A novel mutation in the connexin 46 gene (GJA3) causes autosomal dominant zonular pulverulent cataract in a Hispanic family.

PURPOSE: A five-generation Hispanic pedigree with autosomal dominant zonular pulverulent cataract was studied to identify the causative mutation in connexin 46 (Cx46), a gap junction protein responsible for maintaining lens homeostasis. METHODS: Twenty-six individuals from the family were comprehensively clinically examined. DNA was extracted from their peripheral blood samples. The DNA was used for automated genotyping with fluorescently labeled microsatellite markers and for mutation detection by automated sequencing. RESULTS: A novel D3Y missense mutation in GJA3 segregated with autosomal dominant (AD) zonular pulverulent cataract throughout the family. The mutation was absent in the unaffected individuals in the family and in 230 control chromosomes. CONCLUSIONS: A novel mutation causing AD zonular pulverulent cataract has been identified in a Hispanic Central American family. This is the first report of a mutation in GJA3 causing autosomal dominant congenital cataract (ADCC) in this ethnic group. It is also the first reported cataract-causing mutation in the NH2-terminal region of the Cx46 protein.

Facial hemangioma, and associated malformations: a case report.

Facial hemangioma can be isolated lesions or associated with a wide variety of systemic findings. We report a 9-month-old girl who shows an extensive facial hemangioma, intracranial and extracranial vascular malformations, a Dandy-Walker malformation and congenital cardiac malformations. This patient serves as an ample reason why children with similar cutaneous lesions should be carefully evaluated for other associated defects.

An unusual cystic appearance of disseminated low-grade gliomas.

We report five cases of pediatric disseminated low-grade gliomas of the brainstem or spinal cord that exhibited an unusual, cystic pattern. Leptomeningeal disease was present in three of these at diagnosis, and was detected shortly afterwards in the other two. Four patients are alive up to 5 years later, following minimal to no intervention, while one is dead.

Cranial magnetic resonance imaging examination of normal term neonates: a pilot study.

This pilot study's aim was to determine, using magnetic resonance imaging (MRI), if and to what extent asymptomatic intracranial hemorrhage occurs in normal term neonates after uncomplicated vaginal deliveries. Eight normal, term, vaginally delivered infants and three cesarean-section deliveries used as controls underwent cranial MRI. No sedation was administered. Small subdural hematomas of the falx cerebri or tentorium cerebelli were found in half of those with an uneventful vaginal delivery. Pediatric follow-up, on average 3.9 years after the MRI study was performed, demonstrated normal growth and development. It appears that more data is needed to confirm the observation that the intracranial hemorrhages described should not be considered the etiology for neurologic abnormalities present in symptomatic neonates.

The effect of tiagabine on spasticity in children with intractable epilepsy: a pilot study.

Preliminary pharmacologic evidence suggests that tiagabine, a new presynaptic gamma-aminobutyric acid-uptake inhibitor developed as an antiepileptic drug, may also relieve spasticity. This pilot study assessed the drug's efficacy in 14 children with congenital or acquired spastic quadriplegia and concomitant intractable epilepsy refractory to treatment with multiple antiepileptic drugs. The primary outcome variable was change in motor function; the secondary outcome was change in seizure frequency. Tiagabine was initiated at 0.1-0.2 mg/kg/day and then gradually titrated upward until seizures ceased, adverse effects supervened, or the maximum dose of 1.1 mg/kg/day was reached. When a modified Ashworth scale was used to assess motor function, a mean improvement of approximately 50% was observed. Common findings included improved tone, strength, coordination, range of motion, and relaxation of extremities, with less ataxia and wobbling. Mean reduction in seizure frequency was 50-74%. Randomized, double-blind controlled studies are needed to confirm the suggested efficacy of tiagabine in relieving chronic spasticity in children with neurodevelopmental disorders.

X-linked lissencephaly with absent corpus callosum and ambiguous genitalia.

Lissencephaly has been described in over 10 distinct malformation syndromes. Recently, we have recognized 5 children from four unrelated families with an almost identical disorder comprising lissencephaly with a posterior-to-anterior gradient and only moderate increase in thickness of the cortex, absent corpus callosum, neonatal-onset epilepsy, hypothalamic dysfunction including deficient temperature regulation, and ambiguous genitalia in genotypic males. Our observation of 5 affected males in one of these families is consistent with an X-linked pattern of inheritance. However, it differs in many regards from the X-linked form of isolated lissencephaly sequence that is associated with mutations of the XLIS (DCX) gene. Therefore, we propose that this disorder comprises a new X-linked malformation syndrome, which we refer to as X-linked lissencephaly with ambiguous genitalia (XLA-G).

