Clinical and genetic spectrum of an orphan disease MPAN: a series with new variants and a novel phenotype.

INTRODUCTION: Pathogenic variations in C19orf12 are responsible for two allelic diseases: mitochondrial membrane protein-associated neurodegeneration (MPAN); and spastic paraplegia type 43 (SPG43). MPAN is an orphan disease, which presents with spasticity, dystonia, peripheral nerve involvement, and dementia. The pattern of iron accumulation on brain MRI may be a clue for the diagnosis of MPAN. SPG43, on the other hand, is characterised by progressive lower limb spasticity without brain iron accumulation. We here present clinical and genetic findings of MPAN patients with potentially pathogenic C19orf12 variants. MATERIALS AND METHODS: Patients from 13 different families having progressive motor symptoms with irritative pyramidal signs and brain iron accumulation were screened for C19orf12 gene variants. RESULTS: C19orf12 screening identified seven variants associated with MPAN in eight patients from seven families. We associated two pathogenic variants (c.24G > C; p.(Lys8Asn) and c.194G > A; p.(Gly65Glu)) with the MPAN phenotype for the first time. We also provided a genetic diagnosis for a patient with an atypical MPAN presentation. The variant c.32C > T; p.(Thr11Met), common to Turkish adult-onset MPAN patients, was also detected in two unrelated late-onset MPAN patients. CONCLUSIONS: Genetic analysis along with thorough clinical analysis supported by radiological findings will aid the differential diagnosis of MPAN within the neurodegeneration with brain iron accumulation spectrum as well as other disorders including hereditary spastic paraplegia. Dystonia and parkinsonism may not be the leading clinical findings in MPAN patients, as these are absent in the atypical case. Finally, we emphasise that the existence of frameshifting variants may bias the age of onset toward childhood.

NOTCH3 Variants in Patients with Suspected CADASIL.

Background: Cerebral autosomal dominant arteriopathy with subcortical infarctions and leukoencephalopathy (CADASIL) is the most common hereditary form of cerebral small vessel disease. It is clinically, radiologically, and genetically heterogeneous and is caused by NOTCH3 mutations. Methods: In this study, we analyzed NOTCH3 in 368 patients with suspected CADASIL using next-generation sequencing. The significant variants detected were reported along with the clinical and radiological features of the patients. Results: Heterozygous NOTCH3 changes, mostly missense mutations, were detected in 44 of the 368 patients (~12%). Conclusions: In this single-center study conducted on a large patient group, 30 different variants were detected, 17 of which were novel. CADASIL, which can result in mortality, has a heterogeneous phenotype among individuals in terms of clinical, demographic, and radiological findings regardless of the NOTCH3 variant.

[Tolosa-Hunt Syndrome; clinical and brain MRI features and treatment]. / Tolosa-Hunt Sendromu; klinigi, kranyal MR özellikleri ve tedavisi.

Tolosa-Hunt Syndrome (THS) is an idiopathic condition characterized by periorbital and hemicranial pain, ipsilateral oculomotor and sixth cranial nerve involvement, good response to steroids, granulomatous inflammation of the cavernous sinus or the top of the orbita. A 25 year- old- male patient presented with severe burning burn pain near the left eye with double vision. The left eye exhibited semiptosis, limited outward gaze, and difficulty in the downward outward gaze. No history of trauma or drug use was reported. Cranial Magnetic Resonance Imaging (MRI) showed thickening cavernous sinus walls to the left, while contrasted MRI sections suggested inflammation as indicated by intense staining. Cerebral arterial and venous angiography were normal. Parenteral treatment with 1mg/kg methylprednisolon commenced. The pain passed on the third day of treatment. Ophthalmoplegia began improving in the third week. The clinical symptoms were completely over after the third month of the clinic. The pain did not recur after corticotheraphy started. The cranial MRI of the patient was reviewed in a comparative perspective in the first and third months of the clinic. Inflammation was observed to get better. THS should always be considered in painful ophthalmoplegia cases. Cranial MRI towards the cavernous sinus, in particular, would suffice for diagnosis, provided that the vertex of orbita is not affected.

