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Background: Monocarboxylate transporter 8 (MCT8) is a thyroid hormone transmembrane transporter protein. MCT8 deficiency induces severe X-linked psychomotor retardation. Previous reports have documented delayed myelination in the central white matter (WM) in these patients; however, the regional pattern of myelination has not been fully elucidated. Here, we describe the regional evaluation of myelination in four patients with MCT8 deficiency. We also reviewed the myelination status of previously reported Japanese patients with MCT8 deficiency based on magnetic resonance imaging (MRI).Case Reports: Four patients were genetically diagnosed with MCT8 deficiency at the age of 4–9 months. In infancy, MRI signal of myelination was observed mainly in the cerebellar WM, posterior limb of internal capsule, and the optic radiation. There was progression of myelination with increase in age.Discussion: We identified 36 patients with MCT8 deficiency from 25 families reported from Japan. The available MRI images were obtained at the age of Conclusion: The sequential pattern of myelination in patients with MCT8 deficiency was largely similar to that in normal children; however, delayed myelination of the deep anterior WM was a remarkable finding. Further studies are required to characterize the imaging features of patients with MCT8 deficiency.

Objectives The software “SyMRI” generates different MR contrasts and characterizes tissue properties based on a single acquisition of a multi-dynamic multi-echo (MDME)-FLAIR sequence. The aim of this study was to assess the applicability of “SyMRI” in the assessment of myelination in preterm and term-born neonates. Furthermore, “SyMRI” was compared with conventional MRI. Methods A total of 30 preterm and term-born neonates were examined at term-equivalent age using a standardized MRI protocol. MDME sequence (acquisition time, 5 min, 24 s)–based post-processing was performed using “SyMRI”. Myelination was assessed by scoring seven brain regions on quantitative T1-/T2-maps, generated by “SyMRI” and on standard T1-/T2-weighted images, acquired separately. Analysis of covariance (ANCOVA) (covariate, gestational age (GA) at MRI (GAMRI)) was used for group comparison. Results In 25/30 patients (83.3%) (18 preterm and seven term-born neonates), “SyMRI” acquisitions were successfully performed. “SyMRI”-based myelination scores were significantly lower in preterm compared with term-born neonates (ANCOVA: T1: F(1, 22) = 7.420, p = 0.012; T2: F(1, 22) = 5.658, p = 0.026). “SyMRI”-based myelination scores positively correlated with GAMRI (T1: r = 0.662, n = 25, p ≤ 0.001; T2: r = 0.676, n = 25, p ≤ 0.001). The myelination scores based on standard MRI did not correlate with the GAMRI. No significant differences between preterm and term-born neonates were detectable. Conclusions “SyMRI” is a highly promising MR technique for neonatal brain imaging. “SyMRI” is superior to conventional MR sequences in the visual detection of delayed myelination in preterm neonates. Key Points • By providing multiple MR contrasts, “SyMRI” is a time-saving method in neonatal brain imaging. • Differences concerning the myelination in term-born and preterm infants are visually detectable on T1-/T2-weighted maps generated by “SyMRI”. • “SyMRI” allows a faster and more sensitive assessment of myelination compared with standard MR sequences. Electronic supplementary material The online version of this article (10.1007/s00330-019-06325-2) contains supplementary material, which is available to authorized users.

Glutaminyl-tRNA synthetase (QARS) deficiency has been described to be a cause of a neurodegenerative disorder associated with severe developmental delay, microcephaly, delayed myelination, and intractable epilepsy. The epilepsy is thought to be more severe than other tRNA synthetase disorders. Only a few cases have been reported in the literature and there is little information about response to different treatment options. The ketogenic diet is a high-fat, low-carbohydrate diet that is used in treatment resistant epilepsy of various etiologies. There are reports that the diet can also improve neuro-cognitive parameters. The authors report a case of a patient with glutaminyl-tRNA synthetase deficiency and treatment resistant seizures where there was a marked and early favorable response in terms of seizures, alertness and behavior to the ketogenic diet.

