Episodic Dystonia and Hallucinations Due to DLAT Genes

occasional(a) Dystonia and Hallucinations Due to DLAT GenesTitle Carbamazepine responsive Episodic Dystonia and Hallucination kayoed-of-pocket(p) to Pyruvate Dehydrogenase E2 (DLAT) cistron diversityFatema J Serajee1, Salman Rashid2, and AHM M Huq1ABSTRACTBACKGROUND PDH E2 need callable(p) to DLAT versions is a very r be condition with only 4 inform cases to date.METHODS We describe a 15-year-old girl with mild intellectual disability, paroxysmal dystonia and bilaterally symmetrically symmetrical basal ganglia getal abnormalities on brain magnetic resonance imaging. Additional neurophysiological, imaging, metabolic and exome sequencing studies were performed.RESULTS scrap metabolite testing, and GLUT1 and PRRT2 mutation analysis were ostracize. A repeat brain magnetic resonance imaging revealed Eye-of-the-tiger- theatre. Exome sequencing determine homozygous valine to glycine revolution at aminic group acid mail service 157 in the DLAT gene. Bioinformatic and fami ly analyses indicated that the variation was likely pathogenic. Patients s dystonia was responsive to low window glass carbamazepine. On weaning carbamazepine, diligent developed hallucinations which resolved after carbamazepine was restarted.CONCLUSIONS PDH E2 want callable to DLAT mutation has a more benignant course compared to mutual forms of PDH E1 wishing cod to X-linked PDHA1 mutations. All known cases of PDH E2 deprivation due to DLAT mutations assign the features of episodic dystonia and intellectual disability. Our patients dystonia and hallucinations responded well to low window glass carbamazepine.IntroductionPyruvate Dehydrogenase (PDH) E2 deficiency is a rare pediatric neurometabolic disorder due to mutation in DLAT gene ( inquiry et al., 2005 McWilliam et al., 2010). Only 4 cases with DLAT gene mutations have previously been inform (Head et al., 2005 McWilliam et al., 2010). All share the features of dystonia and some degree of developmental delay and f eature of speech globus pallidus quest abnormalities on brain MRI. This disease tends to have more benign course as compared to PDH E1 deficiency (Head et al., 2005 Huq et al., 1991 McWilliam et al., 2010 Patel et al., 2012). We report an additional case with DLAT mutation with new phe nonype and treatment information.Case ReportA 15-year-old girl presented with paroxysmal episodes of left lower extremity weakness and stiffening for the last 8 eld. These episodes were triggered by exercise only no exacerbating or relieving factors were noted. on that point was no associated aura, revision of consciousness, incontinence or otherwise associated neurological symptoms. Her parents were endorse cousins, but family history was negative for known genetic disorders. Birth and prehistorical medical histories were also unremarkable. Patient had a speech delay but met her other childhood milestvirtuosos appropriately. Later, she developed academic difficulties and at 15 years of time she was performing at a 4th grade level. At presentation, the patient had a normal examination except for some cognitive and reading difficulties. At the time of initial presentation to a pediatric neurologist at 7 years of age, an MRI of the brain revealed bilateral T2 hyperintensities in the basal ganglia. In addition, she was found to have decreased NAA rush and the suggestion of a lactate peak on MR spectroscopy. EEG, EMG and look conductions studies were unremarkable.Over the years the patient was considered to have paroxysmal kinesiogenic dyskinesia and was treated with carbamazepine (100 mg daily). The patient was initially evaluated by us at age of 14 years. Metabolic work up for serum lactate, serum amino acids, acyl carnitine profile, serum copper and ceruluplasmin and GLUT1 or PRRT2 mutation analysis were unremarkable. Repeat MRI revealed basal ganglia channelise changes including Eye of the tiger sign ( meet 1). MR spectroscopy studies were suboptimal.Exome sequencin g was performed through with(predicate) Ambry laboratory as previously describe (Serajee and Huq, 2015). The patient had homozygous c.470TG (p.V157G) alteration in the DLAT (Dihydrolipoamide ethanoyl grouptransferase (PDHC E2) gene suggesting the diagnosis of pyruvate dehydrogenase E2 deficiency, a rare cause of pyruvate dehydrogenase