Psychogenic movement disorders in children: a report of 15 cases and a review of the literature.

Data on psychogenic movement disorders (PMD) in children are scarce, with most existing literature relating to adults only. We report 15 cases with the aim of highlighting the clinical characteristics, risk factors, comorbidity, treatment, outcome, and prognosis of PMD in children. Only 13% of cases had onset before age 10, with the mean age at onset being 12.3 years. Females were predominantly affected (F:M = 4:1). The most common types of movement disorders seen were dystonia (47%), tremor (40%), and gait disorders (13%). Multiple hyperkinetic phenomenologies were observed in many cases. Abrupt onset and precipitation by minor injuries, and stressful life events were commonly reported. Clinical clues on examination suggesting a psychogenic origin were similar to those identified in adults. A distinct feature of PMD in children was the predominant involvement of the dominant limb. The underlying psychiatric diagnosis was conversion disorder in the majority of cases. Time from symptom onset until diagnosis of a PMD varied broadly (between 2 weeks and 5 years). Treatment with cognitive and behavioral therapy and rehabilitation by a multidisciplinary team led to improvement in most cases. However, treatment was much more effective in children with a short time from symptom onset to diagnosis and treatment.

Longitudinal study evaluating a seating system using a sacral pad and kneeblock for children with cerebral palsy.

PURPOSE: Adaptive seating systems using sacral pads and kneeblocks are commonly used throughout the UK with children with complex motor disorders to improve their posture and stability in sitting. We sought to evaluate how effective these systems are for a group of children with cerebral palsy. METHOD: A six-visit trial was performed to examine whether this combination controls pelvic and hip positioning. Twenty-three children with cerebral palsy aged 7 - 14 years participated (11 females and 12 males). The kneeblocks (active intervention) were removed for a period in the middle of the trial. Force exerted through the kneeblock, pressure exerted on the sacral pad and postural alignment was measured for change. RESULTS: Statistically significant differences before and after kneeblock removal were found for force at the kneeblock, but no difference was found in pressure at the sacral pad. No statistically significant correlations between force and pressure or posture were found. CONCLUSION: The results indicate that seating systems using a sacral pad and kneeblock may not improve overall posture but may improve hip position in children with cerebral palsy.

Three or more copies of the proteolipid protein gene PLP1 cause severe Pelizaeus-Merzbacher disease.

We describe five boys from different families with an atypically severe form of Pelizaeus-Merzbacher disease (PMD) who have three, and in one case, five copies of the proteolipid protein (PLP1) gene. This is the first report of more than two copies of PLP1 in PMD patients and clearly demonstrates that severe clinical symptoms are associated with increased PLP1 gene dosage. Previously, duplications, deletions and mutations of the PLP1 gene were reported to give rise to this X-linked disorder. Patients with PLP1 duplication are usually classified as having either classical or transitional PMD rather than the more rare severe connatal form. The clinical symptoms of the five patients in this study included lack of stable head control and severe mental retardation, with three having severe paroxysmal disorder and two dying before the first year of life. Gene dosage was determined using interphase FISH (fluorescence in situ hybridization) and the novel approach of multiple ligation probe amplification (MLPA). We found FISH unreliable for dosage detection above the level of a duplication and MLPA to be more accurate in determination of specific copy number. Our finding that three or more copies of the gene give rise to a more severe phenotype is in agreement with observations in transgenic mice where severity of disease increased with Plp1 gene dosage and level of overexpression. The patient with five copies of PLP1 was not more affected than those with a triplication, suggesting that there is possibly a limit to the level of severity or that other genetic factors influence the phenotype. It highlights the significance of PLP1 dosage in CNS myelinogenesis as well as the importance of accurate determination of PLP1 gene copy number in the diagnosis of PMD and carrier detection.

Epilepsy in inborn errors of metabolism.

Although inborn errors of metabolism are rarely found to be the cause of epilepsy, seizures are a frequent symptom in metabolic disorders. In a few of these, epilepsy responds to specific treatment by diet or supplementation. However, in most, no such treatment is available and conventional antiepileptic drugs must be used, often with no great success. However, because uncontrolled epilepsy will hamper development and may even lead to further cerebral damage, treatment is necessary. Seizure types are rarely specific for a particular metabolic disorder, nor are EEG findings. Other symptoms and findings must be taken into account in order to achieve a diagnosis and, in some cases, specific management. We review the main characteristics of epilepsy due to inborn errors of energy metabolism, to disturbed neuronal function due to accumulation of storage products, to toxic effects and to disturbed neurotransmitter systems. We also discuss vitamin-responsive epilepsies and a number of other metabolic disorders focusing on possible pathogenetic mechanisms and their implication for diagnosis and treatment.