Background Congenital disorders of glycosylation (CDGs) are genetic diseases caused by pathogenic variants of genes involved in protein or lipid glycosylation. De novo variants in the SLC35A2 gene, which encodes a UDP‐galactose transporter, are responsible for CDGs with an X‐linked dominant manner. Common symptoms related to SLC35A2 variants include epilepsy, psychomotor developmental delay, hypotonia, abnormal facial and skeletal features, and various magnetic resonance imaging (MRI) findings. Methods Whole‐exome sequencing was performed on the patient's DNA, and candidate variants were confirmed by Sanger sequencing. cDNA analysis was performed to assess the effect of the splice site variant using peripheral leukocytes. The X‐chromosome inactivation pattern was studied using the human androgen receptor assay. Results We identified a de novo splice site variant in SLC35A2 (NM_005660.2: c.274+1G>A) in a female patient who showed severe developmental delay, spastic paraplegia, mild cerebral atrophy, and delayed myelination on MRI, but no seizures. The variant led to an aberrant splicing resulting in an in‐frame 33‐bp insertion, which caused an 11‐amino acid insertion in the presumptive cytoplasmic loop. X‐inactivation pattern was random. Partial loss of galactose and sialic acid of the N‐linked glycans of serum transferrin was observed. Conclusion This case would expand the phenotypic spectrum of SLC35A2‐related disorders to delayed myelination with spasticity and no seizures.

As a stable environmental contaminant, nonylphenol (NP) has been shown to induce some neurological deficits in the cerebellum, although the underlying mechanism is still unknown. In the present study, we aimed to investigate the effects of perinatal exposure to NP on myelination, an important process essential for the intact cerebellar function, in the offspring cerebellum. Exposure to NP delayed the myelination in the offspring cerebellum during perinatal period. The myelination recovered in the cerebellum of offspring exposed to NP over time, and returned to normal in adulthood. In addition, perinatal exposure to NP reduced mature oligodendrocytes (myelin-forming glial cells) and increased astrocytes in the offspring cerebellum. BMP signaling is believed to negatively regulate oligodendrogliogenesis and myelination. In the present study, BMP4, p-Smad1/5, and ID4, key members of BMP signaling, were increased in the cerebellum of offspring exposed to NP. Taken together, these lines of evidence suggest that the activation of BMP signaling may underlie the decreased oligodendrogliogenesis and increased astrogliogenesis, and the consequent delay of myelination in the cerebellum of offspring perinatally exposed to NP.

Myelin is a vital element of normal brain development and structure. Myelination is most prominent during the first two years of life and proceeds until the age of 30. Abnormal myelination is related to several neurological and neuropsychiatric disorders such as Alzheimer’s disease and multiple sclerosis. Recently, abnormal myelin content has also been reported in children with epilepsy. Furthermore, more and more literature hints at a link between abnormal myelination and epilepsy, hence it is worthwhile to evaluate the benefits of non-invasive myelin imaging. In this literature review, we provide an overview of the current evidence of myelin abnormalities in epilepsy from imaging and histological studies. After preselection, 21 histological and 21 in vivo imaging studies were identified. Primarily, epilepsy is found to be associated with a reduced myelin content. This review shows that the currently available literature does not provide a complete view into the nature of myelin abnormalities in epilepsy. However, the reported literature is indicative of a relation between the pathophysiology of epilepsy and the myelin content. More studies that apply myelin-specific imaging techniques are needed to determine whether the myelin abnormalities are an underlying cause of epilepsy, or a consequence of the excessive activity in epilepsy.

Background Waardenburg syndrome type 1 (WS1) can be distinguished from Waardenburg syndrome type 2 (WS2) by the presence of dystopia canthorum. About 96% of WS1 are due to PAX3 mutations, and SOX10 mutations have been reported in 15% of WS2. Case presentation This report describes a patient with WS1 who harbored a novel SOX10 nonsense mutation (c.652G > T, p.G218*) in exon 3 which is the penultimate exon. The patient had mild prodromal neurological symptoms that were followed by severe attacks of generalized seizures associated with delayed myelination of the brain. The immature myelination recovered later and the neurological symptoms could be improved. This is the first truncating mutation in exon 3 of SOX10 that is associated with neurological symptoms in Waardenburg syndrome. Previous studies reported that the neurological symptoms that associate with WS are congenital and irreversible. These findings suggest that the reversible neurological phenotype may be associated with the nonsense mutation in exon 3 of SOX10. Conclusions When patients of WS show mild prodromal neurological symptoms, the clinician should be aware of the possibility that severe attacks of generalized seizures may follow, which may be associated with the truncating mutation in exon 3 of SOX10. Electronic supplementary material The online version of this article (10.1186/s12887-018-1139-2) contains supplementary material, which is available to authorized users.

