Genetic Disorders in Egypt

We recently mapped the disease locus for severe autosomal recessive lamellar ichthyosis (LI) to chromosome 14q11 and showed complete linkage with TGM1, the gene encoding transglutaminase 1. We have now identified point mutations in TGM1 in two of the multiplex LI families used in the linkage study. Each nucleotide change causes a non-conservative amino acid substitution of histidine for one of two adjacent arginine residues in exon 3 of the gene (Arg141His, Arg142His). Within the transglutaminase family, these arginines are invariant within a conserved region, distant from the catalytic site of the enzyme. We hypothesize that these mutations adversely affect formation of crosslinks essential in production of cornified cell envelopes and a normal stratum corneum layer of the skin.

Childhood sexual abuse is associated with an increased incidence of age-concurrent and adult psychopathology. Little is known, however, about the biological manifestations and sequelae of childhood sexual abuse. In this study, we characterized the hypothalamic-pituitary-adrenal axis of a self-selected sample of sexually abused and control girls recruited from a prospective longitudinal study. Plasma ACTH and total and free cortisol responses to ovine CRH (oCRH) stimulation were measured in 13 sexually abused and 13 control girls, aged 7-15 yr. Psychiatric profiles and 24-h urinary free cortisol (UFC) measures were also obtained. Sexually abused girls had a greater incidence of suicidal ideation (chi 2 = 4.51; df = 1; P < 0.05), suicide attempts (chi 2 = 4.51; df = 1; P < 0.05), and dysthymia (chi 2 = 8.85; df = 1; P < 0.01) than control girls. Sexually abused girls showed significantly lower basal (t = 2.1; df = 24; P < 0.05), and net oCRH stimulated (t = 2.2; df = 24; P < 0.05) ACTH levels and significantly reduced total ACTH responses (t = 2.5; df = 24; P < 0.05) compared with control subjects. Their total and free basal and oCRH-stimulated plasma cortisol levels and 24-h UFC measures, however, were similar to those in controls. The attenuated plasma ACTH with corresponding robust plasma cortisol responses to oCRH stimulation and normal 24-h UFC measures in sexually abused girls suggest a dysregulatory disorder of the HPA axis in these individuals. This may reflect pituitary hyporesponsiveness to oCRH. The ability of sexually abused subjects to correct for the proposed pituitary hyporesponsiveness to CRH may be related to their young age and the presence of intact glucocorticoid feedback regulatory mechanisms.

Joubert syndrome (JS) is a recessively inherited developmental brain disorder with several identified causative chromosomal loci. It is characterized by hypoplasia of the cerebellar vermis and a particular midbrain-hindbrain "molar tooth" sign, a finding shared by a group of Joubert syndrome-related disorders (JSRDs), with wide phenotypic variability. The frequency of mutations in the first positionally cloned gene, AHI1, is unknown. We searched for mutations in the AHI1 gene among a cohort of 137 families with JSRD and radiographically proven molar tooth sign. We identified 15 deleterious mutations in 10 families with pure JS or JS plus retinal and/or additional central nervous system abnormalities. Mutations among families with JSRD including kidney or liver involvement were not detected. Transheterozygous mutations were identified in the majority of those without history of consanguinity. Most mutations were truncating or splicing errors, with only one missense mutation in the highly conserved WD40 repeat domain that led to disease of similar severity. AHI1 mutations are a frequent cause of disease in patients with specific forms of JSRD.