Publications by authors named "Didem Ardicli"

13 Publications

  • Page 1 of 1

Unraveling neuronal ceroid lipofuscinosis type 2 (CLN2) disease: A tertiary center experience for determinants of diagnostic delay.

Eur J Paediatr Neurol 2021 Jun 4;33:94-98. Epub 2021 Jun 4.

Hacettepe University Faculty of Medicine, Department of Pediatrics, Division of Pediatric Neurology, Ankara, Turkey. Electronic address:

Objective: To evaluate the clinical phenotype, disease course, laboratory, and genetic features of patients with CLN2 disease over a 20 year period with a special emphasis on risk factors for diagnostic delay.

Methods: Thirty patients (23 families) with CLN2 disease, evaluated between 1996 and 2019 in a tertiary referral center in Turkey, were included. Clinical features, diagnostic pathway, disease course, genetic data, electrophysiological, and neuroimaging findings were analyzed, retrospectively. The patients diagnosed between 1996 and 2009, and 2010-2019 were defined as group 1 (G1), and group 2 (G2), respectively. Patients in these two groups were also compared.

Results: The median age at symptom-onset was 36 months (20 months-7 years). Most common presenting symptoms were seizures (70%), followed by language delay (43%), and psychomotor regression (27%). Median age at diagnosis was 5.2 years (1.6-11 years) with a median 27 months (1 month-7 years) of diagnostic delay. Age at diagnosis was earlier in G2 (4.6 years vs 7 years, p = 0.002), with a shorter time to diagnosis (21 months vs 39 months, p = 0.004). Median time between the onset of first symptoms and death was 8.3 years (SE 1.0). Electroencephalograms (EEG) revealed abnormal features predominantly in posterior hemispheral regions and a photoparoxysmal response to intermittent photic stimulation was detected in 53% of the patients. Cerebellar (96%)/cerebral atrophy (83%), and white matter changes (57%) were the most common radiological abnormalities.

Conclusions: Most of our patients presented with late-infantile onset seizures. Despite increased availability of enzymatic and molecular testing, there is still a considerable diagnostic delay.
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http://dx.doi.org/10.1016/j.ejpn.2021.05.015DOI Listing
June 2021

Selenoprotein N-related myopathy: a retrospective natural history study to guide clinical trials.

Ann Clin Transl Neurol 2020 11 10;7(11):2288-2296. Epub 2020 Oct 10.

The Dubowitz Neuromuscular Centre, Developmental Neuroscience Program, UCL Great Ormond Street Institute of Child Health, Great Ormond Street Hospital, London, UK.

Objective: To describe clinical features and disease progression of Selenoprotein N-related myopathy in a large multicenter cohort of patients.

Methods: Cross-sectional multicenter data analysis of 60 patients (53 families) with Selenoprotein N-related myopathy and single-center retrospective longitudinal analysis of 25 patients (21 families) over a median period of 5.3 years.

Results: The majority of patients (46/60, 77%) presented before age 2 years with hypotonia, poor head/neck control, and developmental delay. At last assessment (median age 14 years; range 2.5 to 36 years), 10/60 patients had minimal or no ambulation. Ventilatory support was initiated in 50/60 patients at a mean Forced Vital Capacity (FVC) of 38% and at a median age of 13 years. Forty-five/60 patients developed scoliosis (at median age 12.1 years) and 18 had scoliosis surgery at a median age of 13.6 years. Five children needed nasogastric feeds and/or gastrostomy. Longitudinal data analysis on 25 patients showed progressive decline of Hammersmith functional motor scores (estimated annual change -0.55 point), time to walk 10 meter, time standing from sitting, and from lying. Sixteen patients had weights < 2nd centile. The estimated change in FVC % per year was -2.04, with a 95% CI (-2.94, -1.14).

Conclusions: This comprehensive analysis of patients with Selenoprotein N-related myopathy further describes the clinical course of this rare condition. The observed functional motor and respiratory data provide evidence of the slow decline patients experience over time which is useful when considering therapeutic intervention.
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http://dx.doi.org/10.1002/acn3.51218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7664282PMC
November 2020

Long-term effects of vagus nerve stimulation in refractory pediatric epilepsy: A single-center experience.

