Intramuscular Hydroxocobalamin Research Articles

A Brief Overview of the Diagnosis and Treatment of Cobalamin (B12) Deficiency.

An increasing number of adult individuals are at risk of vitamin B12 deficiency, either from reduced nutritional intake or impaired gastrointestinal B12 absorption. This study aims to review the current best practices for the diagnosis and treatment of individuals with vitamin B12 deficiency. A narrative literature review of the diagnosis and treatment of vitamin B12 deficiency. Prevention and early treatment of B12 deficiency is essential to avoid irreversible neurological consequences. Diagnosis is often difficult due to diverse symptoms, marked differences in diagnostic assays' performance and the unreliability of second-line biomarkers, including holo-transcobalamin, methylmalonic acid and total homocysteine. Reduced dietary intake of B12 requires oral supplementation. In B12 malabsorption, oral supplementation is likely insufficient, and parenteral (i.e. intramuscular) supplementation is preferred. There is no consensus on the optimal long-term management of B12 deficiency with intramuscular therapy. According to the British National Formulary guidelines, many individuals with B12 deficiency due to malabsorption can be managed with 1000 µg intramuscular hydroxocobalamin once every two months after the initial loading. Long-term B12 supplementation is effective and safe, but responses to treatment may vary considerably. Clinical and patient experience strongly suggests that up to 50% of individuals require individualized injection regimens with more frequent administration, ranging from daily or twice weekly to every 2-4 weeks, to remain symptom-free and maintain a normal quality of life. 'Titration' of injection frequency based on measuring biomarkers such as serum B12 or MMA should not be practiced. There is currently no evidence to support that oral/sublingual supplementation can safely and effectively replace injections. This study highlights the interindividual differences in symptomatology and treatment of people with B12 deficiency. Treatment follows an individualized approach, based on the cause of the deficiency, and tailored to help someone to become and remain symptom-free.

C8 (Clinical Case) A 10-Month-Old Male with Macrocytic Anemia and Hypoalbuminemia

Abstract Introduction/Background Transcobalamin-II Deficiency (TCII-Deficiency) is a rare autosomal-recessive metabolic condition, resulting in ineffective transport and uptake of Vitamin B12. Clinical features of pancytopenia, failure to thrive, diarrhea, and developmental delay typically present between 1-12 months of age1. Case Description A 10-month-old term, previously well male with a normal newborn screen, presented with a one-month history of decreased energy, failure to thrive, and diarrhea. He had a two-week history of gross motor regression with lower limb and periorbital edema. Examination was notable for perioral rash, severe diaper dermatitis, buccal ulcerations, pallor, and generalised edema including ascites. There was no organomegaly or any dysmorphic features. Investigations revealed macrocytic anemia, thrombocytopenia, worsening neutropenia, hypoalbuminemia, hypertriglyceridemia, and hypogammaglobulinemia (Table 1). Vitamin B12 and B9 levels were normal. Bone marrow biopsy was hypocellular, and ruled out aplastic anemia and leukemia. Intestinal biopsy showed generalized edema from duodenum to rectum with GVHD-like injury pattern, and evidence for protein-losing enteropathy (PLE). Required therapy included numerous RBC, platelet, and albumin transfusions and enteral feeding. A disorder of vitamin B12 metabolism, specifically TCII-Deficiency, was suspected based on clinical presentation with no other clear explanation. Serum MMA was highly elevated at 24,154 nmol/L (0-500 nmol/L) as was homocysteine at 27.3 umol/L (4.7-10.3 umol/L). Whole-exome sequencing identified two mutations in TCN2. Treatment with intramuscular vitamin B12 resulted in reduction of urinary MMA level to 5.6 umol/mmol Cr (< 2 umol/mmol Cr) in 10 days. Discussion Over the next months of treatment with intramuscular hydroxocobalamin, the MMA, homocysteine, albumin and CBC normalized and all clinical complications were resolved. Gross motor skills returned to normal, with only mild persistent speech delay. TCII-Deficiency often presents with a heterogeneous constellation of symptoms. In this case, the differential included several hematologic and gastrointestinal pathologies, including DGAT1 deficiency (due to hypertriglyceridemia, diarrhea, and PLE) and CHAPLE syndrome (due to low immunoglobulins and PLE). MMA and homocysteine levels are often markedly elevated in B12 metabolism defects, and can justify initiation of treatment with cyanocobalamin/hydroxocobalamin (Vitamin B12) while awaiting confirmatory genetic testing2. Conclusion TCII-Deficiency is a rare cause of macrocytic anemia; early consideration and treatment with intramuscular vitamin B12 leads to dramatic symptom improvement and is important for paediatricians to recognize. Clinical Pearls: • Clinicians should consider B12 metabolism defects on their differential in a young child who has macrocytic anemia with normal B12 levels. • Paediatricians can use MMA and homocysteine levels to assess for B12 metabolism defects while awaiting genetic testing.

