Publications by authors named "Kristin Engelstad"

41 Publications

Circulating markers of NADH-reductive stress correlate with mitochondrial disease severity.

J Clin Invest 2021 01;131(2)

Howard Hughes Medical Institute, Department of Molecular Biology, and.

Mitochondrial disorders represent a large collection of rare syndromes that are difficult to manage both because we do not fully understand biochemical pathogenesis and because we currently lack facile markers of severity. The m.3243A>G variant is the most common heteroplasmic mitochondrial DNA mutation and underlies a spectrum of diseases, notably mitochondrial encephalomyopathy lactic acidosis and stroke-like episodes (MELAS). To identify robust circulating markers of m.3243A>G disease, we first performed discovery proteomics, targeted metabolomics, and untargeted metabolomics on plasma from a deeply phenotyped cohort (102 patients, 32 controls). In a validation phase, we measured concentrations of prioritized metabolites in an independent cohort using distinct methods. We validated 20 analytes (1 protein, 19 metabolites) that distinguish patients with MELAS from controls. The collection includes classic (lactate, alanine) and more recently identified (GDF-15, α-hydroxybutyrate) mitochondrial markers. By mining untargeted mass-spectra we uncovered 3 less well-studied metabolite families: N-lactoyl-amino acids, β-hydroxy acylcarnitines, and β-hydroxy fatty acids. Many of these 20 analytes correlate strongly with established measures of severity, including Karnofsky status, and mechanistically, nearly all markers are attributable to an elevated NADH/NAD+ ratio, or NADH-reductive stress. Our work defines a panel of organelle function tests related to NADH-reductive stress that should enable classification and monitoring of mitochondrial disease.
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http://dx.doi.org/10.1172/JCI136055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7810486PMC
January 2021

Regulatory environment for novel therapeutic development in mitochondrial diseases.

J Inherit Metab Dis 2020 Dec 24. Epub 2020 Dec 24.

Department of Biostatistics, Mailman School of Public Health, Columbia University, New York, New York, USA.

At present, there is just one approved therapy for patients with mitochondrial diseases in Europe, another in Japan, and none in the United States. These facts reveal an important and significant unmet need for approved therapies for these debilitating and often fatal disorders. To fill this need, it is critical for clinicians and drug developers to work closely with regulatory agencies. In the United States, mitochondrial disease patients and clinicians, the United Mitochondrial Disease Foundation, and pharmaceutical industry members have engaged with the Food and Drug Administration to educate each other about these complex and heterogeneous diseases and about regulatory requirements to obtain approvals for novel therapies. Clinical development of therapies for rare diseases has been facilitated by the 1983 US Orphan Drug Act (ODA) and similar legislation in Japan and the European Union. Further legislation and regulatory guidance have expanded and refined regulatory flexibility. While regulatory and financial incentives of the ODA have augmented involvement of pharmaceutical companies, clinicians, with patient advocacy groups and industry, need to conduct natural history studies, develop clinical outcome measures, and identify potential supportive surrogate endpoints predictive of clinical benefit, which together are critical foundations for clinical trials. Thus, the regulatory environment for novel therapeutic development is conducive and offers flexibility for mitochondrial diseases. Nevertheless, flexibility does not mean lower standards, as well-controlled rigorous clinical trials of high quality are still required to establish the efficacy of potential therapies and to obtain regulatory agency approvals for their commercial use. This process is illustrated through the authors' ongoing efforts to develop therapy for thymidine kinase 2 deficiency.
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http://dx.doi.org/10.1002/jimd.12353DOI Listing
December 2020

Glut1 Deficiency Syndrome (Glut1DS): State of the art in 2020 and recommendations of the international Glut1DS study group.

Epilepsia Open 2020 Sep 13;5(3):354-365. Epub 2020 Aug 13.

Department of Neurology and Pediatrics Vagelos College of Physicians and Surgeons at Columbia University New York NY USA.

Glut1 deficiency syndrome (Glut1DS) is a brain energy failure syndrome caused by impaired glucose transport across brain tissue barriers. Glucose diffusion across tissue barriers is facilitated by a family of proteins including glucose transporter type 1 (Glut1). Patients are treated effectively with ketogenic diet therapies (KDT) that provide a supplemental fuel, namely ketone bodies, for brain energy metabolism. The increasing complexity of Glut1DS, since its original description in 1991, now demands an international consensus statement regarding diagnosis and treatment. International experts (n = 23) developed a consensus statement utilizing their collective professional experience, responses to a standardized questionnaire, and serial discussions of wide-ranging issues related to Glut1DS. Key clinical features signaling the onset of Glut1DS are eye-head movement abnormalities, seizures, neurodevelopmental impairment, deceleration of head growth, and movement disorders. Diagnosis is confirmed by the presence of these clinical signs, hypoglycorrhachia documented by lumbar puncture, and genetic analysis showing pathogenic variants. KDT represent standard choices with Glut1DS-specific recommendations regarding duration, composition, and management. Ongoing research has identified future interventions to restore Glut1 protein content and function. linical manifestations are influenced by patient age, genetic complexity, and novel therapeutic interventions. All clinical phenotypes will benefit from a better understanding of Glut1DS natural history throughout the life cycle and from improved guidelines facilitating early diagnosis and prompt treatment. Often, the presenting seizures are treated initially with antiseizure drugs before the cause of the epilepsy is ascertained and appropriate KDT are initiated. Initial drug treatment fails to treat the underlying metabolic disturbance during early brain development, contributing to the long-term disease burden. Impaired development of the brain microvasculature is one such complication of delayed Glut1DS treatment in the postnatal period. This international consensus statement should facilitate prompt diagnosis and guide best standard of care for Glut1DS throughout the life cycle.
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http://dx.doi.org/10.1002/epi4.12414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469861PMC
September 2020

The North American mitochondrial disease registry.

J Transl Genet Genom 2020 28;4:81-90. Epub 2020 Apr 28.

Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA.

