The MMACHC variant c.158T>C: Mild clinical and biochemical phenotypes and marked hydroxocobalamin response in cblC patients.

Mutations in MMACHC cause cobalamin C disease (cblC, OMIM 277400), the commonest inborn error of vitamin B12 metabolism. In cblC, deficient activation of cobalamin results in methylcobalamin and adenosylcobalamin deficiency, elevating methylmalonic acid (MMA) and total plasma homocysteine (tHcy). We retrospectively reviewed the medical files of seven cblC patients: three compound heterozygotes for the MMACHC (NM_015506.3) missense variant c.158T>C p.(Leu53Pro) in trans with the common pathogenic mutation c.271dupA (p.(Arg91Lysfs*14), "compounds"), and four c.271dupA homozygotes ("homozygotes"). Compounds receiving hydroxocobalamin intramuscular injection monotherapy had age-appropriate psychomotor performance and normal ophthalmological examinations. In contrast, c.271dupA homozygotes showed marked psychomotor retardation, retinopathy and feeding problems despite penta-therapy (hydroxocobalamin, betaine, folinic acid, l-carnitine and acetylsalicylic acid). Pretreatment levels of plasma and urine MMA and tHcy were higher in c.271dupA homozygotes than in compounds. Under treatment, levels of the compounds approached or entered the reference range but not those of c.271dupA homozygotes (tHcy: compounds 9.8-32.9 µM, homozygotes 41.6-106.8 (normal (N) < 14); plasma MMA: compounds 0.14-0.81 µM, homozygotes, 10.4-61 (N < 0.4); urine MMA: compounds 1.75-48 mmol/mol creatinine, homozygotes 143-493 (N < 10)). Patient skin fibroblasts all had low cobalamin uptake, but this was milder in compound cells. Also, the distribution pattern of cobalamin species was qualitatively different between cells from compounds and from homozygotes. Compared to the classic cblC phenotype presented by c.271dupA homozygous patients, c.[158T>C];[271dupA] compounds had mild clinical and biochemical phenotypes and responded strikingly to hydroxocobalamin monotherapy.

Unexpected Complication of Hydroxocobalamin Administration for Refractory Vasoplegia in Orthotopic Liver Transplant: A Case Report.

A 40-year-old male with alcoholic cirrhosis and end-stage renal disease presented for simultaneous liver and kidney transplantation. Hemodialysis was utilized intraoperatively during liver transplantation. During the procedure, the patient developed refractory hypotension and ultimately received hydroxocobalamin for vasoplegia. Shortly after administration, the hemodialysis machine ceased working after a "blood leak" alarm developed. Without the ability to continue intraoperative dialysis, the kidney transplantation portion of his surgery was postponed. The patient was transferred to the intensive care unit, where he underwent continuous renal replacement therapy overnight, and his kidney transplant proceeded the following morning.

Methylene Blue Monotherapy Compared With Combination Therapy With Hydroxocobalamin for the Treatment of Refractory Vasoplegic Syndrome: ARetrospective Cohort Study.

OBJECTIVE: To compare the efficacy of methylene blue with combination therapy with hydroxocobalamin in patients experiencing vasoplegic syndrome after cardiac surgery. DESIGN: Retrospective cohort study. SETTING: Tertiary medical center. PARTICIPANTS: Patients who received methylene blue with or without hydroxocobalamin for refractory vasoplegic syndrome rescue therapy. MEASUREMENTS AND MAIN RESULTS: The primary outcome was 0.the ability to maintain mean arterial pressure (MAP) >60 mmHg beyond 1hour after study drug administration. Other pertinent outcomes included MAP at hours 6, 12, and 24 post-administration; both raw and proportional changes of vasopressor doses from baseline at hours 1, 6, 12, and 24 post-administration; and change in pulmonary artery catheter hemodynamics. Overall, 28 doses were administered in 14 patients in the monotherapy group and 17 doses (10 methylene blue, 7 hydroxocobalamin) were administered in 6 patients in the combination therapy group. There were no differences in ability to maintain MAP at 1hour, with 71% of the monotherapy and 82% of combination therapy patients meeting MAP goals (p = 0.49). Pairwise comparisons demonstrated vasopressor reductions at 6, 12, and 24hours in both groups, but only significant reductions at 1hour were observed in the combination therapy group (-0.06 µg/kg/min; p = 0.003) but not in the monotherapy group (-0.015 µg/kg/min; p = 0.14). CONCLUSION: This is the first study to compare methylene blue monotherapy with combination therapy, which suggests there may be an advantage to combination therapy. Further characterization of ideal dosing, timing, and agent selection should be investigated on a larger scale format.

