Background: Charcot-Marie-Tooth (CMT) disease is a heterogeneous group of inherited peripheral motor and sensory neuropathies with several modes of inheritance: autosomal dominant, X-linked, and autosomal recessive (AR) CMT. A locus responsible for the demyelinating form of ARCMT was assigned to the 5q23-q33 region (CMT4C) by homozygosity mapping. Recently, 11 mutations were identified in the SH3TC2 (KIAA1985) gene in 12 families with demyelinating ARCMT from Turkish, Iranian, Greek, Italian, or German origin. Objective: To identify mutations in the SH3TC2 gene. Methods: The authors searched for SH3TC2 gene mutations in 10 consanguineous CMT families putatively linked to the CMT4C locus on the basis of haplotype segregation and linkage analysis. Results: Ten families had mutations, eight of which were new and one, R954X, recurrent. Six of the 10 mutations were in exon 11. Onset occurred between ages 2 and 10. Scoliosis or kyphoscoliosis and foot deformities were found in almost all patients and were often inaugural. The median motor nerve conduction velocity values (≤34 m/s) were not correlated with disease duration. The functional disability score was ≤3, indicating that the patients could walk without help. Unexpectedly, typical giant axons were observed on biopsies from a large Algerian family. Conclusions: Charcot-Marie-Tooth type 4C (CMT4C) is less severe than other autosomal recessive (AR) CMT. Intrafamilial variability is important, making phenotype-genotype correlations difficult, but spine deformities are clearly a hallmark of CMT4C. In the presence of scoliosis, a neurologic examination is recommended. Giant axons on biopsies are also suggestive of CMT4C. For genetic analysis, the R954X mutation should be looked for before systematic sequencing of exon 11.

Background: In adult patients with a slowly progressive demyelinating neuropathy, it may be difficult to distinguish between a hereditary neuropathy and chronic inflammatory demyelinating polyneuropathy (CIDP). The authors previously observed clustering of macrophages around endoneurial blood vessels in sural nerve biopsies from patients with CIDP. Objectives: To quantitate macrophage clustering around endoneurial blood vessels in CIDP vs hereditary neuropathies. Methods: The authors studied 21 patients with CIDP, 18 patients with hereditary neuropathies, and 5 normal sural nerves. Numbers of macrophages, T-cells, and blood vessels were counted after immunohistochemical staining. The presence of three or more macrophages around one blood vessel was defined as a cluster. In a subsequent validation analysis, 65 stored biopsy specimens obtained from patients with a chronic neuropathy were re-evaluated for perivascular macrophage clustering according to criteria derived from the quantitative analysis of the first 221 biopsies in a blinded fashion. Results: The percentage of endoneurial vessels with macrophage clusters was higher in CIDP than in hereditary neuropathies (CIDP median = 9.4, range 0 to 48; hereditary NP median = 0, range 0 to 7.7; p < 0.001). The evaluation of the 65 further biopsies showed that the presence of one perivascular macrophage cluster per fascicle proved to be a valid criterion to differentiate between inflammatory and other forms of neuropathy (χ2 test p = 0.0000025, sensitivity 75%, specificity 72%). Conclusion: The presence of clusters of macrophages around endoneurial vessels in sural nerve biopsies may serve as a useful additional marker for establishing the pathologic diagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP).

Sural nerve findings in a patient with the features of the syndrome of multiple mucosal neuromas are described. Hypertrophy with onion-bulb formation without signs of segmental de- and re-myelination or axonal de- and regeneration of myelinated fibers was found.

