Ebru Canda

Previously Unreported Biallelic Mutation in DNAJC19: Are Sensorineural Hearing Loss and Basal Ganglia Lesions Additional Features of Dilated Cardiomyopathy and Ataxia (DCMA) Syndrome?

BACKGROUND Dilated cardiomyopathy (DCM), non-progressive cerebellar ataxia (A), testicular dysgenesis, growth failure, and 3-methylglutaconic aciduria are the hallmarks of DNAJC19 defect (or DCMA syndrome) due to biallelic mutations in DNAJC19. To date DCMA syndrome has been reported in 19 patients from Canada and in two Finnish siblings. The underlying pathomechanism is unknown; however, DNAJC19 is presumed to be involved in mitochondrial membrane related processes (e.g., protein import and cardiolipin remodeling). Here, we report an additional patient with progressive cerebellar atrophy and white matter changes. PATIENT AND METHODS A Turkish boy presented at age 2 months with dilated cardiomyopathy (initially worsening then stabilizing in the second year of life), growth failure, bilateral cryptorchidism, and facial dysmorphism. Mental and motor developmental were, respectively, moderately and severely delayed. Profound intentional tremor and dyskinesia, spasticity (particularly at the lower extremities), and dystonia were observed. Sensorineural hearing loss was also diagnosed. MRI showed bilateral basal ganglia signal alterations. Plasma lactate levels were increased, as was urinary excretion of 3-methylglutaconic acid. He deceased aged 3 years. RESULTS Sanger Sequencing of DNAJC19 confirmed the clinical diagnosis of DNAJC19 defect by revealing the previously unreported homozygous stop mutation c.63delC (p.Tyr21*). Investigation of enzymes of mitochondrial energy metabolism revealed decreased activity of cytochrome c oxidase in muscle tissue. DISCUSSION Sensorineural hearing loss and bilateral basal ganglia lesions are common symptoms of mitochondrial disorders. This is the first report of an association with DNAJC19 defect.

Two novel mutations in acid α-glucosidase gene in two patients with Pompe disease.

Abstract Pompe disease is an autosomal recessive lysosomal glycogen storage disorder (GSD) caused by acid α-glucosidase (GAA) deficiency. Pompe disease has a broad genotypic and phenotypic spectrum. The infantile-onset form is the most severe form and presents with hypotonia and cardiomyopathy in early infancy. The probands who died were found to have GSD type II based on clinical and biochemical findings. We report two families with Pompe disease in whom the parents’ molecular analysis revealed two novel mutations: c.2045A>G (p.Q682R) and c.763C>T (p.Q255X).

Evaluation of Cardiovascular Involvement and Cytokine Levels in Patients with Mucopolysaccharidosis

Ad dress for Cor res pon den ce Ebru Canda MD, Ege University Faculty of Medicine, Department of Pediatrics, Division of Metabolism and Nutrition, İzmir, Turkey Phone: +90 232 290 12 45 E-mail: ebru.canda@gmail.com ORCID ID: orcid.org/0000-0002-9175-1998 Re cei ved: 07.10.2018 Ac cep ted: 17.10.2018 1Ege University Faculty of Medicine, Department of Pediatrics, Division of Metabolism and Nutrition, İzmir, Turkey 2Ege University Faculty of Medicine, Department of Biochemistry, İzmir, Turkey 3Ege University Faculty of Medicine, Department of Pediatrics, Division of Cardiology, İzmir, Turkey Ebru Canda1, Melis Köse1, Mehtap Kağnıcı1, Meral Dondurmacı2, Sema Kalkan Uçar1, Eser Sözmen2, Reşit Ertürk Levent3, Mahmut Çöker1

Clinical, Neuroimaging, and Genetic Features of Patients with L-2-Hydroxyglutaric Aciduria

39 ©Copyright 2018 by Ege University Faculty of Medicine, Department of Pediatrics and Ege Children’s Foundation The Journal of Pediatric Research, published by Galenos Publishing House. Ad dress for Cor res pon den ce Ebru Canda MD, Ege University Faculty of Medicine, Department of Pediatrics, Division of Pediatric Metabolism and Nutrition, İzmir, Turkey Phone: +90 505 525 29 16 E-mail: ebru.canda@gmail.com ORCID ID: orcid.org/0000-0002-9175-1998 Re cei ved: 06.11.2017 Ac cep ted: 25.12.2017 1Ege University Faculty of Medicine, Department of Pediatrics, Division of Pediatric Metabolism and Nutrition, İzmir, Turkey 2Ege University Faculty of Medicine, Department of Radiology, İzmir, Turkey 3Ege University Faculty of Medicine, Department of Biochemistry, İzmir, Turkey 4Ege University Faculty of Medicine, Department of Genetics, İzmir, Turkey Ebru Canda1, Melis Köse1, Havva Yazıcı1, Esra Er1, Cenk Eraslan2, Sema Kalkan Uçar1, Sara Habif3, Emin Karaca4, Hüseyin Onay4, Ferda Özkınay4, Mahmut Çoker4

