Veronica Saletti

Sepiapterin reductase deficiency: A Treatable Mimic of Cerebral Palsy

Sepiapterin reductase deficiency (SRD) is an under‐recognized levodopa‐responsive disorder. We describe clinical, biochemical, and molecular findings in a cohort of patients with this treatable condition. We aim to improve awareness of the phenotype and available diagnostic and therapeutic strategies to reduce delayed diagnosis or misdiagnosis, optimize management, and improve understanding of pathophysiologic mechanisms.

Intrathecal methotrexate affects cognitive function in children with medulloblastoma

BackgroundCognitive impairment occurs after malignant brain tumor treatment in children, following brain radiotherapy and systemic and intrathecal chemotherapy. Objectives1) To compare two groups of children who underwent surgery for cerebellar medulloblastoma with their cousins and siblings, assessing intelligence, executive function, attention, visual perception, and short-term memory. Both groups were treated with the same combined radiotherapy–chemotherapy, but differed in that only one group received intrathecal methotrexate (MTX+). 2) To relate these measures to MRI findings (leukomalacia). ResultsThe two groups performed worse than their control subjects in all tests. The MTX+ group younger than 10 years performed significantly worse in all tests, particularly executive ones. The group older than 10 years performed significantly worse only in short-term memory. Younger patients without MTX performed significantly worse than controls only in some neuropsychological measures; there were no differences between older patients and control subjects. Only in the MTX+ group was there a direct correlation between extent of leukomalacia and performance in some tests. ConclusionsThe administration of intrathecal methotrexate to children with medulloblastoma worsens the cognitive deficits induced by chemotherapy and radiotherapy. The use of intrathecal methotrexate in the treatment of medulloblastoma and other malignancies should be reassessed.

Late neuropsychological and behavioural outcome of children surgically treated for craniopharyngioma.

Abstract Late outcome in 12 children treated by radical surgery for craniopharyngioma is presented. None of the patients presented underwent fractionated traditional or stereotactic radiotherapy. The results show no neurological (except visual dysfunction in 6 subjects), cognitive or short-term memory deficits. Three children were found to have a minor attention deficit. In 5 cases “frontal lobe” malfunctioning was disclosed, and in 5 there were bursts of unpredictable anger. Three children showed worsening of functioning at school: a combination of various causes is suggested to explain the worsening of academic performances. The size of the sample calls for a careful evaluation of results, with due consideration for the influence of various factors on outcome. Multicentre studies are required to increase the sample size and achieve more general conclusions.

MRI Features of Cerebral Lesions and Cognitive Functions in Preterm Spastic Diplegic Children

The aim of this study is to further clarify the relation between the pattern of cognitive impairment in spastic diplegic children born preterm and MRI features of cerebral lesions. The cognitive profile by Wechsler Scale of a sample of 30 children aged 6 years, 8 months to 14 years, 7 months was assessed, and the correlations between the Full Scale, Verbal, and Performance IQ and periventricular leukomalacia features on MRI were investigated. A significant difference was observed between the mean Verbal and Performance IQ, indicating a specific failure in the visuoperceptual functions of spastic diplegic children born preterm. Periventricular leukomalacia was detected in all children. The severity of ventricular dilatation, the degree and extent of white matter reduction, optic radiation involvement, and the thinning of the posterior corpus callosum correlated significantly with the Full Scale and Performance IQ: no correlation was observed between the Verbal IQ and any of the MRI features analyzed. In spastic diplegic children, an MRI examination between the ages of 1 and 2 years may be helpful in predicting a specific neuropsychological pattern of dysfunction and in defining an early intervention program.

Neuropsychologic effects of frontal lobe epilepsy in children.

Most published neuropsychologic studies on frontal lobe epilepsy have been performed on mixed groups of adults and adolescents with epilepsies of varying etiology. The cognitive profile of frontal lobe epilepsy in children has not been defined. The purpose of this study was to assess neuropsychologic performance in children with frontal lobe epilepsy. Intelligence and executive functions were examined in eight children (age 67/12 years to 1311/12 years) with frontal lobe epilepsy. Performance was related to the focus side, seizure frequency, and age of epilepsy onset. Frontal lobe epilepsy was associated with a range of frontal dysfunctions, but IQ was generally spared. Left focus was associated with deficits in categorization, verbal long-term memory, and detailed visuospatial analysis. Frequent seizures correlated with attention difficulties and inability to inhibit impulsive responses. Children whose epilepsy appeared before age 6 years had reduced ability to change behavioral strategies. Frontal epileptic activity alone can cause selective frontal deficits, the severity and nature of which are related to side, seizure frequency, and age of epilepsy onset. These findings require confirmation on larger series of selected children. (J Child Neurol 2002;17:661-667).

