Submission Details

*CP *was first reported in relation to autosomal recessive aceruloplasminemia in 1987 (Miyajima H et al., PMID: 3574673). Aceruloplasminemia is a disorder characterized by systemic and cerebral iron accumulation, with the classic clinical triad of retinal degeneration, diabetes mellitus and neurologic disease that typically manifests in individuals between their 30s and 70s. Neurologic features, including movement disorders (such as blepharospasm, grimacing, facial and cervical dystonia, tremor, and chorea) and ataxia (gait disturbance and dysarthria), reflect the distribution of iron deposition in the brain. Several variants (e.g., missense, splice site, frameshift) have been reported in multiple probands in four publications (PMID: 32235485; PMID: 29503155; PMID: 40043514; PMID: 3574673) and are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts) has been reached. The mechanism of pathogenicity is reported to be loss of function. This gene-disease relationship is also supported by animal models, where recessive, chemically induced mutant mice exhibit reduced iron oxidation and export from astrocytes to the blood-brain barrier (BBB), leading to decreased iron transfer to the brain (PMID: 40184642). Functional studies in HEK293T cells expressing wild-type and mutant ceruloplasmin, testing protein secretion, copper incorporation, and ferroxidase/oxidase activity, showed that several missense variants led to loss or reduction of ferroxidase activity (GO:0004322) and defective copper loading (GO:0005507), consistent with disease pathogenicity (PMID: 40043514). In summary, there is definitive evidence supporting the relationship between CP and autosomal recessive aceruloplasminemia. This has been repeatedly demonstrated in both research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen IEM GCEP at the meeting on October 10 (SOP Version 11).

CP was first reported in relation to autosomal recessive aceruloplasminemia in 1987 (Miyajima H et al., PMID: 3574673). Aceruloplasminemia is a disorder characterized by systemic and cerebral iron accumulation, with the classic clinical triad of retinal degeneration, diabetes mellitus and neurologic disease that typically manifests in individuals between their 30s and 70s. Neurologic features, including movement disorders (such as blepharospasm, grimacing, facial and cervical dystonia, tremor, and chorea) and ataxia (gait disturbance and dysarthria), reflect the distribution of iron deposition in the brain. Several variants (e.g., missense, splice site, frameshift) have been reported in multiple probands in four publications (PMID: 32235485; PMID: 29503155; PMID: 40043514; PMID: 3574673) and are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts) has been reached. The mechanism of pathogenicity is reported to be loss of function. This gene-disease relationship is also supported by animal models, where recessive, chemically induced mutant mice exhibit reduced iron oxidation and export from astrocytes to the blood-brain barrier (BBB), leading to decreased iron transfer to the brain (PMID: 40184642). Functional studies in HEK293T cells expressing wild-type and mutant ceruloplasmin, testing protein secretion, copper incorporation, and ferroxidase/oxidase activity, showed that several missense variants led to loss or reduction of ferroxidase activity (GO:0004322) and defective copper loading (GO:0005507), consistent with disease pathogenicity (PMID: 40043514). In summary, there is definitive evidence supporting the relationship between CP and autosomal recessive aceruloplasminemia. This has been repeatedly demonstrated in both research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen IEM GCEP at the meeting on October 10 (SOP Version 11).