deficiency. both parents and one brother were heterozygous carriers and another brother was homozygous normal. The p.V157G alteration (c.470TG), is in coding exon 3 of the DLAT gene, solvings from a T to G substitution at nucleotide position 470. The valine at codon 157 is replaced by glycine, an amino acid with dis homogeneous properties. The V157 amino acid position is highly hold in all available vertebrate species. The p.V157G alteration is predicted to be in all likelihood damaging by Polyphen and deleterious by SIFT in silico analyses. The V157 amino acid is located within the biotin/lipoyl attachment domain of the DHAT protein. The DLAT c.4 70TG alteration was not observed in healthy cohort databases such as NHLBI Exome Sequencing Project (ESP) or the 1000 Genomes Project or the Database of Single radix Polymorphisms (dbSNP). Based on data from the HGMD, only the four alterations report by Head et al. (2005) and McWilliam et al. (2010) have been observed within the DLAT gene to date (Head et al., 2005McWilliam et al., 2010). These accommodate one missense alteration, two splice alterations, and one small in-frame cold shoulder. Based on the above evidence, the homozygous c.470TG (p.V157G) alteration was considered pathogenic.Her parents refused treatment with the ketogenic diet. When carbamazepine was weaned off due to parental concerns of side effects, within few weeks, patient developed hallucinations. Parents reported resolution of symptoms after carbamazepine was restarted.DiscussionThe Pyruvate Dehydrogenase Complex proceeds in the oxidative decarboxylation of pyruvate to acetyl coenzyme A. The intricate cont ains three subunits E1, E2 and E3 (Patel and Roche, 1990). The most commons form of pyruvate dehydrogenase deficiency is due to mutations partakeing the E1 subunit, and results in a variety of clinical manifestations depending upon the residual function of the enzyme (Huq et al., 1991Patel et al., 2012). E1 subunit is encoded by PDHA1 gene of X chromosome. Most patients present in infancy with lactic acidosis, ataxia and hypotonia, either chronically or episodically (Huq et al., 1991Patel et al., 2012). The mutation in our patient is in the E2 subunit (dihydrolipoamide acetyltransferase), which forms the structural message of the enzyme and functions in accepting the acetyl groups and transfer reflect them to coenzyme A, an essential step preceding the spellbind of glucose into the TCA cycle (Head et al., 2005Patel and Roche, 1990). E2 subunit is encoded by DLAT gene located on chromosome 11q23.1.To date, however, in that location are only four reported cases of pyruvate dehyd rogenase deficiency caused by alterations in the DLAT gene, making it a very rare cause of the condition (Head et al., 2005McWilliam et al., 2010). In addition, Robinson et al reported an additional patient with reduced E2 dihydrolipoyl transacetylase enzyme activity (32% of the cut back and undetectable E2 immunoreactive protein (Robinson et al., 1990). For this patient, no gene mutation data is available (Robinson et al., 1990). The patient reported by Robinson et al. had a different phenotype compared to our patient and four other genetically confirmed DLAT mutation cases and had profound retardation and microcephaly (Robinson et al., 1990).Head et al. (2005) first described two unrelated individuals with PDH deficiency caused by homozygous non-protein truncating mutations in the DLAT gene (Head et al., 2005). One patient demonstrated a deletion of glutamic acid in the outer lipoyl domain of the protein, whereas the second expressed a missense mutation in the catalytic site, lea ding to a substitution of leucine for phenylalanine. both patients were male children born of first-cousin parents. These patients presented with a less severe phenotype compared to individuals with the more common type of PDH caused by alterations in the PDHA1 gene encoding the E1 subunit, and their common features include episodic dystonia, hypotonia, ataxia, and developmental delay(Head et al., 2005). Episodes of dystonia were often triggered by stress or fever, and developmental progress appeared to slow after the episodes as well. Additional reported features include inconsolable crying, nystagmus and abnormal eye movements, ptosis, drooling, jerky head movements, arching of the