- Mol Genet Metab Rep. 2020 Nov 30;25:100682.
Genetic cause of heterogeneous inherited myopathies in a cohort of Greek patients
Ioannis Zaganas 1 2, Vasilios Mastorodemos 2, Martha Spilioti 3, Lambros Mathioudakis 1, Helen Latsoudis 1, Kleita Michaelidou 1, Dimitra Kotzamani 1, Konstantinos Notas 3, Konstantinos Dimitrakopoulos 4, Irene Skoula 1, Stefanos Ioannidis 2, Eirini Klothaki 2, Sophia Erimaki 5, Georgios Stavropoulos 4, Vassilios Vassilikos 4, Georgios Amoiridis 5, Georgios Efthimiadis 3, Athanasios Evangeliou 6, Panayiotis Mitsias 2 5 7
Inherited muscle disorders are caused by pathogenic changes in numerous genes. Herein, we aimed to investigate the etiology of muscle disease in 24 consecutive Greek patients with myopathy suspected to be genetic in origin, based on clinical presentation and laboratory and electrophysiological findings and absence of known acquired causes of myopathy. Of these, 16 patients (8 females, median 24 years-old, range 7 to 67 years-old) were diagnosed by Whole Exome Sequencing as suffering from a specific type of inherited muscle disorder. Specifically, we have identified causative variants in 6 limb-girdle muscular dystrophy genes (6 patients; ANO5, CAPN3, DYSF, ISPD, LAMA2, SGCA), 3 metabolic myopathy genes (4 patients; CPT2, ETFDH, GAA), 1 congenital myotonia gene (1 patient; CLCN1), 1 mitochondrial myopathy gene (1 patient; MT-TE) and 3 other myopathy-associated genes (4 patients; CAV3, LMNA, MYOT). In 6 additional family members affected by myopathy, we reached genetic diagnosis following identification of a causative variant in an index patient. In our patients, genetic diagnosis ended a lengthy diagnostic process and, in the case of Multiple acyl-CoA dehydrogenase deficiency and Pompe's disease, it enabled specific treatment to be initiated. These results further expand the genotypic and phenotypic spectrum of inherited myopathies.
2. J Inherit Metab Dis . 2021 Jan;44(1):178-192.
Consensus guidelines for the diagnosis and management of pyridoxine-dependent epilepsy due to α-aminoadipic semialdehyde dehydrogenase deficiency
Curtis R Coughlin 2nd 1, Laura A Tseng 2, Jose E Abdenur 3, Catherine Ashmore 4, François Boemer 5, Levinus A Bok 6, Monica Boyer 3, Daniela Buhas 7, Peter T Clayton 8, Anibh Das 9, Hanka Dekker 10, Athanasios Evangeliou 11, François Feillet 12 13, Emma J Footitt 14, Sidney M Gospe Jr 15 16, Hans Hartmann 9, Majdi Kara 17, Erle Kristensen 18, Joy Lee 19, Rina Lilje 20, Nicola Longo 21, Roelineke J Lunsing 22, Philippa Mills 8, Maria T Papadopoulou 11, Phillip L Pearl 23, Flavia Piazzon 24, Barbara Plecko 25, Arushi G Saini 26, Saikat Santra 4, Damayanti R Sjarif 27, Sylvia Stockler-Ipsiroglu 28, Pasquale Striano 29 30, Johan L K Van Hove 1, Nanda M Verhoeven-Duif 31, Frits A Wijburg 2, Sameer M Zuberi 32, Clara D M van Karnebeek 2 33
Pyridoxine-dependent epilepsy (PDE-ALDH7A1) is an autosomal recessive condition due to a deficiency of α-aminoadipic semialdehyde dehydrogenase, which is a key enzyme in lysine oxidation. PDE-ALDH7A1 is a developmental and epileptic encephalopathy that was historically and empirically treated with pharmacologic doses of pyridoxine. Despite adequate seizure control, most patients with PDE-ALDH7A1 were reported to have developmental delay and intellectual disability. To improve outcome, a lysine-restricted diet and competitive inhibition of lysine transport through the use of pharmacologic doses of arginine have been recommended as an adjunct therapy. These lysine-reduction therapies have resulted in improved biochemical parameters and cognitive development in many but not all patients. The goal of these consensus guidelines is to re-evaluate and update the two previously published recommendations for diagnosis, treatment, and follow-up of patients with PDE-ALDH7A1. Members of the International PDE Consortium initiated evidence and consensus-based process to review previous recommendations, new research findings, and relevant clinical aspects of PDE-ALDH7A1. The guideline development group included pediatric neurologists, biochemical geneticists, clinical geneticists, laboratory scientists, and metabolic dieticians representing 29 institutions from 16 countries. Consensus guidelines for the diagnosis and management of patients with PDE-ALDH7A1 are provided.