Aim: The North American Mitochondrial Disease Consortium (NAMDC) comprises a network of 17 clinical centers with a mission to conduct translational research on mitochondrial diseases. NAMDC is a part of the Rare Disease Clinical Research Network (RDCRN) and is funded by the National Institutes of Health. To foster its mission, NAMDC has implemented a comprehensive Mitochondrial Disease Clinical Registry (hereafter NAMDC Registry), collected biosamples deposited into the NAMDC Biorepository, defined phenotypes and genotypes of specific disorders, collected natural history data, identified outcome measures, characterized safety and long-term toxicity and efficacy of promising therapies, and trained young investigators interested in patient-oriented research in mitochondrial disease.

Methods: Research conducted by NAMDC is built on the foundation of the Clinical Registry. Data within the registry are encrypted and maintained in a centralized database at Columbia University Medical Center. In addition to clinical data, NAMDC has established a mitochondrial disease biorepository, collecting DNA, plasma, cell, and tissue samples. Specimens are assigned coded identifiers in compliance with all relevant regulatory entities and with emerging NIH guidelines for biorepositories. NAMDC funds two pilot projects each year. Pilot grants are small grants typically supporting an early stage concept to obtain preliminary data. Pilot grants must enhance and address major issues in mitochondrial medicine and specific areas of need for the field and for the successful outcome of NAMDC. The grant selection process is facilitated by input from multiple stakeholders including patient organizations and the strategic leadership of NAMDC. To train new mitochondrial disease investigators, NAMDC has established a Fellowship Program which offers a unique training opportunity to senior postdoctoral clinical fellows. The fellowship includes a 6-month period of intensive training in clinical trial methodology through the Clinical Research Enhancement through Supplemental Training program and equivalent programs at the other sites, along with rotations up to 3 months each to two additional consortium sites where a rich and varied training experience is provided. Nine core educational sites participate in this training program, each offering a summer grant program in mitochondrial medicine funded by our NAMDC partner the United Mitochondrial Disease Foundation (www.umdf.org). All clinical research in NAMDC depends on the participation of mitochondrial disease patients. Since individual mitochondrial disorders are often extremely rare, major communication and recruitment efforts are required. Therefore, NAMDC has forged a very close partnership with the premier patient advocacy group for mitochondrial diseases in North America, the United Mitochondrial Disease Foundation (UMDF).

Results: The NAMDC Registry has confirmed the clinical and genetical heterogeneity of mitochondrial diseases due to primary mutations in mitochondrial DNA or nuclear DNA. During the 8 years of this NIH-U54 grant, this consortium, acting in close collaboration with a patient advocacy group, the UMDF, has effectively addressed these complex diseases. NAMDC has expanded a powerful patient registry with more than 1600 patients enrolled to date, a website for education and recruitment of patients (www.namdc.org), a NAMDC biorepository housed at the Mayo Clinic in Rochester, MN, and essential diagnostic guidelines for consensus research. In addition, eight clinical studies have been initiated and the NAMDC fellowship program has been actively training the next generation of mitochondrial disease clinical investigators, of which six have completed the program and remain actively involved in mitochondrial disease research.

Conclusion: The NAMDC Patient Registry and Biorepository is actively facilitating mitochondrial disease research, and accelerating progress in the understanding and treatment of mitochondrial diseases.
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http://dx.doi.org/10.20517/jtgg.2020.12DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7323997PMC
April 2020

Implementation of population-based newborn screening reveals low incidence of spinal muscular atrophy.

Genet Med 2020 Aug 18;22(8):1296-1302. Epub 2020 May 18.

Newborn Screening Program, Division of Genetics, Wadsworth Center, New York State Department of Health, Albany, NY, USA.

Purpose: Spinal muscular atrophy (SMA) was added to the Recommended Uniform Screening Panel (RUSP) in July 2018, following FDA approval of the first effective SMA treatment, and demonstration of feasibility of high-throughput newborn screening using a primary molecular assay. SMA newborn screening was implemented in New York State (NYS) on 1 October 2018.

Methods: Screening was conducted using DNA extracted from dried blood spots with a multiplex real-time quantitative polymerase chain reaction (qPCR) assay targeting the recurrent SMN1 exon 7 gene deletion.

Results: During the first year, 225,093 infants were tested. Eight screened positive, were referred for follow-up, and confirmed to be homozygous for the deletion. Infants with two or three copies of the SMN2 gene, predicting more severe, earlier-onset SMA, were treated with antisense oligonucleotide and/or gene therapy. One infant with ≥4 copies SMN2 also received gene therapy.

Conclusion: Newborn screening permits presymptomatic SMA diagnosis, when treatment initiation is most beneficial. At 1 in 28,137 (95% confidence interval [CI]: 1 in 14,259 to 55,525), the NYS SMA incidence is 2.6- to 4.7-fold lower than expected. The low SMA incidence is likely attributable to imprecise and biased estimates, coupled with increased awareness, access to and uptake of carrier screening, genetic counseling, cascade testing, prenatal diagnosis, and advanced reproductive technologies.
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http://dx.doi.org/10.1038/s41436-020-0824-3DOI Listing
August 2020

Mitochondrial diseases in North America: An analysis of the NAMDC Registry.

Neurol Genet 2020 Apr 2;6(2):e402. Epub 2020 Mar 2.