A novel CLN8 mutation in late-infantile-onset neuronal ceroid lipofuscinosis (LINCL) reveals aspects of CLN8 neurobiological function.

The late‐infantile‐onset forms of neuronal ceroid lipofuscinosis (LINCL) are the most genetically heterogeneous group among the autosomal recessive neuronal ceroid lipofuscinoses (NCLs), with causative mutations found in CLN1, CLN2, CLN5, CLN6, CLN7 (MFSD8), and CLN8 genes. Homozygous mutations in CLN8 are associated with two distinct phenotypes: progressive epilepsy and mental retardation (EPMR), first identified in Finland; and a variant of late‐infantile NCL (v‐LINCL) described in a subset of Turkish and Italian patients. The function of the protein encoded by CLN8 is currently unknown. Here we report the identification of an Italian v‐LINCL patient with a complete isodisomy of chromosome 8, leading to homozygosity of a maternally‐inherited 3‐bp deletion in CLN8 gene (c.180_182delGAA, p.Lys61del). Notably, uniparental disomy (UPD) has never been described associated with the NCLs. In addition, we provide evidence of the biological role of CLN8 characterized by expressing in different neuronal cell models the native protein, the protein carrying the mutation identified here, or three additional missense mutations previously described. Our results, validated through a gene silencing approach, indicate that CLN8 plays a role in cell proliferation during neuronal differentiation and in protection against cell death. Hum Mutat 30:1–13, 2009.

Unilateral frontal lobe epilepsy affects executive functions in children.

Very few studies to date have investigated the neuropsychological changes detectable in children suffering from frontal lobe epilepsy (FLE). The aim of the present study was to assess the effects of FLE on cognitive and executive functions in childhood. The sample includes 17 children with a frontal epileptogenic focus (10 right and 7 left), with no evidence of anatomical brain damage. These subjects were assessed by means of a battery of tests to investigate executive functioning. The results emphasised the presence of selective impairments of frontal lobe functions without evidence of deficits in global intellectual functioning. No side-specific deficits were detected, while an earlier onset of epilepsy and the duration of the disorder, but not the seizures frequency, were found to correspond with more severe deficits in some specific frontal lobe functions.

Treatment for Chiari 1 malformation (CIM): analysis of a pediatric surgical series

Children may present a peculiar picture of CIM, as syncopes and acute paraparesis. In a series of 99 children operated for CIM at FINCB there were no major surgical morbidity nor mortality. The preoperative symptoms improved more in this pediatric series than in the adult cases treated at the same institution in the same period; a reason could be the shorter duration of symptoms and another the children plasticity. An untreated nonsyndromic craniosynostosis was present in 10 cases. In our hands, the results of the limited extradural decompression were poor. In some CIM associated with psychiatric symptoms an unexpected improvement was observed after tonsilar resection. The associated Syringomyelia reduced in more than 80% of children and disappeared in a significant number. The rare associated tethered cord (5%) needed a double treatment, detethering by itself being insufficient to treat also tonsillar descent. The clinical symptoms are often more serious in children than in the adults, but the results of surgery, especially on the syrinx, are better.

Neuroradiological diagnosis of Chiari malformations

Chiari malformations 1, 2, 3 represent different degrees of herniation of posterior fossa content into the cervical canal (Chiari 1 and 2), or through an upper-cervical meningocele (Chiari 3), whereas Chiari 4 anomaly consists of hypoplasia of the cerebellum. Chiari 1 malformation (CM1) is the commonest anomaly; it is probably related to a mesodermal defect that create a congenitally small posterior fossa, subsequent overcrowding of its contents and herniation through the foramen magnum. The diagnosis of CM1 is based on the demonstration of the downward displacement and particular shape of the cerebellar tonsils into the upper cervical spinal canal associated with obliteration of the subarachnoid spaces at the level of the foramen magnum. MRI has a fundamental role in the correct identification of the anatomical aspects of this malformation and associated anomalies and represents the imaging modality of choice.

A CDKL5 mutated child with precocious puberty

To date, 43 patients have been described with mutations in or involving the CDKL5 gene. The typical phenotype includes early‐onset, often intractable epileptic seizures and severe mental retardation with very limited progress in psychomotor development. Most patients also show impaired social interaction with avoidance of eye‐to‐eye contact, and some clinical features reminiscent of Rett syndrome (RTT), including stereotypic hand movements, lack of purposeful hand use, acquired microcephaly, and generalized hypotonia. We report on the case of a 5‐year‐old girl with a de novo CDKL5 gene mutation who developed early puberty, which has not been described before.