Clinical Neuroscience

[Quantitative analysis of the genes determining spinal muscular atrophy]


NOVEMBER 30, 2009

Clinical Neuroscience - 2009;62(11-12)

[Spinal muscular atrophy (SMA) is one of the most common autosomal recessive diseases, affecting approximately one in 10.000 live births and with a carrier frequency of approximately one in 35. The disease is caused by a deficiency of the ubiquitous protein survival of motor neuron (SMN), which is encoded by the SMN1 and SMN2 genes. Due to a single nucleotide polymorphism in exon 7, SMN2 produces less full-length transcript than SMN1 and cannot prevent neuronal cell death at physiologic gene dosages. On the other hand, the copy number of SMN2 affects the amount of SMN protein produced and the severity of the SMA phenotype. SMN gene dosage analysis can determine the copy number of SMN1 to detect carriers and patients heterozygous for the absence of SMN1 exon 7. This study provides copy number estimation of SMN1 gene by real-time PCR technique in 56 SMA type I., II., III. patients, 159 parents and healthy relatives and in 152 undefined SMA patients. Among the family members, 91 carriers have been detected and in 56 patients homozygous deletion of SMN1 exon 7 has been confirmed. Moreover, in 12 patients compound heterozygosity of SMN1 exon 7 mutation has been detected, thus providing the possible diagnosis of SMA. In 94 patients, copy number of SMN2 has also been evaluated and a good correlation has been found with the phenotype of the disease. Due to the genetic complexity and the high carrier frequency, accurate risk assessment and genetic counselling are particularly important for the families. These new results provide improvement of the diagnostic service in SMA in Hungary with focus on proper genetic counselling and possible enrolment of the patients in future therapeutic interventions.]



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[New vistas and views in the concept of generalized epilepsies]


[The aim of this work is to show explicitly why the “idiopathic generalized epilepsy” concept becomes outfashioned and untenable. As the concept of “generalized epilepsies” is from long ago closely related to the thalamo-cortical system, we briefly summarize the functional anatomy, the double working mode of the thalamo-cortical system in different vigilance states and it’s role in development of the spike - wave pattern. The next part shows weaknesses of this concept from the EEG, seizure semiology, and neuroimaging point of view. Further experimental and clinical arguments are accumulated from the reflex epileptic features in IGE, indicating local/regional cortical hyperexcitability. A separate part is devoted to genetic aspects of the question. Lastly implications to epilepsy classification are shown and an outlook toward a unified epilepsy concept is provided. The epileptic disorder of the thalamo-cortical system is responsible for the development of “generalized", synchronous spike-wave paroxysms as the common neurophysiological background in “primary” - idiopathic and in “secondary” generalized epilepsies. This disorder is specifically related to the burstfiring working mode of the thalamo-cortical system during NREM sleep (is an epileptic exageration of it). The “generalized” epilepsy category should be abandoned, being misleading. Epilepsies are proposed to be classified according to their network properties and relations to different physiological systems of the brain. The different phenotypes, named earlier idiopathic (primary) generalized, or symptomatic (secondary) generalized (with encephalopathic features), should be delineated depending on the following factors: 1. speed and extent of syncronization within the thalamo-cortical system, 2. the way how the thalamo-cortical system is involved, 3. which kind of cortical triggers play role, 4. the degree and level of the disorder (restricted to the molecular level or extended to the level of structural alterations - in the cortex or more diffusely, 5. genetic targets and features.]

Clinical Neuroscience

[Guillain–Barré syndrome in childhood]

