Investigation of genotype-phenotype and familial features of Turkish dystrophinopathy patients.

Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are X-linked recessive allelic muscle diseases caused by dystrophin gene mutations. Eight hundred thirty-seven patients admitted between 1997 and 2022 were included in the study. Two hundred twenty patients were analyzed by multiplex PCR (mPCR) alone. Five hundred ninety-five patients were investigated by multiplex ligation-dependent probe amplification (MLPA), and 54 patients were examined by sequencing. Deletion was detected in 60% (132/220) of the cases in the mPCR group only and in 58.3% (347/595) of the cases with MLPA analysis. The rates of deletion and duplication were 87.7% and 12.3%, respectively, in the MLPA analysis. Single exon deletions were the most common mutation type. The introns 43-55 (81.8%) and exons 2-21 (13.1%) regions were detected as hot spots in deletions. It was determined that 89% of the mutations were suitable for exon skipping therapy. The reading frame rule did not hold in 7.6% of D/BMD cases (17/224). We detected twenty-five pathogenic/likely pathogenic variants in sequencing, five of which were novel variants. Nonsense mutation was the most common small mutation (44%). 21% of DMD patients were familial. We detected germline mosaicism in four families (4.3%) in the large rearrangement group and one gonosomal mosaicism in a family with a nonsense mutation. This is the largest study examining genotype and phenotype data in Turkish D/BMD families investigated by MLPA analysis. The reading frame hypothesis is not valid in all cases. Sharing the genotype and phenotype characteristics of these cases in the literature will shed light on the molecular structure of DMD and guide gene therapy research. In genetic counseling, carrier screening in the family and possible gonadal mosaicism should be emphasized.

Alternative splicing expands the clinical spectrum of NDUFS6-related mitochondrial disorders.

PURPOSE: We describe 3 families with Charcot-Marie-Tooth neuropathy (CMT), harboring a homozygous NDUFS6 NM_004553.6:c.309+5G>A variant previously linked to fatal Leigh syndrome. We aimed to characterize clinically and molecularly the newly identified patients and understand the mechanism underlying their milder phenotype. METHODS: The patients underwent extensive clinical examinations. Exome sequencing was done in 4 affected individuals. The functional effect of the c.309+5G>A variant was investigated in patient-derived EBV-transformed lymphoblasts at the complementary DNA, protein, and mitochondrial level. Alternative splicing was evaluated using complementary DNA long-read sequencing. RESULTS: All patients presented with early-onset, slowly progressive axonal CMT, and nystagmus; some exhibited additional central nervous system symptoms. The c.309+5G>A substitution caused the expression of aberrantly spliced transcripts and negligible levels of the canonical transcript. Immunoblotting showed reduced levels of mutant isoforms. No detectable defects in mitochondrial complex stability or bioenergetics were found. CONCLUSION: We expand the clinical spectrum of NDUFS6-related mitochondrial disorders to include axonal CMT, emphasizing the clinical and pathophysiologic overlap between these 2 clinical entities. This work demonstrates the critical role that alternative splicing may play in modulating the severity of a genetic disorder, emphasizing the need for careful consideration when interpreting splice variants and their implications on disease prognosis.

Anaemia-based screening for resistance to thyroid hormone alpha in children.