Department of Neurology (E.B., V.E., S.D., K.E., X.Q.R., M.H.), Columbia University Medical Center, New York; Department of Biostatistics (Y.L., V.C., J.K., J. Grier, R.B., J.L.P.T.), Mailman School of Public Health, Columbia University, New York; Radboudumc (R.S.), Nijmegen, The Netherlands; Department of Pediatrics (B.H.C.), Northeast Ohio Medical University and Akron Children's Hospital; Genetics Unit (A.K.), Massachusetts General Hospital, Boston; Department of Pediatrics (G.D.V.), State University of New York at Buffalo; Departments of Neurosciences and Pediatrics (R.H.), University of California at San Diego; Department of Pediatrics (J.L.K.V.H., A.L.), University of Colorado School of Medicine, Aurora; Department of Molecular and Human Genetics (F.S.), Baylor College of Medicine, Houston, TX; Texas Children's Hospital (F.S.), Houston; Joint BCM-CUHK Center of Medical Genetics (F.S.), Prince of Wales Hospital, ShaTin, New Territories, Hong Kong; Department of Neurology (S.P.), Cleveland Clinic, OH; Departments of Genetics and Genome Sciences and Pediatrics (J.K.B., S.D.D.), and Center for Human Genetics, University Hospitals Cleveland Medical Center, Case Western Reserve University, OH; Departments of Neurology and Clinical Genomics (R.H.G.), Mayo Clinic, Rochester, MN; Department of Neurology (R.P.S.), University of Washington, Seattle Children's Hospital; Department of Pediatrics (G.M.E.), Stanford University, Palo Alto, CA; Department of Medicine (P.W.S.), University of Florida at Gainesville; Genetics and Genomic Sciences at the Icahn School of Medicine at Mount Sinai (J. Ganesh), New York; Mitochondrial Medicine Frontier Program (Z.Z.-C., M.J.F., A.C.G.), Division of Human Genetics, The Children's Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine; University of Pennsylvania Perelman School of Medicine (Z.Z.-C.), Philadelphia; Department of Neurology (M.T.), McMasters University, Toronto, Ontario, Canada; Department of Neurology (A.G.), Children's National Health Network, Washington, DC; Office of Dietary Supplements (K.C.), National Institutes of Health, Bethesda, MD; and Eunice Kennedy Shriver National Institute of Child Health and Human Development (D.K.), National Institutes of Health, Bethesda, MD.

Objective: To describe clinical, biochemical, and genetic features of participants with mitochondrial diseases (MtDs) enrolled in the North American Mitochondrial Disease Consortium (NAMDC) Registry.

Methods: This cross-sectional, multicenter, retrospective database analysis evaluates the phenotypic and molecular characteristics of participants enrolled in the NAMDC Registry from September 2011 to December 2018. The NAMDC is a network of 17 centers with expertise in MtDs and includes both adult and pediatric specialists.

Results: One thousand four hundred ten of 1,553 participants had sufficient clinical data for analysis. For this study, we included only participants with molecular genetic diagnoses (n = 666). Age at onset ranged from infancy to adulthood. The most common diagnosis was multisystemic disorder (113 participants), and only a minority of participants were diagnosed with a classical mitochondrial syndrome. The most frequent classical syndromes were Leigh syndrome (97 individuals) and mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (71 individuals). Pathogenic variants in the mitochondrial DNA were more frequently observed (414 participants) than pathogenic nuclear gene variants (252 participants). Pathogenic variants in 65 nuclear genes were identified, with and being the most commonly affected. Pathogenic variants in 38 genes were reported only in single participants.

Conclusions: The NAMDC Registry data confirm the high variability of clinical, biochemical, and genetic features of participants with MtDs. This study serves as an important resource for future enhancement of MtD research and clinical care by providing the first comprehensive description of participant with MtD in North America.
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http://dx.doi.org/10.1212/NXG.0000000000000402DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7164977PMC
April 2020

Exploring mTOR inhibition as treatment for mitochondrial disease.

Ann Clin Transl Neurol 2019 09 6;6(9):1877-1881. Epub 2019 Aug 6.

Department of Neurology, Columbia University Irving Medical Center, New York, New York, 10032.

Leigh syndrome and MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) are two of the most frequent pediatric mitochondrial diseases. Both cause severe morbidity and neither have effective treatment. Inhibiting the mammalian target of rapamycin (mTOR) pathway has been shown in model mice of Leigh syndrome to extend lifespan and attenuate both the clinical and pathological progression of disease. Based on this observation, we treated two children with everolimus, a rapamycin analogue. The child with Leigh syndrome showed sustained benefit, while the child with MELAS failed to respond and died of progressive disease. We discuss possible mechanisms underlying these disparate responses to mTOR inhibition.
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http://dx.doi.org/10.1002/acn3.50846DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6764630PMC
September 2019

A De Novo Mutation in Causes Generalized Dystonia in 2 Unrelated Children.

Child Neurol Open 2016 Jan-Dec;3:2329048X15627937. Epub 2016 Apr 4.

Department of Neurology, Columbia University Medical Center, New York, NY, USA.

Dystonia is often associated with the symmetrical basal ganglia lesions of Leigh syndrome. However, it has also been associated with mitochondrial mutations, with or without Leber hereditary optic neuropathy. The m.14459G>A mutation in 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.
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http://dx.doi.org/10.1177/2329048X15627937DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5417276PMC
April 2016

Paroxysmal eye-head movements in Glut1 deficiency syndrome.

Neurology 2017 Apr 24;88(17):1666-1673. Epub 2017 Mar 24.

From the Colleen Giblin Research Laboratory (K.E., D.C.D.), Division of Pediatric Neurology, Department of Neurology (T.S.P., R.P.), Department of Ophthalmology, Edward S. Harkness Eye Institute (S.A.K.), Mahoney-Keck Center for Brain and Behavior Research (M.E.G.), Department of Neuroscience (M.E.G.), and the Departments of Neurology, Psychiatry, and Ophthalmology (M.E.G.), Columbia University College of Physicians and Surgeons, New York, NY; Department of Neurology (T.S.P.), Washington University School of Medicine, St. Louis, MO; First Department of Pediatrics (R.P.), National and Kapodistrian University of Athens, Aghia Sofia Hospital, Greece; Kavli Institute for Neuroscience (M.E.G.), Columbia University; and the Division of Neurobiology and Behavior (M.E.G.), New York State Psychiatric Institute, New York.

Objective: To describe a characteristic paroxysmal eye-head movement disorder that occurs in infants with Glut1 deficiency syndrome (Glut1 DS).

Methods: We retrospectively reviewed the medical charts of 101 patients with Glut1 DS to obtain clinical data about episodic abnormal eye movements and analyzed video recordings of 18 eye movement episodes from 10 patients.