Recently, haploinsufficiency of PURA has been identified as an essential cause of 5q31.3 microdeletion syndrome, which is characterized by severe psychomotor developmental delay, epilepsy, distinctive features, and delayed myelination. A new 5q31.2-q31.3 microdeletion that included PURA was identified in a patient with infantile spasms. Approximately 50% of patients with PURA-related neurodevelopmental disorders exhibited epilepsy regardless of whether they harbor a 5q31.3 deletion or PURA mutation. Patients with the 5q31.3 deletion or a PURA mutation should be carefully monitored for epileptic seizures.

Myelin is essential for rapid and efficient action potential propagation in vertebrates. However, the molecular mechanisms regulating myelination remain incompletely characterized. For example, even before myelination begins in the PNS, Schwann cells must radially sort axons to form 1:1 associations. Schwann cells then ensheathe and wrap axons, and establish polarized, subcellular domains, including apical and basolateral domains, paranodes, and Schmidt-Lanterman incisures. Intriguingly, polarity proteins, such as Pals1/Mpp5, are highly enriched in some of these domains, suggesting that they may regulate the polarity of Schwann cells and myelination. To test this, we generated mice with Schwann cells and oligodendrocytes that lack Pals1. During early development of the PNS, Pals1-deficient mice had impaired radial sorting of axons, delayed myelination, and reduced nerve conduction velocities. Although myelination and conduction velocities eventually recovered, polyaxonal myelination remained a prominent feature of adult Pals1-deficient nerves. Despite the enrichment of Pals1 at paranodes and incisures of control mice, nodes of Ranvier and paranodes were unaffected in Pals1-deficient mice, although we measured a significant increase in the number of incisures. As in other polarized cells, we found that Pals1 interacts with Par3 and loss of Pals1 reduced levels of Par3 in Schwann cells. In the CNS, loss of Pals1 affected neither myelination nor the establishment of polarized membrane domains. These results demonstrate that Schwann cells and oligodendrocytes use distinct mechanisms to control their polarity, and that radial sorting in the PNS is a key polarization event that requires Pals1. Significance statement: This paper reveals the role of the canonical polarity protein Pals1 in radial sorting of axons by Schwann cells. Radial sorting is essential for efficient and proper myelination and is disrupted in some types of congenital muscular dystrophy.

A girl with cardio-facio-cutaneous (CFC) syndrome due to a BRAF gene mutation (c.1454T→C, p.L485S) experienced repetitive epileptic spasms at the corrected age of 4 months. Electroencephalograms revealed hypsarrhythmia, and magnetic resonance imaging identified delayed myelination and a hypoplastic corpus callosum. Various antiepileptic treatments, including adrenocorticotropic hormone therapy, were ineffective, although transient seizure control was achieved by a ketogenic diet and clorazepate dipotassium. However, seizures with epileptic foci at the bilateral posterior temporal areas re-aggravated and remained intractable; severe psychomotor delay persisted. This case indicated that infantile spasms in CFC syndrome can be difficult to control and may be accompanied by severe psychomotor retardation and abnormal myelination.

The effect of raised intracranial pressure (ICP), due to infantile hydrocephalus, on the process of myelination has been suggested in the literature. In this study 19 hydrocephalic infants were followed-up with anterior fontanelle pressure (AFP) measurement (assessment of ICP), MRI (assessment of the myelination process and the CSF volume), and neurodevelopmental testing (NDT). There was a high correlation (r = 0.80) between the myelination and NDT scores. The size of the CSF volume showed a poor correlation with the mean AFP, the degree of myelination and the NDT scores. There was, however, a significant correlation between the mean AFP and the degree of myelination (r = 0.67) and also between the mean AFP and the NDT scores (r = 0.70). Longer-term follow-up (mean = 27 months) showed a significant correlation between the early progress of myelination and later developmental level (r = 0.78). Most of the children with a severely delayed myelination, preoperatively, showed a recovery of myelination following CSF drainage. It was concluded that: (1) raised ICP is related to developmental outcome, through the process of myelination; (2) the delay in myelination can be (partially) reversible; and (3) CSF volume is of minor importance regarding neurodevelopment.

To evaluate the prognostic value of delayed myelination at the onset of cryptogenic West syndrome, the relationship between the seizure or developmental outcome and myelination was examined. Cranial magnetic resonance imaging studies were performed in nine cryptogenic cases. Infantile spasms were controlled in all patients, but three cases showed a mild developmental delay at 2 years after onset. Delayed myelination was observed in three cases (33.3%) on T(1)-weighted images and in two cases (22.2%) on T(2)-weighted images. In the present study, neither the seizure outcome nor developmental status was positively correlated with the existence of delayed myelination at the onset of cryptogenic West syndrome.

