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In the development of a new diagnostic motor performance test to spare more children from painful muscle biopsy, seven functional items were used to measure muscle strength and muscle endurance in a prospective study on new patients. Over a 2-year period, 22 patients (12 males, 10 females; mean age 8y 1mo [SD 2y 6mo], range 4-11y) were recruited for the study. They had all been referred with suspected myopathy. The motor performance test was administered before muscle biopsy. Validity of the seven items was assessed using logistic regression analysis and receiver operating characteristic (ROC) analysis. Two items were withdrawn from the test because they were not suitable for children aged 4 to 5 years. The five remaining items were: Heels, Circuit, Stairs, Jump, and Gowers. A full logistic regression model including these five items was fitted to the total population of 90 patients suspected of having myopathy (from this study and our previous study) to make the best prediction of whether myopathy was present. The ROC area under the curve of the diagnostic prediction model was 0.92 (95% confidence interval [CI] 0.87-0.98) and 0.89 (95% CI 0.87-0.92) after bootstrap correction. This indicated the high diagnostic power that can be expected for future, similar patients. This non-invasive and child-friendly motor performance test can improve diagnostic procedure and, therefore, spare more children from unnecessary muscle biopsy. [ABSTRACT FROM AUTHOR]

Aim: To establish which instrument is the most valid and reliable measure of muscle strength in children aged 4-11 years and can improve the diagnostic procedure in children with suspected myopathy to spare more of them from muscle biopsy., Methods: In a prospective study over a 2 year period, 22 patients aged 4-11 years were recruited. They had all been referred to our specialist centre on the suspicion of myopathy. Hand-held dynamometry, the Jamar dynamometer and a new Motor Performance Test were administered before muscle biopsy. Validity was assessed by the power to discriminate between patients with and without myopathy using logistic regression analysis and receiver operating characteristic (ROC) analysis. The area under the ROC curve (AUC) was calculated as a measure of the diagnostic power., Results: Comparison of the three instruments showed that the Motor Performance Test had the highest validity. Hand-held dynamometry generally had lower validity and showed wide variation in the 11 muscle groups. The Jamar dynamometer had very low validity in early stage myopathy., Conclusion: The Motor Performance Test was the most valid and reliable instrument to indicate the presence of myopathy in children. This objective, non-invasive and child-friendly instrument can improve the diagnostic procedure and exclude more children without myopathy from muscle biopsy., (Copyright © 2011 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)

Objective: To determine the functional development of children born after treatment of mild-to-moderate gestational hypertension with labetalol versus methyldopa, and no antihypertensive treatment., Design: Historical cohort study., Setting: Twelve Dutch hospital departments of obstetrics., Population: Live-born children born in these hospitals and prenatally exposed to labetalol, methyldopa, or bed rest because of mild-to-moderate gestational hypertension., Methods: Central nervous system development was measured with standard tests at 4-10 years of age. Linear regression techniques and Pearson's chi-square tests were used to compare the groups with regard to the outcome measures., Main Outcome Measures: Intelligence quotient (IQ), concentration, motor development, and behaviour at primary school age., Results: A total of 202 children were included in the analyses. More children exposed to labetalol had attention deficit hyperactivity disorder (ADHD) than those exposed to methyldopa (OR 2.3; 95% CI 0.7-7.3), or those born to women who had been admitted for bed rest (OR 4.1; 95% CI 1.2-13.9). Sleeping problems seemed to be reported more frequently after prenatal methyldopa exposure than after exposure to labetalol (OR 3.2; 95% CI 0.6-16.7) or bed rest (OR 4.5; 95% CI 0.9-23.2), although the differences were not statistically significant. Test scores on other aspects of functional development did not differ between the three groups., Conclusions: In this hypothesis-generating study, labetalol exposure in utero seemed to increase the risk of ADHD among children of primary school age, whereas prenatal methyldopa exposure might influence sleep. Further studies with appropriate sample sizes are warranted to determine the long-term effects of antihypertensive medications.

An important phase in the step cycle is foot contact. When the moment of foot contact differs from the one expected, a fast response is needed. Such a mismatch can be caused by hitting a support surface earlier or later than expected. To study this, experiments were performed with healthy young adults who walked on a platform that was unexpectedly at a lowered (5 cm) or at a level height. Glasses blocked the lower visual field. In the unexpectedly lowered trials, the absence of expected heel contact triggered responses in the ipsilateral anti-gravity muscles [ipsilateral medial gastrocnemius (MGi), ipsilateral rectus femoris (RFi)] and contralateral flexor muscles [contralateral tibialis anterior (TAc), contralaterial biceps femoris (BFc)] with latencies of 47-69 ms. After the delayed heel contact, enhanced activity was found in the MGi, RFi, and TAc muscles. This specific muscle synergy was presumably activated to arrest the forward propulsion of the body. In contrast, when the surface was unexpectedly at level height, the subjects expected to step down, and the leg briefly yielded. A muscle synergy was activated at 46-81 ms that flexed the ipsilateral knee (TAi, BFi, RFi) and extended the contralateral one (MGc, BFc) to unload the perturbed leg and delay the contralateral swing phase. Both conditions triggered a fast functionally relevant muscle synergy because of a mismatch between the expected and actual sensory feedback at the moment of foot contact. The results are consistent with an internal model that compares the expected with the actual sensory feedback. The short latency of the response suggests a subcortical, possibly cerebellar pathway.

