Summary: Individuals with carnitine palmitoyltransferase I (CPT-I) deficiency cannot metabolize long-chain fatty acids and can develop life-threatening hypoglycaemia. We present a boy with CPT-I deficiency maintained on a very low-fat diet with nighttime uncooked cornstarch feedings for 5 1/2 years with good success. He has had normal growth and no episodes of hypoglycaemia or adverse side-effects. We found that he was homozygous for a previously undescribed mutation, T314I, in the CPT1A protein.

BACKGROUND:Although hyperhomocyst(e)inemia (Hyper-Hcy) may predispose to atherosclerosis and venous thrombosis, the mechanisms of stroke associated with Hyper-Hcy are not defined.METHODS:Clinical and biochemical phenotypes and genetic features of three unrelated patients with premature stroke and severe Hyper-Hcy due to cystathionine beta-synthase (CBS) deficiency are described. Plasma Hcy and amino acids were measured by fluorescence polarization immune assay and ion exchange chromatography. Analysis of the CBS and methylenetetrahydrofolate reductase genes was performed by restriction enzyme digestion and sequence analysis.RESULTS:Two of the three index cases had no known diagnosis of homocystinuria and initially presented with embolic cerebral and retinal infarction in mid-adulthood. Mechanisms of cerebrovascular disease were carotid intraluminal thrombosis, arterial dissection, and possible cardiac embolism. Family screening revealed additional members with clinically silent homocystinuria and severe Hyper-Hcy. Excluding tall stature in two individuals, all had mild phenotypes, without classic findings of CBS deficiency. Plasma total and free Hcy, methionine, and urine Hcy were elevated. Genotyping revealed heterozygous CBS mutations (I278T, D444N, G307S) in affected individuals.CONCLUSION:Artery-to-artery embolism and dissection may cause stroke in young adults with homocystinuria. The results also support a rationale for screening for Hyper-Hcy in young adults with stroke without a phenotype suggestive of classic homocystinuria.

Background and Purpose— Epidemiological studies have described an association between low vitamin B6 (measured as pyridoxal 5′-phosphate [PLP]) and ischemic stroke, independent of homocysteine (tHcy). We investigated B6 status, tHcy, and inflammation (measured by C-reactive protein [CRP]) in patients with stroke and controls. Methods— Consecutive cases with new ischemic stroke were compared with matched controls. Fasting tHcy, PLP, and CRP were measured. Results— The adjusted odds ratio of low PLP in the highest compared with the lowest CRP quartile was 16.6 (2, 139.9, P =0.01). Age, CRP, supplemental vitamin use, and albumin were independent predictors of PLP (P <0.05 for all). No relationship was observed between CRP and tHcy. Conclusion— The relationship between inflammation and low B6 status may partially explain the findings of previous epidemiological studies.

Background: Data are conflicting concerning risk for ischemic stroke associated with hyperhomocyst(e)inemia (hyper-Hcy) and a common polymorphism in the gene encoding 5,10-methylenetetrahydrofolate reductase (MTHFR 677C→T), which predisposes to hyper-Hcy in vivo. Methods: Search of MEDLINE, Science Citation Index, and abstracts of conference proceedings revealed relevant articles. Exposure was defined as follows: 1) prevalence of hyper-Hcy; 2) absolute difference in the mean Hcy concentration between subjects with and without ischemic stroke; and 3) the MTHFR TT genotype frequency. Outcome was defined as ischemic stroke with or without neuroimaging. Inclusion criteria were retrospective and prospective studies with reported odds ratios (OR) or hazard ratios (HR) or arithmetic mean Hcy levels. Exclusion criteria were absence of OR or HR, outcome defined as carotid atherosclerosis or intima–media thickening, stroke in patients younger than 18 years old, and studies in languages other than English. Statistical analyses for between-study heterogeneity and pooled risk estimates were performed using Stata software (Stata Corporation, College Station, TX). Results: Among 16 studies (1,487 stroke and 2,554 nonstroke cases), the pooled mean Hcy level in patients with ischemic stoke was 2.32 μmol/L (95% CI, 1.6 to 3.04; p < 0.001) greater than that in those without ischemic stroke. Among 14 included studies (1,769 stroke and 7,400 nonstroke cases), the pooled OR estimate of ischemic stroke associated with hyper-Hcy was 1.79 (95% CI, 1.61 to 2.0; p < 0.001). Among 19 included studies (2,788 stroke and 3,962 nonstroke cases), the OR associated with the TT genotype was 1.23 (95% CI, 0.96 to 1.58; p = 0.1). Conclusion: These data support an association between mild-to-moderate hyper-Hcy and ischemic stoke. The MTHFR TT genotype may have a small influence in determining susceptibility to ischemic stoke.

