Objective: To describe detailed neuropathology findings from an autopsy case of dopa-responsive dystonia (DRD) with genetically confirmed tyrosine hydroxylase deficiency (THD).

Background: DRD comprises a group of rare monogenic conditions, characterized by a relatively static dystonic phenotype and disease course with marked and sustained response to low doses of dopamine. Previously, only three autopsy cases of confirmed GTP Cyclohydrolase-1 (GCH-1) related DRD had been reported. THD is a rare form of DRD and it`s histological changes are unknown.

Methods: Paraffin embedded brain tissue sections from a patient (male, 49 years) with genetically confirmed compound heterozygous mutation in the TH gene (c.1127C>T, p.A376V and c.1493A>G, p.D498G), previously published (Schiller et al., 2004), were examined histologically. In addition to haematoxylin & eosin staining, immunohistochemistry with following antibodies and dilutions were applied to respective brain tissue: glial fibrillary acidic protein (GFAP; 1:1,000, Dako), tau (1:600, AT8, Autogen Bioclear, Calne, UK), Aβ (1:200, Dako), α-synuclein (1:50, Novacastra, Newcastle, UK), ubiquitin (1:200, Dako, Ely, UK) and p62 (1:100, BD Bio-science, Oxford, UK).

Results: The salient histological feature was a striking pallor of neuromelanin containing neurons in the midbrain substantia nigra without obvious decrease in cell density, whereas neuromelanin content in the neurons of the motor nucleus of the vagus nerve appeared preserved. Immunohistochemical studies provided no evidence of pathological accumulation of proteins such as a-synuclein and amyloid-β, showed no ubiquitin or p62 positive intranuclear inclusions to suggest trinucleotide repeat expansion disorder and also showed no evidence of cerebral amyloid angiopathy. Hyperphosphorylated tau pathology was restricted to rare neuropil threads in the transentorhinal cortex with no apparent neurofibrillary tangle or glial tau pathology. Quantification of neuromelanin-containing midbrain neurons as well as TH-positive striatal terminals comparing this case to patients with confirmed GCH-1, DYT1, sporadic dystonia, Parkinson´s disease and healthy controls is currently ongoing.

Conclusions: This work provides the first description of histological changes in THD, indicating a predominant loss of neuromelanin-pigment from midbrain neurons. It remains to be seen in how far this might constitute a DRD-specific change in comparison to other dystonic conditions.

References: Schiller A, Wevers RA, Steenbergen GCH, Blau N, Jung HH. Long-term course of L-dopa-responsive dystonia caused by tyrosine hydroxylase deficiency. Neurology 2004; 63: 1524–1526.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/neuropathology-of-dopa-responsive-dystonia-due-to-tyrosine-hydroxylase-deficiency/