MRI Features Predictive of Aicardi-Goutieres Syndrome 8

PEDIATRIC NEUROLOGY BRIEFS A MONTHLY JOURNAL REVIEW

Vol. 29, No. 1 January 2015

Editor EDITORIAL John J. Millichap, MD 2015 Relaunch as Open Access Pediatric Neurology Briefs 2 Founding Editor John J. Millichap, MD and J. Gordon Millichap, MD Pediatr Neurol Briefs 2015;29(1):2. http://dx.doi.org/10.15844/pedneurbriefs-29-1-1 J. Gordon Millichap, MD

Editorial Advisory Board SEIZURE DISORDERS Leon G. Epstein, MD Ketogenic Diet as Preferred Treatment of Fires 3 Douglas R. Nordli, Jr., MD John J. Millichap, MD and J. Gordon Millichap, MD Pediatr Neurol Briefs 2015;29(1):3. http://dx.doi.org/10.15844/pedneurbriefs-29-1-2 Contributing Editors Nancy L. Kuntz, MD Remission of Childhood-onset Epilepsy 4 Vamshi K. Rao, MD Jena M. Krueger, MD and Douglas R. Nordli, Jr., MD Charles N. Swisher, MD Pediatr Neurol Briefs 2015;29(1):4. http://dx.doi.org/10.15844/pedneurbriefs-29-1-3

MUSCLE DISORDERS Delay in Diagnosis of Duchenne Muscular Dystrophy 5 Vamshi K. Rao, MD and Nancy L. Kuntz, MD Pediatr Neurol Briefs 2015;29(1):5. http://dx.doi.org/10.15844/pedneurbriefs-29-1-4

METABOLIC DISORDERS Fatty Acyl-CoA Reductase 1 Deficiency 6 Charles N. Swisher, MD Pediatr Neurol Briefs 2015;29(1):6. http://dx.doi.org/10.15844/pedneurbriefs-29-1-5

HEADACHE DISORDERS Cyclic AMP Accumulation in Migraine Induction 7 Ana B. Chelse, MD and Leon G. Epstein, MD Pediatr Neurol Briefs 2015;29(1):7. http://dx.doi.org/10.15844/pedneurbriefs-29-1-6

HEREDO-DEGENERATIVE DISORDERS

MRI Features Predictive of Aicardi-Goutieres Syndrome 8

CC BY 4.0 | OPEN ACCESS J. Gordon Millichap, MD Pediatr Neurol Briefs 2015;29(1):8. http://dx.doi.org/10.15844/pedneurbriefs-29-1-7

PEDIATRIC NEUROLOGY BRIEFS © 1987-2015, ISSN 1043-3155 (print) 2166-6482 (online), is published monthly by Pediatric Neurology Briefs Publishers, PO Box 11391, Chicago, IL 60611. This work is licensed under the Creative Commons Attribution 4.0 International License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Mission: Pediatric Neurology Briefs is an Open Access (OA) continuing education service designed to expedite and facilitate the review of current scientific information for physicians and other health professionals. Disclaimer: While the information is believed to be true and accurate at publication, neither the authors nor the editors nor the publisher can accept any legal responsibility for any error or omissions. The publisher makes no warranty, express or implied, with respect to the material contained herein. Visit Pediatric Neurology Briefs online : http://www.pediatricneurologybriefs.com. Current Issue DOI: http://dx.doi.org/10.15844/pedneurbriefs-29-1 Vol. 29, No. 1 PEDIATRIC NEUROLOGY BRIEFS January 2015

EDITORIAL

2015 Relaunch as Open Access Pediatric Neurology Briefs

John J. Millichap MD1,2* and J. Gordon Millichap, MD1,2 1Division of Neurology, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL 2Departments of Pediatrics and Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL *Correspondence: Dr. John J. Millichap, E-mail: [email protected]

