Stephen Kahler - Academia.edu (original) (raw)

Papers by Stephen Kahler

Neurology, Feb 8, 2000

The objective of this study was to investigate genes involved in the metabolism and function of v... more The objective of this study was to investigate genes involved in the metabolism and function of vitamin D as candidate genes for genetic susceptibility to MS. Restriction fragment length polymorphisms and highly polymorphic microsatellite markers within or very close to the 1,25(OH) 2 D 3 receptor (VDR) [12q14], the vitamin D binding protein (DBP) [4q12], and the 25(OH)D 3 1␣-hydroxylase [12q13] loci were analyzed for linkage or association with MS. We found no evidence for linkage or association of these candidate genes with MS in the Canadian population.

The Journal of Pediatrics, Aug 1, 1989

Although propionic acidemia and methylmalonic acidemia, two disorders of branched-chain amino aci... more Although propionic acidemia and methylmalonic acidemia, two disorders of branched-chain amino acid metabolism often complicated by chronic anorexia and vomiting, are not usually treated with parenteral nutrition for fear of amino acid overload and exacerbation of biochemical derangements, we gave long-term parenteral nutrition to two critically ill patients with these disorders. Health and growth were restored, and there was minimal production of abnormal metabolites. The dramatic clinical and biochemical improvement of these patients bolsters the concept that most of the toxic metabolites produced in these diseases are not related to the administered load of nutrient precursors, but rather to endogenous turnover of amino acids, particularly during a chronic catabolic state. Suppression of catabolism can produce striking biochemical and clinical improvement. With appropriate monitoring, parenteral nutrition can be used safely in the management of patients with these disorders.

American journal of medical genetics, Nov 20, 1995

Fryns syndrome is an autosomal recessive multiple congenital anomaly syndrome characterized by di... more Fryns syndrome is an autosomal recessive multiple congenital anomaly syndrome characterized by diaphragmatic hernia, unusual facies, and distal limb hypoplasia. It was first reported as a lethal condition. We report on a three-year-old survivor with Fryns syndrome, and provide a review on the outcome of other survivors. Patients who survive the neonatal period represent 14% of reported cases. Characteristics of survivors include less frequent diaphragmatic hernia and milder lung hypoplasia, absence of complex cardiac malformation, and neurologic impairment. Multiple central nervous system abnormalities have been reported in Fryns syndrome, including agenesis of the corpus callosum, DandyWalker abnormality, cerebellar heterotopias, cerebellar hypoplasia, enlarged ventricles, and hypoplasia of the olfactory bulbs. Our patient exhibited profound mental retardation. He had malformations of gyration and sulcation, particularly around the central sulcus, and hypoplastic optic tracts beyond the optic chiasm. Understanding of long-term outcome of survivors is important for counseling of families with Fryns syndrome. Careful brain examination is advised; however, a normal radiological brain examination does not preclude developmental delay. The spectrum of individual outcome and of associated anomalies indicates that individual evaluation, including imaging for structural brain malformation, is strongly advised.

Journal of Inherited Metabolic Disease, Sep 1, 1995

A new acylcarnitine was observed in the plasma and urine of a patient with isolated 3-methylcroto... more A new acylcarnitine was observed in the plasma and urine of a patient with isolated 3-methylcrotonyl-CoA carboxylase deficiency. Analysis by tandem mass spectrometry of the methyl ester and butyl ester and their fragment ion spectra identified it as a 3-hydroxy-C5-acylcarnitine. Fibroblasts from a second patient were incubated with deuterium-labelled leucine. Incorporation of label in the new acylcamitine identified its origin from leucine, and thus confirmed the structure as 3-hydroxyisovalerylcarnitine. The presence of elevated amounts of this metabolite, plus a small amount of 3-methylcrotonylcarnitine in plasma, was diagnostic for isolated 3-methylcrotonyl-CoA carboxylase deficiency. Other conditions in which a hydroxy-C5-acylcarnitine was present were readily differentiated by the abnormal elevation of other acylcarnitines.

