New Insights of Phospholipase A2 Associated Neurodegeneration Phenotype Based on the Long-Term Follow-Up of a Large Hungarian Family.

INTRODUCTION: Phospholipase A2-associated Neurodegeneration (PLAN) is a group of neurodegenerative diseases associated with the alterations of PLA2G6. Some phenotype-genotype association are well known but there is no clear explanation why some cases can be classified into distinct subgroups, while others follow a continuous clinical spectrum. METHODS: Long-term neurological, and psychiatric follow-up, neuropathological, radiological, and genetic examinations, were performed in three affected girls and their family. RESULTS: Two 24-years old twins and their 22-years old sister harbored the p.P622S, and p.R600W mutation in PLA2G6. The age of onset and the most prominent presenting symptoms (gaze palsy, ataxia, dystonia, psychomotor regression indicated atypical neuroaxonal dystrophy (ANAD), however, optic atrophy, severe tetraparesis would fit into infantile neuroaxonal dystrophy (INAD). All siblings had hyperintensity in the globi pallidi and substantiae nigrae which is reported in ANAD, whereas it is considered a later neuroradiological marker in INAD. The slow progression, rigidity, bradykinesis, and the prominent psychiatric symptoms indicate PLA2G6-related dystonia-parkinsonism. Abnormal mitochondria, lipid accumulation and axonal spheroids were observed in the muscle and nerve tissue. Brain deposition appeared 6 years following the initial cerebellar atrophy. Mild MRI alterations were detected in the asymptomatic carrier parents. CONCLUSION: The colorful clinical symptoms, the slightly discordant phenotype, and the neuroimaging data in the family supports the view that despite the distinct definition of age-related phenotypes in PLAN, these are not strict disease categories, but rather a continuous phenotypic spectrum. The mild MRI alterations of the parents and the family history suggest that even heterozygous pathogenic variants might be associated with clinical symptoms, although systematic study is needed to prove this.

CANOMAD syndrome with respiratory failure.

CANOMAD (chronic ataxic neuropathy, ophthalmoplegia, M-protein agglutination, disialosyl antibodies) syndrome is a rare polyneuropathy. IgM paraproteins react with ganglioside-containing disialylated epitopes resulting in dorsal root ganglionopathy and B-lymphocyte infiltration of cranial and peripheral nerves. Clinical features include ataxia, slight muscle weakness, areflexia, sensory- and cranial nerve symptoms. Case studies have reported the efficacy of rituximab and intravenous immunoglobulin (IVIg) treatments. We present the case of a 57-year-old man, who had difficulty walking, with numbness and clumsiness in all limbs. He had areflexia, vibratory sensation loss and ataxia. Laboratory tests showed IgM monoclonal components and disialosyl antibodies in the serum. Nerve conduction studies indicated severe sensorimotor demyelinating polyneuroradiculopathy. Despite IVIg and rituximab treatments, the patient's disease course gradually worsened and he died of respiratory failure. Neuropathological examination revealed dorsal column- and dorsal root atrophy with mixed mononuclear cell infiltration. This article aims to draw attention to this syndrome, and the use of early potent immunosuppressive treatment to improve patients' quality of life.

Genotypic and phenotypic spectrum of the most common causative genes of Charcot-Marie-Tooth disease in Hungarian patients.

Charcot-Marie-Tooth neuropathy (CMT) is a genetically and clinically heterogeneous group of neuromuscular disorders with an overall prevalence of 1 per 2500. Here we report the first comprehensive genetic epidemiology study of Hungarian CMT patients. 409 CMT1 and 122 CMT2 patients were enrolled and genetic testing of PMP22, GJB1, MPZ, EGR2 and MFN2 genes were performed routinely. NDRG1 and CTDP1 genes were screened only for founder mutations in Roma patients. Causative genetic mutations were identified in 67.2% of the CMT1 and in 33.6% of the CMT2 cases, which indicates an overall success rate of 59.9% in the study population. Considering all affected individuals, alterations were most frequently found in PMP22 (40.5%), followed by GJB1 (9.2%), MPZ (4.5%), MFN2 (2.5%), NDRG1 (1.5%), EGR2 (0.8%) and CTDP1 (0.8%). The phenotypic spectrum and the disease severity of the studied patients also varied broadly. Deafness and autoimmune disorders were more often associated with PMP22 duplication, while MFN2 and GJB1 mutations were frequently present with central nervous system abnormalities. Our study may be helpful in determining the strategy of genetic diagnostics in Hungarian CMT patients.

