Phenotype expansion and development in Kosaki overgrowth syndrome.

We expand the Kosaki overgrowth syndrome (KOGS) phenotype by over 70% to include 24 unreported KOGS symptoms, in a first male patient, the third overall associated with the PDGFRB c.1751C>G p.(Pro584Arg) mutation. Eighteen of these symptoms are unique to our patient, the remaining six are shared with other patients. Of the 24 unreported features overall, 6 show marked phenotype evolution and varying time of onset. The triangular face detected at 14 months and long palpebral fissures with lateral ectropion at 4 years are present in other members of the cohort. The remaining 4 are unique to Patient 5: pronounced macrocephaly from birth, increasingly triangular anterior skull from 14 months, camptodactyly, emerging at 4 years and worsening joint contractures from 6 years. Compilation of all new symptoms reported here with published clinical data further identifies at least 18 clinical parameters common to all cases to date, encompassing both known KOGS-associated PDGFRB mutations. We therefore propose a set of 18 core KOGS symptoms, with 16 present in early childhood. These results should also impact diagnostic/prognostic scope, intervention and outcome potential for KOGS patients, particularly for developmentally progressive conditions such as scoliosis and myofibroma.

Recessive Mutations in POLR3B Encoding RNA Polymerase III Subunit Causing Diffuse Hypomyelination in Patients with 4H Leukodystrophy with Polymicrogyria and Cataracts.

The diagnosis of 4H leukodystrophy (hypomyelination, hypogonadotropic hypogonadism, and hypodontia) is based on clinical findings and magnetic resonance imaging (MRI). Recently, mutations of the genes encoding Pol III (RNA polymerase III) subunit A (POLR3A) and subunit B (POL3B) have been identified as the genetic causes of hypomyelination. We describe two Polish female siblings aged 5 and 10 years with compound heterozygous mutations in POLR3B. They both presented with similar clinical symptoms and MRI findings presenting as 4H leukodystrophy, and the association of polymicrogyria and cataract. According to our observation in young children with the absence of hypogonadotropic hypogonadism, brain MRI pattern is very essential in proper early diagnosis of 4H leukodystrophy. All clinical and radiological results are of course helpful, however genetic conformation is always necessary.

EEG abnormalities preceding the epilepsy onset in tuberous sclerosis complex patients - a prospective study of 5 patients.

Tuberous sclerosis complex (TSC) is a multisystem, autosomal dominant disorder characterized by multiple hamartomas development. Epilepsy is the most common symptom appearing in 80-90% of the patients mainly in the first year of life. A prompt and early seizure control is crucial and can prevent development of an epileptic encephalopathy and secondary mental retardation. Therefore the very early identification of seizures seems to be of a great importance. We present the cases of 5 patients diagnosed with TSC prenatally or perinatally and regularly monitored (at 4-6 weeks intervals) with EEG before the epilepsy onset. The patients' age at baseline varied from 9 days to 9 weeks. In all of the patients epileptiform discharges preceded the epilepsy onset. The time interval between abnormality detection on EEG and the epilepsy onset varied from 1 to 8 days. The patient's age at the epilepsy onset ranged from the 17th day to the 5th month of life. In one patient the EEG was abnormal from the beginning and in this patient the epileptic seizures started from the neonatal period. In the rest of the patients (4/5) the EEG remained normal throughout the first months of life. In all of the children epilepsy started with focal motor seizures. Our study is the first prospective one showing the results of the EEG monitoring in TSC patients and the natural evolution of the EEG patterns in patients with the seizures types other than infantile spasms.

Proton MR Spectroscopy in Patients with Leigh Syndrome.