P77 Management of vitamin B12 deficiency in primary care during the COVID-19 pandemic: Do all patients need to come in?

IntroductionNot all causes of vitamin B12 deficiency require intramuscular hydroxocobalamin (IMH). NICE guidance states that diet-related deficiency can be treated orally, but pernicious anaemia must be excluded via anti-intrinsic factor antibodies (anti-IFAB). Our aim was to audit the management of B12 deficiency during the COVID-19 pandemic when reducing footfall is vital. Then, implement staff education strategies to improve adherence to guidance.MethodsData for patients who received IMH from March-June 2020 was retrospectively analysed for: full blood count (FBC), B12, folate and anti-IFAB levels. These patients were sent letters to have blood tests for the missing investigations. Results were presented at meetings and flowchart-posters were distributed. Audit was closed with prospective data for patients who requested IMH from September-October 2020.ResultsFrom 46 patients identified, 82.6% had B12 and folate checked prior to therapy commencement, but 23.7% had an untreated folate deficiency. 79.3% of patients receiving IMH had never been tested for anti-IFAB; none of those tested were positive. A lack of awareness of the NICE guidance was identified as a key cause for non-adherence. Following the intervention, all 34 patients were appropriately investigated. Out of these, 8.8% had positive anti-IFAB levels and following a review of their clinical histories, all patients were commenced on appropriate therapy.DiscussionIMH can have great benefit; but it is invasive, has financial and nursing-time implications, and increases the risk of contagion via footfall in the practice. Thus, this multi-cycle audit shows that appropriate investigations prior to commencing therapy is key.

Long-term outcome of a patient with Transcobalamin deficiency caused by the homozygous c.1115_1116delCA mutation in TCN2 gene: a case report

BackgroundTranscobalamin deficiency is a rare autosomal recessive inborn error of cobalamin transport (prevalence: < 1/1000000) which clinically manifests in early infancy.Case presentationWe describe the case of a 31 years old woman who at the age of 30 days presented with the classical clinical and laboratory signs of an inborn error of vitamin B12 metabolism. Family history revealed a sister who died at the age of 3 months with a similar clinical syndrome and with pancytopenia. She was started on empirical intramuscular (IM) cobalamin supplements (injections of hydroxocobalamin 1 mg/day for 1 week and then 1 mg twice a week) and several transfusions of washed and concentrated red blood cells. With these treatments a clear improvement in symptoms was observed, with the disappearance of vomiting, diarrhea and normalization of the full blood count. At 8 years of age injections were stopped for about two and a half months causing the appearance of pancytopenia. IM hydroxocobalamin was then restarted sine die. The definitive diagnosis could only be established at 29 years of age when a genetic evaluation revealed the homozygous c.1115_1116delCA mutation of TCN2 gene (p.Q373GfsX38).Currently she is healthy and she is taking 1 mg of IM hydroxocobalamin once a week.ConclusionsOur case report highlights that early detection of TC deficiency and early initiation of aggressive IM treatment is likely associated with disease control and an overall favorable outcome.