Three novel mutations and genetic epidemiology analysis of the Gap Junction Beta 1 (GJB1) gene among Hungarian Charcot-Marie-Tooth disease patients.

Pathogenic variants of the gap junction beta 1 (GJB1) gene are responsible for the Charcot-Marie-Tooth neuropathy X type 1 (CMTX1). In this study, we report the mutation frequency of GJB1 in 210 Hungarian CMT patients and the phenotype comparison between male and female CMTX1 patients. Altogether, 13 missense substitutions were found in the GJB1 gene. Among them, 10 have been previously described as pathogenic variants (p.Arg15Trp, p.Val63Ile, p.Leu89Val, p.Ala96Gly, p.Arg107Trp, p.Arg142Gln, p.Arg164Trp, p.Arg164Gln, p.Pro172Ala and p.Asn205Ser), while 3 were novel, likely pathogenic alterations (p.Val13Glu, p.Glu186Gly, p.Met194Ile). These variants were not present in controls and were predicted as disease causing by in silico analysis. The frequency of the variants was 6.7% in our cohort which refers to a common cause of hereditary neuropathy among Hungarian patients. In addition to the classical phenotype, CNS involvement was proved in 26.1% of the CMTX1 patients. GJB1 pathogenic alterations were found mainly in males but we also detected them in female probands. The statistical analysis of CMTX1 patients revealed a significant difference between the two genders regarding the age of onset, Charcot-Marie-Tooth neuropathy and examination scores.

[A rare case of thermoregulation disorder: Shapiro syndrome]. / Shapiro-szindróma, azaz a termoregulációs zavar ritka esete.

Anomalies of the corpus callosum are the most frequent malformations of the central nervous system. The triad of spontaneous periodic hypothermia and hyperhydrosis with the agenesis of corpus callosum is described as Shapiro syndrome. Shapiro syndrome is a very rare condition and it can occur in every age group. The presence of agenesis of corpus callosum is not a strict criteria of the syndrome; the most important presenting symptom is paroxysmal hypothermia. Although the definite cause of recurrent hypothermia is unknown, dysfunction of the hypothalamus is suspected. From therapeutic aspects, only supportive therapy is available. In this report the authors present the first Shapiro syndrome case diagnosed in Hungary. The main symptoms of the 21-year-old male patient were recurrent hyperhydrosis with hypothermia resulting in severe general malaise. The skull magnetic resonance imaging demonstrated agenesis of corpus callosum. The patient was treated with clonidine resulting in significant improvement of symptoms.

Diagnostic yield of five minutes compared to three minutes hyperventilation during electroencephalography.

PURPOSE: To investigate whether hyperventilation (HV) for 5min increases the diagnostic yield of electroencephalography (EEG) compared to 3min HV. METHODS: data were evaluated from 1084 consecutive patients, from three European centres, referred to EEG on suspicion of epilepsy. Seizures and interictal EEG abnormalities precipitated during the first 3min and during the last 2min of the HV period (totally 5min) were determined. RESULTS: Eight hundred seventy-seven patients (81%) completed 5min HV. Seizures were precipitated during the first 3min of HV in 21 patients, and during the last 2min in four more patients. Interictal EEG abnormalities were precipitated in the first 3min of HV in 16 patients, and during the last 2min in 7 more patients. Psychogenic nonepileptic seizures occurred in eight patients during the first 3min of HV and in two more patients during the last 2min. No adverse events occurred during the last 2min of HV, but eight patients (1%) stopped HV during the last 2min because they were not able to hyperventilate further. CONCLUSION: 16% of seizures and 30% of interictal EEG abnormalities triggered by HV occurred during the last 2min of HV, suggesting the clinical usefulness of prolonged hyperventilation for 5min. The vast majority of patients (99%) who are able to hyperventilate for 3min can complete 5min HV, without additional adverse events.

[Retinal ganglion cell layer and visual function in patients with progressive external ophthalmoplegia caused by common mtDNA deletion]. / Retinalis idegrostréteg és látásfunkciók az mtDNS common deléciója által okozott progresszív ophthalmoplegia externa esetében.