The aim of the present study was to investigate whether children with developmental apraxia of speech (DAS) show a deficit in planning syllables in speech production. Six children with DAS and six normally speaking (NS) children produced high- and low-frequency of occurrence syllable utterances, in which the syllable structure was systematically manipulated in an otherwise unchanging phoneme sequence. Anticipatory coarticulation, using second formant trajectories, and durational structure were analysed. The results showed stronger coarticulation in the children with DAS when compared to the normally speaking children, but in contrast to our expectations, in neither group was a systematic effect of syllable structure on the second format trajectory found. Effects of syllable structure did emerge for durational structure in that durational adjustments were found in the segments of the second syllable. These adjustments were less systematic in children with DAS when compared to normally speaking children. Furthermore, at the prosodic level, normally speaking children showed metrical contrasts that were not realized by the children with DAS. The latter results are interpreted as evidence for a problem in the planning of syllables in speech production of children with DAS, in particular concerning prosodic aspects, which is discussed in relation to the automation of speech production.

The aim of this study was to enhance our insight into the underlying deficit in developmental apraxia of speech (DAS). In particular, the involvement of planning and/or programming of speech movements in context was tested by analysing coarticulatory cohesion. For this purpose, second formant frequency measurements were conducted in repetitions of nonsense utterances ([[symbol: see text]] C = /s,x,b,d/; V = /i.a.u/), and compared across nine children with DAS, six normally speaking (NS) children and six adult women. The results showed both intra- and intersyllabic anticipatory coarticulation in NS children and adult women, in which the intersyllabic coarticulation was stronger in NS children than in adult women. The children with DAS showed more variability as compared to NS children, made, on average, less distinction between the vowels, and showed individually idiosyncratic coarticulation patterns. These results are discussed in the light of a delay as well as a deviance of speech development in children with DAS.

Problems in reading and spelling may arise from poor perception of speech sounds. To study the integrity of phonological access in children with developmental dyslexia (mean age 8 years, 9 months) as compared to two control groups of children (age-matched and matched on reading level), identification and discrimination functions of the features voicing and place-of-articulation were assessed. No differences were found between groups with respect to identification of place-of-articulation. With respect to identification of the voicing contrast, children with developmental dyslexia performed poorer than age-matched controls, but similar to reading-level controls. For the voicing as well as the place-of-articulation contrast, children with developmental dyslexia discriminated poorer than both control groups. This pattern of identification and discrimination performance is discussed relative to the multidimensionality of the speech perception system. The clinical relevance of these perception tasks could be demonstrated by significant negative correlations between performance on the perception tasks and reading and spelling ability. This provided additional support for a functional relation between speech perception and reading and spelling in developmental dyslexia.

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.

In a previous study a diagnostic procedure was developed to assess motoric involvement in clear cases of developmental apraxia of speech (DAS) and spastic dysarthria, as well as normal-speaking children. The aim of the present study is to cross-validate this diagnostic procedure. To achieve this aim the maximum performance tasks of the protocol, consisting of maximum vowel and fricative prolongation, and maximum syllable repetition, were administered to less clear cases of DAS and spastic dysarthria, children with a speech disorder of unknown origin and newly selected normal-speaking children (total number of children in the study, 72; aged predominantly between 4 and 12 years). The results showed that spastic dysarthria can be diagnosed on the basis of the maximum rate of repetitive sequences ('papa...', tata...','kaka...') in combination with maximum vowel prolongation. DAS can be diagnosed on the basis of the maximum rate of alternating sequences ('pataka...') in combination with maximum fricative prolongation. Using the diagnosis of speech-language pathologists as a criterion, sensitivity and specificity values were obtained ranging from 89 to 100%. Among the children with a speech disorder of unknown origin significant dysarthric or apraxic involvement was observed. Thus, it can be concluded that the diagnostic procedure yields quantitative measures of the degree to which dysarthria or apraxia plays a role in the development and maintenance of speech disorders in children.