Results: A documented history of paroxysmal abnormal eye movements was found in 32/101 patients (32%), and a detailed description was available in 18 patients, presented here. Episodes started before age 6 months in 15/18 patients (83%), and preceded the onset of seizures in 10/16 patients (63%) who experienced both types of episodes. Eye movement episodes resolved, with or without treatment, by 6 years of age in 7/8 patients with documented long-term course. Episodes were brief (usually <5 minutes). Video analysis revealed that the eye movements were rapid, multidirectional, and often accompanied by a head movement in the same direction. Eye movements were separated by clear intervals of fixation, usually ranging from 200 to 800 ms. The movements were consistent with eye-head gaze saccades. These movements can be distinguished from opsoclonus by the presence of a clear intermovement fixation interval and the association of a same-direction head movement.

Conclusions: Paroxysmal eye-head movements, for which we suggest the term aberrant gaze saccades, are an early symptom of Glut1 DS in infancy. Recognition of the episodes will facilitate prompt diagnosis of this treatable neurodevelopmental disorder.
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http://dx.doi.org/10.1212/WNL.0000000000003867DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5405761PMC
April 2017

Brain microvasculature defects and Glut1 deficiency syndrome averted by early repletion of the glucose transporter-1 protein.

Nat Commun 2017 01 20;8:14152. Epub 2017 Jan 20.

Department of Pathology &Cell Biology, Columbia University Medical Center, New York, New York 10032, USA.

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.
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http://dx.doi.org/10.1038/ncomms14152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5263887PMC
January 2017

Analysis of Gait Disturbance in Glut 1 Deficiency Syndrome.

J Child Neurol 2016 11 10;31(13):1483-1488. Epub 2016 Aug 10.

Department of Neurology, Columbia University Medical Center, New York, NY, USA

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.
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http://dx.doi.org/10.1177/0883073816661662DOI Listing
November 2016

Attitudes toward prevention of mtDNA-related diseases through oocyte mitochondrial replacement therapy.

Hum Reprod 2016 May 2;31(5):1058-65. Epub 2016 Mar 2.

Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA

Study Question: Among women who carry pathogenic mitochondrial DNA (mtDNA) point mutations and healthy oocyte donors, what are the levels of support for developing oocyte mitochondrial replacement therapy (OMRT) to prevent transmission of mtDNA mutations?

Summary Answer: The majority of mtDNA carriers and oocyte donors support the development of OMRT techniques to prevent transmission of mtDNA diseases.

What Is Known Already: Point mutations of mtDNA cause a variety of maternally inherited human diseases that are frequently disabling and often fatal. Recent developments in (OMRT) as well as pronuclear transfer between embryos offer new potential options to prevent transmission of mtDNA disease. However, it is unclear whether the non-scientific community will approve of embryos that contain DNA from three people.

Study Design, Size, Duration: Between 1 June 2012 through 12 February 2015, we administered surveys in cross-sectional studies of 92 female carriers of mtDNA point mutations and 112 healthy oocyte donors.

Participants/materials, Setting, Methods: The OMRT carrier survey was completed by 92 female carriers of an mtDNA point mutation. Carriers were recruited through the North American Mitochondrial Disease Consortium (NAMDC), the United Mitochondrial Disease Foundation (UMDF), patient support groups, research and private patients followed at the Columbia University Medical Center (CUMC) and patients' referrals of maternal relatives. The OMRT donor survey was completed by 112 women who had donated oocytes through a major ITALIC! in vitro fertilization clinic.

Main Results And The Role Of Chance: All carriers surveyed were aware that they could transmit the mutation to their offspring, with 78% (35/45) of women, who were of childbearing age, indicating that the risk was sufficient to consider not having children, and 95% (87/92) of all carriers designating that the development of this technique was important and worthwhile. Of the 21 surveyed female carriers considering childbearing, 20 (95%) considered having their own biological offspring somewhat or very important and 16 of the 21 respondents (76%) were willing to donate oocytes for research and development. Of 112 healthy oocyte donors who completed the OMRT donor survey, 97 (87%) indicated that they would donate oocytes for generating a viable embryo through OMRT.

Limitations, Reasons For Caution: Many of the participants were either patients or relatives of patients who were already enrolled in a research-oriented database, or who sought care in a tertiary research university setting, indicating a potential sampling bias. The survey was administered to a select group of individuals, who carry, or are at risk for carrying, mtDNA point mutations. These individuals are more likely to have been affected by the mutation or have witnessed first-hand the devastating effects of these mutations. It has not been established whether the general public would be supportive of this work. This survey did not explicitly address alternatives to OMRT.

Wider Implications Of The Findings: This is the first study indicating a high level of interest in the development of these methods among women affected by the diseases or who are at risk of carrying mtDNA mutations as well as willingness of most donors to provide oocytes for the development of OMRT.

Study Funding/competing Interests: This work was conducted under the auspices of the NAMDC (Study Protocol 7404). NAMDC (U54NS078059) is part of the NCATS Rare Diseases Clinical Research Network (RDCRN). RDCRN is an initiative of the Office of Rare Diseases Research (ORDR) and NCATS. NAMDC is funded through a collaboration between NCATS, NINDS, NICHD and NIH Office of Dietary Supplements. The work was also supported by the Bernard and Anne Spitzer Fund and the New York Stem Cell Foundation (NYSCF). Dr Hirano has received research support from Santhera Pharmaceuticals and Edison Pharmaceuticals for studies unrelated to this work. None of the other authors have conflicts of interest.

Trial Registration Number: Not applicable.
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http://dx.doi.org/10.1093/humrep/dew033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4840023PMC
May 2016

Diagnosing Glucose Transporter 1 Deficiency at Initial Presentation Facilitates Early Treatment.

J Pediatr 2016 Apr 22;171:220-6. Epub 2016 Jan 22.

Division of Pediatric Neurology, Department of Neurology, Colleen Giblin Research Laboratory, Columbia University College of Physician and Surgeons, New York, NY. Electronic address:

Objective: To profile the initial clinical events of glucose transporter 1 deficiency syndrome (Glut1 DS) in order to facilitate the earliest possible diagnosis.