KOLLÁR Katalin, LIPTAI Zoltán, ROSDY Beáta, MÓSER Judit

[Background - Guillain-Barré syndrome (GBS) is clinically well known since 1916. It can occur at any age. Its main characteristic is acute rapidly ascending flaccid paresis. It is a neuro-immunologic disorder with heterogeneous background. In Hungary we could not find reports about big paediatric population with GBS. Patient and method - We analysed retrospectively the data of 38 children diagnosed and treated with GBS at the Neurological Department of Paul Heim Children’s Hospital or at the Paediatric Department of St. László Hospital from January 2000 till April 2008. We analysed the clinical characteristics, seriousness of clinical signs, laboratory results, and electrophysiological features of them as well documented the preceding illness. We observed the effectiveness of our treatment; we measured the speed and time of the healing process and documented the residual clinical signs. Results - 35 children could be classified as having acute inflammatory demyelinating polyneuropathy (AIDP), 2 as having acute motor axonal neuropathy (AMAN) and 1 as Miller-Fisher syndrome. By those patients who at the very beginning did not show the characteristic clinical signs, electrophysiology helped in establishing the diagnosis. By one child spinal MRI with gadolinium supported our diagnosis. Those children, who lost their ambulation, got immunotherapy: intravenous immunoglobulin (IVIG) or plasmapheresis (PEX). Both method seemed to be effective. None of our patients died. All were cured. By five patients residual clinical symptoms could be found. Conclusion - The disease process, the relative incidence of each subtype of GBS is nearly similar to that in Western Europe and North America according to the literature. By the currently used immune therapy most of the pediatric patients recover fully within a short time.]

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[Nusinersen in the treatment of spinal muscular atrophy]

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[Until recently, the diagnosis of spinal muscular atrophy (SMA) has been associated with severe life-long motor disability in adults and with early death in infants. The new experimental therapeutic approaches of the last few years have become more and more promising, while nusinersen was approved for the treatment of SMA in December 2016 in the USA, and in May 2017 in Hungary. Our paper presents mechanisms and clinical benefits of this new medication, and highlights some of the other therapeutic strategies still in experimental stages.]

Clinical Neuroscience


KAREN Eskesen, TAJTI János, HORTOBÁGYI Tibor, SZOK Délia, VÉCSEI László, LARS Edvinsson

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Clinical Neuroscience

Life threatening rare lymphomas presenting as longitudinally extensive transverse myelitis: a diagnostic challenge

TOLVAJ Balázs, HAHN Katalin, NAGY Zsuzsanna, VADVÁRI Árpád, CSOMOR Judit, GELPI Ellen, ILLÉS Zsolt, GARZULY Ferenc

Background and aims – Description of two cases of rare intravascular large B-cell lymphoma and secondary T-cell lymphoma diagnosed postmortem, that manifested clinically as longitudinally extensive transverse myelitis (LETM). We discuss causes of diagnostic difficulties, deceptive radiological and histological investigations, and outline diagnostic procedures based on our and previously reported cases. Case reports – Our first case, a 48-year-old female was admitted to the neurological department due to paraparesis. MRI suggested LETM, but the treatments were ineffective. She died after four weeks because of pneumonia and untreatable polyserositis. Pathological examination revealed intravascular large B-cell lymphoma (IVL). Our second case, a 61-year-old man presented with headache and paraparesis. MRI showed small bitemporal lesions and lesions suggesting LETM. Diagnostic investigations were unsuccessful, including tests for possible lymphoma (CSF flow cytometry and muscle biopsy for suspected IVL). Chest CT showed focal inflammation in a small area of the lung, and adrenal adenoma. Brain biopsy sample from the affected temporal area suggested T-cell mediated lymphocytic (paraneoplastic or viral) meningoencephalitis and excluded diffuse large B-cell lymphoma. The symptoms worsened, and the patient died in the sixth week of disease. The pathological examination of the presumed adenoma in the adrenal gland, the pancreatic tail and the lung lesions revealed peripheral T-cell lymphoma, as did the brain and spinal cord lesions. Even at histological examination, the T-cell lymphoma had the misleading appearance of inflammatory condition as did the MRI. Conclusion – Lymphoma can manifest as LETM. In cases of etiologically unclear atypical LETM in patients older than 40 years, a random skin biopsy (with subcutaneous adipose tissue) from the thigh and from the abdomen is strongly recommended as soon as possible. This may detect IVL and provide the possibility of prompt chemotherapy. In case of suspicion of lymphoma, parallel examination of the CSF by flow cytometry is also recommended. If skin biopsy is negative but lymphoma suspicion remains high, biopsy from other sites (bone marrow, lymph nodes or adrenal gland lesion) or from a simultaneously existing cerebral lesion is suggested, to exclude or prove diffuse large B-cell lymphoma, IVL, or a rare T-cell lymphoma.