Objectives-To report the occurrence of the autosomal recessive form of demyelinating Charcot-Marie-Tooth disease (CMT) with a locus on chromosome 5q23-33 in six non-related European families, to refine gene mapping, and to define the disease phenotype.Methods-In an Algerian patient with autosomal recessive demyelinating CMT mapped to chromosome 5q23-q33 the same unique nerve pathology was established as previously described in families with a special form of autosomal recessive demyelinating CMT. Subsequently, the DNA of patients with this phenotype was tested from five Dutch families and one Turkish family for the 5q23-q33 locus.Results-These patients and the Algerian families showed a similar and highly typical combination of clinical and morphological features, suggesting a common genetic defect. A complete cosegregation for markers D5S413, D5S534, D5S636, and D5S410 was found in the families. Haplotype construction located the gene to a 7 cM region between D5S643 and D5S670. In the present Dutch families linkage disequilibrium could be shown for various risk alleles and haplotypes indicating that most of these families may have inherited the underlying genetic defect form a common distant ancestor.Conclusions-This study refines the gene localisation of autosomal recessive demyelinating CMT, mapping to chromosome 5q23-33 and defines the phenotype characterised by a precocious and rapidly progressive scoliosis in combination with a relatively mild neuropathy and a unique pathology. Morphological. alterations in Schwann cells of the myelinated and unmyelinated type suggest the involvement of a protein present in both Schwann cell types or an extracellular matrix protein rather than a myelin protein. The combination of pathological features possibly discerns autosomal recessive demyelinating CMT with a gene locus on chromosome 5q23-33 from other demyelinating forms of CMT disease.

Objective: To evaluate the cognitive profiles of children with Noonan syndrome (NS) and to relate these profiles to measures of overall clinical severity.Study design: Thirty-five children with NS between the ages:of 7 and 18 years were tested on their intellectual, psychosocial, and academic functioning. The diagnosis of NS was established on the presence of a typical Face, the characteristic heart defect, thorax deformity, short stature, affected first-degree relative(s), and cryptorchidism in male subjects.Results: The total group of children with NS (n = 35) achieved significantly lower mean full-scale IQ verbal IQ (VIQ), and performance IQ (PIQ) scores (between 85.9 and 89.3) than expected based on normative data. The individual full-scale IQ scores varied between 48 and 130. Because of th;s wide range of individual scores, the mean group values are not extremely informative. The mean full-scale IQ for the group with moderate NS (n = 19) is 90.8; for the children with severe NS (n = 16) the mean Full-scale IQ is 80.6. The patterns of discrepancies between VIQ and PIQ are: (I) an extreme discrepancy between VIQ and PIQ is most likely to emerge in children with severe NS with (low) average intellectual abilities; (2) children with moderate NS are more likely to attain similarities in VIQ and PIQ scores; and (3) children with moderate NS demonstrate a particular pattern of discrepancy between VIQ and PIQ (ie, VIQ > PIQ).Conclusion: For children with NS, the findings on physical examination are indicative of the pattern of cognitive abilities. NS is not associated with substantial deficits in the level of intellectual functioning or with a single/unitary cognitive pattern. Severe NS expression, however, predicts in part a specific pattern of deficits and capacities in cognitive functioning.

Reflex sympathetic dystrophy (RSD) (recently reclassified as complex regional pain syndrome type I) is a syndrome occurring in extremities and, when chronic, results in severe disability and untractable pain. RSD may be accompanied by neurologic symptoms even when there is no previous neurologic lesion. There is no consensus as to the pathogenic mechanism involved in RSD. To gain insight into the pathophysiology of RSD, we studied histopathology of skeletal muscle and peripheral nerve from patients with chronic RSD in a lower extremity.In eight patients with chronic RSD, an above-the-knee amputation was performed because of a nonfunctional limb. Specimens of sural nerves, tibial nerves, common peroneal nerves, gastrocnemius muscles, and soleus muscles were obtained from the amputated legs and analyzed by light and electron microscopy.In all patients, the affected leg showed similar neurologic symptoms such as spontaneous pain, hyperpathy, allodynia, paresis, and anesthesia dolorosa. The nerves showed no consistent abnormalities of myelinated fibers. In four patients, the C-fibers showed electron microscopic pathology. In all patients, the gastrocnemius and soleus muscle specimens showed a decrease of type I fibers, an increase of lipofuscin pigment, atrophic fibers, and severely thickened basal membrane layers of the capillaries.In chronic RSD, efferent nerve fibers were histologically unaffected; from afferent fibers, only C-fibers showed histopathologic abnormalities. Skeletal muscle showed a variety of histopathologic findings, which are similar to the histologic abnormalities found in muscles of patients with diabetes.