The aim of the present study was to evaluate MRS findings in patients with Leigh syndrome. We report our results of HMR spectroscopic studies performed in six patients (aged four months to ten years) with clinically proved Leigh syndrome. All examinations were done with 1.5 T scanner using an eight-channel phased array head coil. HMRS data were obtained using 2D-chemical shift imaging (CSI) and SVS sequences with short (30 ms) and long (135 ms) echo time. The MR spectra were acquired in multiple voxel localized in deep gray matter and periventricular white matter. The results were compared to the control group data. In most of our patients we found bilateral lesions in the basal ganglia and brain stem. HMRS data revealed elevated lactate in the affected areas, significantly diminished NAA/Cr ratio. The relatively high Cho/Cr ratio in the gray and white matter was also noted. HMRS is an important tool for non-invasive brain tissue analysis in Leigh syndrome.

Congenital CNS tumors diagnosed on prenatal MRI.

Congenital tumors form a unique group among pediatric neoplasms. They are different from other tumor groups in this population not only due to the onset time but also to their histopathology, anatomic location, biologic behavior and prognosis. The development of fetal MRI allowed early diagnosis of these tumors. Three fetuses with congenital central nervous system (CNS) tumors were diagnosed prenatally and confirmed with histopathology. Prenatal ultrasonography (US) and magnetic resonance imaging (MRI) were performed. After birth MRI or computed tomography (CT) were carried out. In one case a large intra-axial brain tumor was diagnosed with solid, cystic and hemorrhagic elements. After surgery the tumor turned out to be choroid plexus carcinoma. In the second case craniopharyngioma arising from the suprasellar region was diagnosed on the basis of prenatal MRI and confirmed. In the third case extra-axial meningioma-like tumor was visualized on fetal MRI. After surgery it turned out to be desmoplastic infantile astrocytoma. Intracranial teratoma, the most typical CNS congenital tumor, was not diagnosed in our material. Our cases were rarely encountered neoplasms: choroid plexus carcinoma, craniopharyngioma and desmoplastic infantile astrocytoma. The examinations were repeated after birth and did not add significant information. In utero diagnostics is easier and safer than postnatal imaging of the sick baby that may require life-support equipment, and provides information of equal value.

SURF1 missense mutations promote a mild Leigh phenotype.

UNLABELLED: SURF1 gene mutations are the most common cause of Leigh syndrome (LS), a rare progressive neurodegenerative disorder of infancy, characterized by symmetric necrotizing lesions and hypervascularity in the brainstem and basal ganglia, leading to death before the age of 4 years. Most of the reported mutations create premature termination codons, whereas missense mutations are rare. The aim of the study was to characterize the natural history of LS patients carrying at least one missense mutation in the SURF1 gene. Nineteen such patients (8 own cases and 11 reported in the literature) were compared with a reference group of 20 own c.845_846delCT homozygous patients, and with other LS(SURF-) cases described in the literature. Disease onset in the studied group was delayed. Acute failure to thrive and hyperventilation episodes were rare, respiratory failure did not appear before the age of 4 years. Dystonia, motor regression and eye movement dissociation developed slowly. The number of patients who survived 7 years of life totaled 9 out of 15 (60%) in the 'missense group' and 1 out of 26 (4%) patients with mutations leading to truncated proteins. IN CONCLUSION: (i) The presence of a missense mutation in the SURF1 gene may correlate with a milder course and longer survival of Leigh patients, (ii) normal magnetic resonance imaging (MRI) findings, normal blood lactate value, and only mild decrease of cytochrome c oxidase (COX) activity are not sufficient reasons to forego SURF1 mutation analysis in differential diagnosis.

Brain Metastases from Ewing's Sarcoma. A Report of Two Cases and Review of the Literature.

Ewing's sarcoma accounts for approximately 30% of primary malignant bone tumors, mainly in children and young adults. At the time of diagnosis many patients already have metastatic spread of the disease, most often to the lungs and skeletal system. Intracerebral metastases are rare - the reported incidence is up to 4.3%. We describe two cases of metastatic deposits within the brain tissue. Signal intensity of the lesions was similar to that of meningioma on all sequences. Strong homogenous enhancement after gadolinium administration was also similar to meningioma.

Non-neuronopathic Gaucher disease due to saposin C deficiency.