Purpose: Validity and reproducibility of the Jamar dynamometer were evaluated in children aged 4-11 years., Method: Hand grip strength was measured on the dominant side and non-dominant side in 67 patients who had been referred to our specialist centre in the past 3 years because of suspected myopathy. All the patients had had muscle biopsy. Sixteen out of the 67 patients proved to have myopathy, while 51 had no myopathy. The investigator was blinded against the true diagnosis and clinical course of the patients at the time of testing. Validity was assessed by the power to discriminate between patients with and without myopathy, using logistic regression analysis and receiver operating characteristic (ROC) analysis. The area under the ROC curve (AUC) was calculated as a measure of the discriminative power. Sensitivity (Se) and specificity (Sp) were assessed at a specifically chosen cut-off point. Reproducibility was assessed by evaluating the test-retest reliability in a stratified random sample of 40 patients who returned for remeasurements, using the intraclass correlation coefficient (ICC)., Results: AUCs ranged from 0.78 - 0.82. At an Se = 81% cut-off point, Sp varied from 67-73%. ICCs ranged from 0.91-0.93., Conclusions: The Jamar dynamometer had discriminative power in children with suspected myopathy. Reproducibility was high. The Jamar dynamometer was a good, but not completely accurate, test for myopathy.

The authors report four adult-onset ataxia telangiectasia (AT) patients belonging to two families lacking pronounced cerebellar ataxia but displaying distal spinal muscular atrophy. AT was proven by genetic studies showing ATM mutations and a reduced level of ATM. ATM activity, as measured by phosphorylation of p53, was close to normal, indicating that the p53 response is not the only factor in preventing neural damage in anterior horn cells in AT.

To spare more children from painful muscle biopsy, a new non-invasive diagnostic motor performance test is undergoing development. Fifteen functional items were used to measure muscle strength and muscle endurance in 68 patients (47 males, 21 females; mean age 7y 8mo, SD 2y 2mo; range 4 to 11y), who had been referred to our specialist centre in the past 3 years on suspicion of myopathy. All the patients had undergone muscle biopsy. To correct the patients' outcomes for age, sex, and body size, regression prediction equations were obtained from a stratified random sample of 64 normally developing primary-school children aged 4 to 11 years (32 males, 32 females; mean age 8y 1mo, SD 2y 4mo). Feasibility was evaluated on the basis of five criteria. Validity was assessed using logistic regression analysis, receiver operating characteristic analysis, and sensitivity and specificity at a specifically chosen cut-off point. Reproducibility was evaluated by test-retest reliability in a stratified random sample of 40 patients who returned for re-measurements using the intraclass correlation coefficient. Seven items satisfied all five feasibility criteria, had high diagnostic power, and high test-retest reliability. The motor performance test can improve diagnostic procedure in children suspected of having myopathy.

Objective: To evaluate validity and reproducibility of hand-held dynamometry in 11 different muscle groups in children., Design and Patients: Maximum isometric muscle strength was measured with a calibrated hand-held dynamometer in 61 patients aged 4-11 years who had been referred to our specialist centre in the past 3 years because of suspected myopathy. All the patients had had muscle biopsy., Methods: Validity was assessed by the power to discriminate between patients with and without myopathy, using logistic regression analysis and receiver operating characteristic analysis and sensitivity and specificity at a specifically chosen cut-off point. Reproducibility was evaluated by test-retest reliability in a stratified random sample of 40 patients who returned for re-measurements, using the intraclass correlation coefficient and the standard error of measurement., Results: In the patients, areas under the receiver operating characteristic curve ranged from 0.66 to 0.88. At a specifically chosen cut-off point, sensitivity varied from 73% to 87%, while specificity varied from 54% to 80%. Intraclass correlation coefficients ranged from 0.73 to 0.91. The standard error of measurement ranged from 3.3 N to 12.2 N., Conclusion: Performance of hand-held dynamometry varied widely in the 11 muscle groups. Highest performance was observed in the elbow flexors. Test-retest reliability of the mean value of 2 efforts was generally higher than the maximum value.

We report the findings in five muscle and three sural nerve biopsies, and in one postmortem plexus specimen, from six patients with hereditary neuralgic amyotrophy (HNA). We found that the sensory nerves are definitely involved in HNA despite the mainly motor symptoms, and that lesions in nerves and muscles are more widespread throughout the peripheral nervous system than clinically presumed, but, simultaneously, very focally affect isolated fascicles within individual nerves.

Objective: To investigate the effectiveness of botulinum neurotoxin (BoNT) type A in reducing salivary flow rate in children with cerebral palsy (CP) with severe drooling., Methods: During a controlled clinical trial, single-dose BoNT injections into the submandibular salivary glands were compared with scopolamine treatment. Forty-five school-aged children were included. Salivary flow rates from all major glands were obtained at baseline and compared with measurements during the interventions. Basic statistics consisted of analysis of difference scores., Results: Compared with baseline, the mean decrease in submandibular flow was 25% during scopolamine and 42% following BoNT injections. The difference scores were significant with maximum reductions 2, 4, and 8 weeks following BoNT. Of all children, 95% responded during scopolamine. Response rates for BoNT were significantly lower and varied from 69% at 2 weeks to 49% at 24 weeks after injection (the end of the study). Four patients discontinued scopolamine therapy because of side effects. Only incidentally mild side effects were reported from BoNT., Conclusions: Intraglandular BoNT injections significantly reduce salivary flow rate in the majority of drooling CP children, demonstrating high response rates up to 24 weeks. The procedure is simple to perform, effective, and safe when ultrasound guidance is used. The anticholinergic effect of BoNT exceeds that of scopolamine. As anticholinergic drugs are frequently contraindicated because of side effects, BoNT injections offer an alternative in the treatment of drooling.

