Brain Calcification in a Young Adult with Abnormal Copper Metabolism

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).

Video 1.

Baseline: Segment 1 showed dystonia in the limbs and trunk of the patient when walking; Segment 2 showed impaired tandem walking; Segment 3 showed bradykinesia (predominant in the right side).

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).

FIG. 1.

(1) (A) Axial CT images of the proband showing bilateral symmetric calcification in the cerebellum, brainstem, thalamus, basal ganglia, and frontal lobe; (B) axial T1‐weighted images of the proband showing bilateral symmetric hyperintensities in the brainstem, thalamus, and basal ganglia; (C) axial T2‐weighted images of the proband showing concurrence of hyperintense and hypointense signal in the brainstem, thalamus, and basal ganglia; (D) axial FLAIR‐weighted images of the proband showing concurrence of hyperintense and hypointense signal in the brainstem, thalamus, and basal ganglia; (E) axial CT images of the proband's bother showing bilateral symmetric calcification in the cerebellum, brainstem, thalamus, and basal ganglia. (2) family pedigrees. I‐1:Father; I‐2: Mother; II‐1:Brother; II‐2: Proband. PFBC: Primary familial brain calcification; WD: Wilson disease. (3) validation of the ATP7B mutations (NM_000053.3): c.2804C > T p.(Thr935Met) and c.2120A > G p.(Gln707Arg) by sanger sequencing. Chromatograms of the proband and his family members are shown. The proband harbored compound heterozygous c.2804C > T and c.2120A > G mutations, his brother and father harbored a heterozygous c.2804C > T mutation, and his mother harbored a heterozygous c.2120A > G mutation. The position of the mutation is marked with a red arrow. (4) validation of the MYORG mutations (NM_020702.3): c.794C > T p.(Thr265Met) and c.191G > A p.(Gly64Glu) by sanger sequencing. Chromatograms of the proband and his family members are shown. The proband and his brother harbored compound heterozygous c.794C > T and c.191G > A mutations, his father harbored a heterozygous c.794C > T mutation, and his mother harbored a heterozygous c.191G > A mutation. The position of the mutation is marked with a red arrow.

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. ¹

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, ² and calcium deposition demonstrate as hyperintensities both on T1 and T2‐weighted images. ³

Hypoparathyroidism due to copper deposition in parathyroid glands has been reported in WD, ⁴ 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. ⁵ 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. ⁶ 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 to ACMG guidelines. ⁶ , ⁷ , ⁸ , ⁹ , ¹⁰ Therefore, the patient was diagnosed with co‐occurrence of WD and PFBC, and his brother was diagnosed with PFBC.

This is the first case diagnosed with both WD and PFBC. These results support the need to consider the possibility of multiple disorders in cases where the clinical findings cannot be explained by one diagnosis alone. Moreover, recessive disorders should also keep in mind despite the absence of consanguinity.

The dystonia‐ataxia‐parkinsonism symptoms were mildly relieved after copper chelation therapy, including sodium dimercaptopropane sulfonate injection, penicillamine tablets (375 mg tid po) and zinc sulfate tablets (50 mg tid po), suggesting the main symptomatology was caused by WD. No relief of the muscle cramping indicated that muscle cramping in the patient and his brother was more likely to result from PFBC. However, the symptoms relapsed when he came back for a follow‐up visit in 6 months (Video S2). Brain CT showed no obvious change compared with baseline (Figure S1). The condition was still progressing slowly during follow‐up, so symptomatic treatment, levodopa and benserazide hydrochloride tablets (125 mg tid po) and baclofen tablets (10 mg tid po), has been added recently.

Video 2.

Follow up: 6 months later: Segment 1 showed dystonia in the limbs and trunk of the patient when walking (aggravated mildly compared to baseline); Segment 2 showed impaired tandem walking; Segment 3 showed bradykinesia (predominant in the right side).

Author Roles

1. Research Project: A. Conception, B. Organization, C. Execution;

2. Statistical Analysis: A. Design, B. Execution, C. Review and Critique;

3. Manuscript Preparation: A. Writing of the first draft, B. Review and Critique;

Y.B.H.: 1A, 1B, 1C, 3A;

J.Y.L.: 1A, 1B, 1C, 3A;

H.F.S.: 1A, 3B.

Disclosures

Ethical Compliance Statement: The authors confirm that the approval of an institutional review board was not required for this work; written informed consent was obtained. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.

Funding Sources and Conflict of Interest: This work was supported by 1.3.5 project for disciplines of excellence, West China Hospital, Sichuan University (ZYJC18038). The authors declare that there are no conflicts of interest relevant to this work.

Financial Disclosures for the previous 12 months: The authors declare that there are no additional disclosures to report.

Supporting information

Figure S1. Axial CT images of the proband after 6 months showing bilateral symmetric calcification in the cerebellum, brainstem, thalamus, basal ganglia, and frontal lobe without obvious change compared to that of baseline.