Efficacy of intramuscular hydroxocobalamin supplementation in cats with cobalamin deficiency and gastrointestinal disease.

BackgroundIn humans, absorption and tissue retention rates of intramuscularly administered hydroxocobalamin (OH‐Cbl) are superior compared to cyanocobalamin (CN‐Cbl). Supplementation with OH‐Cbl has not been described in cats.ObjectivesTo evaluate effects of parenteral OH‐Cbl supplementation on clinical signs, serum Cbl and methylmalonic acid (MMA) concentrations in hypocobalaminemic cats with gastrointestinal disease.AnimalsTwenty‐three client‐owned cats.MethodsProspective study. Serum Cbl and MMA concentrations were determined at enrollment (t0), immediately before the 4th OH‐Cbl IM injection (300 μg, given q2 weeks) (t1), and 4 weeks after the 4th injection (t2). Severity of clinical signs (activity, appetite, vomiting, diarrhea, body weight) was graded at each time point and expressed as clinical disease activity score.ResultsMedian clinical disease activity score decreased significantly from t0 (6; range, 2‐10) to t1 (1; range, 0‐6) and t2 (1; range, 0‐9). Median serum Cbl concentration increased significantly from 111 pmol/L (range, 111‐218; reference range, 225‐1451 pmol/L) at t0 to 1612 pmol/L (range, 526‐14 756) (P < .001) at t1, and decreased again significantly to 712 pmol/L (range, 205‐4265) (P < .01) at t2. Median baseline serum MMA concentration at t0 (802 nmol/L; range, 238‐151 000; reference range, 120‐420 nmol/L) decreased significantly (P < .001) to 199 nmol/L (range, 29‐478) at t1, and was 205 nmol/L (range, 88‐734) at t2. Serum MMA concentrations normalized in 22/23 cats at t1, and were not significantly higher at t2 compared to t1.Conclusions and Clinical ImportanceThe herein described OH‐Cbl injection scheme appears efficacious for normalization of cellular Cbl deficiency in cats with gastrointestinal disease.

Favorable course of previously undiagnosed Methylmalonic Aciduria with Homocystinuria (cblC type) presenting with pulmonary hypertension and aHUS in a young child: a case report

BackgroundCobalamin C (cblC) defect is the most common inborn error of Vitamin B12 metabolism often causing severe neurological, renal, gastrointestinal and hematological symptoms. Onset with pulmonary hypertension (PAH) and atypical hemolytic-uremic syndrome (aHUS) is rare.Case presentationWe describe the case of a 2-years old child, previously in good health, admitted to the hospital with severe respiratory symptoms, rapid worsening of clinical conditions, O2 desaturation and palmo-plantar edema. The patient showed PAH and laboratory findings compatible with aHUS. cblC defect, an inborn error of metabolism, was identified as the cause of all the symptoms described (cardiac, respiratory and renal involvement). Results of neonatal screening for inborn errors of metabolism had been negative.Administration of IM OHCbl (intramuscular hydroxocobalamin), oral betaine and symptomatic treatment with diuretics and anti-hypertensive systemic and pulmonary drugs induced dramatic improvement of both cardiac and systemic symptoms.ConclusionsIn this case of cblC defect the metabolic treatment completely reverted symptoms of aHUS and PAH. The course was favorable, and the prognosis is what we foresee for the future.