Comparative Evaluation of Stroke Awareness of Individuals Whose First-Degree Relatives had a Stroke and that of Individuals Whose First-Degree Relatives Did Not.

OBJECTIVE: To assess the stroke awareness levels of individuals whose first-degree relatives had a stroke and to compare the results with those of individuals whose first-degree relatives did not have a stroke. MATERIALS AND METHODS: This cross-sectional study was conducted between March and May 2019, with first-degree relatives of patients who had a stroke (group 1) and a comparable set of individuals whose first-degree relatives did not have a stroke (group 2). Participants were asked to complete a questionnaire asking about signs and symptoms, risk factors, treatment options, information sources, responses after the development of stroke, and early treatment of stroke. RESULTS: In response to the questions about the signs and symptoms of stroke, group 1 mentioned dizziness and comprehension disorder as a symptom of stroke more frequently than the other group. Stress was the second most frequently mentioned risk factor (by 81% of group 1 and 80.5% in group 2). When the participants were asked about the sources of information about stroke, family circle and friends were the most frequently mentioned sources for both groups. CONCLUSION: The present study can serve as a guide in planning training to improve stroke awareness in the future, especially by including individuals whose first-degree relatives had a stroke.

Cranial MR characteristics of Cerebral Palsy cases and correlation of findings with clinical results.

Ali A, Yalçin R, Ünlüer-Gümüstas A. Cranial MR characteristics of Cerebral Palsy cases and correlation of findings with clinical results. Turk J Pediatr 2019; 61: 525-537. The aim of this study was to compare cranial Magnetic Resonance (MR) imaging findings in cerebral palsy (CP) patients with clinical findings and evaluate damage ascribed to prenatal, natal and postnatal reasons by preterm, term or postterm characteristics. One thousand, one hundred CP patients registered at Dr. Ayten Bozkaya State Hospital of Cerebral Palsy Children and Rehabilitation Center from 2007 to 2010 were included in the study retrospectively. Cranial MR images studied in Bursa State Hospital Radiology Unit were evaluated by `a single senior MRI radiologist`. The most common abnormality was cerebral atrophy (80.2%) followed by periventricular leukomalacia (PVL) (49.9%). The most common type was spastic tetraplegia (67.9%), and the second most common type was hypotonic CP (15.6%). The percentage of congenital central nervous system (CNS) abnormality was 14.09%. The most common abnormality was corpus callosum (CC) agenesis and colpocephaly (2.3%). The least common conditions were cortical dysplasia, heterotopia and rhombencephalosynapsis. The percentage of cases born to consanguineous parents was 19.2%. In Hypoxic Ischemic Encephalopathy (HIE) patients born to consanguineous parents, PVL was cystic and moderate. Consanguineous marriage was statistically significant in the patients with cortical dysplasia and heterotopia (p < 0.04), delay in myelination (p < 0.001) and thalamus involvement (p < 0.008). Consanguineous marriage was also statistically significant in spastic diparetic (p < 0.017), hypotonic (p < 0.001) and bedridden patients (p < 0.006). The presence of both congenital CNS anomaly and PVL was only revealed in spastic tetraparetic type. Twentynine% of the cases were premature, while 66.4% were term children. Low birth weight (32.7%) constituted a risk factor for all clinical types, except mixed type CP. The percentage of patients with natal causes only was 21.5%. Kernicterus, cerebrovascular causes and HIE accounted for 6.3%, 2.9% and 54.4% of the cases, respectively. This study may indicate the importance of consanguineous marriage, natal and postnatal care properties as the underlying causes of CP beyond the clinical management related to delivery and allow us to identify strategies for possible measures.

A database for screening and registering late onset Pompe disease in Turkey.