BACKGROUND: The hypothyroid phenotype associated with resistance to thyroid hormone alpha (RTH-α) is associated with a diverse clinical picture. On the other hand, thyroid-stimulating hormone (TSH) levels are normal. Free triiodothyronine (fT3) and free thyroxine (fT4) levels can also be normal; however, normo- or macrocytic anaemia is usually present in reported cases. Diagnosis is challenging and there is limited data regarding screening methods. OBJECTIVE: The study aimed to assess the efficiency of a screening strategy for RTH-α. SUBJECTS AND METHODS: Out of a total of 6540 children evaluated at the outpatient clinics of paediatric neurology over 2 years and who underwent complete blood count and thyroid function tests, 432 were found to have anaemia. Within this group, we identified 42 children without an underlying specific neurological aetiology who exhibited normo- or macrocytic anaemia, normal TSH levels, fT3 levels in the upper half of the normal range or high, and fT4 levels in the lower half of the normal range or low. We excluded one patient who had already been diagnosed with RTH-α and nine patients could not be reached. Subsequently, clinical evaluation, biochemical assessment, and THRA sequencing analysis were conducted on 32 children. The findings were compared with those of the known RTH-α patients in our unit. RESULTS: The median age of the patients was 5.7 (5.1-7.4) years, and 22 of them were males (69%). The main reasons for assessment in paediatric neurology clinics were autism spectrum disorder (n = 12, 38%), epilepsy (n = 11, 34%), and delay in developmental stages (n = 8, 25%). Constipation was present in five of the cases (16%), while the closure of the anterior fontanelle and tooth eruption were delayed in two cases (6%) and one case (3%), respectively. The median length/height and weight standard deviation (SD) scores were 0.3 [(-0.8)-(1.1)] and -0.1 [(-0.8)-(0.3)], respectively. The median fT3, fT4, and TSH levels were 4.6 (4.2-5.0) pg/mL, 0.9 (0.8-1.0) ng/dL, and 2.2 (1.8-3.1) uIU/mL, respectively. Thirteen of the patients (41%) had high fT3 levels, while none of them had low fT4 levels. The normo- or macrocytic anaemia rate was 47% (normocytic/macrocytic, n = 8/7) at the time of reassessment. Serum creatine kinase (CK) was elevated in five patients (16%; one had anaemia). None of the subjects had a pathological variant in THRA. Known RTH-α patients had significantly lower median height SD score, higher rates of delayed tooth eruption and closure of the anterior fontanelle, lower haemoglobin levels, and higher mean corpuscular volume (MCV) and CK levels as compared to those found without RTH-α. CONCLUSIONS: This approach found one known patient with RTH-α but did not reveal any new cases. Notably, normo- or macrocytic anaemia did not persist in nearly half of the screened patients. A screening strategy that takes clinical findings and prominent laboratory features suggestive of RTH-α into account could lower unnecessary genetic analysis of THRA in patients presenting with neurological problems.

Evaluation of the Patients with the Diagnosis of Pontocerebellar Hypoplasia: A Multicenter National Study.

Pontocerebellar hypoplasia (PCH) is a heterogeneous group of neurodegenerative disorders characterized by hypoplasia and degeneration of the cerebellum and pons. We aimed to identify the clinical, laboratory, and imaging findings of the patients with diagnosed PCH with confirmed genetic analysis. We collected available clinical data, laboratory, and imaging findings in our retrospective multicenter national study of 64 patients with PCH in Turkey. The genetic analysis included the whole-exome sequencing (WES), targeted next-generation sequencing (NGS), or single gene analysis. Sixty-four patients with PCH were 28 female (43.8%) and 36 (56.3%) male. The patients revealed homozygous mutation in 89.1%, consanguinity in 79.7%, pregnancy at term in 85.2%, microcephaly in 91.3%, psychomotor retardation in 98.4%, abnormal neurological findings in 100%, seizure in 63.8%, normal biochemistry and metabolic investigations in 92.2%, and dysmorphic findings in 51.2%. The missense mutation was found to be the most common variant type in all patients with PCH. It was detected as CLP1 (n = 17) was the most common PCH related gene. The homozygous missense variant c.419G > A (p.Arg140His) was identified in all patients with CLP1. Moreover, all patients showed the same homozygous missense variant c.919G > T (p.A307S) in TSEN54 group (n = 6). In Turkey, CLP1 was identified as the most common causative gene with the identical variant c.419G > A; p.Arg140His. The current study supports that genotype data on PCH leads to phenotypic variability over a wide phenotypic spectrum.

Feasibility of virtual reality and comparison of its effectiveness to biofeedback in children with Duchenne and Becker muscular dystrophies.