Asparagine synthetase deficiency (ASD) is a newly identified neurometabolic disorder characterized by severe congenital microcephaly, severe global developmental delay, intractable seizure disorder, and spastic quadriplegia. Brain MRI showed brain atrophy, delayed myelination, and simplified gyriform pattern.We report ASD deficiency in a 2- and 4-year-old sibling. On them, we described clinical, biochemical, and molecular findings, and we compared our results with previously reported cases.We identified a homozygous novel missense mutation in ASNS gene in both probands and we demonstrated low CSF and plasma asparagine in both patients.Clinicians should suspect ASD deficiency in any newborn presented with severe congenital microcephaly followed by severe epileptic encephalopathy and global developmental delay. CSF asparagine level is low in this disorder while plasma may be low.

Isolated developmental delay (IDD) is a common disorder in preschool and school-age children. Conventional magnetic resonance imaging (MRI) usually does not disclose abnormalities, but a myelination delay is suspected as causative or associated factor. N-acetyl-aspartate is a surrogate marker of neuronal integrity but also of axonal integrity. The goal of our study is to determine whether magnetic resonance spectroscopy (MRS) is able to detect alterations in the white matter supporting the hypothesis of delayed myelination in children with IDD and normal MRI.In this cross-sectional study, we enrolled 12 consecutive children meeting the criteria if IDD and aged between 3 and 12 years (mean 7.25 years) and 11 healthy children as control group (mean age 7.18, range 3-12 years) on whom we performed conventional MRI and MRS. We did not include children with abnormal MRI. Single voxel (8 cm(3)) was placed in the white matter of the left centrum semiovale. The mode of acquisition was probe-p (PRESS technique) with a TR of 2500 milliseconds and a TE of 30 milliseconds. We measured the metabolite concentration of n-acetyl-aspartate (NAA), choline (Ch), creatine (Cr) y myo-inositol (mI), and ratios of NAA, Ch, and mI to creatine.In children with IDD, we found a significant decrease of the following ratios: NAA/Cr (P.016), NAA/Ch (P.026), and NAA/mI (P.023) in relation to controls. The mean NAA/Cr ratio in IDD children was 1.92 (SD 0.14), and in controls it was 2.09 (SD 0.14); t = 2.62, fd (freedom degrees) = 21, P.016. No differences were seen in the remaining ratios.The lower NAA/Cr ratio in children with IDD in relation to controls may be a promising marker of this disorder and supports the hypothesis of delayed myelination. MRS can provide important information in children with neurodevelopmental disorders.

N-acetylaspartate (NAA) contributes to the most prominent signal in proton magnetic resonance spectroscopy (1H-MRS) of the adult human brain. We report the absence of NAA in the brain of a 3-year-old child with neurodevelopmental retardation and moderately delayed myelination. Since normal concentration of NAA in body fluids is hardly detectable, 1H-MRS is a noninvasive technique for identifying neurometabolic diseases with absent NAA. This report puts NAA as a neuronal marker to question. Ann Neurol 2001;49:518–521

Fukuyama-type congenital muscular dystrophy (FCMD) is characterized by congenital muscular dystrophy and associated with neuropathological anomalies. However, the issue of whether the radiological findings of white-matter lesions represent delayed myelination, demyelination or other problems remains controversial. We present serial radiological findings, including MR spectroscopy (MRS), in a child with FCMD. These findings indicate a correlation between the imaging abnormalities and the choline/creatine ratio, suggesting the possible usefulness of MRS in addition to MRI for following FCMD patients.

Whether the pathologic origin of white matter lesions in Fukuyama type of congenital muscular dystrophy (FCMD) is delayed myelination or dysmyelination is a controversial issue. This study investigated pathologic distribution in white matter with heavily T 2 -weighted images using fluid-attenuated inversion recovery (FLAIR) pulse sequence. For detection of abnormal white matter lesions, FLAIR images were approximately twice as sensitive as T 2 -weighted images and five times as sensitive as T 1 -weighted images of spin echo sequence. The distribution of the white matter lesions was disseminated and not correlated with cortical disarrangement. The distribution was not consistent with delayed myelination. These findings support the evidence found using in vitro proton-NMR spectroscopy that the pathologic origin of white matter lesions is dysmyelination. When conventional magnetic resonance imaging is used, masked white matter lesions are easy to misidentify as delayed myelination instead of disseminated developmental dysmyelination. The lesions in the white matter of FCMD are masked because of brain development.

