A family with seizures and minor features of tuberous sclerosis and a novel TSC2 mutation.

The authors studied nine members of a family that demonstrated a limited form of tuberous sclerosis complex (TSC). Cutaneous findings were limited to hypopigmented macules in four patients. Five family members had recurrent seizures, and three of these had migrational defects of the cerebral mantle. Mutational analysis of TSC2 indicated the presence of the novel missense change 3106T-->C, 1036S-->P in all family members with seizures. The findings suggest that this mild variant form of TSC is due to a novel TSC2 mutation.

Periventricular nodular heterotopia in patients with filamin-1 gene mutations: neuroimaging findings.

BACKGROUND: The filamin-1 (FLN-1) gene is responsible for periventricular nodular heterotopia (PNH), which is an X-linked dominant neuronal migration disorder. OBJECTIVE: To review the clinical and imaging findings in a series of patients with documented filamin-1 mutations. MATERIALS AND METHODS: A retrospective review of the medical records and MR studies of a series of patients with PNH and confirmed FLN-1 mutations was done. There were 16 female patients (age range: .67-71 years; mean = 28.6) with filamin-1 gene mutations. RESULTS: In six of the patients the same mutation was inherited in four generations in one pedigree. In a second pedigree, a distinct mutation was found in two patients in two generations. In a third pedigree, a third mutation was found in four patients in two generations. The remaining four patients had sporadic de novo mutations that were not present in the parents. Ten patients had seizures, and all patients had normal intelligence. In all 16 patients MR demonstrated bilateral near-continuous PNH. There were no consistent radiographic or clinical differences between patients carrying different mutations. CONCLUSION: Patients with confirmed FLN-1 gene mutations are usually female and have a distinctive MR pattern of PNH. Other female patients with this same MR pattern probably harbor FLN-1 mutations and risk transmission to their progeny. This information is important for genetic counseling.

The neuropathology of phenylketonuria: human and animal studies.

UNLABELLED: Pathologic changes in the brain of untreated phenylketonuria (PKU) patients occur in structures that develop post-natally, i.e. in myelination of subcortical white matter and spinal cord and in the growth of axons, dendrites and synapses in cerebral cortex. In addition, a small minority of brains show evidence of progressive white matter degeneration (leucodystrophy). The pathologic changes are thought to be due to toxic effects of phenylalanine and/or its metabolites. It is assumed that they can be prevented by dietary therapy during infancy and childhood, but direct confirmation by neuropathologic studies is lacking. The recently discovered genetic mouse mutant Pah(enu2) provides an excellent animal model in which effects of PKU on brain development, including dendritic and synaptic development in cerebral cortex, can be assessed. In human PKU, there needs to be neuropathologic study of the brains from PKU patients, particularly adults, with a history of dietary therapy. Special attention needs to be paid to the study of white matter in such cases, in view of recent reports of white matter lesions on MRI despite dietary treatment. CONCLUSION: Careful correlation is needed between neuropathology, magnetic resonance imaging white matter changes, dietary history and clinical findings. Finally, neuropathologic investigation is needed to determine whether progressive degeneration of the white matter (leucodystrophy) poses a risk to adults in whom dietary therapy has been discontinued.

Reorganization of the hand somatosensory cortex following perinatal unilateral brain injury.

Functional magnetic resonance imaging was used to map the hand somatosensory cortices of nine hemiparetic young adult patients with perinatal unilateral brain injury in the sensorimotor area and five normal subjects. Stimulation of the paretic hand by periodic manual squeezing produced activation in the contralateral hemisphere of three patients and in the ipsilateral hemisphere of three other patients. Paretic hand stimulation produced no activation in either hemisphere of the remaining three patients. Therefore, one-third of the patients demonstrated functional "plasticity" of the brain in the form of inter-hemispheric relocation of the hand somatosensory function. The volume and pattern of activation for both hands was altered for those patients that showed evidence of cortical reorganization to the opposite hemisphere. This differs from the hand motor system, which exhibited inter-hemispheric reorganization in a higher proportion of a related group of hemiparetic subjects.

Genetic and neuroradiological heterogeneity of double cortex syndrome.

