Molecular genetic diagnostics of tuberous sclerosis complex in Bulgaria: six novel mutations in the TSC1 and TSC2 genes.

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by the development of hamartomas localized in various tissues which can occur in the skin, brain, kidney and other organs. TSC is caused by mutations in the TSC1 and TSC2 genes. Here we report the results from the first molecular testing of 16 Bulgarian patients and one Romanian patient in whom we found six novel mutations: four in the TSC22 gene, of which one is nonsense, two frame shift and one large deletion of 16 exons; and two in the TSC1 gene, one nonsense and other frame shift. In addition, we detected 10 previously reported mutations; some of which are described only once in the literature. Our data is similar to the previous studies with exception of the larger number of TSC1 mutations than that reported in the literature data. In total, 40% (4/10) of the mutation in the TSC2 gene are located in the GTPase-activating protein domain, while 50% (3/6) are in the TSC1 gene and clustered in exon 15. All the cases represent the typical clinical symptoms and meet the clinical criteria for TSC diagnosis. In 35% of our cases the family history was positive. Our results add novel findings in the genetic heterogeneity and pathogenesis of TSC. The genetic heterogeneity might correlate to the clinical variability among the TSC-affected families, which makes the genetic counselling a real challenge.

Association between loss of dp140 and cognitive impairment in duchenne and becker dystrophies.

The presence of variable degrees of non progressive cognitive impairment is recognized as a clinical feature of patients with Duchenne and Becker muscular dystrophies (DMD and BMD), but its pathogenesis still remains a matter of debate. A number of findings have proved that rearrangements located in the second part of the dystrophin ( DMD ) gene seem to be preferentially associated with cognitive impairment. Dp140 is a distal dystrophin isoform, mainly expressed during fetal brain development, whose role for neuropsychological functioning was suggested. The aims of the current study were to explore the possible association between cognitive impairment and DNA mutations affecting the regulatory regions of Dp140, as well as to compare the neuropsychological functioning of patients affected with DMD and Intermediate muscular dystrophy (IMD) with those affected by Becker muscular dystrophy (BMD). Fiftythree patients genetically diagnosed with DMD, IMD and BMD, subdivided according to sites of mutations along the DMD gene, underwent a neuropsychological assessment, evaluating their general cognitive abilities, verbal memory, attention and executive functions. Twenty patients with mutations, terminating in exon 44 or starting at exon 45 were tested by polymerase chain reaction (PCR) amplification of microsatellites STR44, SK12, SK21 and P20 DXS269, in order to evaluate the integrity of the Dp140 promoter region. According to our statistical results, there was not a significant difference in terms of general intelligence between the allelic forms of the disease, a higher frequency of mental retardation was observed in DMD patients. The patients with BMD had better results on tests, measuring long-term verbal learning memory and executive functions. We found that patients lacking Dp140 performed more poorly on all neuropsychological tests compared to those with preserved Dp140. Overall, our findings suggest that the loss of Dp140 is associated with a higher risk of intellectual impairment among patients with dystrophinopathies and highlights the possible role of this distal isoform in normal cognitive development.

Definite and suspected multiple sclerosis in children: long-term follow-up and magnetic resonance imaging findings.

Twenty-five children at the ages of 3 to 18 years with an initial diagnosis of acute disseminated encephalomyelitis were followed in the Clinic of Child Neurology for a period of 2 to 8 years. In 10 children, there were data for clinically definite or laboratory-supported definite multiple sclerosis. The other 15 children in our study were considered as having suspected multiple sclerosis. Brain magnetic resonance imaging (MRI) performed in 15 children disclosed multiple hyperintense lesions on T2-weighted imaging in 13 children: 10 with definite multiple sclerosis and 3 with suspected multiple sclerosis. The clinical manifestations did not always correspond to the size and location of the MRI lesions of demyelination. Follow-up revealed normalization of the neurologic examination in 18 patients (72%) and abnormal neurologic findings in 7 patients (28%) (6 children with definite multiple sclerosis and 1 with suspected multiple sclerosis). Magnetic resonance imaging follow-up in children with definite multiple sclerosis disclosed a reduction in the size of the lesions in 3; enlargement or new lesions were established in the other 7 cases, and 2 cases were without clinical signs of new attacks. Correlation was done concerning the findings of the cerebrospinal fluid examination, transcranial magnetic stimulation, evoked potentials, computed tomography, and MRI. The role of MRI for an early diagnosis of multiple sclerosis in children is discussed. The dynamic follow-up of the pathologic changes is of prognostic significance for the course of the disease that could be a definite cessation of the process in acute disseminated encephalomyelitis cases or transition to multiple sclerosis.

Subacute sclerosing panencephalitis with atypical onset: clinical, computed tomographic, and magnetic resonance imaging correlations.

