Approach to Neurometabolic Diseases from a Pediatric Neurological Point of View

How to Cite This Article: Karimzadeh P. Approach to Neurometabolic Diseases from a Pediatric Neurological Point of View. Iran J Child Neurol. 2015 Winter;9(1): 1-16. AbstractObjectiveNeurometabolic disorders are an important group of diseases that mostly arepresented in newborns and infants.Neurological manifestations are the prominent signs and symptoms in this groupof diseases. Seizures are a common sign and are often refractory to antiepileptic drugs in untreated neurometabolic patients.The onset of symptoms for neurometabolic disorders appears after an interval ofnormal or near normal growth and development.Additionally, affected childrenmay fare well until a catabolic crisis occurs.Patients with neurometabolic disorders during metabolic decompensation havesevere clinical presentation, which include poor feeding, vomiting, lethargy,seizures, and loss of consciousness.This symptom is often fatal but severe neurological insult and regression inneurodevelopmental milestones can result as a prominent sign in patients whosurvived.Acute symptoms should be immediately treated regardless of the cause.A number of patients with neurometabolic disorders respond favorably and, insome instances, dramatically respond to treatment.Early detection and early intervention is invaluable in some patients to preventcatabolism and normal or near normal neurodevelopmental milestones.This paper discusses neurometabolic disorders, approaches to this group ofdiseases (from the view of a pediatric neurologist), clinical and neurologicalmanifestations, neuroimaging and electroencephalography findings, earlydetection, and early treatment. ReferencesFiliano JJ. Neurometabolic Disease in the Newborn. ClinPerinatol 33, 2006, 411-479.Van Karnebeek CDM, Stockler S. Treatable inborn errors of metabolism causing intellectual disability: A systematic literature review. Molecular Genetics and Metabolism, 105, 2012, 369-381.Abdel-Salam GMH, Abdel-Kader AA, Effat L, Gouda A, Hindawy A, El-Gammal MA. Clinical, Electroencephalographic (EEG), Neuroradiological and Molecular Correlations in Late-Detected Phenylketonuria (PKU) Patients.Egypt J. Neurol. Psychiat. Neurosurg., 2005, 42(2):391-406.Karimzadeh P, Ahmadabadi F, Jafari N, Shariatmadari F, Nemati H, Ahadi A, KarimiDardashti S, Mirzarahimi M, Dastborhan Z, ZareNoghabi J. Study on MRI Changes in Phenylketonuria in Patients Referred to Mofid Hospital/ Iran. Iran J Child Neurol. 2014 spring 8(2):53-56.Karimzadeh P, Jafari N, Ahmad Abadi F, Jabbedari S, Taghdiri MM, Alaee MR, Ghofrani M, Tonekaboni SH, NejadBiglari H. Propionic Acidemia: Diagnosis and Neuroimaging Findings of This Neurometabolic Disorder. Iran J Child Neurol. 2014 Winter; 8(1):58-61.Ozand PT, Rashed M, Gascon GG, Youssef NG, Harfi H, Rahbeeni Z, et al. Unusual presentations of propionic acidemia. Brain Dev 1994;16(Suppl):46-57 .Karimzadeh P, Jafari N, Jabbehdari S, Taghdiri MM, Nemati H, Saket S, Alaee MR, Ghofrani M, Tonakebni SH. Methylmalonicacidemia: Diagnosis and Neuroimaging Findings of This Neurometabolic Disorder (An Iranian Pediatric Case Series). Iran J Child Neurol. 2013 Summer; 7(3): 63-66.Radmanesh A, Zaman T, Ghanaati H, Molaei S, Robertson RL, ZamaniAA. Methylmalonicacidemia: brain-imaging findings in 52 children and a review of the literature. PediatrRadiol 2008 Oct;38(10):1054-6.Karimzadeh P, Ahmadabadi F, Jafari N, Jabbehdari S, Alaee MR, Ghofrani M, Taghdiri MM, Tonekaboni SH. Biotinidase Deficiency: A Reversible Neurometabolic Disorder (An Iranian Pediatric Case Series). Iran J Child Neurol. 