body, butt end shuffling, stiffening of the limbs, episodic clenching of the hands, head lag and hypotonia. Brain MRI findings in each patient included focal signal abnormality in the basal ganglia with high T2 signal and low T1 signal in the globus pallidus which was matched with an abnormality of en ergy metabolism (Head et al., 2005). The authors concluded that mutations in the DLAT gene are an extremely rare cause of PDH deficiency and that patients with this type of PDH may be more likely to respond to a ketogenic diet (Head et al., 2005). McWilliam et al. (2010) also described two sisters born of non-consanguineous parents affected with pyruvate dehydrogenase E2 deficiency caused by compound heterozygous splice mutations in the DLAT gene (McWilliam et al., 2010). clinical features were like those described in Head et al. (2005), including progressive episodic dystonia, cognitive impairment, and globus pallidus hyperintensity on brain MRI. some(prenominal) patients were treated with a modified ketogenic diet and the parents reported improvements in concentration, picturesque motor control, and decreased fatigue (McWilliam et al., 2010).Previous reports noted the phenotypic crossing to patients with PKAN, and suggested investigation for PDH E2 deficiency in patients suspect ed to have atypical PKAN with negative genetic testing (Head et al., 2005McWilliam et al., 2010). PKAN is one of several diseases classified under the comprehensive of neurodegeneration with brain iron appeal (NBIA). It is caused by a mutation in the pentothenate kinase 2 gene, an abnormality of coenzyme A metabolism (Zhou et al., 2001). CoPAN (Coenzyme A synthetase protein-associated neurodegeneration) is another NBIA that affects the deductive reasoning of coenzyme A. It is caused by a mutation in coenzyme A synthetase (COASY) gene (Schneider, 2016Tonekaboni and Mollamohammadi, 2014). clinical features of PKAN and CoPAN also include ataxia, dystonia, chorea and Parkinsonism, cognitive decline and psychiatric manifestations (Schneider, 2016Tonekaboni and Mollamohammadi, 2014). In NBIA, whether iron accumulation is a cause or an effect of the disease process is still not known (Schneider, 2016Tonekaboni and Mollamohammadi, 2014).In our patient, the pattern of MRI changes in the b ilateral globus pallidus is remarkably like that seen in PKAN and CoPAN, revealing the eye-of-the-tiger sign . On brain MRIs of patients with PKAN and CoPAN, the central hyperintensity of the eye-of-the-tiger sign is thought to be due to the tissue necrosis, while the surrounding hypointensity is attributed to the iron accumulation (Dusi et al., 2014Kumar et al., 2006). Other diseases including cortical basal degeneration, multisystem atrophy, multiple sclerosis and neurofibromatosis may have similar neuro-radiological findings. However, these diseases differ from PKAN in their clinical behavior and pattern of MR abnormalities (Kruer et al., 2012). PKAN and CoPAN also affect the substantia nigra (Kruer et al., 2012) however, the involvement of the substantia nigra has not yet been reported in cases of PDH E2 deficiency due to DLAT mutations. Out of the four previously reported cases of PDH E2 deficiency due to DLAT mutation, only two patients had serial MRI scans. In one patient, th e brain MRI was normal at one year of age but follow up at 6 years-old showed an abnormal hyperintense T2 signal in the bilateral globus pallidus. In the other patient, similar lesions were noticed at 15 months-old that remained unchanged on follow up at 2 and 6 years of age (Head et al., 2005). As opposed to the eye-of-the-tiger sign seen in our patient, all the previously reported cases showed homogenous basal ganglia hyperintensities (Head et al., 2005McWilliam et al., 2010). As discussed above, PKAN and CoPAN result from a defect in coenzyme A synthesis (Schneider, 2016Tonekaboni and Mollamohammadi, 2014). PDH E2 deficiency due to DLAT mutations, on the other hand, affects the transfer of acetyl group formed by decarboxylation of pyruvate to coenzyme A (Kumar et al., 2006McWilliam et al., 2010Patel and Roche, 1990). It is possible that the clinical and radiological similarities of PKAN, CoPAN and PDH E2 deficiency are due to shared abnormalities in the acetyl-CoA metabolism.Like our patient, the 4 previously reported DLAT