Clinical, Biochemical and Molecular Characteristics of Fifteen Patients with Mucopolysaccharidosis Type II in Western Turkey

34 ©Copyright 2018 by Ege University Faculty of Medicine, Department of Pediatrics and Ege Children’s Foundation The Journal of Pediatric Research, published by Galenos Publishing House. Ad dress for Cor res pon den ce Havva Yazıcı MD, Ege University Faculty of Medicine, Department of Pediatrics, Division of Pediatrics Metabolism and Nutrition, İzmir, Turkey Phone: +90 505 711 22 52 E-mail: havvaya@gmail.com ORCID ID: orcid.org/0000-0002-2564-7420 Re cei ved: 03.11.2017 Ac cep ted: 12.12.2017 1Ege University Faculty of Medicine, Department of Pediatric, Division of Pediatrics Metabolism and Nutrition, İzmir, Turkey 2Ege University Faculty of Medicine, Department of Genetics, İzmir, Turkey Havva Yazıcı1, Ebru Canda1, Esra Er1, Sema Kalkan Uçar1, Hüseyin Onay2, Ferda Özkınay2, Mahmut Çoker1

Evalution of Demographic and Clinical Characterictics of Patients with GM2 Gangliosidosis

12 ©Copyright 2018 by Ege University Faculty of Medicine, Department of Pediatrics and Ege Children’s Foundation The Journal of Pediatric Research, published by Galenos Publishing House. Ad dress for Cor res pon den ce Esra Er MD, Ege University Faculty of Medicine, Department of Pediatrics Metabolism and Nutrition İzmir, Turkey Phone: +90 535 452 56 19 E-mail: esrabn@hotmail.com ORCID ID: orcid.org/0000-0001-8867-0508 Re cei ved: 07.10.2017 Ac cep ted: 29.12.2017 1Ege University Faculty of Medicine, Department of Pediatrics Metabolism and Nutrition, İzmir, Turkey 2Ege University Faculty of Medicine, Department of Radiology, İzmir, Turkey 3Ege University Faculty of Medicine, Department of Medical Biochemistry, İzmir, Turkey Esra Er1, Ebru Canda1, Havva Yazıcı1, Cenk Eraslan2, Eser Sözmen3, Sema Kalkan Uçar1, Mahmut Çoker1

Single center experience of biotinidase deficiency: 259 patients and six novel mutations.

Abstract Background Biotinidase deficiency (BD) is an autosomal recessively inherited disorder of biotin recycling. It is classified into two levels based on the biotinidase enzyme activity: partial deficiency (10%–30% enzyme activity) and profound deficiency (0%–10% enzyme activity). The aims of this study were to evaluate our patients with BD, identify the spectrum of biotinidase (BTD) gene mutations in Turkish patients and to determine the clinical and laboratory findings of our patients and their follow-up period. Methods A total of 259 patients who were diagnosed with BD were enrolled in the study. One hundred and forty-eight patients were male (57.1%), and 111 patients were female (42.9%). Results The number of patients detected by newborn screening was 221 (85.3%). By family screening, 31 (12%) patients were diagnosed with BD. Seven patients (2.7%) had different initial complaints and were diagnosed with BD. Partial BD was detected in 186 (71.8%) patients, and the profound deficiency was detected in 73 (28.2%) patients. Most of our patients were asymptomatic. The most commonly found variants were p.D444H, p.R157H, c.98_104delinsTCC. The novel mutations which were detected in this study are p.D401N(c.1201G>A), p.A82G (c.245C>G), p.F128S(c.383T>C), c617_619del/TTG (p.Val207del), p.A287T(c.859G>A), p.S491H(c.1471A>G). The most common mutation was p.R157H in profound BD and p.D444H in partial BD. All diagnosed patients were treated with biotin. Conclusions The diagnosis of BD should be based on plasma biotinidase activity and molecular analysis. We determined the clinical and genetic spectra of a large group of patients with BD from Western Turkey. The frequent mutations in our study were similar to the literature. In this study, six novel mutations were described.

Recurrent ketoacidosis: Is it a ketone metabolism disorder?

INTRODUCTION: Two defects of ketogenesis have been reported in the human so far; mitochondrial 3-hydroxy-3-methyl glutaryl CoA synthase (Mhs) and 3-hydroxymethyl-3-glutaryl CoA lyase (HL) deficiencies. Defects of ketone utilization (ketolysis) can be the result of enzyme deficiency of succinyl CoA: 3 oxoacid CoA transferase (SCOT) or methylacetoacetyl CoA thiolase - beta ketothiolase (MAT). Our aim was to evaluate the clinical and laboratory findings of patients who were diagnosed with ketone metabolism disorders. METHODS: Patients who were diagnosed with ketone metabolism disorders were examined retrospectively. RESULTS: Four patients had HL deficiency, 3 patients had MAT deficiency and 2 patients had SCOT deficiency. The median age of the patients was 5 years (6 months – 15.5 years) and the mean age of first metabolic decompensation was 7.7 months (22 days - 19 months). A patient with MAT deficiency was asymptomatic and diagnosed by family screening. Two patients developed severe neurological deficit like spastic tetraparesis. It was seen that decompensation attacks developed after poor feeding, vomiting and infections such as gastroenteritis. DISCUSSION AND CONCLUSION: In the case of unexplained metabolic acidosis attacks, ketone metabolism disorders should be kept in mind. Acute decompensation may occur at different ages, clinical severity may be variable. Early diagnosis and appropriate treatment are very important in terms of mortality and morbidity.

