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Biomedical subjects

S G Kahler

Publications and source records attributed to S G Kahler.

At least 19 recordsLinked to original sources
PubMed2006

Autism and environmental genomics.

Autism spectrum disorders (ASD) are defined by behavior and diagnosed by clinical history and observation but have no biomarkers and are presumably, etiologically and biologically heterogeneous. Given brain abnormalities and high monozygotic concordance, ASDs have been framed as neurobiologically based and highly genetic, which has shaped the research agenda and in particular criteria for choosing candidate ASD genes. Genetic studies to date have not uncovered genes of strong effect, but a move toward "genetic complexity" at the neurobiological level may not suffice, as evidence of systemic abnormalities (e.g. gastrointestinal and immune), increasing rates and less than 100% monozygotic concordance support a more inclusive reframing of autism as a multisystem disorder with genetic influence and environmental contributors. We review this evidence and also use a bioinformatic approach to explore the possibility that "environmentally responsive genes" not specifically associated with the nervous system, but potentially associated with systemic changes in autism, have not hitherto received sufficient attention in autism genetics investigations. We overlapped genes from NIEHS Environmental Genome Project, the Comparative Toxicogenomics Database, and the SeattleSNPs database of genes relevant to the human immune and inflammatory response with linkage regions identified in published autism genome scans. We identified 135 genes in overlap regions, of which 56 had never previously been studied in relation to autism and 47 had functional SNPs (in coding regions). Both our review and the bioinformatics exercise support the expansion of criteria for evaluating the relevance of genes to autism risk to include genes related to systemic impact and environmental responsiveness. This review also suggests the utility of environmental genomic resources in highlighting the potential relevance of particular genes within linkage regions. Environmental responsiveness and systems impacts consistent with system-wide findings in autism are thus supported as important considerations in identifying the numerous and complex modes of gene-environment interaction in autism.

Animals↗
PubMed2001

Hepatic storage of glycogen in Niemann-Pick disease type B.

We report 2 patients with confirmed Niemann-Pick disease, type B, with previous diagnoses of glycogen storage disease based on excessive glycogen on liver biopsy specimens. These cases emphasize the importance of a complete evaluation, including biochemical confirmation, for patients with suspected metabolic storage diseases.

Child, Preschool↗
PubMed2000

Acute hydrocephalus in nonketotic hyperglycinemia.

We present four patients with typical neonatal onset non-ketotic hyperglycinemia (NKH) who developed hydrocephalus requiring shunting in early infancy. Brain imaging revealed acute hydrocephalus, a megacisterna magna or posterior fossa cyst, pronounced atrophy of the white matter, and an extremely thin corpus callosum in all. The three older patients had profound developmental disabilities. This suggests that the development of hydrocephalus in NKH is an additional poor prognostic sign.

Acute Disease↗
PubMed2000

Acylcarnitines in plasma and blood spots of patients with long-chain 3-hydroxyacyl-coenzyme A dehydrogenase defiency.

The acylcarnitines in plasma and blood spots of 23 patients with proven deficiency of long-chain 3-hydroxyacylcoenzyme A dehydrogenase were reviewed. Long-chain 3-hydroxyacylcarnitines of C14:1, C14, C16 and C18:1 chain length, and long-chain acylcarnitines of C12, C14:1, C14, C16, C18:2 and C18:1 chain length were elevated. Acetylcarnitine was decreased. In plasma, elevation of hydroxy-C18:1 acylcarnitine over the 95th centile of controls, in combination with an elevation of two of the three acylcarnitines C14, C14:1 and hydroxy-C16, identified over 85% of patients with high specificity (less than 0.1% false positive rate). High endogenous levels of long-chain acylcarnitines in normal erythrocytes reduced the diagnostic specificity in blood spots compared with plasma samples. The results were also diagnostic in asymptomatic patients, and were not influenced by genotype. Treatment with diet low in fat and high in medium-chain triglyceride decreased all disease-specific acylcarnitines, often to normal, suggesting that this assay is useful in treatment monitoring.

3-Hydroxyacyl CoA Dehydrogenases↗
PubMed2000

Acylcarnitines in fibroblasts of patients with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency and other fatty acid oxidation disorders.