Objective: To investigate the clinical effectiveness of botulinum neurotoxin type A (BoNT) to reduce drooling in children with cerebral palsy (CP)., Methods: A controlled clinical trial was performed in which the results of single-dose BoNT injections in the submandibular glands were compared with treatment with scopolamine. Forty-five children who had CP and experienced severe drooling were enrolled. Drooling severity was measured at baseline, during application of scopolamine, and at different intervals after BoNT injections up to 24 weeks, using the Drooling Quotient (DQ), the Teacher Drooling Scale (TDS), and Visual Analog Scales (VAS)., Results: Drooling was reduced during scopolamine application as well as after BoNT injections. Compared with baseline, the mean DQ showed a significant decrease throughout the study. Greatest reductions were achieved 2 to 8 weeks after BoNT injection. No significant differences were found between scopolamine measurements and those up to 24 months after BoNT injection. Using VAS, parents recorded the effect on drooling in which significant differences were found between baseline VAS score and all follow-up assessments. According to our definition of "success to therapy," demanding a 2-point decrease on the TDS, 61.5% of patients responded to BoNT injections. Analysis of the DQ demonstrated a response rate of 53% of the patients to scopolamine and 48.7% to BoNT until 24 weeks after BoNT injections, the actual duration of this study. As a reaction to scopolamine, 71.1% of the patients had moderate to severe side effects. Only nonsevere, incidental side effects were reported after BoNT injections., Conclusions: During scopolamine application as well as after intraglandular BoNT injections, a clinically relevant reduction in drooling was achieved in children with CP, demonstrating maximum effect 2 to 8 weeks after injections. This is the first controlled clinical trial that confirmed a significant effect of BoNT injections in the treatment of drooling. General anesthesia was needed for all children. BoNT injections show fewer and less serious side effects than transdermal scopolamine treatment.

Background and Purpose: Sjögren-Larsson syndrome (SLS) is a neurocutaneous syndrome caused by a genetic enzyme deficiency in lipid metabolism. Our purpose was to characterize the nature of the cerebral involvement in SLS., Methods: MR imaging was performed in 18 patients (aged 5 months to 45 years) and repeated in 14. Single-voxel proton MR spectra were acquired from cerebral white matter and gray matter in 16 patients, with follow-up studies in 11. LCModel fits were used to determine brain metabolite levels., Results: MR imaging showed retardation of myelination and a mild persistent myelin deficit. A zone of increased signal intensity was seen in the periventricular white matter on T2-weighted images. Proton MR spectroscopy of white matter revealed a prominent peak at 1.3 ppm, normal levels of N-acetylaspartate, and elevated levels of creatine (+14%), choline (+18%), and myo-inositol (+54%). MR imaging and proton MR spectroscopy of gray matter were normal. In the two patients examined during the first years of life, abnormalities on MR imaging and proton MR spectroscopy gradually emerged and then stabilized, as in all other patients., Conclusion: Abnormalities on MR imaging and proton MR spectroscopy emerge during the first years of life and are similar in all patients with SLS, but the severity varies. The changes are confined to cerebral white matter and suggest an accumulation of lipids, periventricular gliosis, delayed myelination, and a mild permanent myelin deficit.

Drooling frequently occurs in children with multiple handicaps; application of anticholinergic drugs is a potential strategy to treat drooling. A computer aided search of original studies concerning the treatment of drooling was carried out. The methodological and statistical integrity of the identified studies were assessed with previously defined criteria. The articles were weighed for their separate contribution to the evidence. The search resulted in 64 reports, of which seven studies passed the screening and were subjected to further assessment and discussion by three referees. Because of the small number of reports and the methodological restriction within the studies, no meta-analysis could be performed. No general conclusion could be made about the efficacy of anticholinergic drugs in treatment of drooling in children with multiple handicaps. There was some evidence that three anticholinergic drugs (benztropine, glycopyrrolate, and benzhexol hydrochloride) are effective in the treatment of drooling, but it could not be concluded that one drug is preferable.

Nijmegen breakage syndrome (NBS) is an autosomal recessive disorder, due to defects in the NBS1 gene and belongs to the DNA repair disorders. We report neuropathological findings of the first ever recognised case of the about 60 described cases of NBS. This patient showed severe microcephaly with a simplified gyral pattern especially in the frontal lobes. There were no signs of a degenerative disease, or of a primary migration disorder. A bulge on top of the corpus callosum, most probably a very large remnant of the involuting striae longitudinales mediales et laterales, was found. This can be considered as an incomplete development of limbic structures. The severe diminishment of neocortical neurones suggests an important role for the NBS1 gene in corticogenesis in man, as suggested earlier in animal studies of other DNA-repair genes.

Muscle cramps are one of the most frequently occurring neuromuscular features. They occur normally in healthy persons, can be the manifestation of one of several cramp syndromes, but can also be the expression of various underlying neuromuscular disorders. We review the various types and boundaries of cramps, ranging from true muscle cramps to electromyographic silent muscle contractures (for example, Brody's disease) and cramps associated with dystrophinopathies. In addition, we delineate true muscle cramp from muscle stiffness and muscle twitching. Finally, we propose a workup in a patient suspected of having muscle cramps.

Hereditary neuropathy with liability to pressure palsies is associated with a deficiency in the Peripheral Myelin Protein 22 (PMP22). Most hereditary neuropathy with liability to pressure palsies cases are caused by a deletion of a 1.5 Mb region on chromosome 17p11.2-12 encompassing the PMP22 gene. We describe a hereditary neuropathy with liability to pressure palsies family that lacks the common deletion, but carries a small deletion spanning the 3' region of the PMP22 gene, causing only a partial deletion of one copy of the gene.

