Aceruloplasminemia via the CP Gene

Aceruloplasminemia is an iron accumulation disorder resulting in retinal degeneration, diabetes mellitus and neurological disease. Symptom onset occurs between ages 25 and 60 with individuals initially presenting with anemia. Neurologic findings include ataxia and muscle movement impairment including grimacing, blepharospasm, tremors, chorea, and facial/neck dystonia (Kono 2012; Miyajima 2003). Genetic testing is helpful in the differential diagnosis of Aceruloplasminemia from other neurodegeneration with brain iron accumulation (NBIA) disorders including neuroferritinopathy, PLA2G6-associated neurodegeneration as well as copper metabolic disorders (Wilson and Menkes disease), Huntington’s disease, dystonia, and Parkinson’s disease. Treatments for Aceruloplasminemia include iron chelating agents, fresh frozen plasma containing ceruloplasmin, and antioxidants (Miyajima 2003).

Aceruloplasminemia is inherited in an autosomal recessive manner through pathogenic variants in the CP gene. Missense mutations leading to impaired secretion, copper incorporation, and enzymatic activity occur throughout the coding region and represent about half of the reported causative variants in the CP gene (Hellman et al. 2002; Hellman et al. 2002). Frameshift, splice site and nonsense variants represent ~30%, 15% and 15% of cases respectively (Kono 2012). No clear genotype-phenotype correlations exist for Aceruloplasminemia (Miyajima 2003).

The CP gene encodes the ceruloplasmin enzyme that is expressed both as a soluble serum and membrane bound protein through alternative splicing and omission of exon 19. Serum ceruloplasmin is involved in iron homeostasis and plays a role in mobilization of iron from tissue stores and transportation across the basolateral surface of enterocytes. Membrane bound ceruloplasmin is present in astrocytes and is thought to serve as an antioxidant in the central nervous system (Kono 2012; Miyajima 2015).

Clinical sensitivity is problematic as absence of serum ceruloplasmin is mirrored in other disorders including Wilson’s disease. To date, large ceruloplasminemia patient cohort studies have not been performed to assess clinical sensitivity of CP genetic testing. Therefore, clinical sensitivity of this test is currently unknown. Analytical sensitivity should be high because all pathogenic variants reported are detected by this method.

This test provides full coverage of all coding exons of the CP gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).