Gaucher disease is generally caused by a deficiency of the lysosomal enzyme glucocerebrosidase. The degradation of glycosphingolipids requires also the participation of sphingolipid activator proteins. The prosaposin PSAP gene codes for a single protein which undergoes post-translational cleavage to yield four proteins named saposins A, B, C and D. Saposin (SAP-) C is required for glucosylceramide degradation, and its deficiency results in a variant form of Gaucher disease. In this report, we present clinical, biochemical, and molecular findings in a 36-year-old man and his 30-year-old sister with non-neuronopathic Gaucher disease due to SAP-C deficiency. Very high levels of chitotriosidase activity, chemokine CCL18, and increased concentration of glucosylceramide in plasma and normal beta-glucosidase activity in skin fibroblasts were observed in the patients. A molecular genetics study of the PSAP gene enabled the identification of one missense mutation, p.L349P, located in the SAP-C domain and another mutation, p.M1L, located in the initiation codon of the prosaposin precursor protein. The presented findings describe the first cases where the non-neuronopathic Gaucher disease has been definitely demonstrated to be a consequence of SAP-C deficiency. Three previously described cases in the literature displayed a Gaucher type 3 phenotype.

Transalar sphenoidal encephalocele. A case report.

Classification of cranial encephalocele is based on the anatomic location of the skull defect. Basal sphenoidal encephaloceles are the least common form of encephalocele whose pathogenesis can be congenital, traumatic, tumoral or spontaneous. We present a case of a very rare basal encephalocele protruding through a defect in the greater wing of the sphenoid bone into the pterygoid fossa.

Brain MRI in fetuses with cardiac tumours.

Tuberous sclerosis complex (TSC) is an autosomal dominant multisystem disorder which affects the skin, brain, heart and other organs. It is caused by mutations of two genes: TSC1 (on chromosome 9q34) or TSC2 (on 16p13.3). 70% of cases are sporadic with new mutations. This study aimed to highlight the utility of prenatal MRI as an adjunct imaging modality in the diagnosis and prognosis of tuberous sclerosis complex. Prenatal ultrasound and magnetic resonance imaging were performed in seven fetuses at a gestational age of 30, 32, 34 and 35 weeks using a 1.5 T MRI scanner. SSFSE,T2- and FGRE/T1-weighted images were obtained in axial, coronal and sagittal planes. Postnatal MRI was performed in two cases. Intracardiac tumors (rhabdomyomas) were revealed on ultrasound in all fetuses. On sonographic examination the brain tissue appeared normal in all cases. Brain MRI revealed focal low-signal-intensity lesions, localized along the walls of the lateral ventricles of five fetuses. Another hypointense lesion was seen at the grey/white matter junction in one case. Brain MRI of two fetuses was normal. The diagnosis of TSC was established in five cases. Postnatal MRI in two cases confirmed prenatal findings. MRI allows more complete evaluation of the fetus and helps to determine the diagnosis and prognosis in cases of TSC. The use of prenatal MR imaging in addition to prenatal sonography has the potential to improve genetic counseling and prenatal diagnosis of patients with tuberous sclerosis.

Apparent diffusion coefficient is increased in children with tuberous sclerosis complex personal experience and review of the literature.

Diffusion-weighted imaging (DWI) provides information on tissue integrity and shows increased sensivity in detecting brain white matter disease compared to traditional T2-weighted MRI. We compared apparent diffusion coefficient (ADC) values in brain lesions and normal appearing white matter (NAWM) in patients with tuberous sclerosis complex (TSC) to normal brain tissue in the control group. MRI and DWI were performed in 14 patients with TSC (age range 7-16 years) and in 18 age-matched normal control subjects. ADC values measured from 44 supratentorial cortical tubers, 37 white matter lesions, 80 NAWM were compared to those in control subjects. Statistical analysis was performed using Kruskal-Wallis and Mann-Whitney U tests. The highest ADCs were measured in cortical tubers (mean ADC, 1.24×10-3 mm(2)/s), followed in descending order by WM lesions (mean ADC, 1.07×10-3 mm(2)/s), NAWM (mean ADC, 0.83×10-3 mm(2)/s). We found a significant difference in ADC values of gray, WM lesions and NAWM in TSC patients compared to the control group (p<0,0001). Elevated ADC values in NAWM in TSC patients may be caused by subtle depletion of myelin sheaths and looseness of structures within the brain parenchyma due to underlying migration disorders.

