Kristin Engelstad
Columbia University Medical Center
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Featured researches published by Kristin Engelstad.
Neurology | 2004
Petra Kaufmann; Dikoma C. Shungu; Mary Sano; Sarah Jhung; Kristin Engelstad; Effie Mitsis; Xiangling Mao; S. Shanske; Michio Hirano; Salvatore DiMauro; D. C. De Vivo
Objective: To evaluate the role of chronic cerebral lactic acidosis in mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). Methods: The authors studied 91 individuals from 34 families with MELAS and the A3243G point mutation and 15 individuals from two families with myoclonus epilepsy and ragged red fibers (MERRF) and the A8344G mutation. Subjects were divided into four groups. Paternal relatives were studied as controls (Group 1). The maternally related subjects were divided clinically into three groups: asymptomatic (no clinical evidence of neurologic disease) (Group 2), oligosymptomatic (neurologic symptoms but without the full clinical picture of MELAS or MERRF) (Group 3), and symptomatic (fulfilling MELAS or MERRF criteria) (Group 4). The authors performed a standardized neurologic examination, neuropsychological testing, MRS, and leukocyte DNA analysis in all subjects. Results: The symptomatic and oligosymptomatic MELAS subjects had significantly higher ventricular lactate than the other groups. There was a significant correlation between degree of neuropsychological and neurologic impairment and cerebral lactic acidosis as estimated by ventricular MRS lactate levels. Conclusions: High levels of ventricular lactate, the brain spectroscopic signature of MELAS, are associated with more severe neurologic impairment.
Neurology | 2009
Michael Rotstein; J. Doran; Hongyuan Yang; Paivi M. Ullner; Kristin Engelstad; D. C. De Vivo
Alternating hemiplegia of childhood (AHC) is a neurodevelopmental syndrome of uncertain etiology.1 It is characterized by onset of hemiplegic, tonic, or dystonic episodes occurring before the age of 18 months. Progressive ataxia and cognitive impairment are frequent. AHC has been reported to be caused by mutations in the ATP1A2 and the CACNA1A genes,2,3 but most cases of AHC remain genetically undiagnosed. Glut1 deficiency syndrome (Glut1 DS, OMIM 606777) is a disorder of brain energy metabolism caused by impaired glucose transport into the brain mediated by the facilitative glucose transporter Glut1, encoded by the GLUT1 gene.4 The hallmark of the disease is low CSF glucose concentration.5 Classic presentation of Glut1 DS includes epilepsy, developmental delay, acquired microcephaly, cognitive impairment, spasticity, ataxia, and dystonia. Paroxysmal movement disorders with or without epilepsy have been described as well, such as paroxysmal episodes of abnormal head or eye movements, intermittent ataxia,4 and paroxysmal exercise-induced dyskinesias.5 The ketogenic diet may have a beneficial effect on symptom control and development.4 We report a child with AHC found to have a mutation in the GLUT1 gene. Case report. The patient is now 10 years old. There is no pertinent family history. The perinatal period and initial development were normal. He walked unassisted at 14 months and was noted to fall more frequently than his peers. At 2 years he began having episodes of ataxia and slurred speech, lasting for 10–15 minutes. From 2.5 years asymmetry was noted during the episodes, with right or left sided hemiplegia, unilateral facial weakness, and slurred speech lasting for 3–4 hours. The episodes included pallor and irritability. Upon awakening he was asymptomatic, and within an hour would start to show unilateral weakness. Episodes were mitigated or aborted by beverages or candy. There were no eye movement abnormalities. He was diagnosed with AHC. Treatment with flunarizine made the events milder and shorter. He has shown gradual cognitive deterioration. Current neuropsychologic evaluation showed full-scale IQ of 51. He has gradually developed a mild ataxic gait. Head circumference has decreased from the 50th percentile to below the third percentile. Brain MRI was normal. Two lumbar punctures showed CSF glucose concentrations of 35 and 39 mg/dL, and serum glucose concentrations of 99 and 80 mg/dL. CSF lactate was 1.07 mM. The ketogenic diet was poorly tolerated with severe weight loss. The patient is currently supplementing his diet with cornstarch, which has made the events milder and less frequent. We evaluated him at age 10 years for Glut1 DS. Methods. Erythrocyte 3-O-methyl-d-glucose uptake and GLUT1 mutational analysis were performed as described elsewhere.4 Results. Patient uptake of 3-O-methyl-d-glucose was 53% (figure, A), Vmax for 3-O-methyl-d-glucose uptake was 52% (patient: 500 fmol/s/106 cells, controls:1,000 fmol/106 cells, 909 fmol/106 cells), and Km was 97% (patient: 1.3 mM, controls: 1.4 mM and 1.3 mM). GLUT1 mutational analysis revealed a single nucleotide replacement CGG>TGG at nucleotide 277, resulting in a heterozygous R93W missense mutation in exon 4. Parents’ analysis was normal. This mutation is located in the first cytosolic loop of Glut1 (figure, B). R93W or R93Q mutations have been described previously in Glut1 DS associated with a typical epileptic phenotype.6 Figure Glut1 protein: Functional and structural analysis Discussion. AHC patients may have cerebral glucose deficiency. Low glucose metabolism was found in the frontal lobes, putamen, and cerebellum of patients with AHC as measured by 18F-fluorodeoxyglucose PET.7 This pattern of cortical and cerebellar glucose hypometabolism also has been described in Glut1 DS.6 We describe a child with Glut1 DS presenting with episodes of alternating hemiplegia, progressive ataxia, cognitive deterioration, and decelerating head growth. Other than the episodes starting after the age of 18 months, the phenotype is typical for AHC.2 The hallmark of Glut1 DS is low CSF glucose concentration, usually below 40 mg/dL.4,5 A literature search of AHC cases failed to show CSF findings in this population. Episodes of AHC are triggered by physical activity, environmental stress, and certain foods but not by fasting.2 We recommend that children with AHC be tested for hypoglycorrhachia, especially if symptoms are induced by physical activity or fasting. If the glucose concentration is low, further evaluation as described in this case should be performed. Early treatment with the ketogenic diet should be considered in all children with Glut1 DS.