New syndrome characterized by hypomyelination with atrophy of the basal ganglia and cerebellum.

BACKGROUND AND PURPOSE: Leukoencephalopathies of unknown origin constitute a considerable problem in child neurology. The purpose of our ongoing study of the subject was to define new disease entities among them by using primarily MR imaging pattern recognition. METHODS: We identified seven unrelated patients with a distinct MR imaging pattern consisting of hypomyelination and atrophy of the basal ganglia (neostriatum) and cerebellum (H-ABC). We reviewed the clinical, MR imaging, MR spectroscopic, and laboratory data. RESULTS: Clinically, the patients' diseases were characterized by variably disturbed early development followed by increasing extrapyramidal movement abnormalities, ataxia, and spasticity. Mental capacity was variably affected, but it appeared to be relatively preserved. Parents were not related, and none of their siblings were affected. No metabolic defect was found. Follow-up MR imaging demonstrated atrophy of the cerebral white matter, neostriatum, and cerebellum, which was most pronounced in the most clinically severe cases. Single-voxel proton MR spectroscopic results were normal in the parietal cortex. In the cerebral white matter, myo-inositol and creatine levels were elevated; this finding was compatible with gliosis. N-acetylaspartate and choline levels were normal, suggesting that neither axonal loss nor active demyelination occurred. Proton MR spectroscopic imaging revealed relatively decreased N-acetylaspartate levels in the frontal region. CONCLUSION: The uniform and highly characteristic MR imaging findings, in combination with the similarities in the clinical findings, provide evidence of a distinct nosologic entity. The acronym H-ABC is offered to indicate patients sharing these clinical and MR imaging features.

Idiopathic catastrophic epileptic encephalopathy presenting with acute onset intractable status.

PURPOSE: To delineate a catastrophic childhood epileptic syndrome of unknown cause presenting with persistent intractable multifocal status. METHODS: Case note review. RESULTS: Six children aged 5 months to 6 years presented with focal seizures that progressed within days to intractable multifocal seizures with or without secondary generalisation, which recurred every few minutes and persisted for weeks. One developed impaired consciousness shortly before seizures started. The two younger children showed mild developmental delay before onset but the others were normal. The seizures were unresponsive to all conventional anticonvulsants, steroids or pyridoxine and could only be controlled with doses of thiopentone sufficient to cause electrical suppression. MRI scans were initially normal but later showed focal cortical swelling followed by generalised atrophy. Two developed hepatomegaly, with a normal liver biopsy in one and steatosis in the other. No cause has been found even after neuropathological investigation. Three have died, two within 3 months of onset, while the three survivors have very severe neurological impairment and continued seizures. CONCLUSION: The similarity of the clinical features suggests that this is a consistent clinical syndrome.

Changes in postural alignment when using kneeblocks for children with severe motor disorders.

PURPOSE: Children with severe motor disorders often use adaptive seating devices to improve their postural alignment with aim of helping to prevent the development of deformity. Little objective evidence exists about their effectiveness, and this study sought to measure changes in postural alignment when using/not using the active element in one adaptive seating system. METHOD: A seating system that uses a sacral pad and kneeblock was examined. This seating device aims to neutralize the angular deviation of the hips and pelvis in order to give a stable base for functional sitting. Change in postural alignment was measured in 23 children with severe motor impairment (GMFCS 5) when using and when not using the kneeblock devices, immediately, and after a delay of one month. RESULTS: We found that the removal or replacement of kneeblocks effected hip abduction and rotation on one side only, but no other immediate effect on joint angles and overall body posture. CONCLUSIONS: The postural management of children with neurological conditions requires further objective outcome measurement on which to base clinical practice, and improvement of posture is one of a number of factors which should be considered when providing adaptive seating to this group of children.

A comparative exploration of the thoughts of parents and therapists regarding seating equipment for children with multiple and complex needs.

PURPOSE: We investigated the opinions of parents and therapists of children using adaptive seating systems in order to understand their common areas of interest or disagreement. METHOD: Parents and therapists participated in answering a questionnaire regarding their child's response to, and comfort in their individual adaptive seating system. The children all had a motor disorder involving all four limbs and did not have verbal communication skills. Questionnaire was analysed using non-parametric statistics for quantitative questions and by keyword analysis of qualitative questions. The results were then further categorized into the domains of the International Classification of Functioning, Disability and Health (ICF). RESULTS: Parents and therapists showed differences in key areas: Parents concentrated on personal and environmental factors to explain their satisfaction or otherwise of the chair, whereas therapists concentrated on body function and structures; to the exclusion of all other domains of seated function. CONCLUSIONS: Based on these findings, we suggest further investigation of these seating systems, concentrating on the activity and participation of the children themselves, although considering all domains of functioning.

