Cerebrospinal fluid synaptic proteins as useful biomarkers in tyrosine hydroxylase deficiency.

Tyrosine hydroxylase (TH) deficiency is an inborn error of dopamine biosynthesis and a cause of early parkinsonism. Two clinical phenotypes have been described. Type "B": early onset severe encephalopathy; type "A": later onset, less severe and better response to L-dopa. We aimed to study the expression of several key dopaminergic and gabaergic synaptic proteins in the cerebrospinal fluid (CSF) of a series of patients with TH deficiency and their possible relation with the clinical phenotype and response to L-DOPA. Dopamine transporter (DAT), D2-receptor and vesicular monoamine transporter (VMAT2) were measured in the CSF of 10 subjects with TH deficiency by Western blot analysis. In 3 patients, data of pre- and post-treatment with L-DOPA were available, and in one of them, GABA vesicular transporter was determined. Results were compared to an age-matched control population. The concentration of D2-receptors in CSF was significantly higher in patients with TH deficiency than in controls. Similarly, DAT and vesicular monoamine transporter type 2 were up-regulated. Studies performed before L-DOPA, and on L-DOPA therapy showed a paradoxical response with D2 receptor expression increase as L-Dopa doses and homovanillic concentration gradually raised in a B phenotype patient. The opposite results were found in two patients with A phenotype. However, this is a very small sample, and further studies are needed to conclude robust differences between phenotypes. Synaptic proteins are detectable in the CSF and their quantification can be useful for understanding the pathophysiology of neurotransmitter defects and potentially to adjust and personalize treatments in the future.

Parkinsonism and inborn errors of metabolism.

Parkinsonism is a frequent neurological syndrome in adulthood but is very rare in childhood. Early forms of Parkinsonism have many distinctive features as compared to Parkinsonism in adults. In fact, rather than Parkinsonism, the general concept "hypokinetic-rigid syndrome" (HRS) is more accurate in children. In general, the terms "dystonia-parkinsonism", "parkinsonism-plus", or "parkinsonism-like" are preferred to designate these forms of paediatric HRS. Inborn errors of metabolism (IEM) constitute an important group amongst the genetic causes of Parkinsonism at any age. The main IEM causing Parkinsonism are metal-storage diseases, neurotransmitter defects, lysosomal storage disorders and energy metabolism defects. IEM should not be neglected as many of them represent treatable causes of Parkinsonism. Here we review IEMs causing this neurological syndrome and propose diagnostic approaches depending on the age of onset and the associated clinical and neuroimaging features.