Epilepsy Behav 2020 09 27;110:107147. Epub 2020 Jun 27.

Hacettepe University Faculty of Medicine, Department of Pediatric Neurology; currently retired from Hacettepe University, Department of Pediatric Neurology.

Introduction: Vagus nerve stimulation (VNS) has been used as an adjunctive therapy for both children and adults with refractory epilepsy, over the last two decades. In this study, we aimed to evaluate the long-term effects and tolerability of VNS in the pediatric drug-resistant epilepsy (DRE) and to identify the predictive factors for responsiveness to VNS.

Methods: We retrospectively reviewed the medical records of pediatric patients who underwent VNS implantation between 1997 and 2018. Patients with ≥50% reduction of seizure frequency compared with the baseline were defined as "responders". The clinical characteristics of responders and nonresponders were compared.

Results: A total of 58 children (male/female: 40/18) with a mean follow-up duration of 5.7 years (3 months to 20 years) were included. The mean age at implantation was 12.4 years (4.5 to 18.5 years). Approximately half (45%) of our patients were responders, including 3 patients (5.8%) who achieved seizure freedom during follow-up. The age of seizure-onset, duration of epilepsy, age at implantation, and etiologies of epilepsy showed no significant difference between responders and nonresponders. Responders were more likely to have focal or multifocal epileptiform discharges (63%) on interictal electroencephalogram (EEG), when compared to nonresponders (36%) (p = .07). Vocal disturbances and paresthesias were the most common side effects, and in two patients, VNS was removed because of local reaction.

Conclusion: Our series had a diverse etiological profile and patients with transition to adult care. Long-term follow-up showed that VNS is an effective and well-tolerated treatment modality for refractory childhood onset epilepsy. Age at implantation, duration of epilepsy and underlying etiology are not found to be predictors of responsiveness to VNS. Higher response rates were observed for a subset of patients with focal epileptiform discharges.
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http://dx.doi.org/10.1016/j.yebeh.2020.107147DOI Listing
September 2020

A novel case of MSTO1 gene related congenital muscular dystrophy with progressive neurological involvement.

Neuromuscul Disord 2019 06 27;29(6):448-455. Epub 2019 Mar 27.

Dubowitz Neuromuscular Centre, MRC Centre for Neuromuscular Diseases, UCL Great Ormond Street Institute of Child Health, London, UK; NIHR Great Ormond Street Hospital Biomedical Research Centre, UCL Great Ormond Street Institute of Child Health, London, UK. Electronic address:

Recessive mutations in the MSTO1 gene, encoding for a mitochondrial distribution and morphology regulator, have been recently described in a very limited number of patients with multisystem involvement, mostly characterized by myopathy or dystrophy, cerebellar ataxia, pigmentary retinopathy and raised creatine kinase levels. Here we report an additional patient with recessive MSTO1-related muscular dystrophy (MSTO1-RD), and clinical and radiological evidence of progressive cerebellar involvement. Whole-exome sequencing identified two novel MSTO1 missense variants, c.766C > T (p. (Arg256Trp) and c.1435C > T (p. (Pro479Ser), predicted as damaging by in silico tools. We also report a distinct pattern of selective involvement on muscle MRI in MSTO1-RD. This case confirms a consistent MSTO1-related neuromuscular phenotype and in addition suggests a progressive neurological component at least in some patients, in keeping with the mitochondrial role of the defective protein.
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http://dx.doi.org/10.1016/j.nmd.2019.03.011DOI Listing
June 2019

Clinical outcomes of two patients with a novel pathogenic variant in : response to asparagine supplementation and review of the literature.

Hum Genome Var 2019 22;6:24. Epub 2019 May 22.

1Faculty of Medicine and University Hospital Cologne, Department of Pediatrics, University of Cologne, 50931 Cologne, Germany.