The aim of this study was to search for the frequency of late onset Pompe disease (LOPD) among patients who had a myopathy with unknown diagnosis registered in the pre-diagnostic part of a novel registry for LOPD within a collaborative study of neurologists working throughout Turkey. Included in the study were 350 patients older than 18 years who have a myopathic syndrome without a proven diagnosis by serum creatine kinase (CK) levels, electrodiagnostic studies, and/or muscle pathology, and/or genetic tests for myopathies other than LOPD. Acid alpha glucosidase (GAA) in dried blood spot was measured in each patient at two different university laboratories. LOPD was confirmed by mutation analysis in patients with decreased GAA levels from either both or one of the laboratories. Pre-diagnostic data, recorded by 45 investigators from 32 centers on 350 patients revealed low GAA levels in a total of 21 patients; from both laboratories in 6 and from either one of the laboratories in 15. Among them, genetic testing proved LOPD in 3 of 6 patients and 1 of 15 patients with decreased GAA levels from both or one of the laboratories respectively. Registry was transferred to Turkish Neurological Association after completion of the study for possible future use and development. Our collaborative study enabled collection of a considerable amount of data on the registry in a short time. GAA levels by dried blood spot even from two different laboratories in the same patient may not prove LOPD. LOPD seemed to be rarer in Turkey than in Europe.

Serum Levels of sRAGE Are Associated with Body Measurements, but Not Glycemic Parameters in Patients with Prediabetes.

BACKGROUND: Our aim was to assess serum levels of the soluble receptor for advanced glycation end products (sRAGE) and to examine their association with anthropometric and metabolic parameters in patients with prediabetes and obese controls. METHODS: The two study groups were composed of 42 patients with prediabetes and diabetic neuropathy and 42 age-, gender-, body weight (BW)-, and body mass index (BMI)-matched obese adults as the control group. Prediabetes was diagnosed by the following criteria issued by the American Diabetes Association: impaired fasting glucose [fasting plasma glucose (FPG) level of 100-125 mg/dL], impaired glucose tolerance (2 hr plasma glucose level of 140-199 mg/dL after a 75 grams oral glucose challenge), or a glycated hemoglobin (HbA1C) level of 5.7%-6.4%. RESULTS: There were no differences between the groups in terms of age, gender distribution, BW, or BMI. Despite these similarities, patients with prediabetes had higher FPG, HbA1c, and 2-hr postchallenge glucose levels, higher systolic and diastolic blood pressure, and larger waist and hip circumferences compared with the obese controls. Lipid measurements, complete blood counts, kidney and liver function tests, high-sensitivity C-reactive protein, and sRAGE levels were similar between the two groups. We found significant negative correlations between sRAGE levels and BW, BMI, waist and hip circumferences, waist-to-hip ratios, and low-density lipoprotein (LDL) cholesterol levels. There were no significant correlations with other parameters, including demographic, metabolic, and blood pressure measurements. CONCLUSIONS: In contrast to glycemic parameters, serum levels of sRAGE were negatively correlated with body measurements indicative of obesity in the prediabetic state. In addition, the negative correlation with LDL cholesterol levels suggests that sRAGE has a more robust association with metabolic syndrome than with prediabetes.

Cerebral Vein Thrombosis after Spinal Anaesthesia with Pregnancy.

Thrombosis of cerebral veins or thrombosis of cortical and deep veins that empty into the sinuses can cause serious neurological syndromes. Cerebral vein thrombosis is seen, especially between the ages of 20-35. The predisposing factors in 80% of patients can be determined. Pregnancy, postpartum period and spinal anaesthesia are among the predisposing factors. Diagnosis of the disease is difficult due to the variety of clinical signs and symptoms. Headache is the most common reason for admission to the hospital. Thromboembolic events in pregnancy are an important reason of maternal morbidity and mortality. Most cases of cerebral venous thrombosis in pregnancy occur in the postpartum period. Confusion, convulsions and respiratory arrest occurred in 37-year-old female patient after 3 hours from operation. Cerebral vein thrombosis was diagnosed, owing to laboratory and neuroradiological findings. In this article, we have emphasised the importance of clinical evaluation of pregnant patients with cerebral vein thrombosis after spinal anaesthesia.