3 . J Pediatr Endocrinol Metab . 2020 Nov 12;34(1):127-130.
Delayed phenylketonuria diagnosis: a challenging case in child psychiatry
Aspasia E Serdari 1, Christina Zompola 2, Athanasios Evangeliou 3
Objectives: Phenylalanine hydroxylase deficiency is an autosomal recessive inborn error of phenylalanine metabolism.
What is new?: Εven in cases with negative newborn screening for inborn errors of metabolism, the possibility of a metabolic disorder including PKU should be considered in any child presenting symptoms of developmental disorders. Late diagnosed PKU patients require a more specialized and individualized management than if they were early treatment cases.
Case presentation: We discuss a case of a child with typical autistic symptomatology, in whom years later a diagnosis of phenylketonuria was set, even neonatal screening was negative. Τhe patient was placed on a phenylalanine-restricted diet. After a period of clinical improvement, severe behavioral problems with aggressiveness and anxiety were presented. Less restrictive diet ameliorated the symptomatology.
Conclusion: This case highlights the major medical importance of adequate newborn screening policy, in order to avoid missed diagnosed cases. PKU may be presented as autism spectrum disorder. Dietary management needs individualized attentive monitoring.
4. Adv Nutr . 2020 Nov 16;11(6):1583-1602.
To Keto or Not to Keto? A Systematic Review of Randomized Controlled Trials Assessing the Effects of Ketogenic Therapy on Alzheimer Disease
Maria G Grammatikopoulou 1, Dimitrios G Goulis 2, Konstantinos Gkiouras 1, Xenophon Theodoridis 1, Kalliopi K Gkouskou 3, Athanasios Evangeliou 4, Efthimis Dardiotis 5, Dimitrios P Bogdanos 1 6
Alzheimer disease (AD) is a global health concern with the majority of pharmacotherapy choices consisting of symptomatic treatment. Recently, ketogenic therapies have been tested in randomized controlled trials (RCTs), focusing on delaying disease progression and ameliorating cognitive function. The present systematic review aimed to aggregate the results of trials examining the effects of ketogenic therapy on patients with AD/mild cognitive impairment (MCI). A systematic search was conducted on PubMed, CENTRAL, clinicaltrials.gov, and gray literature for RCTs performed on adults, published in English until 1 April, 2019, assessing the effects of ketogenic therapy on MCI and/or AD compared against placebo, usual diet, or meals lacking ketogenic agents. Two researchers independently extracted data and assessed risk of bias with the Cochrane tool. A total of 10 RCTs were identified, fulfilling the inclusion criteria. Interventions were heterogeneous, acute or long term (45-180 d), including adherence to a ketogenic diet, intake of ready-to-consume drinks, medium-chain triglyceride (MCT) powder for drinks preparation, yoghurt enriched with MCTs, MCT capsules, and ketogenic formulas/meals. The use of ketoneurotherapeutics proved effective in improving general cognition using the Alzheimer's Disease Assessment Scale-Cognitive, in interventions of either duration. In addition, long-term ketogenic therapy improved episodic and secondary memory. Psychological health, executive ability, and attention were not improved. Increases in blood ketone concentrations were unanimous and correlated to the neurocognitive battery based on various tests. Cerebral ketone uptake and utilization were improved, as indicated by the global brain cerebral metabolic rate for ketones and [11C] acetoacetate. Ketone concentrations and cognitive performance differed between APOE ε4(+) and APOE ε4(-) participants, indicating a delayed response among the former and an improved response among the latter. Although research on the subject is still in the early stages and highly heterogeneous in terms of study design, interventions, and outcome measures, ketogenic therapy appears promising in improving both acute and long-term cognition among patients with AD/MCI. This systematic review was registered at www.crd.york.ac.uk/prospero as
5. J Neuromuscul Dis 2020;7(3):247-256.
Evaluation of Genotypes and Epidemiology of Spinal Muscular Atrophy in Greece: A Nationwide Study Spanning 24 Years
Kyriaki Kekou 1, Maria Svingou 1, Christalena Sofocleous 1 2, Niki Mourtzi 3, Evangelia Nitsa 4, George Konstantinidis 5, Sotiris Youroukos 3, Konstantinos Skiadas 6, Marina Katsalouli 6, Roser Pons 3, Antigoni Papavasiliou 7, Charalabos Kotsalis 7, Evangelos Pavlou 8, Athanasios Evangeliou 9, Efstathia Katsarou 10, Konstantinos Voudris 10, Argirios Dinopoulos 11, Pelagia Vorgia 12, George Niotakis 13, Nikolaos Diamantopoulos 14, Iliada Nakou 15, Vasiliki Koute 16, George Vartzelis 17, George-Konstantinos Papadimas 18, Constantinos Papadopoulos 18, Georgios Tsivgoulis 19, Joanne Traeger-Synodinos 1
Background: Promising genetic treatments targeting the molecular defect of severe early-onset genetic conditions are expected to dramatically improve patients' quality of life and disease epidemiology. Spinal Muscular Atrophy (SMA), is one of these conditions and approved therapeutic approaches have recently become available to patients.