INTRODUCTION/AIMS: The utilization of virtual reality (VR) and biofeedback training, while effective in diverse populations, remains limited in the treatment of Duchenne and Becker muscular dystrophies (D/BMD). This study aimed to determine the feasibility of VR in children with D/BMD and compare the effectiveness of VR and biofeedback in children with D/BMD. METHODS: The study included 25 children with D/BMD. Eight children in the control group participated in a routine follow-up rehabilitation program, while the remaining children were randomly assigned to the VR (n = 9) and biofeedback (n = 8) groups for a 12-week intervention. The following evaluations were performed before, during (week 6), and after treatment: Muscle pain and cramps, laboratory studies, muscle strength, timed performance, function (Motor Function Measurement Scale-32, Vignos, and Brooke Scales), and balance (Pediatric Functional Reach Test and Balance Master System). Motivation for rehabilitation was determined. RESULTS: The median ages were 9.00 (VR), 8.75 (biofeedback), and 7.00 (control) years. The study found no significant differences between groups in pretreatment assessments for most measures, except for tandem step width (p < .05). VR and biofeedback interventions significantly improved various aspects (pain intensity, cramp frequency, cramp severity, muscle strength, timed performance, functional level, and balance) in children with D/BMD (p < .05), while the conventional rehabilitation program maintained patients' current status without any changes. The study found VR and biofeedback equally effective, with VR maintaining children's motivation for rehabilitation longer (p < .05). DISCUSSION: The study showed that both VR and biofeedback appear to be effective for rehabilitation this population, but additional, larger studies are needed.

High diagnostic rate of trio exome sequencing in consanguineous families with neurogenetic diseases.

Consanguineous marriages have a prevalence rate of 24% in Turkey. These carry an increased risk of autosomal recessive genetic conditions, leading to severe disability or premature death, with a significant health and economic burden. A definitive molecular diagnosis could not be achieved in these children previously, as infrastructures and access to sophisticated diagnostic options were limited. We studied the cause of neurogenetic disease in 246 children from 190 consanguineous families recruited in three Turkish hospitals between 2016 and 2020. All patients underwent deep phenotyping and trio whole exome sequencing, and data were integrated in advanced international bioinformatics platforms. We detected causative variants in 119 known disease genes in 72% of families. Due to overlapping phenotypes 52% of the confirmed genetic diagnoses would have been missed on targeted diagnostic gene panels. Likely pathogenic variants in 27 novel genes in 14% of the families increased the diagnostic yield to 86%. Eighty-two per cent of causative variants (141/172) were homozygous, 11 of which were detected in genes previously only associated with autosomal dominant inheritance. Eight families carried two pathogenic variants in different disease genes. De novo (9.3%), X-linked recessive (5.2%) and compound heterozygous (3.5%) variants were less frequent compared to non-consanguineous populations. This cohort provided a unique opportunity to better understand the genetic characteristics of neurogenetic diseases in a consanguineous population. Contrary to what may be expected, causative variants were often not on the longest run of homozygosity and the diagnostic yield was lower in families with the highest degree of consanguinity, due to the high number of homozygous variants in these patients. Pathway analysis highlighted that protein synthesis/degradation defects and metabolic diseases are the most common pathways underlying paediatric neurogenetic disease. In our cohort 164 families (86%) received a diagnosis, enabling prevention of transmission and targeted treatments in 24 patients (10%). We generated an important body of genomic data with lasting impacts on the health and wellbeing of consanguineous families and economic benefit for the healthcare system in Turkey and elsewhere. We demonstrate that an untargeted next generation sequencing approach is far superior to a more targeted gene panel approach, and can be performed without specialized bioinformatics knowledge by clinicians using established pipelines in populations with high rates of consanguinity.

Sural Sparing Pattern and Sensory Ratio as Electrodiagnostic and Prognostic Markers in Pediatric Guillain-Barré Syndrome.

BACKGROUND: We aimed to evaluate the presence of sural sparing pattern (SSP) and sensory ratio in pediatric Guillain-Barré syndrome (GBS), their distribution to subtypes, and their relationship with demographic and clinical features with a focus on the disability and muscle strength. METHODS: This single-center retrospective study was conducted on pediatric GBS patients of both sexes with 2 years follow-up and two nerve conduction studies in which SSP and sensory ratio were calculated. Three subgroups of SSP were formed by separate calculation of median (SSP-m) and ulnar (SSP-u) and both median and ulnar sensory nerve action potentials (SNAPs; SSP-total). Muscle strength and disability were evaluated with the Medical Research Council (MRC) sum score and Hughes functional grading scale (HFGS), respectively. RESULTS: SSP total was identified in 70.6% (n: 24) of the patients, while sensory ratio >1 was observed in 20 (66.7%) patients. Patients with SSP-m, SSP-u, SSP-total, or sensory ratio >1 had higher HFGS scores, while patients with SSP-m, SSP-u, or SSP-total had lower MRC sum scores. SSP parameters were significantly associated with muscle strength and disability scores in acute motor axonal neuropathy patients. CONCLUSION: Both SSP and sensory ratio can be used for diagnostic and prognostic purposes. Disability and muscle strength are associated with SSP and sensory ratio in pediatric GBS.