A standardized tool to measure and describe scleral colour in osteogenesis imperfecta.

BACKGROUND: Blue colouration of the sclera is a distinctive feature of unknown aetiology in osteogenesis imperfecta (OI). It has value as a diagnostic marker, for distinguishing prognostically distinct subtypes of the condition, and has been reported to undergo rapid unexplained changes concurrently to fractures. Description of the feature is currently hampered by lack of a clinical tool. METHODS: A range of blue reference colour chips from an internationally recognized standard (the Munsell system) was used under standardized viewing conditions, by two independent observers with normal colour perception, to classify the scleral colour of affected individuals. RESULTS: A total of 43 individuals affected by OI of a wide variety of severity with ages from 5 to 63 years were observed. All individuals in the sample had blue sclerae, and all colours seen could be matched to a Munsell standard within the hue range of 7.5B (blue) to 5PB (purple-blue). There was little variation in observed chroma (saturation), and observations of hue showed poor inter-observer reliability (r = 0.17 +/- 0.34: 95% CI). However, levels of value (lightness) showed wide variability and good inter-observer reliability (r = 0.63 +/- 0.14: 95% CI). CONCLUSIONS: A practical tool for the description of the colour of the sclera in individuals with OI can be constructed using the colours from the Munsell system varying in value (lightness) with hue: 2.5 PB and chroma: 2.

Frameshift mutation in GJA12 leading to nystagmus, spastic ataxia and CNS dys-/demyelination.

Mutations in GJA12 have been shown to cause Pelizaeus-Merzbacher-like disease (PMLD). We present two additional patients from one family carrying a homozygous frameshift mutation in GJA12. Both presented initially with nystagmus. The older girl developed ataxia first, then progressive spastic ataxia. The younger boy suffered from severe sensory neuropathy. Magnetic resonance imaging (MRI) of both children showed progressive demyelination in addition to dysmyelination, and also characteristic brainstem abnormalities. In children with nystagmus, ataxia and dysmyelination, mutation analysis of GJA12 should be considered early, especially if inheritance is autosomal recessive.

Virchow-Robin spaces on magnetic resonance images: normative data, their dilatation, and a review of the literature.

INTRODUCTION: Virchow-Robin spaces (VRS) are perivascular spaces in the brain and can be visualized on magnetic resonance images (MRI). We attempt to provide a better understanding of the significance of VRS for pathological and physiological processes by reviewing the literature, presenting normative data for the first time, and proposing a definition for the dilatation of the VRS on MRI that is based on shape rather than size. METHODS: We evaluated the VRS in 125 healthy subjects (age range 1-30 years) using high-resolution 3D images, and in 36 patients (age range 2-16 years) with normal MRI, using routine clinical sequences. RESULTS: VRS were visible in all high-resolution images of the 125 healthy subjects. Two of them revealed dilated VRS, giving a prevalence of 1.6%. VRS could be visualized in 29 (80%) of the 36 paediatric clinical scans; none was dilated. It was demonstrated that the visibility of VRS on MRI is sequence-dependent. CONCLUSION: From the results of this study and the literature on the nature and pathology of VRS, we conclude that VRS on MR images of healthy individuals are normal findings, even if they are dilated. A judgement on whether dilated VRS in an individual patient is a normal variant or part of a disease process can be made by taking into account the appearance of the adjacent tissue on MRI and the clinical context.

Understanding the information needs of general practitioners managing a rare genetic disorder (osteogenesis imperfecta).

BACKGROUND: Lack of adequate knowledge is a common problem in medicine, but is a particular problem in a rapidly advancing field like genetics. This study uses the example of a rare genetic disorder (osteogenesis imperfecta) to understand the information needs of primary care physicians (GPs). OBJECTIVES: To determine whether a knowledge gap is recognised, how GPs currently attempt to overcome it, and what features of an information resource are preferred by GPs. METHODS: GPs of children affected by osteogenesis imperfecta in and around Greater London were interviewed, using both questionnaire-based semi-structured interview and a qualitatively analysed open-ended discussion. Consultations in both primary and tertiary care settings over a 5-year period were compared. RESULTS: Problems due to osteogenesis imperfecta were presented to GPs in about one third of consultations with these patients. GPs reported finding such patients difficult to manage due to lack of knowledge. Knowledge from tertiary sources, which was authoritative, accessible and relevant, was preferred, particularly when reasoning was explained. Primary literature and clinical guidelines were not favoured. CONCLUSIONS: Empirical evidence supports and elaborates theoretical models for provision of clinically useful information. A model for improved information services using authoritative web-based information linked to electronic patient records is suggested.

