Mechanisms for nonrecurrent genomic rearrangements associated with CMT1A or HNPP: rare CNVs as a cause for missing heritability.

Genomic rearrangements involving the peripheral myelin protein gene (PMP22) in human chromosome 17p12 are associated with neuropathy: duplications cause Charcot-Marie-Tooth disease type 1A (CMT1A), whereas deletions lead to hereditary neuropathy with liability to pressure palsies (HNPP). Our previous studies showed that >99% of these rearrangements are recurrent and mediated by nonallelic homologous recombination (NAHR). Rare copy number variations (CNVs) generated by nonrecurrent rearrangements also exist in 17p12, but their underlying mechanisms are not well understood. We investigated 21 subjects with rare CNVs associated with CMT1A or HNPP by oligonucleotide-based comparative genomic hybridization microarrays and breakpoint sequence analyses, and we identified 17 unique CNVs, including two genomic deletions, ten genomic duplications, two complex rearrangements, and three small exonic deletions. Each of these CNVs includes either the entire PMP22 gene, or exon(s) only, or ultraconserved potential regulatory sequences upstream of PMP22, further supporting the contention that PMP22 is the critical gene mediating the neuropathy phenotypes associated with 17p12 rearrangements. Breakpoint sequence analysis reveals that, different from the predominant NAHR mechanism in recurrent rearrangement, various molecular mechanisms, including nonhomologous end joining, Alu-Alu-mediated recombination, and replication-based mechanisms (e.g., FoSTeS and/or MMBIR), can generate nonrecurrent 17p12 rearrangements associated with neuropathy. We document a multitude of ways in which gene function can be altered by CNVs. Given the characteristics, including small size, structural complexity, and location outside of coding regions, of selected rare CNVs, their identification remains a challenge for genome analysis. Rare CNVs may potentially represent an important portion of "missing heritability" for human diseases.

Effectiveness of pharmaceutical therapy of ADHD (Attention-Deficit/Hyperactivity Disorder) in adults - health technology assessment.

BACKGROUND: Attention-Deficit/Hyperactivity Disorder (ADHD) is a mental disorder. Symptoms include hyperactivity, lack of attentiveness, and frivolousness. This disorder always begins in childhood, but can remain through adulthood. ADHD affects all areas of life and limits the quality of life due to its symptoms and the high rate of associated disorders that can develop. An established form of therapy is using stimulant medications, most commonly, containing Methylphenidate as the active ingredient. However, in Germany this ingredient is not approved for adults suffering from ADHD. Therefore, many adults cannot obtain appropriate medication to treat this disorder. OBJECTIVE: The following report (Health Technology Assessment [HTA]) examines the effectiveness and cost-effectiveness of the medical treatment of ADHD in adults as well as the ethical, social and legal aspects thereof. METHODS: In August 2009, a systematic literature search is performed in all relevant scientific databases. The selected citations fulfill predetermined inclusion criteria. The data in the publications is then systematically extracted, reviewed and assessed. A manual search of citations is conducted as well. RESULTS: NINETEEN STUDIES FULFILL THE INCLUSION CRITERIA: nine randomised controlled studies (RCT), five meta-analyses, three economic studies and two studies relevant to the legal aspects of the HTA. All RCT reveal that adult patients who receive medication containing a stimulant (Methylphenidate and Amphetamine) and Atomoxetine, see a reduction of ADHD symptoms compared to the placebo-treated patients. The drug response rate among the control group ranges from 7 to 42%; in the treatment group from 17 to 59.6%. The meta-analyses confirm the findings of the RCT. In light of the control group, it can be ascertained that there are higher annual costs (both direct and indirect) for patients with ADHD. The average annual medical expenses for an adult with ADHD were 1,262 $ in 1998 and 1,673 $ in 2001 (the converted and inflation-adjusted rate for 2009: between 1,270 and 1,619 Euro). The use of stimulants use may impair the patient's ability to drive, travel or do sports. No relevant studies can be identified concerning the ethical, social and/or legal aspects of stimulant medication for ADHD patients. DISCUSSION/CONCLUSION: Medical treatment, particularly including Methylphenidate and Atomoxetine, proves to have a positive effect. In order to attain an optimal drug response, dosing must be determined on an individual basis. There is a need of high-quality studies that directly compare various agents - an aspect which is relevant to medical effectiveness of a therapy. No definite statement can be made about the cost-effectiveness of the medical treatment of ADHD in adults. More health economic studies are therefore required. Apart from the unquestionable mental indication, it is already recommended by health economic reasons to establish the conditions for an adequate treatment with these medicaments also for adults.

Value of 99mTc-TRODAT-1 SPECT to predict clinical response to methylphenidate treatment in adults with attention deficit hyperactivity disorder.

BACKGROUND: In a previous study, binding of Tc-TRODAT-1 to the dopamine transporter (DAT) was found to be higher in patients with attention deficit hyperactivity disorder (ADHD) as compared to healthy controls. AIM: To determine whether the degree of Tc-TRODAT-1 binding to the striatal DAT may have a predictive role on the response to methylphenidate (MPH) in patients with ADHD. METHODS: Twenty-two adult patients suffering from ADHD underwent a brain SPECT scan with Tc-TRODAT-1. After the scan patients received MPH, individually medicated up to 60 mg.day. Severity of illness was estimated using the Clinical Global Impression (CGI-S) Scale before treatment. Ten weeks after the beginning of MPH treatment the improvement in global symptoms was rated by the Clinical Global Improvement Scale (CGI-I). RESULTS: Before treatment 17/22 patients with ADHD presented with higher striatal DAT binding as compared to age-matched healthy controls (+23.8%; P<0.01). After treatment with MPH a significant improvement of ADHD symptoms was demonstrated by the CGI-I in 16 of these 17 patients (CGI-S before: 4.8; CGI-I after MPH: 1.9; P<0.01). Five patients showed reduced DAT binding prior to therapy (-14.4%; P=0.04); these patients did not respond to MPH therapy (CGI-S before: 4.5; CGI-I after MPH: 4.2; P=0.40). CONCLUSION: Our findings suggest that ADHD patients with primarily elevated binding of Tc-TRODAT-1 to the striatal DAT responded better to therapy with MPH as compared to those with normal or low DAT binding. Consequently, our results - even if obtained on a small collective indicate that measurement of DAT may be an important prognostic predictor for therapy response to MPH.