Efficacy of oral compared with intramuscular vitamin B-12 supplementation after Roux-en-Y gastric bypass: a randomized controlled trial

After Roux-en-Y gastric bypass (RYGB), patients often develop a vitamin B-12 deficiency. Our objective was to investigate whether oral supplementation increases and normalizes low vitamin B-12 concentrations (vitamin B-12>200 pmol/L) in RYGB patients as compared to intramuscular injections. A randomized controlled trial in RYGB patients with subnormal serum B-12 concentrations was performed. One group (IM B-12) received bimonthly intramuscular hydroxocobalamin injections (2000 µg as loading dose and 1000 µg at follow-up) for 6 mo. The second group (oral B-12) received daily doses of oral methylcobalamin (1000 µg). Serum vitamin B-12 was determined at baseline (T0) and at 2 (T1), 4 (T2), and 6 mo (T3) after start of treatment. Concentrations of the secondary markers methylmalonic acid (MMA) and homocysteine (Hcy) were measured at T0 and T3. Fifty patients were included and randomized, 27 in IM B-12 and 23 in oral B-12. The median vitamin B-12 concentration at T0 was 175 pmol/L (range: 114-196 pmol/L) for IM B-12 and 167 pmol/L (range: 129-199 pmol/L) for oral B-12. Vitamin B-12 normalized in all individuals, and there was no significant difference in vitamin B-12 between the two groups. MMA and Hcy concentrations decreased significantly after 6 mo within each group (P<0.001 and P<0.001 for MMA and P=0.03 and P=0.045 for Hcy, respectively). There was no significant difference between the groups at 6 mo for both MMA and Hcy (P=0.53 and P=0.79). The efficacy of oral vitamin B-12 supplementation was similar to that of hydroxocobalamin injections in the present study. Oral supplementation can be used as an alternative to hydroxocobalamin injections to treat RYGB patients with low values of serum vitamin B-12. This trial was registered at clinicaltrials.gov as NCT02270749.

Vitamin B12 deficiency neuropathy: A clinical and electrophysiological study

Objectives Vitamin B12 deficiency is a metabolic disorder with many causes. The neurological features of vitamin B12 deficiency are heterogeneous [2] . Peripheral neuropathy often described [3] , but its frequency and its type is controversial [1] . The present study was conducted to describe electro-clinical presentations of peripheral neuropathy in patients with vitamin B12 deficiency. Methods A Retrospective review of 32 subjects with neurological abnormalities due to vitamin B12 deficiency, were subjected to a detailed motor and sensory nerve conduction studies of median, ulnar, external popliteal sciatic, internal popliteal sciatic and sural nerves. Patients that have another reason for neuropathy or another disease that can effect nerve conduction studies were excluded. Results The median age of the patients was 51 (± 16.57) years old, (range 18–84 years old), sex ratio (M/F) was 1.66 (20/12). Clinical features of neuropathy: paraesthesia, hyporeflexia, ataxia and limb weakness were present in 20 (62.5%) patients. Electromyography showed abnormal nerve conduction in 25 (78.12%) patients and it was normal in 7 (21.88%) patients. On nerve conduction study: 16 (50%) had axonal impairment, 3 (9.3%) had demyelinating neuropathy and 6 (18.75%) had mixed features. Eleven patients (34.37%) presented a pure sensory impairment and 14 (43.75%) presented mixed pattern sensory and motor impairment. All cases underwent treatment with intramuscular hydroxocobalamin treatment (daily injection of 1000 μg cyanocobalamin for 4 weeks, followed by injections of 1000 μg each month) with marked clinical and haematological improvement. Conclusion We conclude that nearly 80% patients with neurologic manifestations of vitamin B12 deficiency had evidence of peripheral neuropathy which is mainly axonal with some demyelinating features. Sensory and motor nerve conduction were affected. Evolution is generally good if the treatment was initiated early.

Cobalamin D Deficiency Identified Through Newborn Screening.