Journal of Child Neurology | 2013
Jacqueline Montes; Michelle Blumenschine; Sally Dunaway; Aliza Alter; Kristin Engelstad; Ashwini K. Rao; Claudia A. Chiriboga; Douglas M. Sproule; Darryl C. De Vivo
Weakness and fatigue are captured by the 6-minute walk test, but the relationship between these symptoms is uncertain. Comparison across neuromuscular diseases has not been examined. A cohort study of 114 patients with spinal muscular atrophy, Duchenne/Becker muscular dystrophy, myasthenia gravis, and energy failure syndromes were included. Percent-predicted distance on the 6-minute walk test was computed from normative values to determine weakness. Fatigue was determined by the decrement in distance from the first to sixth minute. Weakness was seen across all groups (61.9%) but significant fatigue was seen only in spinal muscular atrophy (21.0%). Other groups showed little fatigue. Correlation between weakness and fatigue was significant only in spinal muscular atrophy (R = –0.71; P < .001). Longitudinally, distance walked declined only in Duchenne/Becker muscular dystrophy. In spinal muscular atrophy, weakness did not change, but fatigue increased significantly. These findings suggest independent mechanisms underlying weakness and fatigue in diverse neuromuscular conditions.
Neurology | 2014
Nora Weiduschat; Petra Kaufmann; Xiangling Mao; Kristin Engelstad; Veronica J. Hinton; Salvatore DiMauro; Darryl C. De Vivo; Dikoma C. Shungu
Objective: To establish cerebral metabolic features associated with the A3243G mitochondrial DNA mutation with proton magnetic resonance spectroscopic imaging (1H MRSI) and to assess their potential as prognostic biomarkers. Methods: In this prospective cohort study, we investigated 135 clinically heterogeneous A3243G mutation carriers and 30 healthy volunteers (HVs) with 1H MRSI. Mutation carriers included 45 patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS); 11 participants who would develop the MELAS syndrome during follow-up (converters); and 79 participants who would not develop the MELAS syndrome during follow-up (nonconverters). The groups were compared with respect to MRSI metabolic indices of 1) anaerobic energy metabolism (lactate), 2) neuronal integrity (N-acetyl-l-aspartate [NAA]), 3) mitochondrial function (NAA; lactate), 4) cell energetics (total creatine), and 5) membrane biosynthesis and turnover (total choline [tCho]). Results: Consistent with prior studies, the patients with MELAS had higher lactate (p < 0.001) and lower NAA levels (p = 0.01) than HVs. Unexpectedly, converters showed higher NAA (p = 0.042), tCho (p = 0.004), and total creatine (p = 0.002), in addition to higher lactate levels (p = 0.032), compared with HVs. Compared with nonconverters, converters had higher tCho (p = 0.015). Clinically, converters and nonconverters did not differ at baseline. Lactate and tCho levels were reliable biomarkers for predicting the risk of individual mutation carriers to develop the MELAS phenotype. Conclusions: 1H MRSI assessment of cerebral metabolism in A3243G mutation carriers shows promise in identifying disease biomarkers as well as individuals at risk of developing the MELAS phenotype.