We describe the clinical and neuropathological presentation of a male with an MECP2 mutation whose sister has Rett syndrome (RS). He presented with severe neonatal encephalopathy and died at the age of 13 months. Mutation analysis of the MECP2 gene demonstrated a 488 - 489 del mutation in his and his sister's copies of the gene. Post mortem examination revealed bilateral polymicrogyria in the perisylvian region. This malformation was visibly more severe than previously described in females with RS and another male with an MECP2 mutation. As bilateral polymicrogyria was described in congenital perisylvian syndrome, the presented patient could be regarded as having suffered from a severe form of this syndrome. We conclude that MECP2 screening should be considered in males with severe neonatal encephalopathy and in males and females with a bilateral polymicrogyria syndrome.

The spectrum of nonmuscular involvement in six children with merosin-negative congenital muscular dystrophy is described. In all children, biochemical, neuroradiologic, cardiac, and neurophysiologic studies were performed. Cerebral structures that were myelinated at gestation, including internal capsule, corpus callosum, brainstem, and cerebellar white matter, demonstrated no abnormalities, whereas the periventricular and subcortical white matter, which were myelinated in the first postnatal year, demonstrated signs of leukoencephalopathy. Cerebrospinal fluid analysis revealed an elevated albumin cerebrospinal fluid to serum ratio in the younger children. Electroencephalogram results were abnormal in the two elder children. One child suffered from congestive cardiomyopathy. The increase in nerve conduction velocity in these children over the years lagged behind those of healthy patients, pointing to a demyelinating neuropathy. We conclude that in merosin-negative congenital muscular dystrophy patients, nonmuscular involvement includes the central and peripheral nervous system and the heart. The pattern of myelination of the brain and nerve conduction slowing suggests a myelination arrest. Merosin deficiency can give rise to a congestive cardiomyopathy, which is of no clinical relevance in the majority of children.

Nijmegen breakage syndrome (NBS) is a rare chromosomal-instability syndrome associated with defective DNA repair. Approximately 90% of NBS patients are homozygous for a truncating mutation of the NBS1 gene. As development of the immune system relies on recombination, which involves repair of DNA breaks, one might predict that mutations in the NBS1 gene could cause immunodeficiency. We immunologically investigated the world's largest series of NBS patients (n = 74), confirmed immunodeficiency, and found a discrepancy between relatively normal IgM concentrations, and decreased IgG and IgA concentrations. In addition, a significant relation between low IgA and low IgG levels was found. These data are compatible with a defective class switching in NBS and can be explained by a role of the NBS1 protein in DNA repair, signal transduction, cell cycle regulation or apoptosis.

Unlabelled: Drooling beyond the age of 4 years is pathological, particularly if it occurs in children with neurological and developmental impairment and disability. Considering the therapeutic spectrum of botulinum toxin A and in view of the innervation of the salivary glands, we postulated that intraglandular injections into the submandibular glands with botulinum toxin A could reduce the secretion of saliva and consequently decrease drooling. Three patients with cerebral palsy and severe drooling were selected and evaluated over a 4-month period. Under ultrasound guidance, one dose of botulinum toxin A was injected bilaterally into the submandibular glands. Saliva secretion was measured at baseline and repeated four times during the following 4 months. In the three patients, maximal salivary flow rate of the sublingual and submandibular glands was reduced by 51% to 63%. The time of the maximal effect differed among the three children. The parents reported a satisfactory reduction of drooling throughout the whole study period. No objectionable disturbances of oral functions were observed. There was mild transient thickening of saliva in one of the patients., Conclusion: The application of botulinum toxin A to the submandibular gland is a promising technique to reduce salivary flow rate and probably an alternative in the treatment of drooling in children with cerebral palsy.

Sjögren-Larsson syndrome (SLS) is an autosomal recessively inherited neurocutaneous disorder caused by a deficiency of the microsomal enzyme fatty aldehyde dehydrogenase (FALDH). We report the clinical characteristics and the results of molecular studies in 19 SLS patients. Patients 1-17 show the classical triad of severe clinical abnormalities including ichthyosis, mental retardation and spasticity. Most patients were born preterm, and all patients exhibit ocular abnormalities and pruritus. Electro-encephalography shows a slow background activity, without other abnormalities. MRI of the brain shows an arrest of myelination, periventricular signal abnormalities of white matter and mild ventricular enlargement. Cerebral (1)H-MR spectroscopy reveals a characteristic, abnormal lipid peak. The degree of white matter abnormality in the MRIs and the height of the lipid peak in (1)H-MR spectra do not correlate with the severity of the neurological signs. The clinical presentation and the clinical course is strikingly similar in these patients. Patient 18 shows a mild phenotype that essentially contains the same, but less severe, clinical features. Patient 19 exhibits the typical, but very mild, dermatological and ocular abnormalities, without any clinical neurological involvement. The diagnosis of SLS was confirmed by demonstration of the enzyme defect in cultured skin fibroblasts. Furthermore, as might be predicted from the essential role of FALDH in leucotriene B(4) (LTB(4)) metabolism, elevated urinary concentrations of LTB(4) and 20-OH-LTB(4) were found in all patients studied. Molecular studies of the FALDH gene revealed eight different mutations, including three new ones: a large 26-base pair deletion (21-46del), a missense mutation (80C-->T) and an insertion mutation (487-488insA). The vast majority of SLS patients seem to be severely affected independent of their genotype.

