Episodic Dystonia and Hallucinations Due to DLAT Genes

Episodic Dystonia and illusions Due to DLAT GenesTitle Carbamazepine responsive Episodic Dystonia and Hallucination callable to Pyruvate Dehydrogenase E2 (DLAT) element sportsmanFatema J Serajee1, Salman Rashid2, and AHM M Huq1ABSTRACTBACKGROUND PDH E2 inadequateness ascribable to DLAT mutations is a very rare condition with only 4 reported cases to naming.METHODS We describe a 15-year-old female child with mild intellectual disability, paroxysmal dystonia and reversible basal ganglia aim ab habitualities on brain MRI. Additional neurophysiological, imaging, metabolic and exome sequencing studies were performed.RESULTS turn metabolite testing, and GLUT1 and PRRT2 mutation analysis were negative. A repeat brain MRI revealed Eye-of-the-tiger-sign. Exome sequencing identified homozygous valine to glycine alteration at amino group stifling position 157 in the DLAT broker. Bioinformatic and family analyses indicated that the alteration was likely pathogenic. Patients s dystonia was responsive to low dose carbamazepine. On weaning carbamazepine, unhurried developed hallucinations which resolved after carbamazepine was restarted.CONCLUSIONS PDH E2 wish referable to DLAT mutation has a more benign course compared to common forms of PDH E1 deficiency out-of-pocket to X-linked PDHA1 mutations. All known cases of PDH E2 deficiency due to DLAT mutations share the features of casual dystonia and intellectual disability. Our patients dystonia and hallucinations responded soundly to low dose carbamazepine.IntroductionPyruvate Dehydrogenase (PDH) E2 deficiency is a rare pediatric neurometabolic disease due to mutation in DLAT broker ( promontory et al., 2005 McWilliam et al., 2010). Only 4 cases with DLAT element mutations stomach previously been reported ( proposition et al., 2005 McWilliam et al., 2010). All share the features of dystonia and some degree of developmental delay and characteristic globus pallidus signal abnormalities on brain MRI. This disea se 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 phenotype and treatment information.Case ReportA 15-year-old girl presented with paroxysmal episodes of left lower extremity weakness and stiffening for the last 8 years. These episodes were triggered by exercise but no exacerbating or relieving factors were noted. in that respect was no associated aura, alteration of consciousness, incontinence or opposite associated neurological symptoms. Her parents were second cousins, but family history was negative for known genetic disorders. Birth and past medical checkup histories were also unremarkable. Patient had a speech delay but met her other childhood milest is appropriately. Later, she developed academic difficulties and at 15 years of age she was playacting at a 4th grade level. At presentation, the patient had a normal exami nation except for some cognitive and reading difficulties. At the beat of initial presentation to a pediatric neurologist at 7 years of age, an MRI of the brain revealed reversible T2 hyperintensities in the basal ganglia. In addition, she was set in motion to have lessen NAA peak and the suggestion of a lactate peak on MR spectroscopy. EEG, EMG and nerve 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 signal changes including Eye of the tiger sign (Figure 1). MR spectroscopy studies were suboptimal.Exome sequencing was performed through and through Ambry laboratory as previously depict (Serajee and Huq, 2015). The patient had homozygous c.470TG (p.V157G) alteration in the DLAT (Dihydrolipoamide acetyltransferase (PDHC E2) gene suggesting the diagnosis of pyruvate dehydrogenase E2 deficiency, a rare piddle of pyruvate dehydrogenase deficiency. Both parents and hotshot 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, results from a T to G substitution at nucleotide position 470. The valine at codon 157 is replaced by glycine, an amino acid with dissimilar properties. The V157 amino acid position is highly conserved in all open vertebrate species. The p.V157G alteration is predicted to be probably 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.470TG 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 Nucleotide Polymorphisms (dbSNP). Based on data from the HGMD, only the four alterations reported 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 include ace missense alteration, two splice alterations, and one small in-frame deletion. 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 functions in the oxidative decarboxylation of pyruvate to acetyl coenzyme A. The composite plant contains three subunits E1, E2 and E3 (Patel and Roche, 1990). The most common form of pyruvate dehydrogenase d eficiency is due to mutations affecting 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 core of the enzyme and functions in accepting the acetyl groups and transferring them to coenzyme A, an essential step preceding the entrance 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, there are only four reported cases of pyruvate dehydrogenase deficiency caused by alterations in the DLAT gene, making it a very rare cause of the condition (Head et al., 2005McWilliam e t al., 2010). In addition, Robinson et al reported an additional patient with reduced E2 dihydrolipoyl transacetylase enzyme activity (32% of the control and undetectable E2 immunoreactive protein (Robinson et al., 1990). For this patient, no gene mutation data is open (Robinson et al., 1990). The patient reported by Robinson et al. had a disaccordent 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, leading to a substitution of leucine for phenylalanine. Both patients were male children natural of first-cousin parents. These patients p resented 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 included episodic dystonia, hypotonia, ataxia, and developmental delay(Head et al., 2005). Episodes of dystonia were oft triggered by stress or fever, and developmental progress appeared to slow after the episodes as well. Additional reported features included inconsolable crying, nystagmus and abnormal eye movements, ptosis, drooling, jerk head movements, arching of the body, bottom 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 compatible with an abnormality of energy transfiguration (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. Both patients were treated with a modified ketogenic diet and the parents reported improvements in concentration, fine motor control, and decreased fatigue (McWilliam et al., 2010).Previous reports noted the phenotypic overlap to patients with PKAN, and suggested investigation for PDH E2 deficiency in patients suspected to have atypical PKAN with negative genetic testing (Head et al., 2005McWilliam et al., 2010). PKAN is one of several diseases classified under t he umbrella of neurodegeneration with brain iron accumulation (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 synthesis 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 dec 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 manakin of MRI changes in the bilateral 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, the 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 pa tient, 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 unconnected 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 affecte d 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 reformatory 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. 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