Cognitive function, behaviour and quality of life in children with myotonic dystrophy type 1 in South - Eastern Norway.

BACKGROUND: Cognitive and behavioural problems may be predominant in the clinical picture of myotonic dystrophy (DM1) in childhood. This can lead to a diagnostic delay and thus prevent optimal therapeutic measures. OBJECTIVE: To obtain an overview of children with DM1 in our health region and study their cognitive and behavioural function, quality of life and neurological status. METHODS: Patients diagnosed with DM1 were recruited to this cross-sectional study through local habilitation teams of our health region. Neuropsychological testing and physical examination were performed for the majority. For some patients information was retrieved from medical records and through telephone interviews. A questionnaire was administered regarding quality of life. RESULTS: 27 subjects <18 years diagnosed with DM1 were identified, giving a frequency of DM1 of 4.3/100 000 in this age group. Twenty consented to participate. Five had congenital DM1. Most of the participants had only mild neurological deficits. Two with congenital type had hydrocephalus requiring a shunt. Ten, whereof none with congenital DM1, had a cognitive function within normal range. Three were diagnosed with an autism spectrum disorder, and additional three were reported with autistic traits. Many parents reported social and school problems for their child. CONCLUSIONS: Intellectual disability and varying degrees of autistic behaviour were quite common. Motor deficits were most often mild. A strong focus regarding support at school and in social communication is needed for children growing up with DM1.

Neurogenic bladder dysfunction in children. / Nevrogene blæreforstyrrelser hos barn.

Neurogenic bladder dysfunction is the cause of a small proportion of urinary problems in children. Various neurological conditions can result in a change in neural control of the bladder, and also the colon. Some of these conditions are apparent at birth; others are discovered later, and it is important that the primary health service be aware of them, so that targeted treatment can be provided.

Lower urinary tract dysfunction in children - a practical approach. / Vannlatingsforstyrrelser hos barn ­ en praktisk tilnærming.

More than 10 % of schoolchildren suffer from lower urinary tract dysfunction, often leading to contact with the healthcare system. The problem is socially limiting as well as mentally and physically demanding for children and their parents, and it is important to offer treatment. This article describes a structured approach that can form the basis for correct diagnosis and treatment.

[Juvenile-onset muscular diseases]. / Muskelsykdommer med debut i barnealder.

Children with muscular diseases constitute an important group in paediatric neurology. Some of the conditions are very serious and require extensive interdisciplinary treatment and facilitation. There is some degree of optimism regarding the possibility of causal treatment in some of the conditions.

Prenatal exposure to bisphenol A interferes with the development of cerebellar granule neurons in mice and chicken.

In mice, prenatal exposure to low doses of bisphenol A has been shown to affect neurogenesis and neuronal migration in cortex, resulting in disturbance of both neuronal positioning and the network formation between thalamus and cortex in the offspring brain. In the present study we investigated whether prenatal exposure to bisphenol A disturbs the neurodevelopment of the cerebellum. Two different model systems were used; offspring from two strains of mice from mothers receiving bisphenol A in the drinking water before mating, during gestation and lactation, and chicken embryos exposed to bisphenol A (in the egg) on embryonic day 16 for 24h before preparation of cerebellar granule cell cultures. In the cerebellum, tight regulation of the level of transcription factor Pax6 is critical for correct development of granule neurons. During the development, the Pax6 level in granule neurons is high when these cells are located in the external granule layer and during their migration to the internal granule layer, and it is then reduced. We report that bisphenol A induced an increase in the thickness of the external granule layer and also an increase in the total cerebellar Pax6 level in 11 days old mice offspring. In cultured chicken cerebellar granule neurons from bisphenol A injected eggs the Pax6 level was increased day 6 in vitro. Together, these findings indicate that bisphenol A may affect the granule neurons in the developing cerebellum and thereby may disturb the correct development of the cerebellum.

Glucocorticoids dexamethasone and hydrocortisone inhibit proliferation and accelerate maturation of chicken cerebellar granule neurons.

