Alteration of the serotoninergic system in fatal familial insomnia.

We read with interest that Wanschitz and colleagues found a substantial increase in tryptophan hydroxylase-immunoreactive neurons in the pons (superior central nucleus) and medulla (raphe obscurus nucleus) of fatal familial insomnia (FFI) patients, suggesting that a serotoninergic system impairment represents the functional substrate of some typical FFI symptoms. We report the lumbar cerebrospinal fluid (CSF) concentrations of monoamine metabolites in 3 FFI subjects (1 female) of 2 unrelated Italian families already described. We measured 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG) by a gas chromatographic, mass spectroscopic method previously described. The central component of MHPG was calculated according to the formula [total CSF MHPG] 2 0.9 [free plasma MHPG]. FFI patients had the typical point mutation at codon 178 of the prion protein gene combined with methionine at codon 129 of the mutated allele. Lumbar puncture was performed in a standardized fashion 13 (in 1 case) and 6 (in 2 cases) months after disease onset. Average ages (6 standard error of the mean) at the time of CSF collection for the 3 FFI patients and 24 controls were 55 6 2 and 47 6 3 years. The CSF level of 5-HIAA in FFI patients (37.63 6 4.13ng/ml) was significantly higher (p , 0.0001) than that in controls (18.72 6 1.95ng/ml). There were no significant differences between controls and FFI patients with respect to lumbar CSF levels of HVA (FFI 44 6 1.2ng/ml, controls 42 6 2.3ng/ml) and corrected CSF MHPG (FFI 6.46 6 0.8ng/ml, controls 5.34 6 0.2ng/ml). Our results in FFI patients are consistent with increased central serotonin [5-hydroxytryptophan (5-HT)] turnover and with the findings of Wanschitz et al., attended by normal dopaminergic activity and a slight increase in central noradrenergic function. However, we caution against an oversimplified explanation of an altered serotoninergic system as the only functional substrate for all symptoms of FFI. The hallmark of FFI is selective degeneration of anteroventral (AV) and mediodorsal (MD) thalamic nuclei, which constitute an important control station in the so-called central autonomic network, including several areas of the telencephalon, hypothalamus, and brain stem interconnected via parallel, functionally specific, and neurochemically complex pathways. The 5-HT system is one of these pathways and has been implicated in the regulation of the sleep–wake cycle and cardiovascular system, but its effects are subordinate to the control of higher diencephalic centers and the subtype of 5-HT receptors involved. The crucial role of the AV and MD thalamic nuclei in regulating sleep and integrating autonomic and endocrine responses critical for homeostasis has been confirmed by studies showing that wake–sleep and autonomic features comparable to FFI may be reproduced in experimental animals by kainic acid injection into the MD and the reticular nucleus of the thalamus. Lesions to the thalamus disrupt the cortical– limbic circuitry with a cascade effect on the functions of many systems. For instance, there is pharmacological evidence of GABAergic system involvement in FFI patients. Thus, while confirming increased activity of the serotoninergic system in FFI, we believe that it represents just one of the many biochemical systems involved.