Profound midbrain atrophy in patients with Wilson’s disease and neurological symptoms?

Abstract

Wilson's disease (WD) is characterized by impaired hepatic copper secretion and subsequent copper accumulation in many organs predominantly liver and brain, secondary to loss of function mutations in the copper transport protein ATP7B. If the disease is recognized too late or treatment is not adequate, brain copper accumulation leads to progressive neurodegeneration with a variety of clinical symptoms. The nigrostriatal dopaminergic system seems rather vulnerable. Midbrain atrophy, however, has not been recognized as one of the prime features of patients with WD. Here we report quantification of midbrain diameter in 41 patients with WD. Data were correlated to the severity of neurological symptoms and the integrity of dopaminergic neurons measured via dopamine transporter binding. For control, we measured midbrain diameter in 18 patients with no evidence for brainstem dysfunction and 5 patients with progressive supranuclear palsy (PSP). Patients with WD had a reduced midbrain diameter (15.5 +/- 0.4 mm) compared to controls (18.5 +/- 0.2 mm). WD patients without neurological symptoms had midbrain diameter that were not different from controls (18.0 +/- 0.3 mm), while patients with neurological symptoms showed midbrain atrophy similar to patients with PSP (14.4 +/- 0.3 mm versus 14.1 +/- 0.3). There was a strong and significant correlation between midbrain atrophy and the severity of neurological symptoms (r= -0.68, p < 0.001) while midbrain atrophy and dopamine transporter binding correlated significantly but was less pronounced (r=0.46, p < 0.001). In summary, we were able to show, that midbrain diameter is an easy to perform quantification of neurodegeneration induced by brain copper accumulation and that other structures than substantia nigra dopaminergic neurons seem to contribute to midbrain atrophy in WD.

Morphological and functional imaging in neurological and non‐neurological Wilson's patients

“…In neuropathological terms, general brain atrophy is not obligatory; however, very often insular, cortical, cerebellar, and putamenal atrophy are present . Patients with the neurological type of Wilson's disease are also afflicted with degeneration of the midbrain …”

Study on Lesion Assessment of Cerebello-Thalamo-Cortical Network in Wilson’s Disease with Diffusion Tensor Imaging

“…Copper accumulation usually causes severe clinical manifestations, including liver failure, hepatitis [3], cirrhosis [4], premature death [5], and motor [6], emotion, cognitive impairments [7]. The neuropathological hallmark of the disease is neuronal loss and atrophy in lenticular nucleus, as well as in the midbrain [8], thalamus, and other parts of the basal ganglia [5]. …”

Establishment of hepatic and neural differentiation platforms of Wilson’s disease specific induced pluripotent stem cells

“…3D). It has been previously suggested that neurological WD correlates with deficit of dopaminergic neurons and may contribute to midbrain atrophy (Barthel et al, 2003;Strecker et al, 2006). Therefore, the generation of WD specific dopaminergic neurons may provide an ideal platform for better investigation of the midbrain specific neurological defects of WD in vitro.…”