What is the safe observation period for seizure recurrence in pediatric emergency departments?

BACKGROUND: Afebrile seizures are the common causes of emergency department (ED) admissions in childhood, and there is limited data on the observation period in emergency service follow-up of these patients in terms of seizure recurrence in the literature. This study aims to determine the seizure recurrence time in afebrile seizures and the risk factors that determine it. METHODS: Patients aged between 1 month and 18 years with afebrile seizures were included in the study. Seizure recurrence times, demographic data, diagnosis of epilepsy, use of antiseizure medications, Electroencephalography (EEG) and imaging results, structural abnormalities, hospitalizations, and treatments were recorded. RESULTS: The median age of 623 patients included in the study was 42 months (16.0-94.0 months) and 59.9% were male. Epilepsy was diagnosed in 372 (59.7%) of the patients. Short-acting benzodiazepine was administered in 249 of the cases. The mean observation time of the patients was 36 hours (24-98 hours). Electroencephalography (EEG) was applied in 437 (70.1%) of the patients and abnormality was detected in 53.5%. Seizure recurrence was observed in 149 patients (23.9%). The median time of seizure recurrence was 1.0 hour (0.5-4.0 hours). Eighty-six percent of the seizure recurrences (n = 129) occurred within the first six hours and 95.3% (n = 142) within the first 12 hours. Risk factors included a history of febrile seizures (p = 0.001, OR = 2.7), not receiving short-acting benzodiazepine therapy (p = 0.026, OR 1.7), previous structural abnormalities (p = 0.018, OR 1.8), and cluster seizures (p = 0.001, OR 6.7) for all patients and also EEG abnormalities in pediatric ED for first seizure (p = 0.012, OR 2.4). CONCLUSION: Patients with a history of febrile seizure, previous structural abnormalities, cluster seizures, EEG abnormalities in pediatric ED, and patients who didn't receive BZD treatment were at risk for seizure recurrence in the early period. Since most seizure recurrences occur within the first 6 hours, this period is the most critical time for recurrence risk.

Heterogeneity of PNPT1 neuroimaging: mitochondriopathy, interferonopathy or both?

BACKGROUND: Biallelic variants in PNPT1 cause a mitochondrial disease of variable severity. PNPT1 (polynucleotide phosphorylase) is a mitochondrial protein involved in RNA processing where it has a dual role in the import of small RNAs into mitochondria and in preventing the formation and release of mitochondrial double-stranded RNA into the cytoplasm. This, in turn, prevents the activation of type I interferon response. Detailed neuroimaging findings in PNPT1-related disease are lacking with only a few patients reported with basal ganglia lesions (Leigh syndrome) or non-specific signs. OBJECTIVE AND METHODS: To document neuroimaging data in six patients with PNPT1 highlighting novel findings. RESULTS: Two patients exhibited striatal lesions compatible with Leigh syndrome; one patient exhibited leukoencephalopathy and one patient had a normal brain MRI. Interestingly, two unrelated patients exhibited cystic leukoencephalopathy resembling RNASET2-deficient patients, patients with Aicardi-Goutières syndrome (AGS) or congenital CMV infection. CONCLUSION: We suggest that similar to RNASET2, PNPT1 be searched for in the setting of cystic leukoencephalopathy. These findings are in line with activation of type I interferon response observed in AGS, PNPT1 and RNASET2 deficiencies, suggesting a common pathophysiological pathway and linking mitochondrial diseases, interferonopathies and immune dysregulations.

The psychometric properties of Turkish version of the Modified Paediatric Mini Mental Scale.

