[From intellectual disability to new treatment modalities of fragile X syndrome]. / Fra mental retardering til målrettet behandling ved fragilt X-syndrom.

In 1943 a large family with X-linked mental retardation was described by Martin & Bell. This family had what we know today as fragile X syndrome, the most common inherited form of intellectual disability. Current knowledge about the specific gene, the encoded protein and the pathophysiological mechanisms involved has made it possible to develop pharmacological treatment trials. Fragile X syndrome therefore is on its way as model disorder for targeted treatments in genetic medicine, and this article reviews clinical and therapeutic aspects of the syndrome.

[Carriers of fragile X syndrome can present with a broad spectrum of clinical disorders]. / Anlægsbærere for fragilt X-syndrom kan udvise et bredt spektrum af kliniske manifestationer

Fragile X syndrome, fragile X-associated tremor/ataxia syndrome (FXTAS) and fragile X-associated primary ovarian insufficiency (FXPOI) are three clinically distinct disorders caused by expansions of a CGG repeat sequence in the non-coding part of the FMR1. FXTAS and FXPOI are seen in carriers of smaller repeat expansions (55-200). Carriers were for many years thought to be clinically unaffected, but along with the discovery of FXPOI and FXTAS a growing number of additional clinical manifestations have been identified. We wish to make Danish physicians more aware of these conditions which we review in this paper.

[22q11 deletion syndrome]. / 22q11-deletionssyndrom.

22q11 deletion syndrome (formerly named CATCH22, DiGeorge, Velo-Cardio-Facial, Caylor, Kinouchi and Shprintzen syndrome) occurs in approximately 1/2000 to 4000 children. The genetic lesion is remarkably uniform, occurring mainly as 3 or 1.5 MB deletions in the 22q11.2 region. However, the clinical manifestations are variable and manifestation in several organ systems often occur. In this review we describe the various manifestations of the syndrome. Finally, we suggest strategies for diagnosing, evaluating and organizing the treatment for Danish patients with this syndrome.

Methylphenidate-evoked changes in striatal dopamine correlate with inattention and impulsivity in adolescents with attention deficit hyperactivity disorder.

Abnormal central dopamine (DA) neurotransmission has been implicated in the impulsivity, inattention, and hyperactivity of attention deficit hyperactivity disorder (ADHD). We hypothesized that a pharmacological challenge with methylphenidate (MP) at a therapeutic dose increases extracellular DA concentrations in proportion to the severity of these specific ADHD symptoms. To test this hypothesis, we measured by PET the effect of acute challenge with MP on the availability of striatal binding sites for [11C]raclopride (pB), an index of altered interstitial DA concentration, in nine unmedicated adolescents (1 female, 8 males; age 13.7 +/- 1.8 years) with a current diagnosis of ADHD. We estimated the pB of [11C]raclopride for brain dopamine D2/3 receptors first in a baseline resting condition, and again after an acute challenge with MP (0.3 mg/kg, p.o.), and calculated the percentage change in (%DeltapB) in left and right striatum. On another day, measurements of impulsivity and inattention were performed using a computerized continuous performance test. There was a significant correlation between the magnitude of %DeltapB in the right striatum and the severity of inattention and impulsivity. MP-evoked %DeltapB correlated with standard scores for impulse control (r = 0.68; P = 0.02), attention (r = 0.81; P = 0.005), information processing (r = 0.66; P = 0.02), and consistency of attention, or variability (r = 0.60; P = 0.04). In conclusion, the results link inattention and impulsivity with sensitivity of brain DA receptor availability to an MP challenge, corroborating the hypothesis that MP serves to potentiate decreased DA neurotransmission in ADHD.

ADHD: increased dopamine receptor availability linked to attention deficit and low neonatal cerebral blood flow.

Attention-deficit-hyperactivity disorder (ADHD), while largely thought to be a genetic disorder, has environmental factors that appear to contribute significantly to the aetiopathogenesis of the disorder. One such factor is pretern birth with vulnerable cerebrovascular homeostasis. We hypothesised that cerebral ischaemia at birth could contribute to persistent deficient dopaminergic neurotransmission, which is thought to be the pathophysiological basis of the disorder. We examined dopamine D(2/3) receptor binding with positron emission tomography (PET) using [11C] raclopride as a tracer, and continuous reaction times (RT) with a computerized test of variables (TOVA) in six adolescents (12-14 years of age, one female) who had been examined with cerebral blood flow (CBF) measurements at preterm birth and had a subsequent history of attention deficit. We found that high dopamine receptor availability ('empty receptors') was linked with increased RT and RT variability, supporting the concept of a dopaminergic role in symptomatology. High dopamine receptor availability was predicted by low neonatal CBF, supporting the hypothesis of cerebral ischaemia as a contributing factor in infants susceptible to ADHD.