Keywords: Neurology; Pediatrics; Child Development; Nervous System Diseases; Brain Diseases Pediatric Neurology Briefs (PNB) has been by appropriate supplementary citations. John J. Millichap published monthly since 1987 as a continuing education becomes the journal Editor and is supported by J. Gordon service designed to expedite and facilitate review of current Millichap, as Founding Editor, the Editorial Advisory medical literature concerning pediatric neurology. In 2015, Board, and invited expert Contributing Editors. PNB is relaunched as an open access, peer-reviewed, Despite the changes in editorial structure and journal with an expanded editorial board. PNB has a new distribution, the mission of PNB remains the same: website and content management system capable of “Pediatric Neurology Briefs is a continuing education organizing peer-review and providing improved indexing, service designed to expedite and facilitate the review of DOI assignment, and online full-text article view. current scientific research and advances in child neurology Digitization of back issues, archiving, and inclusion in and related subjects.” The Editors of PNB are indebted to PubMed are future goals. The new online open access PNB the enduring support of subscribers to the print version for aims to reach more physicians, researchers, and other the past 28 years and look forward to the addition of new healthcare providers with highlights of the latest advances in readers of the open access journal. Comments and pediatric neurology and commentaries by specialists in the suggestions from readers are welcome and may be sent to field. the Editor at [email protected]. PNB has reviewed and referenced articles from over 200 journals since inception. So far, PNB consists of Disclosures 28 volumes with greater than 3200 articles, and includes The author(s) have declared that no competing interests exist. 10,000 citations referencing the works of approximately 28,000 scholarly authors. Prior to the advent of the internet, References the Editor periodically compiled and published the PNB 1. Millichap JG, editor. Progress in pediatric neurology. 1st ed. Chicago: Pediatric Neurology Briefs Publishers; 1991. articles in book form with index, according to subject 2. Millichap JG, editor. Progress in pediatric neurology II. 2nd ed. heading and in chronological order [1-3]. Chicago: Pediatric Neurology Briefs Publishers; 1994. In 2012, PNB became available online with the 3. Millichap JG, editor. Progress in pediatric neurology III. 3rd ed. digital edition that was designed and introduced by Gordon Chicago: Pediatric Neurology Briefs Publishers; 1997. T. Millichap, the interim Managing Editor. The new website 4. Krueger JM, Nordli, DR. Remission of Childhood-onset Epilepsy. allowed PNB to become a publishing partner with both the Pediatr Neurol Briefs. 2015;29(1):4. http://dx.doi.org/10.15844/ World Health Organization's HINARI Program and EIFL. pedneurbriefs-29-1-3. These services provide equitable online access to the major 5. Rao VK, Kuntz NL. Delay in Diagnosis of Duchenne Muscular journals in biomedical sciences for eligible not-for-profit Dystrophy. Pediatr Neurol Briefs. 2015;29(1):5. http://dx.doi.org/ 10.15844/pedneurbriefs-29-1-4. health institutions and libraries, making PNB available in 6. Swisher CN. Fatty acyl-CoA reductase 1 deficiency. Pediatr Neurol more than 100 developing countries, benefiting many Briefs. 2015;29(1):6. http://dx.doi.org/10.15844/pedneurbriefs-29-1-5. thousands of health workers and researchers, and in turn, 7. Chelse AB, Epstein LG. Cyclic AMP accumulation in migraine. Pediatr contributing to improve world health. Neurol Briefs. 2015;29(1):7. http://dx.doi.org/10.15844/pedneurbriefs- In 2015, the new editorial board will select articles, 29-1-6. invite authors, and oversee peer-review of all submitted 8. Millichap, JG. MRI features predictive of Aicardi-Goutieres syndrome. articles. Source article criteria include recent publication in Pediatr Neurol Briefs. 2015;29(1):8. http://dx.doi.org/10.15844/ a peer-reviewed journal and a topic of clinical value to pedneurbriefs-29-1-7. practicing pediatric neurologists. PNB covers a comprehensive group of subject areas related to progress in pediatric neurology including, but not limited to, Seizure [4], Muscle [5], Metabolic [6], Headache [7], and Heredo- Degenerative Disorders [8]. Contributing Editors provide detailed summaries of published articles, followed by commentaries based on their experience and corroborated

Pediatric Neurology Briefs 2015;29(1):2. http://dx.doi.org/10.15844/pedneurbriefs-29-1-1 ISSN: 1043-3155 (print) 2166-6482 (online) ©2015 The Author(s). This work is licensed under a Creative Commons Attribution 4.0 International License. 2 Vol. 29, No. 1 PEDIATRIC NEUROLOGY BRIEFS January 2015

SEIZURE DISORDERS

Ketogenic Diet as Preferred Treatment of FIRES

John J. Millichap MD1,2 and J. Gordon Millichap, MD1,2* 1Division of Neurology, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL 2Departments of Pediatrics and Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL *Correspondence: Dr. J. Gordon Millichap, E-mail: [email protected]