BACKGROUND: Children with neurological diseases suffer from neurocognitive problems due to both the disease and the treatment processes. Therefore, it is necessary that a battery can be used to determine and track the cognitive function of these children. The aim of this study is to establish the Turkish version of the Modified Paediatric Mini Mental Scale (MPMMS), ensure its cultural adaptation, and test the validity and reliability of the Turkish version of the MPMMS. METHODS: Sixty-five children with the neurological condition were enrolled in this methodological study. The subjects' age, height, weight, and body mass index were recorded. The MPMMS and the social function subscale of the Paediatric Evaluation of Disability Inventory (PEDI) were used to assess the participants' cognitive function. The construct validity of the questionnaire was determined by the correlation between the MPMMS and the social function subscale of the PEDI. Cronbach's alpha was calculated to determine internal consistency. To determine test-retest reliability, 32 children were assessed 7-14 days after the initial assessment, and the intraclass correlation coefficient (ICC) was calculated. RESULTS: The mean age of the participants was 9.26 ± 3.87 years. A very strong significant correlation was found between the MPMMS and social function subscale of the PEDI (r = 0.935, p = 0.000). The internal consistency of the MPMMS was excellent (Cronbach's alpha = 0.932). CONCLUSIONS: The Turkish version of the MPMMS has excellent validity and reliability and can be used by professionals in various health care settings to determine children's cognitive abilities.

Examination of the psychometric properties of pediatric-modified total neuropathy score in Turkish children with cancer.

BACKGROUND: Evaluation of chemotherapy-induced peripheral neuropathy has gained importance in symptom management of pediatric patients with cancer. This study aimed to perform the Turkish validity and reliability study of the Pediatric-Modified Total Neuropathy Score (Ped-mTNS). METHODS: A methodological, descriptive, and cross-sectional design was used in the study. Forty children aged between 5 and 18 and were treated for cancer and 40 age- and gender-matched healthy children (control group) were included in the study. The mean scores of the items on the Ped-mTNS were compared, and item-total score correlations were evaluated. Cronbach's alpha coefficient of the Ped-mTNS was calculated for internal consistency. FINDINGS: Cronbach's alpha value of the scale was found as 0.709. The item-total correlations of the scale items ranged from 0.260 to 0.658. The mean score of cancer patients on the Ped-mTNS was found as 4.4 ± 3.8. DISCUSSION: Ped-mTNS scores of children with cancer indicated more deficits than those of the control group. In the evaluation of children in the patient and control groups, a difference was found in terms of light touch sensation, which is one of the sensory symptoms in the items of the Ped-mTNS, and pin sensibility and strength, which are among the clinical symptoms. APPLICATION TO PRACTICE: The Ped-mTNS was determined to be a valid and reliable measurement tool for children with cancer aged between 5 and 18 in the Turkish population.

Evaluation of vincristine-induced peripheral neuropathy in children with cancer: Turkish validity and reliability study.

BACKGROUND: The evaluation of peripheral neuropathy in children receiving Vincristine treatment is challenging. This study examined the Turkish validity and reliability of the Total Neuropathy Score-Pediatric Vincristine (TNS-PV) measurement tool, which can measure Vincristine-induced peripheral neuropathy symptoms in children with cancer. METHODS: A total of 53 children aged 5-17 years who received Vincristine treatment in two pediatric hematology-oncology centers participated in the study. Data was collected using the Total Neuropathy Score-Pediatric Vincristine (TNS-PV), the Common Terminology Criteria for Adverse Events (CTCAE), the Wong-Baker FACES Pain Scale, and the Adolescent Pediatric Pain Tool (APPT). The correlation between the TNS-PV total score and other scales and the inter-rater reliability coefficient was evaluated. FINDINGS: Of the children, 81.1% were diagnosed with ALL and 13.2% with Ewing Sarcoma. Cronbach's alpha values of form A and B of the TNS-PV scale were 0.628 and 0.639, respectively. As the cumulative Vincristine dose increased, the children's scores on TNS-PV were higher. A moderate and significant positive correlation was found between the TNS-PV form A total score and the worst subjective symptoms a, b (A), strength, tendon reflexes, and autonomic / constipation (r = 0.441, r = 0.545, r = 0.472, r = 0.536, p < 0.01). DISCUSSION: The TNS-PV form B total score was found to have a moderate level, significant correlation with CTCAE sensory neuropathy score and Wong-Baker FACES Pain Scale, and a high level, significant positive correlation with CTCAE motor neuropathy score. APPLICATION TO PRACTICE: The TNS-PV is valid and reliable for measuring Vincristine-induced peripheral neuropathy in practice in Turkish children 5 years and older.

