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Late Onset Multiple Acyl-CoA Dehydrogenase Deficiency: A Rare Treatable Neurometabolic Disorder

Annals of Indian Academy of Neurology ¦ Volume 25 ¦ Issue 5 ¦ September-October 2022 983 2. Yamashiro K, Kurita N, Urabe T, Hattori N. Role of the gut microbiota in stroke pathogenesis and potential therapeutic implications. Ann Nutr Metab 2021;77:36‐44. 3. Mohammed Y, Kootte RS, Kopatz WF, Borchers CH, Büller HR, Versteeg HH, et al. The intestinal microbiome potentially affects thrombin generation in human subjects. J Thromb Haemost 2020;18:642‐50. 4. Xu K, Gao X, Xia G, Chen M, Zeng N, Wang S, et al. Rapid gut dysbiosis induced by stroke exacerbates brain infarction in turn. Gut 2021;70:1486‐94. 5. Xiang L, Lou Y, Liu L, Liu Y, Zhang W, Deng J, et al. Gut microbiotic features aiding the diagnosis of acute ischemic stroke. Front Cell Infect Microbiol 2020;10:587284. 6. Vermeer CV. Vitamin K: The effect on health beyond coagulation–An overview. Food Nutr Res 2012;56:5329. 7. Huang L, Wang T, Wu Q, Dong X, Shen F, Liu D, et al. Analysis of microbiota in elderly patients with acute cerebral infarction. PeerJ 2019;7:e6928. 8. Li H, Li H, Zhang X, Zhang X, Pan D, Pan D, et al. Dysbiosis characteristics of gut microbiota in cerebral infarction patients. Transl Neurosci 2020;11:124‐33. 9. Li N, Wang X, Sun C, Wu X, Lu M, Si Y, et al. Change of intestinal microbiota in cerebral ischemic stroke patients. BMC Microbiol 2019;19:191. 10. Wang W, Li X, Yao X, Cheng X, Zhu Y. The characteristics analysis of intestinal microecology on cerebral infarction patients and its correlation with apolipoprotein E. Medicine (Baltimore) 2018;97:e12805. 11. Yin J, Liao SX, He Y, Wang S, Xia GH, Liu FT, et al. Dysbiosis of gut microbiota with reduced Trimethylamine‐N‐Oxide level in patients with large‐artery atherosclerotic stroke or transient ischemic attack. J Am Heart Assoc 2015;4:e002699. 12. Parada Venegas D, De la Fuente MK, Landskron G, González MJ, Quera R, Dijkstra G, et al. Short chain fatty acids (SCFAs)‐mediated gut epithelial and immune regulation and its relevance for inflammatory bowel diseases. Front Immunol 2019;10:277. 13. Chen R, Xu Y, Wu P, Zhou H, Lasanajak Y, Fang Y, et al. Transplantation of fecal microbiota rich in short chain fatty acids and butyric acid treat cerebral ischemic stroke by regulating gut microbiota. Pharmacol Res 2019;148:104403.


Late Onset Multiple Acyl-CoA Dehydrogenase Deficiency: A Rare Treatable Neurometabolic Disorder
Sir, Multiple acyl-CoA dehydrogenase deficiency (MADD) also called glutaric aciduria (GA) type II, is a rare inborn error of metabolism that affects the oxidation of fatty acids and catabolism of branched-chain amino acids namely lysine and tryptophan. MADD occurs due to a defect in electron-transfer flavoprotein (ETF) encoded by ETFA and ETFB genes or electron-transfer flavoprotein dehydrogenase (ETFDH) encoded by ETFDH gene. We describe an adolescent boy with recurrent vomiting, unprovoked seizures and progressive muscle weakness who was diagnosed with MADD.
A 12-year-old boy presented with progressive difficulty in squatting, rising from squatting position and climbing stairs for seven months. He had difficulty in rising from supine but no difficulty in rising arms or buttoning shirts. He had difficulty in swallowing, hypophonia, and jaw, neck, and leg pain with inability to walk for two days. He had lost his head control and had breathing difficulty at presentation. There was no history of visual or hearing disturbances, eyelids drooping, eye movement restriction, or deviation of angle of mouth. There were no sensory disturbances or involuntary movements. There were no antenatal risk factors; he was born at term by forceps delivery with birth weight of 2400 g with no neonatal concerns.
His premorbid development was normal. Family history was non-contributory. He had recurrent vomiting from 7 years of age and unprovoked generalized seizures twice at 9 and 11 years of age. Investigations elsewhere at 9 years showed a normal Computed Tomography scan (CT) brain with an abnormal EEG, for which he was managed with valproate and clobazam.
Anthropometry assessment was normal weight 35 kg (IAP z score -0.79), height 148 cm (IAP z score -0.6), and head circumference of 53.2 cm. He had acidotic breathing, stable vitals, and SaO2 of 97% in room air. His higher mental functions were normal. Cranial nerve examination revealed normal fundus, jaw weakness, bulbar weakness, and hypophonia. Generalized wasting and proximal > distal weakness of lower > upper limbs was observed. Hypotonia and hyporeflexia was noted. There were no cerebellar or extrapyramidal signs. Systemic examination did not reveal any organomegaly. Provisional diagnosis of metabolic myopathy was considered.