2013 Autumn; 7(4):47- 52.Karimzadeh P, Pirzadeh Z, Ahmadabadi F, Jafari N, Jabbehdari S, Nemati H, Ghofrani M, Taghdiri MM, Tonekaboni SH, Mohammad-Reza Sharbatdaralaei. Glutaricaciduria type 1: diagnosis and neuroimaging findings of this neurometabolic disorder in an Iranian pediatric case series. International Journal of Developmental Disabilities 05/2014; DOI: 10.1179/2047387714Y.0000000039.Bernier FP, Boneh A, Dennett X, Chow CW, Cleary MA, Thorburn DR. Diagnostic criteria for respiratory chain disorders in adults and children. Neurology. 2002;59:1406–11.Wolf NI, Smeitink AM. Mitochondrial disorders: A proposal for consensus diagnostic criteria in infants and children. Neurology. 2002;59:1402–5.Majamaa K, Moilanen JS, Uimonen S, et al. Epidemiology of A3243G, the mutation for mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes: Prevalence of the mutation in an adult population. Am J Hum Genet. 1998;63:447–54.Lamont PJ, Surtees R, Woodward CE, Leonard JV, Wood NW, Harding AE. Clinical and laboratory findings in referrals for mitochondrial DNA analysis. Arch Dis Child, Arch Dis Child. 1998 Jul;79(1):22-7.Ferri R. Neurometabolic Disorders.Arch Neurol. 2005;62:1045-1046.PapettiL, ParisiP, LeuzziV, NardecchiaF, NicitaF, UrsittiF, Marra F, Paolino MC, Spalice A. Metabolic epilepsy: an update. Brain & Development. 2013 Oct;35(9):827-41.Salpietro V, Phadke R, Saggar A, Hargreaves IP, Yates R, Fokoloros C, Mankad K, Hertecant J, Ruggieri M, McCormick D, KinaliM. Zellweger syndrome and secondary mitochondrial myopathy. Eur J Pediatr. 2014 Oct 7 (Article in press).Schulz A, Kohlschütter A. NCL Disorders: Frequent Causes of Childhood Dementia. Iran J Child Neurol.2013 Winter; 7(1):1-8.Jalanko A, Braulke T. Neuronal ceroidlipofuscinoses. Biochim Biophys Acta 2009;1793:697-709.Karimzadeh P, Jafari N, NejadBiglari H, Jabbeh Dari S, Ahmad Abadi F, Alaee MR, Nemati H,  SaketS, Tonekaboni SH, Taghdiri MM, Ghofrani M. GM2-Gangliosidosis (Sandhoff and Tay-Sachs disease): Diagnosis and Neuroimaging Findings(An Iranian Pediatric Case Series). Iran J Child Neurol. 2014 Summer;8(3): 55-60.Vanier MT, Duthel S, Rodriguez-Lafrasse C, et al. Genetic heterogeneity in Niemann-Pick C disease: a study using somatic cell hybridization and linkage analysis. Am J Hum Genet. 1996;58(1):118-125.Vanier MT. Niemann-Pick disease type C. Orphanet J Rare Dis. 2010;5:16.Meikle PJ, Hopwood JJ, Clague AE, et al. Prevalence of lysosomal storage disorders. JAMA. 1999; 281(3):249-254.Patterson MC, Hendriksz CJ, Walterfang M, et al. Recommendations for the diagnosis and management of Niemann-Pick disease type C: an update. Mol Genet Metab. 2012 ;106(3):330-3.Karimzadeh P, Tonekaboni SH, Ashrafi MR, Shafeghati Y, Rezayi A, Salehpour S, Ghofrani M, Taghdiri MM, Rahmanifar A, Zaman T, Aryani O, Shoar BN, Shiva F, Tavasoli A, and Houshmand M. Effects of Miglustat on Stabilization of Neurological Disorder in Niemann-Pick Disease Type C: Iranian Pediatric Case Series.J Child Neurol. 2013 Dec;28(12):1599-606.Gropman A. Imaging of Neurogenetic and Neurometabolic Disorders of childhood.Current Neurology and NeuroscienceReport. 2004. 4:139-146.Youssef-Turki IB, Kraoua I, Smirani S, Mariem K, Rhouma HB, Rouissi A, Gouider-Khouja N. Epilepsy Aspects and EEG Patterns in Neuro-Metabolic Diseases, Journal of Behavioral and Brain Science.2011. 1: 69-74.PapettiL, ParisiP, LeuzziV, Nardecchiac F, NicitaF, UrsittiF, MarraF, PaolinoMC,SpaliceA. Metabolic epilepsy: an update. Brain & Development. Article in press.Nov 2012