The Effect of Nusinersen Therapy on Laboratory Parameters of Patients with Spinal Muscular Atrophy.

INTRODUCTION: We evaluated the effect of nusinersen on clinical and laboratory parameters and presented its safety and effect on laboratory parameters. METHODS: Two groups were formed from among patients with spinal muscular atrophy (SMA) followed up between September 2017 and June 2021: group 1, SMA type 1; group 2, SMA type 2 and 3. The laboratory parameters were evaluated in groups 1 and 2 between doses. Motor scale tests were performed on patients before each dose of nusinersen. RESULTS: Twenty seven patients (group 1; n = 13, group 2; n = 14) were included. The mean age (±standard deviation) at the onset of symptoms was 3 ± 1.21 (range, 1.5-6) months in group 1 and 12 ± 4.27 (range, 8-24) months in group 2. No significant laboratory treatment-related abnormalities and adverse effects were observed. The cerebrospinal fluid protein levels and the frequency of conventional LP were higher in group 1. Serum creatinine (Cr) levels were higher in group 1 before the first dose and higher in group 2 before the fifth dose (p < 0.05). With treatment, the Cr levels of group 1 decreased and group 2 remained constant or increased. We observed that the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders and Hammersmith Functional Motor Scale-Expand scores increased as our patients received treatment (p < 0.05). CONCLUSION: Our results support the safety and efficacy of nusinersen. However, changes in Cr levels according to the clinical type and treatment suggested that serum Cr could be a candidate marker for treatment follow-up.

The COVID-19 pandemic restrictions affect the healthcare and health status of paediatric patients with neuromuscular diseases: a developing country perspective.

PURPOSE: The COVID-19 pandemic has forced the rapid and unprecedented reorganisation of current practices in the treatment of neuromuscular disorders (NMD). Cessation of care and treatments can worsen the underlying condition, exacerbate symptoms, and increase anxiety, leading to a vicious circle and increased management concerns. This study aims to determine the changes in healthcare and health status of children with NMD from a developing country perspective. MATERIALS AND METHODS: Forty-seven children with NMD were included in this cross-sectional study. The participants were contacted via phone call. The survey conducted for the study was included demographic data, changes and problems in healthcare, perceived health status change, and satisfaction with the services provided. Descriptive statistics were used to characterise the sample. RESULTS: The mean age of the children was 7.86 ± 3.45 years. The participants encountered 24.83 ± 26.54% of difficulties in getting medication care, and there was 69.95 ± 24.47% disruption in accessing routine medical care. The participants' rehabilitation sessions were disrupted in the 78.54 ± 14.93%, and there were 95.83 ± 10.03% deficiencies in therapists' informing. Children with NMD indicated that their perceived health status decreased compared to before pandemic in all parameters. CONCLUSION: This study highlights the unfavourable indirect effect of the COVID-19 pandemic restrictions on healthcare and health status of paediatric patients with NMD. Since the COVID-19 pandemic is an uncertain process, the solutions or modifications should be promptly put into effect to improve the healthcare and health status of children with NMD.

Inflammation and endothelial dysfunction in pediatric migraine patients.

