More severe ADAMTS13 Deficiency in Homozygous versus Compound Heterozygous Carriers of the ADAMTS13 c.4143_4144dupA Mutation in Congenital Thrombotic Thrombocytopenic Purpura (cTTP): Impact on Disease Onset?

Introduction: Congenital thrombotic thrombocytopenic purpura (cTTP) is an autosomal recessive disease characterized by acute episodes of thrombotic microangiopathy. cTTP has a clinically heterogeneous course and its genotype-phenotype correlation remains incompletely understood. In 2006, the Hereditary TTP Registry (ClinicalTrials.gov NCT01257269) was initiated to gain understanding of this ultra-rare and often fatal disease. At this Registry, residual ADAMTS13 activity, ADAMTS13 mutations, clinical course, possible triggers of acute disease and treatment requirements are recorded.

Methods: The Hereditary TTP Registry is an international cohort study. Individual data were analyzed from 123 cTTP patients, who were enrolled between 2006 and the end of 2017. Diagnosis of cTTP was confirmed by a severely deficient ADAMTS13 activity (< 10% of normal) in the absence of a functional inhibitor and the presence of ADAMTS13 mutations on both alleles. Genetic analysis was performed through ADAMTS13 gene amplification and sequencing of all 29 exons with flanking intron-exon boundaries using multiplexed PCR reactions with published primers. Clinical and laboratory data were recorded for each patient retrospectively up to enrolment, and prospectively during annual follow-up by physicians responsible for patient care. Here, we report the identified mutations, residual ADAMTS13 activity and related clinical data at enrolment with specific emphasis on the recurring ADAMTS13 c.4143_4144dupA mutation.

Results: In the 123 patients with confirmed cTTP, we identified 99 different ADAMTS13 mutations. The most frequent observed mutations were c.4143_4144dupA (exon 29; p.Glu1382Argfs*6; n = 60 alleles), c.3178C>T (exon 24; p.Arg1060Trp; n = 13), and c.577C>T (exon 6; p.Arg193Trp; n = 11). For carriers of ADAMTS13 c.4143_4144dupA, the age at diagnosis was lower in compound heterozygous (median 4 years, range 2–52, n = 16) than in homozygous patients (median 23 years, range 1–48, n = 22) (p = 0.040). In parallel, we found a larger proportion of patients with a disease onset at age < 1 year of age in compound heterozygous versus homozygous patients (44% versus 27%) despite the fact that residual ADAMTS13 activity was < 1% in only 8/14 compound heterozygous, but in 18/20 homozygous carriers. For the other assessed clinical parameters, no marked differences between compound heterozygotes and homozygotes was observed. Apart from two patients in the USA, all patients were from the Scandinavian or Central European regions.

Conclusions: Data from the Hereditary TTP Registry suggest an earlier disease onset in compound heterozygous carriers of ADAMTS13 c.4143_4144dupA as compared with homozygous carriers despite the fact that the latter have an absent ADAMTS13 activity (< 1%) more often (90%) than the former group (57%). The reason for this unexpected finding needs further study.