Short‐chain enoyl‐CoA hydratase (SCEH or ECHS1) deficiency is a rare inborn error of metabolism caused by biallelic mutations in the gene ECHS1 (OMIM 602292). Clinical presentation includes infantile‐onset severe developmental delay, regression, seizures, elevated lactate, and brain MRI abnormalities consistent with Leigh syndrome (LS). Characteristic abnormal biochemical findings are secondary to dysfunction of valine metabolism. We describe four patients from two consanguineous families (one Pakistani and one Irish Traveler), who presented in infancy with LS. Urine organic acid analysis by GC/MS showed increased levels of erythro‐2,3‐dihydroxy‐2‐methylbutyrate and 3‐methylglutaconate (3‐MGC). Increased urine excretion of methacrylyl‐CoA and acryloyl‐CoA related metabolites analyzed by LC‐MS/MS, were suggestive of SCEH deficiency; this was confirmed in patient fibroblasts. Both families were shown to harbor homozygous pathogenic variants in the ECHS1 gene; a c.476A > G (p.Gln159Arg) ECHS1variant in the Pakistani family and a c.538A > G, p.(Thr180Ala) ECHS1 variant in the Irish Traveler family. The c.538A > G, p.(Thr180Ala) ECHS1 variant was postulated to represent a Canadian founder mutation, but we present SNP genotyping data to support Irish ancestry of this variant with a haplotype common to the previously reported Canadian patients and our Irish Traveler family. The presence of detectable erythro‐2,3‐dihydroxy‐2‐methylbutyrate is a nonspecific marker on urine organic acid analysis but this finding, together with increased excretion of 3‐MGC, elevated plasma lactate, and normal acylcarnitine profile in patients with a Leigh‐like presentation should prompt consideration of a diagnosis of SCEH deficiency and genetic analysis of ECHS1. ECHS1 deficiency can be added to the list of conditions with 3‐MGA.

Background: Antioxidant enrichment of LDL can increase its resistance to oxidation and hence reduce its atherogenicity. The objective of the present study was to investigate whether in vivo supplementation with nonalcoholic red wine extract and quercetin can increase the oxidative resistance of LDL, and also whether the supplementation has any effect on other antioxidative micronutrients present in the blood. Methods: Twenty-one male subjects were supplemented with a placebo drink for 2 weeks and randomized into two groups. One group (n = 11) received the red wine extract (1 g/day, equivalent to 375 mL of red wine) and the other group (n = 10) quercetin (30 mg/day) for 2 weeks, followed by a 5-week washout period. Results: In the red wine extract-supplemented group, ex vivo copper-initiated oxidation of LDL (lag phase, mean ± SD) was 40 ± 11 min at the baseline, and increased significantly to 47 ± 6 min [P <0.05 compared with placebo (38 ± 4 min) and the washout values (40 ± 5 min)]. In the quercetin-supplemented group, the lag phase was 44 ± 11 and 40 ± 5 min for the baseline and placebo, respectively, and increased significantly to 51 ± 7 min [P <0.05 compared with placebo and washout (41 ± 9 min)] after supplementation. Plasma lipids (triglycerides, total cholesterol, LDL- and HDL-cholesterol) did not change during the study period. Supplementation with red wine extract or quercetin had no effect on plasma vitamin C and E, retinol, and carotenoid concentrations. Conclusions: Alcohol-free red wine extract and one of its components, quercetin, can inhibit LDL oxidation after in vivo supplementation; such “inhibition” is unrelated to changes in antioxidant vitamin and carotenoid concentrations.

The resistance of isolated low density lipoprotein (LDL) to copper-initiated oxidation is often used as a measure of effectiveness of an antioxidant intervention. Prior to oxidation, excess salt and EDTA are removed via dialysis or gel filtration of the LDL sample. However, there is concern over whether the antioxidant content of dialyzed or gel-filtered LDL is truly representative of native LDL extracted from a blood sample. Previously, the experiments done after the storage of native and dialyzed LDL at -80 degrees C showed that the dialysis step can cause a loss of up to 60% in the tocopherol and carotenoid content of LDL. In the present study, a comparison of the micronutrient concentration in freshly prepared dialyzed and native LDL from 35 subjects showed that after the correction for cholesterol, only lycopene (13%, P < 0.001) and to a lesser extent alpha-carotene (8%, P < 0.02) were significantly decreased, and the absolute fall in concentration was far smaller than previously reported. Other experiments done with smaller numbers of samples suggested that there were minimal micronutrient losses following gel filtration and that it was important to include 10 micromol/L EDTA in the dialysis and elution buffer; otherwise micronutrient losses did occur. In summary, immediate dialysis of freshly isolated LDL in the presence of 10 micromol/L EDTA does not cause any major loss in the concentration of tocopherol and most carotenoids.

