Neuromuscular disease genetics in under-represented populations: increasing data diversity.

Neuromuscular diseases (NMDs) affect ∼15 million people globally. In high income settings DNA-based diagnosis has transformed care pathways and led to gene-specific therapies. However, most affected families are in low-to-middle income countries (LMICs) with limited access to DNA-based diagnosis. Most (86%) published genetic data is derived from European ancestry. This marked genetic data inequality hampers understanding of genetic diversity and hinders accurate genetic diagnosis in all income settings. We developed a cloud-based transcontinental partnership to build diverse, deeply-phenotyped and genetically characterized cohorts to improve genetic architecture knowledge, and potentially advance diagnosis and clinical management. We connected 18 centres in Brazil, India, South Africa, Turkey, Zambia, Netherlands and the UK. We co-developed a cloud-based data solution and trained 17 international neurology fellows in clinical genomic data interpretation. Single gene and whole exome data were analysed via a bespoke bioinformatics pipeline and reviewed alongside clinical and phenotypic data in global webinars to inform genetic outcome decisions. We recruited 6001 participants in the first 43 months. Initial genetic analyses 'solved' or 'possibly solved' ∼56% probands overall. In-depth genetic data review of the four commonest clinical categories (limb girdle muscular dystrophy, inherited peripheral neuropathies, congenital myopathy/muscular dystrophies and Duchenne/Becker muscular dystrophy) delivered a ∼59% 'solved' and ∼13% 'possibly solved' outcome. Almost 29% of disease causing variants were novel, increasing diverse pathogenic variant knowledge. Unsolved participants represent a new discovery cohort. The dataset provides a large resource from under-represented populations for genetic and translational research. In conclusion, we established a remote transcontinental partnership to assess genetic architecture of NMDs across diverse populations. It supported DNA-based diagnosis, potentially enabling genetic counselling, care pathways and eligibility for gene-specific trials. Similar virtual partnerships could be adopted by other areas of global genomic neurological practice to reduce genetic data inequality and benefit patients globally.

Vitamin D and Nerve Conduction In Pediatric Type-1 Diabetes Mellitus.

INTRODUCTION: The aim of this study is to investigate a possible association between vitamin D deficiency and diabetic peripheral neuropathy in pediatric patients with type 1 diabetes mellitus. MATERIALS-METHODS: Twenty-nine patients with type 1 diabetes mellitus and 19 healthy controls were included to the study. All individuals were evaluated for diabetic peripheral neuropathy with nerve conduction studies. Complete blood cell count, biochemical investigations, serum vitamin D levels, hemoglobin A1c levels were recorded. RESULTS: No statistically significant differences between the diabetes and control groups in terms of gender, age, body weight, height, body mass index, systolic and diastolic blood pressures, laboratory investigations, serum vitamin D levels and nerve conduction studies was found. Patients with diabetes were grouped as patients with normal serum vitamin D levels and patients with vitamin D deficiency. Sensory nerve action potential of sural nerve and motor peroneal nerve velocity were statistically significantly lower in diabetic patients with vitamin D deficiency compared to diabetic patients with normal vitamin D levels (p 0.009 and 0.005 respectively). CONCLUSION: Our results suggested that hypovitaminosis D might lead to development of neuropathic changes particularly on the lower limb nerves even in the early stages of the disease. It should be kept in mind that patients with hypovitaminosis D should be elaborately examined and closely followed up for the development of diabetic neuropathic changes, even if glucose control is achieved.

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.

Risk Factors of Post-Stroke Epilepsy in Children; Experience from a Tertiary Center and a Brief Review of the Literature.

OBJECTIVES: Acute seizures and post-stroke epilepsy have been reported more frequently in patients with pediatric stroke than adults. Acute seizures in the first days of a stroke may deteriorate stroke and ischemia-related neurodegeneration and contribute to the development of post-stroke epilepsy. In this study, we aimed to investigate risk factors for the development of post-stroke epilepsy in children with arterial ischemic stroke. MATERIALS AND METHODS: We recruited 86 children with arterial ischemic stroke. We analyzed variables, including age at admission, gender, complaints at presentation, focal or diffuse neurologic signs, neurologic examination findings, laboratory investigations that were conducted at admission with stroke (complete blood cell count, biochemical-infectious-metabolic-immunological investigations, vitamin B12 levels, vitamin D levels), neuroimaging results, etiologies, time of the first seizure, time of remote seizures, and development of neurologic deficit retrospectively. Seizures during the first six hours after stroke onset were defined as 'very early seizures'. 'Early seizures' were referred to seizures during the first 48 h. Patients who experienced two or more seizures that occurred after the acute phase of seizures were classified as 'epileptic.' A binary logistic regression analysis was used to estimate risk factors. RESULTS: An acute seizure was detected in 59% and post-stroke epilepsy developed in 41% of our cohort. Binary logistic regression analysis demonstrated that 'very early seizures' increased epilepsy risk six-fold. Epilepsy was 16 times higher in patients with 'early seizures'. Low vitamin D levels were defined as a risk factor for post-stroke epilepsy. CONCLUSION: Seizures in the very early period (within the first six hours) are the most significant risk factors for the development of post-stroke epilepsy Further studies regarding seizure prevention and neuroprotective therapies are needed because post-stroke epilepsy will affect long term prognosis in patients with pediatric stroke.