Mitochondrial fatty acid oxidation disorders cause hypoglycaemia, hepatic dysfunction, myopathy, cardiomyopathy and encephalopathy. Despite their recognition for more than 15 years, diagnosis and treatment remain difficult. To help design rational diagnostic and therapeutic strategies, we studied the pathophysiology of accumulating metabolites in a whole-cell system. Acylcarnitines were quantified in cells and media of cultured fibroblasts after incubation with L-carnitine and fatty acids. Following incubation with palmitate, long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD)-deficient fibroblasts compared with controls showed elevation of hydroxypalmitoyl- and palmitoyl-carnitine and reduction of C10- and shorter acylcarnitines, and following incubation with linoleate an increase in C14:2-, C18:2- and hydroxy-C18:2- acylcarnitines and reduction in C10:1-acylcarnitines. Hydroxyacylcarnitines remained more intracellular compared to corresponding saturated acylcarnitines. Incubation with decanoate and octanoate showed absence of hydroxylated acylcarnitines and correction of secondary metabolic disturbances, suggesting that optimal treatment should include medium-chain triglycerides of these chain lengths. Fibroblasts of patients with other fatty acid oxidation disorders showed distinct elevations of disease-specific acylcarnitines. This acylcarnitine analysis allows the diagnosis of LCHAD deficiency and its differentiation from other fatty acid oxidation disorders, which can pose difficulties in vivo. The strategy has allowed in-depth analysis with different substrates, providing suggestions for the rational design of treatment trials.

3-Hydroxyacyl CoA Dehydrogenases↗
PubMed2000

Leigh disease caused by the mitochondrial DNA G14459A mutation in unrelated families.

Leigh disease can be caused by defects of both nuclear and mitochondrially encoded genes. One mitochondrial DNA mutation, G14459A, has been associated with both respiratory chain complex I deficiency and Leber's hereditary optic neuropathy, with or without dystonia. Here, we report the occurrence of this mutation in 3 complex I-deficient patients from 2 separate pedigrees who presented with Leigh disease, with no evidence or family history of Leber's hereditary optic neuropathy or dystonia.

Adolescent↗
PubMed1999

Treatment of pyruvate carboxylase deficiency with high doses of citrate and aspartate.

A patient with severe pyruvate carboxylase deficiency presented at age 11 weeks with metabolic decompensation after routine immunization. She was comatose, had severe lactic acidemia (22 mM) and ketosis, low aspartate and glutamate, elevated citrulline and proline, and mild hyperammonemia. Head magnetic resonance imaging showed subdural hematomas and mild generalized brain atrophy. Biotin-unresponsive pyruvate carboxylase deficiency was diagnosed. To provide oxaloacetate, she was treated with high-dose citrate (7.5 mol/kg(-1)/day(-1)), aspartate (10 mmol/kg(-1)/day(-1)), and continuous drip feeding. Lactate and ketones diminished dramatically, and plasma amino acids normalized, except for arginine, which required supplementation. In the cerebrospinal fluid (CSF), glutamine remained low and lysine elevated, showing the treatment had not normalized brain chemistry. Metabolic decompensations, triggered by infections or fasting, diminished after the first year. They were characterized by severe lactic and ketoacidosis, hypernatremia, and a tendency to hypoglycemia. At age 3(1/2) years she has profound mental retardation, spasticity, and grand mal and myoclonic seizures only partially controlled by anticonvulsants. The new treatment regimen has helped maintain metabolic control, but the neurological outcome is still poor.

Amino Acids↗
PubMed1998

One-methyl group metabolism in non-ketotic hyperglycinaemia: mildly elevated cerebrospinal fluid homocysteine levels.