AIM: Mitochondrial (mt) disorders are metabolic conditions with multiorgan involvement, which often cause neuroophtalmological symptoms. The aim of the study was to investigate the relation between progressive external ophthalmoplegia (PEO), visual pathway and mitochondrial DNA (mtDNA) mutations in patients younger than 55 years of age. METHODS: Five female patients (35 to 53 years of age) with mithochondrial disease were investigated. Automated threshold perimetry (Octopus G2 test), scanning laser polarimetry (GDx-VCC and GDx-ECC) and Fourier-domain optical coherence tomography (RTVue-100 OCT) were used in addition to detailed ophthalmological examination and evaluation of visually evoked potentials (VEP). Frequent mutations of the mtDNA were investigated in the patients' blood and muscle samples. RESULTS: PEO of various severity levels was found in all patients, using clinical tests. Genetic testing showed "common deletion" of mtDNA in all cases. For both eyes of 4 patients functional and structural ophthalmic tests had normal results. In one patient decreased visual acuity, reduced retinal nerve fiber layer thickness and prolonged L3 VEP latency time were found without optic disc damage and visual field deterioration. CONCLUSION: In 4 of our 5 patients with PEO due to common deletion of mtDNA retinal ganglion cells and visual function remained normal for a long period of life.

[Inclusion body myositis--a rarely recognized disorder]. / Zárványtestes myositis--egy ritikán felismert betegség.

Inclusion body myositis is the most common disabling inflammatory myopathy in the elderly. It is more frequent in men and after the age of 50 years. Inflammatory and degenerative features coexist. There is a T-cell mediated autoimmunity driven by in situ clonally expanded cytotoxic CD8-positive T-cells invading non-necrotic muscle fibres expressing MHC-I antigen. The hallmarks of degeneration are the deposition of protein aggregates and the formation of vesicles. The course of the disease is slow and the diagnosis is usually set after several years. The muscle weakness and wasting is assymetric, affecting predominantly distal muscles of the upper extremity and proximal muscles of the legs. The signs and clinical course can be characteristic, but the diagnosis is established by muscle biopsy. There is currently no evidence based effective treatment for sIBM. Prednisone, azathioprine, methotrexate, cyclosporine and IFN-beta failed. Oxandrolon did not improve symptoms. Treatment with intravenous immunglobuline (IVIG) induced in some patients a transient improvement of swallowing and of muscle strenght, but the overall study results were negative. A T-cell depleting monoclonal antibody (alemtuzumab), in a small uncontrolled study slowed down disease progression for a six-month period. Repeated muscle biopsies showed the reduction of T-cells in the muscle and the suppression of some degeneration associated molecules. An effective therapeutic mean should act on both aspects of the pathomechanism, on the inflammatory and the degenerative processes as well.

Cathodal transcranial direct current stimulation over the parietal cortex modifies facial gender adaptation.

Previous studies have observed that prolonged adaptation to a face will bias the perception of a subsequent one. This phenomenon is known as figural or face after-effect. Although currently the topic of face adaptation enjoys utmost popularity, we still don't know much about the neural process underlying it. The aim of the present study was to determine, using transcranial direct current stimulation (tDCS), how the retinotopically organised primary visual cortex (V1) and higher-level, non-retinotopic right lateral temporo-parietal areas interact with facial adaptation processing. Seventeen healthy subjects received 10 min anodal, cathodal or sham stimulation over these areas during a facial adaptation task. Cathodal stimulation of the right temporo-parietal cortex reduces the magnitude of facial adaptation while stimulation over the V1 results in no significant effects. These data imply that mainly lateral temporo-parietal cortical areas play role in facial adaptation and in facial gender discrimination, supporting the idea that the observed after-effects are the result of high-level, configurational adaptation mechanisms.

The effect of sleep deprivation on median nerve somatosensory evoked potentials.

The purpose of the study was to determine the effect of one night's sleep deprivation on the early and middle-latency median nerve (MN) somatosensory evoked potentials (SEPs). In 20 healthy volunteers, SEPs in response to electrical stimulation of the MN at the wrist were recorded for the 100-ms post-stimulus period, before and after one night of sleep deprivation. The P14 latency was significantly prolonged after sleep deprivation. We found significant increases in the amplitudes of the early parietal (N20-P24) and the frontal middle-latency (P45-N60) components following sleep deprivation. Our results indicate that somatosensory processing is altered after sleep deprivation.