Sodium-valproate

Abstract

Multiple acyl-CoA dehydrogenase deficiency and exacerbation of lipid storage myopathy: case report A 38-year-old woman developed multiple acyl-CoA dehydrogenase deficiency (MADD) and exacerbation of lipid storage myopathy during treatment with sodium valproate for bipolar affective disorder. The woman, who had a 6-month history of progressive proximal muscle weakness with rapid deterioration over the preceding three days, was admitted with profound weakness, lactic acidosis and cardiorespiratory arrest. Twelve months prior to her admission, she was started on quetiapine and sodium valproate [routes and dosages not stated] for bipolar affective disorder. There was no arthritis, rash, myalgia, fever, nausea, vomiting or hypoglycaemia and no family history of neuromuscular disease. At presentation, creatine kinase (CK) level was 2210 U/L. The following antibodies were negative: anti-tripartite motifcontaining protein (TRIM21/Ro-52), antialanyl tRNA synthetase (PL-12), anti-isoleucyl tRNA synthetase (OJ), anti-glycyl tRNA synthetase (EJ), anti-threonyl tRNA synthetase (PL-7), anti-signal recognition particle (SRP), anti-histidyl tRNA synthetase (Jo-1), anti-nucleolar protein complex (PM-Scl 100), anti-DNA-dependent protein kinase (Ku), anti-small ubiquitin-like modifier activating enzyme (SAE1), anti-nuclear matrix protein (NXP2), antimelanoma differentiation-associated gene 5 (MDA5), anti-transcription intermediary factor-1 (TIFc), and antihelicase protein (Mi2b and Mi2a). Thereafter, inadequate tissue was retrieved on needle for muscle biopsy. Electromyography showed myopathic features. Subsequently, she was diagnosed with polymyositis and exacerbation of the underlying undiagnosed lipid storage myopathy was suspected. The woman’s quetiapine and sodium valproate were stopped and she was treated with prednisolone and azathioprine with improvement in muscle power to near normal. The next year, she developed recurrent weakness primarily of her neck musculature leading to a ’dropped head’. This time her serum CK level was 234 U/L. Total carnitine and acylcarnitine profile were within normal limits. Muscle biopsy revealed mild necrotising myopathy, with ultrastructural features of intra-myofibrillar vacuoles with excess fat and glycogen and mitochondrial abnormalities with ragged red fibers. MHC I and II stains were negative but there was intense myofibre sarcolemmal staining for the membrane attack complex (MAC) and a mild increased in the number of interstitial macrophages as indicated by CD68 staining. She was treated with methylprednisolone and immune-globulin with improvement and stabilised on prednisolone, azathioprine and immune-globulin. Neck extensors and limb strength returned to near premorbid levels. After four years, she had further recurrence of weakness that responded to two doses of rituximab. Seven years following her initial presentation, she had a further relapse of proximal myopathy, without CK elevation. During her disease course, there were no other features indicating metabolic disturbance, such as recurrent episodes of vomiting, hypoglycaemia or metabolic acidosis. A repeat muscle biopsy revealed absence of inflammation; however, persistence of lipid and glycogen in muscle fibers with mitochondrial abnormalities was noted. In view of frequent relapses of disease, she was referred to the Metabolic Clinic where an abnormal acylcarnitine profile was observed, with elevation in mediumto long-chain fatty acids, in a pattern highly suggestive of disordered fatty acid oxidation (C4, C5, C6, C8, C10 and C12). Urine organic acid analysis revealed increase in ethylmalonate. Next generation sequencing for electron transfer flavoprotein subunit alpha and beta (ETFA and EFTB) and electron transfer flavoprotein dehydrogenase (ETFDH) was positive for one known pathogenic variant in the ETFDH gene (ETFDH c.1367C>T; p. His401Arg) and a further likely pathogenic variant in the ETFDH gene (ETFDH c.1202A>G; p. Pro456Leu), indicating the diagnosis of MADD. These mutations were further confirmed by Sanger sequencing. Parental studies confirmed that these mutations were inherited on separate alleles. She was advised to avoid prolonged fasting and was started on a high-carbohydrate, low-fat diet, and riboflavin with no further relapse of condition to date.