The use of hypothermia: a role in the treatment of neonatal asphyxia?

Perinatal asphyxia remains one of the most devastating neurologic processes. Although the understanding of the pathophysiology after perinatal asphyxia is extensive, there are few therapeutic interventions available to prevent or even mitigate the devastating process that unfolds after injury. The search for a safe and efficacious therapy has prompted scientists and clinicians to consider various promising therapies. One such therapy is therapeutic hypothermia. On the basis of adult, pediatric, and animal research, there is increasing evidence to suggest that therapeutic hypothermia may be an effective intervention to lessen the secondary neuronal injury that ensues after a hypoxic-ischemic insult. In this article the historic and modern-day uses of therapeutic hypothermia are first reviewed. The pathophysiology of neonatal asphyxia is examined next, with emphasis on the changes that occur when therapeutic hypothermia is implemented. Potential side-effects of the therapy in the neonate and the debate over systemic vs selective hypothermia are discussed. Lastly, although hypothermia as a potential treatment modality for neonates with hypoxic-ischemic encephalopathy is supported by numerous studies, the need for well-designed multicenter trials with detailed patient entry criteria and therapeutic conditions is emphasized.

Interferon beta-1b and childhood multiple sclerosis.

The long-term treatment with interferon beta-1b of a 7-year-old male with relapsing-remitting multiple sclerosis is documented. Thirty-two months after initiating treatment, he demonstrates dramatic clinical improvement, without relapse, despite high titers of neutralizing antibodies to interferon beta-1b. It appears reasonable to attribute a role in his improvement to interferon beta-1b.

Topiramate for intractable childhood epilepsy.

To better define the efficacy and tolerability of the new anticonvulsant topiramate in pediatric patients, the clinical courses of 49 children with intractable seizures were monitored during topiramate therapy. The 80% of children who had complex partial seizures experienced better seizure control with topiramate than the 20% who had generalized seizures. Efficacy was greatest with doses between 2.5 and 7.5 mg/kg/day. More than half the children on topiramate experienced adverse effects which could interfere with learning at school, but 20% demonstrated increased alertness or improved behavior. Topiramate is effective and may be considered as part of the treatment pathway for complex partial seizures in children, although careful monitoring of cognitive function is required.

Use of the pediatric symptom checklist in the pediatric neurology population.

The purpose of this study was to evaluate the effectiveness of the Pediatric Symptom Checklist (PSC) as a mental health screening instrument in a busy pediatric neurology population in comparison with more lengthy, time-consuming assessment methods. One hundred two children were screened using the PSC. PSC results were compared with scores on the Child Behavior Checklist (CBCL), results from structured interviews, and ratings of adaptive functioning using the Children's Global Assessment Scale (CGAS). Thirty-nine of the patients (38%) scored 63 or above on the CBCL, indicating psychosocial impairment. Using a cutoff score of 22, the PSC correctly identified 35 of these 39 positive cases (sensitivity 89.7) and 48 of the 63 children with CBCL scores below 63 (specificity 76.2). CGAS scores were significantly negatively correlated with PSC scores (r = -0.60, P < 0.05). The PSC correctly identified 85.9% of children who scored 70 or below on the CGAS. Among the 53 children with psychiatric diagnoses on the basis of the interview, 41 scored above the cutoff of 22 on the PSC. Results suggest that the PSC is an efficient and accurate screen for identification of mental health problems in the pediatric neurology population.

Neurologic outcomes in children with post-pump choreoathetosis.

Eleven children who had post-pump choreoathetosis develop after cardiopulmonary bypass were evaluated in their perioperative course to determine factors that may correlate with their neurologic outcome. Results showed that preoperative cyanosis is associated with the development of a basal ganglia lesion. An acquired basal ganglia lesion and preoperative cyanosis are associated with persistence of post-pump choreoathetosis. The combination of cyanotic heart disease and a scan-identified basal ganglia lesion indicates a poor prognosis for the patient with persistent post-pump choreoathetosis. Also, the presence of total circulatory arrest is associated with a decrease in developmental quotient but not the persistence of post-pump choreoathetosis.