We investigated two brothers with Scheie syndrome whose only complaint was exercise intolerance. In the quadriceps muscle biopsy of both patients, between the normal muscle fibres an increased number of markedly swollen periodic acid-Schiff-positive fibroblasts were seen. Ultrastructurally, these cells showed an accumulation of enlarged lysosomes, partly filled with electro-dense material. We hypothesize that the accumulation of pathological fibroblasts may interfere with intramuscular force transmission resulting in exercise intolerance.

Neuronal migration disorders of the cerebral cortex form a heterogeneous group of abnormalities, characterised by mental retardation, epilepsy and hypotonia. They are prevalent in 1% of the population and in 20-40% of the untreatable forms of epilepsy. Disorders at the start of the migration result in nodular heterotopias. Bilateral periventricular nodular heterotopias are X-linked disorders, in which cortical neurons are unable to leave their position at the ventricular surface due to the absence of filamin 1. The large group of lissencephalies can be divided into a number of syndromes, each of which is characterised by a gene mutation (LIS1, DCX, RELN). These mutations result in agyria and pachygyria, which are characteristic for this group. A number of these abnormalities, especially the smaller nodular heterotopias and focal cortical dysplasia, may be treated by neurosurgical excision.

In the development of the cerebral cortex, two phases can be distinguished: (a) the formation of the preplate, a superficial layer essential for a normal lamination of the cerebral cortex; (b) the formation of the cortical plate. The cortical plate divides the preplate into a superficial marginal zone (the future layer I) and the subplate. The transient subplate is important for the formation of thalamocortical projections. Most cortical neurons arise in the ventricular zone of the pallium and migrate along radial glial cells (radial migration) to the cortical plate. The gamma-aminobutyric acid (GABA)ergic cortical interneurons, however, originate from the ganglionic eminences and reach the cerebral cortex through tangential migration.

Tyrosine hydroxylase deficiency was confirmed biochemically and genetically in four unrelated Dutch patients. The patients have a hypokinetic-rigid parkinsonian syndrome with symptoms in early infancy (3 to 6 months of age). Only sporadic dystonic movements were seen. There was no diurnal fluctuation. All patients showed a rapid favorable response to low-dose L-dopa/carbidopa treatment. Motor performance improved but did not fully normalize. The patients have mild mental retardation.

A previously healthy 11-year old girl with three episodes of alternating facial palsy is described. On examination during the third relapse a severe essential hypertension was diagnosed, accompanied by abnormalities on cerebral imaging, cardiac and fundoscopic investigations. Antihypertensive treatment normalized the hypertension. No relapse of the facial palsy occurred since. The objective of this communication is to draw the attention to hypertension as a possible cause of recurrent facial paralysis in children, to stress the importance of measuring the blood pressure and taking a thorough family history in every patient presenting with facial palsy.

Two cases of neuralgic amyotrophy (idiopathic brachial plexus neuropathy) in children are presented and combined with a review of the literature. Difficulties in establishing the diagnosis are illustrated, and we give an overview of the phenotype of childhood neuralgic amyotrophy and its distinctions from the adult type. Pain, in adult cases present in over 95% of the cases, is less frequent in children, and its absence by no means excludes the diagnosis. In children under 8 weeks of age, the literature shows that a subsequent osteomyelitis of the shoulder or arm always seems to be involved, which warrants a close follow-up. Overall, recovery is less favourable in children, but when they fully recover they seem to do so in a shorter period of time than adults. We conclude that neuralgic amyotrophy in children is distinct from the adult variety, and that it has a definite place in the differential diagnosis of a sudden limp arm, even if it is painless.

Purpose: To describe imaging findings and their neuropathologic correlate in patients with cerebrotendinous xanthomatosis (CTX)., Materials and Methods: Computed tomographic (CT) and magnetic resonance (MR) images in 24 patients with symptoms (mean age at time of imaging, 37 years; mean disease duration, 18 years) were reviewed for site and frequency of brain, spinal cord, and Achilles tendon involvement. Two patients died, and imaging findings were compared with postmortem neuropathologic findings., Results: Apart from nonspecific supratentorial atrophy and deep white matter changes, more typical hyperintense lesions were seen on T2-weighted images in the dentate nucleus (in 79% of patients), globus pallidus, substantia nigra, and inferior olive and extended into adjacent white matter as disease progressed. In these locations, lipid crystal clefts and perivascular macrophages, neuronal loss, demyelination, fibrosis, and reactive astrocytosis were found at microscopic examination. Hypointensity was sometimes found on T2-weighted images in the dentate nucleus and was related to deposition of hemosiderin and calcifications. CT depicted fewer lesions; all had low attenuation, except for the calcifications. Spinal cord MR imaging revealed increased signal intensity in the lateral and dorsal columns on T2-weighted images. Achilles tendon xanthomas displayed intermediate signal intensity on T1- and T2-weighted images., Conclusion: The typical pattern of MR imaging findings reflects the classic histopathologic findings and should prompt the diagnosis of CTX.

Neuromuscular characteristics were documented in ten patients with biochemically and genetically confirmed cerebrotendinous xanthomatosis. An array of genotypes was found in these patients. Only one patient complained of muscle weakness, while clinical signs of peripheral neuropathy were present in six patients. Electromyogram showed predominantly axonal neuropathy in seven patients. Neurogenic changes were seen in muscle biopsies of nine patients. Sural nerve biopsies of three patients showed features of axonal neuropathy. In addition, in one patient, extensive onion bulb formation was seen, which is indicative of a primarily demyelinating process. Five patients had normal mitochondrial respiratory chain enzyme activity. It is concluded that myopathy is not a feature of cerebrotendinous xanthomatosis and that the most prominent neuromuscular abnormality is sensorimotor axonal polyneuropathy.