The use of intravenous hydroxocobalamin as a rescue in methylene blue-resistant vasoplegic syndrome in cardiac surgery.

Vasoplegic syndrome is a well-recognized complication during cardiopulmonary bypass (CPB) and is associated with increased morbidity and mortality, especially when refractory to conventional vasoconstrictor therapy. This is the first reported case of vasoplegia on CPB unresponsive to methylene blue whereas responsive to hydroxocobalamin, which indicates that the effect of hydroxocobalamin outside of the nitric oxide system is significant or that the two drugs have a synergistic effect in one or multiple mechanisms.

Milder clinical and biochemical phenotypes associated with the c.482G>A (p.Arg161Gln) pathogenic variant in cobalamin C disease: Implications for management and screening.

INTRODUCTION: Cobalamin C disease is a multisystemic disease with variable manifestations and age of onset. Genotype-phenotype correlations are well-recognized in this disorder. Here, we present a large cohort of individuals with cobalamin C disease, several of whom are heterozygous for the c.482G>A pathogenic variant (p.Arg161Gln). We compared clinical characteristics of individuals with this pathogenic variant to those who do not have this variant. To our knowledge, this study represents the largest single cohort of individuals with the c.482G>A (p.Arg161Gln) pathogenic variant. METHODS: A retrospective chart review of 27 individuals from 21 families with cobalamin C disease who are followed at our facility was conducted. RESULTS: 13 individuals (48%) are compound heterozygous with the c.482G>A (p.Arg161Gln) on one allele and a second pathogenic variant on the other allele. Individuals with the c.482G>A (p.Arg161Gln) pathogenic variant had later onset of symptoms and easier metabolic control. Moreover, they had milder biochemical abnormalities at presentation which likely contributed to the observation that 4 individuals (31%) in this group were missed by newborn screening. CONCLUSION: The c.482G>A (p.Arg161Gln) pathogenic variant is associated with milder disease. These individuals may not receive a timely diagnosis as they may not be identified on newborn screening or because of unrecognized, late onset symptoms. Despite the milder presentation, significant complications can occur, especially if treatment is delayed.

An infant and mother with severe B12 deficiency: vitamin B12 status assessment should be determined in pregnant women with anaemia.

The vitamin B12 status of infants depends on maternal B12 status during pregnancy, and during lactation if breastfed. We present a 9-month-old girl who was admitted to the metabolic unit for assessment of developmental delay. She was exclusively breastfed and the introduction of solids at 5 months was unsuccessful. Investigations revealed pancytopenia, undetectable B12 and highly elevated methylmalonic acid and homocysteine. Methylmalonic acid and homocysteine normalised following B12 injections. Marked catch-up of developmental milestones was noted after treatment with B12. Investigations of parents showed normal B12 in the father and combined B12 and iron deficiency in the mother. Maternal B12 deficiency, most likely masked by iron deficiency, led to severe B12 deficiency in the infant. Exclusive breastfeeding and a subsequent failure to wean exacerbated the infant's B12 deficiency leading to developmental delay. This case highlights the need for development of guidelines for better assessment of B12 status during pregnancy.

Methionine synthase reductase deficiency (CblE): A report of two patients and a novel mutation.

IMPORTANCE: Functional methionine synthase reductase deficiency, also known as cobalamin E disorder, is a rare autosomal recessive inherited disease that results in an impaired remethylation of homocysteine to methionine. It presents with macrocytic anemia, hyperhomocysteinemia, and hypomethioninemia, and may also be accompanied with neurological impairment. CLINICAL PRESENTATION: We describe two new cases of unrelated girls with megaloblastic anemia misclassified at first as congenital dyserythropoietic anemia with development of neurologic dysfunction in one of them. INTERVENTION: The posterior finding of biochemical features (hyperhomocysteinemia and hypomethioninemia) focused the diagnosis on the inborn errors of intracellular vitamin B12. Subsequent molecular analysis of the methionine synthase reductase (MTRR) gene revealed compound heterozygosity for a transition c.1361C > T (p.Ser454Leu) and another, not yet described in literature, c.1677-1G > A (p.Glu560fs) in one patient, and a single homozygosis mutation, c.1361C > T (p.Ser545Leu) in the other one. These mutations confirmed the diagnosis of cobalamin E deficiency. CONCLUSION: Treatment with hydroxocobalamin in combination with betaine appears to be useful for hematological improvement and prevention of brain disabilities in CblE-affected patients. Our study widens the clinical, molecular, metabolic, and cytological knowledge of deficiency MTRR enzyme.