Cystlike white matter lesions in tuberous sclerosis.

PURPOSE: To investigate the presence of small cystlike structures in the cerebral hemispheric white matter on MR images of patients with tuberous sclerosis. METHODS: The MR images of 18 consecutive patients with tuberous sclerosis were reviewed retrospectively. RESULTS: Eight of the 18 patients were found to have cystlike structures in the cerebral white matter. The signal intensity of these lesions was isointense with cerebrospinal fluid on T1-, proton density-, and T2-weighted images. Four patients were imaged with a fluid-attenuated inversion recovery sequence, which in each case also showed fluid-type signal in these areas. Three of the patients had CT for correlation, and these scans supported the diagnosis of cystic lesions. Cysts ranged in number from one to 12 per patient and were usually smaller than 1 cm. The most common location was adjacent to the occipital horn or trigone of the lateral ventricle (six of eight patients). Less frequent sites were near the frontal horns, in the corpus callosum, and in the deep white matter near the body of the lateral ventricle. Cysts in five patients were either immediately adjacent to a cortical tuber or in the center of a white matter dysplastic lesion. A cyst in one patient had septa, and none of the cysts enhanced. CONCLUSIONS: Cystlike structures in the cerebral hemispheric white matter were seen on the MR images of 44% of 18 patients with tuberous sclerosis. Whether these findings represent cystic degeneration of dysplastic tissue or are unrelated to the disease process of tuberous sclerosis is unknown. More than one pathogenesis may exist.

Long-term outcomes of conventional therapy for infantile spasms.

Infantile spasms (IS) is an age-specific epilepsy which responds to anticonvulsant therapy but has a generally poor prognosis for normal psychomotor development. The subgroup of infants with a cryptogenic aetiology or whose therapy is initiated promptly is thought to have a more favourable prognosis. We retrospectively reviewed 28 infants with IS treated between 1990 and 1996 with adrenocorticotropic hormone (ACTH), valproic acid (VPA), or both, in order to correlate therapeutic response with long-term outcome. Mean age at onset of treatment was 6.4 months, with 57% of patients started within 1 month of IS appearance. IS was considered cryptogenic in 39%. The majority of infants responded to ACTH or VPA with a reduction in spasms of 75% or more. Total remission of seizures occurred in 52%. Death occurred in eight patients; mean duration of follow-up for survivors was 55 months. All subgroups based on age, aetiology, or treatment had poor outcomes, commonly with residual epilepsy, cerebral palsy or mental retardation. Conventional treatment for IS, even when initially successful in reducing spasms, is inadequate when viewed from a long-term developmental perspective, suggesting the need for novel innovative approaches for treating IS.

A deletion in the long arm of chromosome 18 in a child with serum carnosinase deficiency.

The dipeptides carnosine and anserine, found exclusively in meats, are hydrolyzed in serum by the enzyme carnosinase. Several reports of serum carnosinase deficiency describe a variable phenotype, which ranges from normal to severe psychomotor retardation, hypotonia, and myoclonic seizures in the first year of life. We report the case of a 30-mo-old girl with hypotonia, developmental delays, and tremor. Although consuming nominal quantities of meal, she excreted large amounts of carnosine and anserine. A strict meat-free diet ameliorated, but did not eliminate, these abnormalities. Serum carnosinase activity was found to be extremely low. Analysis of this child's chromosomes revealed a terminal deletion of chromosome 18 with breakpoint at q21.3. Neither parent exhibited this deletion, suggesting it was generated de novo in the patient or in a parental germ cell. Molecular studies showed that the patient's paternal chromosome 18 was deleted. Urinary carnosine excretion and serum carnosinase activity were normal in the patient's father. The mother had low carnosinase activity. The patient's brother exhibited moderate hypercarnosinuria and intermediate enzyme activity, consistent with the carrier state for carnosinase deficiency. Cumulatively, these findings suggest that the locus for this enzyme resides on the distal long arm of chromosome 18, and they are consistent with an unusual mechanism for the inheritance of this, typically autosomal recessive, condition. We conclude that this patient is likely hemizygous for the defect, having received the deficiency allele from her mother and, by virtue of the chromosomal deletion, no allele from her father. This represents the first report of a chromosomal abnormality in association with serum carnosinase deficiency and should aid in further localization of the gene encoding serum carnosinase.

Benign familial neonatal convulsions; psychosocial adjustment to the threat of recurrent seizures.

