Linkage of an important gene locus for tuberous sclerosis to a chromosome 16 marker for polycystic kidney disease.

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder of unknown aetiology that affects numerous body systems including skin, brain and kidneys. Some TSC has been linked to chromosome 9, additional TSC genes on chromosomes 11 and 12 have been proposed, but the majority of TSC families remain unlinked. Using TSC families in which data had excluded linkage to chromosome 9, we failed to detect linkage with loci on chromosomes 11, 12 and others. One marker examined was D16S283, the closest locus on the proximal side of the polycystic kidney disease type 1 (PKD1) gene. Linkage between TSC and D16S283 demonstrated a lod score of 9.50 at theta = 0.02 with one family independently presenting a lod score of 4.44 at theta = 0.05. These data reveal an important TSC locus near the region of PKD1 on chromosome 16p13.

Cerebral venous sinus thrombosis in children: a multicenter cohort from the United States.

This study presents a large multicenter cohort of children with cerebral venous thrombosis from 5 centers in the United States and analyzes their clinical findings and risk factors. Seventy patients were included in the study (25 neonates, 35%). The age ranged from 6 days to 12 years. Thirty-eight (55%) were younger than 6 months of age, and 28 (40%) were male. Presenting features included seizures (59%), coma (30%), headache (18%), and motor weakness (21%). Common neurological findings included decreased level of consciousness (50%), papilledema (18%), cranial nerve palsy (33%), hemiparesis (29%), and hypotonia (22%). Predisposing factors were identified in 63 (90%) patients. These included infection (40%), perinatal complications (25%), hypercoagulable/hematological diseases (13%), and various other conditions (10%). Hemorrhagic infarcts occurred in 40% of the patients and hydrocephalus in 10%. Transverse sinus thrombosis was more common (73%) than sagittal sinus thrombosis (35%). Three children underwent thrombolysis, 15 patients received anticoagulation, and 49 (70%) were treated with antibiotics and hydration. Nine (13%) patients (6 of them neonates) died. Twenty-nine patients (41%) were normal, whereas 32 patients (46%) had a neurological deficit at discharge. Seizures and coma at presentation were poor prognostic indicators. In conclusion, cerebral venous thrombosis predominantly affects children younger than age 6 months. Mortality is high (25%) in neonatal cerebral venous thrombosis. Only 18 (25%) patients were treated with anticoagulation or thrombolysis.

Prolonged hemiplegic episodes in children due to mutations in ATP1A2.

BACKGROUND: Familial hemiplegic migraine (FHM) is an unusual migraine syndrome characterised by recurrent transient attacks of unilateral weakness or paralysis as part of the migraine aura. Genetically and clinically heterogeneous, FHM1 is caused by mutations in CACNA1A and FHM2 by mutations in ATP1A2. AIM: Three children with prolonged hemiplegia were tested for mutations in CACNA1A or ATP1A2. METHODS: Mutations in CACNA1A and ATP1A2 were screened for by denaturing high performance liquid chromatography and confirmed by sequencing. Expression studies were performed to characterise the functional consequences of these mutations. RESULTS: No mutation was found in the FHM1 gene while three mutations were identified in the FHM2 gene. All three mutations were missense: two were novel and one was de novo; none was found in controls. Functional studies in HeLa cells showed complete loss of mutant pump function without interfering with the wild-type pump, consistent with haploinsufficiency. CONCLUSION: We identified novel disease causing mutations in the FHM2 gene. Genetic screening for FHM should be considered in a child with prolonged hemiplegia even if there is no prior history or family history of migraine or hemiplegic episodes.

Unexpected acute neurologic toxicity in the treatment of children with acute lymphoblastic leukemia.