Asparagine synthetase deficiency (ASNSD, OMIM #615574) is a rare autosomal recessive neurometabolic inborn error that leads to severe cognitive impairment. It manifests with microcephaly, intractable seizures, and progressive cerebral atrophy. Currently, there is no established treatment for this condition. In our pediatric cohort, we discovered, by whole-exome sequencing in two siblings from Turkey, a novel homozygous missense mutation in asparagine synthetase at NM_133436.3 (_v001): c.1108C>T that results in an amino acid exchange p.(Leu370Phe), in the C-terminal domain. After identification of the metabolic defect, treatment with oral asparagine supplementation was attempted in both patients for 24 months. Asparagine supplementation was well tolerated, and no further disease progression was observed during treatment. One of our patients showed mild developmental progress with increased levels of attention and improved nonverbal communication. These results support our hypothesis that asparagine supplementation should be further investigated as a treatment option for ASNSD. We further reviewed all previously reported ASNSD cases with regard for their clinical phenotypes and brain imaging findings to provide an essential knowledge base for rapid diagnosis and future clinical studies.
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http://dx.doi.org/10.1038/s41439-019-0055-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6531480PMC
May 2019

Diagnostic Pathway to Nonsense Mutation Dystrophinopathy: A Tertiary-Center, Retrospective Experience.

Neuropediatrics 2019 02 19;50(1):41-45. Epub 2018 Nov 19.

Department of Pediatric Neurology, Hacettepe University Children's Hospital, Ankara, Turkey.

Up to 15% of Duchenne's muscular dystrophy (DMD) is caused by nonsense mutations (nm-DMD). In this study, we aimed to evaluate the age at diagnosis, presentations, and diagnostic approach in 43 nm-DMD boys. The mean age at presentation and diagnosis was 3 years and 4 years, respectively. Presenting signs or symptoms were asymptomatic creatine kinase (CK) elevation (40%), muscle weakness (30%), motor delay (18%), and walking difficulties (12%). Multiplex polymerase chain reaction (PCR) of the most commonly deleted exons were negative ( = 17), and muscle biopsy was consistent with dystrophinopathy ( = 24). In all patients, multiplex ligation-dependent probe amplification (MLPA) followed by direct sequencing of all exons, revealed nm-DMD. Mean age at genetic diagnosis was 6 years 8 months. Patients were evaluated in two-time periods, between 2006 and 2011 (Group I:  = 10) and 2011 and 2017 (Group II:  = 33). The mean age at diagnosis/genetic confirmation in Group I and in Group II was 3 years 9 months/10 years, and 4 years 1 month/5 years 9 months, respectively. Most frequently performed first step diagnostic tests in Group I and Group II were muscle biopsy and MLPA.Our study reflects the change in the age at genetic diagnosis and diagnostic approach to nm-DMD depending on the advances and availability of genetic testing.
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http://dx.doi.org/10.1055/s-0038-1675626DOI Listing
February 2019

Targeted sequencing with expanded gene profile enables high diagnostic yield in non-5q-spinal muscular atrophies.

Hum Mutat 2018 09 25;39(9):1284-1298. Epub 2018 Jul 25.

Institute of Human Genetics, Center for Molecular Medicine Cologne, Institute of Genetics, and Center for Rare Diseases Cologne, University of Cologne, Cologne, Germany.

Spinal muscular atrophies (SMAs) are a heterogeneous group of disorders characterized by muscular atrophy, weakness, and hypotonia due to suspected lower motor neuron degeneration (LMND). In a large cohort of 3,465 individuals suspected with SMA submitted for SMN1 testing to our routine diagnostic laboratory, 48.8% carried a homozygous SMN1 deletion, 2.8% a subtle mutation, and an SMN1 deletion, whereas 48.4% remained undiagnosed. Recently, several other genes implicated in SMA/LMND have been reported. Despite several efforts to establish a diagnostic algorithm for non-5q-SMA (SMA without deletion or point mutations in SMN1 [5q13.2]), data from large-scale studies are not available. We tested the clinical utility of targeted sequencing in non-5q-SMA by developing two different gene panels. We first analyzed 30 individuals with a small panel including 62 genes associated with LMND using IonTorrent-AmpliSeq target enrichment. Then, additional 65 individuals were tested with a broader panel encompassing up to 479 genes implicated in neuromuscular diseases (NMDs) with Agilent-SureSelect target enrichment. The NMD panel provided a higher diagnostic yield (33%) than the restricted LMND panel (13%). Nondiagnosed cases were further subjected to exome or genome sequencing. Our experience supports the use of gene panels covering a broad disease spectrum for diseases that are highly heterogeneous and clinically difficult to differentiate.
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http://dx.doi.org/10.1002/humu.23560DOI Listing
September 2018

