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[CYANIDE POISONING AND ITS TREATMENT].
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Maculopathy and retinal degeneration in cobalamin C methylmalonic aciduria and homocystinuria.
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The optic neuropathy of pernicious anemia.
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State of the art of biochemical genetics.
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Pernicious anemia (PA) subsequent to insulin-dependent diabetes mellitus and idiopathic thrombocytopenic purpura, and effects of oral cobalamin on PA.
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Function of vitamin B12 in the central nervous system as revealed by congenital defects.
The 13 cases of methylcobalamin (MeCbl) deficiency presenting in early infancy have all been developmentally delayed, and the majority have had seizures, hypotonia, lethargy, and microcephaly. The CNS injury appears to occur during the first 6 months of postnatal life. The same symptoms are seen in acquired cobalamin (Cbl) deficiency in the same age group. MRI performed at age 18-19 months and after 13-14 months of large amounts of Cbl, in two cases showed delayed myelination, most pronounced in the cerebrum. Isolated MeCbl deficiency is the consequence of cblE and G mutations where the lesion is of a single Cbl-dependent enzyme, the methyltransferase. One effect of a deficiency of MeCbl, and of the associated failure of the methionine synthase reaction, is, therefore, an impairment of myelination of the brain of the newborn. The slow, but usually incomplete, improvement in psychomotor status after years of treatment with Cbl may be related to the eventual myelination. However, the hypotonia, lethargy, and impaired responsiveness react to treatment with Cbl within 24-48 hours, which suggests an expression of MeCbl deficiency on the CNS distinct from the delayed myelination. Although there is much to be learned, it is now clear that a normally functioning Cbl-dependent methyl transferase is required for development and function of the human brain.
Pernicious anemia presenting with acute generalized thrombocytopenic purpura.
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Cobalamin disorder Cbl-C presenting with late-onset thrombotic microangiopathy.
Two siblings, a boy age 12 and his sister age 4 years, presented with proteinuria and hematuria, hypertension, and chronic hemolytic anemia. At age 13 years, the boy developed an episode of severe hypertensive encephalopathy and transient renal failure. Both children are attending normal school, have no neurologic symptoms, and only minimal pigmentary retinal abnormalities. Renal biopsy showed a chronic thrombotic microangiopathic nephropathy. Both patients had hyperhomocysteinemia and mild methylmalonic aciduria. Fibroblasts showed decreased cobalamin uptake, reduced methyl- and adenosyl-cobalamin formation, and deficient incorporation of formate and propionate, compatible with the Cbl-C complementation group, but milder than that found in cells from most patients. Both patients and their father carry a balanced reciprocal translocation. Parenteral hydroxycobalamin treatment reduced the homocysteine levels, and methylmalonic acid disappeared. Increasing the dosage of hydroxycobalamin from 1 to 2.5, then 5 mg daily together with betaine, further reduced homocysteine levels (boy from 118 to 23 microM and girl from 59 to 14 microM). With this treatment, hemolysis has stopped, hematuria has disappeared, proteinuria has almost normalized, and creatinine clearance has been stable. Investigations for chronic thrombotic microangiopathy should include testing for this unusual but treatable disorder, regardless of age of presentation.
Unusual mitochondria in the hepatocytes of rats treated with a vitamin B12 analogue.
Adult male rats were administered hydroxy-cobalamin (c-lactam) (HCCL), a vitamin B12 analogue, by means of osmotic mini-pumps. The metabolic effects of HCCL are similar to those produced by simple dietary deficiency of vitamin B12 (Frenkel et al., 1976), but the morphological alterations in hepatic mitochondria are quite different in the two treatments. In HCCL-treated animals, hepatic mitochondria showed significant increases in number. In one rat, the hepatic mitochondria frequently had a single, elongated, circumferentially-oriented crista, with the inner compartment being occupied by a greatly augmented matrix. Such organelles appeared to be capable of division, as indicated by medially-partitioned forms. Numerous hooded mitochondria were present in the hepatic cells of the same animal. Almost every mitochondrion of whatever morphology was partially or completely shrouded by a cistern of rough endoplasmic reticulum. These mitochondrial morphological changes may be related to the chronic metabolic changes in this animal model of methylmalonic aciduria.
cblE type of homocystinuria due to methionine synthase reductase deficiency: functional correction by minigene expression.
The cblE type of homocystinuria is a rare autosomal recessive disorder caused by impaired reductive activation of methionine synthase. Although earlier biochemical studies proposed that the methionine synthase enzyme might be activated by two different reducing systems, mutations were reported in only the methionine synthase reductase gene (MTRR) in cblE patients. The pathogenicity of MTRR mutations, however, has not yet been tested functionally. We report on nine patients of European origin affected by the cblE type of homocystinuria. They presented between 2 weeks and 3 years of age (median age 4 weeks) with anemia, which was macrocytic in only three patients, and with neurological involvement in all but two cases. Bone marrow examination performed in seven patients showed megaloblastic changes in all but one of them. All patients exhibited moderate to severe hyperhomocysteinemia (median plasma total homocysteine [Hcy] 92 mumol/L, range 44-169), while clearly reduced methionine was observed only in four cases. Pathogenic mutations were identified in both parental alleles of the MTRR gene in all patients. Five known (c.903+469T>C, c.1361C>T, c.1459G>A, c.1557-4_1557+3del7, and c.1622_1623dupTA) and three novel mutations (c.7A>T, c.1573C>T, and c.1953-6_1953-2del5) were detected. Importantly, transfection of fibroblasts of cblE patients with a wild-type MTRR minigene expression construct resulted in a significant approximately four-fold increase of methionine synthesis, indicating correction of the enzyme defect. Our study shows a link between a milder predominantly hematological presentation and homozygosity for the c.1361C>T mutation, but no other obvious genotype-phenotype correlation. The identification of mutations in the MTRR gene, together with restoration of methionine synthesis following MTRR minigene expression in cblE cells confirms that this disease is caused by defects in the MTRR gene.