BACKGROUND: Inflammation and endothelial dysfunction are the suggested underlying mechanisms in migraine. Pentraxins, C-reactive protein, erythrocyte sedimentation rate, neutrophil to lymphocyte ratio, platelet to lymphocyte ratio are good indicators of inflammation. Alterations in insulin levels and insulin sensitivity may trigger endothelial dysfunction. This study evaluates the association between migraine and serum biomarkers of inflammation and endothelial dysfunction in children. METHODS: Children with migraine and healthy subjects were recruited. Serum samples were obtained in an attack-free period. We collected data on serum levels of complete blood cell count, C-reactive protein, erythrocyte sedimentation rate, pentraxin-3, and data from biochemical investigations. We compared these with clinical data such as age, sex, disease duration, attack frequency, attack duration, analgesic use, family history, and Pediatric Migraine Disability Assessment Questionnaire scores. RESULTS: We assessed samples from 32 children (11 boys, 21 girls) with migraine and 19 healthy controls (8 boys, 11 girls). We found significantly higher pentraxin-3, insulin, and insulin resistance in patients with migraine (P = 0.001, P = 0.032, and P = 0.008, respectively). A positive directional correlation is found between pentraxin-3 and Pediatric Migraine Disability Assessment Questionnaire scores. The best cut-off values for pentraxin-3 is determined between 12.75 pg/mL to 15 pg/mL in migraineurs. CONCLUSIONS: In conclusion increased pentraxin-3 levels support the suggestions that inflammation plays a role in pediatric migraine. The vascular endothelial dysfunction is observed by a rise in insulin and insulin resistance levels. Our findings support the idea that ongoing inflammation and vascular endothelial dysfunction between attacks may play a role in migraine pathogenesis in children.

Blood neurofilament light chain and thrombospondin-1 levels of patients with autism spectrum disorder.

BACKGROUND: Neurofilaments are intermediary filaments associated with neurodegenerative processes. Thrombospondin-1 (TSP-1) is a biological marker playing a role in synaptogenesis. This study aimed to investigate serum neurofilament light chain (NFL), and TSP1 levels of patients with autism spectrum disorder (ASD) compared to typically developing (TD) children. METHODS: Forty-three patients with ASD and forty-five TD children were included. Serum biomarker levels were measured using the sandwich ELISA technique. The Childhood Autism Rating Scale (CARS) was implemented to measure the severity of ASD. RESULTS: NFL and TSP1 levels did not differ between study groups (For NFL, ASD = 47.8 ± 11.4 vs. TD = 48.2 ± 15.3 pg/mL, p = 0.785; for TSP1, ASD = 224.4 ± 53.7 vs. TD = 224.7 ± 69.0 ng/mL, p = 0.828). Stereotyped behavior and sensory sensitivity domain of the CARS scale was negatively correlated with serum TSP-1 (r = -0.390, p = 0.010) and NFL (r = -0.377, p = 0.013) levels. Age was also positively correlated with NFL levels (r = 0.332, p = 0.030) in the ASD groups but not in the TD group. DISCUSSION: Our results did not support the neurodegenerative process of ASD. Future studies are needed to investigate neuroprogression in a longitudinal follow-up.

Genomic variants causing mitochondrial dysfunction are common in hereditary lower motor neuron disease.

Hereditary lower motor neuron diseases (LMND) other than 5q-spinal muscular atrophy (5q-SMA) can be classified according to affected muscle groups. Proximal and distal forms of non-5q-SMA represent a clinically and genetically heterogeneous spectrum characterized by significant overlaps with axonal forms of Charcot-Marie-Tooth (CMT) disease. A consensus for the best approach to molecular diagnosis needs to be reached, especially in light of continuous novel gene discovery and falling costs of next-generation sequencing (NGS). We performed exome sequencing (ES) in 41 families presenting with non-5q-SMA or axonal CMT, 25 of which had undergone a previous negative neuromuscular disease (NMD) gene panel analysis. The total diagnostic yield of ES was 41%. Diagnostic success in the cohort with a previous NMD-panel analysis was significantly extended by ES, primarily due to novel gene associated-phenotypes and uncharacteristic phenotypic presentations. We recommend early ES for individuals with hereditary LMND presenting uncharacteristic or significantly overlapping features. As mitochondrial dysfunction was the underlying pathomechanism in 47% of the solved individuals, we highlight the sensitivity of the anterior horn cell and peripheral nerve to mitochondrial imbalance as well as the necessity to screen for mitochondrial disorders in individuals presenting predominant lower motor neuron symptoms.

Biallelic Mutations in ADPRHL2, Encoding ADP-Ribosylhydrolase 3, Lead to a Degenerative Pediatric Stress-Induced Epileptic Ataxia Syndrome.

