Heterozygosity for ARID2 loss-of-function mutations in individuals with a Coffin-Siris syndrome-like phenotype.

Chromatin remodeling is a complex process shaping the nucleosome landscape, thereby regulating the accessibility of transcription factors to regulatory regions of target genes and ultimately managing gene expression. The SWI/SNF (switch/sucrose nonfermentable) complex remodels the nucleosome landscape in an ATP-dependent manner and is divided into the two major subclasses Brahma-associated factor (BAF) and Polybromo Brahma-associated factor (PBAF) complex. Somatic mutations in subunits of the SWI/SNF complex have been associated with different cancers, while germline mutations have been associated with autism spectrum disorder and the neurodevelopmental disorders Coffin-Siris (CSS) and Nicolaides-Baraitser syndromes (NCBRS). CSS is characterized by intellectual disability (ID), coarsening of the face and hypoplasia or absence of the fifth finger- and/or toenails. So far, variants in five of the SWI/SNF subunit-encoding genes ARID1B, SMARCA4, SMARCB1, ARID1A, and SMARCE1 as well as variants in the transcription factor-encoding gene SOX11 have been identified in CSS-affected individuals. ARID2 is a member of the PBAF subcomplex, which until recently had not been linked to any neurodevelopmental phenotypes. In 2015, mutations in the ARID2 gene were associated with intellectual disability. In this study, we report on two individuals with private de novo ARID2 frameshift mutations. Both individuals present with a CSS-like phenotype including ID, coarsening of facial features, other recognizable facial dysmorphisms and hypoplasia of the fifth toenails. Hence, this study identifies mutations in the ARID2 gene as a novel and rare cause for a CSS-like phenotype and enlarges the list of CSS-like genes.

Acquired von Willebrand syndrome as side effect of valproic acid therapy in children is rare.

To determine the frequency and clinical relevance of acquired von Willebrand syndrome (aVWS) due to antiepileptic therapy by valproic acid, we investigated 50 consecutive children in three neuropediatric institutions. Coagulation factors were determined in local laboratories before and three times after starting therapy with valproic acid. Parameters of von Willebrand factor (VWF) were additionally investigated in a reference laboratory including multimeric analysis. Significant changes in the coagulation system were found concerning fibrinogen (decreased from 287 +/- 70 mg/dl to 222 +/- 67 mg/dl; p < 0.001) and platelet count. Changes of VWF parameters were also found but no patient developed laboratory defined aVWS. We conclude that the bleeding tendency observed in some children undergoing antiepileptic therapy with valproic acid is not due to aVWS.

MFN2 mutation distribution and genotype/phenotype correlation in Charcot-Marie-Tooth type 2.

Mutations in mitofusin 2 (MFN2) have been reported in Charcot-Marie-Tooth type 2 (CMT2) families. To study the distribution of mutations in MFN2 we screened 323 families and isolated patients with distinct CMT phenotypes. In 29 probands, we identified 22 distinct MFN2 mutations, and 14 of these mutations have not been reported before. All mutations were located in the cytoplasmic domains of the MFN2 protein. Patients presented with a classical but rather severe CMT phenotype, since 28% of them were wheelchair-dependent. Some had additional features as optic atrophy. Most patients had an early onset and severe disease status, whereas a smaller group experienced a later onset and milder disease course. Electrophysiological data showed in the majority of patients normal to slightly reduced nerve conduction velocities with often severely reduced amplitudes of the compound motor and sensory nerve action potentials. Examination of sural nerve specimens showed loss of large myelinated fibres and degenerative mitochondrial changes. In patients with a documented family history of CMT2 the frequency of MFN2 mutations was 33% indicating that MFN2 mutations are a major cause in this population.

Treatment of primary malignant rhabdoid tumor of the brain: report of three cases and review of the literature.

PURPOSE: Primary malignant rhabdoid tumor (MRT) of the central nervous system is an extremely aggressive tumor predominantly related to early childhood, with characteristic histopathological findings but unclear histogenesis. Owing to its low incidence, little knowledge exists concerning the best therapeutic strategy. METHODS AND MATERIALS: Three children of our hospital with MRT of the brain underwent a maximum tumor resection followed by multidrug chemotherapy and radiation therapy to the craniospinal axis. RESULTS: Relapse was disseminated along the spinal subarachnoid spaces in one child and occurred at the primary tumor site in the other two patients. Maximum survival was 15 months from diagnosis. CONCLUSION: A review of patients reported in the literature and a comparison to our patients reveals a high propensity to early local relapse and meningeal dissemination. In the absence of more effective therapeutic options, we recommend multidisciplinary treatment of patients in good general condition and with resectable disease. In particular, following radiation therapy, tumor remissions and delay of tumor regrowth have been observed.