Hidroxocobalamina no tratamento de intoxicações por cianeto / Hydroxocobalamin in the treatment of cyanide poisoning

CONTEXTO: A intoxicação por cianeto pode ser considerada uma intoxicação rara porém de extrema gravidade. A causa mais comum de exposição aguda ao cianeto é a inalação de fumaça em incêndios. Nos casos de intoxicação, além das medidas de suporte clínico, como suplementação de oxigênio, a terapia com antídotos deve ser realizada. Dentre os antídotos disponíveis (hidroxocobalamina, nitrito de amila, nitrito de sódio, tiossulfato de sódio, 4-dimetilaminofenol e edetato de dicobalto), a hidroxocobalamina é apontada como o antídoto de primeira linha. Atualmente, tais medicamentos não estão disponíveis no Brasil. EVIDÊNCIAS CIENTÍFICAS: Dentre as melhores evidências recuperadas, após buscas por revisões sistemáticas, encontram-se 4 estudos observacionais realizados na França, sendo um de delineamento prospectivo e os demais retrospectivos (um total de 345 pacientes estudados). A maioria dos pacientes foi exposta ao cianeto por inalação de fumaça em incêndios domésticos, exceto por um estudo que avaliou principalmente tentativas de suicídio com ingestão de cianeto. Como intervenção, os estudos preconizaram uma dose inicial de 5g de hidroxocobalamina em infusão de 15-30 min, a qual foi administrada em aproximadamente 20 min após o contato com o serviço de emergência ainda em âmbito pré-hospitalar, com a possibilidade de doses adicionais em pacientes não responsivos (até um total de 15g). Como resultados, a mortalidade variou de 28-42% considerando todos os indivíduos que receberam a hidroxocobalamina. Entre os indivíduos com intoxicação confirmada laboratorialmente, 33-36% vieram a falecer, sendo poupados até mesmo indivíduos com níveis plasmáticos potencialmente letais, nestes a morte ocorreu em 36-39% dos casos. A parada cardíaca se apresentou como uma complicação comum (38%). A presença de sequelas no momento da alta hospitalar foi de 10-14%, sendo confusão, perda de memória e síndrome cerebelar as mais comuns. A hidroxocobalamina apresentou um perfil de segurança favorável, apenas com incidência de efeitos adversos leves. Dentre eles, o mais comum foi a apresentação de coloração vermelho-rosa na pele e urina e, mais raramente, aumento da pressão arterial. Após a avaliação crítica com a proposta do sistema GRADE, as evidências de eficácia atualmente disponíveis foram classificadas com qualidade muito baixa e as evidências de segurança com qualidade moderada. DISCUSSÃO: A hidroxocobalamina se apresenta como um agente potencialmente efetivo no tratamento de intoxicações por cianeto. Suas evidências devem ser interpretadas com cautela devido às limitações de suas fontes. O delineamento descritivo não permite o testes das variadas hipóteses, sem, portanto, ser quantificada a influência do acaso sobre os resultados obtidos. Da mesma forma, a ausência de controles e ajustes estatísticos não afasta a influência de fatores de confusão, sendo esses, importantes fontes de viés nos estudos observacionais. Com os custos considerados nas análises econômicas, ela se apresenta também como uma opção potencialmente custo-efetiva e com baixo impacto orçamentário. Todavia, outros fatores além da qualidade das evidências, como as barreiras para a sua devida implementação, devem ser considerados na elaboração de uma recomendação sobre seu uso. DECISÃO FINAL: Após as considerações provenientes da Consulta Pública, os membros da CONITEC presentes na 40ª reunião do plenário do dia 08/09/2015 deliberaram, por unanimidade, recomendar a incorporação do Cloridrato de hidroxocobalamina na concentração de 5 g injetável no tratamento de intoxicações por cianeto. Foi assinado o Registro de Deliberação nº 149/2015. DECISÃO: Incorporar a hidroxocobalamina no tratamento de intoxicações por cianeto, no âmbito do Sistema Único de Saúde ­ SUS, dada pela Portaria nº 9 de 28 de janeiro de 2016 publicado no DOU nº 20 de 29 de janeiro de 2016.

