Posts Tagged ‘dystonia’

Two brothers with MEPAN Syndrome: A Rare Genetic Disorder

Reporter: Amandeep Kaur

In the early 40s, a married couple named Danny and Nikki, had normal pregnancy and delivered their first child in October 2011.  The couple was elated after the birth of Carson because they were uncertain about even conceiving a baby. Soon after birth, the parents started facing difficulty in feeding the newborn and had some wakeful nights, which they used to called “witching hours”. For initial six months, they were clueless that something was not correct with their infant. Shortly, they found issues in moving ability, sitting, and crawling with Carson. Their next half year went in visiting several behavioral specialists and pediatricians with no conclusion other than a suggestion that there is nothing to panic as children grow at different rates.

Later in early 2013, Caron was detected with cerebral palsy in a local regional center. The diagnosis was based on his disability to talk and delay in motor development. At the same time, Carson had his first MRI which showed no negative results. The parents convinced themselves that their child condition would be solved by therapies and thus started physical and occupational therapies. After two years, the couple gave birth to another boy child named Chase in 2013. Initially, there was nothing wrong with Chase as well. But after nine months, Chase was found to possess the same symptoms of delaying in motor development as his elder brother. It was expected that Chase may also be suffering from cerebral palsy. For around one year both boys went through enormous diagnostic tests starting from karyotyping, metabolic screen tests to diagnostic tests for Fragile X syndrome, lysosomal storage disorders, Friedreich ataxia and spinocerebellar ataxia. Gene panel tests for mitochondrial DNA and Oxidative phosphorylation (OXPHOS) deficiencies were also performed. No conclusion was drawn because each diagnostic test showed the negative results.

Over the years, the condition of boys was deteriorating as their movements became stiffer and ataxic, they were not able to crawl anymore. By the end of 2015, the boys had an MRI which showed some symmetric anomalies in their basal ganglia indicating a metabolic condition. The symptoms of Carson and Chase was not even explained by whole exome sequencing due to the absence of any positive result. The grievous journey of visits to neurologist, diagnostic tests and inconclusive results led the parents to rethink about anything happened erroneous due to them such as due to their lifestyle, insufficient intake of vitamins during pregnancy or exposure to toxic agents which left their sons in that situation.

During the diagnostic odyssey, Danny spent many restless and sleepless nights in searching PubMed for any recent cases with symptoms similar to his sons and eventually came across the NIH’s Undiagnosed Diseases Network (UDN), which gave a light of hope to the demoralized family. As soon as Danny discovered about the NIH’s Diseases Network, he gathered all the medical documents of both his sons and submitted the application. The submitted application in late 2015 got accepted a year later in December 2016 and they got their first appointment in early 2017 at the UDN site at Stanford. At Stanford, the boys had gone through whole-genome sequencing and some series of examinations which came back with inconclusive results. Finally, in February 2018, the family received some conclusive results which explained that the two boys suffer from MEPAN syndrome with pathogenic mutations in MECR gene.

  • MEPAN means Mitochondrial Enoyl CoA reductase Protein-Associated Neurodegeneration
  • MEPAN syndrome is a rare genetic neurological disorder
  • MEPAN syndrome is associated with symptoms of ataxia, optic atrophy and dystonia
  • The wild-type MECR gene encodes a mitochondrial protein which is involved in metabolic processes
  • The prevalence rate of MEPAN syndrome is 1 in 1 million
  • Currently, there are 17 patients of MEPAN syndrome worldwide

The symptoms of Carson and Chase of an early onset of motor development with no appropriate biomarkers and T-2 hyperintensity in the basal ganglia were matching with the seven known MEPAN patient at that time. The agonizing journey of five years concluded with diagnosis of rare genetic disorder.

Despite the advances in genetic testing and their low-cost, there are many families which still suffer and left undiagnostic for long years. To shorten the diagnostic journey of undiagnosed patients, the whole-exome and whole-genome sequencing can be used as a primary tool. There is need of more research to find appropriate treatments of genetic disorders and therapies to reduce the suffering of the patients and families. It is necessary to fill the gap between the researchers and clinicians to stimulate the development in diagnosis, treatment and drug development for rare genetic disorders.

The family started a foundation named “MEPAN Foundation” (https://www.mepan. org) to reach out to the world to educate people about the mutation in MECR gene. By creating awareness among the communities, clinicians, and researchers worldwide, the patients having rare genetic disorder can come closer and share their information to improve their condition and quality of life.

