After WES analysis, we found that the index patient (Fig.1a) carried two heterozygous variants (c.606dupA and c.2689delC) within CP gene, which were validated by Sanger sequencing. The known frameshift variant c.606dupA (Fig.1b) in exon 3 results in the repetition of adenine in the coding region 606, the change of amino acid 203 from aspartic acid to arginine and the creation of a new reading frame, ending at the downstream codon 5. The nonsense variant c.2689delC (Fig.1c) in exon 6, resulting in the change of 897 amino acid from leucine to termination, is first reported worldwide. This novel variant was absent from public database including Exome Aggregation Consortium (ExAC), Genome Aggregation Database (gnomAD), and our in-house WES database containing 500 Chinese controls. The two variants were classified as pathogenic variants according to the American College of Medical Genetics and Genomics (ACMG) standards and guidelines. The son of the index patient was genetically tested to have a heterozygous variant c.2689delC.
The index patient is a 53-year-old Chinese woman carrying two heterozygous pathogenic variants within CP gene, who was genetically diagnosed with ACP. She presented memory loss for three months when first visit in our department of neurology two years ago. Brain MRI showed excessive intracranial paramagnetic material deposition. She had a 19-year history of type 1 diabetes, diabetic ketoacidosis, diabetic retinopathy and mild anemia. Ceruloplasmin was low as 18 mg/L, serum ferritin was high as 858.3ng/mL, and serum iron was 6.73mmol/L. Therefore, ACP was considered in differential diagnosis with Wilson’s disease (WD). UWDRS score was 17/320. In addition, cardiac doppler ultrasound showed that the patient had atrial septal defect.
One and half year after the diagnosis, the patient rehospitalized for developing walking instability, accompanied by involuntary shaking of hands, anxiety, and occasional sudden tension or fear. Brain MRI and susceptibility weighted Imaging (SWI) showed iron deposition in nuclei, thalamus, red nucleus and substantia nigra of bilateral basal ganglia, and iron deposition on brain surface (Fig.1d-f). Hepatic MRI and diffusion-weighted imaging (DWI) showed hepatomegaly with reduced T2WI signal (Fig.1g). The UWDRS score progressed to 70/320, other psychological scales indicated poor mood, anxiety and emotional indifference. Later ophthalmic consultation showed no obvious abnormality of retina (Fig.1h, i).
The cases with genetic testing and complete diagnostic and treatment process reported in English in the past decade were included, and 49 cases out of 30 articles were screened out (Table 1). Adding the case in the current study, 33 out of 50 cases had neurological symptoms. As shown in Table 2, the average age of onset (AAO) of symptoms was 35.2 years, and the average age of diagnosis was 48.8 years, which means that the average delay was 13.6 years. Among them, the average delay of 33 patients with neurological symptoms was 15.7 years, while that of 17 patients without neurological symptoms was 8.8 years.
The AAO of neurological symptoms was 52.2 years while that of anemia is hard to determine, with some patients being found anemic in their thirties and forties, and some cases being described as having developed anemia during a vague period of childhood. Therefore, the specific AAO of anemia cannot be calculated with certainty. Based on the 15 cases in which the AAO of anemia was described in detail, their average AAO is 29.7 years old. Similarly, the AAO of diabetes mellitus was not determined at the time of consultation or was not reflected in the case reports for some patients, and the average AAO was 37.3 years in the 16 cases with detailed description. These two values above can provide certain reference value.
In addition, from the information extracted from these 50 cases, we also got the first diagnosis departments of the patients, which appeared in the department of hematology, endocrinology, neurology, and other (orthopedics, gastroenterology, etc.). Due to the data volume and uncertainty of description, it is difficult to calculate a convincing proportion. Neurological symptoms occurred in 66% of patients, anemia in 82%, diabetes in 70%, and retinal disease in 28%. Except the undescribed or untested cases, almost all patients had low transferrin saturation, hyperferritinemia, low or undetectable serum ceruloplasmin, and imaging findings of abnormal iron deposition in the brain and liver. Cognitive decline (77%) was most common among patients with neurological symptoms, followed by ataxia in 53%, hyperkinetic movement disorders in 43%, parkinsonism in 33%, and psychiatric changes in 17%. Most patients have more than one kind of neurological symptom.