Mutations in the X-linked doublecortin gene appear in many sporadic cases of double cortex (DC; also known as subcortical band heterotopia), a neuronal migration disorder causing epilepsy and mental retardation. The purpose of this study was to examine why a significant percentage of sporadic DC patients had been found not to harbor doublecortin mutations and to determine whether clinical features or magnetic resonance imaging scan appearance could distinguish between patients with and without doublecortin mutations. Magnetic resonance imaging scan analysis differentiated patients into the following four groups: anterior biased/global DC with doublecortin mutation (16 of 30; 53%), anterior biased/global DC without mutation (8 of 30; 27%), posterior biased DC without mutation (3 of 30; 10%), and limited/unilateral DC without mutation (3 of 30; 10%). The presence of these atypical phenotypes suggests that other genetic loci or mosaicism at the doublecortin locus may be responsible for this diversity of DC cases.

Two 22q telomere deletions serendipitously detected by FISH.

Cryptic telomere deletions have been proposed to be a significant cause of idiopathic mental retardation. We present two unrelated subjects, with normal G banding analysis, in whom 22q telomere deletions were serendipitously detected at two different institutions using fluorescence in situ hybridisation (FISH). Both probands presented with several of the previously described features associated with 22q deletions, including hypotonia, developmental delay, and absence of speech. Our two cases increase the total number of reported 22q telomere deletions to 19, the majority of which were identified by cytogenetic banding analysis. With the limited sensitivity of routine cytogenetic studies (approximately 2-5 Mb), these two new cases suggest that the actual prevalence of 22q telomere deletions may be higher than currently documented. Of additional interest is the phenotypic overlap with Angelman syndrome (AS) as it raises the possibility of a 22q deletion in patients in whom AS has been ruled out. The use of telomeric probes as diagnostic reagents would be useful in determining an accurate prevalence of chromosome 22q deletions and could result in a significantly higher detection rate of subtelomeric rearrangements.

Mutations in filamin 1 prevent migration of cerebral cortical neurons in human periventricular heterotopia.

Long-range, directed migration is particularly dramatic in the cerebral cortex, where postmitotic neurons generated deep in the brain migrate to form layers with distinct form and function. In the X-linked dominant human disorder periventricular heterotopia (PH), many neurons fail to migrate and persist as nodules lining the ventricular surface. Females with PH present with epilepsy and other signs, including patent ductus arteriosus and coagulopathy, while hemizygous males die embryonically. We have identified the PH gene as filamin 1 (FLN1), which encodes an actin-cross-linking phosphoprotein that transduces ligand-receptor binding into actin reorganization, and which is required for locomotion of many cell types. FLN1 shows previously unrecognized, high-level expression in the developing cortex, is required for neuronal migration to the cortex, and is essential for embryogenesis.

Regional differences in synaptogenesis in human cerebral cortex.

The formation of synaptic contacts in human cerebral cortex was compared in two cortical regions: auditory cortex (Heschl's gyrus) and prefrontal cortex (middle frontal gyrus). Synapse formation in both cortical regions begins in the fetus, before conceptual age 27 weeks. Synaptic density increases more rapidly in auditory cortex, where the maximum is reached near postnatal age 3 months. Maximum synaptic density in middle frontal gyrus is not reached until after age 15 months. Synaptogenesis occurs concurrently with dendritic and axonal growth and with myelination of the subcortical white matter. A phase of net synapse elimination occurs late in childhood, earlier in auditory cortex, where it has ended by age 12 years, than in prefrontal cortex, where it extends to midadolescence. Synaptogenesis and synapse elimination in humans appear to be heterochronous in different cortical regions and, in that respect, appears to differ from the rhesus monkey, where they are concurrent. In other respects, including overproduction of synaptic contacts in infancy, persistence of high levels of synaptic density to late childhood or adolescence, the absolute values of maximum and adult synaptic density, and layer specific differences, findings in the human resemble those in rhesus monkeys.

Allogeneic bone marrow transplantation for Alexander's disease.

In this case report, we evaluate the efficacy of allogeneic bone marrow transplantation (BMT) in a 7-month-old female with the infantile form of Alexander's disease. Based on research that describes Alexander's disease as a leukodystrophy which may result from an unidentified enzyme deficiency, we attempted marrow transplantation to reverse or arrest the patient's neurological deterioration. Despite an initial return to her pretransplant neurological state, the patient's neurological status deteriorated. Marrow transplantation was not effective in changing her prognosis with Alexander's disease.

Use of barbiturates in the treatment of cyclic vomiting during childhood.