This is the first report that describes the clinical and histological findings in a patient suffering from pure congenital fibre type disproportion (CFTD), who had two biopsies with an interval of 16 years. Additionally, we compared the clinical signs and symptoms of the present case to those of 35 CFTD cases reviewed from the literature. From this we conclude that smallness of type I fibre diameter is not a characteristic feature during the course of pure CFTD. This suggests that CFTD is a time-locked diagnosis.

Cerebrotendinous xanthomatosis (CTX) is a lipid storage disease caused by a deficiency of the mitochondrial enzyme 27-sterol hydroxylase (CYP 27), due to mutations in its gene. In this study we report on mutations in 58 patients with CTX out of 32 unrelated families. Eight of these were novel mutations, two of which were found together with two already known pathogenic mutations. Twelve mutations found in this patient group have been described in the literature. In the patients from 31 families, mutations were found in both alleles. In the literature, 28 mutations in 67 patients with CTX out of 44 families have been described. Pooling our patient group and the patients from the literature together, 37 different mutations in 125 patients out of 74 families were obtained. Identical mutations have been found in families from different ethnic backgrounds. In 41% of all the patients, CYP 27 gene mutations are found in the region of exons 6-8. This region encodes for adrenodoxin and haem binding sites of the protein. Of these 125 patients, a genotype-phenotype analysis was done for 79 homozygous patients harbouring 23 different mutations, out of 45 families. The patients with compound heterozygous mutations were left out of the genotype-phenotype analysis. The genotype-phenotype analysis did not reveal any correlation.

During human gait, transmission of cutaneous reflexes from the foot is controlled specifically according to the phase of the step cycle. These reflex responses can be evoked by nonnociceptive stimuli, and therefore it is thought that the large-myelinated and low-threshold Abeta afferent fibers mediate these reflexes. At present, this hypothesis is not yet verified. To test whether Abeta fibers are involved the reflex responses were studied in patients with a sensory polyneuropathy who suffer from a predominant loss of large-myelinated Abeta fibers. The sural nerve of both patients and healthy control subjects was stimulated electrically at a nonnociceptive intensity during the early and late swing phases while they walked on a treadmill. The responses were studied by recording electromyographic (EMG) activity of the biceps femoris (BF) and tibialis anterior (TA) of the stimulated leg. In both phases, large facilitatory responses were observed in the BF of the healthy subjects. These facilitations were reduced significantly in the BF of the patients, indicating that Abeta fibers mediate these reflexes. In TA similar results were obtained. The absolute response magnitude across the two phases was significantly smaller for the patients than for the healthy subjects. The TA responses for the healthy subjects were on average facilitatory during early swing and suppressive during end swing. Both facilitations and suppressions were considerably smaller for the patients, indicating that both types of responses are mediated by Abeta fibers. It is concluded that low-threshold Abeta sensory fibers mediate these reflexes during human gait. The low threshold and the precise phase-dependent control of these responses suggest that these responses are important in the regulation of gait. The loss of such reflex activity may be related to the gait impairments of these patients.

Background: Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive disorder of bile acid synthesis. A diagnosis of CTX should be considered in patients with premature bilateral cataracts, intractable diarrhea, neurological signs and symptoms, and tendon xanthomas, especially in the Achilles tendons. The prevalence of these signs and symptoms increases with age., Objectives: To investigate signs and symptoms, age at onset, and age at diagnosis in 32 patients with biochemically and genetically confirmed CTX, and to compare this clinical spectrum with reports in the literature., Methods: Retrospective analysis of records of all patients with CTX at our hospital (27 adults and 5 children). After a MEDLINE search in the English, French, and German literature, 181 patients with CTX (165 adults and 16 children) were identified worldwide., Results: Of our 32 patients with CTX, 31 (97%) had cataracts and neurological signs and symptoms, predominantly pyramidal signs (26 [81%]); 21 (66%) had low intelligence and 18 (56%) had cerebellar signs. Only 13 (41%) had visible or palpable tendon xanthomas at the time of diagnosis. In total, 16 patients (50%) had chronic, intractable diarrhea that started in childhood. These findings were in contrast with the literature, where tendon xanthomas were reported in 89% and diarrhea in only 2 patients., Conclusions: We believe that CTX is underdiagnosed worldwide. We recommend that the presence of 2 of the 4 clinical hallmarks of CTX prompt thorough metabolic screening, including determination of urine bile alcohol excretion and serum cholestanol level, because CTX is a treatable disease.

On investigation of 101 attacks in 24 patients with hereditary neuralgic amyotrophy (HNA) from nine different families, we found that HNA can run two distinct courses: a 'classic' relapsing-remitting and a chronic undulating type with exacerbations. Only one type occurred per family, suggesting genetic heterogeneity. This is supported by the finding that only in a family with 'classic type' HNA are data of linkage analysis compatible with linkage to the 17q24-q25 interval which harbours a locus for the disease. The average number of attacks per patient during a follow-up of 26 years was four in the classic form of HNA and five in the chronic undulating type. All patients suffered from residual symptoms on follow-up, with a median Rankin score of 2 in both groups, showing that long-term prognosis is less favourable than previously reported.

We report on an additional fourth case of Prader-Willi (PW)-like phenotype and an interstitial deletion of 6q. Despite sharing clinical characteristics, patients with a PW-like phenotype and a deletion of 6q, have features which distinguish them from Prader-Willi syndrome (PWS) patients. This case emphasizes the need to examine patients with suspected PWS, but who are negative for recognizable deletions of 15q11-q13 or uniparental maternal disomy of chromosome 15, for a deletion of 6q.