Juvenile type of Niemann-Pick type C disease and our study in Iranian NPC patients

How to Cite This Article: Karimzadeh P. Juvenile type of Niemann-Pick type C disease and our study in Iranian NPC patients. Iran J Child Neurol. 201 5 Autumn;9:4(Suppl.1): 5-6.Pls see Pdf.

Diagnostic Criteria For Pediatric Mitochondrial Disorders

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Ethylmalonic Aciduria and Report of One Case from Iran

This condition is due to deficiency in electron transport flavoprotein or electron transport fluvoprotein dehydrogenase.The clinical presentation is characteristic of fatty acid oxidation disorders. This disorder is poor prognostic and death in infancy is common.The central nervous system involving causes neurodevelopmental delay, hypotonia, and head lag. Different type of seizures such as infantile spasm and generalized tonic clonic seizure begin in infancy and become refractory to antiepileptic drugs. Also episodes of status epilepticus are frequent. Neurological exam shows manifestation of upper motor neuron disease including exaggerated deep tendon reflex, ankle clonus and positive Babinski sign.Infectious disease and Intercurrent illnesses may lead to neurological deterioration and coma or death in the first few years of life. Also hemorrhagic episodes, for example, petechiae, ecchymose, hematuria and blood in stool associated with infectious disease is common manifestation.The hematologic investigations show no evidence of abnormalities in clotting and platelet function.The facial features of these patients resemble to each other and are mildly dismorphic. Sometimes the nasal bridge is depressed.Neuroimaging evaluation revealed delayed myelination and frontotemporal atrophy with high T2 intensity in basal ganglia.Acute catabolic state with crises of lactic academia and hypoglycemia are frequent but lactate and pyruvate can remain high between attacks.During attacks lactate level as high as 17 mmol/l and acidosis is more severe with PH values of 7.05 to 7.10.The major metabolic abnormality is high excretion of ethylmalonic acid in the urine.This disorder is transmitted in an autosomal recessive trait and boys and girls have been reported in same family.Ethyl malonicaciduria is lethal during infancy or first few years of life. Treatment with carnitine, vitamin C, vitamin D and riboflavin did not show dramatic effect. Diet with restricted methionine is helpful for decrease excretion of ethylmalonic acid in the urine and decrease the level of serum lactate and pyruvate.Case presentation A 2-year-old boy was referred to author’ clinic for evaluation of neurodevelopmental delay.He was the product of first pregnancy of consanguineous parents born by cesarean section.He had rolling and creeping but did not have the ability of sitting, standing and walking. He could not speak. He had a history of admission for bloody stool after 20 days of birth but hematologic evaluation did not confirm abnormal evidence.Neurological exam showed cerebral hypotonia (hypotonicity with no weight bearing and exaggerated deep tendon reflex). MRI revealed abnormal signal intensity in periventricular white matter and basal ganglia.Routine lab exam and venous blood Gas, ammonia and high performance liquid chromatography were in normal limits. Serum lactate level was mildly elevated.Urine organic acid showed high ethlymalonic acid 2125 mmol/molcreatinine (normal<17), therefore the diagnosis of ethyl malonicacidurai was confirmed.