Intraosseous hydroxocobalamin versus intravenous hydroxocobalamin compared to intraosseous whole blood or no treatment for hemorrhagic shock in a swine model.

OBJECTIVE: To determine if intraosseous (IO) hydroxocobalamin can improve systolic blood pressure (SBP) in a swine model after severe hemorrhagic shock. METHODS: Thirty six swine (45-55 kg) were anesthetized, intubated, and instrumented with continuous femoral and pulmonary artery pressure monitoring and then hemorrhaged such that 30 percent of their blood volume was extracted over 20 minutes. Five minutes later, animals were randomly assigned to receive 500 mL IO whole blood, 150 mg/kg IO or intravenous (IV) hydroxocobalamin in 180 mL of saline, or no treatment and then monitored for 60 minutes. A sample size of eight animals per group was based on a power of 80 percent, an alpha of 0.05, and a small effect size to detect a difference in SBP between groups. Outcome data were analyzed using repeated measures analysis of variance (RMANOVA). RESULTS: RMANOVA outcome analysis detected a significant difference between groups (p < 0.05). IO whole blood, IO hydroxocobalamin, and IV hydroxocobalamin groups were similar to each other, but significantly different compared to controls regarding SBP, mean arterial pressure (MAP), systemic vascular resistance, and heart rate. Differences in SBP and MAP were sustained throughout the experiment. At 60 minutes, the comparison among the groups, IO whole blood, IO hydroxocobalamin, IV hydroxocobalamin, and control, was the following: SBP 78.2 versus 83.7 versus 75.1 versus 55.3 mm Hg; MAP 62.7 versus 65 versus 60 versus 43 mm Hg. There was a significant interaction by time in lactate values (p < 0.01) such that control animal lactate values increased over time (3.3 mmol/L) compared to IO whole blood, IO or IV hydroxocobalamin treated animals (1.1, 1.6, 1.3 mmol/L). CONCLUSIONS: IO hydroxocobalamin improved SBP, MAP, compared to no treatment and was similar to IO whole blood and IV hydroxocobalamin in this animal model of severe hemorrhage. Moreover, whereas serum lactate was improving in all treated groups, it was deteriorating in the control group.

Successful Use of Hydroxocobalamin and Sodium Thiosulfate in Acute Cyanide Poisoning: A Case Report with Follow-up.

Hydroxocobalamin is an effective first-line antidote used mainly in monotherapy of cyanide poisonings, while the opinions are different on the effects of its combination with sodium thiosulfate. A 58-year-old male committed a suicide attempt by ingesting of 1200-1500 mg of potassium cyanide; he was unconscious for 1-1.5 min. after ingestion with the episode of generalized seizures. On admission to the ICU, the patient was acidotic (pH 7.28; HCO3 14.0 mmol/L, base excess -12.7 mmol/L, saturation O2 0.999) with high serum lactate (12.5 mmol/L). Hydroxocobalamin was administered 1.5 hr after ingestion in two subsequent intravenous infusions at a total dose of 7.5 g. The infusion was followed by continuous intravenous administration of 1 mL/hr/kg of 10% sodium thiosulfate at a total dose of 12 g. No complications and adverse reactions were registered. Serum lactate decreased to 0.6 mmol/L the same day, and arterial blood gases became normal (pH 7.49; HCO3 27.2 mmol/L, base excess 2.2 mmol/L, saturation O2 0.994). The follow-up examination 5 months later revealed no damage of basal ganglia and cerebellum on magnetic resonance imaging. The neurological examination revealed no pathological findings. On the ocular coherence tomography, the retinal nerve fibres layer was normal. In visual evoked potentials, there was a normal evoked complex on the left eye and minor decrease in amplitude on the right eye. Combination of hydroxocobalamin and sodium thiosulfate can have a positive effect on the survival without long-term neurological and visual sequelae in the cases of massive cyanide poisonings due to the possibility of a potentiation or synergism of hydroxocobalamin effects by sodium thiosulfate. This synergism can be explained by the different time-points of action of two antidotes: the initial and immediate effect of hydroxocobalamin, followed by the delayed, but more persistent effect of sodium thiosulfate.