Cobalamin D deficiency (cblD) is one of the least common cobalamin metabolism disorders. It may result in isolated homocystinuria, isolated methylmalonic aciduria, or combined methylmalonic aciduria and homocystinuria (cblD-combined). Only seven cases of the combined cblD form have been reported to date. Due to the rarity of this disorder, the presentation and symptoms are not well described. We present an eighth case of the cblD-combined subtype, who had a positive newborn screen (NBS) on day of life 3. She was symptomatic and developed lethargy and poor oral intake at 8days of life. She was treated with 10% dextrose, folinic acid, intramuscular hydroxocobalamin, and betaine. Despite the early initiation of treatment, she developed complications of the disease and was found to have abnormal brain imaging findings at 17days of age and macular atrophy at 3months of age and has global developmental delay. We provide detailed description of her presentation, her treatment, and her complications to aid in the understanding of this rare disorder, which is very similar to the more common cobalamin C disorder (cblC).

Diagnosis &amp; Management of Vitamin B12 Deficiency in Primary Care – Are we following the guidelines?

Background: Vitamin B12 deficiency is common in primary care but its treatment practices vary across centres. One important cause of B12 deficiency is pernicious anaemia (identified by intrinsic factor antibodies), which is a risk factor for developing gastric carcinoma, and should be excluded. Additionally, recent evidence has suggested that some patients have been continued on B12 injections with no clear clinical indication. Recently,guidelines were produced to improve the investigation and management of B12 deficiency. Hence, this audit studied the investigation and management of B12 deficiency and adherence to clinical guidelines in a general practice (GP) in north-west England.Aim: To evaluate the appropriate diagnosis and management of vitamin B12 deficiency in our primary care centre against recognized standards.Methods: Clinical data of patients currently on oral cyanocobalamin and/or intramuscular hydroxocobalamin injections over a 1-year period were audited.Results: Thirty-eight patients (66% females, 34% males) receiving treatment for B12 deficiency were identified. Of these, 55% (21/38) had intrinsic factor antibodies checked and 52% (13/25) were managed according to the guidelines. 100% (8/8) of patients with dietary B12 deficiency (non-vegans) and 75% (3/4) of B12-deficient patients on long-term metformin have had follow-up serum B12 monitoring.Discussion: There is a need to improve the investigation for B12 deficiency, adherence to clinical guidelines, and documentation of patients’ diagnoses, treatment plans, dietary statuses, and required monitoring. We anticipate that adhering to guidelines when appropriate, with clear documentation, will improve the diagnosis and management of vitamin B12 deficiency so that safe prescribing and potential cost savings can be achieved.

Clinical presentation, gene analysis and outcomes in young patients with early-treated combined methylmalonic acidemia and homocysteinemia (cblC type) in Shandong province, China

ObjectivesTo estimate the incidence of MMA on newborn screening in Shandong province from May 2011 to May 2014 and summarize the clinical presentation, biochemical features, mutation analysis, and treatment regime of early-treated patients with cblC disease. MethodsBetween May 2011 and May 2014, 35,291 newborns were screened for MMA in Jinan maternal and Child Care Hospital, Shandong province. The levels of C3, C3/C2, methionine and tHcy were measured. Most patients received treatment with intramuscular hydroxocobalamin after diagnosis. Metabolic parameters, clinical presentation and mental development were followed up. ResultsNine patients were identified among 35,291 by newborn screening, giving an estimated incidence of 1:3920 live births for MMA, and all were classified as cblC disease. Among them, five patients received treatment with intramuscular hydroxocobalamin and two patients did not receive any treatment. One patient died of metabolic crises triggered by infection at the age of 38days. Seven different mutations (c.609G>A, c.455_457delCCC, c.394C>T, c.445_446insA, c.658_660delAAG, c.452A>G and IVS1+1G>A) were detected. The mutations (c.455_457delCCC and IVS1+1G>A) are novel. Five patients who received treatment had favorable metabolic response, with both reduction of urine MMA and tHcy and increase of methionine. We obtained 7 records of DQ assessment. The five patients who received treatment presented with developmental delay and obvious neurological manifestations. In two patients who did not receive any treatment, case 8 presented with severe mental retardation and developmental delay, while case 9 had nearly normal DQ values at the age of 11/12years. ConclusionOur study characterized variable phenotypes of neurodevelopment in early-treated cblC patients diagnosed on newborn screening. The long-term outcomes of cblC disease are unsatisfactory in spite of conventional treatment and improvement of biochemical abnormalities. Although the number of patients is too small, the information provided in this work is of value in highlighting possible genotype–phenotype correlation that influences outcomes in cblC disease by future studies.