Pelizaeus-Merzbacher- Disease (PMD) and Pelizaeus-Merzbacher-like disease (PMLD)

How to Cite This Article: Karimzadeh P. Pelizaeus-Merzbacher- Disease (PMD) and Pelizaeus-Merzbacher-like disease (PMLD). Iran J Child Neurol Autumn 2014;8:4 (suppl.1):9-10. Pls see pdf

Fabry Disease (A Kind of Lysosomal Storage Disease)

How to Cite this Article: Karimzadeh P. Fabery Disease (A kind of Lysosomal Storage Disease). Iran J Child Neurol Autumn 2012; 6:4(suppl. 1):6. Pls See PDF

Antiepileptic Drug-Related Adverse Reactions and Factors Influencing These Reactions

How to Cite This Article: Karimzadeh P, Bakrani V. Antiepileptic Drug-Related Adverse Reactions And Factors Influencing These Reactions. Iran J Child Neurol. 2013 Summer; 7(3):23-27. ObjectiveAccording to the basic role of drug side effects in selection ofan appropriate drug, patient compliance and the quality of life inepileptic patients, and forasmuch as new dugs with unknown side effect have been produced and introduced, necessity of this research and similar studies is explained. This study was conducted to evaluate the incidence and clinical characteristics of anti epileptic drug (AED) related adverse reactions in children treated with AEDs.Material & MethodsIn this descriptive study, children less than 14 years old with AEDside effects referred to the Children’s Medical Center and MofidChilderen’s Hospital (Tehran, Iran) were evaluated during 2010-2012.The informations were: sex, age, incriminating drug, type of drug side effect, incubation period, history of drug usage, and patient and family allergy history. Exclusive criterions were age more than 14 years old and reactions due to reasons other than AEDs (Food, bite, non-AEDs, etc.).ResultsA total of 70 patients with AED reaction were enrolled in thisstudy. They included 26 (37%) females and 44 (63 %) males. The maximum rate of incidence was seen at age less than 5 years old. All the patients had cutaneous eruptions that the most common cutaneous drug eruption was maculopapular rash. The incidence of systemic and laboratory adverse events was less than similar studies. The most common culprit was phenobarbital (70%) and the least common was lamotrigine (1.4%).ConclusionIn this study, we found higher rates of drug rash in patients treated with aromatic AEDs and lower rates with non-aromatic AEDs. Various endogenous and environmental factors may influence the propensity to develop these reactions. Refrences1. Blume WT, Lu¨ders HO, Mizrahi E, et al. Glossary of descriptive terminology for ictal semiology: report of the ILAE task force on classification and terminology. Epilepsia 2001; 42: 1212Y1218. 2. Atlas:Epilepsy care in the world 2005.Available at: www.who.int/mental_health/neurology/epilepsy_atlas_introdion.pdf. Accessed October 9, 2010. 3. Noorbala AA, Bagheri Yazdi SA, Yasamy MT, et al. Mental health survey of the adult population in Iran. Br J Psychiatry 2004;184:70Y73. 4. Mohammadi MR, Ghanizadeh A, Davidian H, et al. Prevalence of epilepsy and comorbidity of psychiatric disorders in Iran. Seizure 2006;15:476Y482. 5. McAuley JW, Lott RS. Seizure disorders. In: Koda-Kimble MA, Young LY, Kradjan WA, et al, eds.Applied Therapeutics: The Clinical Use of Drugs. 9th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2008:54-1Y54-38. 6. Perucca E, Beghi E, Dulac O, et al. Assessing risk to benefit ratio in antiepileptic drug therapy. Epilepsy Res 2000; 41: 107Y139. 7. Mansur AT, Pekcan Yasar S, Goktay F. Anticonvulsant hypersensitivity syndrome. Clinical and laboratory features. Int J Dermatol 2008; 47: 1184-9. 8. Bahareh Malekafzali,Franak Najibi, Cutaneous reactions of anticonvulsant drugs, in Jdermatology 2012;47:1. 9. Brandon D. Newell, Maryam Moinfar,_ Anthony J. Mancini,_and Amy Jo Nopper. Retrospective Analysis of 32 Pediatric Patients with Anticonvulsant Hypersensitivity Syndrome   (ACHSS).2009; Pediatric Dermatology 26 : 5; 536–546. 10. Sharma VK, Sethuraman G, kumear B. Cotaneous adverse drug reactions: Clinical pattern and causative agents, A 6 years Series from chandigarh, India. Postgrad Med 2001; 47: 95-9. 11. Sushma M, Noel MV, Ripika MC, Jamef J,.Guido S. Cutaneous adverse drug reactions: A 9 Year Study from a sath Indian hospital. Safety 2005; 14(8): 567-70