Hereditary deficiency of prothrombin is a rare autosomal recessive bleeding disorder, with severe bleeding diathesis in homozygotes, but rarely resulting in intracranial haematoma. We describe two infants of consanguineous parents, presenting with acute subdural haematoma. Because such haematomas in infancy are highly indicative of trauma caused by child battering and because the socio-economic status of the family was unstable, there was a suspicion of child battering. However, further investigations revealed a bleeding diathesis due to a prothrombin deficiency. DNA analysis of the prothrombin gene showed homozygosity for a novel mutation, substituting Lys for Glu at codon 7 and resulting in decreased specific clotting activity. We discuss the probability of bleeding diathesis versus child battering in the aetiology of intracranial haematoma.

Sjögren-Larsson syndrome (SLS) was originally described as a triad of spasticity, mental retardation and congenital ichthyosis. The syndrome reflects an underlying deficiency of microsomal fatty aldehyde dehydrogenase (FALDH). We report on clinical data concerning pregnancy, labor and neonatal period in 15 patients. Pregnancies were uncomplicated, except for preterm rupture of membranes in three pregnancies, and the occurrence of preterm birth. Mean gestational age was 35.3 weeks (S.D. 2.4 weeks), and preterm birth was found in 73% of the children, while all children were born before or in the 38th week of gestation. Birth weight was normal for gestational age in all patients. The neonatal period was free from serious complications, apart from hemolytic disease in two patients. Preterm birth was found in 7% of the healthy siblings, reflecting the normal population. Prematurity and spasticity are intrinsic and concurrent parts of SLS, without causal relation. SLS should be considered in every neonate with congenital ichthyosis, especially if the child is born preterm. A possible explanation for preterm birth in SLS could be the defective inactivation of leukotriene B4 (LTB4), which recently has been demonstrated in patients with SLS.

Recently, a new disease entity has been defined: the disease of vanishing white matter. This leukoencephalopathy has an autosomal-recessive mode of inheritance. No cause or biochemical marker is known. We studied cerebrospinal fluid amino acids in five patients with the disease and found a consistent, moderate elevation of cerebrospinal fluid glycine in all. The ratio of cerebrospinal fluid to plasma glycine was elevated in four patients, in two patients reaching the level considered diagnostic for nonketotic hyperglycinemia. The activity of the glycine cleavage system was found to be normal in lymphoblasts in two patients. The elevation of cerebrospinal fluid glycine in the disease of vanishing white matter is either caused by a primary disturbance of glycine metabolism or is secondary to excitotoxic brain damage.

We describe seven Dutch patients from six families with a slowly progressive, mainly spinal cord syndrome that remained for many years the sole expression of cerebrotendinous xanthomatosis (CTX). MRI demonstrated white matter abnormalities in the lateral and dorsal columns of the spinal cord. Post-mortem examination of one of the patients showed extensive myelin loss in these columns. An array of genotypes was found in these patients. We conclude that 'spinal xanthomatosis' is a clinical and radiological separate entity of CTX that should be included in the differential diagnosis of 'chronic myelopathy'.

An overview is given of the current knowledge on the human tyrosine hydroxylase gene and on the biochemical aspects of diagnosing defects in this gene. Diagnostic biochemical findings are described in four cases of genetically confirmed tyrosine hydroxylase deficiency. Decreased CSF levels of homovanillic acid (HVA) and 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG), together with normal pterin and CSF tyrosine and 5-hydroxyindoleacetic acid (5-HIAA) concentrations are the diagnostic hallmarks of tyrosine hydroxylase deficiency. At the metabolite level the diagnosis can only be made reliably in CSF. Strict adherence to a standardized lumbar puncture protocol and adequate reference values are essential for diagnosis of this 'new' treatable neurometabolic disorder. Measurements of HVA, vanillylmandelic acid (VMA) or catecholamines in urine are not relevant for diagnosing tyrosine hydroxylase deficiency. The diagnosis should be considered in all children with unexplained hypokinesia and other extrapyramidal symptoms. Three of our patients are homozygous for a mutation in exon 6 (698G > A) of the tyrosine hydroxylase gene and one patient was compound heterozygous for the same mutation and a novel truncating mutation in exon 3 (291delC).

Objective: To determine the spectrum of clinical and MRI/1H MRS features of patients with fatty aldehyde dehydrogenase (FALDH) deficiency., Background: The Sjogren-Larsson syndrome (SLS) was originally defined as a clinical triad consisting of ichthyosis, spastic di- or tetralegia, and mental retardation, with autosomal recessive inheritance. By now, both the deficiency of the enzyme FALDH, and the genetic mutations on chromosome 17 responsible for this deficiency, have been identified. SLS, defined by fibroblast FALDH deficiency, seems to be a much broader syndrome., Methods: The clinical findings of 11 FALDH-deficient patients of different ages and one patient with the characteristic SLS-like ichthyosis, but without FALDH deficiency, were evaluated in relation to their cerebral MRI, and to 1H MRS in six patients., Results: The severity of neurologic symptoms showed considerable variation. Fundoscopic perifoveal glistening dots and the characteristic SLS-like ichthyosis were present in all patients. Serial MRI findings showed evidence of retarded myelination and a variable degree of dysmyelination. 1H MRS showed an accumulation of free lipids in the periventricular white matter, even before the stage of visible dysmyelination., Conclusions: The neurologic consequences of FALDH deficiency show considerable variation. The characteristic pattern of ichthyosis and retinal degeneration are seen consistently, yet they are not pathognomonic. MRI and 1H MRS findings suggest an accumulation of long-chain fatty alcohol intermediates, resulting in retarded myelination and dysmyelination.