Treatment of vitamin B12 deficiency-methylcobalamine? Cyancobalamine? Hydroxocobalamin?-clearing the confusion.

Vitamin B12 (cyancobalamin, Cbl) has two active co-enzyme forms, methylcobalamin (MeCbl) and adenosylcobalamin (AdCbl). There has been a paradigm shift in the treatment of vitamin B12 deficiency such that MeCbl is being extensively used and promoted. This is despite the fact that both MeCbl and AdCbl are essential and have distinct metabolic fates and functions. MeCbl is primarily involved along with folate in hematopiesis and development of the brain during childhood. Whereas deficiency of AdCbl disturbs the carbohydrate, fat and amino-acid metabolism, and hence interferes with the formation of myelin. Thereby, it is important to treat vitamin B12 deficiency with a combination of MeCbl and AdCbl or hydroxocobalamin or Cbl. Regarding the route, it has been proved that the oral route is comparable to the intramuscular route for rectifying vitamin B12 deficiency.

Intraosseous versus intravenous infusion of hydroxocobalamin for the treatment of acute severe cyanide toxicity in a Swine model.

OBJECTIVES: Easily administrated cyanide antidotes are needed for first responders, military troops, and emergency department staff after cyanide exposure in mass casualty incidents or due to smoke inhalation during fires involving many victims. Hydroxocobalamin has proven to be an effective antidote, but cannot be given intramuscularly because the volume of diluent needed is too large. Thus, intraosseous (IO) infusion may be an alternative, as it is simple and has been recommended for the administration of other resuscitation drugs. The primary objective of this study was to compare the efficacy of IO delivery of hydroxocobalamin to intravenous (IV) injection for the management of acute cyanide toxicity in a well-described porcine model. METHODS: Twenty-four swine (45 to 55 kg) were anesthetized, intubated, and instrumented with continuous mean arterial pressure (MAP) and cardiac output monitoring. Cyanide was continuously infused until severe hypotension (50% of baseline MAP), followed by IO or IV hydroxocobalamin treatment. Animals were randomly assigned to receive IV (150 mg/kg) or IO (150 mg/kg) hydroxocobalamin and monitored for 60 minutes after start of antidotal infusion. The primary outcome measure was the change in MAP after antidotal treatment from onset of hypotension (time zero) to 60 minutes. A sample size of 12 animals per group was determined by group size analysis based on power of 80% to detect a one standard deviation of the mean MAP between the groups with an alpha of 0.05. Whole blood cyanide, lactate, pH, nitrotyrosine (nitric oxide marker) levels, cerebral and renal near infrared spectrometry (NIRS) oxygenation, and inflammatory markers were also measured. Repeated-measures analysis of variance was used to determine statistically significant changes between groups over time. RESULTS: At baseline and at the point of hypotension, physiologic parameters were similar between groups. At the conclusion of the study, 10 out of 12 animals in the IV group and 10 out of 12 in IO group survived (p = 1.0). Both groups demonstrated a similar return to baseline MAP (p = 0.997). Cardiac output, oxygen saturation, and systemic vascular resistance were also found to be similar between groups (p > 0.4), and no difference was detected between bicarbonate, pH, and lactate levels (p > 0.8). Cyanide levels were undetectable after the hydroxocobalamin infusion throughout the study in both groups (p = 1.0). Cerebral and renal NIRS oxygenation decreased in parallel to MAP during cyanide infusion and increased after antidote infusion in both groups. Serum nitrotyrosine increased during cyanide infusion in all animals and then decreased in both study arms after hydroxocobalamin infusion (p > 0.5). Serum cytokines increased starting at cyanide infusion and no difference was detected between groups (tumor necrosis factor-α, interleukin [IL]-1ß, IL-6, and IL-10). CONCLUSIONS: The authors found no difference in the efficacy of IV versus IO hydroxocobalamin in the treatment of severe cyanide toxicity in a validated porcine model.

Hydroxocobalamin supplementation and erythropoisis stimulating agent hyporesponsiveness in haemodialysis patients.