Study Design: We retrospectively reviewed 133 patients with Glut1 DS from a single institution. Family interviews and medical record reviews identified the first clinical event(s) reported by the caregivers.

Results: Average age of the first event was 8.15 ± 11.9 months (range: 0.01-81). Ninety-one patients experienced the first symptom before age 6 months (68%). Thirty-three additional patients (25%) presented before age 2 years. Only 9 patients (7%), reported the first event after age 2 years. Seizures were the most common first event (n = 81, 61%), followed by eye movement abnormalities (n = 51, 38%) and changes in muscle strength and tone (n = 30, 22%). Eye movement abnormalities, lower cerebrospinal fluid glucose values, and lower Columbia Neurological Scores correlated with earlier onset of the first event (r: -0.17, 0.22, and 0.25 respectively, P < .05). There was no correlation with age of first event and red blood cell glucose uptake or mutation type.

Conclusions: Glut1 DS is a treatable cause of infantile onset encephalopathy. Health care providers should recognize the wide spectrum of paroxysmal events that herald the clinical onset of Glut1 DS in early infancy to facilitate prompt diagnosis, immediate treatment, and improved long-term outcome.
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http://dx.doi.org/10.1016/j.jpeds.2015.12.030DOI Listing
April 2016

CoQ Deficiency Is Not a Common Finding in GLUT1 Deficiency Syndrome.

JIMD Rep 2016 29;29:47-52. Epub 2015 Nov 29.

Department of Neurology, Colleen Giblin Laboratories for Pediatric Neurology Research, Columbia University, 710 West 168th Street, New York, NY, 10032, USA.

CoQ deficiency has been recently described in tissues of a patient with GLUT1 deficiency syndrome. Here, we investigated patients and mice with GLUT1 deficiency in order to determine whether low CoQ is a recurrent biochemical feature of this disorder, to justify CoQ supplementation as therapeutic option.CoQ levels were investigated in plasma, white blood cells, and skin fibroblasts of 16 patients and healthy controls and in the brain, cerebellum, liver, kidney, muscle, and plasma of 4-month-old GLUT1 mutant and control mice.CoQ levels in plasma did not show any difference compared with controls. Since most of the patients studied were on a ketogenic diet, which can alter CoQ content in plasma, we also analyzed white blood cells and cultured skin fibroblasts. Again, we found no differences. In mice, we found slightly reduced CoQ in the cerebellum, likely an epiphenomenon, and activity of the mitochondrial respiratory chain enzymes was normal.Our data from GLUT1 deficiency patients and from GLUT1 model mice fail to support CoQ deficiency as a common finding in GLUT1 deficiency, suggesting that CoQ deficiency is not a direct biochemical consequence of defective glucose transport caused by molecular defects in the SLC2A1 gene.
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http://dx.doi.org/10.1007/8904_2015_493DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5059199PMC
November 2015

Topography of brain glucose hypometabolism and epileptic network in glucose transporter 1 deficiency.

Epilepsy Res 2015 Feb 11;110:206-15. Epub 2014 Dec 11.

Department of Neurology, Division of Pediatric Neurology, Colleen Giblin Research Laboratory, Columbia University College of Physician & Surgeons, United States.

Rationale: (18)F fluorodeoxyglucose positron emission tomography ((18)F FDG-PET) facilitates examination of glucose metabolism. Previously, we described regional cerebral glucose hypometabolism using (18)F FDG-PET in patients with Glucose transporter 1 Deficiency Syndrome (Glut1 DS). We now expand this observation in Glut1 DS using quantitative image analysis to identify the epileptic network based on the regional distribution of glucose hypometabolism.

Methods: (18)F FDG-PET scans of 16 Glut1 DS patients and 7 healthy participants were examined using Statistical parametric Mapping (SPM). Summed images were preprocessed for statistical analysis using MATLAB 7.1 and SPM 2 software. Region of interest (ROI) analysis was performed to validate SPM results.

Results: Visual analysis of the (18)F FDG-PET images demonstrated prominent regional glucose hypometabolism in the thalamus, neocortical regions and cerebellum bilaterally. Group comparison using SPM analysis confirmed that the regional distribution of glucose hypo-metabolism was present in thalamus, cerebellum, temporal cortex and central lobule. Two mildly affected patients without epilepsy had hypometabolism in cerebellum, inferior frontal cortex, and temporal lobe, but not thalamus. Glucose hypometabolism did not correlate with age at the time of PET imaging, head circumference, CSF glucose concentration at the time of diagnosis, RBC glucose uptake, or CNS score.

Conclusion: Quantitative analysis of (18)F FDG-PET imaging in Glut1 DS patients confirmed that hypometabolism was present symmetrically in thalamus, cerebellum, frontal and temporal cortex. The hypometabolism in thalamus correlated with the clinical history of epilepsy.
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http://dx.doi.org/10.1016/j.eplepsyres.2014.11.007DOI Listing
February 2015

Identification of a novel nemaline myopathy-causing mutation in the troponin T1 (TNNT1) gene: a case outside of the old order Amish.

Muscle Nerve 2015 May 17;51(5):767-72. Epub 2015 Feb 17.

Department of Neurology, Columbia University, 180 Fort Washington Avenue, New York, New York, 10032, USA.

Introduction: Nemaline myopathy (NM) is a congenital neuromuscular disorder often characterized by hypotonia, facial weakness, skeletal muscle weakness, and the presence of rods on muscle biopsy. A rare form of nemaline myopathy known as Amish Nemaline Myopathy has only been seen in a genetically isolated cohort of Old Order Amish patients who may additionally present with tremors in the first 2-3 months of life.

Methods: We describe an Hispanic male diagnosed with nemaline myopathy histopathologically and subsequently confirmed by next generation gene sequencing.

Results: Direct sequencing revealed that he is homozygous for a pathogenic nonsense variant c.323C>G (p.S108X) in exon 9 of the TNNT1 gene.