Megalencephaly, mega corpus callosum, and complete lack of motor development: a previously undescribed syndrome.

We report on 3 sporadic cases of in utero onset megalencephaly. Children were born to healthy nonconsanguineous parents after uneventful pregnancies. Head circumferences were just above the 97th centile at birth in 2 patients, 2 cm above the 97th centile in 1 patient, and subsequently increased to 4.5-6.5 cm above the 97th centile at age 5 years. All patients completely lacked motor and speech development and showed very little intellectual progress. There was a distinctive facial aspect with frontal bossing, low nose bridge, and large eyes, but no cutaneous abnormalities and no signs of other organ involvement. Magnetic resonance imaging showed bilateral megalencephaly with a broad corpus callosum, enlarged white matter, and focally thick gray matter, resulting in pachygyric appearance of the cortex. Opercularization was incomplete, and the Sylvian fissures were wide. Somatosensory evoked potentials in 1 patient showed normal latencies of cervical and contracortical potentials but bilaterally increased cortical amplitudes. To the best of our knowledge, no similar case observations have been recorded previously.

Alterations of brain metabolites in metachromatic leukodystrophy as detected by localized proton magnetic resonance spectroscopy in vivo.

The brain morphology and chemistry of seven children with late infantile (4/7) and juvenile (3/7) forms of metachromatic leukodystrophy (MLD) were investigated by magnetic resonance imaging (MRI) and localized proton magnetic resonance spectroscopy (MRS). Patients who were examined at least 6 months after the onset of symptoms (6/7) had severe leukodystrophic changes on MRI. Proton MRS revealed a marked reduction of the neuronal marker N-acetylaspartate in white and grey matter and elevated lactate in demyelinated areas. In contrast to other leukodystrophies MLD patients showed a generalized increase of brain myo-inositol (2- to 3-fold in white matter), indicating a specific role in the pathophysiology of demyelination in MLD.

Aromatic L-amino acid decarboxylase deficiency: an extrapyramidal movement disorder with oculogyric crises.

Aromatic L-amino acid decarboxylase (AADC) deficiency results in an impaired synthesis of catecholamines and serotonin, and has been reported only in two middle eastern families. We report on a European family with an affected child. The child showed the characteristic clinical picture of an extrapyramidal movement disorder, oculogyric crises and vegetative symptoms seen in the three patients described previously. Treatment with a combination of the AADC cofactor pyridoxine, the monoamine oxidase B inhibitor selegiline and bromocriptine was started during the fifth year of life and showed only a moderate clinical improvement in contrast to patients who have been treated since the first year of life.

Preliminary report of a multi-center study on the West syndrome.

During a 12-month period, 54 infants with the West syndrome (10 idiopathic, 44 symptomatic) referred to 10 major children's hospitals for initial treatment were evaluated to obtain comprehensive data on clinical findings and current treatment modalities. Prominent features included prevalence of prenatal and perinatal etiologies, severe neurological deficits and disturbed psychomotor development as well as patient-specific spectrum of seizure manifestations. Characteristic behavioural abnormalities before onset of spasms are an early indicator for the West syndrome. Therapeutic management varied considerably. Response to ACTH/steroid regiments was more favourable than to non-ACTH/steroid regimens. The most frequent serious adverse reactions during the initial treatment period were arterial hypertension and infections. Improved therapeutic strategies based on detailed initial patient assessment and systematic monitoring of beneficial effects and adverse reactions are necessary for future trials.

Congenital muscular dystrophy with cerebral and ocular malformations (cerebro-oculo-muscular syndrome).

Two children with the features of the "Muscle, Eye and Brain (MEB) Disease" (SANTAVUORI 1977), i.e. congenital muscular dystrophy (CMD), cerebral malformations and ocular abnormalities are reported and correlations with other inherited autosomal recessive syndromes of CMD, Fukuyama type of CMD and the Walker-Warburg syndrome discussed. The association of CMD and cerebral lesions indicate an unfavourable clinical prognosis.

Multiple sclerosis in childhood: report of 15 cases.

We report the preliminary results of an ongoing study of multiple sclerosis (MS) in childhood. The investigations include an analysis of the clinical picture and course. Multiple sclerosis in early childhood may present atypically, with a symptomatology suggesting diffuse encephalomyelitis, meningeal reaction, brain oedema, seizures, impaired consciousness and in some cases take a lethal course. Imaging studies including MRI and MR-spectroscopy, CSF-analysis, electrophysiology (VEP, BAEP, SER), and virological and immunological investigations are performed. So far 15 children have been studied. Their age at the onset of the disease ranged from 3 to 15 years. Abnormal CSF-findings with pleocytosis and oligoclonal IgG bands were present in 11 and 10 out of 15 patients respectively. MRI revealed numerous white matter lesions in the brain stem and cerebral hemispheres. VEP, BAEP and SER's were abnormal in most children. Proton magnetic resonance spectra from plaques exhibited a 50-80% decrease in N-acetyl aspartate, which is a potential marker of vital neuronal tissue, a decrease of the creatine pool and an increase of choline-containing compounds. Lactate was not increased. Our observations of MS in early childhood cast doubt on some of the previous notions concerning a latency period of several years between the exposure to a still unknown agent and the manifestation of MS. In view of atypical features in the initial phase, it would seem desirable to record cases of encephalomyelitis of undetermined origin as potential cases of MS and to register the further course for verification or exclusion.