Non-ketotic hyperglycinaemia (NKH) is a rare, severe brain disease caused by deficient glycine cleavage enzyme complex activity resulting in elevated glycine concentrations. Recent experience suggests that factors in addition to glycine kinetics are involved in its pathogenesis. The glycine cleavage reaction through the formation of methylenetetrahydrofolate is an important one-methyl group donor. A deficiency in one-methyl group metabolites, in particular of choline, has been hypothesized in NKH. We investigated metabolites involved in one-methyl group metabolism in plasma and CSF of 8 patients with NKH, and monitored the effect of treatment with choline in one patient. Plasma and CSF choline and phosphatidylcholine concentrations were normal, except for a low plasma choline in the single neonate studied. Choline treatment did not change brain choline content, and was not associated with clinical or radiological improvement. Methionine concentrations and, in one-patient, S-adenosylmethionine and 5-methyltetrahydrofolate concentrations were normal in CSF. Homocysteine concentrations in CSF, however, were slightly but consistently elevated in all four patients examined, but cysteine, cysteinylglycine and glutathione were normal. Serine is important in the transfer of one-methyl groups from mitochondria to cytosol. Serine concentrations were normal in plasma and CSF, but dropped to below normal in CSF in three patients on benzoate treatment. These observations add to our understanding of the complex metabolic disturbances in NKH.

Amino Acid Metabolism, Inborn Errors↗
PubMed1996

Acute pancreatitis in an infant with lactic acidosis and a mutation at nucleotide 3243 in the mitochondrial DNA tRNALeu(UUR) gene.

UNLABELLED: The A to G point mutation at position 3243 of the mitochondrial DNA tRNALeu(UUR) gene is commonly found in patients with the syndrome of mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS). A male patient was referred at 7 months with failure to thrive, developmental delay, microcephaly and hypotonia since age 2 months. He had developed lactic acidosis and increasingly frequent seizures since age 5 months. The patient was admitted at 15 months with pleural and pericardial effusions, which resolved. Three weeks later he developed evidence of pancreatitis with hyperglycemia, sudden profound increase in lactic acidosis and increased serum lipase. He died unexpectedly the next day of cardiorespiratory collapse following an acute gastro-intestinal hemorrhage. Analysis of mitochondrial DNA (mtDNA) in muscle showed heteroplasmy for the mutation MTTL1*MELAS3243G (> 95%). Infants with this mutation commonly present with failure to thrive, significant developmental delay, and hypotonia, while stroke-like episodes occur later in survivors. They usually have lactic acidosis and a high percentage of mutant mtDNA in muscle. CONCLUSION: Respiratory chain disorders including the mtDNA MTTL1*MELAS3243G mutation should be suspected in infants with this systemic and neurologic presentation. Pancreatic dysfunction, both acute and chronic, needs to be added to the list of symptoms of disorders of the respiratory chain.

Acidosis, Lactic↗
PubMed1996

Evidence for locus heterogeneity in the Bethlem myopathy and linkage to 2q37.

The Bethlem myopathy, a childhood onset autosomal dominant myopathy with joint contractures, has recently been localized to 21q in a series of Dutch families and the alpha 1 and alpha 2 subunits of type VI collagen (COL6A1 and COL6A2) have been postulated as candidate genes. We investigate a large family of French Canadian descent (family 1489) in which the Bethlem myopathy is segregating. Family 1489 is unlinked to the region of interest on 21q, thus demonstrating locus heterogeneity within the Bethlem myopathy classification. In view of the localization of the genes coding the alpha 1 and alpha 2 subunits of type VI collagen on chromosome 21q, we carried out linkage analysis on chromosome 2q where the alpha 3 subunit of type VI collagen has been localized. We demonstrate linkage to markers in this region, define the region of disease gene localization, and confirm by FISH analysis that COL6A3 is located within the interval of interest making COL6A3 a feasible candidate gene for the Bethlem myopathy.

Chromosome Mapping↗
PubMed1996

A case of duplication of 13q32-->qter and deletion of 18p11.32-->pter with mild phenotype: Patau syndrome and duplications of 13q revisited.

A mild clinical phenotype is described in a patient with duplication of 13q32-->qter and a small deletion of 18p11.32-->pter. The 8 year old white male presented with psychomotor retardation, tethered cord, soft, fleshy ears, and normal facial features except for thin lips. The karyotype was found to be 46, XY, der(18)t(13;18) (q32;p11.32) pat confirmed by fluorescence in situ hybridisation (FISH). A review of earlier studies showed that features of trisomy 13 are found in cases of duplication of bands 13q14 to qter. None of the cardinal features of trisomy 13 was seen in this patient. The absence of polydactyly, hernias, urogenital abnormalities, and haemangiomas contrast this condition with both trisomy 13 and duplication of 13q14-22-->qter. Possible explanations for lack of Patau syndrome in this patient could include restriction of the critical region for Patau syndrome to duplication 13q14-->13q32 with variable expression, gene interactions, or interchromosomal effects.