Neuroprotective Effects of Lacosamide and Memantine on Hyperoxic Brain Injury in Rats.

In neonates supraphysiological oxygen therapy has been demonstrated to cause neuronal death in hippocampus, prefrontal cortex, parietal cortex, and retrosplenial cortex. There is a need for the detection of novel neuroprotective drugs. Neuroprotective effects of lacosamide or memantine have been demonstrated in adult patients with ischemia, trauma and status epilepticus. The effects in immature brains may be different. This study aimed to evaluate neuroprotective effects of lacosamide and memantine treatment in a hyperoxia-induced brain injury model in immature rats. This study was performed in the Animal Experiments Laboratory of Dokuz Eylul University Faculty of Medicine. Neonatal Wistar strain rat pups were exposed to hyperoxia (80% oxygen + 20% nitrogen) for five days postnatally. They were divided into five groups; hyperoxia + lacosamide, hyperoxia + memantine, hyperoxia + lacosamide and memantine, hyperoxia + saline, control groups. After termination of the experiment, brain tissues were examined. Neuron counting in examined regions were found to be higher in hyperoxia + memantine and hyperoxia + lacosamide and memantine groups than hyperoxia + saline group. The presence of apoptotic cells evaluated with TUNEL and active Caspase-3 in hyperoxia + memantine and hyperoxia + lacosamide and memantine groups were found to be lower compared to hyperoxia + saline group. This study demonstrates that neuron death and apoptosis in newborn rat brains after hyperoxia is reduced upon memantine treatment. This is the first study to show the effects of memantine and lacosamide on hyperoxia-induced damage in neonatal rat brains.

Retrospective analysis of children with myelin oligodendrocyte glycoprotein antibody-related disorders.

BACKGROUND: Knowledge has been expanding on myelin oligodendrocyte glycoprotein (MOG) antibody-associated central nervous system disorders. We delineate the clinical and paraclinical findings and outcome of our pediatric patients with MOG antibody seropositive disease. METHODS: We retrospectively analyzed the clinical presentation, cerebrospinal fluid findings, magnetic resonance imaging (MRI) studies, course and outcome of children seropositive for anti-MOG IgG. RESULTS: Total 20 children with neurological symptoms and serum anti-MOG IgG were identified from six centers in Turkey. Median age at onset was 9 years (mean 8.8 ±â€¯5.0 years, range: 1.5-16.5 years). Final diagnoses were acute disseminated encephalomyelitis (ADEM) (n = 5), ADEM + optic neuritis (n = 4), neuromyelitis optica spectrum disorder (NMOSD) (n = 3), myelitis (n = 2), relapsing optic neuritis (n = 2), multiphasic DEM (n = 3), and unclassified relapsing demyelinating disease (n = 1). Seven/20 (35%) children experienced a single episode while 13/20 (65%) had a least one relapse during follow-up. On MRI, subcortical white matter, brainstem, and corpus callosum were preferentially involved regions. Full recovery was observed in 15/20 (75%) children. CONCLUSION: MOG autoimmunity in children has a wide clinical spectrum, tendency to relapse, and a favourable outcome compared with other relapsing demyelinating diseases.

Changes of primary headache related white matter lesions in pediatric patients.

Bayram E, Yis U, Paketçi C, Okur D, Polat I, Çakmakci H, Hiz S, Anlar B. Changes of primary headache related white matter lesions in pediatric patients. Turk J Pediatr 2018; 60: 380-384. We aimed to describe the long-term prognosis of white matter lesions detected on magnetic resonance imaging in children with primary headache. Children who were admitted with the complaint of headache and had nonspecific white matter lesions on magnetic resonance imaging were included in the study. The clinical findings of the patients were reinvestigated using the same magnetic resonance imaging scanner and acquisition protocol after at least a two year period. Magnetic resonance imaging results of the patients were documented in detail. Findings of the baseline and follow-up studies were compared with each other by the same radiologist. Among the 11 patients, 8 ( 72.7%) were male and 3 (27.3%) were female. Mean age of patients at the time of second imaging was 12.9±2.3 years. Eight (72.7%) had migraine without aura, 1 (9.1%) had tension-type headache and 2 (18.2%) had migraine with aura. The mean clinical follow-up period of the patients was 4.31±1.31 years. All patients had low headache frequency on the last control visit when compared to the first clinical findings. The follow-up magnetic resonance imaging studies showed two newly developed white matter lesions in two patients who had migraine without aura and the white matter lesions disappeared in the patient who had tension-type headache, compared to the baseline neuroimaging. Findings of the baseline and long-term follow-up magnetic resonance imaging studies of the patients with primary headache showed no significant changes in terms of the location, size and laterality. Repeated neuro-imaging studies are not warranted in the absence of the progression in clinical findings.