Neural tube defects (NTDs) are the most common congenital malformations and are considered to have a multifactorial origin, having both genetic and environmental components. Periconceptional folate administration reduces the recurrence and occurrence risk by 70-100%. Recently we discovered the first genetic risk factors for NTDs: the 677 C-->T and the 1298 A-->C mutations in the methylenetetrahydrofolate reductase gene explaining at the most 35-50% of the protective effect of folate. In this study we further explored the genetic component of NTDs by analysing the coding region, including the intron-exon boundaries and signal sequences of the folate receptor genes by SSCP analysis. Among 39 patients with spina bifida (SB), 47 mothers with a child with SB, and 10 controls, no polymorphism was present in the folate receptor alpha (FR-alpha) gene or in the folate receptor beta (FR-beta) gene.

A 19-month-old girl presented with severe neurologic symptoms associated with exanthem subitum. Human herpesvirus type 7 (HHV-7) DNA was detected in the CSF and serum, and supported by serologic studies. The patient was diagnosed with encephalopathy due to an acute HHV-7 infection. Neuron-specific enolase in the CSF was strongly elevated during the acute stage of infection, suggesting that the encephalopathy was due to viral invasion of the brain.

The effects of combination therapy with chenodeoxycholic acid (CDCA) and simvastatin on serum cholestanol, low-density lipoprotein (LDL) cholesterol, and lathosterol levels were investigated in seven adult patients with cerebrotendinous xanthomatosis (CTX) who were on long-term treatment with CDCA. The patients were treated with a combination of CDCA 750 mg daily and an increasing dose of simvastatin from 10 mg to 40 mg daily for a period of 6 months. We found a significant effect of this combination therapy compared with CDCA alone in terms of decreasing the serum cholestanol and LDL cholesterol levels, particularly with a daily dose of 40 mg simvastatin. The mean cholestanol level decreased from 9.27 micromol/L (baseline) to 6.69 micromol/L (40 mg simvastatin), while the mean LDL cholesterol level decreased from 5.08 mmol/L (baseline) to 3.04 mmol/L (40 mg simvastatin). No side effects were reported, and there were no effects on the clinical condition, cerebral magnetic resonance imaging (MRI), visual evoked potentials, and electroencephalographic features. We conclude that a combination of 750 mg CDCA and 40 mg simvastatin daily is effective to further reduce serum cholestanol, LDL cholesterol, and lathosterol in adult CTX patients treated with long-term CDCA. Whether this combination treatment will be effective for the long-term prevention of neurological deterioration and atherosclerosis remains to be established.

The authors report a child with a spinal muscular atrophy (SMA)-like picture, cardiomyopathy, and cytochrome c oxidase (COX) deficiency. Electromyography and muscle biopsy showed findings typical of SMA. However, COX staining of the muscle was negative. DNA analysis did not detect deletions in the survival motor neuron (SMN) gene. The lactate and lactate-to-pyruvate ratios were increased in blood and CSF. COX activity was decreased in muscle and fibroblasts. Western blot analysis showed reduced contents for all COX subunits. Patients with clinical features resembling SMA but with an intact SMN gene should be screened for a mitochondrial disorder.

We report the biochemical hallmarks of tyrosine hydroxylase deficiency with emphasis on reliable diagnostic strategies of four new cases of an inborn error of tyrosine hydroxylase (TH). Three of our patients from different parts of the Netherlands were found homozygous for a mutation in exon 6 (G698A) of the TH gene, and one patient was found compound heterozygous for the same mutation and an additional mutation in exon 3. The first clinical symptoms of hypokinesia, rigidity of arms and legs and axial hypotonia, developed between 3 and 7 months of age. Cerebrospinal fluid investigations revealed a characteristic metabolite constellation in every case: low homovanillic acid (HVA) and 3-methoxy-4-hydroxyphenylethyleneglycol concentrations in the presence of normal reference range 5-hydroxyindolacetic acid concentrations. Strict adherence to a standardized lumbar puncture protocol and adequate age-related reference values are essential for diagnosis of this "new" treatable neurometabolic disorder. Urinary measurements of HVA, vanillylmandelic acid, and catecholamines can lead to false-negative conclusions. All patients showed a remarkable clinical improvement on a low dose of L-dihydroxyphenylalanine/ (S)-2-(3,4-dihydroxybenzyl)-2-hydrazinpropionic acid. During treatment, cerebrospinal fluid HVA, and 3-methoxy-4-hydroxy-phenylethyleneglycol increased substantially.

In six families with hereditary neuropathy with liability to pressure palsies (HNPP) the 17p11.2 deletion was absent, but single strand conformation-analysis and subsequent sequencing demonstrated a heterozygous G-insertion in a stretch of six Gs at nt 276281 of the PMP22 gene, resulting in a frame shift after Gly94. Haplotype comparison of the six families revealed common ancestry. We compared the phenotype of 23 patients from these six families with the phenotype of 63 patients of 17 families with the common deletion. The patients with the G-insertion showed the clinical, electrophysiological and morphological characteristics of common HNPP, but in addition they had significantly more neuropathic features, mimicking hereditary motor and sensory neuropathy type I (HMSN I) or Charcot-Marie-Tooth disease type 1 (CMT1). To explain this distinct phenotype we suggest that, by translation of the mutated gene, a markedly changed polypeptide is formed without the normal cytoplasmic C-terminal of the native protein, resulting in a loss of function similar to that with the common deletion, but exerting an extra disturbance of Schwann cell functions, probably by hampering normal myelin formation or maintenance.