We report here on a Japanese male infant with megalocornea-mental retardation (MMR) syndrome. He had megalocornea (corneal diameter: 13 mm) without glaucoma, developmental retardation, hypotonia, frontal bossing, high-arched palate, carp-like mouth, micrognathia, and delayed myelination. He seems to be included in Verloes type of the MMR syndrome.

A 3.5-year-old girl with tyrosinemia is reported. A computed tomography scan of the abdomen revealed multiple hepatic nodules. Brain magnetic resonance imaging revealed bilateral high-signal changes confined to the globus pallidus on T2-weighted images. Globus pallidus lesions likely represented neuropathologic changes such as astocytosis, delayed myelination, and status spongiosus (myelin splitting and vacuolation).

A finger lozalization task was used to investigate interhemispheric transfer of tactile information and the processing of sequential tactile information in 7- and 9-year-old “average” readers and 9-year-old reading disabled boys. The performance of the reading disabled group on interhemispheric transfer and sequential processing was comparable to or worse than the 7-year-old average readers. Significant correlations linked the reading disabled boys' performance on the finger localisation task with their reading skills, performance on perceptual/motor tasks and knowledge of order in the time domain. The results are interpreted in terms of delayed myelination of interhemispheric and intrahemispheric pathways in the reading disabled.

Magnetic resonance imaging (MRI) was used in high-risk infants to assess the myelination process and its relationship with neurologic outcome. The time period when delayed myelination is best detected by MRI was also studied. MRI was performed in 39 high-risk infants (i.e., preterm infants, infants with respiratory distress syndrome, or with neonatal convulsions and asphyxia). In 10 of 11 infants with normal development, MRI revealed a normal myelination pattern before 2 months of age, and in 11 of 13 infants after 2 months of age. Conversely, in infants with poor outcomes, MRI demonstrated delayed myelination patterns in only 1 of 4 infants before 2 months of age but in 9 of 11 infants after 2 monthes of age. In patients with poor outcomes, delayed myelination was found more frequently after rather than before 2 months of age. These findings demonstrate that delayed myelination detected by MRI is useful in predicting the neurologic outcome of high-risk infants, especially after 2 months of age.

The authors examined 15 patients with delayed myelination of the optic nerve and pseudo optic atrophy of Beauvieux. Three cases presented with albinism. In one patient the diagnosis of generalized hypomyelination of the brain was confirmed by the Nuclear Magnetic Resonance technique.The prognosis is relatively favourable. Follow-up examinations showed that in the majority of the patients the delay in myelination will be made good. Visual acuity could be measured in six patients and varied from 0.1 to 0.6.

Item does not contain fulltext Monitoring effects of a ketogenic diet in GLUT1 deficiency syndrome without seizures is difficult. Neuroimaging is considered uninformative. We report the case of a boy with neurodevelopmental delay, severe ataxia, an E54X-mutation in the SLC2A1 gene (previously GLUT1), and neuroimaging abnormalities indicative of delayed myelination. Six months on a ketogenic diet resulted in an improved high subcortical white matter signal on T2-weighted images and a reduced N-acetylaspartate/creatine ratio. We conclude that delayed subcortical myelination may occur in GLUT1 deficiency syndrome as a nonspecific finding reflecting developmental delay. In patients without seizures, cranial magnetic resonance imaging and magnetic resonance spectroscopy may prove useful tools to monitor the response to a ketogenic diet.

Two unrelated children and their siblings of Arab origin were diagnosed as having GM1 gangliosidosis on the basis of clinical features and markedly low levels of β-galactosidase. The T2-weighted magnetic resonance images of the brain revealed certain characteristic features, including delayed myelination and abnormal appearance of the subcortical white matter, internal capsule, and basal ganglia. Their mutation analysis showed two novel mutations, which have not been described in an Arabic population. ( J Child Neurol 2005;20:57—60).