Objective: Analysis of genetic and clinical data from SMA patients referred to the single public-sector provider of genetic services for the disease throughout Greece followed by a retrospective assessment in the context of epidemiology and genotype-phenotype associations.
Methods: Molecular genetic analysis and retrospective evaluation of findings for 361 patients tested positive for SMA- and 862 apparently healthy subjects from the general population. Spearman rank test and generalized linear models were applied to evaluate secondary modifying factors with respect to their impact on clinical severity and age of onset.
Results: Causative variations- including 5 novel variants- were detected indicating a minimal incidence of about 1/12,000, and a prevalence of at least 1.5/100,000. For prognosis a minimal model pertaining disease onset before 18 months was proposed to include copy numbers of NAIP (OR = 9.9;95% CI, 4.7 to 21) and SMN2 (OR = 6.2;95% CI, 2.5-15.2) genes as well as gender (OR = 2.2;95% CI, 1.04 to 4.6).
Conclusions: This long-term survey shares valuable information on the current status and practices for SMA diagnosis on a population basis and provides an important reference point for the future assessment of strategic advances towards disease prevention and health care planning.
6. Biomed J Sci & Tech Res 20(2)-2019.
Low Glycemic Index Diet for Epilepsy. A liberalized Ketogenic Diet or A Different Nutritional Therapeutical Process? Facts and Hypothesis Athanasios Evangeliou1*, Eftherpi Dalpa1, Maria Papadopoulou1, Astrinia Skarpalezou2, Irene Katsanika1, Olga Grafakou3, Dimitrios Tsiptsios4 and Martha Spilioti.
The low glycemic index diet (LGID) was applied to seventeen patients who had previously been treated with the ketogenic diet (KD) but had demonstrated either partial (n=9) or no (n=8) improvement in seizure control. In 3 out of 8 patients in whom the KD failed, transition to the LGI diet led to reduction in seizure frequency by 30 to 70 %.In the group with an initial partial response to the KD, four out of 9 patients demonstrated a further reduction in seizure frequency while on the LGID, by 20, 20, 30 and 40% respectively. Two of the 9 patients maintained the seizure control previously achieved on the KD and the remaining 3 patients deteriorated/ presented an increase in number of seizures. During the LGID improvement in seizure control was combined with preservation of ketosis although markedly reduced in comparison to the KD and with reduced blood glucose below the level of 90 mg/dL. Deterioration of seizure control in a patient after an initial improvement during the LGID was combined with an elevation of blood glucose levels while ketone bodies remained unchangeable. In addition, patients who did not benefit from the LGID had difficulty in maintaining glucose levels under 90 mg/dL. Our data give evidence that the low glycemic index diet may have a different therapeutic mechanism from ketogenic diet.
7. Integr Mol Med, 2019
The effect of creatine supplementation on seizure control in children under ketogenic diet: A pilot study.
The effect of creatine supplementation on seizure control in children under ketogenic diet: A pilot study.
Introduction: The ketogenic diet improves cell energy and mitochondrial function and supplemental creatine can similarly improve cell energy. Our aim is to investigate the role of creatine as an adjunctive therapy to the ketogenic diet. Material and methods: A prospective study was carried out in 22 children with refractory epilepsy. All patients were initially on ketogenic diet and none was seizure free, although 12 children had benefited. Results: Creatine supplementation produced a complete cessation of seizures in 2 patients and a 70% to 90% reduction in seizure frequency was reported in additional five patients. Creatine was well-tolerated and did not change the level of ketosis. Conclusions: Although these data involve a small cohort, the effects of creatine were uniformly positive or neutral. We suggest that creatine supplementation may increase the effectiveness of the ketogenic diet in seizure reduction, likely by increasing phosphocreatine and enhancing brain energy balance.
8. Am J Kidney Dis . 2019 Oct;74(4):510-522.
The P274S Mutation of Lecithin-Cholesterol Acyltransferase (LCAT) and Its Clinical Manifestations in a Large Kindred
Nikolaos Fountoulakis 1, Eirini Lioudaki 1, Dimitra Lygerou 1, Eleftheria-Kleio Dermitzaki 1, Ioanna Papakitsou 1, Vasiliki Kounali 1, Adriaan G Holleboom 2, Spyros Stratigis 1, Christina Belogianni 1, Paraskevi Syngelaki 1, Stavros Stratakis 1, Athanasios Evangeliou 3, Hariklia Gakiopoulou 4, Jan Albert Kuivenhoven 2, Ron Wevers 5, Eugene Dafnis 1, Kostas Stylianou
Rationale & objective: Lecithin-cholesterol acyltransferase (LCAT) catalyzes the maturation of high-density lipoprotein. Homozygosity for loss-of-function mutations causes familial LCAT deficiency (FLD), characterized by corneal opacities, anemia, and renal involvement. This study sought to characterize kidney biopsy findings and clinical outcomes in a family with FLD.