Occipital cortex dysgenesis with white matter changes due to mutations in Laminin a2.

Yis U, Dixit V, Isikay S, Karakaya M, Baydan F, Diniz G, Polat I, Hiz-Kurul S, Çirak S. Occipital cortex dysgenesis with white matter changes due to mutations in Laminin a2. Turk J Pediatr 2017; 59: 338-341. Laminin α2 related congenital muscular dystrophy is one of the most common congenital muscular dystrophies of childhood with or without clinical evidence of central nervous system involvement. It may be associated with significant white matter abnormalities resembling leukodystrophies. In this study, we elaborated on two cases with laminin α2 related congenital muscular dystrophy who had occipital cortex dysgenesis in addition to characteristic white matter abnormalities. Although laminin α2 related congenital muscular dystrophy with white matter abnormalities is known, the association with occipital cortex dysplasia has been not well recognized by clinical colleagues.

Schwartz-Jampel syndrome with gastroduodenal bleeding.

Schwartz-Jampel syndrome is a rare autosomal recessive disorder with joint contractures, generalized myotonia, skeletal anomalies, and facial dysmorphism. The patients with Schwartz-Jampel syndrome have muscle stiffness and electromyography reveals complex, repetitive discharges as myotonic discharges. It is unusual for a Schwartz-Jampel syndrome case to have recurrent gastrointestinal bleeding episodes. The stable endothelial barrier is provided by perlecan which is an important component of vascular structures. Thus, perlecan deficiency may cause recurrent gastroduodenal bleeding. Our report is unique with being the first reported Schwartz-Jampel syndrome case with gastrointestinal bleeding.

Myelin Oligodendrocyte Glycoprotein Antibody Persistency in a Steroid-Dependent ADEM Case.

Myelin oligodendrocyte glycoprotein (MOG) is a candidate target antigen in demyelinating central nervous system diseases, including acute disseminated encephalomyelitis (ADEM), neuromyelitis optica, and multiple sclerosis. It may give prognostic information regarding monophasic or recurrent course of the disease. MOG antibodies have been shown to be positive in high titers during the first episode of ADEM with rapidly decreasing to undetectable limits after recovery. However, persistent MOG antibodies are considered as a predicting factor for multiple sclerosis, optic neuritis relapses, and incomplete recovery of ADEM. Here we report a unique case with persistent MOG antibodies presented with multiphasic ADEM-like attacks. A 6-year-old girl was consulted with encephalopathy, gait disturbance, and oculomotor nerve palsy. Periventricular white matter lesions were seen on cranial magnetic resonance imaging studies. ADEM was diagnosed and treated with steroid. During follow-up, she experienced repeated episodes after steroid therapy termination. We were able to search MOG antibody at the ninth attack. The positivity of this antibody remained. It was thought to be associated with steroid-dependent course, and azathioprine and intravenous human immunoglobulin treatment were added. Patients with persistent MOG antibodies may benefit from addition of immunosuppressant agents, which may decrease the number of attacks.

Importance of acrocyanosis in delayed walking.

We present a four-year-old wth ethylmalonic encephalopathy who presented with delayed walking. She had bilateral hyperintense lesions in the basal ganglia. Molecular analysis revealed a homozygous c.3G>T mutation in the ETHE1 gene. She did not have typical findings of the disease including recurrent petechia, chronic diarrhea and acrocyanosis was very subtle and orthostatic. She benefited from riboflavine and Q10 treatments. We suggest that acrocyanosis should be questioned and examined in patients with motor delay.

A novel mutation in the mitochondrial DNA cytochrome b gene (MTCYB) in a patient with Prader Willi syndrome.

In recent years, it has been suggested that defects in energy metabolism may accompany Prader Willi syndrome. Mutations in the mitochondrial cytochrome b gene have been commonly associated isolated mitochondrial myopathy and exercise intolerance, rarely with multisystem disorders. The authors describe a novel mutation (mt. 15209T>C) in mitochondrial cytochrome b gene in a 2-year-old girl with Prader-Willi syndrome with a clinical history of lactic acidosis attacks, renal sodium loss, hepatopathy, progressive cerebral atrophy, and sudden death. The authors suggest that atypical clinical findings in patients with Prader-Willi syndrome should direct the physician to search for a mitochondrial disease.

A rare form of heteropagus twinning: three-armed infant with spinal dysraphism.

An ectopic or accessory limb attached to the back is an extremely rare and strange condition, and there are only a few documented cases in the worldwide literature. The first case was described by Jones and Larkin (1889). There are several theories regarding the origin of this condition. Asymmetric conjoined twinning which is located dorsally in the vertebral column (rachipagus) is the most probable diagnosis of our patient. Conjoined twinning is very rare and the incidence is 1 per 50 000 live births. Rachipagus is even rarer, with no more than 30 case reports so far (Chadha et al. (1993, 2006)). In this report, we present a patient who underwent successful surgical excision of a third arm attached to the back in the midline over the low-dorsal region. Differential diagnoses including teratoma and fetus in fetu are discussed.