BACKGROUND: Our current protocol for treatment of childhood acute lymphoblastic leukemia (ALL) was designed to assess the efficacy of methotrexate (MTX) plus L-asparaginase and of etopisode (VP-16) plus cytarabine (ARA-C) during intensive consolidation and continuation therapies and to determine the feasibility of intensifying MTX therapy by the use of divided oral doses of MTX. The protocol was associated with unexpected acute neurotoxicity. There are few reports of such toxic effects during therapy for ALL. PURPOSE: This report describes these toxic effects and outlines our successful approach to the problem. METHODS: The standard four-drug induction regimen consisted of vincristine, L-asparaginase, daunorubicin, and prednisone. In consolidation therapy, oral MTX was given in divided doses (dMTX) of 25 mg/m2 every 6 hours four times daily in four weekly courses concomitant with weekly triple intrathecal therapy--MTX, ARA-C, and hydrocortisone--plus one dose of leucovorin 24 hours after triple intrathecal therapy. Consolidation treatment ended with three daily doses of intravenous VP-16 and ARA-C. The first 16 months of continuation therapy included 6-week cycles of dMTX and L-asparaginase, both given every other week for 5 weeks, with 6-mercaptopurine nightly, and then two doses of VP-16 plus ARA-C and one dose of triple intrathecal therapy. RESULTS: Twenty-five of the 138 patients evaluated had acute neurotoxicity. Ten of the first 72 experienced a seizure or episode of transient neurological deficit 9-11 days following the administration of intravenous ARA-C, VP-16, and triple intrathecal therapy. Despite discontinuation of intrathecal ARA-C, which eliminated simultaneous intravenous and intrathecal treatment with ARA-C, acute neurotoxicity was observed in six previously unaffected patients and six of 42 patients treated after the elimination of intrathecal ARA-C. Therefore, as a second amendment, oral leucovorin was given 24 and 36 hours after dMTX and intrathecal MTX in continuation therapy. No acute neurotoxicity has been seen in 24 patients subsequently entered in the study. CONCLUSION: These findings suggest that folate replacement due to administration of leucovorin modulated MTX toxicity and/or modified an interaction among VP-16, ARA-C, intrathecal therapy, and the central nervous system.

Reye's syndrome in adults. A case report and review of the literature.

Adult Reye's syndrome (ARS) is an infrequently diagnosed condition that typically affects patients younger than age 35 years. We describe a 61-year-old man with ARS occurring after influenza B-USSR infection and aspirin use. The diagnosis of ARS was confirmed by oil-red-O stain of liver biopsy tissue and subsequent electron microscopy. We review the literature on ARS and compare the clinical features and management of ARS with pediatric Rye's syndrome. This case is of interest to practitioners treating adult patients because it demonstrates that the patient population at risk for Reye's syndrome is broader than generally believed.

Prolonged course of meningitis due to an arachnoid cyst.

An infected arachnoid cyst was found in a child with bacterial meningitis and prolonged fever. Surgical drainage of the cyst resulted in rapid improvement.

Basal ganglia and thalamic infarction in children. Cause and clinical features.

BACKGROUND: We present the signs, symptoms, and radiographic features of 36 children with ischemic infarctions of the basal ganglia, internal capsule, or thalamus. PATIENTS AND METHODS: The series includes 14 males and 22 females ranging in age from newborn to 13 years. Twenty-seven patients were evaluated with computed tomography, 34 with magnetic resonance imaging, 16 with magnetic resonance angiography, and 10 with conventional cerebral angiography. Thirty patients had unilateral lesions (16 left, 14 right) and 6 had bilateral infarctions. RESULTS: The most common presenting symptom was hemiplegia (30 of 36). Other children presented with aphasia (5 of 36), seizures (5 of 36), altered consciousness (5 of 36), and hemisensory changes (5 of 36). Four of 6 patients with bilateral lesions presented with altered mental status, but the location of a unilateral infarction within the thalamus or basal ganglia did not predict the clinical presentation. CONCLUSIONS: The risk factors for basal ganglia infarction in children are diverse, but systemic hypertension does not play a major role in children. The vascular occlusion often occurred in the large arteries, with secondary occlusion of the smaller penetrating arteries. Most children with a single unilateral infarction have a good prognosis.