Study design: Prospective observational study.
Setting & participants: 2 (related) index patients with clinically apparent FLD were initially identified. 110 of 122 family members who consented to genetic analysis were also studied.
Predictors: Demographic and laboratory parameters (including lipid profiles and LCAT activity) and full sequence analysis of the LCAT gene. Kidney histologic examination was performed with samples from 6 participants.
Outcomes: Cardiovascular and renal events during a median follow-up of 12 years. Estimation of annual rate of decline in glomerular filtration rate.
Analytical approach: Analysis of variance, linear regression analysis, and Fine-Gray competing-risk survival analysis.
Results: 9 homozygous, 57 heterozygous, and 44 unaffected family members were identified. In all affected individuals, full sequence analysis of the LCAT gene revealed a mutation (c.820C>T) predicted to cause a proline to serine substitution at amino acid 274 (P274S). Homozygosity caused a complete loss of LCAT activity. Kidney biopsy findings demonstrated lipid deposition causing glomerular basement membrane thickening, mesangial expansion, and "foam-cell" infiltration of kidney tissue. Tubular atrophy, glomerular sclerosis, and complement fixation were associated with worse kidney outcomes. Estimated glomerular filtration rate deteriorated among homozygous family members at an average annual rate of 3.56 mL/min/1.73 m2. The incidence of cardiovascular and renal complications was higher among homozygous family members compared with heterozygous and unaffected members. Mild thrombocytopenia was a common finding among homozygous participants.
Limitations: The presence of cardiovascular disease was mainly based on medical history.
Conclusions: The P274S LCAT mutation was found to cause FLD with renal involvement. Tubular atrophy, glomerular sclerosis, and complement fixation were associated with a worse renal prognosis.
9. Curr Pharm Biotechnol . 2017 Nov 10;18(8):628-637.
Clinical Applications of Intravenous Immunoglobulins in Child Neurology
Maria Gogou 1, Efimia Papadopoulou-Alataki 1, Martha Spilioti 2, Sofia Alataki 1, Athanasios Evangeliou 1
Background: While there are guidelines for the use of intravenous immunoglobulins in children with Guillain-Barre syndrome and myasthenia gravis based on high-level evidence studies, data are scarce for the majority of neurologic disorders in this age group. Neuronal antibodies are detected in children with seizures of autoimmune etiology. Intravenous immunoglobulins with their broad immunomodulatory mechanism of action could be ideally effective in different forms of immunedysregulated intractable epilepsies such as autoimmune epilepsy and autoimmune Rasmussen encephalitis. We conducted a systematic review of the literature for evidence of the use of intravenous immunoglobulins in a variety of neurologic diseases in childhood.
Method: A comprehensive literature search was conducted using Pubmed as the medical database source without date range. Prospective studies in pediatric groups including objective measures of clinical outcomes were systematically selected.
Results: A total of 11 prospective studies were identified in the literature demonstrating a favorable effect of this therapeutic option in children with drug-resistant epilepsy and in cases of encephalitis. No serious adverse effects were reported. No prospective studies about the use of intravenous immunoglobulins in children with demyelinating disorders or neurologic paraneoplasmatic syndromes were found.
Conclusion: In this review, we summarize the recent advances in the field of intravenous immunoglobulins used in pediatric neurological diseases. Literature data supports a beneficial effect in this age group. Whilst awaiting the results of large scale studies, administration of intravenous immunoglobulins could be justified in refractory child epilepsy. Otherwise, its use should be guided by the individual needs of each child, depending on the underlying neurological disease.
10. Indian Pediatr . 2017 Aug 15;54(8):667-673.
Cardiac Manifestations in Children with Inborn Errors of Metabolism
Kyriaki Papadopoulou-Legbelou 1, Maria Gogou, Athanasios Evangeliou
Need and purpose: Cardiac involvement is a part of many inborn errors of metabolism, but has not been systematically studied. This review focuses on studies describing cardiac manifestations of inborn errors of metabolism in childhood.
Methods: Two independent reviewers searched the topic using PubMed database. Studies published within 20 years were considered, without applying any restrictions related to study design. Despite the small number of existing systematic studies on the topic, several case series/reports were identified.