Glucocorticoid (GC) treatment in premature infants may have detrimental effects on the immature brain. Here we show that GCs dexamethasone (Dex) and hydrocortisone (HC) reduce proliferation and induce differentiation of chicken embryo cerebellar neurons in vivo and in vitro. Granule neurons incorporating bromodeoxyuridine were reduced in the internal granular layer (IGL) after 24-h exposure to both substances on embryonic day 17, with Dex about 100-fold more potent than HC. The effects were blocked by GR antagonist RU 38486. Both GCs also increased the expression of neuronal differentiation markers microtubule-associated protein 2 (Map2) and neuronal nuclei protein (NeuN), measured by western blotting of whole cerebellar lysates and immunohistochemistry, respectively. Treatment of cerebellar granule neuron cultures with both GCs significantly reduced the percentage of proliferating-cell nuclear antigen (PCNA) positive neurons and increased NeuN positive neurons, with similar dose-response relationship as in vivo. The cytostatic agent cytosine arabinoside showed comparable effects both on proliferation and differentiation. In conclusion, the effects of Dex and HC on chicken cerebellar granule neuron proliferation are GR mediated and reflect their pharmacological potency. In addition, the effects on differentiation may be related to a cell cycle block per se, since cytosine arabinoside mimicked the effect of the GCs.

Transfection of chicken cerebellar granule neurons used to study glucocorticoid receptor regulation by nuclear receptor 4A (NR4A).

Transfection is a useful tool for studying molecular signalling pathways. However, neurons have proven hard to transfect. In the present paper we have optimized a new electroporation procedure using the Cellaxess(®) system for transient transfection of adherent primary neurons from chicken (Gallus gallus) and compared it to a liposome based procedure using Metafectene(®) Pro. In order to evaluate the two methods, glucocorticoid receptor (GR) function was chosen as a test. GRs are expressed in high amounts in the cerebellum. GR is regulated by another nuclear receptor (NGFI-B, the first member found in the NR4A family). We first showed that forskolin and phorbol ester activated an NR4A-dependent reporter gene indicating that members of the NR4A nuclear receptor family are present endogenously and upregulated by external stimuli. Then, transfected NGFI-B was shown to antagonize the dexamethasone-activated transcriptional activation by endogenous GR, leading to the conclusion that NR4A-family members are important modulators of GR mediated regulatory processes in the cerebellum, as in other cell types. Both transfection methods proved useful. While the electroporation technique yielded small rings with many transfected cells optimal for microscopy studies, the liposome based method resulted in transfected cells evenly distributed in the dish rendering this method well suited for biochemical studies.

Low-potency glucocorticoid hydrocortisone has similar neurotoxic effects as high-potency glucocorticoid dexamethasone on neurons in the immature chicken cerebellum.

High-potency glucocorticoids (GC) are used in the prophylaxis and treatment of neonatal bronchopulmonal dysplasia, but there is concern about side effects on the developing brain. Recently, the low-potency GC hydrocortisone (HC) has been suggested as an alternative to high-potency GC. We compared the neurotoxic effects of HC with the high-potency GC dexamethasone (DEX) in chicken cerebellum. A single dose of GC was injected into the egg at embryonic day 16 and the death of granule neurons in histologic sections of the cerebellar cortex was examined 24 h later. DEX and HC showed a similar dose-dependent induction of morphological apoptosis and caspase-3 activation in the internal granular layer. A doubling of the apoptosis rate compared to the basal rate was seen for the highest dose of DEX (5 mg/kg) and medium dose of HC (1 mg/kg). In cultures of embryonic chicken cerebellar granule cells, DEX and HC increased cell death and induced rapid caspase-3 activation in a similar dose-dependent manner. Transfection of granule cells with a luciferase reporter gene revealed that the dose needed for the activation of gene transcription (classical signalling pathway) with DEX was much lower than for HC. In conclusion, HC does not present itself as a safer drug than DEX in this model. In addition, it appears that DEX and HC induce apoptosis in immature granule neurons via a non-genomic (non-classical) mechanism.

Chicken cerebellar granule neurons rapidly develop excitotoxicity in culture.

Rat cerebellar granule cell culture is widely used as a model to study factors that control neuronal differentiation and death (e.g. excitotoxicity). However, a main drawback of this model is its dependence on depolarizing culture condition (25 mM potassium). In addition, it is quite expensive to maintain and requires animal facilities. Here we report that cerebellar granule neuron cultures from chicken may be used as an alternative model to study excitotoxicity. Surprisingly, fetal chicken cells may be grown in a physiological potassium concentration (5 mM potassium). They develop excitotoxicity rapidly in culture (fully developed at 3 days in vitro), and respond to glutamate excitotoxicity similar to rat cultures (ROS production and activation of caspase-3).