Related Article: Singh RK, Joshi SM, Potter DM, Leber SM, Carlson MD, Shellhaas RA. Cognitive outcomes in febrile infectious-related epilepsy syndrome treated with the ketogenic diet. Pediatrics. 2014;134(5):e1431-5. Keywords: Epilepsy; Ketogenic diet; Encephalitis Investigators from the University of Alabama, of polyunsaturated fatty acids (PUFAs), elevated GABA Birmingham, AL, and University of Michigan, Ann Arbor, and decreased glutamate levels in CSF, and effects on MI, report 2 children who presented with FIRES and noradrenergic system, benzodiazepine receptor, glycolysis prolonged AED-resistant status epilepticus. Patient 1 tested and on activated potassium channels (K-ATP). negative for infectious, metabolic, genetic, and autoimmune Compared to antiepileptic drugs, the safety of the etiologies. The EEG showed burst suppression that diet is generally regarded as high. However, the recent transitioned to periodic epileptiform discharges, and a brain increased popularity of the diet has drawn attention to the MRI showed changes consistent with bilateral mesial long-term but reversible effects on blood lipids and arterial sclerosis. Patient 2 EEG showed burst suppression followed function. The use of diets with less fat, such as the modified by temporal seizure foci, and a normal MRI. Infectious, Atkins diet and low glycemic index treatment, is proposed rheumatologic, and autoimmune investigations were as a safer alternative. Discontinuation of the diet after 6 negative. Seizures were treated successfully with the months to 2 years if seizures are controlled should be ketogenic diet (4:1 ratio) in the acute and chronic stages of considered, but a hasty removal of an effective therapy the encephalopathy. Both children were maintained on the based on preliminary adverse data should be discouraged. diet along with AEDs for several months (20 and 18-month follow-up). Their cognitive outcome was moderately Disclosures impaired (IQ 71 and 62) and they returned to school with The author(s) have declared that no competing interests exist. some academic accommodations and an individualized education plan (IEP). Early treatment with the ketogenic References diet is recommended as the preferred treatment for acute and 1. Singh RK, Joshi SM, Potter DM, Leber SM, Carlson MD, Shellhaas RA. Cognitive outcomes in febrile infection-related epilepsy syndrome long-term management of FIRES. [1] treated with the ketogenic diet. Pediatrics. 2014;134(5):e1431-5. http://dx.doi.org/10.1542/peds.2013-3106. PubMed PMID: 25332495. COMMENTARY. Febrile infection-related epilepsy 2. Mikaeloff Y, Jambaque I, Hertz-Pannier L, Zamfirescu A, Adamsbaum syndrome (FIRES) is a pseudo-encephalitic epileptic C, Plouin P, et al. Devastating epileptic encephalopathy in school-aged encephalopathy that presents with drug-resistant status children (DESC): a pseudo encephalitis. Epilepsy Res. 2006;69(1):67- 79. http://dx.doi.org/10.1016/j.eplepsyres.2006.01.002. PubMed PMID: epilepticus in previously healthy school-aged children [2]. 16469483. The underlying pathophysiology is usually undetermined 3. van Baalen A, Hausler M, Plecko-Startinig B, Strautmanis J, Vlaho S, but may be immune-mediated. Treatment with Gebhardt B, et al. Febrile infection-related epilepsy syndrome without anticonvulsants (e.g. phenobarbital, topiramate), detectable autoantibodies and response to immunotherapy: a case series immunoglobulin, steroids, and plasmapheresis) has limited and discussion of epileptogenesis in FIRES. Neuropediatrics. 2012;43(4):209-16. http://dx.doi.org/10.1055/s-0032-1323848. PubMed success [3], and the ketogenic diet is more effective [1]. PMID: 22911482. Numerous theories are advanced for the mechanism of the 4. Bough KJ, Rho JM. Anticonvulsant mechanisms of the ketogenic diet. ketogenic diet but none is proven. The list of proposed Epilepsia. 2007;48(1):43-58. http://dx.doi.org/10.1111/j.1528- mechanisms [4] begins with an anesthetic effect of ketone 1167.2007.00915.x. PubMed PMID: 17241207. bodies and is followed by changes in electrolyte, pH, and 5. Millichap JG, Jones JD, Rudis BP. Mechanism of anticonvulsant action water balance. Studies in the Clinic and in laboratory of ketogenic diet. Studies in animals with experimental seizures and in animals found the anticonvulsant effect of the diet is children with petit mal epilepsy. Am J Dis Child. 1964;107(6):593-604. http://dx.doi.org/10.1001/archpedi.1964.02080060595008. PubMed independent of a respiratory or metabolic acidosis, unrelated PMID: 14133819. to diuresis, and correlated with a negative systemic balance 6. DeVivo DC, Leckie MP, Ferrendelli JS, McDougal DB, Jr. Chronic of sodium and potassium, effects similar to those of ketosis and cerebral metabolism. Ann Neurol. 1978;3(4):331-37. acetazolamide [5]. Subsequent theories include an increase http://dx.doi.org/10.1002/ana.410030410. PubMed PMID: 666275. in cerebral energy reserves with no observed change in brain pH, water content or electrolytes [6], the inhibitory actions

Pediatric Neurology Briefs 2015;29(1):3. http://dx.doi.org/10.15844/pedneurbriefs-29-1-2 ISSN: 1043-3155 (print) 2166-6482 (online) ©2015 The Author(s). This work is licensed under a Creative Commons Attribution 4.0 International License. 3 Vol. 29, No. 1 PEDIATRIC NEUROLOGY BRIEFS January 2015

SEIZURE DISORDERS

Remission of Childhood-onset Epilepsy

Jena M. Krueger MD1,2 and Douglas R. Nordli, Jr., MD1,2* 1Division of Neurology, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL 2Departments of Pediatrics and Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL *Correspondence: Dr. Douglas R. Nordli, Jr., E-mail: [email protected]