Early diagnosis and improved treatment are leading to the potential for increased reproductive capability in homocystinuria due to cystathionine β-synthase (CβS) deficiency, but information about reproductive outcome and risk of thromboembolism in pregnancy is limited. To provide further information, clinical and biochemical information was obtained on women with maternal homocystinuria, on their pregnancies and on the offspring. This information included blood sulphur amino acids and total homocysteine, CβS gene mutations and developmental and cognitive scores in the offspring. The study involved 15 pregnancies in 11 women, of whom 5 were pyridoxine-nonresponsive and 6 were pyridoxine-responsive. Complications of pregnancy included pre-eclampsia at term in two pregnancies and superficial venous thrombosis of the leg in a third pregnancy. One pregnancy was terminated and two pregnancies resulted in first-trimester spontaneous abortions. The remaining 12 pregnancies produced live-born infants with normal or above-normal birth measurements. One offspring has multiple congenital anomalies that include colobomas of the iris and choroid, neural tube defect and undescended testes. He is also mentally retarded and autistic. A second offspring has Beckwith–Wiedemann syndrome. The remaining 10 offspring were normal at birth and have remained normal. There was no relationship between the severity of the biochemical abnormalities or the therapies during pregnancy to either the pregnancy complications or the offspring outcomes. The infrequent occurrences of pregnancy complications, offspring abnormalities and maternal thromboembolic events in this series suggest that pregnancy and outcome in maternal homocystinuria are usually normal. Nevertheless, a cautious approach would include careful monitoring of these pregnancies with attention to metabolic therapy and possibly anticoagulation.

