Knowledge on rare diseases and orphan drugs

The worldwide disease prevalence is estimated at 1/220,000 based on population genetic studies, with 628 cases reported in the literature and no sex predominance. Approximately 35,000 patients may be undiagnosed globally. The aggregated carrier frequency of pathogenic variants (PV) is 1/236, with some PVs more frequent in specific populations due to a founder effect.

The first signs of the disease can be chronic and mild, or severe and acute—such as an early onset stroke. Manifestations can vary even among family members with the same genotype. Deficiency of adenosine  2 (DADA2) can affect 22 organs and can result in 135 signs and symptoms. It can roughly be categorized in four phenotypes which are not mutually exclusive: 1) presymptomatic (identified by family screening), 2) autoinflammatory/vasculitic, 3) hematologic and 4) immunodeficient. The inflammatory/vasculitic phenotype is characterized by episodic fever, inflammation and/or manifestations of vasculitis such as ischemia and necrosis of different tissues and organs leading to internal bleeding, strokes, neuropathies, and other vasculitis-related complications. Cutaneous manifestations (livedo racemosa, skin ulcers, necrosis, rashes, etc.) are reported in a majority of patients. The hematologic phenotype is characterized by variable anemia (red cell aplasia or autoimmune hemolytic anemia), neutropenia, thrombocytopenia, or pancytopenia. Patients may also present with lymphoproliferative disease. The immunodeficient phenotype is characterized by recurrent/opportunistic infections associated with hypogammaglobulinemia and lymphopenia.

DADA2 is a rare autosomal recessive disease caused by mutations in the adenosine deaminase 2 gene (ADA2) resulting in a loss of function or reduced function, of the ADA2 enzyme. Currently there are > 165 mutations in ADA2 associated with this disease.

Disease suspicion is based on clinical features and family history. Diagnosis is confirmed by measuring serum or plasma ADA2 activity (normal ranges may vary by laboratory) and/or targeted ADA2 sequencing. ADA2 is included in most gene panels for inborn errors of immunity and autoinflammatory syndromes. A complete clinical examination (blood pressure, ophthalmology, blood tests including biochemical analysis, liver/renal function tests and cell count, brain MRI/MRA, abdominal ultrasound, and any necessary additional organ-specific test) is essential to fully establish the phenotype.

The differential diagnosis includes: 1)  (classic and/or cutaneous) polyarteritis nodosa or Sneddon syndrome for the vasculitic phenotype; 2)  Diamond-Blackfan anemia, Evans Syndrome, thrombocytopenic purpura and different autoimmune lymphoproliferative disease for the hematologic phenotype ; 3) different forms of congenital neutropenia and other primary immunodeficiencies.

Prenatal testing is possible when a PV was identified in the family.

Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.

Management of the disease requires a multidisciplinary team. Lifelong TNFi is the treatment of choice for DADA2 patients with vasculitis, stroke and/or evidence of persistent systemic inflammation. Antiaggregants, anticoagulants and antithrombotics should be avoided due to potential risk of brain hemorrhage. Hematopoietic stem cell transplantation (HSCT) is recommended for patients with bone marrow failure, refractory immune cytopenia, refractory vascular involvement and severe immunodeficiency. Antimicrobial prophylaxis and immunoglobulin replacement or routine inactivated vaccines should be considered for immunodeficient patients. Preventive TFNi treatment in asymptomatic patients is subject of contention.

Small cohorts estimate mortality at ~ 8% before age 30, but it may be higher due to underdiagnosis. Prognosis mainly depends on complications from vasculitis (acute strokes) or recurrent infections. Severe manifestations can be life-threatening or cause disability if unmanaged.

Last update: December 2024 - Expert reviewer(s): Dr Eugene CHAMBERS