BACKGROUND: Cyclic vomiting is an uncommon disorder that can be described as recurrent, self-limiting, fairly uniform episodes of intractable nausea and vomiting with no identifiable organic cause, separated by symptom-free intervals. There is no established therapeutic regimen for this disorder. METHODS: Fourteen children referred to the Pediatric Gastroenterology Clinic were diagnosed with cyclic vomiting from May 1984 to January 1995. Vomiting, the predominant symptom, was present in all children and was severe enough to require hospitalization in 11. Associated symptoms included abdominal ain, headache, nausea, aura, and fever. Diagnostic studies were done to rule out organic causes as indicated in individual patients. Daily phenobarbital was prescribed in all 14 patients. The dose ranged from 30 to 120 mg/hs, (mean 2 mg.kg-1.day-1), with a median dose of 60 mg/hs [corrected]. Prior therapy with propranolol (3 patients) and butalbital (2 patients) had been ineffective. RESULTS: Eleven patients had complete resolution of their symptoms, and 3 patients had marked improvement in their symptoms with infrequent attacks of reduced severity. The only side effects associated with long-term phenobarbital therapy were behavioral in nature, namely hyperactivity and disruptive behavior at school. CONCLUSIONS: The results of our series of 14 patients, all of whom received barbiturates, support the usefulness of this therapeutic approach. Hence we feel that daily low-dose phenobarbital therapy is a safe and effective therapy in preventing episodes of cyclic vomiting in children.

Periventricular heterotopia: an X-linked dominant epilepsy locus causing aberrant cerebral cortical development.

Periventricular heterotopia (PH) involves dramatic malformations of the human cerebral cortex. Here we show that PH is closely linked to markers in distal Xq28 (maximal two-point lod score = 4.77 for F8C at theta = 0; maximal multipoint lod score = 5.37), so that affected females are obligatory mosaics for the mutation; that PH is lethal to at least some affected males; that PH malformations consist of well-differentiated cortical neurons filling the adult subependymal zone; and that individuals with PH are at high risk for epilepsy, though they have no other neurological or external stigmata. The PH gene may represent an important epilepsy susceptibility locus in addition to playing a key role in normal cortical development.

Functional magnetic resonance studies of the reorganization of the human hand sensorimotor area after unilateral brain injury in the perinatal period.

Functional magnetic resonance imaging was used to map the hand sensorimotor area of hemiparetic adolescents and young adults who had suffered unilateral brain damage in the perinatal period. Unlike normal subjects, who exhibit cortical activation primarily contralateral to voluntary finger movements, the hemiparetic patients' intact hemispheres were equally activated by contralateral and ipsilateral finger movements. Our findings are consistent with previous clinical observations and animal experiments which suggest that the immature brain is able to reorganize in response to focal injury.

Periventricular heterotopia and epilepsy.

We report a family with nodular subependymal masses of heterotopic gray matter occurring in six members in four generations. Only female members of the family are affected, and there is a high rate of spontaneous abortion, consistent with X-linked dominant inheritance, and lack of viability in affected males. Both in this family and in sporadic cases of subependymal heterotopias there is a high frequency of convulsive disorders, suggesting that epilepsy may be the major clinical manifestation of this developmental defect.

Cyclic AMP metabolism in fragile X syndrome.

Cyclic AMP (cAMP) metabolism was studied in platelets from a series of 14 patients with fragile X syndrome (fra X) and 21 control individuals. 1-Isobutyl-3-methylxanthine was used to inhibit phosphodiesterase and thus measure cAMP production, prostaglandin E1 was used to assess receptor-mediated cAMP accumulation, and forskolin was used to directly stimulate the catalytic subunit. In patients with fra X, basal production was 63% of that of control subjects (p = 0.019). Prostaglandin E1- and forskolin-stimulated production were 61% (p = 0.039) and 56% (p = 0.012) of that of control subjects, respectively. cAMP production in 8 patients with fra X overlapped the control range, whereas measures of production in 6 patients formed a cluster with values lower than any of the 21 control subjects assayed, suggesting possible biochemical heterogeneity within patients with fra X. Results obtained from the group of patients with fra X suggest possible abnormal function or regulation of the catalytic subunit of adenylate cyclase in at least a subgroup of patients with fra X. Variability of biochemical findings in patients with fra X may reflect the known high variability of the clinical syndrome.

Effects of changes in the periphery on development of the corticospinal motor system in the rat.