Conclusions: Cardiomyopathy is the most frequent heart disorder in most metabolic defects. Heart rhythm disorders are mainly encountered in mitochondrial disorders and acidemias, whereas valvular dysfunction is a prominent finding in storage disorders. Cardiac involvement in mitochondrial disorders, congenital disorders of glycosylation and acidemias usually constitute an early symptom. On the contrary, in storage disorders, heart problems are revealed in later stages during routine multisystemic evaluation, with the exception of Pompe disease. As a variety of cardiac manifestations can be found in inborn errors of metabolism, these children should be systematically screened for heart problems during their follow-up.
11. Indian J Pediatr . 2017 Mar;84(3):231-233.
Dilated Cardiomyopathy as the Only Clinical Manifestation of Carnitine Transporter Deficiency
Kyriaki Papadopoulou-Legbelou 1, Maria Gogou 2 3, Vaia Dokousli 1, Maria Eboriadou 1, Athanasios Evangeliou 1
The authors present a case of carnitine transporter deficiency, which was unmasked after an episode of respiratory distress resistant to treatment with bronchodilators. Chest radiograph showed cardiomegaly; electrocardiogram showed left ventricular hypertrophy and echocardiography revealed dilated cardiomyopathy. Heart failure therapy was initiated and metabolic screening was requested, as family history was indicative of inborn errors of metabolism. Very low levels of free carnitine and carnitine esters in blood were found and genetic testing confirmed the diagnosis of carnitine transporter deficiency. After oral supplementation with L-carnitine, symptoms gradually ameliorated and heart function had fully recovered. Sequence analysis in the SLC22A5 gene revealed the missense mutation c.1319C > T (p.Th440Met) in homozygous state. Homozygous c.1319C > T (p.Th440Met) mutation has not been associated with a pure cardiac phenotype before.
12. Eur J Paediatr Neurol . 2016 Jul;20(4):555-9.
Valproate effect on ketosis in children under ketogenic diet
Martha Spilioti 1, Evangelos Pavlou 1, Maria Gogou 2, Irene Katsanika 3, Efimia Papadopoulou-Alataki 3, Olga Grafakou 3, Anastasia Gkampeta 1, Argyrios Dinopoulos 4, Athanasios Evangeliou 3
Introduction: Although ketogenic diet has been proven useful in the management of intractable seizures, interactions with other medicines have been reported. This study reports two patients on co-administration with ketogenic diet and valproate appearing undesirable side effects after increase or decrease of valproate pharmaceutical levels.
Methods: Totally 75 patients suffering from drug-resistant epilepsy were treated with ketogenic diet in our departments. Their age varied from 6 months to 9 years. All patients were followed for at least 12 months and up to five years. Clinical and laboratory variables have been regularly assessed.
Results: In 75 patients treated with ketogenic diet and valproate at the same time treatment was well tolerated. Two patients presented mild to moderate undesirable effects. In these patients the removal of valproate treatment resulted in an increase of ketosis with respective clinical signs. The conversion of the diet from 4:1 to 1:1 and 2,5:1 respectively resulted in reduction of ketosis and clinical improvement.
Conclusion: In the majority of cases co-administration of valproate and ketogenic diet seems to be safe. In two cases, valproate appeared to have a negative effect on ketosis (and weaning it led to over-ketosis). This interaction is worthy of future study.
13. Eur J Hum Genet . 2015 Aug;23(8):1051-61.
Truncated prelamin A expression in HGPS-like patients: a transcriptional study
Florian Barthélémy 1, Claire Navarro 1, Racha Fayek 1, Nathalie Da Silva 1, Patrice Roll 2, Sabine Sigaudy 2, Junko Oshima 3, Gisèle Bonne 4, Kyriaki Papadopoulou-Legbelou 5, Athanasios E Evangeliou 5, Martha Spilioti 6, Martine Lemerrer 7, Ron A Wevers 8, Eva Morava 9, Andrée Robaglia-Schlupp 2, Nicolas Lévy 2, Marc Bartoli 2, Annachiara De Sandre-Giovannoli 2
Premature aging syndromes are rare genetic disorders mimicking clinical and molecular features of aging. A recently identified group of premature aging syndromes is linked to mutation of the LMNA gene encoding lamins A and C, and is associated with nuclear deformation and dysfunction. Hutchinson-Gilford progeria syndrome (HGPS) was the first premature aging syndrome linked to LMNA mutation and its molecular bases have been deeply investigated. It is due to a recurrent de novo mutation leading to aberrant splicing and the production of a truncated and toxic nuclear lamin A precursor (prelamin AΔ50), also called progerin. In this work and based on the literature data, we propose to distinguish two main groups of premature aging laminopathies: (1) HGPS and HGP-like syndromes, which share clinical features due to hampered processing and intranuclear toxic accumulation of prelamin A isoforms; and (2) APS (atypical progeria syndromes), due to dominant or recessive missense mutations affecting lamins A and C. Among HGPS-like patients, several deleted prelamin A transcripts (prelamin AΔ50, AΔ35 and AΔ90) have been described. The purpose of this work was to characterize those transcripts in eight patients affected with HGP-like rare syndromes. When fibroblasts were available, the relationships between the presence and ratios of these transcripts and other parameters were studied, aiming to increase our understanding of genotype-phenotype relationships in HGPS-like patients. Altogether our results evidence that progerin accumulation is the major pathogenetic mechanism responsible for HGP-like syndromes due to mutations near the donor splice site of exon 11.