Ototoxicity of sodium nitroprusside is not due to nitric oxide.
Sodium nitroprusside (SNP) has been used as a donor for nitric oxide (NO) to study the effects of NO on the mammalian cochlea. In the present study, we set out to determine whether NO was the chemical responsible for the ototoxic effects seen after the application of SNP at the round window membrane of the adult guinea pig cochlea. In the first instance, NO released from S-nitrosocysteine, a compound not related to cyanide, has no toxic effect on the hair cells of the cochlea. Light-exposed SNP that could no longer produce NO, light-exposed SNP to which acetylcysteine (ATC) or hydroxycobalamin (HCL) was added to eliminate cyanide, and freshly prepared SNP to which ATC or HCL was added were also tested. Six groups of animals consisting of three animals in each group were used. The single chemical or combination of chemicals stated above was soaked in a piece of gelfoam that was then applied to the round window membrane of the animal under ketamine-xylasine anesthesia. The animals were reanesthetized 3 days later and perfused for scanning electron microscopy and hair cell quantitative analysis. The results showed that, in animals given S-nitrosocysteine, no hair cell loss was noted, while light-exposed SNP led to severe hair cell damage similar to that seen after the administration of fresh SNP. In animals treated with the mixture of light-exposed SNP and ATC or HCL, or fresh SNP with ATC or HCL, ototoxicity was significantly attenuated. These results have convincingly demonstrated that NO at a certain level is not destructive to auditory hair cells and the hair cell loss observed after SNP application is most likely due to the cyanide released from the SNP instead of NO.
Methylmalonic aciduria with homocystinuria.
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Biochemical diagnosis and outcome of 2 years treatment in a patient with combined methylmalonic aciduria and homocystinuria.
We describe a patient with methylmalonic aciduria and homocystinuria due to a defect in cobalamin metabolism of the Cbl-C type mutant (McKusick 277400). Our case was diagnosed within the first 2 months of life by amino acid analysis (ion-exchange chromatography) and by biochemical studies in cultured fibroblasts ([14C]propionate incorporation, methionine and serine formation). We discuss the clinical course and the biochemical evolution after 2 years of hydroxycobalamin treatment that led to an improvement in general clinical condition and neurological performance.
Vitamin B12-induced reduction of platelet monoamine oxidase activity in patients with dementia and pernicious anaemia.
Platelet monoamine oxidase (MAO) activity has previously been shown to be increased in patients with senile dementia of Alzheimer type (SDAT) and in patients with megaloblastic anaemia. Moreover, low serum B12 levels were found to be 4-5 times more frequent in SDAT compared with an unselected population of similar age. In the present investigation, platelet MAO activity was estimated in 14 SDAT patients with relatively low serum B12 levels and in 4 patients with pernicious anaemia. Before B12 therapy, platelet MAO activity was significantly increased in both patient groups compared with a control group. After B12 therapy, platelet MAO activity was significantly reduced in both patient groups to apparently normal levels. The present results show that B12 status is a controlling factor of platelet MAO activity and confirm that a significant connection exists between vitamin B12 deficiency and primary degenerative dementia disorders, such as SDAT.
Treatment of cobalamin deficiency in dementia, evaluated clinically and with cerebral blood flow measurements.
We investigated the relation between cobalamin deficiency, clinical changes and brain function in dementia patients. On admittance to the clinic, 24 patients had cobalamin deficiency, and dementia with additional symptoms of delirium. During cobalamin supplementation, the patients underwent repeated regional cerebral blood flow (rCBF) studies, psychiatric evaluations, and in some cases assessment with MMSE and the Organic Brain Syndrome scale. Fifteen patients who showed mild to moderate dementia improved clinically, and also showed a concomitant increase in their general CBF after treatment. In contrast, 9 patients who were severely demented showed no obvious clinical improvement, and no general blood flow change, although some regional flow increases were seen in sensory motor areas. We conclude that symptoms which probably indicated superimposed delirium such as clouding of consciousness, disorientation and clinical fluctuation, responded to the vitamin B12 supplementation, while the underlying dementia condition remained basically unchanged. The clinical improvement was also mirrored in general and focal rCBF changes.
MRI of the spinal cord in myelopathy complicating vitamin B12 deficiency: two additional cases and a review of the literature.
Focal spinal cord lesions have been present in all previously reported cases of MRI appearances in myelopathy complicating vitamin B12 deficiency. We describe two further cases showing mild atrophy only and review the salient features of the previous 11 publications. MRI findings reflect quite closely the known pathological changes in this condition.