mutation cases presented with dystonia and intellectual disability, with a more benign course than those affected with the PDH E1 subunit deficiency (Head et al., 2005McWilliam et al., 2010) . In this regard, PDH E2 deficiency due to DLAT mutation is like PDH deficiency due E3 binding protein deficiency (Head et al., 2005). Serum and CSF lactate were elevated in only one patient, but all demonstrated characteristic hyperintense T2 and hypointense T1 signal in the bilateral globus pallidi on brain MRI. In 3 out of the 4 patients, ketogenic diet was helpful in alleviation of the disease symptomology(Head et al., 2005McWilliam et al., 2010). Our patients had hallucination, which was not described in other 4 reported patients. Her dystonia and hallucinations responded to low dose carbamazepine. Our case thus expands upon the phenotype for PDH E2 deficiency associated with the DLAT gene mutation.Reference ListDusi, S., Valletta, L., Haack, T.B ., Tsuchiya, Y., Venco, P., Pasqualato, S., Goffrini, P., Tigano, M., Demchenko, N., Wieland, T., Schwarzmayr, T., Strom, T.M., Invernizzi, F., Garavaglia, B., Gregory, A., Sanford, L., Hamada, J., Bettencourt, C., Houlden, H., Chiapparini, L., Zorzi, G., Kurian, M.A., Nardocci, N., Prokisch, H., Hayflick, S., Gout, I., and Tiranti, V. (2014). Exome chronological succession reveals mutations in CoA synthase as a cause of neurodegeneration with brain iron accumulation. Am. J. Hum. Genet. 94, 11-22.Head, R.A., Brown, R.M., Zolkipli, Z., Shahdadpuri, R., King, M.D., Clayton, P.T., and Brown, G.K. (2005). Clinical and genetic spectrum of pyruvate dehydrogenase deficiency dihydrolipoamide acetyltransferase (E2) deficiency. Ann. Neurol. 58, 234-241.Huq, A.H., Ito, M., Naito, E., Saijo, T., Takeda, E., and Kuroda, Y. (1991). Demonstration of an unstable variant of pyruvate dehydrogenase protein (E1) in well-behaved fibroblasts from a patient with congenital lactic acidemia. Pediatr. Res. 30, 11-14.Kruer, M.C., Boddaert, N., Schneider, S.A., Houlden, H., Bhatia, K.P., Gregory, A., Anderson, J.C., Rooney, W.D., Hogarth, P., and Hayflick, S.J. (2012). Neuroimaging features of neurodegeneration with brain iron accumulation. AJNR Am. J. Neuroradiol. 33, 407-414.Kumar, N., Boes, C.J., Babovic-Vuksanovic, D., and Boeve, B.F. (2006). The eye-of-the-tiger sign is not pathognomonic of the PANK2 mutation. Arch. Neurol. 63, 292-293.McWilliam, C.A., Ridout, C.K., Brown, R.M., McWilliam, R.C., Tolmie, J., and Brown, G.K. (2010). Pyruvate dehydrogenase E2 deficiency a potentially treatable cause of episodic dystonia. Eur. J. Paediatr. Neurol. 14, 349-353.Patel, K.P., OBrien, T.W., Subramony, S.H., Shuster, J., and Stacpoole, P.W. (2012). The spectrum of pyruvate dehydrogenase complex deficiency clinical, biochemical and genetic features in 371 patients. Mol. Genet. Metab 105, 34-43.Patel, M.S., and Roche, T.E. (1990). Molecular biology and biochemistry of pyruvate dehydrogenase co mplexes. FASEB J. 4, 3224-3233.Robinson, B.H., MacKay, N., Petrova-Benedict, R., Ozalp, I., Coskun, T., and Stacpoole, P.W. (1990). Defects in the E2 lipoyl transacetylase and the X-lipoyl containing component of the pyruvate dehydrogenase complex in patients with lactic acidemia. J. Clin. Invest 85, 1821-1824.Schneider, S.A. (2016). Neurodegeneration with Brain press out Accumulation. Curr. Neurol. Neurosci. Rep. 16, 9.Serajee, F.J., and Huq, A.M. (2015). Homozygous Mutation in Synaptic Vesicle Glycoprotein 2A Gene Results in Intractable Epilepsy, Involuntary Movements, Microcephaly, and Developmental and Growth Retardation. Pediatr. Neurol. 52, 642-646.Tonekaboni, S.H., and Mollamohammadi, M. (2014). Neurodegeneration with brain iron accumulation an overview. Iran J. Child Neurol. 8, 1-8.Zhou, B., Westaway, S.K., Levinson, B., Johnson, M.A., Gitschier, J., and Hayflick, S.J. (2001). A novel pantothenate kinase gene (PANK2) is defective in Hallervorden-Spatz syndrome. Nat. Genet. 28, 345-349.Figure 1 Legend MRI of the brainA. axial T2 kitchen range screening hyperintensity in bilateral globus pallidus, which is surrounded by a hypointense signalB. Axial T1 image showing hypointensity in bilateral globus pallidusC. Coronal T2 FLAIR image showing hyperintensity in bilateral globus pallidus, which is surrounded by a ring of hypointense signal (eye-of-the-tiger sign)