Confirmation of linkage in X-linked infantile spasms (West syndrome) and refinement of the disease locus to Xp21.3-Xp22.1.

The syndrome of infantile spasms, hypsarrhythmia, and mental retardation (West syndrome) is a classical form of epilepsy, occurring in early infancy, which is etiologically heterogeneous. In rare families, West syndrome is an X-linked recessive condition, mapped to Xp11.4-Xpter (MIM 308350). We have identified a multi-generation family from Western Canada with this rare syndrome of infantile spasms, seen exclusively in male offspring from asymptomatic mothers, thereby confirming segregation as an X-linked recessive trait. Using highly polymorphic microsatellite CA-repeat probes evenly distributed over the entire X chromosome, linkage to markers DXS7110, DXS989, DXS1202, and DXS7106 was confirmed, with a maximum LOD score of 3.97 at a theta of 0.0. The identification of key recombinants refined the disease-containing interval between markers DXS1226 and the adrenal hypoplasia locus (AHC). This now maps the X-linked infantile spasms gene locus to chromosome Xp21.3-Xp22.1 and refines the interval containing the candidate gene to 7.0 cM. Furthermore, this interval overlaps several loci previously linked with either syndromic or non-syndromic X-linked mental retardation (XLMR), including one recognized locus implicated in neuroaxonal processing (radixin, RDXP2). Collectively, these studies lend strong support for the presence of one or more genes intrinsic to brain development and function, occurring within the critical interval defined between Xp21.3-Xp22.1.

Cervical spine anomalies in fetal alcohol syndrome.

Fifty cases of well-documented fetal alcohol syndrome were reviewed with the intent of describing the cervical vertebral anomalies. Thirty-eight cases had adequately detailed x-ray examination to be included in this study. Of these, 19 or 53% showed congenital fusion of two or more cervical vertebrae. The associated findings were minor anomalies on the intravenous pyelogram (IVP) in three of 18 IVPs done, mild to moderate microcephaly in 53%, and significant congenital heart anomalies in 41%. Although the vertebral anomalies bear a resemblance to the Klippel Feil syndrome, it is thought that the two syndromes are separate. The patterns of occurrence of the vertebral anomalies are different in the two groups, and the visceral expression of the disorder is also different. The major visceral anomaly in the Klippel Feil syndrome being in the genitourinary system and in the fetal alcohol syndrome being in the cardiovascular system. The patterns, however, are close enough to imply teratogenic event as the etiology in the Klippel Feil group. The occurrence of neck fusion in the fetal alcohol syndrome is common enough for it to be used in making the diagnosis.

Malignant hyperthermia: characterization of erythrocyte membranes from individuals at risk.

Structural and functional characteristics of erythrocytes and isolated erythrocyte membranes from known malignant hyperthermia (MH) carriers have been examined in the hope of deriving some information concerning the underlying molecular basis of this genetic abnormality, which may represent a state of generalized membrane involvement. The increase in erythrocyte osmotic fragility which has previously been noted in porcine MH was found not to apply to the human disorder and there was evidence that in some individuals at risk osmotic fragility was in fact reduced. Although no alteration in erythrocyte membrane phospholipid profiles was detected, membrane cholesterol levels were reduced in all three definite carriers examined as well as in approximately half of the possible MH carriers investigated. No evidence for associated changes in membrane protein sulfhydryl group latency or in temperature-dependent perturbations of membrane fluidity using a stearic acid spin probe could be detected. Finally, since alterations at the level of skeletal muscle membrane -Ca++ interaction have been implicated in the pathogenesis of MH, we have examined in detail the influence of temperature on the Ca++-stimulated components of the Mg++-dependent ATPase of erythrocyte membranes from known MH carriers but no evidence of any abnormality could be found. Since MH carriers detection based solely on measurements of plasma creatine phosphokinase elevations may yield equivocal results, a decrease in erythrocyte membrane cholesterol content may provide a convenient means of identifying such individuals at risk.

Erythrocyte membrane enzyme abnormalities in two hereditary disorders of muscle.

Enzymatic properties of erythrocyte membranes in Duchenne muscular dystrophy (DMD) and malignant hyperthermia (MH), two genetically determined abnormalities of skeletal muscle, were examined. Acetylcholinesterase (AChE) and ATPase activities were chosen for investigation since alterations in these enzymes have been demonstrated in animal models of dystrophy. A significant decrease in Na+,K+-ATPase activity was noted in DMD patients and a number of possible DMD carriers, suggesting that this enzyme may provide a useful marker of the carrier state in carriers not exhibiting an elevation in plasma creatine phosphokinase activity. No abnormalities in AChE were demonstrable in any of our DMD patients, indicating that human dystrophy is biochemically distinct from certain animal models of dystrophy (e.g., dystrophic mice) where erythrocyte AChE is decreased. In contrast, evidence was found in two known MH carriers, who had normal erythrocyte ATPase activities, for the presence of an altered membrane AChE characterized by an increase in substrate affinity and a large decrease in maximal hydrolytic rate. While the exact relevance of this membrane defect, if any, to the pathogenesis of MH remains to be seen, the presence of this modified enzyme may serve to identify those individuals in a family where a positive history of MH exists who are at risk of developing a hyperthermic crisis during anesthesia.

Chemical compositional studies of erythrocyte membranes in Duchenne muscular dystrophy.

Erythrocytes from patients with Duchenne muscular dystrophy (DMD) are known to possess a number of structural and functional abnormalities, including an increased osmotic fragility and potassium permeability, a decreased deformability and altered electrophoretic behaviour. To explore the possible chemical basis of these changes, the compositional properties of erythrocyte membranes from patients with DMD and a number of suspected carriers for this disorder have been investigated. Quantitative analyses of membrane cholesterol, sialic acid and major phospholipid classes were normal in both groups of individuals and no alterations in the arrangement of membrane amino and sulfhydryl groups could be detected. It is suggested that increased levels of cellular calcium, possibly occurring as the result of a defect in active calcium extrusion, could account for the structural and functional abnormalities of erythrocytes in DMD.

Nonketotic hyperglycinemia. Glycine accumulation due to absence of glycerine cleavage in brain.

Glycine concentrations were measured in plasma and cerebrospinal fluid of five patients in different types of hyperglycinemia to determine why severe neurologic deterioration is confined to the so-called nonketotic form of hyperglycinemia. Glycine content and glycine-cleavage enzyme activity were also determined in brain obtained in autopsy from three of these patients. Spinal-fluid glycine concentrations were 15 to 30 times above normal in patients with nonketotic hyperglycinemia, but were normal in those with hyperglycinemias of undetermined type who had comparable elevations of plasma glycine. Glycine content was two to four times above normal in several brain regions, and brain glycine cleavage enzyme activity was absent in two patients dying of nonketotic hyperglycinemia. By contrast, glycine content was normal and glycine cleavage activity present in the brain of an infant who died of hyperglycinemia of unknown cause. These results suggest that elevated glycine levels may be harmless in blood, but lethal in brain.