Improving Bariatric Patient Aftercare Outcome by Improved Detection of a Functional Vitamin B12 Deficiency.

Vitamin B12 deficiency is common after bariatric surgery. Vitamin B12 is a poor predictor of functional vitamin B12 status, since deficiencies might even occur within the reference limits. Therefore, vitamin B12 deficiencies with serum vitamin B12 levels are between 140 and 200pmol/L remain undetected. Methylmalonic acid (MMA), however, will detect these deficiencies as accumulates due to functional intracellular vitamin B12 deficiencies. MMA is a relative expensive analysis and is therefore not generally available. To lower the costs, we only request MMA when vitamin B12 levels are between these levels. As a result, more biochemical deficiencies are found. However, it was not known whether bariatric patients with vitamin B12 levels between 140 and 200pmol/L would benefit from supplementation. Bariatric patients with vitamin B12 levels between 140 and 200pmol/L with (n = 45) and without (n = 45) intramuscular hydroxocobalamin injections were compared. Treated patients showed a significant increase of vitamin B12 levels (P < 0.001) and a significant decrease in MMA levels (P < 0.001). Biochemical improvement occurs in both patients with and without clinical symptoms. The control group showed a significant increase of MMA levels (P < 0.001). To examine whether biochemical benefits of vitamin B12 supplementation are correlated with clinical improvement, patient records were checked for complaints. Complaints were disappeared after treatment, while no improvement was seen in untreated patients. This study shows that all bariatric patients with vitamin B12 levels between 140 and 200pmol/L benefit clinical and biochemical from vitamin B12 supplementation, regardless the MMA levels.

Hydroxocobalamin supplementation and erythropoisis stimulating agent hyporesponsiveness in haemodialysis patients

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). 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. 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. 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.

Effect of Intramuscular Hydroxocobalamin for Carpal Tunnel Syndrome: Randomized Controlled Trial

Effect of Intramuscular Hydroxocobalamin for Carpal Tunnel Syndrome: Randomized Controlled Trial

Response to: Hydroxocobalamin for cobalamin C: which dosage? by V. Wiwanitkit

To the editor, Intramuscular hydroxocobalamin (OHCbl) has been used empirically for the management of cblC patients for decades. Its beneficial effects are very clear in the newborn period, with patients achieving metabolic improvement shortly after its initiation. However, the optimal regimens for long-term management of cblC remain undefined and are complicated by the great heterogeneity of this condition. It is common practice to continue patients on the same 1-mg dose of OHCbl started in the newborn period throughout their lives. Furthermore, several of these patients are weaned from a daily dose to weekly or every other week as they grow older, mainly because of the concerns associated with daily intramuscular injections and the lack of evidence to do otherwise. It is also unclear whether disease-related complications, such as progressive visual loss, are intrinsic to the natural history of the disease or due to sub-optimal metabolic control and can be modified by therapy. OHCbl is a medication with few recognized adverse effects. Elevated blood pressure has been reported to occur in a dose-dependent fashion in patients given 5,000 and 10,000 mg of intravenous OHCbl. These doses are 200to 500-fold above the dose we have used (Uhl et al. 2006, 2008). Whether chronic doses of 25 mg hydroxocobalamin will have a similar effect remains to be determined. While we agree with Dr. Wiwanitkit in that the results presented in our case report may only represent a short-term outcome, we disagree with his contention that “there are some reports on the long term of using OHCbl and there is no finding that the dose adaptation brings a significant improvement on the outcome”. The opposite is suggested by the only report we are aware of that has attempted a dose escalation. Van Hove et al. (2002) demonstrated convincingly that increasing subcutaneous OHCbl from 1 to 5 mg daily was required to achieve clinical and metabolic control in two patients with cblC and thrombotic microangiopathy. On the other hand, the findings reported by Andersson et al. (1999) suggested cblC is a developmental disorder, not that OHcbl therapy was ineffective. These authors did not attempt dose adaptation studies. We welcome his comments as they highlight what we have emphasized in our report: a well-planned, long-term clinical trial of higher doses of OHCbl will be needed to determine whether it is possible to slow or ameliorate cblC disease-related complications.