Child↗
PubMed1996

Double mutant fibrillin-1 (FBN1) allele in a patient with neonatal Marfan syndrome.

It is now well established that defects in fibrillin-1 (FBN1) cause the variable and pleiotropic features of Marfan syndrome (MFS) and, at the most severe end of its clinical spectrum, neonatal Marfan syndrome (nMFS). Patients with nMFS have mitral and tricuspid valve involvement and aortic root dilatation, and die of congestive heart failure, often in the first year of life. Although mutations in classical MFS have been observed along the entire length of the FBN1 mRNA, mutations in nMFS appear to cluster in a relatively small region of FBN1, approximately between exons 24 and 34. Here we describe the appearance of two FBN1 mutations in a single allele of an infant with nMFS. The changes were within six bases of each other in exon 26. One was a T3212G transversion resulting in an I1071S amino acid substitution and the second was an A3219T transversion resulting in an E1073D amino acid substitution. This is the first reported double mutant allele in FBN1.

Alleles↗
PubMed1996

Rapid diagnosis of homocystinuria and other hypermethioninemias from newborns' blood spots by tandem mass spectrometry.

We report a new method for the diagnosis of homocystinuria and other hypermethioninemias from dried blood spots on newborn screening cards, based on isotope-dilution tandem mass spectrometry. The mean concentration of methionine in 909 unaffected newborns was 19 micromol/L (CV 44%). The variability of results was reduced when the concentration of methionine was expressed relative to that of another amino acid in the same specimen. The mean ratio of methionine to leucine plus isoleucine for these same newborn blood spots was 0.16 (CV 25%). In newborn samples from a collection categorized by a Guthrie bacterial inhibition assay as true positive, unaffected, or falsely positive for hypermethioninemias, the ratio of methionine to leucine for each true-positive specimen was at least 2.5 times greater than for respective age-matched unaffected blood specimens. The ratio for falsely positive samples did not differ from that for unaffected blood samples. We predict that the ratio of methionine to leucine plus isoleucine determined by tandem mass spectrometry will successfully detect hypermethioninemias with very low rates for false positives and false negatives.

Blood Specimen Collection↗
PubMed1995

Benzoate therapy and carnitine deficiency in non-ketotic hyperglycinemia.

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.

Amino Acid Metabolism, Inborn Errors↗
PubMed1995

Fryns syndrome survivors and neurologic outcome.

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, Dandy-Walker 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.

Abnormalities, Multiple↗
PubMed1995

Hemangioma, supraumbilical midline raphé, and coarctation of the aorta with a right aortic arch: single causal entity?

Most congenital cutaneous hemangiomas are a sporadic occurrence. Hemangiomas have been found in association with coarctation of the aorta and a right aortic arch. A separate association has been noted of midline ventral defects with hemangiomas. We report on a patient with multiple hemangiomas, coarctation of the aorta and a right aortic arch, a superaumbilical midabdominal raphé and sternal cleft. Our patient represents an overlap between these two conditions. Review of the literature identified four additional patients with a similar combination of anomalies. The clinical overlap between these 5 patients suggests that they are variants of the same conditions and represent a spectrum of defects that includes hemangiomas, midline ventral defects, aortic arch abnormalities and brain malformation.

Aorta↗
PubMed1995

Confirmation of locus heterogeneity in the pure form of familial spastic paraplegia.

Familial spastic paraplegia (FSP), characterized by progressive spasticity of the lower extremities, is in its "pure" form generally of autosomal dominant inheritance pattern. Hazan et al. [Nat Genet 5:163-167, 1993] reported tight linkage of a large FSP family to the highly polymorphic microsatellite marker D14S269 with z (theta) = 8.49 at theta = 0.00 They further demonstrated evidence for locus heterogeneity when they showed that 2 FSP families were unlinked to this region. We have subsequently studied 4 FSP families (3 American, one British) and excluded the disease locus in these families for approximately 30 cM on either side of D14S269, thereby confirming evidence for locus heterogeneity within the spastic paraplegia diagnostic classification.

Chromosomes, Human, Pair 14↗