Magnetic resonance imaging in tuberous sclerosis.

Twenty-five patients with tuberous sclerosis were studied with magnetic resonance imaging (MRI), and these findings were compared with those of computed cranial tomography (CCT) and with the clinical severity of the disease. Multiple high-signal MRI lesions involving the cerebral cortex are characteristic of tuberous sclerosis and probably correspond to the hamartomas and gliotic areas seen pathologically. These cortical lesions were only occasionally seen with CCT. The periventricular calcific lesions characteristic of tuberous sclerosis are better visualized with CCT than with MRI, but the larger periventricular calcifications produce low-signal MRI abnormalities. Seven patients had high-signal MRI lesions of the cerebellum; small calcific cerebellar lesions were also noted with CCT in three patients. As in earlier studies, no clear correlation was seen between the number of abnormalities visible with CCT and the clinical severity of the disease. By contrast, the more severely affected patients tend to have a higher number of cerebral cortical lesions detected with MRI. Thus, MRI may be useful in predicting the eventual clinical severity of younger children with newly diagnosed tuberous sclerosis.

See-saw nystagmus associated with Chiari malformation.

See-saw nystagmus has been seen with tumors of the parasellar region and diencephalon, brain-stem vascular lesions, syringobulbia, and after trauma. We report see-saw nystagmus in an adult with a Chiari malformation that was diagnosed by magnetic resonance imaging and confirmed intraoperatively. This patient's condition improved after surgical decompression. An association between see-saw nystagmus and Chiari malformation is potentially important because early diagnosis and decompression may improve neurologic function and prevent further deterioration.

A locus for paroxysmal kinesigenic dyskinesia maps to human chromosome 16.

OBJECTIVE: To use genetic linkage analysis to localize a gene for paroxysmal kinesigenic dyskinesia (PKD) in a three generation African-American kindred. BACKGROUND: PKD is a rare autosomal dominant disorder characterized by episodic choreiform or dystonic movements that are brought on or exacerbated by voluntary movement. There are individuals with the clinical features of PKD but with no family history of the disease, but whether these sporadic cases represent spontaneous mutations of PKD or have a distinct condition is unknown. METHODS: A genome-wide linkage scan of polymorphic microsatellites at 25 cM resolution was performed to localize a gene for PKD in one African-American kindred. Pairwise multipoint linkage analyses were performed at different penetrance estimates. RESULTS: Evidence for linkage of the kinesigenic form of paroxysmal dyskinesia to chromosome 16 was obtained. A maximum lod score of 4.40 at theta = 0 was obtained with D16S419. Critical recombinants place the PKD gene between D16S3100 and D16S771. CONCLUSIONS: A paroxysmal kinesigenic dyskinesia (PKD) locus lies within an 18 cM interval on 16p11.2-q11.2, between D16S3100 and D16S771. A gene for infantile convulsions with paroxysmal choreoathetosis has also been mapped to this region. These two regions overlap by approximately 6 cM. These two diseases could be caused by different mutations in the same gene or two distinct genes may lie within this region.

Hemisomatic spasms in children.

We report two children with hemisomatic spasms caused by neoplastic lesions in the region of the ipsilateral cerebellopontine angle. In this condition, seizure misdiagnoses are frequent and EEGs are normal, even ictally. MRI should be performed early to prevent delay of appropriate treatment.

Detection of tuberous sclerosis in parents by magnetic resonance imaging.

We performed a detailed physical examination and MRI without gadolinium DTPA contrast in 60 couples with at least 1 child having tuberous sclerosis (TS). Eight parents had TS diagnosed by physical examination, family history, or various diagnostic procedures including MRI. Eight additional subjects and 6 control subjects had nonspecific high-signal white matter changes on MRI. MRI confirmed the diagnosis of TS in only 1 parent without physical findings of the disease, similar to the results of earlier studies using computed cranial tomography. CT may be less sensitive than MRI but is probably more specific for TS. Either CT or MRI may occasionally help substantiate the diagnosis of TS in a parent with few other findings. Both studies may need to be done in some parents to maximize the accuracy of genetic counseling.