On evaluation, blood glucose level was low (patient value: 55 mg/dL) and urine ketones were 3+. Arterial blood gas analysis revealed pH of 7.26, bicarbonate of 10.3 mmol/L, and blood lactate of 5 mmol/l. Plasma ammonia was elevated (patient value: 227 µg/dL, normal range: 27-102 µg/dL). Serum creatine kinase (patient value: 58520 U/L, normal reference range: 46-171 U/L) and CKMB (patient value: > 300 ng/ml, normal range: 0-6.22 ng/ml) were elevated. Echocardiography was normal. Electromyography (EMG) was suggestive of myopathic process. Serum amino acid analysis revealed elevated proline. Urinary organic acid analysis by Gas Chromatography -mass spectometry (GCMS) revealed elevated lactic, ethylmalonic, 2-hydroxyglutaric, adipic, suberic, sebacic, and glutaric acids along with hexonylglycine. Acylcarnitine profile showed elevated levels of C4-DC, C6, C6-DC, C8, C10, C12, and C14. Awaiting the exome sequencing reports, child was managed with intravenous dextrose fluids, bicarbonate, nasogastric high calorie feeds with protein and fat restriction, levetiracetem and supplementation of riboflavin, coenzyme Q, carnitine, and thiamine. He showed gradual improvement and in two weeks, was ambulant, off nasogastric feeds with normalization of serum creatine kinase. Exome sequencing revealed a homozygous missense variation c.587C>A in the exon 5 of ETFDH gene that results in amino acid substitution of histidine for proline at codon 196 (p.Pro196His). This p.Pro196His has not been reported in the 1000 genome and gnomAD databases. This variant was seen to be in the 4Fe-4S ferredoxin-type, iron-sulphur binding domain of the protein.
[1] The reference codon is conserved across all species. Due to lack of functional evidence this is classified as variant of uncertain origin using the American College of Medical Genetics guidelines. No variants in ETFA or ETFB were identified in the patient. Diagnosis of multiple acyl-CoA dehydrogenase deficiency was considered based on the biochemical and genetic testing findings. Both parents were noted to be heterozygous carriers for the same mutation. His younger brother (11-year-old) is well and screening for him and is also advised and awaited.
MADD is an autosomal recessive disorder with an estimated birth incidence of 1: 250,000. [2] This disorder is characterized by three distinct phenotypes, namely, neonatal form with or without congenital anomalies and late onset form with muscle weakness. [3] The phenotype among late-onset MADD ranges from acute severe metabolic decompensation in childhood to asymptomatic adults. Chronic muscle weakness, muscle pain, and exercise intolerance were the common symptoms reported in this sub-type while these patients may also manifest episodic vomiting, encephalopathy, and hypoglycaemia. [4] Respiratory insufficiency, cardiomyopathy and hepatopathy have also been described. [4] Urinary organic acid shows an elevated 2-hydroxyglutaric acid, glutaric, adipic, butyric, lactic, suberic, sebacic, ethylmalonic, and isovaleric acids. Acylcarnitine analysis shows an increase in short, medium, and long-chain acylcarnitines C4-C18. [3] Muscle biopsy demonstrates lipid storage myopathy. Diagnosis may be challenging as biochemical abnormalities are often mild or atypical. Genetic testing is often used to confirm diagnosis. [2] In a cohort of 350 patients with late onset MADD, mean age at presentation was 19.6 y and chronic muscle weakness was twice as common as acute decompensation. [4] Majority had ETFDH mutations (93%) and were riboflavin responsive (98.4%). In a Chinese cohort of 13 patient's age at symptom onset varied from 26 to 57 years. [5] Interestingly, a few had masseter weakness similar to our patient. Dramatic riboflavin responsiveness was also documented in this cohort.
To the best of our knowledge, only three patients with MADD have been published from India. The first report described bilateral symmetrical hyperintensity and diffusion restriction involving globus pallidi in an infant; the second, a young male with bipolar affective disorder with metabolic profile suggestive of GA type II and the third, a young male with myopathy. [6][7][8] Patients with late onset MADD have good survival on treatment. Nevertheless, treating clinicians must be aware of the mortality risk (5%) during metabolic decompensation. [4] This highlights the need for a sick-day plan and awareness of the patient's family to seek emergent medical treatment during such metabolic crises. Our patient has done well at one year follow-up on appropriate diet, high dose riboflavin, carnitine, coenzyme Q, and sick-day management plan.
Late onset MADD should be considered among children and young adults presenting with episodic or chronic muscle weakness especially in clinical setting of recurrent unexplained episodes of vomiting and metabolic crisis. Riboflavin responsiveness has been well established in this disorder. Sick day plan is of utmost importance because of the mortality risk during acute metabolic crises. Neonatal screening can enable presymptomatic diagnosis and early treatment.