Neonatal-Onset Recurrent Guillain-Barré Syndrome-Like Disease: Clues for Inherited CD59 Deficiency.

Neuropediatrics 2017 12 11;48(6):477-481. Epub 2017 Aug 11.

Department of Pediatric Neurology, Faculty of Medicine, Hacettepe University, Ankara, Turkey.

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http://dx.doi.org/10.1055/s-0037-1604483DOI Listing
December 2017

Congenital mirror movements in a patient with alpha-dystroglycanopathy due to a novel POMK mutation.

Neuromuscul Disord 2017 Mar 23;27(3):239-242. Epub 2016 Dec 23.

Department of Pediatric Neurology, Faculty of Medicine, Hacettepe University, Ankara, Turkey. Electronic address:

Dystroglycanopathies are a heterogeneous group of muscular dystrophies often associated with variable brain and eye involvement. Glycosylated alpha-dystroglycan (ADG) plays a key role in the development and stability of basement membranes as well as organizing axon guidance in the central nervous system. Congenital mirror movements, either isolated or in association with several genetic syndromes, are defined as inability to perform unimanual movements. We report an adolescent boy with limb-girdle muscular dystrophy due to ADG deficiency and coexisting congenital mirror movements. Genetic work-up revealed a novel homozygous missense mutation in the protein O-mannose kinase (POMK) gene. To our knowledge, this is the first patient in the literature with POMK mutation and congenital mirror movements.
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http://dx.doi.org/10.1016/j.nmd.2016.12.008DOI Listing
March 2017

Reversible Hypertensive Myelopathy-The Spinal Cord Variant of Posterior Reversible Encephalopathy Syndrome.

Neuropediatrics 2017 Apr 29;48(2):115-118. Epub 2016 Dec 29.

Department of Pediatric Neurology, Hacettepe University, Ankara, Turkey.

The posterior reversible encephalopathy syndrome (PRES) is a well-known clinical and radiologic entity mainly affecting the territory of the posterior cerebral circulation. Spinal cord involvement is extremely rare, and as of yet, only a few cases have been reported in the literature. The present case describes a reversible, longitudinal spinal cord lesion in a patient with high blood pressure. We discuss the differential diagnosis of longitudinal myelopathy and focus on the clinical presentation, diagnosis, and management of the "spinal cord variant of PRES."
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http://dx.doi.org/10.1055/s-0036-1597612DOI Listing
April 2017

Variants in the Oxidoreductase PYROXD1 Cause Early-Onset Myopathy with Internalized Nuclei and Myofibrillar Disorganization.

Am J Hum Genet 2016 Nov 13;99(5):1086-1105. Epub 2016 Oct 13.

Department of Pediatric Neurology, Hacettepe University Children's Hospital, 06100 Ankara, Turkey.