Delayed acquisition of developmental motor and cognitive milestones is a common clinical expression of many etiological processes. Imaging exams of developmentally delayed children often show no structural brain alterations despite suspicion of brain maturation delay. MRI studies increasingly suggest that white matter myelination finely reflects the progression in functional brain maturation. In this volumetric MRI study, we sought to evaluate whether developmental delay in children with normal conventional MRI exams is associated with reduced myelinated white matter. A total of 100 children (mean age, 4.4 years) with developmental delay and 50 normally developing age-matched control children underwent 3-D MRI to measure the volume of myelinated white matter. Patients showed a significant reduction in the relative content of myelinated white matter (accounting for 19.8% of brain volume in patients and 21.4% in control subjects, P = 0.005). The observed difference was equivalent to a 3.2-year myelination delay. Although the whole hemispheres were invariably symmetrical, the volume of myelinated white matter was asymmetrical in 30% of patients and 10% of control subjects (P = 0.006). We conclude that volumetric assessment of white matter may reveal a reduction in brain myelination beyond early childhood in developmentally delayed children showing normal brain appearance. This finding further emphasizes the view of white matter myelination as an indicator of functional brain maturation.

Sandhoff's disease is a rare, genetic lysosomal storage disease leading to delayed myelination or demyelination. Although neuroimaging findings in this disease have been reported previously, magnetic resonance spectroscopy findings have not been reported. In this report, we present magnetic resonance imaging and magnetic resonance spectroscopy features of two cases with Sandhoff's disease. Magnetic resonance spectroscopy revealed findings indicating widespread demyelination in both cases and neuroaxonal loss and anaerobic metabolism in the second case. Magnetic resonance spectroscopy could provide useful information in the explanation of the clinical picture of cases with Sandhoff's disease. ( J Child Neurol 2003;18:425—428).

An etiologic evaluation of 86 patients with infantile spasms is presented and the place of cranial magnetic resonance imaging (MRI) findings within this spectrum is discussed. A total of 103 cranial MRIs, performed between 4 and 72 months of age, were analyzed and classified according to the etiologic and pathophysiologic aspects. Ninety-one percent of cases were diagnosed as symptomatic infantile spasms, and hypoxic-ischemic encephalopathy was the primary cause (30%). The most common involvement was thinning of the corpus callosum in 43 patients (50%), followed by dilation of cerebral ventricles in 32 (36%), delayed myelination in 23 (26.7%), lesions of diencephalic deep gray matter in 17 (19.7%), and enlargement of the subarachnoid space in 12 (14%). Thin corpus callosum and diffuse atrophy were changes mainly associated with hypoxic-ischemic encephalopathy, whereas delayed myelination seemed to be independent from a specific etiology. The results showed that cranial MRI may provide considerable information regarding not only the etiology but also the pathophysiology of infantile spasms. ( J Child Neurol 2003;18:241—246).

A Japanese boy with interstitial deletion of the long arm of chromosome 14, including band 14q31, is described. The characteristic dysmorphic facial features, such as dolichocephaly, bushy eyebrows, horizontal narrow palpebral fissures, long philtrum, etc, and mental and motor developmental delay were observed. Other characteristic clinical manifestations were anuresis and status nonepileptic myoclonia. The finding of delayed myelination of the cerebral white matter was observed on magnetic resonance examination, suggesting that an unknown factor related to myelination in the central nervous system might be localized in band 14q31. ( J Child Neurol 1999;14:756-758).

Research on children with Joubert syndrome has focused on brain structural abnormalities and associated clinical symptoms. The degree of developmental delay has not been objectively reported. We investigated the neurobehavioral development of children with Joubert syndrome through neurobehavioral assessment in the largest sample to date. Thirty-two parents of children with Joubert syndrome completed the Child Development Inventory and magnetic resonance imaging (MRI) data was gathered on 17 of these children. Results indicate that 94% were severely impaired according to the Child Development Inventory, with age being positively correlated with degree of neurobehavioral impairment. The average developmental age of our sample was 19 months (63% below chronological age). Severity of illness as measured by the General Development scale of the Child Development Inventory and severity of illness as measured by MRI (overall severity rating) did not yield consistent data regarding severity of the midbrain and cerebellar malformations. Similarly, markers of abnormal cerebral development such as cortical atrophy and delayed myelination were independent of severity of illness ratings on the Child Development Inventory. The degree of developmental delay in Joubert syndrome and the severity of gross central nervous system malformations appear independent. (J Child Neurol 1998;13:391-397).

Most SIDS deaths occur between 2 and 4 months of age. Neural transformations may be important in SIDS. Evidence of delayed myelination has been found in SIDS victims. However a simple neuro-developmental model is insufficient to explain SIDS. The age of death profile is reportedly similar for pre-term and full-term SIDS victims. Another developmental change is that IgG levels are lowest when SIDS risk peaks, and there is data linking SIDS and infections. Prone position may also increase risk. While a developmental model emphasizing neural transformation is useful, other factors affect risk also.

