A 6Mb deletion in band 2q22 due to a complex chromosome rearrangement associated with severe psychomotor retardation, microcephaly and distinctive dysmorphic facial features.

High-resolution analyses of complex chromosome rearrangements (CCR) have demonstrated in individuals with abnormal phenotypes that not all seemingly balanced CCRs based on G-banding are completely balanced at breakpoint level. Here we report on an apparently balanced de novo CCR involving chromosomes 2, 3 and 5 present in a 6-month-old girl. She was referred for genetic evaluation because of severe psychomotor retardation, distinctive dysmorphic features and microcephaly. A 1Mb resolution array-CGH analysis of DNA from the patient revealed a deletion of about 6Mb for chromosome 2. FISH analysis showed that the deletion interval found in band 2q22 mapped at the translocation breakpoint, and that the ZFHX1B gene, which is known to be involved in the Mowat-Wilson syndrome, is located within the deletion interval. To our knowledge this is the first case of a complex chromosomal rearrangement associated with Mowat-Wilson syndrome. Our data illustrate the important role for high-resolution investigation of apparently balanced chromosome rearrangements in patients with unexplained psychomotor retardation and/or other clinical features, and should contribute to our understanding of the mechanisms involved in chromosome rearrangement.

Differentiating normal myelination from hypoxic-ischemic encephalopathy on T1-weighted MR Images: a new approach.

BACKGROUND AND PURPOSE: Hypoxic-ischemic cerebral changes can be difficult to distinguish from normal myelination on T1-weighted images. We hypothesized that comparing signal intensity (SI) of brain structures on T1-weighted images enables differentiation of myelination from hypoxic-ischemic brain damage. MATERIALS AND METHODS: T1-weighted images, obtained in 57 infants aged 1-104 days and born after a gestational age of 35 weeks or older, were retrospectively evaluated. Subjects were assigned to a patient (n = 23, with perinatal hypoxic-ischemic encephalopathy [HIE] stage 2/3) or a control group (n = 34). In each subject, an SI score was assigned to 19 brain structures on the basis of pairwise comparisons with the other 18 structures. In both groups, mean total SI scores were calculated for the 19 structures. Independent samples t tests assessed whether the mean total score of a structure differed significantly between the 2 groups. Logistic regression assessed which comparison was best to distinguish between the groups and to predict the presence of hypoxic-ischemic injury. RESULTS: In patients, mean total SI scores for posterolateral putamen (PP) and peri-Rolandic cortex (PC) were significantly higher (P = .000 for both). Mean total SI scores of the posterior limb of internal capsule (PLIC) and the corona radiata (CR) were significantly lower in patients (P = .000 and 0.005, respectively). Two comparisons (PLIC versus CR, PP versus PC) were best to distinguish patients and controls and to predict absence or presence of HIE (P < .0001). CONCLUSION: SI changes due to hypoxia-ischemia can be differentiated from normal myelination by comparing SI of 4 brain structures on T1-weighted images.

Is there a way to predict outcome in (near) term neonates with hypoxic-ischemic encephalopathy based on MR imaging?

BACKGROUND AND PURPOSE: It has previously been demonstrated that comparison of signal intensity (SI) between selected brain structures on T1-weighted images enables distinction between the absence or presence of hypoxic-ischemic (HI) brain injury in young infants. The aim of the present study was to assess whether this method of brain structure T1-weighted SI comparison also enables prediction of outcome. MATERIALS AND METHODS: Survivors of a group of 57 children with neonatal HI encephalopathy (HIE) grade 2 or 3 according to Sarnat and Sarnat and controls who underwent neonatal MR imaging were retrospectively assigned to 1 of 3 outcome groups at 5 years of age, depending on developmental outcome: 1) normal, 2) mildly abnormal, and 3) definitely abnormal. Gestational age was not significantly different between the HIE group (range, 35 + 5-42 + 5 weeks; mean, 39 + 4 weeks) and control group (range, 35 + 0-42 + 1 weeks; mean, 39 + 2 weeks). We calculated the predictive values of the neonatal clinical HIE classification according to Sarnat and Sarnat for outcome (neonatal death and developmental outcome in survivors). We assessed which brain structure T1-weighted SI comparison scored best for outcome prediction. Predictive values of that comparison for outcome were calculated for the entire group and for the HIE grade 2 group only, a patient group with highly variable outcome. RESULTS: Of the 57 children, 6 died. Outcome group 1 consisted of 31; group 2, of 14; and group 3, of 6 children. The positive predictive value of the neonatal clinical classification for adverse outcome (outcome group 3 and death) was 52%; and negative predictive value, 100%. These were respectively 45% and 0% in children with HIE grade 2. Of all brain structure T1-weighted SI comparisons, that of the posterior limb of the internal capsule versus the posterolateral putamen scored best for outcome prediction. The positive predictive value for adverse outcome was 69%; and negative predictive value, 98%. In children with HIE grade 2, the positive predictive value and negative predictive value for adverse outcome were 67% and 88%. CONCLUSIONS: Brain structure T1-weighted SI comparisons are helpful to predict outcome in (near) term neonates with HIE. This finding adds to the current knowledge and clinical practice. If the SI in the posterolateral putamen is less than the SI in the posterior limb of the internal capsule, favorable outcome is very likely, whereas if the SI in the posterolateral putamen is equal to or greater than the SI in the posterior limb of the internal capsule, adverse outcome is very likely. In neonates with HIE grade 2 according to Sarnat and Sarnat, prediction of outcome is substantially improved by using these brain structure T1-weighted SI comparisons.