Related Article: Berg AT, Rychlik K, Levy SR, Testa FM. Complete remission of childhood-onset epilepsy: stability and prediction over two decades. Brain. 2014;137(Pt 12):3213-22. Keywords: Epilepsy; Epidemiology; Prognosis Investigators from the Ann and Robert H. Lurie reach complete remission and fall in the category of Children’s Hospital of Chicago, Chicago IL and the Yale “resolved” epilepsy [3]. The Tonbridge study reports up to School of Medicine, New Haven, CT have conducted a 80% of patients have resolved epilepsy by 20 years, prospective cohort study of 613 children with newly although this sample is derived from general practitioners diagnosed epilepsy to evaluate the occurrence of complete and may be biased toward a less complicated population remission and predictive factors. Of the 613 patients when compared to other studies. recruited, 516 were followed for greater than 10 years and Despite positive data regarding the resolution of of those, 328 (63.5%) attained complete remission. Of the epilepsy, a review of Dutch, Japanese, and Canadian studies patients that achieved complete remission, 23 (7%) by Camfield and Camfield, in Halifax, Nova Scotia, experienced a relapse while 311 patients remained in illustrates that seizure resolution is not necessarily complete remission at the end of follow up. Relapse was equivalent to a cure, and those in remission may have poor more likely to occur within the first five years. There were lifestyle outcomes [4]. Even patients with recorded normal no relapses reported after 10 years of complete remission. intelligence have lower markers of social outcome Multivariable analysis indicated focal self-limited epilepsy, (including failure to complete high school, pregnancy uncharacterized epilepsy and uncomplicated epilepsy outside of a stable relationship, never in a romantic patients were more likely to achieve complete remission. relationship >3 months, depression or another psychiatric Patient’s with an age of onset equal to or greater than 10 diagnosis, unemployment, living alone and poverty). years or patient’s with early school or developmental Further research will be needed in the future to problems were less likely to achieve complete remission. determine if early epilepsy factors can be modified to Remission achieved by 2 years after onset was associated improve long term outcomes, including seizure resolution with a higher probability of complete remission, while late and lifestyle outcomes. relapse or pharmacoresistance decreased the chances of complete remission. When patients were divided into Disclosures uncomplicated (normal neurological and imaging exams, The author(s) have declared that no competing interests exist. absence of clear intellectual disability and no identified insult or condition to which epilepsy could be ascribed to) References and complicated (one or more of the previously listed 1. Berg AT, Rychlik K, Levy SR, Testa FM. Complete remission of childhood-onset epilepsy: stability and prediction over two decades. factors) categories, older age of onset remained a risk factor Brain. 2014;137(Pt 12):3213-22. http://dx.doi.org/ to decrease the chance of complete remission in both 10.1093/brain/awu294. PubMed PMID: 25338950; PubMed Central groups. In addition, in uncomplicated patients, early school PMCID: PMC4240301. problems or developmental delays and a family history of 2. Fisher RS, Acevedo C, Arzimanoglou A, Bogacz A, Cross JH, Elger CE, epilepsy were found to decrease the chance of achieving et al. ILAE official report: a practical clinical definition of epilepsy. Epilepsia. 2014;55(4):475-82. http://dx.doi.org/10.1111/epi.12550. complete remission. In the complicated group, imaging PubMed PMID: 24730690. abnormalities and intellectual disabilities were found to 3. Shorvon SD, Goodridge DM. Longitudinal cohort studies of the decrease the chance of complete remission. [1] prognosis of epilepsy: contribution of the National General Practice Study of Epilepsy and other studies. Brain. 2013;136(Pt 11):3497-510. COMMENTARY. The International League Against http://dx.doi.org/10.1093/brain/awt223. PubMed PMID: 24067241. Epilepsy has delineated epilepsy as “resolved” after seizure 4. Camfield PR, Camfield CS. What happens to children with epilepsy freedom for 10 years, with at least 5 years off medication in when they become adults? Some facts and opinions. Pediatr Neurol. 2014;51(1):17-23. http://dx.doi.org/10.1016/j.pediatrneurol.2014.02.020. an official report in January 2014 [2]. Multiple studies, PubMed PMID: 24830766. including the Mayo Clinic Record Linkage Study, the British Tonbridge Study and the National General Practice Study of Epilepsy have noted that over half of children will

Pediatric Neurology Briefs 2015;29(1):4. http://dx.doi.org/10.15844/pedneurbriefs-29-1-3 ISSN: 1043-3155 (print) 2166-6482 (online) ©2015 The Author(s). This work is licensed under a Creative Commons Attribution 4.0 International License. 4 Vol. 29, No. 1 PEDIATRIC NEUROLOGY BRIEFS January 2015