Coexistence of Gaucher Disease and severe congenital neutropenia

Gaucher Disease (GD) is the most common lysosomal storage disorder has traditionally been classified into three clinical phenotypes. Type 3 GD is characterized by neurological involvement but neurological symptoms generally appear later in life than in type 2 disease. Neutropenia is much rarer than other hematological manifestations in GD and has not been scrutinized adequately. Severe congenital neutropenia (SCN) is a rare disease entity which is characterized by a paucity of peripherally circulating neutrophils with arrest of neutrophil maturation at the promyelocyte stage and consequent increased susceptibility to severe and recurrent infections. We report a patient who presented in the first year of life with visceral involvement and severe neutropenia in whom the propositus had a unique coexistence of Gaucher Disease and severe congenital neutropenia associated with a mutation in HAX1. In contrast to his expired siblings he had experienced no severe infections. These clinical observations suggest that enzyme replacement therapy may display a modulating factor with respect to the clinical course of SCN. SYNOPSIS: Our patient is the only report of the combination of Gaucher Disease and Kostmann Syndrome in the literature. The clinical course of our patient is not severe when comparing with exitus siblings and other Kostmann Syndrome patients. But when considering the patients only clinical difference is ERT, this case is very important to emphasise the role of enzyme replacement therapy in bone marrow.

An unusual cause of cavitating leukoencephalopathy: ethylmalonic encephalopathy

Following a mild head trauma 1 week prior, a 6-year-old girl diagnosed with Leigh syndrome was admitted to our Child Neurology Department due to a loss of reaction to external stimuli and swallowing dysfunction. She was able to walk and began to speak at 30 months of age, but then lost the ability to walk at 5 years old, so she had delays and regressions in development. The previous year, the patient was hospitalized due to acute diarrhea, severe lactic acidosis, and encephalopathy. Plasma ammonia level was normal and she recovered with hydration and bicarbonate replacements. Urine organic acids during this metabolic crisis showed elevated ethylmalonic acid levels (96 mmol/mol/crea; reference range 0–15). The physical examination revealed axial hypotonia, muscle weakness, lower limb spasticity, increased deep tendon reflexes, extensor bilateral plantar reflexes, and clonus. The ophthalmic examination identified bilateral tortuosity in retinal veins. Biochemical blood tests showed mildly elevated plasma lactate and C4-acylcarnitine levels, while serum pyruvate, ammonia, amino acids, and creatine kinase levels were normal. Blood tandem mass spectrometry was normal, but urine organic acid examination revealed a 1.2-fold increase in ethylmalonic acid levels. The electroencephalography record demonstrated diffuse encephalopathy. The electromyography was normal. The brain MRI revealed bilateral hyperintensity in the head of the caudate nucleus, subcortical and deep white matter, and cerebellar white matter. It also showed multiple cavitation foci; diffusion-weighted MRI showed diffusion-restricting lesions. Computerized tomography of the cranium showed calcification of the posterior occipital area (Figs. 1, 2). Genetic tests showed a pathogenic, homozygous, c.3G>T (p.Met1Ile) mutation (rs119103249) in the first codon of ETHE1 gene. Ethylmalonic encephalopathy (EE) is caused by mutations in the ETHE1 gene, which codes a mitochondrial sulfur dioxygenase. Accumulation of hydrogen sulfide is attributable to loss-of-function mutations of ETHE1 gene. Therefore, elevated levels of hydrogen sulfide are responsible for the inhibition of cytochrome c oxidase and degradation of short-chain acyl CoA dehydrogenase subunits in the colonic mucosa, muscle, and brain. Vascular lesions in the skin and other organs are observed due to vasoactive and vasotoxic effects [1]. In the literature, multiple cavitations in relation to EE have been reported as rare. Pigeon et al. reported monochorionic twins diagnosed with EE who had neuroimaging changes affecting the white matter, corpus callosum, and basal ganglia as leukoencephalopathy and cavitation [2]. According to the MRI findings of leukoencephalopathy and multiple cavitations, differential diagnosis should consider diseases related to nuclear mitochondrial defects and the spectrum of white matter lesions in OXPHOS (oxidative phosphorylation)-related disorders, for example, mutations in NDUFS1 with isolated complex I deficiency associated with progressive cavitating leukoencephalopathy (PCL), mutations in LYRM7 with the defect of * Nihal Olgac Dundar nodundar@gmail.com