Alternating hemiplegia of childhood: no mutations in the glutamate transporter EAAT1.

Alternating hemiplegia of childhood (AHC) is a severe brain disorder, mainly characterised by episodes of hemiplegia, progressive mental retardation, and other severe paroxysmal and permanent neurological symptoms. Clinically and genetically, there is some overlap with sporadic (SHM) and familial (FHM) hemiplegic migraine, a severe monogenic subtype of migraine. Although no mutations were detected in the FHM1 CACNA1A and FHM2 ATP1A2 genes in sporadic AHC patients, a mutation was found in the FHM2 ATP1A2 gene in a family with AHC. Recently, a missense mutation was found in the SLC1A3 gene that encodes the glutamate transporter EAAT1, in a patient with alternating hemiplegia, episodic ataxia, seizures, and headache. Because of the remarkable clinical similarities and the potential role of glutamate in AHC, we analysed six sporadic patients with AHC for mutations in the SLC1A3 gene. No mutations were found. The SLC1A3 EAAT1 glutamate transporter gene does not seem to be involved in the pathogenesis of AHC.

An unexpected cause of a recurrent cerebral hemorrhage.

A 4-year-old previously healthy boy presented with a non-traumatic right parietal hemorrhage. A second life-threatening left cerebral hemorrhage occurred three weeks later and was decompressed with a craniotomy. Transthoracic echocardiography revealed a hypermobile elongated tumor of the mitral valve. The cardiac tumor was successfully resected three weeks after the craniotomy. Histological examination of the cardiac tumor revealed a papillary lesion of spindle cells with smooth muscle cell differentiation. In view of the histological findings and the clinical symptoms, a cellular myofibroblastic tumor was considered the most likely diagnosis in our patient. Although a cardiac tumor is a rare cause of a cerebral hemorrhage, a cardiac evaluation is recommended in pediatric patients with a cerebral hemorrhage of unknown etiology.

L-Arabinosuria: a new defect in human pentose metabolism.

A female patient, the first child of healthy non-consanguineous parents, presented at the age of 16 months with delayed motor development and facial dysmorphism. In addition she displayed a palatoschizis and multiple skeletal abnormalities as hypoplastic scapulae, hypoplastic os ilea, and an extreme cervical kyphosis. Biochemical investigation of urine revealed no abnormalities except for the presence of large amounts of reducing sugars. The sugar was identified as L-arabinose, which mainly originated from fruit formula in her diet. In addition highly elevated levels of L-arabitol were found in urine, plasma, and cerebrospinal fluid. Although little is known about human arabinose metabolism, we presume that L-arabitol dehydrogenase is deficient in our patient. As polyols are potentially toxic to the central nervous system there could be deleterious long-term effects of this disorder. Withdrawal of dietary fruit led to normalization of polyol levels. The above-mentioned clinical abnormalities are probably not related to this new inborn error of metabolism and should be considered as a separate entity.

A neuroimaging follow up study of a patient with juvenile central nervous system systemic lupus erythematosus.

BACKGROUND: The course of central nervous system systemic lupus erythematosus (CNS-SLE) is largely unknown. New imaging techniques are available to assist in monitoring the disease course. OBJECTIVE: To report a case of juvenile CNS-SLE, in which magnetic resonance imaging (MRI) was used to assess disease activity. CASE REPORT: A 10-year-old female patient with SLE presented with convulsions; MRI and computed tomography (CT) of the cerebrum disclosed abnormalities. Despite adequate treatment, two years later she had a generalised convulsion, and MRI showed new lesions. MR spectroscopy (MRS) indicated neuronal loss, inflammation, and metabolically compromised tissue; magnetisation transfer imaging (MTI) showed an increase in whole brain lesion load. After exclusion of a malignancy, CNS-SLE was the most likely diagnosis, and cyclophosphamide pulses were administered. Initially, multiple sclerosis (MS)-like lesions regressed, but despite maximal immunosuppressive drugs, new lesions formed and disappeared. When immunosuppressive drugs had been stopped for six months MRI showed improved lesions and MTI histograms. DISCUSSION: In this case report, the anatomical substrate, metabolic aspect, neuroimaging, and clinical course of MS-like lesions in a child with CNS-SLE are described. The way in which radiological techniques can support clinical decision making in this young patient with progressive CNS-SLE is illustrated.

Alternating hemiplegia of childhood: no mutations in the second familial hemiplegic migraine gene ATP1A2.

Alternating hemiplegia of childhood (AHC) is a rare disorder mainly characterised by attacks of hemiplegia and mental retardation. AHC has often been associated with migraine. Previously, we have excluded the involvement of the familial hemiplegic migraine (FHM) CACNA1A gene in four patients with AHC. A second gene for FHM was discovered recently: the ATP1A2 gene on chromosome 1q23, coding for the alpha 2 subunit of Na+,K+-ATPase. We performed a mutation analysis of the ATP1A2 gene in six patients, using direct sequencing, but found no mutations in any of the 23 exons. Other cerebral ion channel genes remain candidate genes for AHC.