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Hereditary aceruloplasminemia (OMIM #604290) is a rare autosomal recessive disorder due to mutations of Cp, the gene that encodes the copper-binding protein ceruloplasmin (Cp). The first report of hereditary aceruloplasminemia was published in 1987 in Japan. The patient was a 52-year-old woman who had a movement disorder that resembled Parkinson's disease, blepharospasm, retinal degeneration, and diabetes mellitus. Her serum immunofixation test revealed that her serum Cp concentration was very low. Computed tomography scanning revealed increased amounts of iron in her basal ganglia and liver. Subsequent histologic evaluation confirmed that there was increased iron in her basal ganglia and substantia nigra and in her liver, without increased copper.

The frequency of homozygosity for deleterious Cp mutations in non-consanguineous marriages in Japan was estimated to be 1 per 2,000,000 population. Aceruloplasminemia has been reported in several countries including Japan, China, Ireland, Belgium, France, Italy, and the US. More Japanese patients have been reported than any other nationality. Altogether, about 60 patients with hereditary aceruloplasminemia have been described.

Ceruloplasmin (Cp) biochemistry

Cp is a plasma metalloprotein, an alpha-2 glycoprotein polypeptide of 1046 amino acids. A member of the multi-copper oxidase enzyme family, Cp is the principal copper transport protein in plasma. Cp is synthesized in hepatocytes where it binds copper, and is thereafter secreted into plasma. About 95% of circulating plasma copper is bound to Cp; the remainder is bound to albumin, precuprein, and complexes of copper and amino acids. Each Cp molecule can bind and transport six atoms of copper.

Neuroferritinopathy (OMIM #606159), also known as adult-onset basal ganglia disease, is a progressive movement disorder caused by mutations in the coding region of the ferritin light chain gene (FTL, chromosome 19q13.3–q13.4). Persons with neuroferritinopathy have abnormal ferritin light chain polypeptide, decreased serum ferritin concentrations, and accumulation of iron in the basal ganglia. Curtis and colleagues first described this syndrome in an English kinship in 2001. They also coined the commonly used term “neuroferritinopathy.” Subsequent identification and study of other subjects have revealed additional observations on the genotypes, phenotypes, and epidemiology associated with neuroferritinopathy.

Other mutations of the FTL coding region segregate with a syndrome that comprises hyperferritinemia, absence of iron overload, and absence of ocular cataracts. Mutations of the iron-responsive element of FTL cause a different clinical syndrome characterized by elevated levels of otherwise normal ferritin, cataracts due to ferritin light-chain deposition in the ocular lens, and absence of neurological abnormalities (Chapter 17).

History

In 2001, Curtis and colleagues described late-onset autosomal dominant dystonia that segregated with FTL 460insA in an English kinship. In 2003, Chinnery, Curtis, and colleagues reported a French family in which some members had a similar clinical disorder and the same FTL mutation. In 2007, Chinnery and colleagues compiled observations in 41 patients with neuroferritinopathy and FTL 460insA. They presented between the ages of 38 and 58 years; some had chorea, others had focal dystonia, and others had an akinetic rigid Parkinsonian syndrome. Brain imaging showed basal ganglia cavitation that was confirmed at necropsy.

Mutations in the SLC40A1 (FPN1) gene that encodes ferroportin (OMIM *604653) cause an uncommon, heterogeneous group of iron overload disorders characterized by an autosomal dominant pattern of inheritance (OMIM #606069). Ferroportin hemochromatosis has been described worldwide in a variety of race/ethnicity groups. SLC40A1 mutations cause two major iron overload phenotype patterns, each depending on the particular mutation and its effect on the function of the transcribed ferroportin protein. In many ferroportin hemochromatosis kinships, serum iron measures and complications of iron overload typical of other types of hemochromatosis are relatively uncommon. The collective term “ferroportin disease” or “hemochromatosis type 4” is sometimes used to describe the clinical manifestations of ferroportin mutations.

History

In 1990, an autosomal dominant form of hemochromatosis was reported in a Melanesian pedigree from the Solomon Islands. All affected individuals had serum iron measures and a pattern of liver iron staining similar to those of HFE hemochromatosis, although linkage of this disorder to chromosome 6p was excluded. In 1999, Pietrangelo and colleagues reported a large Italian family that included persons with an iron overload condition that occurred in pattern consistent with autosomal dominant inheritance. Based on microsatellite marker analyses, this disorder was also not linked to chromosome 6p. In 2001, Njajou and colleagues identified the SLC40A1 mutation N144H associated with autosomal dominant hemochromatosis in a large multi-generation family from the Netherlands.

Pyruvate kinase (PK) deficiency (OMIM #266200) is caused by mutations in the PKLR gene that encodes PK (chromosome 1q21). This disorder is the most common erythrocyte enzyme defect that causes hereditary non-spherocytic hemolytic anemia. It is transmitted as an autosomal recessive trait. On the basis of gene frequency, it was estimated that the prevalence of homozygous PK deficiency is 51 cases per million in the US white population. Based on data in a health registry, it was estimated that the prevalence of PK deficiency in northern England is 3.3 per million. PK deficiency has a worldwide distribution, but may be more common among individuals of northern European descent. Herein, the pathophysiology of PK deficiency is discussed. The clinical manifestations of this disorder are reviewed with emphasis on the complication of iron overload.

Etiology and pathogenesis

Mature erythrocytes depend on the glycolytic production of adenosine triphosphate (ATP) to meet metabolic requirements. Deficiencies in several glycolytic enzymes can result in hemolytic anemia. These types of hemolytic anemia are not associated with a distinctive morphologic abnormality of erythrocytes, and thus are known collectively as congenital non-spherocytic hemolytic anemias. Most of these disorders are rare and are transmitted as autosomal recessive disorders.

PK deficiency is the most common erythrocyte glycolytic enzymopathy. The predominant PK isoenzyme present in erythrocytes is the R form, encoded by PKLR. Multiple mutations can lead to PK deficiency, and the type of mutation may determine in part the severity of the clinical phenotype.