Effects of changes in the periphery on development of the corticospinal (CS) motor system were studied in the rat. Unilateral forelimb restraint between ages 5 and 30 days resulted in an increase in the number of CS neurons which persisted in the adult. The effect was most marked ipsilateral to limb restraint where both crossed and uncrossed CS connections were increased, but it also occurred to a lesser extent on the contralateral side. Animals with limb restraint had enlargement of the areas of cerebral cortex in which CS neurons occurred. The enlargement of motor cortex regions and increase in CS neurons closely resembled the changes found in the remaining cerebral hemisphere after neonatal hemispherectomy. The findings in animals with forelimb restraint differed markedly from those after forelimb amputation, where little change occurred in either number or location of CS neurons. Limb restraint initiated at the time of postnatal hemispherectomy had no effects on location or number of CS neurons beyond those of hemispherectomy alone. It is proposed that transient CS axons that occur normally in the postnatal rat may be recruited for formation of permanent connections under very diverse conditions, i.e. hemispherectomy and limb restraint. Failure to observe an additional effect of limb restraint in hemispherectomized animals may be due to the fact that after hemispherectomy all available transient fibers in the remaining hemisphere are recruited for innervation of the side of the spinal cord that has lost its cortical input.

Dendritic and synaptic pathology in mental retardation.

Histologic changes in brains from mentally retarded patients are often subtle and may be limited to abnormalities in the dendritic and synaptic organization of the cerebral cortex. Special methods may be necessary for their demonstration. This review summarizes data on dendritic and synaptic pathology in human mental retardation syndromes. Findings in humans are compared to those in animal models that are of relevance to human disorders. Both in humans and in animal models there is evidence that development modifies the observed changes and that findings differ depending on the developmental age at which the tissue is studied.

Cellular neuropathology of tuberous sclerosis.

The study of cerebral lesions of TSC by special histologic methods suggests that two populations of neurons and glia occur in TSC brains. One is a population of normally differentiated cells that form a normally constituted cortical plate. The other is a group of cells that are poorly differentiated, fail to organize into a normal cortical architecture, and form a variety of abnormal cellular aggregates in cortex and in subcortical locations. The proportion of these abnormal cells varies greatly from patient to patient. In some the central nervous system appears to be entirely spared. In others, only one or a few islands of dysplastic cells occur, whereas in still others a large number, perhaps even a majority, of neuroectodermal cells in the forebrain may be affected. The proportion of total cells that undergo abnormal differentiation apparently is an important factor relative to cortical function in TSC. At present we have no explanation for this marked heterogeneity in expression of the TSC gene or genes, and it remains one of the many unsolved mysteries of this illness.

A follow-up study of intractable seizures in childhood.

One hundred forty-five children with seizures that were refractory to medical therapy for at least 2 years were followed 5 to 20 years after onset. The majority of children with uncontrollable seizures (61%) were mentally retarded, and most of these (73%) had onset of seizures at younger than 2 years of age. Age of onset was significantly later (mean 5.0 +/- 0.5 yr [SEM]) in the group of children with borderline to normal intelligence. Follow-up data showed remission of seizures in a significant proportion of children with borderline or normal intelligence, with a linear decrease of the percentage with persistent seizures at a rate of about 4% per year. Remission of seizures was much less frequent (1.5%/yr) in the group with mental retardation. Seizure type had some effects on outcome. Children with focal atrophic brain lesions did no worse than those without definable pathology on brain-imaging studies.

Discrimination of normal and at-risk preschool children on the basis of neurological tests.

A set of neurological tasks was administered to normal three- and five-year-old preschool children as well as to equal-age children identified as being at-risk for learning disabilities. 12 neurological test items were identified that differentiated normal from at-risk children at one or both ages. Follow-up of the five-year-olds at age seven showed a significant linear relation between scores on neurological tasks and the Wechsler Intelligence Test for Children. The neurological examination at age five also had predictive value regarding class placement at age seven. The findings suggest that a simple neurological test may be helpful for the early identification of preschool children who are at risk for learning difficulties.

Morphometric study of human cerebral cortex development.

Morphometric studies of immature cerebral cortex in humans show developmental changes extending up to the time of adolescence. Growth of dendrites and of synaptic connections occurs during infancy and early childhood. Excess synaptic connections are eliminated during later childhood years. The exuberant connections that occur during infancy may form the anatomical substrate for neural plasticity and for certain types of early learning.