Pantothenate kinase 2 mutation with classic pantothenate-kinase-associated neurodegeneration without 'eye-of-the-tiger' sign on MRI in a pair of siblings.

It has been postulated that all patients with pantothenate kinase 2 (PANK2) mutations causing pantothenate-kinase-associated neurodegeneration (PKAN) are associated with the 'eye-of-the-tiger' sign on MRI. We report a pair of siblings who presented with dystonia and who have been found to be homozygous for 104C>A, S35X mutation, confirming the diagnosis of PKAN. They do not have the typical iron deposition in the globi pallida or substantia nigra on MR imaging.

Neonatal epileptic encephalopathy caused by mutations in the PNPO gene encoding pyridox(am)ine 5'-phosphate oxidase.

In the mouse, neurotransmitter metabolism can be regulated by modulation of the synthesis of pyridoxal 5'-phosphate and failure to maintain pyridoxal phosphate (PLP) levels results in epilepsy. This study of five patients with neonatal epileptic encephalopathy suggests that the same is true in man. Cerebrospinal fluid and urine analyses indicated reduced activity of aromatic L-amino acid decarboxylase and other PLP-dependent enzymes. Seizures ceased with the administration of PLP, having been resistant to treatment with pyridoxine, suggesting a defect of pyridox(am)ine 5'-phosphate oxidase (PNPO). Sequencing of the PNPO gene identified homozygous missense, splice site and stop codon mutations. Expression studies in Chinese hamster ovary cells showed that the splice site (IVS3-1g>a) and stop codon (X262Q) mutations were null activity mutations and that the missense mutation (R229W) markedly reduced pyridox(am)ine phosphate oxidase activity. Maintenance of optimal PLP levels in the brain may be important in many neurological disorders in which neurotransmitter metabolism is disturbed (either as a primary or as a secondary phenomenon).

Approach to the diagnosis of neurotransmitter diseases exemplified by the differential diagnosis of childhood-onset dystonia.

We present our approach to the diagnosis of pediatric neurotransmitter diseases exemplified by the differential diagnosis of children presenting with dystonia. This approach is based upon the primary aim of early diagnosis of treatable conditions and the need for a logical series of investigations. We have tried to be comprehensive with our coverage but are aware that "new" pediatric neurotransmitter diseases continue to be delineated and that, similarly, a proportion of children presenting with dystonia remain undiagnosed. If this is the case, all of the investigations suggested here may need to be performed regardless of age and presentation. However, of more value is a careful clinical reevaluation.

Complex chromosomal rearrangement and associated counseling issues in a family with Pelizaeus-Merzbacher disease.

We report cytogenetic and molecular findings in a family in which Pelizaeus-Merzbacher disease has arisen by a sub-microscopic duplication of the proteolipid protein (PLP1) gene involving the insertion of approximately 600 kb from Xq22 into Xq26.3. The duplication arose in an asymptomatic mother on a paternally derived X chromosome and was inherited by her son, the proband, who is affected with Pelizaeus-Merzbacher disease. The mother also carries a large interstitial deletion of approximately 70 Mb extending from Xq21.1 to Xq27.3, which is present in a mosaic form. In lymphocytes, the mother has no normal cells, having one population with three copies of the PLP1gene (one normal X and one duplication X chromosome) and the other population having only one copy of the PLP1 gene (one normal X and one deleted X chromosome). Her karyotype is 46,XX.ish dup (X) (Xpter --> Xq26.3::Xq22 --> Xq22::Xq26.3 --> Xqter)(PLP++)/46,X,del(X)(q21.1q27.3).ish del(X)(q21.1q27.3)(PLP-). Both ends of the deletion have been mapped by fluorescence in situ hybridization using selected DNA clones and neither involves the PLP1 gene or are in the vicinity of the duplication breakpoints. Prenatal diagnosis was carried out in a recent pregnancy and the complex counseling issues associated with these chromosomal rearrangements are discussed.

Diagnostic considerations in juvenile parkinsonism.