Hydroxocobalamin dose escalation improves metabolic control in cblC

Cobalamin C (cblC), a combined form of methylmalonic acidaemia and hyperhomocysteinaemia, is recognized as the most frequent inborn error of intracellular cobalamin metabolism. This condition can be detected by expanded newborn screening and can have an acute neonatal presentation that is life-threatening if not suspected and promptly treated. Intramuscular (IM) hydroxocobalamin (OHCbl) is the main treatment for patients with cblC, but formal dosing guidelines do not exist. A clinical improvement and a decrease of plasma methylmalonic acid (MMA) and total homocysteine (tHcy) levels, and an increase in methionine are typically observed after its initiation. It is well recognized that despite treatment, long-term complications such as developmental delay and progressive visual loss, may still develop. We describe the biochemical response of a 13-year-old boy with worsening metabolic parameters despite strict adherence to a conventional treatment regimen. We progressively increased the OHCbl dose from 1 to 20 mg IM per day and observed a dose-dependent response with an 80% reduction of plasma MMA (25 to 5.14 micromol/L; normal range <0.27 micromol/L), a 55% reduction of tHcy (112 to 50 micromol/L; normal range: 0-13 micromol/L) and a greater than twofold increase in methionine (17 to 36 micromol/L; normal range: 7-47 micromol/L). This suggests that higher OHCbl doses might be required to achieve an optimal biochemical response in cblC patients, but it is unknown whether it may slow or eliminate other complications. Future clinical trials to determine the benefits of higher-dose OHCbl therapy in patients with cblC and other disorders of intracellular cobalamin metabolism should be planned.

Transcobalamin II deficiency at birth

Transcobalamin II deficiency (# MIM 275350) is a rare, recessively inherited disorder of cobalamin transport that leads to intracellular cobalamin depletion with secondary impairment of methionine synthetase and methyl-malonyl CoA mutase activities. Affected individuals may suffer from long-term neurological sequelae if therapy with intramuscular hydroxocobalamin is not initiated promptly. We report two sisters with complete absence of transcobalamin due to homozygosity for a novel mutation (c.insC110) in the TCN2 gene that leads to a premature stop codon and non-functional protein. The older sister, now 4.5 years old, presented at 6 weeks of age with pancytopenia, protein losing enteropathy and a rapidly declining clinical course. Prompt therapy with 1 mg hydroxocobalamin/day led to full recovery within days. Her now 1.5 year old sister was diagnosed shortly after birth and was started on hydroxocobalamin prior to onset of clinical symptoms. Interestingly, urinary methylmalonic acid excretion was increased significantly during the first days of life suggesting that functional cobalamin deficiency is present also during fetal life, although not giving rise to clinical symptoms until well after birth.

Neuropathie périphérique réversible liée au déficit en vitamine B12

Objective. – To describe an electroclinical presentation of a peripheral neuropathy in a patient who suffered from vitamin B12 deficiency. Patient and methods. – We report the case of a 56-year-old man who, 17 years after a subtotal gastrectomy, presented with a diffuse sensory-motor demyelinating peripheral neuropathy with multifocal alteration of conduction confirmed by electromyography. Its causal relationship with vitamin B12 deficiency was biologically demonstrated. This neuropathy improved within a few days after intramuscular hydroxocobalamin treatment. Both clinical and electrophysiological signs had totally disappeared 3 months later on. Conclusion. – This observation demonstrates that, in spite of its poor outcome reported by several authors, peripheral neuropathy induced by vitamin B12 deficiency can recover completely with substitutive treatment.

