0-TESTO COMPLETO.pdf - Fondazione Santa Lucia

Sezione III: Attività per progetti
BACKGROUND
Hyperphenylalaninemia (HPA) refers to all clinical conditions characterized
by increased amounts of phenylalanine (PHE) in blood and other tissues.
The most severe form of HPA is the classical phenylketonuria (PKU; McKusick
261600), an inherited metabolic disease caused by a deficiency of the
enzyme phenylalanine hydroxylase (PAH; E.C. 1.14.16.1) necessary to convert
phenylalanine in tyrosine, resulting in an accumulation of plasmatic phenylalanine
(> 20 mg/dl). Brain is most vulnerable organ to high PHE levels especially
during the firsts years of life, when high blood PHE levels lead to severe
mental retardation and heavy neuropathological signs; therefore it is necessary
to maintain the blood level of phenylalanine within physiological range
(between 2 and 10 mg/dl). Treatment of PKU consists in a phenylalaninerestricted
diet that must start in the early days of life and that requires exclusion
of several natural foods and supplement of unpleasant synthetic compounds
to avoid nutritional deficiencies. Consequently compliance whit
dietary treatment is often worse and many PKU-patients do not adhere
strictly to diet, resulting in a state of HPA with several neuropsychological
consequences.
Moreover, despite severe impairments are prevented by diet during childhood,
even early and continuously treated PKU patients show cognitive and
behavioural impairments. In particular, frontal/executive skills (working
memory, abstract reasoning, problem solving, planning ability, sustained
attention, inhibitory control, mental flexibility) appear to be prominently deficient
in early-treated PKU. These functions are associated with the pre-
Frontal Cortex (pFC) that, more than other cerebral regions, appears to be
extremely sensible to PHE-induced disturbances. In fact, deficits in working
memory and executive functions are reported in children with higher current
PHE concentrations [Diamond 1994; Schmidt et al. 1994; Weglage et al. 1996;
Welsh et al. 1990] and in adults with early-treated PKU after they relaxed or
stopped the diet [Brumm et al. 2004; Channon et al. 2004; White et al. 2002].
Although there is limited evidences, these data show the pathological effects
of HPA also in well-treated adult patients, thus adults are encouraged to stay
on dietary treatment for as long as possible. So, recently there is a renewed
interest to studying biochemical mechanisms underlying PHE-induced prefrontal
dysfunctions in order to identify alternative approaches. The development
of additional therapeutic strategies for cognitive disturbances in HPA
patients requires the understanding of the mechanism involved in PHEdependent
brain dysfunctions.
Preliminary results suggest that PHE-induced cognitive deficits mainly
depend on the PHE interference with serotonin synthesis by inhibition of
brain tryptophan hydroxylase activity. These results are in agreement with
previous data showing that serotonin (5-HT) is the most affected amine in the
brain of PKU mice [Puglisi-Allegra et al. 2000], and that discontinuation of
PHE-restricted diet determines a dramatic decrease of the 5-HT metabolite, 5-
HIAA, in the CSF of hyperphenylalaninemic adolescents [Lou et al. 1985].
Administration of a drug able to increase serotonin levels is an important
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