We present a girl with proven nonketotic hyperglycinaemia. The pathological findings on MRI were brain atrophy with thinning of the corpus callosum and delayed myelination of the cerebral hemispheres, particularly the parietal lobes.

Magnetic resonance imaging has been found to be useful in assessing brain myelination and provides information on brain maturation. The normal pattern of brain myelination conforms to a fixed sequence, with good pathologic and MRI correlation. Neuropathologic analysis of myelination has shown delayed central myelination in Down syndrome. Delayed myelination on MRI in Down syndrome has not previously been reported. We report a case of Down syndrome with a significant delay in myelination as demonstrated on MRI. This 18-month-old infant had brain myelination equivalent to that expected for an 11-month-old infant. To determine the relative incidence, extent of delayed myelination, and time for recovery to full myelination in Down syndrome, more cases require examination and assessment. Magnetic resonance imaging has the advantage of serial assessment of myelination during brain maturation. (J Child Neurol 1992;7:417-421).

We prospectively performed magnetic resonance imaging (MRI) studies during the neonatal period, and at 4 and 8 months of age, on 15 term infants with hypoxic-ischemic encephalopathy, and compared the results with their neurodevelopmental outcome at 18 months of age. Cerebral palsy developed in nine infants, two infants were classified as having abnormalities of fone and delayed motor milestones that were suggestive of cerebral palsy, and four infants were normal. Structural abnormalities, delayed myelination, or a combination of the two were detected with MRI at 8 months of age in all nine infants with later development of cerebral palsy. Three of the four normal infants and one infant with suggestive abnormallties had normal serial MRI findings. Each of the remaining two infants (one normal, one with suggestive abnormalities) had isolated persistent ventricular dilation on all three MRI studies. Our results suggest that 8 months appears to be the earllest time at which MRI findings correlate well with later adverse neurodevelopmental outcome in this population.

In this prospective study, 26 very preterm infants underwent magnetic resonance (MR) imaging of the brain at 44 weeks postmenstrual age (PMA) for staging of myelination. Neurodevelopmental outcome was assessed at 1 year of age. A significant correlation was demonstrated between delayed myelination and neurodevelopmental outcome (Chi 2 = 16.6, P = .01). A significant correlation was also found between ultrasound (US) findings in the neonatal period and outcome at 1 year (Chi 2 = 22.9, P = .03). To establish the criterion with the best predictive value, a multiple regression analysis was performed with periventricular-intraventricular hemorrhage, periventricular leukomalacia (PVL), and the stage of myelination at 44 weeks PMA as independent variables and neurodevelopmental outcome at 1 year of age as a dependent variable. Staging of myelination with MR imaging in the early postnatal period of very preterm infants had predictive value with regard to neurodevelopmental outcome. Detection of PVL with US, however, showed a better correlation with outcome, a result that seems to limit the potential role of MR imaging in this population for this purpose only.

To the Editor.— The study of Van de Bor et al1 appears to demonstrate differences in myelination between infants with and without periventricular leukomalacia (PVL). However, we feel that it does not demonstrate, as stated, that PVL causes delayed myelination, whereas periventricular-intraventricular hemorhage (PIVH) does not. Because the study group did not contain any survivors with intraparenchymal hemorrhage, caution must be used in stating that PIVH does not influence subsequent myelination. Myelination is a complex process which continues into adulthood.

Sixty-two computed tomographic (CT) scans of 36 patients with congenital muscular dystrophy of Fukuyama type (FCMD) were analysed. A low density area in the cerebral white matter was characteristic of FCMD and a special reference was made to the changes in the white matter low density. It was present in 15 patients out of 36 (42%) and frequently seen in the scans obtained on the younger patients; among 11 scans taken of patients between 1 and 2 years of age, 10 scans (91%) showed the white matter low density. Repeated CT scans were carried out on 26 of the 36 cases. Follow-up study revealed that the white matter low density areas were most apparent around the age of one year and decreased or disappeared at 2 or 3 years of age. From these observations, delayed myelination was suspected for the pathogenesis of the low density area found in FCMD.

SUMMARY The ultrastructure of the spinal cord in 2 cases of Border disease is described. The findings include delayed myelination, demyelination, cavitation of the myelin sheaths and extensive astrogliosis.