Translational Psychiatry, Oct 1, 2016

Propionic acid (PPA) is a ubiquitous short-chain fatty acid, which is a major fermentation produc... more Propionic acid (PPA) is a ubiquitous short-chain fatty acid, which is a major fermentation product of the enteric microbiome. PPA is a normal intermediate of metabolism and is found in foods, either naturally or as a preservative. PPA and its derivatives have been implicated in both health and disease. Whereas PPA is an energy substrate and has many proposed beneficial effects, it is also associated with human disorders involving mitochondrial dysfunction, including propionic acidemia and autism spectrum disorders (ASDs). We aimed to investigate the dichotomy between the health and disease effects of PPA by measuring mitochondrial function in ASD and age-and gender-matched control lymphoblastoid cell lines (LCLs) following incubation with PPA at several concentrations and durations both with and without an in vitro increase in reactive oxygen species (ROS). Mitochondrial function was optimally increased at particular exposure durations and concentrations of PPA with ASD LCLs, demonstrating a greater enhancement. In contrast, increasing ROS negated the positive PPA effect with the ASD LCLs, showing a greater detriment. These data demonstrate that enteric microbiome metabolites such as PPA can have both beneficial and toxic effects on mitochondrial function, depending on concentration, exposure duration and microenvironment redox state with these effects amplified in LCLs derived from individuals with ASD. As PPA, as well as enteric bacteria, which produce PPA, have been implicated in a wide variety of diseases, including ASD, diabetes, obesity and inflammatory diseases, insight into this metabolic modulator from the host microbiome may have wide applications for both health and disease.

PubMed, Oct 1, 1985

We studied the presentation and results of medical therapy in 25 children with sex-linked dominan... more We studied the presentation and results of medical therapy in 25 children with sex-linked dominant hypophosphatemic rickets. The average age at diagnosis was 3.8 years. Reasons for the delay included misdiagnosis and failure to recognize the normal range of serum phosphorus levels in children. Early diagnosis and treatment (before age 1) was associated with normal alignment of the lower limbs. Combination therapy with phosphate and vitamin D2 improved growth and bone mineralization, but did not change the height percentile or limb alignment. Limited use of calcitriol (1,25-dihydroxyvitamin D3) was not helpful in the adolescent but was associated with limited height increase in two younger children. Early diagnosis and medical therapy should prevent bowing of the legs.

American journal of medical genetics, Dec 4, 1995

Five patients presenting with non-ketotic hyperglycinemia in the neonatal period were treated wit... more Five patients presenting with non-ketotic hyperglycinemia in the neonatal period were treated with sodium benzoate to normalize plasma glycine levels. This therapy resulted in seizure reduction and a marked increase in wakefulness. Plasma carnitine deficiency was noted in three of four patients tested, and benzoylcarnitine was identified in plasma, urine, and CSF. Treatment with L-carnitine normalized plasma free carnitine. L-carnitine showed a tendency to increase the glycine conjugation of benzoate. An episode of coma and increased seizures in one patient was associated with a toxic level of benzoate, probably due to insufficient mobilization of glycine for conjugation. High dose benzoate therapy improved the quality of life of surviving patients. Close monitoring of glycine, benzoate and carnitine levels is advised.

American Journal of Medical Genetics, Jul 15, 2008

Native American myopathy (NAM) [OMIM 255995], a putative autosomal recessive disorder, was first ... more Native American myopathy (NAM) [OMIM 255995], a putative autosomal recessive disorder, was first reported in the Lumbee Indians of North Carolina. NAM features include congenital weakness and arthrogryposis, cleft palate, ptosis, short stature, kyphoscoliosis, talipes deformities, and susceptibility to malignant hyperthermia (MH) provoked by anesthesia. This report documents the phenotypic complexity and natural history of this rare congenital disorder in fourteen individuals with NAM. Findings include a previously unreported 36% mortality by age 18.

Human Heredity, 1993

ABSTRACT

Southern Medical Journal, Oct 1, 1985

American journal of medical genetics, Nov 15, 1993

The Brachmann-de Lange syndrome (BDLS) is diagnosed in children on the basis of a distinctive cli... more The Brachmann-de Lange syndrome (BDLS) is diagnosed in children on the basis of a distinctive clinical phenotype which includes retarded physical growth. Because there are no

Clinical Chemistry, 1993

A new method for quantifying specific amino acids in small volumes of plasma and whole blood has ... more A new method for quantifying specific amino acids in small volumes of plasma and whole blood has been developed. Based on isotope-dilution tandem mass spectrometry, the method takes only a few minutes to perform and requires minimal sample preparation. The accurate assay of both phenylalanine and tyrosine in dried blood spots used for neonatal screening for phenylketonuria in North Carolina successfully differentiated infants who had been classified as normal, affected, and falsely positive by current fluorometric methods. Because the mass-spectrometric method also recognizes other aminoacidemias simultaneously and is capable of automation, it represents a useful development toward a broad-spectrum neonatal screening method.

Journal of Inherited Metabolic Disease, Jan 8, 2022

Journal of Bone and Joint Surgery, American Volume, Mar 1, 1980

Journal of Biological Chemistry, 1983

Annals of the New York Academy of Sciences, Apr 1, 1991

Springer eBooks, Sep 21, 2016

The Journal of Pediatrics, Jun 1, 2001