Letter to the editor. A case of inborn choroid plexus carcinoma.

This is a short comment on the article by Balaji et al. "CT and MR Imaging in Choroid Plexus Carcinoma. Report of Two Cases" (The Neuroradiology Journal 2006, 19: 330-333).

Acute fright induces onset of symptoms in vanishing white matter disease-case report.

Vanishing white matter disease is a newly recognised leukoencephalopathy of identified genetic background, characterised by cystic degeneration and progressive vanishing of white matter. The characteristic clinical symptoms are spasticity and ataxia with relatively preserved cognitive functions. A characteristic feature of the disease is the occurrence of the symptoms after a physical stress situation such as mild head trauma or febrile infection. We would like to present a case of a 6-year-old girl whose first symptoms of the disease occurred after being frightened by a horse.

Cerebellar lesions in children with tuberous sclerosis complex.

Cerebellar lesions in tuberous sclerosis complex are less frequent than cerebral findings. We present the magnetic resonance (MR) features of uncommon cerebellar changes found in a large series of children with tuberous sclerosis complex (TSC). MR examinations of 73 children (38 males and 35 females) with TSC were reviewed. Twelve patients with cerebellar lesions were selected. Patients' ages ranged from 2.5 years to 21.25 (median: 10.6). The number, anatomic location, signal intensity and contrast enhancement of these lesions were evaluated. MR studies were performed with a 1.5 T scanner obtaining T1, T2-weighted images and FLAIR sequences. Gadolinium was administrated in all cases. Cerebellar tubers were found in 12 patients (16.4%). The total number of cerebellar tubers was 21. Most cerebellar tubers were hyperintense on T2-weighted and FLAIR images and slightly hypointense on T1-weighted images. Eleven of these lesions (52.38%) revealed contrast enhancement. None of cortical cerebral tubers showed contrast enhancement. Atrophy of seven cerebellar tubers was noticed. The mutation in TSC2 gene was confirmed in eight patients. Cerebellar tubers are uncommon. They were not found in the absence of cerebral tubers and may associated with parenchymal volume loss.

High levels of circulating interleukin-10 in diabetic nephropathy patients.

AIMS: The aim of our study was to analyse the level of circulating interleukin-10 (IL-10) and relate it to the grade of albuminuria in patients with diabetic nephropathy (DN) due to type 1 diabetes mellitus (DM). Since IL-10 has met the criteria for an anti-inflammatory and an immunosuppressive cytokine, its activity may be important for clinical outcome of DN. METHODS: The IL-10 level was measured by ELISA in serum samples from thirty patients with DN due to type 1 DM, and compared with thirty patients with type 1 DM without DN and a control group of thirty, healthy, age- and sex-matched people. RESULTS: We observed a greatly elevated concentration of circulating IL-10 in 30/30 DM patients with DN (mean 140 pg/mL +/- 102), compared to DM patients without DN in whom IL-10 was detectable in only 11/30 patients (0.79 pg/mL +/- 1.24), and the group of healthy people in whom IL-10 was detectable in only 3/30 donors (0.92 pg/mL +/- 0.17). IL-10 appeared to be the strongest independent predictor of albuminuria, followed by HbA1c, diastolic blood pressure and DN duration. There was a positive correlation between the values of IL-10 and albuminuria in DM patients with DN. The patients in the fourth quartile of albuminuria had a distinctly higher concentration of IL-10 than those in the lower quartiles. CONCLUSIONS: The increased concentration of IL-10 in the serum samples from DM patients with DN seems to depend on the severity of the nephropathy. The excessive IL-10 production may indirectly contribute towards DN progression. On the other hand, it may explain the relatively long course of diabetic nephropathy.

