Paroxysmal eye–head movements in Glut1 deficiency syndrome

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 &lt;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.</jats:sec

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

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

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

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

The North American mitochondrial disease registry

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