Mitochondrial 3‐hydroxy‐3‐methylglutaryl‐CoA (HMG Co‐A) synthase (mHS) deficiency is an autosomal recessive disorder of ketone body synthesis which has traditionally been associated with hypoketotic hypoglycemia, hepatomegaly and encephalopathy, presenting in early childhood following a period of fasting. We report the third case of mHS deficiency presenting in the absence of hypoglycemia, with profound biochemical abnormalities and further evidence of potential specific diagnostic biomarkers. A previously well, 20‐month old, unvaccinated male, of nonconsanguineous Polish heritage, presented with encephalopathy, hepatomegaly, severe metabolic acidosis, and mild hyperammonemia following a brief intercurrent illness. The patient was reported to have taken colloidal silver prior to presentation, posing a further diagnostic challenge. Additionally, he developed features suggestive of hemophagocytic lymphohistiocytosis during treatment. While the patient was normoglycemic prior to dextrose administration, the sample was markedly lipemic, with significant hypertriglyceridemia detected. Urine organic acid analysis revealed dicarboxylic aciduria with 4‐hydroxy‐6‐methyl‐2‐pyrone (4HMP) and the presence of three other previously reported putative biomarkers for mHS deficiency. Glutarate was markedly elevated in the initial chromatogram, with a mild increase in 3‐hydroxyglutarate (3HG) persisting. Raised acetylcarnitine was detected on acylcarnitine profile. Molecular genetic analysis of the HMGCS2 gene identified compound heterozygosity for known pathogenic mutations c.634G>A and c.1016+1G>A, confirming the diagnosis of mHS deficiency. This case provides further evidence that hypoglycemia is not invariably present in symptomatic mHS deficiency. We propose that elevated acetylcarnitine, triglycerides, and 3HG are additional biochemical features during acute presentations. With the expansion of novel biomarkers, further cases of this rare disorder may emerge.

Introduction Cobalamin plays an essential role in haematopoiesis, cell metabolism, production of DNA and neuronal function. High serum concentration of cobalamin is a common but underestimated finding. The aetiology of hypercobalaminaemia includes excess vitamin B12 intake, solid neoplasms, haematological malignancies, liver disease, renal failure and autoimmune diseases. Paradoxically, hypercobalaminaemia can be associated with a functional B12 deficiency. A finding of high serum cobalamin should prompt an early and in-depth search for these entities to ensure a favourable prognosis. Case presentation We present a case of a thirteen-year old girl who presented with non-specific symptoms and an incidental finding of a raised serum cobalamin (1400 pg/mL) with initially only minor full blood count (FBC) abnormalities. Upon her assessment in the haematology clinic in OLCHC, repeat FBC results showed progressive anaemia with macrocytosis, a falling platelet count and serum cobalamin concentration of >6000 pg/mL. On repeat the cobalamin had increased to 10926 pg/mL. Urinary methylmalonic acid, plasma total homocysteine, liver and renal function were unremarkable, and she was not taking supplements or oestrogens. A bone marrow aspirate showed findings consistent with early diagnosis of Acute Myeloid Leukaemia (AML). Conclusion This case highlights the importance of hypercobalaminaemia which should be followed by the search for the cause of this finding as early diagnosis can be an important prognostic factor. A possible malignant blood disorder should be considered when serum cobalamin concentrations are above the reference range and where increases due to supplements, inflammatory, renal or liver disease have been excluded. This underscores the importance of laboratories offering numerical values (rather than reporting high results as greater than a cut-off value) for elevated vitamin B12 levels in cases with minor but progressive FBC changes. An increase in the level of B12 may indicate the need for prompt referral to a haematologist for assessment and monitoring.

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donating a methyl group, thus converting homocysteine to methionine. Limited literature exists outlining the risk of metabolic encephalopathy associated with hypermethioninaemia presenting in children with classical Homocystinuria. Here we present one such case, made more remarkable by the absence of treatment with betaine. Case description Our patient was diagnosed on newborn screening on day 4 of life with classical Homocystinuria and had been promptly commenced on a treatment regime. At four weeks of age he presented to his local hospital with poor feeding, vomiting, and lethargy. Following this acute presentation, he was started on IV antibiotics but a source of infection could not be established. Hyponatraemia, hypertension and proteinuria were noted. His renal ultrasound revealed increased echogenicity bilaterally with no evidence of renal vein thrombosis. His brain magnetic resonance imaging (MRI) showed areas of diffusion restriction bilaterally with normal MR spectroscopy and MR angiogram. Intensive care treatment was required, including intubation and ventilation, and antihypertensive treatment. No underlying thrombo-embolic cause could be established. His blood tests which were taken at the time of his acute presentation to his local hospital revealed a methionine of 1329 mmol/L with a normal cystine (23 mmol/ L) and a raised total homocysteine (118 mmol/L) and free homocysteine (11 mmol/L), it was therefore concluded that his presentation was metabolic in origin. These levels improved promptly with further natural protein restriction, increased calorie intake, including intravenous dextrose and electrolytes. The patient made a full recovery; his brain MRI findings normalised. Discussion Hypermethioninaemic encephalopathy is a rare complication of classical Homocystinuria. It has previously been described in association with betaine treatment. We are unaware of any previous publications of this complication in patients not on this medication. In addition to monitoring for long-term complications, we suggest that methionine should be monitored regularly in patients with classical Homocystinuria, in particular during any episodes of acute deterioration.