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.

Chromosomal microarray and exome sequencing in unexplained early infantile epileptic encephalopathies in a highly consanguineous population.

AIM: To identify genetic causes for early infantile epileptic encephalopathies (EIEE) in Turkish children with mostly consanguineous parents. METHODS: In a selected EIEE group (N = 59) based on results of nongenetic and initial genetic testing with unexplained etiology, 49 patients underwent array-based comparative genomic hybridization (aCGH) and 49 patients underwent whole exome sequencing (WES) including 39 with negative aCGH results and 10 with WES-only. RESULTS: Diagnostic yield of aCGH and WES for pathogenic or likely pathogenic variants was 14.3% and 38.8%, respectively. Including de novo variants of uncertain significance linked to compatible phenotypes, increased the diagnostic yield of WES to 61.2%. Out of 38 positive variants, 18 (47.4%) were novel and 16 (42.1%) were de novo. Twenty-one (56.8%) patients had recessive variants inherited from mostly consanguineous healthy parents (85.7%). Fourteen (37.8%) of patients with diagnostic results had positive variants in established EIEE genes. Seizures started during neonatal period in 32.4% patients. Posture or movement disorders were comorbid with EIEE in 40.5% of diagnosed patients. We identified treatable metabolic disorders in 8.1% of patients and pathogenic variants in genes which support using targeted medicine in 19% of patients. CONCLUSIONS: Detailed electro-clinical phenotyping led to expansion of some of the known phenotypes with non-neurological and neurological findings in addition to seizures, as well as suggestion of candidate genes (SEC24B, SLC16A2 and PRICKLE2) and a copy number variant (microduplication of Xp21.1p11.4). The high ratio of recessive inheritance could be important for family counseling.

How do presentation age and CSF opening pressure level affect long-term prognosis of pseudotumor cerebri syndrome in children? Experience of a single tertiary clinic.

BACKGROUND: Diagnosis and treatment of pseudotumor cerebri syndrome in children is still a challenge for clinicians. The aim of this study is to reveal the influence of presentation age and CSF opening pressure on long-term prognosis of pseudotumor cerebri and share our clinical data of the very young age (≤ 5-year) group. METHOD: This retrospective study includes the patients followed by the Marmara University Pediatric Neurology Clinic between years 2012 and 2020 diagnosed with definite, probable, or suggestive pseudotumor cerebri syndrome according to modified Friedman criteria. Patients were classified into three groups according to presentation age: group 1: ≤ 5 years old; group 2: 6-10 years; and group 3 > 10 years old. CSF opening pressure was also categorized into three groups as CSF < 20 cmH20; CSF 20-30 cmH20; and CSF > 30 cmH20. RESULTS: One hundred three patients, 62.1% female (n = 64), were enrolled in the study. Group 1 consisted of 16 patients (60% male), group 2 consisted of 30 patients (63.3% female), and group 3 consisted of 57 patients (66.7% female). The mean CSF opening pressure did not differ between the three age groups in our study (p > 0.05). Treatment response was not correlated with CSF opening pressure. Papilledema presence and level of CSF opening pressure were independent of age (p > 0.05). CONCLUSIONS: Age at presentation and CSF opening pressure at diagnosis are not any predictive factors that influence long-term prognosis of pseudotumor cerebri syndrome in children. Evaluation and follow-up of children should be done in personalized approach.

Respiratory outcome of spinal muscular atrophy type 1 patients treated with nusinersen.

BACKGROUND: Respiratory failure is the leading cause of mortality in spinal muscular atrophy type 1 (SMA1) children. The current study aims to evaluate the effect of nusinersen treatment on respiratory outcome of the patients with SMA1. METHODS: In this retrospective, single-center study, 52 SMA1 patients treated with nusinersen were included in the analysis. Patients were divided into two groups based on their age at the time of their first nusinersen treatment (Group 1: ≤6 months, Group 2: >6 months). Respiratory outcome on the 180th day of treatment is defined as the type of ventilation support (spontaneous breathing, noninvasive ventilation (NIV), and tracheostomized or intubated on invasive mechanical ventilation). Demographic data, respiratory outcome, and Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders scores were obtained from medical records. RESULTS: On the 180th day of treatment, 46 of the 52 (88.4%) children were alive. Prevalence of the mortality was similar in both groups (P = 0.65). The comparison of respiratory outcome in patients between group 1 and group 2 was as follows: spontaneous breathing, 7 (43.7%) versus 4 (13.3%) (P = 0.03); NIV <16 h/day, 3 (18.7%) versus 4 (13.3%) (P = 0.68); invasive mechanical ventilation, 6 (37.5%) versus 22 (73.3%) (P = 0.01). There were no patients using NIV ≥16 h/day. There were significant improvements in Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders scores of the patients at day 180 in comparison with the baseline (P < 0.001). CONCLUSIONS: Early initiation of nusinersen treatment in SMA1 patients may alter the disease's natural course.

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.

Relationships Among 3 Movement Analysis Tests in Preterm Infants.