Nature Communications | 2017
Maoxue Tang; Guangping Gao; Carlos B. Rueda; Hang Yu; David N. Thibodeaux; Tomoyuki Awano; Kristin Engelstad; Maria-Jose Sanchez-Quintero; Hong Yang; Fanghua Li; Huapeng Li; Qin Su; Kara E. Shetler; Lynne A. Jones; Ryan Seo; Jonathan McConathy; Elizabeth M. C. Hillman; Jeffrey L. Noebels; Darryl C. De Vivo; Umrao R. Monani
Haploinsufficiency of the SLC2A1 gene and paucity of its translated product, the glucose transporter-1 (Glut1) protein, disrupt brain function and cause the neurodevelopmental disorder, Glut1 deficiency syndrome (Glut1 DS). There is little to suggest how reduced Glut1 causes cognitive dysfunction and no optimal treatment for Glut1 DS. We used model mice to demonstrate that low Glut1 protein arrests cerebral angiogenesis, resulting in a profound diminution of the brain microvasculature without compromising the blood–brain barrier. Studies to define the temporal requirements for Glut1 reveal that pre-symptomatic, AAV9-mediated repletion of the protein averts brain microvasculature defects and prevents disease, whereas augmenting the protein late, during adulthood, is devoid of benefit. Still, treatment following symptom onset can be effective; Glut1 repletion in early-symptomatic mutants that have experienced sustained periods of low brain glucose nevertheless restores the cerebral microvasculature and ameliorates disease. Timely Glut1 repletion may thus constitute an effective treatment for Glut1 DS.
Journal of the Neurological Sciences | 2012
Valentina Emmanuele; Angels García-Cazorla; Hua-bin Huang; Jorida Coku; Beatriz Dorado; Etty Cortes; Kristin Engelstad; Darryl C. De Vivo; Salvatore DiMauro; Eduardo Bonilla; Kurenai Tanji
Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) is a maternally inherited mitochondrial syndrome characterized by seizures, migrainous headaches, lactic acidosis, vomiting, and recurrent stroke-like episodes. Patients often suffer from cognitive dysfunction of unclear pathogenesis. In this study, we explored a possible link between cognitive dysfunction and hippocampal expression of calbindin D(28KD) (CB), a high affinity calcium-binding protein, in four MELAS patients, using post mortem hippocampal tissues. We found significantly reduced CB levels in all patients by immunohistochemistry, Western blot, and quantitative real-time PCR. Reduction in CB expression has been associated with aging and with neurodegenerative disorders, including Alzheimers disease. We postulate that the reduced CB expression may play a role in the cognitive abnormalities associated with MELAS.
Child Neurology Open | 2016
Yasemin Gulcan Kurt; Jorida Coku; H. Orhan Akman; Ali Naini; Jesheng Lu; Kristin Engelstad; Michio Hirano; Darryl C. De Vivo; Salvatore DiMauro
Dystonia is often associated with the symmetrical basal ganglia lesions of Leigh syndrome. However, it has also been associated with mitochondrial ND mutations, with or without Leber hereditary optic neuropathy. The m.14459G>A mutation in ND6 causes dystonia with or without familial Leber hereditary optic neuropathy. We report heteroplasmic 14459G>A mutations in 2 unrelated children with nonmaternally inherited generalized dystonia and showing bilateral magnetic resonance imaging lesions in nucleus pallidus and putamen. Both children have reached their teenage years, and they are intellectually active, despite their motor problems.
Journal of Child Neurology | 2016
Michelle Blumenschine; Jacqueline Montes; Ashwini K. Rao; Kristin Engelstad; Darryl C. De Vivo
Anticipating potential therapies for Glut 1 deficiency syndrome (Glut1DS) emphasizes the need for effective clinical outcome measures. The 6-minute walk test is a well-established outcome measure that evaluates walking ability in neurological diseases. Twenty-one children with Glut 1 deficiency syndrome and 21 controls performed the 6-minute walk test. Fatigue was determined by comparing distance walked in the first and sixth minutes. Gait was analyzed by stride length, velocity, cadence, base of support, and percentage time in double support. Independent sample t-tests examined differences between group. Repeated-measures analysis of variance evaluated gait parameters over time. Glut 1 deficiency syndrome patients walked less (P < .05), had slower velocities (P < .0001), had shorter stride lengths (P < .0001), spent more time in double support (P < .001), and had increasing variability in base of support (P = .009). Glut 1 deficiency syndrome patients have impaired motor performance, walk more slowly, and have poor balance. The 6-minute walk test with gait analysis may serve as a useful outcome measure in clinical trials in Glut 1 deficiency syndrome.
Pediatric Research | 2010
H Gumus; A O Caglayan; H Per; S Kumandas; Kristin Engelstad; F Kardes; D. C. De Vivo
662 The First Turkish Case of Glucose Transporter Type 1 Deficiency Syndrome (GLUT 1D) with Molecular Studies
Neuropediatrics | 2005
M Henneke; Diane Wang; R Korinthenberg; Juan M. Pascual; Hongyuan Yang; Kristin Engelstad; Knut Brockmann; D. C. De Vivo; J Gärtner