14. Front Hum Neurosci . 2013 Dec 24;7:858.Evidence for treatable inborn errors of metabolism in a cohort of 187 Greek patients with autism spectrum disorder (ASD)
Martha Spilioti 1, Athanasios E Evangeliou 2, Despoina Tramma 2, Zoe Theodoridou 3, Spyridon Metaxas 4, Eleni Michailidi 5, Eleni Bonti 6, Helen Frysira 7, A Haidopoulou 2, Despoina Asprangathou 2, Aggelos J Tsalkidis 8, Panagiotis Kardaras 9, Ron A Wevers 10, Cornelis Jakobs 11, K Michael Gibson 12
We screened for the presence of inborn errors of metabolism (IEM) in 187 children (105 males; 82 females, ages 4-14 years old) who presented with confirmed features of autism spectrum disorder (ASD). Twelve patients (7%) manifested increased 3-hydroxyisovaleric acid (3-OH-IVA) excretion in urine, and minor to significant improvement in autistic features was observed in seven patients following supplementation with biotin. Five diagnoses included: Lesch Nyhan syndrome (2), succinic semialdehyde dehydrogenase (SSADH) deficiency (2), and phenylketonuria (1) (2.7%). Additional metabolic disturbances suggestive of IEMs included two patients whose increased urine 3-OH-IVA was accompanied by elevated methylcitrate and lactate in sera, and 30 patients that showed abnormal glucose-loading tests. In the latter group, 16/30 patients manifested increased sera beta hydroxybutyrate (b-OH-b) production and 18/30 had a paradoxical increase of sera lactate. Six patients with elevated b-OH-b in sera showed improved autistic features following implementation of a ketogenic diet (KD). Five patients showed decreased serum ketone body production with glucose loading. Twelve of 187 patients demonstrated non-specific MRI pathology, while 25/187 had abnormal electroencephalogram (EEG) findings. Finally, family history was positive for 22/187 patients (1st or 2nd degree relative with comparable symptomatology) and consanguinity was documented for 12/187 patients. Our data provide evidence for a new biomarker (3-OH-IVA) and novel treatment approaches in ASD patients. Concise 1 sentence take-home message: Detailed metabolic screening in a Greek cohort of ASD patients revealed biomarkers (urine 3-hydroxyisovaleric acid and serum b-OH-b) in 7% (13/187) of patients for whom biotin supplementation or institution of a KD resulted in mild to significant clinical improvement in autistic features.
15. Case Rep Pediatr . 2013;2013:721871.
Acute pancreatitis with rapid clinical improvement in a child with isovaleric acidemia
Elpis Mantadakis 1, Ioannis Chrysafis, Emmanouela Tsouvala, Athanassios Evangeliou, Athanassios Chatzimichael
Isovaleric acidemia is a rare branched-chain organic acidemia. The authors describe a 3.5-year-old girl with isovaleric acidemia and acute abdominal pain associated with bilious emesis. Elevated serum amylase and abdominal ultrasonography demonstrating an enlarged and edematous pancreas, along with the presence of peripancreatic exudates, confirmed the presence of acute pancreatitis. The patient recovered quickly with intravenous hydration, pancreatic rest, and administration of intravenous L-carnitine. Pancreatitis should be ruled out in the context of vomiting in any patient with isovaleric acidemia. Conversely, branched-chain organic acidemias should be included in the differential diagnosis of any child with pancreatitis of unknown origin.