Long-term outcome in treated combined methylmalonic acidemia and homocystinemia

PurposeTo describe the clinical and biochemical features and long-term outcome of a cohort of eight patients with methylmalonic acidemia and homocystinuria (cbIC).MethodsDocumentation of clinical features at birth and longitudinal follow-up of the biochemical and clinical response to treatment with daily oral carnitine and intramuscular hydroxocobalamin observed during continuous follow-up for an average of 5.7 years. ResultsOur patients had an increased incidence of congenital malformations including microcephaly (<5%) at birth (2 of 8), congenital heart disease (2 of 8), dysmorphic facial features (1 of 8), and thyroglossal duct cyst (1 of 8). Postnatal hydrocephalus (2 of 8) and hip dislocation caused by ligament laxity (1 of 8) were also noted. One patient had profound visual impairment before 6 months of age secondary to cbIC retinopathy, and two patients had abnormal retinal pigmentation with normal visual function. All patients presented with poor growth, feeding problems, and/or seizures. No patients had acute acidotic crises before or after treatment. All patients had dramatic reduction of plasma free homocystine and urine methylmalonic acid excretion after initiation of therapy with carnitine, intramuscular (IM) hydroxocobalamin (OHcbl) and, in two cases, oral betaine. Growth was significantly improved in most cases after the initiation of therapy, and microcephaly was resolved in one patient. All patients were developmentally delayed regardless of age of treatment onset, although two patients had relatively mild developmental delay. ConclusioncbIC patients may have an increased incidence of congenital malformations suggesting prenatal effects of abnormal cbl metabolism. Treatment with IM OHcbl and carnitine successfully corrects the biochemical abnormalities and improves growth. Developmental delay of variable severity is always present regardless of age at diagnosis or treatment onset. Genetics in Medicine, 1999:1(4):146–150.

Prevalence and haemopoietic effects of low serum vitamin B12 levels in geriatric medical patients.

The clinical significance of low serum vitamin B12 levels in elderly people is controversial. We aimed to document the prevalence of a low serum vitamin B12 (< 175 pmol/l) in patients referred to a geriatric medical unit, and to determine whether haemopoiesis is commonly affected in elderly patients with low serum vitamin B12. We studied prospectively 472 consecutive referrals to a geriatric medical unit; fifty-six (13%) had a low serum vitamin B12 level, of whom nineteen (34%) of the fifty-six also had evidence of Fe deficiency (serum ferritin < 45 ng/ml). Low vitamin B12 was associated with a raised mean erythrocyte volume (MCV; mean 96.0 (SD 6.7) fl), compared with a control group (91.7 (SD 6.0) fl; P = 0.001). However, only thirteen (23%) of the fifty-six patients with a low vitamin B12 had an MCV > or = 100 fl. Mean haemoglobin (Hb) levels were not significantly reduced in those with a low vitamin B12. In a subsequent study the haematological response to intramuscular hydroxocobalamin was examined in thirty-four patients with a low serum vitamin B12. Treatment resulted in a significant fall in MCV and rise in Hb; these effects could be detected both in those patients with an initially normal full blood count (change in MCV -1.2 (SD 1.2); Hb +0.5 (SD 0.6); P < 0.01) and in those with macrocytosis and/or anaemia (-9.1 (SD 11.8); +0.8 (SD 1.2); P < 0.05). A low serum vitamin B12 is common in geriatric medical patients. This is usually associated with an upset in erythropoiesis, although the abnormalities are often subtle and may not be apparent on inspection of the full blood count. Elderly patients with serum vitamin B12 < 175 pmol/l should be assumed to have vitamin deficiency even if their full blood count is normal.