Striatal dopamine transporter availability and DAT-1 gene in adults with ADHD: no higher DAT availability in patients with homozygosity for the 10-repeat allele.

In 29 adults with attention deficit hyperactivity disorder (ADHD) striatal dopamine transporter (DAT) availability was assessed by [(99m)Tc]TRODAT-1 SPECT and correlated with 3' VNTR polymorphism of the DAT gene on chromosome 5p15.3. Seventeen patients showed homozygosity for the 10-repeat allele, two homozygosity of the 9 allele and 10 were heterozygous (9-10). No statistically significant difference in DAT availability was found between patients with 10-10 carriers (DAT 1.28 +/- 0.34) and with at least one 9 allele (DAT 1.31 +/- 0.27); when smokers were excluded, DAT availability was 1.38 +/- 0.28 in the 10-10 carriers (n = 12) and 1.42 +/- 0.19 in the 9-10 and 9-9 carriers (n = 7). In conclusion, no higher striatal DAT was found in patients with homozygosity of the 10 allele of the DAT gene in this study. These results differ from a study in 11 Korean children with ADHD, in which 10-10 carriers showed higher DAT availability in [(123)I]IPT SPECT. Discrepancies may be explained by differences in patient's age, ethnical differences, different imaging techniques or the limited number of patients included in both studies.

ADHD in adolescence and adulthood, with a special focus on the dopamine transporter and nicotine.

The persistence of attention deficit hyperactivity disorder (ADHD) into adolescence and adulthood has now been accepted as a clinical entity. The rate of prevalence among adults is assumed to be from 2% to 4%. With increasing age, a symptom change has to be considered; disturbance of attention becomes more prominent, whereas hyperactivity often diminishes or changes to inactivity. Neuroimaging studies show a high striatal dopamine transporter (DAT) availability in most adults with ADHD; this can be reduced by stimulants. Nicotine seems to have a stimulant-like action on the DAT. In most adults with ADHD, therapy has to be multimodal, combining psychotherapy and medication. Methylphenidate is the first-line drug in adult ADHD; further options are amphetamine and noradrenaline reuptake inhibitors. Nonresponders to methylphenidate seem to have no elevated DAT availability prior to therapy. Combination with other psychiatric disorders occurs frequently in adults with ADHD; in these patients additional pharmacological treatment with special regard to the comorbid disease is recommended.

Influence of striatal dopamine transporter availability on the response to methylphenidate in adult patients with ADHD.

In this study, we investigated whether availability of striatal dopamine transporter (DAT) may have an influence on the response of adult patients with attention deficit hyperactivity disorder (ADHD) on methylphenidate (MPH). In 18 non-smoking and non-medicated adult patients with ADHD, availability of DAT was measured with [(99m)Tc] TRODAT-1 SPECT. Then, the patients received methylphenidate (MPH), individually titrated up to 60 mg per day. Ten weeks later, clinical improvement was rated by Clinical Global Impressions scale. In all, 6 patients were classified as non-responders, and 12 responded to MPH. From the non-responders, 5 presented with a DAT availability below that of normal controls of the same age, whereas in the group of responders all patients had elevated DAT availability. There was a significant negative correlation between values for global clinical improvement and striatal DAT availability. In conclusion, ADHD patients with low DAT availability seem not to respond to therapy with MPH.

The dopamine transporter and neuroimaging in attention deficit hyperactivity disorder.

There is evidence that abnormalities within the dopamine system in the brain play a major role in the pathophysiology of attention deficit hyperactivity disorder (ADHD). For instance, dopaminergic psychostimulants, the drugs of first choice in ADHD, interact directly with the dopamine transporter (DAT). Molecular genetic studies suggest involvement of a polymorphism of the DAT gene in ADHD. More recent imaging studies show abnormalities in various brain structures, but particularly in striatal regions. In the current paper we review recent studies in this area. First in vivo measurements of DAT with single photon emission computed tomography (SPECT) in ADHD patients revealed an elevation of striatal DAT density. No differences in DAT density between the left and right side and between putamen and caudate nucleus have been found in [99mTc]TRODAT-1 SPECT of ADHD patients. Patients with ADHD and with a history of nicotine abuse both displayed lower values of DAT density in [99mTc]TRODAT-1 SPECT than non-smokers with ADHD. DAT seem to be elevated in non-smoking ADHD patients suffering from the purely inattentive subtype of ADHD as well as in those with the combined or purely hyperactive/impulsive subtype.

Stimulant-like action of nicotine on striatal dopamine transporter in the brain of adults with attention deficit hyperactivity disorder.

Eleven adult patients with attention deficit hyperactivity disorder (ADHD) without medication, consuming 7-40 cigarettes per day, showed statistically significant lower values for striatal dopamine transporter (DAT) measured by [99mTc]TRODAT-1 SPECT compared to 11 non-smoking drug-naive patients with ADHD, matched for sex and age, despite higher ADHD scores for the smokers. Because stimulants have been shown to reduce primarily elevated DAT density in adults with ADHD, it can be suggested that nicotine acts in a similar way on striatal DAT as do stimulants.