Journal of Inherited Metabolic DiseaseVolume 24, Issue 2 p. 303-304 Article New England Consortium: A model for medical evaluation of expanded newborn screening with tandem mass spectrometry S. Albers, Corresponding Author S. Albers [email protected] New England Consortium of Metabolic Programs, USA[email protected]Search for more papers by this authorS. E. Waisbren, S. E. Waisbren New England Consortium of Metabolic Programs, USASearch for more papers by this authorM. G. Ampola, M. G. Ampola New England Consortium of Metabolic Programs, USASearch for more papers by this authorT. G. Brewster, T. G. Brewster New England Consortium of Metabolic Programs, USASearch for more papers by this authorL. W. Burke, L. W. BurkeSearch for more papers by this authorL. A. Demmer, L. A. Demmer New England Consortium of Metabolic Programs, USASearch for more papers by this authorJ. Filiano, J. Filiano New England Consortium of Metabolic Programs, USASearch for more papers by this authorR. M. G. Greenstein, R. M. G. Greenstein New England Consortium of Metabolic Programs, USASearch for more papers by this authorC. L. Ingham, C. L. Ingham New England Consortium of Metabolic Programs, USASearch for more papers by this authorM. S. Korson, M. S. Korson New England Consortium of Metabolic Programs, USASearch for more papers by this authorD. Marsden, D. Marsden New England Consortium of Metabolic Programs, USASearch for more papers by this authorR. C. Schwartz, R. C. Schwartz New England Consortium of Metabolic Programs, USASearch for more papers by this authorM. R. Seashore, M. R. Seashore New England Consortium of Metabolic Programs, USASearch for more papers by this authorV. E. Shih, V. E. Shih New England Consortium of Metabolic Programs, USASearch for more papers by this authorH. L. Levy, H. L. Levy New England Consortium of Metabolic Programs, USASearch for more papers by this author S. Albers, Corresponding Author S. Albers [email protected] New England Consortium of Metabolic Programs, USA[email protected]Search for more papers by this authorS. E. Waisbren, S. E. Waisbren New England Consortium of Metabolic Programs, USASearch for more papers by this authorM. G. Ampola, M. G. Ampola New England Consortium of Metabolic Programs, USASearch for more papers by this authorT. G. Brewster, T. G. Brewster New England Consortium of Metabolic Programs, USASearch for more papers by this authorL. W. Burke, L. W. BurkeSearch for more papers by this authorL. A. Demmer, L. A. Demmer New England Consortium of Metabolic Programs, USASearch for more papers by this authorJ. Filiano, J. Filiano New England Consortium of Metabolic Programs, USASearch for more papers by this authorR. M. G. Greenstein, R. M. G. Greenstein New England Consortium of Metabolic Programs, USASearch for more papers by this authorC. L. Ingham, C. L. Ingham New England Consortium of Metabolic Programs, USASearch for more papers by this authorM. S. Korson, M. S. Korson New England Consortium of Metabolic Programs, USASearch for more papers by this authorD. Marsden, D. Marsden New England Consortium of Metabolic Programs, USASearch for more papers by this authorR. C. Schwartz, R. C. Schwartz New England Consortium of Metabolic Programs, USASearch for more papers by this authorM. R. Seashore, M. R. Seashore New England Consortium of Metabolic Programs, USASearch for more papers by this authorV. E. Shih, V. E. Shih New England Consortium of Metabolic Programs, USASearch for more papers by this authorH. L. Levy, H. L. Levy New England Consortium of Metabolic Programs, USASearch for more papers by this author First published: 01 April 2001 https://doi.org/10.1023/A:1010391623104Citations: 9AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat No abstract is available for this article. REFERENCES 1 American Academy of Pediatrics Ad Hoc Task Force on Definition of the Medical Home. (1992) The medical home. Pediatrics, 90: 774. 2Levy HL, Albers S, Lander E, Lifton R, Page D (2000) Genetic screening of newborns. In: Annual Review of Genomics and Human Genetics, Palo Alto: Annual Reviews, 139–177. Citing Literature Volume24, Issue2April 2001Pages 303-304 ReferencesRelatedInformation

Journal of Inherited Metabolic DiseaseVolume 22, Issue 5 p. 672-673 Article Ornithine carbamoyltransferase deficiency: Unusual clinical findings and novel mutation V. E. Shih, V. E. Shih Neurology Service, Pediatric Service, and Amino Acid Disorder Laboratory, Massachusetts General Hospital, USA Department of Neurology, Harvard Medical School, Boston, Massachusetts, USASearch for more papers by this authorA. P. Safran, A. P. Safran Neurological Service P.C., Framingham, Massachusetts, USASearch for more papers by this authorA. H. Ropper, A. H. Ropper Neurology Department, St. Elizabeth's Medical Center, Brighton, Massachusetts, USASearch for more papers by this authorM. Tuchman, M. Tuchman Biochemical Genetics and Metabolism Laboratories, University of Minnesota Hospital and Clinic, Minneapolis, Minnesota, USASearch for more papers by this author V. E. Shih, V. E. Shih Neurology Service, Pediatric Service, and Amino Acid Disorder Laboratory, Massachusetts General Hospital, USA Department of Neurology, Harvard Medical School, Boston, Massachusetts, USASearch for more papers by this authorA. P. Safran, A. P. Safran Neurological Service P.C., Framingham, Massachusetts, USASearch for more papers by this authorA. H. Ropper, A. H. Ropper Neurology Department, St. Elizabeth's Medical Center, Brighton, Massachusetts, USASearch for more papers by this authorM. Tuchman, M. Tuchman Biochemical Genetics and Metabolism Laboratories, University of Minnesota Hospital and Clinic, Minneapolis, Minnesota, USASearch for more papers by this author First published: 01 June 1999 https://doi.org/10.1023/A:1005502718790Citations: 1AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat No abstract is available for this article. References 1Snebold NG, Rizzo JF3d, Lessell S, Pruett RC (1987) Transient visual loss in ornithine transcarbamoylase deficiency. Am J Ophthalmol, 104: 407–412. 2Tuchman M, Holzknecht RA, Gueron AB, Berry SA., Tsai MY (1992) Six new mutations in the ornithine transcarbamylase gene detected by single-strand conformation polymorphism. Pediatr Res, 32: 600–604. 3Tuchman M, Morizono H, Rajagopal BS, Plante RJ, Allewell NM (1998) The biochemical and molecular spectrum of ornithine transcarbamylase deficiency. J Inher Metab Dis, 21 (supplement1): 40–58. Citing Literature Volume22, Issue5June 1999Pages 672-673 ReferencesRelatedInformation