Gabapentin for familial paroxysmal dystonic choreoathetosis.

We present a 4-year-old girl with stereotyped episodes of inability to speak and dystonic posturing of the face and extremities lasting 20 minutes. An older brother and mother had similar spells in childhood. Routine and video-EEG during events were normal. The diagnosis was non-kinesigenic paroxysmal dystonic choreoathetosis since the episodes were not exacerbated by movement. Gabapentin 10 mg/kg/d eliminated most attacks.

Paroxysmal kinesigenic dyskinesia and infantile convulsions: clinical and linkage studies.

OBJECTIVE: To clinically characterize affected individuals in families with paroxysmal kinesigenic dyskinesia (PKD), examine the association with infantile convulsions, and confirm linkage to a pericentromeric chromosome 16 locus. BACKGROUND: PKD is characterized by frequent, recurrent attacks of involuntary movement or posturing in response to sudden movement, stress, or excitement. Recently, an autosomal dominant PKD locus on chromosome 16 was identified. METHODS: The authors studied 11 previously unreported families of diverse ethnic background with PKD with or without infantile convulsions and performed linkage analysis with markers spanning the chromosome 16 locus. Detailed clinical questionnaires and interviews were conducted with affected and unaffected family members. RESULTS: Clinical characterization and sampling of 95 individuals in 11 families revealed 44 individuals with paroxysmal dyskinesia, infantile convulsions, or both. Infantile convulsions were surprisingly common, occurring in 9 of 11 families. In only two individuals did generalized seizures occur in later childhood or adulthood. The authors defined a 26-cM region using linkage data in 11 families (maximum lod score 6.63 at theta = 0). Affected individuals in one family showed no evidence for a shared haplotype in this region, implying locus heterogeneity. CONCLUSIONS: Identification and characterization of the PKD/infantile convulsions gene will provide new insight into the pathophysiology of this disorder, which spans the phenotypic spectrum between epilepsy and movement disorder.

Nonketotic hyperglycinemia in a patient with the 9p- syndrome.

We describe a newborn infant with 9p- syndrome and nonketotic hyperglycinemia. This unusual occurrence may not have been coincidental and suggests that there may be a gene for nonketotic hyperglycinemia located on the short arm of chromosome 9.

Wilson's disease: evoked potentials and computed tomography.

Multi-modality evoked potentials and computed cranial tomography (CT) were performed in ten patients with Wilson's disease to determine if any of these studies would correlate reliably with neurologic status. While all four patients with CT abnormality had neurologic signs, two additional patients with neurologic findings had normal scans. Evoked responses were normal in nine patients. The remaining patient displayed abnormal visual, brainstem, and somatosensory evoked potentials, and follow-up studies after clinical deterioration revealed worsening of the brainstem and visual evoked potentials. This patient died unexpectedly from a subdural hematoma, and postmortem examination confirmed the radiographic findings of cortical atrophy of the cerebrum and cerebellum and bilateral cystic degeneration of the basal ganglia. However, localized demyelination in the visual, auditory, and sensory pathways was not present. We conclude that the clinical neurologic status of patients with Wilson's disease cannot be reliably predicted by either CT or multi-modality evoked potentials.

Etiology of stroke in children.

Cerebrovascular disorders are more common than once suspected, and our ability to diagnose stroke in children has improved with the development of newer imaging techniques in recent years. Children have a wide array of risk factors that promote cerebral infarction or hemorrhage, and a likely cause can eventually be pinpointed in about two thirds of patients if a thorough diagnostic evaluation is performed. Ideally, a systematic evaluation should confirm the presence of a cerebrovascular lesion and also identify the cause, concentrating initially on the more common or treatable risk factors. Recognition of the cause of a child's stroke is important, because the likelihood of recurrence depends largely on the etiology and whether treatment is available.