MUSCLE DISORDERS

Delay in Diagnosis of Duchenne Muscular Dystrophy

Vamshi K. Rao, MD1 and Nancy L. Kuntz, MD 2,3* 1Division of Neurology, Department of Pediatrics, University of Nebraska Medical Center, Omaha, NE 2Division of Neurology, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL 3Departments of Pediatrics and Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL *Correspondence: Dr. Nancy L. Kuntz, E-mail: [email protected]

Related Article: Mirski KT, Crawford TO. Motor and cognitive delay in Duchenne muscular dystrophy: implication for early diagnosis. J Pediatr. 2014. Epub 2014/08/26. Keywords: Muscular Dystrophy; Developmental Delay; Diagnosis Investigators from Johns Hopkins Hospital, minimal frequency of intellectual impairment is noted [5]. Baltimore, MD, retrospectively reviewed 179 records of Determining factor for cognitive abnormalities in DMD patients with Duchenne muscular dystrophy (DMD) seems to be a differential cumulative loss of brain expressed evaluated between 1989 and 2012. Diagnosis was confirmed isoforms determined by mutation patterns in the gene that by genetic testing or muscle biopsy, and clinical data were seem to localize to a yet unknown glial role of brain complete in 107 patients. Cognitive delay (special education dystrophin. placement or delay in grade progression during primary There is ample evidence to suggest that the school) was present in 45%, and a delay in walking (after presence of dystrophin in the skeletal muscle and brain in the 16th month) in 42%. Cognitive delay and delay in DMD is associated with delay in walking and cognitive walking were strongly associated (P<.0001). The severity of impairments. There are ongoing studies to ascertain a the motor phenotype assessed by age of lost independent specific genotype-phenotype correlation for the known ambulation was not associated with delay in walking or mutations with respect to walking and cognitive delays. In cognitive impairment. The mean age of lost independent the interim, until newborn screening is in place for DMD, a ambulation was 10.9 years. The age of diagnosis for this simple laboratory test such as CK for all children with cohort was not related to delay in walking or cognitive delayed walking (at least >16 months) and cognitive status. The mean age of diagnosis was 5.1 +/- 2 years. impairment will lead to early diagnosis, symptom Neither the age of lost independent ambulation nor the age management and with currently promising clinical trials, a of diagnosis was associated with age of walking. A subject treatment. with DMD who walked at or after 16 months of age had three times the risk of also progressing more slowly in Disclosures school. DMD should be considered in the differential The author(s) have declared that no competing interests exist. diagnosis of global developmental delay. Age of walking is influenced more by cognitive delay than by motor References phenotype. Earlier diagnosis may be possible. Serum 1. Mirski KT, Crawford TO. Motor and cognitive delay in Duchenne muscular dystrophy: implication for early diagnosis. J Pediatr.2014. Epub creatine kinase (CK) should be considered for any preschool 2014/08/26. http://dx.doi.org/10.1016/j.jpeds.2014.07.006. PubMed PMID: boy who begins to walk later than 16 months of age. [1] 25149498. 2. Anderson JL, Head SI, Rae C, Morley JW. Brain function in Duchenne COMMENTARY. DMD is a disorder of progressive muscle muscular dystrophy. Brain. 2002;125(Pt 1):4-13. http://dx.doi.org/ weakness due to a mutation in the dystrophin gene leading 10.1093/brain/awf012. PubMed PMID: 11834588. to an absence of the dystrophin protein. In the muscle, 3. Cotton S, Voudouris NJ, Greenwood KM. Intelligence and Duchenne muscular dystrophy: full scale, verbal, and performance intelligence dystrophin protein is a part of a complex that anchors the quotients. Dev Med Child Neurol. 2001;23:497-501. muscle cytoskeleton to the extracellular framework that http://dx.doi.org/10.1111/j.1469-8749.2001.tb00750.x. PubMed PMID: resists mechanical stress thereby preventing injury. In the 11463183. brain, possibly a signaling role predominates with presence 4. Hendriksen JG, Vles JS. Neuropsychiatric disorders in males with of the full length dystrophin isoforms in the GABAergic duchenne muscular dystrophy: frequency rate of attention-deficit synapses in the cortex, hippocampus and cerebellum [2] and hyperactivity disorder (ADHD), autism spectrum disorder, and obsessive-- compulsive disorder. J Child Neurol. 2008;23(5):477-81. short isoforms localizing to the glia. Impaired full scale, http://dx.doi.org/10.1177/0883073807309775. PubMed PMID: 18354150. verbal and performance intelligence quotients have been 5. Taylor PJ, Betts GA, Maroulis S, Gilissen C, Pedersen RL, Mowat DR, noted in large cohorts of DMD patients [3] along with et al. Dystrophin gene mutation location and the risk of cognitive comorbid psychiatric disorders such as ADHD (11-20%), impairment in Duchenne muscular dystrophy. PloS one. 2010;5(1):e8803. Autism spectrum disorder (3-4%) and OCD (5-60%) [4]. http://dx.doi.org/10.1371/journal.pone.0008803. PubMed PMID: 20098710; PubMed Central PMCID: PMC2808359. Mutations affecting short isoforms contribute to more cognitive delay than full-length isoforms where only a Pediatric Neurology Briefs 2015;29(1):5. http://dx.doi.org/10.15844/pedneurbriefs-29-1-4 ISSN: 1043-3155 (print) 2166-6482 (online) ©2015 The Author(s). This work is licensed under a Creative Commons Attribution 4.0 International License. 5