Clinical, computed tomographic (CT), and magnetic resonance imaging (MRI) correlations of subacute sclerosing panencephalitis with an atypical onset are presented in three children. In all three patients, the disease began similarly, with unilateral neurologic deficit followed by gnosis, praxis, and memory dysfunction corresponding to massive one-sided lesions. The first patient demonstrated right frontal-lobe syndrome and polymorphic extrapyramidal hyperkinesias; MRI showed a large high-signal lesion in the right frontal lobe, while CT was normal. The second patient displayed a disease onset with left-sided hemiparkinsonism and involuntary movements correlating to the MRI finding, ie, a massive rightsided occipitotemporoparietal subcortical lesion. An acute, stroke-like episode represented the first symptom in the third child. CT visualized cerebral, mainly left-sided cortical atrophy. In all three children, CT and MRI revealed significantly progressing brain atrophy at the disease's latest stages. We discuss the role of MRI in detecting early pathologic changes in children with subacute sclerosing panencephalitis.

Clinical manifestations of cerebrovascular hypoplasias in childhood.

The aim of the study was to analyze cerebrovascular hypoplasia in childhood and its clinical manifestations in a clinical population of 205 children aged 3 to 14 years. Cerebrovascular hypoplasias were diagnosed using angiography (n=63), magnetic resonance angiography, and transcranial Doppler ultrasonography. Hypoplasias were localized in the internal carotid artery in 41.9% of patients, in the middle cerebral artery in 54.1%, the anterior cerebral artery in 1.0%, and in the vertebro-basilar system in 3.0%. Clinical manifestations included transient ischemic attacks (21% of patients), cerebral infarcts (17%), progressive unilateral cerebral hemisphere atrophy (1.0%), focal and secondary generalized epileptic seizures (56.1%), and migraine-like headache (4.9%). Hypoplasias of the internal carotid artery and middle cerebral artery manifested as focal and secondary generalized epileptic seizures, transient ischemic attacks, cerebral infarcts, migraine-like headache, and progressive unilateral cerebral hemisphere atrophy, in descending order of frequency. Hypoplasias in the anterior cerebral artery or the basilar artery caused cerebral infarcts, and hypoplasias in the vertebral arteries caused transient ischemic attacks. This article discusses the pathophysiology of ischemia in the territory of the hypoplastic cerebral artery in childhood, as well as possibilities for noninvasive neuroimaging for diagnosis of cerebrovascular hypoplasias.

[Clinical multiplicity of cerebrovascular disorders in childhood]. / Uber die klinische Vielgestaltigkeit der zerebralen Gefässerkrankungen im Kindesalter.

A group of 107 children with vascular diseases of the nervous system aged 3-14 years have been studied. In 100 children of the study group acute disturbances of the brain blood circulation have been found, out of which 37 children were with transitory ischemic attacks; 29 were found to be with brain ischaemia; 22-with haemorrhages (7 cases with subarchnoidal, 9 cases with intracerebral and 6 cases with subarachnoidal-parenchimatose); 5 children had wenous thromboses; 7 children were with spinal strokes. In other 7 children we found the presence of Sturge-Weber syndrome. Congenital vascular malformations have been found in 32 children (30%), out of which 16 children (15%) with loops and stenosis of the extracranial segments of the internal carotid artery, and another 16 children (15%) with AV-malformations. Congenital and acquired heart diseases are found to be primary cause for the strokes in 12 children (11%). Considerable is the rate of the epileptic seizures in the acute stage of the strokes as well as of the residual epileptic syndromes.

[Radionuclear encephalo-angioscintigraphic studies in transitory disorders of brain circulation in childhood]. / Radionukleare Enzephaloangioszintigraphische Untersuchungen bei transitorischen Störungen der Hirnzirkulation im Kindesalter.

Fifteen cases of transient cerebral ischaemia in children have been studied. Radionuclear encephaloangioscintigraphy (RNEAS) with Tc99 DTPA in combination with CT scanning, doppler sonography of extracranial head arteries and EEG were performed in all observed cases. For some children cerebral angiography was done. RNEAS study found out: stenosis of internal carotid artery or a. cerebri media in 5 cases; AV-malformations- 3; ischaemic area- 1, aneurysma- 1; increased blood permeability of the late static scintigraphy- 3. Positive correlation was established between the angioscintigraphic and sonographic findings in the cases with stenosis of internal carotid artery; between angioscintigraphic and CT results in the cases with ischaemia; between RNEAS and angiographic data in cases with AV-malformations, aneurysm and stenosis. In conclusion RNEAS could be considered as a useful, atraumatic screening method within the complex of laboratory examinations for vascular diseases in childhood.