Tuberous sclerosis complex consensus conference: revised clinical diagnostic criteria.

At the recent tuberous sclerosis complex consensus conference, the clinical diagnostic criteria for tuberous sclerosis complex were simplified and revised to reflect both new clinical information about tuberous sclerosis complex and an improved understanding of the disorder derived from molecular genetic studies. Based on this new information, some clinical signs once regarded as pathognomonic for tuberous sclerosis complex are now known to be less specific. No single sign is present in all affected patients, and there is no proof that any single clinical or radiographic sign is absolutely specific for tuberous sclerosis complex. Accordingly, the clinical and radiographic features of tuberous sclerosis complex have now been divided into major and minor categories based on the apparent degree of specificity for tuberous sclerosis complex of each feature. A definitive diagnosis of tuberous sclerosis complex now requires two or more distinct types of lesions, rather than multiple lesions of the same type in the same organ system. Although diagnosis on purely clinical grounds can continue to be difficult in a few patients, there should be little doubt about the diagnosis for those individuals who fulfill these strict criteria. Couples with more than one child with tuberous sclerosis complex, no extended family history, and no clinical features of tuberous sclerosis complex are more likely to have germline mosaicism for tuberous sclerosis than nonexpression of the mutation. Germline mosaicism, while fortunately rare, will not be suspected from either diagnostic criteria or molecular testing until a couple has multiple affected children. Genetic counseling for families with one affected child should include a small (1% to 2%) possibility of recurrence, even for parents who have no evidence of tuberous sclerosis complex after a thorough diagnostic evaluation.

Tuberous Sclerosis Consensus Conference: recommendations for diagnostic evaluation. National Tuberous Sclerosis Association.

At the recent Tuberous Sclerosis Consensus Conference, a subcommittee proposed recommendations to guide the rational use of diagnostic studies in patients with tuberous sclerosis complex. Recommendations were made for diagnostic evaluation at the time of diagnosis, when testing helps both to establish the diagnosis and to identify potential complications. Additional guidelines were proposed for the ongoing surveillance of established patients to detect later complications of tuberous sclerosis complex. In the absence of comprehensive population studies to govern the use of diagnostic studies in individuals with tuberous sclerosis complex, the panel developed guidelines based on the disorder's natural history, concentrating on complications that are common, clinically significant, and more easily managed when found early. Finally, the group made suggestions for the use of diagnostic tests to identify family members who have tuberous sclerosis complex. Although these recommendations should standardize and improve our use of diagnostic studies in individuals with tuberous sclerosis complex, the clinical approach in a given patient must remain flexible enough to meet the needs of individual patients and families.

Magnetic resonance imaging in pediatric neurologic disorders.

We present our initial experience with magnetic resonance imaging (MRI) in 301 pediatric patients with a variety of neurologic disorders. MRI does not require ionizing radiation and can be done easily and safely in children. It is equal or superior to computed cranial tomographic (CT) scans in demonstrating most types of pediatric neurologic disorders. MRI is often superior to CT scans in demonstrating intracranial tumors, although both studies are usually abnormal in highly malignant tumors. No clear advantage was shown with either MRI or CT scans for fluid-filled intracranial lesions. Lesions of the brain stem and upper cervical region, such as Chiari malformation, are well delineated by MRI. Increased signal from the paranasal sinuses was frequently evident by MRI, but, in most instances, there was no clinical indication of sinus disease. Large arteries can be visualized as an area of diminished signal, and intracranial hemorrhage, dural sinus thrombosis, and cerebral infarction were demonstrated. The increased anatomic detail pictured by MRI allows the diagnosis of congenital defects, such as agenesis of the corpus callosum or septum pellucidum, that are not always apparent with CT scans. Although our experience with spinal cord lesions was not extensive, fluid-filled lesions within the cord can be reliably demonstrated.