Adenosine Deaminase Deficiency

CLINICAL CHARACTERISTICS

Adenosine deaminase (ADA) deficiency is a systemic purine metabolic disorder that primarily affects lymphocyte development, viability, and function. The ADA deficiency phenotypic spectrum includes typical early-onset severe combined immunodeficiency (-SCID), diagnosed in infancy (about 80% of individuals), and less severe "delayed" or "late-onset" combined immunodeficiency (-CID), diagnosed in older children and adults (15%-20% of individuals). Some healthy individuals who are deficient in red blood cell ADA (termed "partial deficiency") have been discovered by screening populations or relatives of individuals with -SCID. Newborn screening (NBS) for SCID uses extracts from Guthrie card dried blood spots to measure T-cell receptor excision circle (TREC) DNA by polymerase chain reaction (PCR). Screening specific for ADA deficiency can also be performed by detection of elevated levels of adenosine (Ado) and deoxyadenosine (dAdo) by tandem mass spectrometry (TMS). Both techniques can identify -SCID before affected infants become symptomatic. Untreated -SCID presents as life-threatening opportunistic illnesses in the first weeks to months of life with poor linear growth and weight gain secondary to persistent diarrhea, extensive dermatitis, and recurrent pneumonia. Skeletal abnormalities affecting ribs and vertebra, pulmonary alveolar proteinosis, hemolytic anemia, neurologic abnormalities, and transaminitis may also suggest untreated -SCID. Characteristic immune abnormalities are lymphocytopenia (low numbers of T, B, and NK cells) combined with the absence of both humoral and cellular immune function. If immune function is not restored with enzyme replacement therapy (ERT), gene therapy, or hematopoietic stem cell transplantation (HSCT), children with -SCID rarely survive beyond age one to two years. NBS for SCID does not identify individuals with the -CID phenotype whose TREC numbers are above the threshold values of most screening laboratories. However, -CID is identified by TMS NBS since the ADA substrates Ado and dAdo are increased. As TMS NBS for Ado/dAdo is not yet widely performed, individuals with -CID are more often clinically diagnosed between ages one and ten years ("delayed" onset), or less often in the second to fourth decades ("late"/"adult" onset). Because the immunologic abnormalities are less pronounced than those of -SCID, infections in -CID may not be life-threatening and include recurrent otitis media, sinusitis, upper respiratory infections, and human papilloma viral infections. Untreated individuals with -CID can develop over time chronic pulmonary disease, autoimmunity, atopic disease with elevated immunoglobulin E, and malignancy.

DIAGNOSIS/TESTING: The diagnosis of ADA deficiency is established in a proband with suggestive findings either by biochemical testing showing <1% of ADA catalytic activity in red blood cells or in extracts of dried blood spots (valid in untransfused individuals), or by molecular genetic testing identifying biallelic pathogenic variants in . Frequently, both types of testing are performed.

MANAGEMENT

Newborns with an abnormal NBS result suggestive of -SCID (by either method) require immediate protection from risk factors for infection and referral for a subspecialty immunology evaluation at a center with expertise in both diagnosis of SCID and its genetic causes and SCID treatment protocols. Symptomatic treatment involves treatment of infections and use of immunoglobulin infusions and antibiotics, particularly prophylaxis against pneumonia (formerly ) and fungal infections. Prophylaxis against viral infections depends upon exposure and requires frequent surveillance via viral PCR-based testing, with appropriate targeted virus-specific therapy if present. Correcting the ADA deficiency either systemically or selectively in lymphoid cells employs one of three options: (1) enzyme replacement therapy (ERT) by intramuscular administration of PEGylated ADA, (2) allogeneic HSCT, or (3) autologous hematopoietic stem cell gene therapy (HSC-GT) – the latter two are curative. Often, ERT is initiated first to rapidly correct the metabolic defect and to protect against serious infections as well as neurologic/behavioral abnormalities. It is discontinued at the time HSCT or HSC-GT is performed. The following evaluations are recommended to monitor existing and emerging clinical manifestations and the response to targeted treatment and supportive care: (1) absolute lymphocyte subset counts (T, B, NK cells), quantitative serum immunoglobulin levels, and various in vitro tests of cellular and humoral immune function; (2) total red blood cell deoxyadenosine nucleotides (dAXP) and, if on ERT, plasma ADA activity; and (3) screening for Epstein-Bar virus (EBV)-related lymphoma or other lymphomas after age three years, particularly when lymphocyte counts are declining while on prolonged ERT. To ensure the safety of the infant/older individual with ADA deficiency while treatment to achieve immunocompetence is pending, parents and other care providers need to avoid the following risks of infection: (1) breastfeeding and breast milk until maternal CMV status is established by CMV serologies; (2) exposure to young children, sick contacts, individuals with cold sores, crowded enclosed spaces, and sources of aerosolized fungal spores such as areas of construction or soil manipulation; (3) live viral vaccines for the affected infant as well as household contacts; and (4) transfusion of non-irradiated blood products. Medications to avoid include adenine arabinoside, a substrate for ADA, as an antiviral agent and/or as chemotherapy of malignancies; and pentostatin, a potent ADA inhibitor used to treat some lymphoid malignancies, which would be ineffective in persons with ADA deficiency and would interfere with PEGylated ADA. In an at-risk fetus, when the pathogenic variants causing -SCID in the family are known, prenatal genetic testing may be performed to help prepare for optimal management of an affected infant at birth (i.e., identification of a center with expertise in SCID treatment protocols that can help initiate ERT and the search for an HSCT donor and explain ways to ensure the safety of the infant while awaiting HSCT). If prenatal testing has not been performed, an at-risk newborn clinically suspected of SCID should immediately be placed in an appropriate environment to reduce the risk of infection, and the following testing should be performed before administration of a blood transfusion to allow earliest possible diagnosis and initiation of treatment: identification of the pathogenic variants and measurement of ADA catalytic activity and level of dAXP in red blood cells Various approaches to HSC-GT are under investigation.

GENETIC COUNSELING

ADA deficiency is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial pathogenic variants. An individual who inherits two pathogenic variants will have either -SCID or a delayed or late-onset -CID phenotype that correlates with the least severe pathogenic variant inherited. Once the pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal and preimplantation genetic testing are possible.