Reference: Danny Miller, The diagnostic odyssey: our family’s story, The American Journal of Human Genetics, Volume 108, Issue 2, 2021, Pages 217-218, ISSN 0002-9297, https://doi.org/10.1016/j.ajhg.2021.01.003 (https://www.sciencedirect.com/science/article/pii/S0002929721000033)




https://www.mepan. org

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Reporter: Aviva Lev-Ari, PhD, RN


Fifty years ago, when the curator of the Boston Medical Library, Henry Viets, collated a score of the most important articles that had been published in the first century and a half of the New England Journal of Medicine, 10 of the 20 related to neurologic conditions. Viets HR. A score of significant papers published in the Journal during the last hundred and fifty years. N Engl J Med 1962;266:23-28

On the occasion of its 200th anniversary, one might ask why so many articles on neurologic and psychiatric diseases have been published in the Journal and what impact these pieces have had on their respective fields. Although the Journal is replete with reports of neurologic conditions that have entered the canon of medicine, it has been the large number and the breadth of clinical trials that have redefined neurology and psychiatry as active, therapeutic specialties. This article reviews the evolution of our understanding of neurologic and psychiatric conditions during the past two centuries.

Modern scientific neurology, based on neuropathology and neurophysiology, began after World War II. By 1952, patients with tabes dorsalis and general paresis had practically disappeared from hospital wards. Antimicrobial agents had changed the course of bacterial and tuberculous meningitis, but poliomyelitis was still a nemesis. Denny-Brown‘s Shattuck Lecture on the state of neurology that year in the Journal pronounced that, freed from its preoccupation with syphilology and now separating itself from internal medicine and psychiatry, neurology had “entered on an extremely productive and virile phase.” Denny-Brown DE. The changing pattern of neurologic medicine. N Engl J Med1952;246:839-846

Denny-Brown emphasized recent contributions on the neurologic aspects of liver failure, the recognition that transient ischemic attacks were due to occlusion of the carotid artery, and the emerging understanding of increased intracranial pressure. There was little question at the time that neurologic and psychiatric diseases both acted on the same brain, but Denny-Brown’s position in his Shattuck Lecture marked the emergence of American neurology, pointedly disengaging it from the popular practice of neuropsychiatry and aligning it with internal medicine. He provided a modern manifesto for neurology, which nonetheless remained largely an elegant diagnostic specialty.


A seemingly mundane clinical neurology article in the pages of the Journal had a highly felicitous effect on the relief of human suffering by addressing the problem of sciatica. That 1934 report by Mixter and Barr

Mixter WJ, Barr JS. Rupture of the intervertebral disc with involvement of the spinal canal. N Engl J Med 1934;211:210-215 established intervertebral disk rupture with nerve-root compression as the mechanism and also provided a remarkably sophisticated analysis of cervical-disk herniation and cord compression. It presented detailed instructions for the cure — in both instances, laminectomy. Twelve terse pages provided meticulous clinical descriptions and drawings of the corrective operation (Figure 1FIGURE 1Mixter and Barr’s Descriptions and Operation for Disk Rupture.). The enduring impact of that article, as well as the continuity of attention to this topic in the Journal, was affirmed by a 2007 report on a clinical trial that showed the superiority of surgery over conservative management. Peul WC, van Houwelingen HC, van den Hout WB, et al. Surgery versus prolonged conservative treatment for sciatica. N Engl J Med 2007;356:2245-2256

The excess of ill-advised laminectomies for back pain that followed Mixter and Barr’s article was not their doing; in a less frequently cited but more detailed contribution published in the Journal 6 years after their first report, they state, “We wish to emphasize at this point that a large proportion of the cases of sciatica resolve spontaneously or under conservative orthopedic treatment.” Mixter WJ, Barr JS. Protrusion of the lower lumbar intervertebral disks. N Engl J Med1940;223:523-529

Second article, An influential article in psychiatry from the New England Journal of Medicine with vast secular influence was “Neurasthenia, or Nervous Exhaustion” by George Beard, published in 1869. Beard G. Neurasthenia, or nervous exhaustion. Boston Med Surg J 1869;80:217-221

He spoke of “a condition of the system that is, perhaps, more frequently than any other in our time at least, the cause and effect of disease. . . . Both anemia and neurasthenia are most frequently met with in civilized intellectual communities. They are part of the compensation for our progress and refinement.” Beard G. Neurasthenia, or nervous exhaustion. Boston Med Surg J 1869;80:217-221

The use of the label “neurasthenia,” and probably its reported incidence, expanded greatly after Beard’s article appeared. It was called the “American disease” by the illustrious French neurologist, J.-M. Charcot, who took it up for study as a strictly neurologic condition. By medicalizing the misfortunes of life, for which care is still so frequently sought, physicians became comfortable invoking a patient’s constitutional makeup, as if it were a physical entity, as the substrate for exhaustion, melancholia, depression, discouragement, weakness, and headache.