[MRI in the diagnosis of congenital white matter diseases and other neurodegenerative diseases]. / Wartosc rezonansu magnetycznego w diagnostyce wrodzonych chorób istoty bialej i innych zwyrodnieniowych chorób osrodkowego ukladu nerwowego.

The results of cranial magnetic resonance imaging in 76 children (aged 3 weeks--17 years) with neurometabolic or other neurodegenerative diseases are presented. The number of diagnosed diseases was 22. MR symptomatology of 11 of them is presented. The list of characteristic images includes metachromatic leukodystrophy, mucopolysaccharidoses, X-linked adrenoleukodystrophy, Leigh, Menkes and Pelizaeus-Merzbacher diseases, glutaric aciduria type I, Canavan disease, neuronal ceroid lipofuscinosis, Hallervorden-Spatz and Huntington diseases. The diagnosis of neurometabolic/neurodegenerative diseases cannot be based on MRI alone but in some of them (metachromatic leukodystrophy, adrenoleukodystrophy, Leigh and Menkes diseases, glutaric aciduria type I, Canavan and Hallervorden-Spatz diseases) MRI can strongly suggest the diagnosis.

Naturally occurring V1-env region variants mediate simian immunodeficiency virus SIVmac escape from high-titer neutralizing antibodies induced by a protective subunit vaccine.

Macaques which developed high-titer neutralizing antibodies (htNAb) after immunization with a virion-derived oligomeric envelope glycoprotein subunit vaccine were protected against a homologous simian immunodeficiency virus SIVmac challenge. Here we demonstrate that the htNAb could be overcome by V1-env region variants isolated ex vivo from an SIVmac-infected macaque. The results further suggest that the development of V1-env region neutralization escape mutants is also necessary for survival of the virus in infected macaques. The immunological capacity of a single variable region to induce neutralizing antibodies in vaccinated and infected macaques initiate new ideas for a successful vaccine strategy.

Phase II study of anti-CD4 idiotype vaccination in HIV positive volunteers.

A clinical phase II trial of postinfectional idiotype vaccination was performed in early stage HIV + volunteers. The mAb 13B8.2 is directed against the CDR3-homologous CD4/D1 region implicated in HIV-gp120 binding. We have previously shown that this mAb induces HIV-gp120 cross-reactive immunity. In addition, the mAb 13B8.2 was well tolerated in a clinical phase-Ia trial. In this phase-II trial, 158 patients with 350-500 CD4+ cells/microl blood were randomised to receive either 1.2 mg of alum-precipitated mAb 13B8.2 or placebo. The mAb was well tolerated evoking predominantly local side effects. Multivariant analysis of clinical study endpoints demonstrated a significant response in the verum group (intend-to-treat analysis). Titres of HIV-1 neutralisation in vitro were raised along with HIV/gp120 antigen binding titres. Our data indicate that patients treated with the idiotype vaccine will produce an augmented specific anti-viral immune response. The vaccine might thus have a positive impact on the course of HIV disease.

Prechallenge high neutralizing antibodies and long-lasting immune reactivity to gp41 correlate with protection of rhesus monkeys against productive simian immunodeficiency virus infection or disease development.

To investigate the protective efficacy of various gp130 vaccine preparations, rhesus monkeys were immunized with gp130 oligomers (O-gp130) or two different gp130-monomer preparations (M1-gp130; M2-gp130) and challenged with 50 MID50 of simian immunodeficiency virus (SIV)mac32H. Following challenge the control animals and all animals of the M1- and M2-gp130 group and 1 animal of the O-gp130 group were productively infected, whereas 3 animals of the O-gp130 group resisted the productive virus replication. The protection was correlated with high neutralizing antibodies and a long-lasting immune response to the transmembrane protein gp41. Whereas none of the O-gp130 animals had developed disease symptoms, 3 M1-gp130 animals, 1 M2-gp130 animal, and 2 control animals died as a result of AIDS within 18 months after challenge. Therefore, immunization with virion-derived gp130 oligomers of SIVmac32H can confer protection against the productive infection with SIVmac32H and suppress the development of the AIDS-like disease.