Recently, we showed that homozygosity for the common 677(C-->T) mutation in the methylenetetrahydrofolate reductase (MTHFR) gene, causing thermolability of the enzyme, is a risk factor for neural-tube defects (NTDs). We now report on another mutation in the same gene, the 1298(A-->C) mutation, which changes a glutamate into an alanine residue. This mutation destroys an MboII recognition site and has an allele frequency of .33. This 1298(A-->C) mutation results in decreased MTHFR activity (one-way analysis of variance [ANOVA] P < .0001), which is more pronounced in the homozygous than heterozygous state. Neither the homozygous nor the heterozygous state is associated with higher plasma homocysteine (Hcy) or a lower plasma folate concentration-phenomena that are evident with homozygosity for the 677(C-->T) mutation. However, there appears to be an interaction between these two common mutations. When compared with heterozygosity for either the 677(C-->T) or 1298(A-->C) mutations, the combined heterozygosity for the 1298(A-->C) and 677(C-->T) mutations was associated with reduced MTHFR specific activity (ANOVA P < .0001), higher Hcy, and decreased plasma folate levels (ANOVA P <.03). Thus, combined heterozygosity for both MTHFR mutations results in similar features as observed in homozygotes for the 677(C-->T) mutation. This combined heterozygosity was observed in 28% (n =86) of the NTD patients compared with 20% (n =403) among controls, resulting in an odds ratio of 2.04 (95% confidence interval: .9-4.7). These data suggest that the combined heterozygosity for the two MTHFR common mutations accounts for a proportion of folate-related NTDs, which is not explained by homozygosity for the 677(C-->T) mutation, and can be an additional genetic risk factor for NTDs.

Developmental Medicine & Child NeurologyVolume 39, Issue 2 p. 125-132 Free Access The prevalence of mental retardation: a critical review of recent literature Nel Roeleveld, Nel Roeleveld Seniór Epidemiologist Department of 'Medical Informatics, Epidemiology and Statistics, University of Nijmegen. PO Box 9101,6500 The NetherlandsSearch for more papers by this authorGerhard A. Zielhuis, Gerhard A. Zielhuis Professor of Epidemiology FonsGabreëls Interdisciplinary Centre for Paediatric Neurology. University of Nijmegen, PO Box 9101,0500 HB Nijmegen. The. NetherlandsSearch for more papers by this author Nel Roeleveld, Nel Roeleveld Seniór Epidemiologist Department of 'Medical Informatics, Epidemiology and Statistics, University of Nijmegen. PO Box 9101,6500 The NetherlandsSearch for more papers by this authorGerhard A. Zielhuis, Gerhard A. Zielhuis Professor of Epidemiology FonsGabreëls Interdisciplinary Centre for Paediatric Neurology. University of Nijmegen, PO Box 9101,0500 HB Nijmegen. The. NetherlandsSearch for more papers by this author First published: 29 September 2008 https://doi.org/10.1111/j.1469-8749.1997.tb07395.xCitations: 275AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume39, Issue2February 1997Pages 125-132 ReferencesRelatedInformation

This study addresses the assessment of developmental apraxia of speech (DAS) in children. For this, 11 children with a clear diagnosis of DAS were selected, based on documented speech history and perceptual evaluation of speech. The children with DAS, as well as 11 normal-speaking children, produced singleton real word and nonsense word imitations elicited in a standardised way. Phonetic transcriptions were analysed and errors in consonants classified. The results showed, firstly, that the children with DAS produced similar types of consonant errors as has been reported in the literature, which corroborates the method of elicitation as a valid procedure to assess relevant speech symptoms of DAS. Secondly, a large quantitative difference between children with DAS and normal-speaking children was found, in that children with DAS produced an overall higher rate of singleton consonant errors (substitutions, omissions, distortions) and cluster errors (cluster reductions) than the normal-speaking children. For the DAS group, the substitution-rate, particularly in real words (as opposed to nonsense words), was significantly correlated with severity as rated by two speech and language pathologists. This suggests that substitution-rate yields an adequate measure of severity of DAS. Thirdly, a qualitative difference between both subject groups emerged. Children with DAS did not benefit from the lexical status of the utterance (real versus nonsense word) to the same extent as normal-speaking children. Based on these findings the nature of the underlying deficits in speech production in DAS is discussed.