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Conflicts of interest
There are no conflicts of interest. Sir, Acute ischemic stroke (AIS) is the fifth leading cause of death and disability worldwide.
[1] AIS associated with pregnancy and puerperal period is a rare but devastating complication, with an incidence of 1.5-67.1 strokes/100,000 deliveries, [2][3][4] and pregnant women are more prone to stroke than non-pregnant counterparts. [2] Approximately, 10 percent of strokes occur in the antepartum period, 40 percent occur proximate to delivery, and 50 percent occur in the postpartum period. [2][3][4] The predisposing mechanisms for AIS include altered hemodynamics, pre-eclampsia/eclampsia, peripartum cardiomyopathy, amniotic fluid embolism, and cerebral angiopathy, over and above the traditional risk factors. [5] However, pregnancy was an exclusion criterion for all recanalization trials (thrombolysis and endovascular thrombectomy [EVT]), leading to the absence of evidence for AIS management in these patients. Therefore, treatment was based on data gathered from case reports and series that have proven that thrombolysis and mechanical thrombectomy are both safe and efficacious in this patient population. [5,6] We report three cases of pregnancy-associated stroke with good functional outcomes in the two who underwent EVT and thrombolysis.
CASE 1: A 26-year-old lady, G1P0L0, known case of rheumatic heart disease (RHD) with atrial fibrillation for the past 5 years, post mitral valve replacement one year ago, on warfarin 4 mg daily; International normalized ratio (INR)-1.6, presented to our emergency at 28 weeks period of gestation with sudden onset dizziness and altered sensorium of 3 h duration. She had an irregularly irregular pulse, and her Glasgow Coma Scale (GCS) score was E2V1M5 at presentation, and was intubated because of poor GCS. Reflex movements of all limbs were noted, but ill-sustained on painful stimuli application (National Institute of Health Stroke Severity [NIHSS] score -21; modified Rankin Scale score [mRS] -5). Non-contrast computed tomography (NCCT) head with abdominal shield showed normal brain parenchyma [ Figure 1a] with craniovertebral junction abnormality in the form of basilar invagination and atlantoaxial dislocation [ Figure 2]. CT angiography of head and neck vessels revealed a filling defect in the region of basilar top and proximal P1 segments of both posterior cerebral arteries [ Figure 1b]. Both vertebral arteries had an anomalous course, and the left vertebral artery was hypoplastic. She was thrombolyzed with alteplase and taken up for EVT using a Solitaire device [ Figure 1c and d]. The procedure was partially successful with the distal run-off of the embolus into the right posterior cerebral artery [ Figure 1d]. Post-procedure she improved to E4VtM6 status and was weaned off her ventilatory support and extubated. Three days post-EVT, her NIHSS score improved to 2 and mRS to 1, and she was discharged on low molecular weight heparin. She delivered a healthy girl child by elective cesarean section at 38 weeks of gestation. She is planned for surgery for the craniovertebral junction anomaly.
CASE 2: A 26-year-old lady, G5P0L0A4, known case of RHD and atrial septal defect (ASD) for the past 10 and 18 years respectively, who underwent mitral valve repair and ASD closure 5 years back, was on anticoagulation (warfarin 3 mg once daily; INR-2.5) and single antiplatelet (aspirin 150 mg OD). She was admitted to the department of gynecology and obstetrics at 36 weeks +1 day of gestation for heparin switchover for term preparation as her probability of requiring a cesarean section was high. Warfarin was switched to unfractionated heparin (UFH) infusion with coagulation parameter monitoring. She went into labor at 38 weeks but had poor progression, and the decision for an emergency cesarean section was made, and UFH stopped. Three hours after stopping heparin, she developed sudden onset right upper limb weakness (power -2/5) and numbness (70% decrease in sensations) (NIHSS-6). NCCT head with the abdominal shield was normal. Her two-dimensional echocardiography (2D-ECHO) showed a normal ejection fraction without any clots/vegetation. She had to be managed conservatively for AIS, was taken for emergency cesarean section, and delivered a healthy male child. Six hours post-surgery, UFH was restarted, followed by a switch back to warfarin on discharge (NIHSS-6). Her power gradually improved to 4-/5 with complete resolution of numbness in the ensuing 3 months (NIHSS-3, mRS-2).
CASE 3: A 25-year-old lady, G1P0L0, known case of RHD for 8 years, post percutaneous balloon mitral valvotomy, not on treatment, presented to our emergency with twin pregnancy of 20 weeks period of gestation and sudden onset left hemiplegia of 30 min duration. Her NIHSS and mRS at presentation were 13 and 3, respectively. NCCT head (with abdominal shield) was normal [ Figure 3a] and CT angiography of head and neck vessels revealed a distal right M1-middle cerebral artery (MCA) occlusion [ Figure 3b]. She was thrombolyzed by tissue plasminogen activator (t-PA) followed by EVT