Vol. 29, No. 1 PEDIATRIC NEUROLOGY BRIEFS January 2015

METABOLIC DISORDERS

Fatty Acyl-CoA Reductase 1 Deficiency

Charles N. Swisher, MD1,2* 1Division of Neurology, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL 2Departments of Pediatrics and Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL *Correspondence: Dr. Charles N. Swisher, E-mail: [email protected]

Related Article: Buchert R, Tawamie H, Smith C, Uebe S, Innes AM, Al Hallak B, et al. A peroxisomal disorder of severe intellectual disability, epilepsy, and cataracts due to fatty acyl-CoA reductase 1 deficiency. Am J Hum Genet. 95(5):602-10. Keywords: Peroxisomal disorder; Fatty Acyl-CoA Reductase 1; Developmental delay Investigators from Erlangen, Germany; Calgary, References CA; and Kafranbel, Syria, identified mutations in the gene, 1. Buchert R, Tawamie H, Smith C, Uebe S, Innes AM, Al Hallak B, et al. fatty acyl-CoA reductase 1 (FAR1) deficiency, adding to A peroxisomal disorder of severe intellectual disability, epilepsy, and cataracts due to fatty acyl-CoA reductase 1 deficiency. Am J Hum three other genes involved in plasmalogen biosynthesis, in Genet. 95(5):602-10. http://dx.doi.org/10.1016/j.ajhg.2014.10.003. two families affected by severe intellectual disability, early- 2. Roscher AA, Hoefler S, Hoefler G, Paschke E, Paltauf F, Moser A, et al. onset epilepsy, microcephaly, congenital cataracts, growth Genetic and phenotypic heterogeneity in disorders of peroxisome retardation, and spasticity. Exome analyses revealed a biogenesis--a complementation study involving cell lines from 19 homozygous in-frame indel mutation in two siblings from a patients. Pediatr Res. 1989;26(1):67-72. http://dx.doi.org/10.1203/ 00006450-198907000-00019. PubMed PMID: 2475849. consanguineous family and compound-heterozygous 3. O'Rahilly S. Human genetics illuminates the paths to metabolic disease. mutations in a third unrelated individual. FAR1 reduces Nature. 2009;462(7271):307-14. http://dx.doi.org/10.1038/nature08532. fatty acids to their respective fatty alcohols for the PubMed PMID: 19924209. plasmalogen-biosynthesis pathway. All three mutations abolished the reductase activity of FAR1. The spectrum of clinical features associated with defects in plasmalogen biosynthesis is expanded to include FAR1 deficiency as a cause of syndromic severe intellectual disability with cataracts, epilepsy, and growth retardation but without rhizomelia. Mutations in PEX7, GNPAT, and AGPS are the genes previously described in individuals with rhizomelic chondrodysplasia punctata (RCDP). Defects in plasmalogen-biosynthesis lead to low levels of plasmalogens and to symptoms of RCDP. An increasing number of genetic disorders are recognized that result from defects in peroxisomal biogenesis (eg, Zellweger syndrome). [1]

COMMENTARY. We have come a long way from Garrod’s “one gene, one enzyme” hypothesis regarding metabolic genetic disorders in 1909 and our present explorations of the ever-expanding geography and biochemical intricacy of the genome. Buchert et al. have expanded the etiological spectrum of one of the peroxisomal disorders, namely RCDP, which had formerly been associated with abnormalities in one of three genes to include the gene FAR1, which spares the skeletal system but is associated with severe intellectual disability seen in other forms. The teasing out of clinical findings based on the biochemical activity of specific genes is a quest for many geneticists today, and one elegantly demonstrated in this study. [2,3]

Disclosures The author(s) have declared that no competing interests exist.