Prenatal testing of 12 pregnancies at risk for argininosuccinic aciduria due to argininosuccinate lyase (ASAL) deficiency and three pregnancies at risk for citrullinaemia due to argininosuccinate synthatase (ASAS) deficiency was performed by metabolite detection in amniotic fluid and measurement of enzyme activity in uncultured and cultured chorionic tissue and in cultured amniocytes. From our data and those of previous studies, amniotic fluid argininosuccinate measurement alone is clearly a reliable and rapid diagnostic test for both severe and mild ASAL deficiency if maternal ASAL deficiency can be excluded. For prenatal diagnosis of ASAS deficiency, however, both measurement of the amniotic fluid citrulline level and enzyme assay should be employed.

Cystathionine beta-synthase (CBS) deficiency is an autosomal recessive disorder characterized by homocystinuria and multisystem clinical disease. Patients responsive to pyridoxine usually have a milder clinical phenotype than do nonresponsive patients, and we studied the molecular pathology of this disorder in an attempt to understand the molecular basis of the clinical variation. We previously reported a T833C transition in exon 8 causing a substitution of threonine for isoleucine at codon 278 (I278T). By PCR amplification and sequencing of exon 8 from genomic DNA we have now detected the I278T mutation in 7 of 11 patients with in vivo pyridoxine responsiveness and in 0 of 27 pyridoxine-nonresponsive patients. Two pyridoxine-responsive patients are homozygous and five are heterozygous for I278T. We have now observed the I278T mutation in 41% (9 of 22) of the independent alleles in pyridoxine-responsive patients of varied ethnic backgrounds. In two of the compound heterozygotes we identified a novel mutation (G139R and E144K) in the other allele. The finding that the two patients who are homozygous for I278T have only ectopia lentis and mild bone demineralization suggests that this mutation is associated with both in vivo pyridoxine responsiveness and mild clinical disease. Compound heterozygous patients who have one copy of this missense mutation are likely to retain some degree of pyridoxine responsiveness.

Journal of Inherited Metabolic DiseaseVolume 18, Issue 3 p. 367-367 Short Report Organ donation by a maple syrup urine disease patient V. E. Shih, V. E. Shih Amino Acid Disorder Unit, Massachusetts General Hospital, Building 149, Thirteenth Street, Boston, MA, 02129 USASearch for more papers by this authorB. Stewart, B. Stewart Transplant Unit, Massachusetts General Hospital, Building 149, Thirteenth Street, Boston, MA, 02129 USASearch for more papers by this author V. E. Shih, V. E. Shih Amino Acid Disorder Unit, Massachusetts General Hospital, Building 149, Thirteenth Street, Boston, MA, 02129 USASearch for more papers by this authorB. Stewart, B. Stewart Transplant Unit, Massachusetts General Hospital, Building 149, Thirteenth Street, Boston, MA, 02129 USASearch for more papers by this author First published: 01 May 1995 https://doi.org/10.1007/BF00710437AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL No abstract is available for this article. Volume18, Issue3May 1995Pages 367-367 RelatedInformation

We describe here the first case of neonatal death due to the hyperornithinaemia, hyperammonaemia, and homocitrullinuria (HHH) syndrome and the first prenatal diagnosis of this disorder in a subsequent pregnancy in this family.