ADP-ribosylation, the addition of poly-ADP ribose (PAR) onto proteins, is a response signal to cellular challenges, such as excitotoxicity or oxidative stress. This process is catalyzed by a group of enzymes referred to as poly(ADP-ribose) polymerases (PARPs). Because the accumulation of proteins with this modification results in cell death, its negative regulation restores cellular homeostasis: a process mediated by poly-ADP ribose glycohydrolases (PARGs) and ADP-ribosylhydrolase proteins (ARHs). Using linkage analysis and exome or genome sequencing, we identified recessive inactivating mutations in ADPRHL2 in six families. Affected individuals exhibited a pediatric-onset neurodegenerative disorder with progressive brain atrophy, developmental regression, and seizures in association with periods of stress, such as infections. Loss of the Drosophila paralog Parg showed lethality in response to oxidative challenge that was rescued by human ADPRHL2, suggesting functional conservation. Pharmacological inhibition of PARP also rescued the phenotype, suggesting the possibility of postnatal treatment for this genetic condition.

The Complex Genetic Landscape of Hereditary Ataxias in Turkey and Implications in Clinical Practice.

BACKGROUND: The genetic and epidemiological features of hereditary ataxias have been reported in several populations; however, Turkey is still unexplored. Due to high consanguinity, recessive ataxias are more common in Turkey than in Western European populations. OBJECTIVE: To identify the prevalence and genetic structure of hereditary ataxias in the Turkish population. METHODS: Our cohort consisted of 1296 index cases and 324 affected family members. Polymerase chain reaction followed by Sanger sequencing or fragment analysis were performed to screen for the trinucleotide repeat expansions in families with a dominant inheritance pattern, as well as in sporadic cases. The expansion in the frataxin (FXN) gene was tested in all autosomal recessive cases and in sporadic cases with a compatible phenotype. Whole-exome sequencing was applied to 251 probands, selected based on the family history, age of onset, and phenotype. RESULTS: Mutations in known ataxia genes were identified in 30% of 1296 probands. Friedreich's ataxia was found to be the most common recessive ataxia in Turkey, followed by autosomal recessive spastic ataxia of Charlevoix-Saguenay. Spinocerebellar ataxia types 2 and 1 were the most common dominant ataxias. Whole-exome sequencing was performed in 251 probands with an approximate diagnostic yield of 50%. Forty-eight novel variants were found in a plethora of genes, suggesting a high heterogeneity. Variants of unknown significance were discussed in light of clinical data. CONCLUSION: With the large sample size recruited across the country, we consider that our results provide an accurate picture of the frequency of hereditary ataxias in Turkey. © 2021 International Parkinson and Movement Disorder Society.

Clinical and genetic characterization of PYROXD1-related myopathy patients from Turkey.

Congenital myopathies (CMs) are a heterogeneous group of inherited muscle disorders characterized by muscle weakness at birth, while limb-girdle muscular dystrophies (LGMD) have a later onset and slower disease progression. Thus, detailed clinical phenotyping of genetically defined disease entities are required for the full understanding of genotype-phenotype correlations. A recently defined myopathic genetic disease entity is caused by bi-allelic variants in a gene coding for pyridine nucleotide-disulfide oxidoreductase domain 1 (PYROXD1) with unknown substrates. Here, we present three patients from two consanguineous Turkish families with mild LGMD, facial weakness, normal CK levels, and slow progress. Genomic analyses revealed a homozygous known pathogenic missense variant (c.464A>G, p.Asn155Ser) in family 1 with two affected females. In the affected male of family 2, we found this variant in a compound heterozygous state together with a novel frameshift variant (c.329_332delTCTG, p.Leu112Valfs*8), which is the second frameshift variant known so far in PYROXD1. We have been able to define a large homozygous region in family 1 sharing a common haplotype with family 2 in the critical region. Our data suggest that c.464A>G is a Turkish founder mutation. To gain deeper insights, we performed a systematic review of all published PYROXD1-related myopathy cases. Our analysis showed that the c.464A > G variant was found in 87% (20/23) of the patients and that it may cause either a childhood- or adult-onset phenotype, irrespective of its presence in a homozygous or compound heterozygous state. Interestingly, only four patients had elevated CK levels (up to 1000 U/L), and cardiac involvement was found in few compound heterozygous cases.