Clinical relevance of heterozygosis for aceruloplasminemia

Abstract

Aceruloplasminemia is a rare form of brain iron overload of autosomal recessive inheritance that results from mutations in the CP gene, encoding the iron oxidase ceruloplasmin. Homozygous aceruloplasminemia causes progressive neurodegenerative disease, anemia, and diabetes, and is usually diagnosed late in life upon investigation of anemia, high ferritin, or movement disorders, but its heterozygous state is less characterized and believed to be silent. Here we report two heterozygotes for new mutations causing aceruloplasminemia from whom peripheral blood samples were collected for complete blood counts, iron studies, and genotyping by automated sequencing. We then performed a systematic review of preview reports of heterozygotes with data on genotype and clinical findings. Heterozygosity for aceruloplasminemia invariably causes reduced ceruloplasmin levels, and similarly to previews reports in the literature, our cases did not present with anemia. Mild hyperferritinemia was found only in two reports. Nevertheless, 5 out of 11 variants have been associated with significant neurological symptoms despite the presence of one wild-type alelle. This review contributes to better genetic counseling of heterozygotes for CP gene variants and supports that measuring ceruloplasmin levels may be useful when investigating patients with movement disorders or rare cases of unexplained high ferritin. K E Y W O R D Sceruloplasmin, ferritin, genetic mutation, iron, neurodegeneration

Lifetime risk of autosomal recessive neurodegeneration with brain iron accumulation (NBIA) disorders calculated from genetic databases

“…The same is true for recent reports of dominant inheritance of previously exclusively autosomal recessive disorders. 30 , 31 Our method of estimating the lifetime risk of a genetic disorder cannot be applied to autosomal dominant disorders as population databases would be depleted of their pathogenic variants. Underestimation of the lifetime risk may have occurred due to exclusion of variants non-identifiable by whole exome sequencing, such as large genomic rearrangements, variants in flanking intronic regions that are involved in splicing, or epigenetic modifications.…”

Novel dominant MPAN family with a complex genetic architecture as a basis for phenotypic variability

“… 10 Although aceruloplasminemia is considered an autosomal recessive disease, many reports describe cerebellar ataxia in heterozygous carriers. 11 , 12 In these patients, lower serum ceruloplasmin and copper levels are present, and MRI detects cerebellar atrophy. Although the index case had consistently low serum ceruloplasmin (between 0.08 and 0.11 g/L) and copper levels (between 5.8 and 9.0 μmol/L), family members with mild symptoms and without symptoms were also carriers.…”

Movement Disorders and Liver Disease

“…Symptomatic aceruloplasminemia has also recently been described among heterozygous CP mutation carriers. In these patients, neurological symptoms (particularly MD) predominate, systemic manifestations are rare, serum ferritin levels often normal and ceruloplasmin levels generally mildly below the lower limit of normal 70 …”

“…In these patients, neurological symptoms (particularly MD) predominate, systemic manifestations are rare, serum ferritin levels often normal and ceruloplasmin levels generally mildly below the lower limit of normal. 70 …”