16. Brain. 2010 Mar;133(Pt 3):655-70.
Glucose transporter-1 deficiency syndrome: the expanding clinical and genetic spectrum of a treatable disorder
Wilhelmina G Leen 1, Joerg Klepper, Marcel M Verbeek, Maike Leferink, Tom Hofste, Baziel G van Engelen, Ron A Wevers, Todd Arthur, Nadia Bahi-Buisson, Diana Ballhausen, Jolita Bekhof, Patrick van Bogaert, Inês Carrilho, Brigitte Chabrol, Michael P Champion, James Coldwell, Peter Clayton, Elizabeth Donner, Athanasios Evangeliou, Friedrich Ebinger, Kevin Farrell, Rob J Forsyth, Christian G E L de Goede, Stephanie Gross, Stephanie Grunewald, Hans Holthausen, Sandeep Jayawant, Katherine Lachlan, Vincent Laugel, Kathy Leppig, Ming J Lim, Grazia Mancini, Adela Della Marina, Loreto Martorell, Joe McMenamin, Marije E C Meuwissen, Helen Mundy, Nils O Nilsson, Axel Panzer, Bwee T Poll-The, Christian Rauscher, Christophe M R Rouselle, Inger Sandvig, Thomas Scheffner, Eamonn Sheridan, Neil Simpson, Parol Sykora, Richard Tomlinson, John Trounce, David Webb, Bernhard Weschke, Hans Scheffer, Michél A Willemsen
Glucose transporter-1 deficiency syndrome is caused by mutations in the SLC2A1 gene in the majority of patients and results in impaired glucose transport into the brain. From 2004-2008, 132 requests for mutational analysis of the SLC2A1 gene were studied by automated Sanger sequencing and multiplex ligation-dependent probe amplification. Mutations in the SLC2A1 gene were detected in 54 patients (41%) and subsequently in three clinically affected family members. In these 57 patients we identified 49 different mutations, including six multiple exon deletions, six known mutations and 37 novel mutations (13 missense, five nonsense, 13 frame shift, four splice site and two translation initiation mutations). Clinical data were retrospectively collected from referring physicians by means of a questionnaire. Three different phenotypes were recognized: (i) the classical phenotype (84%), subdivided into early-onset (<2 years) (65%) and late-onset (18%); (ii) a non-classical phenotype, with mental retardation and movement disorder, without epilepsy (15%); and (iii) one adult case of glucose transporter-1 deficiency syndrome with minimal symptoms. Recognizing glucose transporter-1 deficiency syndrome is important, since a ketogenic diet was effective in most of the patients with epilepsy (86%) and also reduced movement disorders in 48% of the patients with a classical phenotype and 71% of the patients with a non-classical phenotype. The average delay in diagnosing classical glucose transporter-1 deficiency syndrome was 6.6 years (range 1 month-16 years). Cerebrospinal fluid glucose was below 2.5 mmol/l (range 0.9-2.4 mmol/l) in all patients and cerebrospinal fluid : blood glucose ratio was below 0.50 in all but one patient (range 0.19-0.52). Cerebrospinal fluid lactate was low to normal in all patients. Our relatively large series of 57 patients with glucose transporter-1 deficiency syndrome allowed us to identify correlations between genotype, phenotype and biochemical data. Type of mutation was related to the severity of mental retardation and the presence of complex movement disorders. Cerebrospinal fluid : blood glucose ratio was related to type of mutation and phenotype. In conclusion, a substantial number of the patients with glucose transporter-1 deficiency syndrome do not have epilepsy. Our study demonstrates that a lumbar puncture provides the diagnostic clue to glucose transporter-1 deficiency syndrome and can thereby dramatically reduce diagnostic delay to allow early start of the ketogenic diet.
17. Curr Pharm Biotechnol . 2009 Nov;10(7):683-90.
Clinical applications of creatine supplementation on paediatrics
Athanasios Evangeliou 1, Konstantina Vasilaki, Paraskevi Karagianni, Nikolaos Nikolaidis
Creatine plays a central role in energy metabolism and is synthesized in the liver, kidney and pancreas. In healthy patients, it is transported via the blood stream to the muscles, heart and brain with high and fluctuating energy demands by the molecule creatine transporter. Creatine, although naturally synthesized in the human body, can be ingested in the form of supplements and is commonly used by athletes. The purpose of this review was to assess the clinical applications of creatine supplementation on paediatrics. Creatine metabolism disorders have so far been described at the level of two synthetic steps, guanidinoacetate N-methyltransferase (GAMT) and arginine: glycine amidinotransferase (AGAT), and at the level of the creatine transporter 1(CrT1). GAMT and AGAT deficiency respond positively to substitutive treatment with creatine monohydrate whereas in CrT1 defect, it is not able to replenish creatine in the brain with oral creatine supplementation. There are also data concerning the short and long-term therapeutic benefit of creatine supplementation in children and adults with gyrate atrophy (a result of the inborn error of metabolism with ornithine delta- aminotransferase activity), muscular dystrophy (facioscapulohumeral dystrophy, Becker dystrophy, Duchenne dystrophy and sarcoglycan deficient limb girdle muscular dystrophy), McArdle's disease, Huntington's disease and mitochondria-related diseases. Hypoxia and energy related brain pathologies (brain trauma, cerebral ischemia, prematurity) might benefit from Cr supplementation. This review covers also the basics of creatine metabolism and proposed mechanisms of action.
