Mutations in the X-linked filamin 1 gene cause periventricular nodular heterotopia in males as well as in females.

Periventricular heterotopia (PH) is a human neuronal migration disorder in which many neurons destined for the cerebral cortex fail to migrate. Previous analysis showed heterozygous mutations in the X-linked gene filamin 1 (FLN1), but examined only the first six (of 48) coding exons of the gene and hence did not assess the incidence and functional consequences of FLN1 mutations. Here we perform single-strand conformation polymorphism (SSCP) analysis of FLN1 throughout its entire coding region in six PH pedigrees, 31 sporadic female PH patients and 24 sporadic male PH patients. We detected FLN1 mutations by SSCP in 83% of PH pedigrees and 19% of sporadic females with PH. Moreover, no PH females (0/7 tested) with atypical radiographic features showed FLN1 mutations, suggesting that other genes may cause atypical PH. Surprisingly, 2/24 males analyzed with PH (9%) also carried FLN1 mutations. Whereas FLN1 mutations in PH pedigrees caused severe predicted loss of FLN1 protein function, both male FLN1 mutations were consistent with partial loss of function of the protein. Moreover, sporadic female FLN1 mutations associated with PH appear to cause either severe or partial loss of function. Neither male could be shown to be mosaic for the FLN1 mutation in peripheral blood lymphocytes, suggesting that some neurons in the intact cortex of PH males may be mutant for FLN1 but migrate adequately. These results demonstrate the sensitivity and specificity of DNA testing for FLN1 mutations and have important functional implications for models of FLN1 protein function in neuronal migration.

[Ventricular outflow tract obstruction by cardiac tumors during ACTH therapy of an infant with tuberous sclerosis].

In an infant with tuberous sclerosis and West syndrome, ACTH treatment was interrupted because of augmentation of the biventricular outflow tract obstruction. A 5-month-old boy, who had been diagnosed to have multiple cardiac tumors since in utero, manifested West syndrome with typical hypsarhythmia in EEG. Several days after starting low dose ACTH treatment, a systolic murmur due to biventricular outflow tract obstruction intensified with ventricular arrhythmia. A tumor in the left ventricular outflow tract was enlarged. Discontinuation of daily administration of ACTH and administration of a beta-blocking agent improved the cardiac problems. Acceleration of blood velocity in the outflow tracts disappeared two months later. Intracardiac morphology and hemodynamic performance should be monitored to avoid critical complications during ACTH treatment in patients with tuberous sclerosis.

Urinary N-methylhistamine in asthmatic children receiving azelastine hydrochloride.

BACKGROUND: Histamine has a particular role in the pathogenesis of bronchial asthma, and many antiallergic drugs have been developed with antihistaminic action in mind. Recently, a sensitive and specific assay for measuring histamine and its metabolites has been developed. There are, however, no reports of the effect of antiallergic drugs on histamine levels in asthmatic patients. OBJECTIVES: To determine the relationship between clinical symptoms and histamine levels in asthmatic patients receiving an antiallergic agent. METHODS: A prospective study was designed in asthmatic children treated with azelastine hydrochloride. The evaluation of clinical symptoms was based on scores of the severity of exacerbations, activities of daily living, quality of sleep, and required therapy. Urinary excretion of N-methylhistamine, a major metabolite of histamine, was measured by double antibody radioimmunoassay. RESULTS: In the patients treated with azelastine, the improvement in clinical symptoms of bronchial asthma correlated significantly with a decrease in urinary N-methylhistamine excretion (r2 = 0.434, P < .001), while no such relationship was noted in patients receiving no antiallergic agent. Urinary N-methylhistamine excretion showed no diurnal change or influence of meals. CONCLUSIONS: Decreased urinary N-methylhistamine excretion may be a direct reflection of the antihistaminic action of azelastine in vivo. Measurement of urinary N-methylhistamine excretion can be used to evaluate the efficacy of agents with antihistaminic action in the treatment of bronchial asthma.

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.

Familial periventricular nodular heterotopia.

We describe herein a 13-year-old girl, her 34-year-old mother and her 60-year-old grandmother who have periventricular heterotopic nodules. The mother has suffered from epileptic seizures since she was 15 years old, but the daughter and grandmother have had no epilepsy. They showed multiple uncalcified nodules on the lateral ventricular walls on CT. On MRI the intensity of the nodules was the same as that of the cerebral gray matter, suggesting heterotopia, and no other cerebral abnormalities were observed. Despite extensive examinations, neither have exhibited evidence of tuberous sclerosis. The periventricular nodular heterotopia observed in this family are a unique form of migration disorders, which may be caused by a dominant mutation.

[Correlation between morphological abnormalities of Chiari malformation and evoked potentials].

We studied correlation between morphological abnormalities of Chiari malformation and evoked potentials (short-latency somatosensory evoked potential [SSEP] and auditory brainstem response [ABR]). On SSEP the inter-peak latency prolongation of P3-N1 was revealed in 6 out of 8 cases with Chiari malformations. The feature of positive wave between P3 and N1 was divided into 2 groups. The tendency of the positivity between P3 and N1 was more marked in cases of prolonged P3-N1 latency and correlated with the medullary kink. On ABR the prolongation of III-V inter-peak latency was revealed in one side in 3 patients Chiari malformations with malformed pons and tegmentum.

Myoclonic astatic epilepsy presenting eyelid myoclonic seizures induced by closing of eyes.

A male infant with myoclonic astatic epilepsy showed myoclonic seizures of the eyelids by closing of the eyes. There was no photosensitivity in EEG with flash-stimulation and he could induce seizures even in total darkness. The latency between a lid closure and onset of seizure discharges on EEG was relatively long (0.3-0.5 second). Epileptic seizures in this patient may be induced via a brainstem reticular formation, and elevated Bell's position seems to be the necessary stimulus to produce seizures.