Juvenile parkinsonism (JP) describes patients in whom the clinical features of parkinsonism manifest before 21 years of age. Many reported cases that had a good response to levodopa have proved to have autosomal recessive juvenile parkinsonism (AR-JP) due to mutations in the parkin gene. With the exception of parkin mutations and dopa-responsive dystonia, most causes are associated with the presence of additional neurological signs, resulting from additional lesions outside of the basal ganglia. Lewy body pathology has only been reported in one case, suggesting that a juvenile form of idiopathic Parkinson's disease may be extremely rare.

Severe infantile neuropathy with diaphragmatic weakness and its relationship to SMARD1.

A group of 13 patients with early onset diaphragmatic palsy in association with a progressive neuropathy is presented. All eight of those tested were found to have mutations in the same gene encoding the immunoglobulin mu-binding protein 2 (IGHMBP2) in patients with spinal muscular atrophy (SMA) with respiratory distress type 1. Six out of these eight patients had either homozygous or compound heterozygous mutations, and two had only a single heterozygous mutation. Detailed analysis of the clinical picture and the neurophysiological and histopathological findings indicated that these patients shared similar characteristics, which were further developed as a set of diagnostic criteria. Some of the most striking of these were early onset of respiratory compromise, a markedly low birth weight, very slow motor nerve conduction velocities and a general decrease in the size of myelinated fibres on sural nerve biopsy. Extensive histological examination of the spinal cord in one patient failed to find any evidence of an SMA. Four out of the five not tested genetically were positive for all diagnostic criteria. None of the cases of early onset neuropathies or spinal muscular atrophies with early respiratory failure reviewed in the literature shares the exact characteristics, but many do have very close similarities. Their classification varies, but the discovery of mutations in IGHMBP2 in cases that are variously classified as SMA plus or severe infantile neuropathy with respiratory distress points to a need for the search for this genetic defect to be widened to include both groups. The fact that we identified other, similar cases of neuropathy and early respiratory failure with and without IGHMBP2 mutations suggests genetic as well as clinical heterogeneity in these infants. It is possible that infants that do not have mutations in the IGHMBP2 gene will be found to have mutations in a similar functioning gene.

Selective decrease in central nervous system serotonin turnover in children with dopa-nonresponsive dystonia.

Childhood dystonia that does not respond to treatment with levodopa (dopa-nonresponsive dystonia, DND) has an unclear pathogenesis and is notoriously difficult to treat. To test the hypothesis that there may be abnormalities in serotonin turnover in DND we measured cerebrospinal fluid (CSF) concentrations of homovanillic (HVA) and 5-hydroxyindoleacetic (HIAA) acids, metabolites of dopamine and serotonin, respectively, in 18 children with dystonia not responsive to levodopa. These were combined with a reference population of 85 children with neurologic or metabolic disease known not to affect dopamine or serotonin metabolism. Because of the known natural age-related decrement in HVA and HIAA concentrations, the results were analyzed using multiple regression using age and DND as predictors of CSF HIAA and HVA concentrations. DND was a highly significant predictor of CSF HIAA concentration (p < 0.001) but not of CSF HVA concentration (p = 0.59). After fitting a regression model, the geometric mean ratio of CSF HIAA in DND compared with the reference range was 0.53 whereas that for CSF HVA was 0.95. We also analyzed CSF HIAA/HVA ratios. After fitting a regression model, we found no dependence on age, and the mean of CSF HIAA/HVA in DND was 0.28 whereas that for the reference range was 0.49 (p < 0.001). We conclude that a significant number of children with DND have reduced CNS serotonin turnover. Treatment with drugs that increase serotonin concentration in the synaptic cleft should be considered in this group of patients.

L-serine in disease and development.

The amino acid L-serine, one of the so-called non-essential amino acids, plays a central role in cellular proliferation. L-Serine is the predominant source of one-carbon groups for the de novo synthesis of purine nucleotides and deoxythymidine monophosphate. It has long been recognized that, in cell cultures, L-serine is a conditional essential amino acid, because it cannot be synthesized in sufficient quantities to meet the cellular demands for its utilization. In recent years, L-serine and the products of its metabolism have been recognized not only to be essential for cell proliferation, but also to be necessary for specific functions in the central nervous system. The findings of altered levels of serine and glycine in patients with psychiatric disorders and the severe neurological abnormalities in patients with defects of L-serine synthesis underscore the importance of L-serine in brain development and function. This paper reviews these recent insights into the role of L-serine and the pathways of L-serine utilization in disease and during development, in particular of the central nervous system.