Generoso G. Gascon

The gene encoding alsin, a protein with three guanine-nucleotide exchange factor domains, is mutated in a form of recessive amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) and primary lateral sclerosis (PLS) are neurodegenerative conditions that affect large motor neurons of the central nervous system. We have identified a familial juvenile PLS (JPLS) locus overlapping the previously identified ALS2 locus on chromosome 2q33. We report two deletion mutations in a new gene that are found both in individuals with ALS2 and those with JPLS, indicating that these conditions have a common genetic origin. The predicted sequence of the protein (alsin) may indicate a mechanism for motor-neuron degeneration, as it may include several cell-signaling motifs with known functions, including three associated with guanine-nucleotide exchange factors for GTPases (GEFs).

Identifying Autism Loci and Genes by Tracing Recent Shared Ancestry

To find inherited causes of autism-spectrum disorders, we studied families in which parents share ancestors, enhancing the role of inherited factors. We mapped several loci, some containing large, inherited, homozygous deletions that are likely mutations. The largest deletions implicated genes, including PCDH10 (protocadherin 10) and DIA1 (deleted in autism1, or c3orf58), whose level of expression changes in response to neuronal activity, a marker of genes involved in synaptic changes that underlie learning. A subset of genes, including NHE9 (Na+/H+ exchanger 9), showed additional potential mutations in patients with unrelated parents. Our findings highlight the utility of “homozygosity mapping” in heterogeneous disorders like autism but also suggest that defective regulation of gene expression after neural activity may be a mechanism common to seemingly diverse autism mutations.

The Efficacy of Divalproex Sodium in the Prophylactic Treatment of Children With Migraine

Objective.—To determine the beneficial use of divalproex sodium as a prophylactic treatment for migraine in children.

Epileptic (Gelastic) Laughter

In the last decade we have encoutered 10 cases in whom we considered laughter to represent either the only or one of several peripheral expressions of an abnormal cerebral electrical discharge. We have distinguished between pathological laughter that may occur in the course of diffuse neurological diseases or as an expression of a dementing process, from that which can be properly called epileptic in nature. We have also distinguished between ictal and postictal laughter. Finally, we have speculated upon the functional implications of epileptic outbursts of laughing, in terms of the possible anatomic substrate and interconnections subserving this fairly unique human expression of emotion, and have pointed out differences in clinical and EEG characteristics that seem to correlate with the different location of the lesions responsible for the discharges.

Combined oral isoprinosine-intraventricular α-interferon therapy for subacute sclerosing panencephalitis

Eighteen patients, 16 boys and 2 girls, aged 5-14 years, with subacute sclerosing panencephalitis (SSPE) were treated with oral isoprinosine (100 mg/kg/day) and intraventricular alpha-interferon 2b (Intron A, Schering Corp.), starting at 500,000 U twice a week and later increasing to 3 million U biweekly. Minimal follow-up of living patients is 12 months; maximal 40 months. On the basis of the Neurological Disability Index (NDI) scores and staging, 8 have treatment-induced remissions (3 improved, 5 arrested), 4 are worse and 6 died. This 44% (8/18) rate of remission/improvement compares well with the 9% (1/11) remission in historical controls in the same institution (p = < 0.05) and 5% spontaneous remission in the literature. Combined oral isoprinosine-intraventricular alpha-interferon appears to be an effective treatment for SSPE.

Subacute sclerosing panencephalitis

Subacute sclerosing panencephalitis (SSPE), a neurodegenerative disease caused by a persistent “slow virus infection” with a mutated measles virus, is endemic in much of the developing world. Its incidence will increase in the USA, not only in immigrants, but also because of the 1988–1990 measles epidemic. This report reviews the pathogenesis, clinical and laboratory diagnosis, and future perspectives in treatment and prevention.

Topical Review Article: Organic Acidurias: A Review. Part 1

Organic acidemias are disorders of intermediary metabolism that lead to accumulation of organic acids in biologic fluids, disturb acid-base balance, and derange intracellular biochemical pathways. Their clinical presentation reflects the resultant systemic disease and progressive encephalopathy. While in some organic acidemias, disturbed acid-base metabolism is the predominant presenting feature, in others it is less prominent or even absent. The etiologies of the more than 50 different phenotypes include impaired metabolism of branched-chain amino acids, vitamins, glucose, lipids, glutathione, and γ-aminobutyric acid and defects of oxidative phosphorylation. Most organic acidemias present with neurologic manifestations, which include acutely or subacutely progressive encephalopathy that involves different parts of the nervous system. The age of presentation and the associated systemic, hematologic, and immune findings provide additional guidelines for differential diagnosis. We summarize major organic acidemias, while emphasizing their usual and unusual neurologic presentations. ( J Child Neurol 1991;6:196-219).

