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Disruptions to hypothalamic-pituitary-adrenal (HPA) axis function have been associated with varying forms of psychopathology in children. Studies suggesting children with ADHD have blunted HPA function have been complicated by the prevalence of comorbid diagnoses and heterogeneity of ADHD. The goals of this research were to assess the relations between waking and stress-response salivary cortisol levels and comorbid disruptive behavior (DBD) and anxiety (AnxD) disorders and problems in boys with ADHD, and to examine whether cortisol levels varied across ADHD subtypes. One hundred seventy elementary school-age boys with ADHD provided salivary cortisol at waking and in reaction to venipuncture. Parent reports were used to assess boys' psychiatric diagnoses and severity of behavioral problems. Boys' comorbid AnxD and anxiety problems were associated with greater cortisol reactivity, whereas boys' comorbid DBD and oppositional problems predicted diminished adrenocortical activity. Reactive cortisol increases were greatest in boys with ADHD and comorbid AnxD, but without DBD. ADHD subtypes were not differentially associated with waking, pre-stress baseline, or reactive cortisol levels. However, comorbid DBD predicted decreased cortisol reactivity in boys with inattentive and hyperactive subtypes of ADHD, but not in boys with combined subtype of ADHD. The results clarify previous patterns of distinct and divergent dysregulations of HPA function associated with boys' varying kinds of psychopathology.

Approximately one in 500 individuals in Western population has autosomal dominant familial hypercholesterolemia due to mutations in the low-density lipoprotein receptor (LDLR) gene. Screening for these mutations is hampered by their large number, except in founder populations. We identified the breakpoint of the >15 kb deletion involving the LDLR gene promoter and exon 1, responsible for more than 60% of French Canadian hypercholesterolemia cases, as well as the breakpoint of the 5 kb deletion of exons 2 and 3 that accounts for an additional 5% of cases. Both deletions appear to be because of homologous recombination by unequal crossing-over between the left arms of Alu repeats. Using RepeatMasker, we determined that 55% of the LDLR gene is composed of Alu elements; thus, it is not surprising that most LDLR rearrangements involve at least one Alu. Furthermore, we developed a rapid polymerase chain reaction-based assay for the French Canadian-1 (>15 kb) and French Canadian-5 (5 kb) hypercholesterolemia alleles. Screening a representative population sample of 943 French Canadian youths whose LDL cholesterol levels were above the 50th percentile allowed us to estimate the prevalence of the >15 kb allele as 0.11% (95% confidence interval, 0.03-0.38).

Childhood-onset spinal muscular atrophy (SMA) is an autosomal recessive neuropathy characterized by selective degeneration of alpha-motor neuron cells of the spinal cord. Age of onset and motor development varies greatly among patients, but the molecular basis of this variability remains unclear. The SMA locus contains two copies of a 500-kb element and deletions within the telomeric element have been shown to be the most common cause of SMA. To study the relationship between genotype and phenotype, 60 SMA families, all but two of which are of French Canadian origin, were screened for deletions in the telomeric survival motor neuron (SMN(T)) and the intact neuronal apoptosis inhibitory protein (NAIP) genes. Combining these results with those obtained for the multicopy microsatellite marker Ag1-CA (D5S1556) indicated that there are at least two types of SMA alleles. Most type I SMA patients are homozygous for large scale deletions involving the entire SMN(T) gene as well as exons 5 and 6 of the NAIP gene. The strong association between the 100-bp allele of Ag1-CA and large scale deletions in populations of diverse ethnic origin suggests that this allele marks an unstable or founder SMA chromosome. In contrast, most chronic SMA patients have at least one SMA allele with either an intragenic SMN(T) deletion or a SMN(C):SMN(T) chimeric gene which replaces the normal SMN(T) gene. The broad continuum of disease presentation in chronic SMA is most likely a consequence of the interaction between different SMA alleles.

Spinal muscular atrophy (SMA) is, after Duchenne muscular dystrophy, the most common neuromuscular disorder in childhood. The gene responsible for childhood SMA has been mapped to the q11.2-q13.3 region of chromosome 5. We have extended our linkage studies of SMA in the French-Canadian population to include microsatellite markers at the D5S125, D5S351, D5S435, JK53CA1/2 and MAP1B loci. These markers span about 4 cM of the SMA candidate region. We observed significant evidence for linkage between SMA and all the markers tested. The analysis of recombinant chromosomes provide evidence for the following genetic order: D5S125-D5S435-MAP1B-3'-JK53CA1/2 and places D5S351 proximal to JK53CA1/2. Furthermore, we confirm the current localization of the SMA gene distal to D5S435. Finally, we provide demonstration of significant linkage disequilibrium between childhood-onset SMA and four of the five marker loci, D5S125, D5S435, D5S351 and JK53CA1/2. Analysis of SMA-region haplotypes suggests that there may be a predominant SMA allele that is present on about 17% of SMA chromosomes in this sample of the French-Canadian population. We conclude that the observed linkage disequilibrium is likely due to genetic drift among regions of Quebec, consistent with this population's early history.

Chronic childhood-onset spinal muscular atrophy (SMA) is, after Duchenne muscular dystrophy, the most common neuromuscular disorder in childhood. Recent linkage analyses have mapped this disease to 5q12-5q14. We show that chronic SMA (Types II and III) is tightly linked to the marker locus D5S39 (Zmax = 5.47 at theta = 0.02) in eight French Canadian families. In contrast to previously published results, we do not observe close linkage between chronic SMA and D5S6 (Zmax = 0.34 at theta = 0.18) or D5S78 (Zmax = 0.25 at theta = 0.21). Last, we present a family that appears to be discordant for this localization but may represent the first example of an incompletely penetrant individual.