BACKGROUND: Long-term haemodialysis patients may be at risk of hydrosoluble vitamin deficiencies. This study aimed to test the hypothesis that in patients with serum B12 < 300 pmol/L, intramuscular hydroxocobalamin reduces erythropoietin requirements whilst maintaining haemoglobin concentrations (Hb). METHODS: Study design was prospective, non-randomized, open label, with single group assignment. In 61 patients hydroxocobalamin 1000 µg was given weekly for 3 weeks and erythropoietin dose adjusted to target a Hb of 11-12 g/L. The primary outcome was the change in erythropoietin requirements at 2 years. Secondary outcomes included assessment of change in biochemical or clinical parameters. RESULTS: The erythropoietin dose reduced from 11 000 ± 7000 (10 000) IU to 5000 ± 6000 (3000) IU per week (P < 0.001) with no change in Hb 116 ± 16 (117) g/L before and after 114 ± 15 (113) g/L (P = 0.488) hydroxocobalamin supplementation. Serum albumin rose from 35 ± 4 (35) g/L to 36 ± 4 (36) g/L (P = 0.03). A significant rise in red cell folate (RCF) and serum vitamin B12 levels was observed. Serum ferritin rose despite a reduction in intravenous iron usage and no significant change in c-reactive protein or transferrin saturation. CONCLUSIONS: In HD patients with B12 < 300 pmol/L, following treatment with hydroxocobalamin there was reduced erythropoietin requirements, maintained Hb and a small but significant rise in the serum albumin. RCF may be low in haemodialysis patients with metabolic cobalamin deficiency and rises significantly after supplementation. Hydroxocobalamin supplementation may have the potential to reduce the cost of anaemia management.

Adult-onset eculizumab-resistant hemolytic uremic syndrome associated with cobalamin C deficiency.

A 20-year-old man was hospitalized for malignant hypertension, mechanical hemolysis, and kidney failure. Kidney biopsy confirmed glomerular and arteriolar thrombotic microangiopathy. Etiologic analyses, which included ADAMTS13 activity, stool culture, complement factor proteins (C3, C4, factor H, factor I, and MCP [membrane cofactor protein]), anti-factor H antibodies, HIV (human immunodeficiency virus) serology, and antinuclear and antiphospholipid antibodies, returned normal results. Malignant hypertension was diagnosed. Ten months later, we observed a relapse of acute kidney injury and mechanical hemolysis. Considering a diagnosis of complement dysregulation-related atypical hemolytic uremic syndrome (HUS), we began treatment with eculizumab. Despite the efficient complement blockade, the patient's kidney function continued to decline. We performed additional analyses and found that the patient's homocysteine levels were dramatically increased, with no vitamin B12 (cobalamin) or folate deficiencies. We observed very low plasma methionine levels associated with methylmalonic aciduria, which suggested cobalamin C disease. We stopped the eculizumab infusions and initiated specific treatment, which resulted in complete cessation of hemolysis. MMACHC (methylmalonic aciduria and homocystinuria type C protein) sequencing revealed compound heterozygosity for 2 causative mutations. To our knowledge, this is the first report of adult-onset cobalamin C-related HUS. Considering the wide availability and low cost of the homocysteine assay, we suggest that it be included in the diagnostic algorithm for adult patients who present with HUS.

A patient with an inborn error of vitamin B12 metabolism (cblF) detected by newborn screening.

A neonate, who was found to have an elevated C3/C2 ratio and minimally elevated propionylcarnitine on newborn screening, was subsequently identified as having the rare cblF inborn error of vitamin B12 (cobalamin) metabolism. This disorder is characterized by the retention of unmetabolized cobalamin in lysosomes such that it is not readily available for cellular metabolism. Although cultured fibroblasts from the patient did not show the expected functional abnormalities of the cobalamin-dependent enzymes, methylmalonyl-CoA mutase and methionine synthase, they did show reduced synthesis of the active cobalamin cofactors adenosylcobalamin and methylcobalamin. Mutation analysis of LMBRD1 established that the patient had the cblF disorder. Treatment was initiated promptly, and the patient showed a robust response to regular injections of cyanocobalamin, and she was later switched to hydroxocobalamin. Currently, at 3 years of age, the child is clinically well, with appropriate development. Adjusted newborn screening cutoffs in Ontario allowed detection of a deficiency that might not have otherwise been identified, allowing early treatment and perhaps preventing the adverse sequelae seen in some untreated patients.