Myelinating mouse spinal cord fragments were cultured in Maximow assemblies. A variable interval after explanation they were exposed to low concentrations of serum from rabbits with experimental allergic encephalomyelitis (EAE). As a general rule, the longer they were kept under EAE serum, the more completely myelination was inhibited. If the experiments were made with low concentrations of EAE serum (about 1%), the number of myelinated cultures was proportional to the number of days by which the application of EAE-serum was delayed. If one worked with EAE-serum at higher concentrations (5%), the cultures on which the serum was applied with a delay from 1 to 5 days were practically completely inhibited in their myelination. If exposed from the 7th day onward only, nearly all of these cultures were able to myelinate and therefore showed myelin, when viewed on day 12 in vitro. If, however, they were left under the same concentrations of EAE-serum for another week, the myelin sheaths disappeared again without leaving any signs of myelin destruction. These cultures showed loose spirals of glial cytoplasma membranes around axons. Cultures in which the application of EAE-serum was delayed for 4–6 days showed differentiated oligodendrocytes and astrocytes, which was not the case in cultures inhibited from the explantation onward.

— Myelinating cultures of rat cerebellum were exposed to the branched-chain amino acids and their α-keto derivatives at concentrations found in maple syrup urine disease. Decreased-to-absent and delayed myelination was produced by α-keto-isocaproic acid at physiological levels. Injury to small cells, probably glia, was also noted. The other metabolites failed to produce any visible damage.

Publisher Summary This chapter discusses the characteristics of the neuropathy sample. The sample for the neuropathologic and epidemiologic studies reported was composed of fetuses and infants whose mothers were enrolled in the National Institute of Neurological Disorders and Stroke (NINCDS) Collaborative Perinatal Project; these infants died during the course of the project, were autopsied, and their neurologic material returned to the project in a useable condition. The male/female ratio and the racial proportions differed between the serially and nonserially sectioned groups. More live-born and stillborn male than female brains were nonserially sectioned. There was an almost equal sex distribution between the serially sectioned live-borns and nonserially sectioned stillborns. The controls for the perinatal telencephalic leukoencephalopathies characterized by two histologic features were infants who had neither histologic feature. The sample for study of delayed myelination differed considerably from these other samples: (1) no lower bound was set for gestational age, (2) the upper bound for the postnatal age was set at 7 days, and (3) the sample was confined to those newborns whose brains were embedded in celloidin and then serially sectioned.

Publisher Summary This chapter discusses the epidemiology of delayed myelination. Small head size and low brain weight are viewed as correlates of impaired neurologic function. Delayed myelination may also be a correlate of impaired function. In newborns, delayed evoked responses may be the most reliable quantitative indicator of delayed myelination. Preterm newborns, however, have illnesses that may have a more immediate effect on evoked responses than on the tinctorial properties of myelin. Thus, the greater sensitivity of evoked responses to metabolic stresses and the more rapid reversibility of their abnormalities may limit their usefulness in assessing myelination delays. A large body of data supports the hypothesis that the myelinating brain is vulnerable to the same factors that retard the growth of other organs. Growth retardation is best expressed by the combination of low birth weight and full-term gestational age variables. Factors such as maternal cigarette smoking, third-trimester uterine bleeding, and low maternal hematocrit explain and provide information about the setting for growth retardation.

The effects of biotin deprivation on ABER were studied in rat pups fed a diet that lacked this compound. Pregnant rats were either fed a normal rat diet (controls) or a special diet without biotin (Teklad, Harlan Sprague Dawley, Madison, WI). After weaning, the respective diets were continued in pups from each group. ABER was tested under chloral hydrate anesthesia (380 mg/kg) using clicks (100 μs, 5/s) and tone bursts (3‐ms duration, 1.5‐ms rise‐fall time at 2, 8, 16, and 32 kHz) presented free field with a driver suspended 8 cm above the vertex in the median plane. Responses were obtained using an active lead from the vertex with a reference electrode in the nose. Blood levels of biotin were measured using a microbiological assay. Animals on the biotin‐free diet showed alopecia and dry, scaly skin. There was no significant difference in ABER threshold in control versus experimental animals. However, there was a significantly longer brain‐stem transmission time (interpeak latencies from waves I to IV) in biotin‐deficient animals. The lowering of serum biotin in experimentals was confirmed by microbiologic assay. These findings suggest that biotin deficiency in the developing rat adversely affects auditory‐nerve and/or brain‐stem development. These effects could be mediated by a delayed myelination of these structures. [Work supported by Deafness Research Foundation.]