Gyrate atrophy (GA) is an autosomal recessive eye disease characterized by progressive loss of vision due to chorioretinal degeneration. It is associated with a deficiency of the mitochondrial enzyme ornithine aminotransferase (OATase) with consequent hyperornithinemia. Although the clinical phenotype is largely confined to the eye, OATase deficiency is a systemic disorder. A step toward delineation of the enzyme defect in GA at the molecular level has been made by cloning and characterizing the cDNA and structural gene for OATase. The structural gene for OATase maps to chromosome 10 (10q26) and OATase-related sequences map to the X chromosome (Xp11.2). A diverse number of mutations at the OATase locus in GA patients of varied ethnic origins have been defined employing polymerase chain reaction and other molecular biological techniques. The majority of these mutations are of the missense type although a splicing mutation in one patient has recently been identified. The functional consequences of some of these mutations have been tested and confirmed in a eukaryotic expression system. These mutations demonstrate the allelic heterogeneity, which extends to both pyridoxine responsive and non-responsive forms of GA, reflecting the clinical and biochemical heterogeneity observed in this disease. The molecular studies in addition to providing information on the structure/function of the enzyme will facilitate understanding of the retinal pathophysiology in this disorder.

Gyrate atrophy (GA), a recessive eye disease involving progressive vision loss due to chorioretinal degeneration, is associated with the deficiency of the mitochondrial enzyme ornithine aminotransferase (OAT), with consequent hyperornithinemia. We and others have reported a number of missense mutations at the OAT locus which result in GA. Here we report a GA patient of Danish/Swedish ancestry in whom one OAT allele produces an mRNA that is missing a single 96-bp exon relative to the normal mRNA. Polymerase-chain-reaction amplification and sequencing revealed a 9-bp deletion covering the splice acceptor region of exon 5, resulting in the absence of exon 5 sequences from the mRNA with no disruption to the reading frame. This mutation, which was not present in 15 other independent GA patients, adds to the array of allelic heterogeneity observed in GA and represents the first example of a splicing mutation associated with this disorder.

Glutamate stimulates resting ventilation by altering neural excitability centrally. Hypoxia increases central ventilatory drive through peripheral chemoreceptor stimulation and may also alter cerebral perfusion and glutamate metabolism locally. Therefore the effect of hypoxia and peripheral chemodenervation on cerebrospinal fluid (CSF) transfer rate of in vivo tracer amidated central nervous system glutamate was studied in intact and chemodenervated pentobarbital-anesthetized dogs during normoxia and after 1 h of hypoxia induced with 10 or 12% O2 in N2 breathing at constant expired ventilation and arterial CO2 tension. Chemodenervation was performed by bilateral sectioning of the carotid body nerves and cervical vagi. CSF transfer rates of radiotracer 13NH4+ and [13N]glutamine synthesized via the reaction, glutamate + NH4(+)----glutamine, in brain glia were measured during normoxia and after 1 h of hypoxia. At normoxia, maximal glial glutamine efflux rate jm = 103.3 +/- 11.2 (SE) mumol.l-1.min-1 in all animals. After 1 h of hypoxia in intact animals, jm = 78.4 +/- 10.0 mumol.l-1.min-1. In denervated animals, jm was decreased to 46.3 +/- 4.3 mumol.l-1.min-1. During hypoxia, mean cerebral cortical glutamate concentration was higher in denervated animals (9.98 +/- 1.43 mumol/g brain tissue) than in intact animals (7.63 +/- 1.82 mumol/g brain tissue) and corresponding medullary glutamate concentration tended to be higher in denervated animals. There were no differences between mean glutamine and gamma-aminobutyric acid concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

A 39-year-old man and his 42-year-old sister, both vegetarians, had episodic confusion for many years, but their mental function was normal between those episodes. They were recently diagnosed with hyperornithinemia, hyperammonemia, and homocitrullinuria syndrome. Hyperammonemia was documented during an episode of confusion in the male sibling but not in his sister. Both had elevated plasma ornithine, glutamine, and alanine levels and persistently low plasma lysine levels. Homocitrulline was present in their urine, and orotic aciduria and orotidinuria developed in the male sibling following ingestion of allopurinol. Studies on their cultured skin fibroblasts showed deficient metabolism of ornithine, indicating a defect in ornithine transport across the mitochondrial membrane. During therapy with citrulline and phenylbutyrate sodium, plasma ornithine levels increased in both patients, while plasma levels of glutamine and alanine decreased to normal. Since therapy started, their clinical conditions have also improved, and no recurrent neurologic dysfunction has occurred during a follow-up period of 20 months.