Randomized Treatment Study of Inosiplex Versus Combined Inosiplex and Intraventricular Interferon-α in Subacute Sclerosing Panencephalitis (SSPE): International Multicenter Study:

The efficacy of oral inosiplex alone (group A) versus combined treatment of inosiplex (Isoprinosine) and intraventricular interferon-α2b (Intron A) (group B) in patients with subacute sclerosing panencephalitis (SSPE) was compared. One hundred and twenty-one patients who met the diagnostic criteria for subacute sclerosing panencephalitis and presented at stage 2 or less were randomized into group A or B. Data were analyzable on 67 patients who met the inclusion criteria and adhered to the protocol. The inosiplex dosage was 100 mg/kg/day to a maximum of 3 g/day, taken orally in three divided doses for 6 months. Interferon-α2b started with 100,000 U/m2 and escalated to 1,000,000 U/m2 over 5 inpatient days and then 1,000,000 U/m2 twice a week for 6 months. Neurologic status was rated by the Neurological Disability Index, Brief Assessment Examination, and stages. Kaplan-Meier survival rates were not statistically significant between group A and group B (log-rank test X2 = .1374, P = .7109). In longitudinal morbidity analyses, regression results were fitted to three outcome measures: the Neurological Disability Index, the Brief Assessment Examination, and stage. Group medians of the estimated regression slopes were then compared using the Wilcoxon rank-sum test. There was no statistically significant difference between the two groups on any of these three measures. Morbidity comparisons of clinical classification of outcomes (improvement, stabilization, worsening after treatment stopped, deterioration) also showed no statistically signficant difference between groups. There were no statistically significant differences between the two treatment groups on any efficacy measure. However, the observed rates of satisfactory outcome (stabilization, improvement) of 34% in group A and 35% in group B were higher than the spontaneous remission rates of 5 to 10% reported in the literature, suggesting that treatment was superior to no treatment. (J Child Neurol 2003;18:819-827).

Central Auditory Processing and Attention Deficit Disorders

Nineteen children who met criteria for attention deficit disorder (ADD) received neurodevelopmental attention testing and central auditory processing (CAP) tests. The CAP tests consisted of the Staggered Spondaic Word (SSW) test and the Willeford battery of tests. Teacher and parent questionnaires (originally devised at the Learning Disabilities Clinic, The Childrens Hospital, Boston) were obtained. There was a very high concordance between the questionnaires and the CAP tests, but a low concordance between the neurodevelopmental measures and the questionnaires. After treatment with central nervous system stimulants, there was again a high concordance between teacher/parent reports and CAP measures, and less than 50% concordance between neurodevelopmental measures and teacher/parent observations. We conclude that the SSW and Willeford battery are sensitive performance indicators of attention disorder. Furthermore, these tests are more useful in titrating response to CNS stimulants than neurodevelopmental assessments and provide objective support for the subjective teacher and parent observations. (J Child Neurol 1986;1:27-33)

PREVALENCE OF DIFFERENT TYPES OF LYSOSOMAL STORAGE DISEASES IN SAUDI ARABIA

SummaryThe frequency of different types of lysosomal storage diseases in 125 referred cases, collected over three years, was compared to the occurrence elsewhere. The data suggest that mucopolysaccharidosis (MPS) type IVA (Morquio disease), multiple sulphatase deficiency, Niemann-Pick disease type B, GM2 gangliosidosis type ‘0’ (Sandhoff disease), and ceroid lipofuscinosis (Jansky-Bielschowsky and Batten-Spielmeyer-Vogt syndromes) are encountered frequently in Saudi Arabia, as compared to other storage diseases. In contrast, some other diseases such as the adult variant of Gauchers disease were not observed. Half of the GM2 gangliosidosis type ‘0’ cases originated from one large tribe in the country. Other conditions did not show tribal predilection. The ceroid lipofuscinosis cases in Saudi Arabia originated from four large families. Consanguineous marriages taking place within tribal boundaries probably account for the pattern observed.