Pediatric Neurology Briefs 2015;29(1):6. http://dx.doi.org/10.15844/pedneurbriefs-29-1-5 ISSN: 1043-3155 (print) 2166-6482 (online) ©2015 The Author(s). This work is licensed under a Creative Commons Attribution 4.0 International License. 6 Vol. 29, No. 1 PEDIATRIC NEUROLOGY BRIEFS January 2015

HEADACHE DISORDERS

Cyclic AMP Accumulation in Migraine Induction

Ana B. Chelse, MD1,2 and Leon G. Epstein, MD1,2* 1Division of Neurology, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL 2Departments of Pediatrics and Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL *Correspondence: Dr. Leon G. Epstein, E-mail: [email protected]

Related Article: Guo S, Olesen J, Ashina M. Phosphodiesterase 3 inhibitor cilostazol induces migraine-like attacks via cyclic AMP increase. Brain. 2014;137(Pt 11):2951-9. Keywords: Migraine; Headache; Cyclic adenosine monophosphate Investigators from Danish Headache Centre, The current study added to this knowledge by showing that Glostrup Hospital, and the University of Copenhagen cilostazol causes an accumulation of cAMP in humans and investigated whether intracellular cyclic AMP accumulation induces migraine attacks. Activation of cAMP-selective induced migraine attacks among 14 migraine patients phosphodeisterases (PDE3 or PDE5) should be considered without aura. Patients either received placebo or cilostazol, as a possible new target in migraine treatment. a selective inhibitor of phosphodeisterase type 3 (PDE3) which prohibits the breakdown of cyclic AMP (cAMP). Disclosures Patients were instructed to record their headache symptoms, The author(s) have declared that no competing interests exist. localization and characteristics by a self-administered questionnaire every hour until 13h post-administration. References Twelve of 14 patients (86%) developed migraine-like 1. Guo S, Olesen J, Ashina M. Phosphodiesterase 3 inhibitor cilostazol induces migraine-like attacks via cyclic AMP increase. Brain. attacks after cilostazol compared with two patients (14%) 2014;137(Pt 11):2951-9. http://dx.doi.org/10.1093/brain/awu244. after placebo. The median time to migraine onset was 6h PubMed PMID: 25161294. post cilostazol (range 3-11). Eleven of 14 (79%) took rescue 2. Kruuse C, Thomsen LL, Birk S, Olesen J. Migraine can be induced by medication cilostazol and 2 (14%) after placebo (P = 0.003). sildenafil without changes in middle cerebral artery diameter. Brain. The headaches induced were similar to their usual migraines 2003;126(Pt 1):241-7. http://dx.doi.org/10.1093/brain/awg009. PubMed PMID: 12477710. and were effectively aborted by their usual migraine 3. Lassen LH, Haderslev PA, Jacobsen VB, Iversen HK, Sperling B, treatment. Nausea was significantly different between the Olesen J. CGRP may play a causative role in migraine. Cephalalgia : an two groups (P = 0.027). Photo- and phonophobia were not international journal of headache. 2002;22(1):54-61. http://dx.doi.org/ significantly different between groups. The authors suggest 10.1046/j.1468-2982.2002.00310.x. PubMed PMID: 11993614. that the intracellular accumulation of cyclic AMP induces 4. Nordgaard JC, Kruse LS, Moller M, Kruuse C. Phosphodiesterases 3 migraine attacks, which furthers our understanding of the and 5 express activity in the trigeminal ganglion and co-localize with migraine pathophysiology. [1] calcitonin gene-related peptide. Cephalalgia : an international journal of headache. 2013;34(7):503-13. http://dx.doi.org/10.1177/033310241351 5345. PubMed PMID: 24322481. COMMENTARY. The initiating mechanisms of migraine attacks are complex and not fully understood. Human experimental migraine models have led to increased knowledge in understanding the migraine pathway. Nitric oxide (NO) has been well established to cause migraines. Studies in healthy volunteers and migraine patients with sildenafil, a highly selective inhibitor of phosphodiesterase type 5 (PDE5) showed that cyclic guanosine monophosphate (cGMP) and cAMP are likely mediator of headache responses elicited by NO [2]. Calcitonin gene- related peptide (CGRP), an endogenous neuropeptide, has also been shown to play a role in migraine attack [3]. CGRP’s vascular effects are also mediated by an increase in cAMP. Prior research showed that PDE3A and PDE5A are each present in the trigeminal ganglion of rats [4]. This work also suggested a link between the cAMP and cGMP pathways in migraine induction. Sildenafil and cilostazol were shown to cause an inhibition of cAMP hydrolysis in the rat trigeminal ganglion through inhibition of PDE3 [4].

Pediatric Neurology Briefs 2015;29(1):7. http://dx.doi.org/10.15844/pedneurbriefs-29-1-6 ISSN: 1043-3155 (print) 2166-6482 (online) ©2015 The Author(s). This work is licensed under a Creative Commons Attribution 4.0 International License. 7 Vol. 29, No. 1 PEDIATRIC NEUROLOGY BRIEFS January 2015

HEREDO-DEGENERATIVE DISORDERS

MRI Features Predictive of Aicardi-Goutieres Syndrome

J. Gordon Millichap, MD1,2* 1Division of Neurology, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL 2Departments of Pediatrics and Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL *Correspondence: Dr. J. Gordon Millichap, E-mail: [email protected]