Conclusions: This report describes a novel pathogenic variant in the TNNT1 gene and represents a nemaline myopathy-causing variant in the TNNT1 gene outside of the Old Order Amish and Dutch ancestry.
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http://dx.doi.org/10.1002/mus.24528DOI Listing
May 2015

Long-term clinical course of Glut1 deficiency syndrome.

J Child Neurol 2015 Feb 30;30(2):160-9. Epub 2014 Apr 30.

Department of Neurology, Columbia University, New York, NY, USA

Our objective is to characterize the long-term course of Glut1 deficiency syndrome. Longitudinal outcome measures, including Columbia Neurological Scores, neuropsychological tests, and adaptive behavior reports, were collected for 13 participants with Glut1 deficiency syndrome who had been followed for an average of 14.2 (range = 8.9-23.6) years. A parent questionnaire assessed manifestations throughout development. The 6-Minute Walk Test captured gait disturbances and triggered paroxysmal exertional dyskinesia. All longitudinal outcomes remained stable over time. Epilepsy dominated infancy and improved during childhood. Dystonia emerged during childhood or adolescence. Earlier introduction of the ketogenic diet correlated with better long-term outcomes on some measures. Percent-predicted 6-Minute Walk Test distance correlated significantly with Columbia Neurological Scores. We conclude that Glut1 deficiency syndrome is a chronic condition, dominated by epilepsy in infancy and by movement disorders thereafter. Dietary treatment in the first postnatal months may effect improved outcomes, emphasizing the importance of early diagnosis and treatment.
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http://dx.doi.org/10.1177/0883073814531822DOI Listing
February 2015

Cerebral metabolic abnormalities in A3243G mitochondrial DNA mutation carriers.

Neurology 2014 Mar 29;82(9):798-805. Epub 2014 Jan 29.

From the Department of Radiology (N.W., X.M., D.S.), Weill Cornell Medical College, New York; and Department of Neurology (P.K., K.M.E., V.H., S.D., D.D.V.), Columbia University College of Physicians and Surgeons, New York, NY.

Objective: To establish cerebral metabolic features associated with the A3243G mitochondrial DNA mutation with proton magnetic resonance spectroscopic imaging ((1)H 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 (1)H 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: (1)H 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.
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http://dx.doi.org/10.1212/WNL.0000000000000169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3945652PMC
March 2014

Weakness and fatigue in diverse neuromuscular diseases.

J Child Neurol 2013 Oct 11;28(10):1277-83. Epub 2013 Jul 11.

1Department of Neurology, Columbia University Medical Center, New York, NY, USA.

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.
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http://dx.doi.org/10.1177/0883073813493663DOI Listing
October 2013

Phenotypic spectrum of glucose transporter type 1 deficiency syndrome (Glut1 DS).

Curr Neurol Neurosci Rep 2013 Apr;13(4):342

Department of Neurology, Columbia University, 710 west 168th Street, New York, NY 10032, USA.

Glut1 deficiency syndrome (Glut1 DS) was originally described in 1991 as a developmental encephalopathy characterized by infantile onset refractory epilepsy, cognitive impairment, and mixed motor abnormalities including spasticity, ataxia, and dystonia. The clinical condition is caused by impaired glucose transport across the blood brain barrier. The past 5 years have seen a dramatic expansion in the range of clinical syndromes that are recognized to occur with Glut1 DS. In particular, there has been greater recognition of milder phenotypes. Absence epilepsy and other idiopathic generalized epilepsy syndromes may occur with seizure onset in childhood or adulthood. A number of patients present predominantly with movement disorders, sometimes without any accompanying seizures. In particular, paroxysmal exertional dyskinesia is now a well-documented clinical feature that occurs in individuals with Glut1 DS. A clue to the diagnosis in patients with paroxysmal symptoms may be the triggering of episodes during fasting or exercise. Intellectual impairment may range from severe to very mild. Awareness of the broad range of potential clinical phenotypes associated with Glut1 DS will facilitate earlier diagnosis of this treatable neurologic condition. The ketogenic diet is the mainstay of treatment and nourishes the starving symptomatic brain during development.
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http://dx.doi.org/10.1007/s11910-013-0342-7DOI Listing
April 2013

Allelic variations of glut-1 deficiency syndrome: the chinese experience.

Pediatr Neurol 2012 Jul;47(1):30-4

Department of Pediatrics, Peking University First Hospital, Beijing, China.

Glucose transporter type 1 deficiency syndrome is characterized by infantile onset seizures, development delay, movement disorders, and acquired microcephaly. The phenotype includes allelic variants such as intermittent ataxia, choreoathetosis, dystonia, and alternating hemiplegia of childhood with or without epilepsy. Dystonias involve allelic variants of glucose transporter type 1 deficiency syndrome. Three Chinese patients presented with paroxysmal behavioral disturbance, weakness, ataxia (especially after fasting), and exercise intolerance. Electroencephalogram findings did not correlate with clinical manifestations. Cranial magnetic resonance imaging produced normal results or mild hypomyelination. Hypoglycorrhachia was evident in all cases. Cerebrospinal fluid glucose ranged from 1.63-2.45 mmol/L. Erythrocyte 3-O-methyl-d-glucose uptake was decreased to 58% in patient 1. Three SLC2A1 disease-causing mutations (761delA, P383H, and R400C) were observed. No patient tolerated ketogenic diets. Two patients responded to frequent meals with snacks. Cerebrospinal fluid evaluation constitutes the diagnostic testing permitting early treatment of glucose transporter type 1 deficiency syndrome. Early diagnosis and treatment improve prognoses.
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http://dx.doi.org/10.1016/j.pediatrneurol.2012.04.010DOI Listing
July 2012

Decreased hippocampal expression of calbindin D28K and cognitive impairment in MELAS.

J Neurol Sci 2012 Jun 5;317(1-2):29-34. Epub 2012 Apr 5.

Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA.

