Hemolytic Anemia, Cd59-Mediated, With Or Without Immune-Mediated Polyneuropathy

A number sign (#) is used with this entry because CD59-mediated hemolytic anemia with or without immune-mediated polyneuropathy (HACD59) is caused by homozygous mutation in the CD59 gene (107271) on chromosome 11p13.

Description

CD59-mediated hemolytic anemia with immune-mediated polyneuropathy is an autosomal recessive disorder characterized by infantile onset of a relapsing-remitting polyneuropathy, often exacerbated by infection, and manifest as hypotonia, limb muscle weakness, and hyporeflexia. Immunosuppressive treatment may result in some clinical improvement (summary by Nevo et al., 2013).

Clinical Features

Yamashina et al. (1990) found that the erythrocytes from a patient thought to have paroxysmal nocturnal hemoglobinuria (PNH; 300818) were devoid of HRF20 (CD59) and that those of his parents were deficient in the protein, compatible with the heterozygous state. The patient, previously described by Ono et al. (1990), was a 22-year-old man with intermittent pallor and hematuria of 9 years' duration. Paroxysmal nocturnal hemoglobinuria had been diagnosed at the age of 13 years when he had an episode of hemolytic anemia and hemoglobinuria. During the subsequent 9 years, Ham and sucrose hemolysis tests were consistently positive, and 9 episodes of hemolysis occurred, with a cerebral infarction during the third and ninth episodes. His father and mother were cousins, but neither had a history of hemolytic anemia or hemoglobinuria. Rosse (1993) pointed out that although the patient had hemolytic anemia and thrombosis typical of PNH, he did not have other features of PNH, which is due to deficiency of PIGA (311770), the molecule that anchors CD59 and several other molecules to the cell surface. Nevo et al. (2013) noted that the patient reported by Yamashina et al. (1990) was not reported to have evidence of polyneuropathy.

Nevo et al. (2013) reported 5 children from 4 unrelated families of North African Jewish descent who presented with infantile onset of relapsing immune-mediated polyneuropathy and chronic hemolysis. One of the families was consanguineous. Disease onset was between age 3 and 7 months and was usually preceded by a minor viral illness. Symptoms included symmetric muscle weakness, hypotonia, and hyporeflexia affecting the lower limbs more than the upper limbs. The first episode lasted from days to weeks and treatment with IV immunoglobulins and corticosteroids resulted in restoration of muscle strength in the upper extremities. However, the disease course was relapsing-remitting in the following months, with exacerbations after infections. There was progressive muscle atrophy of the hands and feet, and persistent paralysis of the lower limbs associated with areflexia. A few of the exacerbations were accompanied by respiratory insufficiency requiring artificial ventilation, and 1 patient developed an acute episode of hemolytic-uremic syndrome during plasmapheresis that resolved. Cognitive development was normal. Laboratory studies during episodes showed acute hemolysis with decreased hemoglobin, increased C-reactive protein, and increased CSF protein levels. Nerve conduction studies showed demyelination with axonal damage in 2 of 3 patients, and spinal MRI showed root enhancement in 2 of 3 patients. Magnetic resonance imaging of the spine performed in 3 patients revealed root enhancement in 2 patients. Immunosuppressive treatment improved the time between relapses and reduced severity, but did not prevent recurrence. One patient died of acute respiratory failure at age 3.5 years.

Inheritance

The transmission pattern of chronic hemolysis and immune-mediated polyneuropathy in the family reported by Nevo et al. (2013) was consistent with autosomal recessive inheritance.

Clinical Management

Hochsmann et al. (2014) reported a female infant with CD59 deficiency who presented at age 7 months with bulbar symptoms, severe hypotonia, and areflexia. During later febrile illnesses, the patient developed acute hemolytic anemia with progressive neurologic deterioration, including T2-weighted hyperintense lesions on brain MRI, seizures, and visual impairment. Flow cytometric analysis of patient peripheral blood cells showed isolated CD59 deficiency. Treatment with eculizumab, an inhibitor of the complement membrane-attack complex, resulted in neurologic improvement about 6 months later. At age 5.5 years, the patient could eat and swallow normally, could walk short distances with support, and had improved cognitive and speech production.

Mapping

CD59 deficiency is caused by mutation in the CD59 gene, which maps to chromosome 11p13 (Heckl-Ostreicher et al., 1993).

Molecular Genetics

Motoyama et al. (1992) identified a homozygous single-nucleotide deletion in the CD59 gene (107271.0001) in the patient with CD59 deficiency and hemolytic anemia reported by Yamashina et al. (1990) and Ono et al. (1990).

In 5 patients from 4 unrelated families of North African Jewish descent with CD59-mediated hemolytic anemia and immune-mediated polyneuropathy, Nevo et al. (2013) identified a homozygous mutation in the CD59 gene (C89Y; 107271.0002). The mutation was initially found by whole-exome sequencing in 2 affected sibs, segregated with the disorder in all families, and was not found in the dbSNP and the Exome Variant Server databases. Haplotype analysis indicated a founder effect. Nevo et al. (2013) suggested that improper activation of the complement system due to lack of CD59 expression may cause damage to red cell membranes and result in myelin and axonal damage.

In a girl with CD59 deficiency, Hochsmann et al. (2014) identified a homozygous truncating mutation in the CD59 gene (107271.0003).

Animal Model

To examine the role of CD59 in protecting host tissues in health and disease, Holt et al. (2001) generated Cd59-deficient (Cd59 -/-) mice by gene targeting in embryonic stem cells. Despite the complete absence of Cd59, mice were healthy and fertile. Red cells in vitro displayed increased susceptibility to complement and were positive in an acidified-serum lysis test. Despite this, Cd59 -/- mice were not anemic but had elevated reticulocyte counts, indicating accelerated erythrocyte turnover. Fresh plasma and urine from these mice contained increased amounts of hemoglobin when compared with littermate controls, providing further evidence for spontaneous intravascular hemolysis. Intravascular hemolysis was increased following administration of cobra venom factor to trigger complement activation.