Medical Therapy in Childhood Psychocognitive Problems

Objective Neurodevelopmental disability is one of the most common problems of children referred to  Pediatric Neurology Clinics. These children may suffer from speech delay, intellectual deficiency and behavioral disorder. Some patients with neurodevelopomental delay, especially those with intellectual disability and speech problems, have abnormal electroencephalograms, without clinical seizure. It seems that treating these patients with antiepileptic drugs normalizes the EEG, thereby preventing the electrical paroxysmal discharges that could be harmful for the developing brain. Several studies reported the use of Valproate, Lamotrigine and Corticosteroid in suppression of subclinical  epileptiform discharges and improvement of developmental behavioral conditions. condition of children with neurodevelopmental delay and elimination of subclinical EEG discharges after 18 months of treatment. Also we used high dose intravenous methyl - prednisolone in a group of children with neurodevelopmental delay and electrical status epilepticus during slow - wave sleep without clinical seizure. In these children results of the appropriate neuro-metabolic tests and magnetic resonance imaging of the brain revealed no abnormality. Because no underlying etiology could be determined, isolated non convulsive status epilepticus was established. After treatment no significant response was observed in these group of children. In another study we used Lamotrigine in children with neurodevelopmental delay, abnormal epileptiform discharges but without clinical seizures. Our results revealed Lamotrigine provides effective control of both subclinical epileptiform discharges and behavioral disorder, without improvement in their cognition. Further studies are needed to investigate and confirm the cognitive and behavioral effects of Lamotrigine in children with psychomotor retardation. &nbsp

Efficacy of Continuous High Dose Midazolam Infusion in Childhood Refractory Generalized Convulsive Status Epilepticus

ObjeciveProlonged and uncontrolled refractory status epilepticus (SE) is a life-threatening medical emergency in children (1,2,3). There is no consensus on the optimal therapy for refractory status epilepticus (1). The aim of this study was to develop a new method for treating patients with refractory status epilepticus.Materials & MethodsTen children with refractory status epilepticus in Mofid Hospital, who did not respond to 10 μg/kg per min of intravenous midazolam, had their dose of midazolam increased to 30 μg/kg per min. All children were monitored for the development of side effects.ResultsTen children with no response to low-dose midazolam were given a higher dose of midazolam, and 5 (50%) children had a good response. These patients had significantly different response to high-dose midazolam.One patient in the high-dose midazolam group was intubated and required mechanical ventilation. The duration of stay in the hospital and PICU and on mechanical ventilation in patients with no response to low-dose midazolam following with other drugs was longer than in the high-dose midazolam group.No death occurred in high dose midazolam group.ConclusionHigh-midazolam dose drip infusion is a safe and effective protocol for refractory status epilepticus in children.Keywords:Refractory status epilepticus; midazolam; mortality; childhoo