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 Alzheimer's disease. We postulate that the reduced CB expression may play a role in the cognitive abnormalities associated with MELAS.
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http://dx.doi.org/10.1016/j.jns.2012.03.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3345503PMC
June 2012

Glut1 deficiency syndrome and erythrocyte glucose uptake assay.

Ann Neurol 2011 Dec;70(6):996-1005

Colleen Giblin Laboratories for Pediatric Neurology Research, Department of Neurology, Columbia University, New York, NY 10032, USA.

Objective: The Glut1 deficiency syndrome (Glut1 DS) phenotype has expanded dramatically since first described in 1991. Hypoglycorrhachia and decreased erythrocyte 3-OMG uptake are confirmatory laboratory biomarkers. The objective is to expand previous observations regarding the diagnostic value of the uptake assay.

Methods: One hundred and nine suspected cases of Glut-1 DS were studied. All cases had a consistent clinical picture and hypoglycorrhachia. The uptake assay was decreased in 74 cases (group 1) and normal in 35 cases (group 2). We identified disease-causing mutations in 70 group 1 patients (95%) and one group 2 patient (3%).

Results: The cut-off for an abnormally low uptake value was increased from 60% to 74% with a corresponding sensitivity of 99% and specificity of 100%. The correlation between the uptake values for the time-curve and the kinetic concentration curve were strongly positive (R(2) = 0.85). Significant group differences were found in CSF glucose and lactate values, tone abnormalities, and degree of microcephaly. Group 2 patients were less affected in all domains. We also noted a significant correlation between the mean erythrocyte 3-OMG uptake and clinical severity (R(2) = 0.94).

Interpretation: These findings validate the erythrocyte glucose uptake assay as a confirmatory functional test for Glut1 DS and as a surrogate marker for GLUT1 haploinsufficiency.
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http://dx.doi.org/10.1002/ana.22640DOI Listing
December 2011

Autonomic symptoms in carriers of the m.3243A>G mitochondrial DNA mutation.

Arch Neurol 2010 Aug;67(8):976-9

Department of Neurology, Columbia University, 710 W 168th St, New York, NY 10032, USA.

Background: The m.3243A>G mutation can cause multisystem medical problems and can affect the autonomic nervous system.

Objective: To study the frequency and spectrum of autonomic symptoms associated with the m.3243A>G mitochondrial DNA point mutation. Design, Setting, and Patients We studied a cohort of 88 matrilineal relatives from 40 families, including 35 fully symptomatic patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS), 53 carrier relatives, and 16 controls using a questionnaire based on existing standard instruments for the evaluation of autonomic dysfunction. We compared the questionnaire with an expert evaluation. We compared data among the 3 groups using the Mantel-Haenszel chi(2) test to determine the statistical significance of differences between groups.

Results: Mutation carriers frequently had symptoms of autonomic dysfunction, specifically gastrointestinal and orthostatic intolerance.

Conclusions: Carriers of the m.3243A>G mutation have frequent autonomic symptoms. The m.3243A>G mutation should be considered as an etiological factor in patients with autonomic dysfunction and a medical or family history suggestive of mitochondrial disease. Because some autonomic symptoms are treatable, early detection and proactive management may mitigate the burden of morbidity.
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http://dx.doi.org/10.1001/archneurol.2010.174DOI Listing
August 2010

Glut1 deficiency: inheritance pattern determined by haploinsufficiency.

Ann Neurol 2010 Dec;68(6):955-8

Colleen Giblin Laboratories for Pediatric Neurology Research, Columbia University, New York, NY, USA.

Two families manifesting Glut1 deficiency syndrome (DS) as an autosomal recessive trait are described. In 1 family, a severely affected boy inherited a mutated allele from his asymptomatic heterozygous mother. A de novo mutation developed in the paternal allele, producing compound heterozygosity. In another family, 2 mildly affected sisters inherited mutations from their asymptomatic heterozygous consanguineous parents. Red blood cell glucose uptake residual activity, a surrogate of haploinsufficiency, correlated with the clinical severity. These cases demonstrate that Glut1 DS may present as an autosomal recessive trait. The clinical pattern of inheritance is determined by the relative pathogenicity of the mutation and the resulting degree of haploinsufficiency.
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http://dx.doi.org/10.1002/ana.22088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2994988PMC
December 2010

Uncovering microdeletions in patients with severe Glut-1 deficiency syndrome using SNP oligonucleotide microarray analysis.

Mol Genet Metab 2010 Jun 17;100(2):129-35. Epub 2010 Mar 17.

Department of Pathology and Cell Biology, College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA.

Glut-1 facilitates the diffusion of glucose across the blood-brain barrier and is responsible for glucose entry into the brain. Impaired glucose transport across the blood-brain barrier results in Glut-1 deficiency syndrome (Glut-1 DS, OMIM 606777), characterized in its most severe form by infantile seizures, developmental delay, acquired microcephaly, spasticity, ataxia, and hypoglycorrhachia. Approximately 93% of patients with Glut-1 DS have identifiable mutations by sequence analysis in SLC2A1 which localizes to chromosome 1p34.2. In this report, we describe seven severe cases of Glut-1 DS, including a set of identical twins, caused by microdeletions in the SLC2A1 region. These patients were all mutation negative by molecular sequencing. Microdeletions ranged in size from 45Kb to 4.51Mb, and all were identified using high resolution single nucleotide polymorphism (SNP) oligonucleotide microarray analysis (SOMA). Cases with microdeletions 82Kb were not resolvable by FISH. All patients had severe epilepsy, significant cognitive and motor delay, ataxia, and microcephaly. MRI changes, when present, were of greater severity than are typically associated with missense mutations in SLC2A1.
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http://dx.doi.org/10.1016/j.ymgme.2010.03.007DOI Listing
June 2010

Acute hyperglycemia produces transient improvement in glucose transporter type 1 deficiency.

Ann Neurol 2010 Jan;67(1):31-40

Department of Neurology, Baylor College of Medicine, Houston, TX, USA.