Some topics in every field turn out to be fraught with specious ideas, and neurology and psychiatry have grappled with many of them. We cannot know whether the absence of articles on phrenology in BMSJ was an implicit message or whether it was a reflection of Boston’s medical orthodoxy. Many positive reports of magnetism applied to nervous conditions and endorsements of autointoxication as the cause of mental diseases were, however, published in the Journal. Briggs LV. A consideration of auto-intoxication and auto-infection as cause of various mental disorders. Boston Med Surg J 1905;152:1-5, 36

Most of these quaint notions simply reflected the medical ideologies of the time. For an example of early continuity of subject matter regarding the nerves that has appeared in the Journal one has only to look at Brown-Séquard’s work on electrical activity of the nervous system and J.C. Warren’s derisive article “Animal Magnetism,” stating that the concept, “which some thirty years ago excited great attention . . . has since been viewed as one of the remarkable impositions on the credulity of mankind.” Warren JC. Animal magnetism. Boston Med Surg J 1814;3:40-46

But the use of electricity for brain disorders is now again invoked through the technology of deep-brain stimulation. Escaping from the stigma of psychosurgery, articles in the Journal have expanded the application of deep-brain stimulation well beyond its usual use in Parkinson’s disease and found substantiation for its use in intractable obsessive–compulsive disorder. Mallet L, Polosan M, Jaafari N, et al. Subthalamic nucleus stimulation in severe obsessive-compulsive disorder. N Engl J Med 2008;359:2121-2134[Erratum, N Engl J Med 2009;361:1027.] and in dystonia. Kupsch A, Benecke R, Muller J, et al. Pallidal deep-brain stimulation in primary generalized or segmental dystonia. N Engl J Med 2006;355:1978-1990 and Vidailhet M, Vercueil L, Houeto JL, et al. Bilateral deep brain stimulation of the globus pallidus in primary generalized dystonia. N Engl J Med 2005;352:459-467

When psychodynamic systems that attributed mental diseases to unconscious conflicts were popularized in the mid-20th century, there was a conspicuous absence of articles about them in theJournal. The exception was psychosomatic medicine. In a 1948 article in the Journal, A.O. Ludwig wrote that “emotional influences acting over longer or shorter periods result at first in disturbed physiology and eventually in structural change. Peptic ulcer is the simplest example . . . [u]lcerative colitis . . . asthma, hay fever and urticaria, certain skin diseases, such as eczema and neurodermatitis, migraine, possibly certain cases of epilepsy; hypertension and rheumatoid arthritis.” Ludwig AO. The practical importance of modern concepts of psychosomatic relations. N Engl J Med 1948;238:175-178. Concerning much of 20th-century psychiatry, including psychoanalysis, however, the Journal spoke through its silence. With the ascent of biologic psychiatry in the first decade of the 21st century, large pragmatic “efficacy” trials identified by their acronyms have appeared in the pages of the Journal — for depression (STAR*D), Trivedi MH, Fava M, Wisniewski SR, et al. Medication augmentation after the failure of SSRIs for depression. N Engl J Med 2006;354:1243-1252 psychosis (CATIE), Lieberman JA, Stroup TS, McEvoy JP, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 2005;353:1209-1223[Erratum, N Engl J Med 2010;363:1092-3.] and dementia (CATIE-AD). Schneider LS, Tariot PN, Dagerman KS, et al. Effectiveness of atypical antipsychotic drugs in patients with Alzheimer’s disease. N Engl J Med 2006;355:1525-1538

These studies affirm the value but expose the shortcomings and risks of medical treatment for mental conditions and suggest that the field may have moved a bit too far, as in a quip by the late Leon Eisenberg, from “brainlessness to mindlessness.” Eisenberg L. Mindlessness and brainlessness in psychiatry. Br J Psychiatry 1986;148:497-508

These articles about psychiatry published in the Journal are influencing that field, as other articles have in neurology and neurosurgery, bringing the study of mental life and its diseases back into contemporary medicine and thereby rejoining the specialties of the brain.

For 200 years, the Journal has seen neurology and psychiatry evolve from a European to an international scope, from an emphasis on diagnosis to an emphasis on treatment, and has published many of the fundamental descriptions of nervous and mental diseases while cultivating a new and potent therapeutic course. One would expect the next 100 years to bring a new outlook on diseases of the nervous system that is based on fundamental biology, but the need for keen observation of the individual patient is not likely to be supplanted.

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