Maximum performance tasks (MPT) were employed to quantify the speech motor capacities of children with dysarthria and developmental apraxia of speech. Specifically, several MPT (i.e. vowel prolongation, fricative prolongation, maximum syllable repetition rate) were conducted among nine carefully selected children with spastic dysarthria, 11 children with developmental apraxia of speech (DAS), and 11 age-matched normal-speaking children. The results indicated that children with spastic dysarthria can be differentiated from both DAS and normal-speaking subjects on only two of the MPT (i.e. monosyllabic repetition rate and vowel prolongation). Children with developmental apraxia of speech, furthermore, differed from the normal-speaking children on fricative prolongation and trisyllabic repetition rate, as well as on measures of trisyllabic repetitive performances (i.e. number of sequencing errors and number of attempts). The findings underscored the clinical importance of MPT for differential diagnosis, and for the quantification of degree of involvement in speech pathology.

Choroid plexus carcinoma is a rare intracranial neoplasm, affecting mainly very young children. The most common site of origin is within one of the lateral ventricles. The diagnosis of choroid plexus carcinoma is based on histological examination. Frequently subarachnoid seeding occurs and investigation at diagnosis should include examination of the cerebrospinal fluid and magnetic resonance imaging of the spinal cord. Extraneural metastases are rare. Prognosis for long-term survival ameliorates. Total surgical resection of the tumor should be attempted. Both radiotherapy and chemotherapy are used as adjuvant therapies for primary tumors. No clear difference in effectiveness of these therapies could be found. However craniospinal irradiation seems to be more effective when leptomeningeal seeding is present.

The performance of two children with traumatic spastic dysarthria, aged 10 and 14 years, on maximum performance tasks was compared with that of two closely matched children with perinatal spastic dysarthria, and reference groups of five children with perinatal spastic dysarthria and five control children with normal speech. Results showed that performance of the perinatal spastic children on all three tasks was poorer than that of their peers with normal speech. In contrast, the traumatic spastic children performed within the normal limits on maximum sound prolongation and fundamental frequency range, but their maximum repetition rate was extremely slow. The overall low performance of the perinatal spastic children could be the result of inadequate motor development in addition to the neurological impairment. The traumatic spastic children--with a normal developmental history--compensated for their impairment by slowing down their speech rate. Therapeutic implications are suggested.

The aim of this study is to quantify diagnostic characteristics related to consonant production of developmental verbal dyspraxia (DVD). For this, a paradigmatic and syntagmatic feature-value analysis of the consonant substitution and omission errors in DVD speech was conducted. Following a three-step procedure, eleven clear cases were selected from a group of 24 children with DVD. The consonants produced in a word and nonsense-word imitation task were phonetically transcribed and transferred to confusion matrices, which allows for a feature and feature-value analysis. The analysis revealed that children with DVD (a) show low percentages of retention for place and manner of articulation and voicing, due to high substitution and omission rates; (b) show a particularly low percentage of retention of place of articulation in words, which, together with error rate, is strongly related to severity of involvement; (c) are inconsistent in their feature realization and feature preference; and (d) show a high syntagmatic error rate. These results form a quantification of diagnostic characteristics. Unexpectedly, however, very few qualitative differences in error pattern were found between children with DVD and a group of 11 age-matched children with normal speech. Thus, although the children with DVD produced higher substitution and omission rates than children with normal speech, the speech profiles of both subject groups are similar. This result stresses the importance of interpreting profiles, not isolated symptoms. The hypothesis to consider DVD as a deficit in the phonological encoding process is discussed.