Objective: Glucose transporter type 1 deficiency syndrome (Glut1-DS) is characterized clinically by acquired microcephaly, infantile-onset seizures, psychomotor retardation, choreoathetosis, dystonia, and ataxia. The laboratory signature is hypoglycorrhachia. The 5-hour oral glucose tolerance test (OGTT) was performed to assess cerebral function and systemic carbohydrate homeostasis during acute hyperglycemia, in the knowledge that GLUT1 is constitutively expressed ubiquitously and upregulated in the brain.

Methods: Thirteen Glut1-DS patients completed a 5-hour OGTT. Six patients had prolonged electroencephalographic (EEG)/video monitoring, 10 patients had plasma glucose and serum insulin measurements, and 5 patients had repeated measures of attention, memory, fine motor coordination, and well-being. All patients had a full neuropsychological battery prior to OGTT.

Results: The glycemic profile and insulin response during the OGTT were normal. Following the glucose load, transient improvement of clinical seizures and EEG findings were observed, with the most significant improvement beginning within the first 30 minutes and continuing for 180 minutes. Thereafter, clinical seizures returned, and EEG findings worsened. Additionally, transient improvement in attention, fine motor coordination, and reported well-being were observed without any change in memory performance.

Interpretation: This study documents transient neurological improvement in Glut1-DS patients following acute hyperglycemia, associated with improved fine motor coordination and attention. Also, systemic carbohydrate homeostasis was normal, despite GLUT1 haploinsufficiency, confirming the specific role of GLUT1 as the transporter of metabolic fuel across the blood-brain barrier. The transient improvement in brain function underscores the rate-limiting role of glucose transport and the critical minute-to-minute dependence of cerebral function on fuel availability for energy metabolism.
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http://dx.doi.org/10.1002/ana.21797DOI Listing
January 2010

The spectrum of movement disorders in Glut-1 deficiency.

Mov Disord 2010 Feb;25(3):275-81

Agia Sofia Hospital, First Department of Pediatrics, University of Athens, Athens, Greece.

To assess the spectrum of movement disorders, we reviewed video recordings and charts of 57 patients with Glut-1 deficiency. Eighty-nine percent of patients with Glut-1 deficiency syndrome had a disturbance of gait. The most frequent gait abnormalities were ataxic-spastic and ataxic. Action limb dystonia was observed in 86% of cases and mild chorea in 75%. Cerebellar action tremor was seen in 70% of patients, myoclonus in 16%, and dyspraxia in 21%. Nonepileptic paroxysmal events occurred in 28% of patients, and included episodes of ataxia, weakness, Parkinsonism and nonkinesogenic dyskinesias. The 40 patients (70%) who were on the ketogenic diet had less severe gait disturbances but more dystonia, chorea, tremor, myoclonus, dyspraxia, and paroxysmal events compared with the 17 patients on a conventional diet. Poor dietary compliance and low ketonuria appear to trigger the paroxysmal events in some patients. Gait disturbances and movement disorders are frequent in patients with Glut-1 deficiency and are signs of chronic and intermittent pyramidal, cerebellar and extrapyramidal circuit dysfunction. These clinical symptoms reflect chronic nutrient deficiency during brain development and may be mitigated by chronic ketosis.
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http://dx.doi.org/10.1002/mds.22808DOI Listing
February 2010

Murine Glut-1 transporter haploinsufficiency: postnatal deceleration of brain weight and reactive astrocytosis.

Neurobiol Dis 2009 Oct 8;36(1):60-9. Epub 2009 Jul 8.

Department of Neurology, Colleen Giblin Laboratories for Pediatric Neurology Research, Columbia University, New York, NY, USA.

Glucose transporter type 1 (Glut-1) facilitates glucose flux across the blood-brain-barrier. In humans, Glut-1 deficiency causes acquired microcephaly, seizures and ataxia, which are recapitulated in our Glut-1 haploinsufficient mouse model. Postnatal brain weight deceleration and development of reactive astrogliosis were significant by P21 in Glut-1(+/-) mice. The brain weight differences remained constant after P21 whereas the reactive astrocytosis continued to increase and peaked at P90. Brain immunoblots showed increased phospho-mTOR and decreased phospho-GSK3-beta by P14. After fasting, the mature Glut-1(+/-) females showed a trend towards elevated phospho-GSK3-beta, a possible neuroprotective response. Lithium chloride treatment of human skin fibroblasts from control and Glut-1 DS patients produced a 45% increase in glucose uptake. Brain imaging of mature Glut-1(+/-) mice revealed a significantly decreased hippocampal volume. These subtle immunochemical changes reflect chronic nutrient deficiency during brain development and represent the experimental correlates to the human neurological phenotype associated with Glut-1 DS.
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http://dx.doi.org/10.1016/j.nbd.2009.06.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2929707PMC
October 2009

Longitudinal changes of mtDNA A3243G mutation load and level of functioning in MELAS.

Am J Med Genet A 2009 Feb;149A(4):584-7

Department of Neurology, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.

Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), one of the most common mitochondrial multisystemic diseases, is most commonly associated with an A-to-G transition at nucleotide position 3243 (A3243G) in mitochondrial DNA. We studied 34 individuals harboring the A3243G mutation for up to 7 years; 17 had the full MELAS phenotype and 17 who were classified as "carrier relatives" because they were either asymptomatic or had some symptoms suggestive of mitochondrial disease but no seizures or strokes. Using the sensitive real-time polymerase chain reaction to quantify the A3243G mutation, we confirmed that the percent mutation decreases progressively in DNA isolated from blood: the average percent decrease was 0.5% per year for fully symptomatic patients and 0.2% per year for oligosymptomatic carrier relatives. We also correlated mutant loads with functional status estimated by the Karnofksky score: even though the mutation load decreases, the level of functioning worsens in fully symptomatic patients, whereas the level of functioning of carrier relatives remains largely unchanged. This study suggests that A3243G mutant load in DNA isolated from blood is neither useful for prognosis nor for functional assessment.
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http://dx.doi.org/10.1002/ajmg.a.32703DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2663596PMC
February 2009