This study establishes PYROXD1 variants as a cause of early-onset myopathy and uses biospecimens and cell lines, yeast, and zebrafish models to elucidate the fundamental role of PYROXD1 in skeletal muscle. Exome sequencing identified recessive variants in PYROXD1 in nine probands from five families. Affected individuals presented in infancy or childhood with slowly progressive proximal and distal weakness, facial weakness, nasal speech, swallowing difficulties, and normal to moderately elevated creatine kinase. Distinctive histopathology showed abundant internalized nuclei, myofibrillar disorganization, desmin-positive inclusions, and thickened Z-bands. PYROXD1 is a nuclear-cytoplasmic pyridine nucleotide-disulphide reductase (PNDR). PNDRs are flavoproteins (FAD-binding) and catalyze pyridine-nucleotide-dependent (NAD/NADH) reduction of thiol residues in other proteins. Complementation experiments in yeast lacking glutathione reductase glr1 show that human PYROXD1 has reductase activity that is strongly impaired by the disease-associated missense mutations. Immunolocalization studies in human muscle and zebrafish myofibers demonstrate that PYROXD1 localizes to the nucleus and to striated sarcomeric compartments. Zebrafish with ryroxD1 knock-down recapitulate features of PYROXD1 myopathy with sarcomeric disorganization, myofibrillar aggregates, and marked swimming defect. We characterize variants in the oxidoreductase PYROXD1 as a cause of early-onset myopathy with distinctive histopathology and introduce altered redox regulation as a primary cause of congenital muscle disease.
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http://dx.doi.org/10.1016/j.ajhg.2016.09.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5097943PMC
November 2016

Cerebral Hyperperfusion in a Child with Stroke-Like Migraine Attacks after Radiation Therapy Syndrome.

Neuropediatrics 2016 Aug 22;47(4):259-62. Epub 2016 Apr 22.

Department of Pediatric Neurology, Faculty of Medicine, Hacettepe University, Ankara, Turkey.

Stroke-like migraine attacks after radiation therapy (SMART) syndrome is a rare complication of cranial radiotherapy characterized by migraine-like headache and transient neurological deficits with typical gyriform enhancement on magnetic resonance imaging (MRI). Potential underlying mechanisms are endothelial damage or dysfunction, vascular instability, vasospasm and, neuronal dysfunction.We report an 11-year-old girl with a primary diagnosis of medulloblastoma presented with acute-onset severe headache and left-sided weakness, 20 months after completing cranial radiotherapy. MRI demonstrated unilateral cortical swelling and concomitant leptomeningeal, gyral contrast enhancement, and MR perfusion imaging showed increased cortical perfusion in the right temporo-parieto-occipital region. Her symptoms resolved spontaneously over several days.SMART syndrome appears to be a reversible, long-term complication of cranial radiotherapy. So far, a limited number of pediatric patients with SMART syndrome have been reported. Prompt recognition of clinical signs and radiological imaging of SMART syndrome may help prevent unnecessary interventions and initiate appropriate diagnostic workup and management.
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http://dx.doi.org/10.1055/s-0036-1582246DOI Listing
August 2016

Clinical characteristics of type 1 diabetes over a 40 year period in Turkey: secular trend towards earlier age of onset.

J Pediatr Endocrinol Metab 2014 Jul;27(7-8):635-41

Unlabelled: OBJective: To determine the demographic and clinical characteristics of type 1 diabetes (T1D) in the past two decades, and to analyze changing trends over the past 40 years.

Methods: Patients with a diagnosis of T1D in 1990-2010 were included. Patients diagnosed in the first half of the period comprised Period I, and those from the second half comprised Period II. Age at onset, gender, seasonal distribution, infectious etiology, and clinical picture at onset are analyzed and compared in two periods. In addition, we compared these data with that of the preceding two decades (1969-1991), which was reported in a previous publication.

Results: A total of 354 children with T1D were included in the study. The median age at diagnosis of T1D was 7 years in the period 1990-2010 in comparison to 9.5 years during the period 1969-1991. Patients were diagnosed mostly in winter and autumn, and 32.3% of the children had an infection at the time of diagnosis. Frequency of diabetic ketoacidosis was 50.8% at diagnosis. The peak age at onset was 4 to 6 years.

Conclusions: Our study provides substantial information about the clinical characteristics of Turkish children. The age of onset of T1D decreased in the past 20 years, as observed in other parts of the world. Our findings also suggest seasonality at onset of T1D. This study shows the changes of demographic and clinical characteristics of T1D in central and northeastern parts of our country over a 40 year period.
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http://dx.doi.org/10.1515/jpem-2013-0320DOI Listing
July 2014
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