Clinical and biochemical outcome after hydroxocobalamin dose escalation in a series of patients with cobalamin C deficiency.

BACKGROUND: CblC deficiency produces a combination of methylmalonic aciduria (MMA) and homocystinuria (HCU), and is the most common error of cobalamin metabolism. Patients present a wide spectrum of symptoms, ranging from early severe multisystemic forms, to milder late-onset phenotypes. Cognitive and visual impairment are nearly constant. Hydroxocobalamin (OHCbl), betaine, folinic acid, levocarnitine and eventually dietary protein restriction are the main therapeutic approaches. Although early introduction of OHCbl is crucial, no standardized protocols regarding dose adaptation exist. No reports on long-term outcomes after high doses of this vitamin have been published. METHODS: In this study five patients with CblC deficiency (early severe forms) were treated with high doses of OHCbl for 18 to 30months. Clinical examinations, neurological assessment, and biochemical studies (plasma total homocysteine (tHcy), amino acids, hydroxocobalamin, and methylmalonic acid in urine) were periodically performed. RESULTS: Variable clinical and biochemical outcomes were observed in patients treated with high doses of OHCbl. The best biochemical response was observed in those children with the worse metabolic control. By contrast, those patients with a concentration of tHcy around 50µmol/l or less showed only minor changes. Clinically, a considerable improvement was observed in those patients with severe problems in communication, expressive language and behavior. CONCLUSIONS: According to our study, high OHCbl doses in CblC deficiency could have a greater benefit in those children with a prior history of suboptimal metabolic control, and also in those with severe neurological phenotypes. More specifically, we observed improvements in communication skills and behavior. These results should encourage further prospective trials to determine the optimal OHCbl regimen and to generate protocols and guidelines in this rare disorder.

[Outcomes of patients with combined methylmalonic acidemia and homocystinuria after treatment].

OBJECTIVE: Combined methylmalonic acidemia with homocystinuria is a common form of methylmalonic acidemia in China. Patients with this disease can progress to death without timely and effective treatment. This study aimed to analyze the treatment outcomes of patients with combined methylmalonic acidemia and homocystinuria. METHOD: From September 2004 to April 2012, 58 patients with combined methylmalonic acidemia and homocystinuria (34 males and 24 females) were diagnosed and treated in our hospital. Fifty cases were from clinical patients including 42 early-onset cases and 8 late-onset cases. Their age when they were diagnosed ranged from 18 days to 30.8 years. The other 8 cases were from newborn screening. All the patients were treated with vitamin B12, betaine, folic acid, vitamin B6, and L-carnitine. The physical and neuropsychological development, general laboratory tests, the levels of amino acids, acylcarnitines, and homocysteine in blood, and organic acids in urine were followed up. RESULT: The follow-up period ranged from 1 month to 7.1 years. Three cases died (all were early-onset cases). In the other patients after treatment, the symptoms such as recurrent vomiting, seizures, lethargy, and poor feeding disappeared, muscle strength and muscle tension were improved, and general biochemical abnormalities such as anemia and metabolic acidosis were corrected. Among the surviving 55 cases, 49 had neurological impairments such as developmental delay and mental retardation. The median levels of blood propionylcarnitine and its ratio with acetylcarnitine, serum homocysteine, and urine methylmalonic acid were significantly decreased (P < 0.01), from 7.73 µmol/L (ranged from 1.5 to 18.61 µmol/L), 0.74 (ranged from 0.29 to 2.06), 97.3 µmol/L (ranged from 25.1 to 250 µmol/L) and 168.55 (ranged from 3.66 to 1032.82) before treatment to 2.74 µmol/L (ranged from 0.47 to 12.09 µmol/L), 0.16 (ranged from 0.03 to 0.62), 43.8 µmol/L (ranged from 17 to 97.8 µmol/L) and 6.81 (ranged from 0 to 95.43) after treatment, respectively. CONCLUSION: Patients with combined methylmalonic acidemia and homocystinuria respond to a combined treatment consisting of supplementation of hydroxycobalamin, betaine, folic acid, vitamin B6 and L-carnitine with clinical and biochemical improvement. But the long-term outcomes are unsatisfactory, with neurological sequelae in most patients.