Related Article: Vanderver A, Prust M, Kadom N, Demarest S, Crow YJ, Helman G, et al. Early-onset Aicardi-Goutieres syndrome: magnetic resonance imaging (MRI) pattern recognition. J Child Neurol. 2014. Epub 2014/12/24. Keywords: Pediatric neuroradiology; Leukodystrophies; Aicardi-Goutières syndrome Investigators from Children’s National Health and a leukoencephalopathy that markedly improved during System Washington, DC, USA: Harvard University, Boston, follow-up and showed resolution of the white matter USA; Leeds Teaching Hospitals, UK; and other abnormalities [4]. international centers review a series of patients with MRIs A-G syndrome is distinguished from Aicardi selected from IRB-approved leukodystrophy biorepositories syndrome. Aicardi syndrome is characterized by agenesis of to identify MRI patterns for recognition of early-onset the corpus callosum, infantile spasms, and chorioretinal Aicardi-Goutieres (A-G) syndrome and scored for a panel of lacunae [5]. Aicardi syndrome affects mainly girls, and is radiologic predictors. MRI features for pattern recognition rare and usually fatal in XXY males [6]. of A-G syndrome are temporal lobe swelling follow-ed by atrophy with temporal horn dilatation, early global cerebral Disclosures atrophy and visible calcifications (94.44% cases of A-G The author(s) have declared that no competing interests exist. syndrome correctly identified with a sensitivity of 90.9% and specificity of 96.9%). The panel of MRI features References predictive of A-G syndrome in young patients (mean age 1. Vanderver A, Prust M, Kadom N, Demarest S, Crow YJ, Helman G, et al. Early-onset Aicardi-Goutieres syndrome: magnetic resonance 1.2 years) differentiates it from other leukodystrophies such imaging (MRI) pattern recognition. J Child Neurol. 2014. Epub as Alexander disease, cytomegalovirus or rubella, 2014/12/24. http://dx.doi.org/10.1177/0883073814562252. PubMed Fukuyama congenital muscular dystrophy, and Walker- PMID: 25535058. Warburg syndrome. An algorithm of early infantile 2. Aicardi J, Goutieres F. A progressive familial encephalopathy in infancy leukodystrophies with and without temporal lobe swelling with calcifications of the basal ganglia and chronic cerebrospinal fluid lymphocytosis. Ann Neurol. 1984;15(1):49-54. http://dx.doi.org/ or temporal lobe dilation and cysts shows the differentiation 10.1002/ana.410150109. PubMed PMID: 6712192. of A-G syndrome from other leukodystrophies based on 3. Stephenson JB. Aicardi-Goutieres syndrome (AGS). Eur J Paediatr MRI analyses. These diseases have slightly different typical Neurol. 2008;12(5):355-8. http://dx.doi.org/10.1016/j.ejpn.2007.11.010. ages of onset versus A-G, and therefore slightly different PubMed PMID: 18343173. ages of available MRI studies. A predominance of patients 4. La Piana R, Tran LT, Guerrero K, Brais B, Levesque S, Sebire G, et al. with A-G syndrome in this study had mutations in TREX1. Spastic paraparesis and marked improvement of leukoencephalopathy in [1] aicardi-goutieres syndrome. Neuropediatrics. 2014;45(6):406-10. http://dx.doi.org/10.1055/s-0034-1393710. PubMed PMID: 25343331.

5. Aicardi J, Lefebvre J. A new syndrome, spasm in flexion, callosal COMMENTARY. Aicardi-Goutieres (A-G) syndrome [2] is agenesis, ocular abnormalities [abstract]. In: Lairy GC, editor. Société an inherited leukoencephalopathy caused by mutations in d'électroencéphalographie et de neurophysiologie clinique de langue one of five genes, including TREX1 and SAMHD1, and française: Paris, December 1–2, 1964. Electroen Clin Neuro. resulting in a phenotype of CSF chronic lymphocytosis, 1965;19(6):606-12. http://dx.doi.org/10.1016/0013-4694(65)90247-6. increased CSF alpha interferon, and a calcifying 6. Millichap JG. A. Neurological Syndromes. New York: Springer; 2013. p. 1-8. http://dx.doi.org/10.1007/978-1-4614-7786-0_1. microangiopathy with abnormal CNS white matter. Autoimmune disorders such as chilblains (pernio) are associated. Classically, the diagnosis of A-G syndrome is suspected when calcifications are identified by CT scan, but with increased availability and high specificity of the MRI, the CT is no longer essential. The disease is rapidly fatal or progresses to a vegetative state. A-G syndrome is both genetically and phenotypically heterogeneous, with a range of severity from life-threatening perinatal illness to mild late infancy onset [3]. An atypical patient is reported with late- onset A-G syndrome, characterized by spastic paraparesis

Pediatric Neurology Briefs 2015;29(1):8. http://dx.doi.org/10.15844/pedneurbriefs-29-1-7 ISSN: 1043-3155 (print) 2166-6482 (online) ©2015 The Author(s). This work is licensed under a Creative Commons Attribution 4.0 International License. 8