during acidosis and after a dietary load of l-isoleucine (75 mg/kg, 3 times daily for 2 days). The urine also contains butanone, particularly during acidosis. The amount of propionate and of glycine and other amino acids in blood and urine is always normal in our patients. Oxidation of l-isoleucine-U-14C to CO2 by cultured skin fibroblasts is about 45% of normal in the B propositus. The precise nature and location of the enzyme defect awaits clarification.Studies of family members reveal that presumed obligate heterozygotes excrete a small excess of α-methyl-β-hydroxybutyrate at all times; the amount can be increased by L-isoleucine feeding. The condition is apparently inherited in autosomal recessive fashion. It is likely that more than one form of mutant allele is responsible for the condition, as it is found in the three different pedigrees described here.Speculation: Investigation of “unexplained,” intermittent metabolic acidosis in childhood has led to the discovery of a “new” disorder of branched chain amino acid catabolism. Gas chromatography coupled with mass spectrometry were important aids to the diagnosis. Rapid escalation of acidosis during catabolic episodes encourages one to suspect that specific metabolites, themselves accumulating during episodic illness, may further inhibit the mutant enzyme. A temperature-sensitive mutant enzyme was not identified in cultured skin fibroblasts.

PAHdb: A locus-specific knowledgebase

PAHdb is an online relational locus‐specific “mutation database” (http://www.mcgill.ca/pahdb) for the human phenylalanine hydroxylase gene (symbol PAH) and its associated phenotypes (protein, metabolic, clinical). When combined with associated information (population distribution of allele, haplotype association, etc.) PAHdb functions as a knowledgebase. From the outset, and in the absence of raw data (e.g., sequence gels), PAHdb has instead been an annotated repository of information about mutations maintained by a team of curators. It is also disease‐oriented, being focused on a variant phenotype (hyperphenylalaninemia (HPA) and its most important form of disease, phenylketonuria (PKU)) resulting from primary dysfunction of the PAH enzyme (EC 1.14.16.1); it is “patient friendly” in that it contains information for those personally involved with HPA/PKU (MIM# 261600). PAHdb also serves its community through direct interaction. Hum Mutat 15:99–104, 2000.