Proton magnetic resonance spectroscopy of linear nevus sebaceus syndrome.

Cerebral metabolites of a patient with linear nevus sebaceus syndrome and hemimegalencephaly were determined at 18 and 30 months of age by localized proton magnetic resonance spectroscopy. Clinically, the patient suffered from hemiparesis and epileptic seizures. At 18 months of age, spectroscopy of the enlarged hemisphere revealed decreased N-acetylaspartate mainly in parietal white matter relative to the unaffected hemisphere. One year later, white matter studies indicated both reduced N-acetylaspartate and elevated myoinositol. In insular gray matter the previously normal concentrations of creatine, choline-containing compounds, myoinositol, and glutamine were increased. The findings are consistent with mild neuroaxonal loss or damage (white matter) and glial proliferation (cortical gray and white matter) of the affected hemisphere. The metabolic disturbances indicate disease progression but are less pronounced than in older patients with hemimegalencephaly.

Wernicke's encephalopathy in a child with acute lymphoblastic leukemia treated with polychemotherapy.

We report on a 3 3/4-year-old girl with acute lymphoblastic leukemia. Polychemotherapy caused a complete remission of the tumor. Six months after treatment was started, the patient developed vomiting and diarrhea necessitating parenteral nutrition. Disturbance of eye movements appeared 4 weeks later. The patient died suddenly 3 days after their manifestation. Autopsy revealed Wernicke's encephalopathy. This case demonstrates the need for thiamine substitution in infants with malignant diseases.

Two brothers with Hennekam syndrome and cerebral abnormalities.

We report two brothers with mental retardation, lymphoedema of the limbs and facial anomalies. Hennekam et al. (Am J Med Genet 34:593-600; 1989) described four patients with identical signs and intestinal lymphangiectasia. To confirm the diagnosis of Hennekam syndrome we undertook a duodenal biopsy from the older brother which revealed intestinal lymphangiectasia. So far only one patient with Hennekam syndrome and cerebral abnormalities has been described. This patient presented with pachygyria in the parietal area. Cerebral MRI in our two cases revealed small subcortical hyperintensities in both patients and a large cystic lesion in the younger patient probably representing an old media infarction.

Epidemiology and clinical manifestations of Lyme borreliosis in childhood. A prospective multicentre study with special regard to neuroborreliosis.

Lyme borreliosis is a tick-borne infection caused by the spirochete Borrelia burgdorferi, whose discovery in 1982 solved an aetiological mystery involving a variety of dermatological and neurological disorders and explained their association with Lyme disease. Lyme borreliosis occurs frequently and is readily treatable with antibiotics. Along with its discovery, however, came the realization that it is difficult to diagnose accurately, especially antibody diagnosis. False-positive antibody results in particular led to gradual widening of the clinical spectrum, and differential diagnosis became increasingly difficult. This prospective, multicentre study presents a systematic description of Lyme borreliosis in childhood, emphasizing epidemiological and clinical issues. Because, predominantly, inpatients were examined, Lyme neuroborreliosis was the focus of the study, with the chief concern being to minimize false-positive results. To this end, we chose to narrow the diagnostic criteria, using the presence of specific antibodies in the cerebrospinal fluid as the determining factor. The epidemiological investigation was focused on the incidence of Lyme neuroborreliosis in childhood in southern Lower Saxony as well as on the prevalence of Lyme neuroborreliosis among acute-inflammatory neurological illnesses in children. The clinical part of the study aimed at establishing criteria for differential diagnosis in addition to the detection of specific antibodies. The detection of specific IgM antibodies using an IgM capture ELISA confirmed the presence of acute Lyme borreliosis. The study examined 208 children with Lyme borreliosis, of whom 169 had Lyme neuroborreliosis, from mid-1986 until the end of 1989. The yearly incidence of Lyme neuroborreliosis in Lower Saxony was 5.8 cases/100,000 children aged 1 to 13. The manifestation index was 0.16, or one case of Lyme neuroborreliosis per 620 infected children, compared with the presence of specific antibodies against B. burgdorferi for children in the same age group and region. Both the seasonal distribution of Lyme borreliosis, which peaked in summer and autumn, as well as the information about when the tick bites took place point to an incubation period of a few weeks. The most frequent manifestation of Lyme neuroborreliosis in childhood was acute peripheral facial palsy, found in 55% of all cases (n = 93). Lyme borreliosis proved to be the most frequently verifiable cause of acute peripheral facial palsy in children, causing every second case of this disorder in summer and autumn.(ABSTRACT TRUNCATED AT 400 WORDS)

Novel mutations in exon 6 of the GFAP gene affect a highly conserved if motif in the rod domain 2B and are associated with early onset infantile Alexander disease.