18. J Child Neurol . 2009 Oct;24(10):1268-72.
Branched chain amino acids as adjunctive therapy to ketogenic diet in epilepsy: pilot study and hypothesis
Athanasios Evangeliou 1, Martha Spilioti, Vai Doulioglou, Panagiota Kalaidopoulou, Anestis Ilias, Astrinia Skarpalezou, Irini Katsanika, Serafia Kalamitsou, Konstantina Vasilaki, Ilias Chatziioanidis, Kiriakos Garganis, Evangelos Pavlou, Sotirios Varlamis, Nikolaos Nikolaidis
A pilot prospective follow-up study of the role of the branched chain amino acids as additional therapy to the ketogenic diet was carried out in 17 children, aged between 2 and 7 years, with refractory epilepsy. All of these patients were on the ketogenic diet; none of them was seizure free, while only 13 had more or less benefited from the diet. The addition of branched chain amino acids induced a 100% seizure reduction in 3 patients, while a 50% to 90% reduction was noticed in 5. Moreover, in all of the patients, no reduction in ketosis was recorded despite the change in the fat-to-protein ratio from 4:1 to 2.5:1. Although our data are preliminary, we suggest that branched chain amino acids may increase the effectiveness of the ketogenic diet and the diet could be more easily tolerated by the patients because of the change in the ratio of fat to protein.
19. Curr Pharm Biotechnol . 2003 Jun;4(3):211-9.
Carnitine metabolism and deficit--when supplementation is necessary?
A Evangeliou 1, D Vlassopoulos
Carnitine is an ammo acid derivative found in high energy demanding tissues (skeletal muscles, myocardium, the liver and the suprarenal glands). It is essential for the intermediary metabolism of fatty acids. Carnitine is indispensable for beta-oxidation of long-chain fatty acids in the mitochondria but also regulates CoA concentration and removal of the produced acyl groups. AcylCoAs act as restraining factor for several enzymes participating in intermediary metabolism. Transformation of AcylCoA into acylcarnitine is an important system for removing the toxic acyl groups. Although primary deficiency is unusual, depletion due to secondary causes, such as a disease or a medication side effect, can occur. Primary carnitine deficiency is caused by a defect in plasma membrane carnitine transporter in muscle and kidneys. Secondary carnitine deficiency is associated with several inborn errors of metabolism and acquired medical or iatrogenic conditions, for example in patients under valproate and zidovuline treatment. In cirrhosis and chronic renal failure, carnitine biosynthesis is impaired or carnitine is lost during hemodialysis. Other chronic conditions like diabetes mellitus, heart failure, Alzheimer disease may cause carnitine deficiency also observed in conditions with increased catabolism as in critical illness. Preterm neonates develop carnitine deficiency due to impaired proximal renal tubule carnitine re-absorption and immature carnitine biosynthesis. Carnitine stabilizes the cellular membrane and raises red blood cell osmotic resistance but has no metabolic influence on lipids in dialysis patients. L-Carnitine has been administered in senile dementia, metabolic nerve diseases, in HIV infection, tuberculosis, myopathies, cardiomyopathies, renal failure anemia and included in baby foods and milk.
20. J Child Neurol . 2003 Feb;18(2):113-8.
Application of a ketogenic diet in children with autistic behavior: pilot study
Athanasios Evangeliou 1, Ioannis Vlachonikolis, Helen Mihailidou, Martha Spilioti, Astrinia Skarpalezou, Nikolaos Makaronas, Ahilleas Prokopiou, Panagiotis Christodoulou, Georgia Liapi-Adamidou, Emmanouel Helidonis, Stylianos Sbyrakis, Jan Smeitink
A pilot prospective follow-up study of the role of the ketogenic diet was carried out on 30 children, aged between 4 and 10 years, with autistic behavior. The diet was applied for 6 months, with continuous administration for 4 weeks, interrupted by 2-week diet-free intervals. Seven patients could not tolerate the diet, whereas five other patients adhered to the diet for 1 to 2 months and then discontinued it. Of the remaining group who adhered to the diet, 18 of 30 children (60%), improvement was recorded in several parameters and in accordance with the Childhood Autism Rating Scale. Significant improvement (> 12 units of the Childhood Autism Rating Scale) was recorded in two patients (pre-Scale: 35.00 +/- 1.41[mean +/- SD]), average improvement (> 8-12 units) in eight patients (pre-Scale: 41.88 +/- 3.14[mean +/- SD]), and minor improvement (2-8 units) in eight patients (pre-Scale: 45.25 +/- 2.76 [mean +/- SD]). Although these data are very preliminary, there is some evidence that the ketogenic diet may be used in autistic behavior as an additional or alternative therapy.
Please cite the 20 more recent or/and important ones