PURPOSE: To investigate the relationships among the Infant Motor Profile (IMP), the Neuro-Sensory Motor Developmental Assessment (NSMDA), and the Alberta Infant Motor Scale (AIMS) in prematurely born infants. METHODS: Sixty-one preterm infants with a birth weight under 2500 g were assessed by the IMP, the NSMDA, and the AIMS. RESULTS: There was a significant correlation between the IMP total score and the AIMS percentile and between the IMP total score and the NSMDA functional levels. There were significant correlations between the AIMS percentile age and the NSMDA functional levels and between the AIMS total scores and the IMP total scores. In the infants with atypical development, the relationship was significant between the AIMS and the IMP; however, there was no relationship between the IMP and the NSMDA. CONCLUSIONS: The 3 movement analysis tests are related. The IMP was found to be consistent with other movement analysis tests.

Transient Splenial Lesion of the Corpus Callosum Related to Migraine with Aura in a Pediatric Patient.

BACKGROUND: Transient splenial lesions of the corpus callosum are rare radiological findings first described in association with epilepsy, antiepileptic drugs and viral encephalitis. However, subsequently more cases were described associated with diverse clinical conditions. CASE REPORT: We describe a 13-year-old girl suffering from migraine with aura presenting with headache, right-sided hemiparesis and encephalopathy. Brain magnetic resonance imaging revealed an ovoid lesion in the splenium of the corpus callosum. The patient's neurological symptoms resolved within 3 days without therapy and the lesion disappeared in follow up magnetic resonance images obtained 3 weeks after the onset of the symptoms. RESULTS: Migraine with aura was considered to be the cause of the lesion. To our knowledge the present case is the first report of a pediatric patient with a diagnosis of migraine with aura presenting with hemiparesis and encephalopathy. CONCLUSIONS: A diagnosis of transient lesion of the corpus callosum should be suspected in patients with migraine with aura presenting with hemiparesis and encephalopathy. A mild course and a good prognosis might be expected in the presence of a splenial lesion of the corpus callosum.

Neural tube defect family with recessive trait linked to chromosome 9q21.12-21.31.

PURPOSE: Meningomyelocele is one of the most common and socioeconomically, psychologically, and physically debilitating neurodevelopmental diseases. A few chromosomal locus and genes have been identified as responsible for the disease; however, clear evidence still needs to be produced. This study aimed to show evidence of a strong genetic linkage in a novel chromosomal locus in a family with this neural tube defect. METHODS: We identified a neural tube defect family in eastern Turkey, where two of six offspring had operations due to thoracolumbar meningomyelocele. The parents were of a consanguineous marriage. We collected venous blood from six offspring of the family. Whole genome linkage analysis was performed in all offspring. RESULTS: A theoretical maximum logarithm of an odds score of 3.16 was identified on chromosome 9q21.12-21.31. This result shows a strong genetic linkage to this locus. CONCLUSIONS: Our results identified a novel chromosomal locus related to meningomyelocele and provide a base for further investigations toward the discovery of a new causative gene.

Gómez-López-Hernández Syndrome: A Rare Cause of Bilateral Nonscarring Alopecia.

Gómez-López-Hernández syndrome is a rare neurocutaneous disorder characterized by the triad of rhombencephalosynapsis, parietal alopecia, and trigeminal anesthesia. We report a 16-year-old girl with bilateral parietotemporal alopecia in whom cranial magnetic resonance imaging revealed rhombencephalosynapsis, suggesting a diagnosis of Gómez-López-Hernández syndrome. Neurologic examination and neuroimaging may be warranted in select patients with parietal alopecia to exclude this uncommon entity.

Effect of antiepilepsy drug therapy on ventricular function in children with epilepsy: a tissue Doppler imaging study.

Impaired cardiac myocardial function may contribute to the risk for sudden unexpected death of a patient with epilepsy. This study aimed to investigate the effect of antiepilepsy drugs (AEDs) on cardiac function in pediatric epileptic patients using standard and tissue Doppler imaging (TDI) echocardiography. This hospital-based, prospective cross-sectional study investigated 52 epileptic children (mean age 9.3 ± 3.1 years) treated with AEDs (duration 2.4-10.0 years) and 36 healthy children (mean age 9.5 ± 4.0 years). In the epilepsy group, standard echocardiography showed increased left ventricular (LV) end-diastolic and end-systolic diameters, an increased LV mass index, and preserved ejection fraction. The patients also exhibited increased mitral peak A-wave velocity and mitral E-wave deceleration time as well as a decreased mitral E/A ratio. The E/Em ratio was significantly higher in the epilepsy group (5.6 ± 1.2) than in the control group (5.2 ± 1.1) (p = 0.016). In the epilepsy group, TDI showed an increased isovolumetric relaxation time and myocardial performance index (MPI). It also exhibited decreased early diastolic velocity (Em) and a decreased mitral annular displacement index in these patients. There were positive correlations between the LV lateral wall MPI (r = 0.231), septal MPI (r = 0.223), and LV mass index (p < 0.05) but no correlation with the duration of AED treatment. The authors detected subclinical ventricular dysfunction associated with AEDs at a preclinical stage. They suggest that TDI can be useful for determining the short- and long-term cardiac effects of AEDs.