Alexander disease is a rare disorder of cerebral white matter due to a dysfunction of astrocytes. The most common infantile form presents as a megalencephalic leukodystrophy. Mutations of the GFAP gene, encoding Glial Fibrillary Acidic Protein, have been recognized as the cause of Alexander disease. Glial Fibrillary Acidic Protein is the major intermediate filament protein in astrocytes, its functional rod domain is conserved in sequence and structure among other intermediate filament proteins. We report here two cases of infantile Alexander disease with early onset and severe course, caused by DE NOVO mutations A364 V and Y366C. Both affected GFAP residues are part of a highly conserved coiled-coil trigger motif in the C-terminal end of segment 2B, probably required for the stability of intermediate filament molecules. Comparable effects are seen with mutations of the corresponding residues of the gene coding for keratin 14, another intermediate filament, this further supports the hypothesis that these positions of the trigger motif are generally critical for a normal function of intermediate filaments.

Autoantibodies to human manganese superoxide dismutase (MnSOD) in children with facial palsy due to neuroborreliosis.

AIM: Acute peripheral facial palsy due to neuroborreliosis is associated with a distal neuritis. In patients with Lyme disease the activity of antioxidant enzymes is decreased. With respect to the pathogenesis of neuroborreliosis, sera of children with acute peripheral facial palsy were investigated for autoantibodies against human manganese superoxide dismutase (MnSOD), which were suspected of raising the oxidative injury of infected tissues. METHODS: Sera of 20 children with acute peripheral palsy with neuroborreliosis, sera of 20 children with facial palsy without reference to Lyme disease and sera of 14 blood donors were tested for antibodies against human MnSOD using an ELISA. RESULTS: The concentrations of IgM autoantibodies to MnSOD of the children with neuroborreliosis were significantly increased, compared with the two control groups. CONCLUSIONS: We propose that the antibodies detected block the protective effects of MnSOD resulting in an increased oxidative inflammation.

Lyme neuroborreliosis in children.

Children are more likely than adults to be bitten by ticks and thus more likely to be infected by Borrelia burgdorferi. In a serosurvey the infection rate measured by immunoglobulin G (IgG) antibodies was 2.6%. In a prospective hospital-based multicentre study 169 children with Lyme neuroborreliosis were examined; the infection was diagnosed by detection of specific immunoglobulin M (IgM) antibodies in the cerebrospinal fluid (CSF) using an IgM capture ELISA. The yearly incidence of Lyme neuroborreliosis was 5.8 cases per 100,000 children aged 1-13. Facial palsy and lymphocytic meningitis account for nearly 90% of all cases with neuroborreliosis indicating striking differences in the clinical spectrum between children and adults. Lyme borreliosis proves to be the most frequently verifiable cause of acute peripheral facial palsy in children, causing every second case of this disorder in the summer and autumn. In cases of facial palsy, nearly all patients with a positive history of tick bite or erythema migrans in the head and neck region show ipsilateral subsequent facial nerve palsy, suggesting a direct invasion via the affected nerve by Borrelia burgdorferi. Lyme borreliosis is the third most frequent cause of lymphocytic meningitis in childhood. Inflammatory changes of the cerebrospinal fluid along with the presence of specific antibodies are mandatory for the diagnosis of Lyme neuroborreliosis. High-dose intravenous penicillin G as well as third-generation cephalosporins prove to be effective in paediatric Lyme neuroborreliosis.

Bacterial meningitis and Lyme neuroborreliosis in childhood.

Neurologic infections represent a major problem in child neurology. Recent research on this issue has had important implications for diagnosis and pathophysiology of infectious diseases of the child's brain, resulting in new therapeutic approaches. A better understanding of the molecular pathophysiology of bacterial meningitis has developed, and therapeutic interventions focus on the host's inflammatory response. Therapeutic trials with dexamethasone in addition to antibiotic treatment have yielded promising results in reducing morbidity and long-term neurologic sequelae in bacterial meningitis. The detection of Lyme borreliosis in 1977 substantially influenced the differential diagnosis of inflammatory central nervous system diseases. Lyme neuroborreliosis proved a main cause of acute peripheral facial palsy and aseptic meningitis in children. An effective antibiotic treatment has become available for a large number of patients with these illnesses.