Brain Calcification in a Young Adult with Abnormal Copper Metabolism

Abstract

A 25-year-old Chinese man presented with dysarthria, dystonia and parkinsonism for 2 years. At the age of 23, he developed mild dysarthria and dystonia of the right upper limb. During the next 2 years, he developed bradykinesia and the dystonia progressively spread to other limbs and trunk. He had a 10-year history of paroxysmal muscle cramping, with each attack lasting several seconds without loss of consciousness, which was diagnosed as epilepsy at a local hospital. Carbamazepine was taken irregularly with limited relief. Neurological examination revealed dysarthria, dystonia in the limbs and trunk, bradykinesia, rigidity, dysdiadochkinesia and impaired tandem walking (Video S1). Laboratory examination revealed decreased serum ceruloplasmin (40.9 mg/L, normal: 210–530 mg/L) and increased urinary excretion of copper (324 μg/24 hr, normal: 15–60 μg/24 hr). Liver enzymes, kidney function, levels of serum/urinary calcium, serum/urinary phosphate, serum parathyroid hormone, 25-hydroxyvitamin D, and plasma lactic acid were normal. Ophthalmological examination detected Kayser-Fleischer (K-F) rings in both eyes. Abdominal ultrasound revealed liver cirrhosis. Electrocardiogram and electroencephalogram were normal. Brain magnetic resonance imaging (MRI) showed hyperintensities in the basal ganglia, thalamus and brainstem on T1-weighted images, which demonstrated concurrence of hyperintense and hypointense signal on T2-weighted and fluid-attenuated inversion recovery (FLAIR) images (Fig. 1 (1)B,C,D). Brain computed tomography (CT) demonstrated bilateral symmetric hyperdensities in the cerebellum, brainstem, thalamus, basal ganglia, and frontal lobe (Fig. 1 (1)A). The patient’s parents were healthy and non-consanguineous. His brother had similar muscle cramping for more than 10 years and normal serum ceruloplasmin and urinary excretion of copper. Similarly symmetric brain hyperdensities was detected by the CT scan in his brother (Fig. 1 (1)E), but not in his parents. Given the low serum ceruloplasmin, increased urinary copper, and presence of K-F rings, a clinical diagnosis of Wilson disease (WD) can be made according to the WD scoring system. Interestingly, both the patient and his brother presented bilateral symmetric brain hyperdensities on CT images, which is more likely to be calcification. Actually, brain CT is generally normal in WD. Moreover, the detected T1 hyperintensities and T2 hyper and hypointensities might be due to deposition of both copper and calcium, as copper deposition has been reported to demonstrate as T1 hyperintensity and concurrence of hyperintense and hypointense signal on T2-weighted images, and calcium deposition demonstrate as hyperintensities both on T1 and T2-weighted images. Hypoparathyroidism due to copper deposition in parathyroid glands has been reported in WD, which may cause secondary brain calcification. However, the absence of endocrine or vitamin D disorders ruled out the diagnosis of WD with secondary brain calcification in our patient. Moreover, his brother’s normal copper metabolism indicated that the calcification was less likely ascribed to WD. Therefore, primary familial brain calcification (PFBC) was considered. In addition, the parents did not show brain calcification while the brother did, indicating a recessive inherited pattern. MYORG, the first recessive PFBC gene, was identified in 2018. Besides, the wide affected areas of calcification, especially the involvement of brainstem in our patient were in line with the characteristic findings of recessive type of PFBC associated with MYORG mutations, which was rarely found in dominant inherited PFBC. Considering the examination results and family history, a diagnosis of co-occurrence of WD with recessive inherited PFBC was most likely. Whole-exome sequencing (WES) was finally performed, which detected compound heterozygous mutations in ATP7B (c.2804C > T and c.2120A > G) and MYORG (c.191G > A and c.794C > T). His parents carried different single variant respectively of the two genes, while his brother carried c.2804C > T of ATP7B and the same compound heterozygous variants of MYORG in the co-segregate analysis, which was in good accordance with their phenotypes (Fig. 1 (2, 3, 4)). All of these mutations were classified as pathogenic variants according