Forty families have experienced benign familial neonatal convulsions (BFNC) since it was first described by Rett and Teubel in 1964. [Rett, A. and Teubel, R. Neugeborenen Krampfe im Rahmen einer epileptisch belasten Familie. Wiener Klinische Wochenschrift 1964; 76: 609-613.] Diagnosis is based on a benign neonatal course, family history, and seizures which usually end spontaneously by six months of age. The absence of subsequent epilepsy makes BFNC a retrospective diagnosis. Consequently there is a considerable length of time during which parents may anxiously follow their child's development. We describe a child with BFNC whose family has experienced five generations of BFNC yet chose to react to the myths and misconceptions of epilepsy and circumvent updated experience supported by the recent medical literature. We have identified three areas in which appropriate physician intervention and patient education may reduce the magnitude of psychosocial disruptions: at the initial seizure, during childrearing and parenting, and in preparation of the patient for future independent decision making. By recognizing the magnitude of social, psychological, and economic disruptions affecting the child and family and by addressing communication issues during the initial diagnosis and follow-up period, we maximize our opportunity to break the cycle of mis-information and anxiety surrounding "benign' seizures.

Developmental neural abnormalities and seizures in epidermal nevus syndrome.

The epidermal nevus syndrome (ENS) is an unusual neurocutaneous disorder consisting of the combination of an epidermal nevus and a central nervous system (CNS), ophthalmological, and/or skeletal abnormality. The study reports four new patients with ENS. Each had a confirmatory biopsy of the epidermal nevus, abnormal neurological examination findings, and documented CNS anatomical studies by imaging or autopsy. The paper also reviews the literature in English to determine neurological abnormalities found in skin-biopsy-proven cases of ENS. Hemi-atrophy, hemimegalencephaly, migrational abnormalities and vascular anomalies were found to be the most frequent intracranial abnormalities associated with ENS. Seizures and/or disabling moderate to severe developmental delays were present in a majority of patients. Seizure onset during the neonatal period or early infancy was associated with major hemispheric malformations. Neuroectodermal-derived ocular lesions were often bilateral. No consistent relation between laterality of the nevus and laterality of CNS abnormalities was found, supporting the gene mosaicism theory of pathogenesis.

Neurologic complications following bone marrow transplantation for sickle cell disease.

A boy with sickle cell anemia underwent bone marrow transplantation (BMT). He was normal on neurological examination, but had radiologic evidence of an old left frontal lobe infarct, multiple cerebral vascular stenoses and moyamoya collaterals. After BMT he developed seizures with extension of the infarct and subarachnoid hemorrhage. One year later angiography revealed worsening stenosis of the M1 segments of both middle cerebral arteries. At that time an increase in von Willebrand's factor with decreased large molecular weight multimers (LvWF) was observed. We speculate that LvWF dependent, shear-induced platelet aggregation, together with endothelial damage may have contributed to the development of neurologic complications in this patient.

X-linked myotubular myopathy: clinical observations in ten additional cases.

X-linked myotubular myopathy (XLMTM) is a recessively inherited disorder, lethal to males in the first months of life. Since the first report in 1969, at least 90 cases have been described in the literature. Diagnosis is confirmed by muscle biopsy. Linkage studies have localized the disorder to the Xq28 region, close to the loci for X-linked hydrocephalus and MASA syndrome. We report on 10 additional cases of XLMTM from six different families. In addition to classic clinical features of XLMTM, our patients showed interesting associated findings which included birth length > 90th centile and large head circumference with or without hydrocephalus in 70%, narrow, elongated face in 80%, and slender, long digits in 60% of cases. There was concordance in the occurrence and severity of hydrocephalus in most sib pairs. These features in a "floppy" male infant serve as clues for early clinical diagnosis of XLMTM, which can then be confirmed by muscle biopsy. Development of polyhydramnios was observed in the third trimester of an at-risk dizygotic twin gestation monitored by serial sonography with confirmation of XLMTM at birth.

Progressive venous occlusion in a neonate with Sturge-Weber syndrome: demonstration with MR venography.

Progressive cerebral sinovenous occlusion in a neonate with Sturge-Weber syndrome was documented by using two-dimensional time-of-flight MR venography. There was no evidence of intraluminal thrombus on routine spin-echo images obtained either before or after the onset of seizures, despite MR venographic evidence in both studies of venous abnormalities.