Clinical Guidance

In the era of newborn screening based on detection of T-cell receptor excision circles (TRECs)/ kappa-deleting recombination excision circles (KRECs) to identify lymphopenia and, increasingly, tandem mass spectrometry (TMS) to detect elevated levels of ADA substrates, ADA deficiency is often identified in asymptomatic infants. Given the broad clinical spectrum of ADA deficiency, determining the diagnosis, prognosis, and need for immediate treatment are challenges for physicians who may have limited experience with ADA deficiency. In this situation, useful guidance can be provided by understanding the correlation between ADA genotype, level of dAXP in red blood cells, ADA catalytic activity in red blood cells, and clinical phenotype.

Source: GeneReviews — "Adenosine Deaminase Deficiency"

Diagnostic Criteria

Adenosine deaminase (ADA) deficiency cannot be diagnosed solely on clinical grounds. The Primary Immune Deficiency Treatment Consortium (PIDTC) has established laboratory-based definitions for severe combined immunodeficiency (SCID) .

Suggestive Findings

The two scenarios in which ADA deficiency may be considered are a and a of any age with suggestive clinical and laboratory findings of combined immunodeficiency (CID). In both scenarios, individuals identified warrant immediate subspecialty immunology evaluation and steps taken to ensure the safety of a baby or older individual pending establishment of the diagnosis and treatment.

Scenario 1: Positive Newborn Screening Result

T-cell receptor excision circles (TRECs) to detect T-cell lymphopenia. As of December 10, 2018, all newborns in the Uni...

Source: GeneReviews — "Adenosine Deaminase Deficiency"

Differential Diagnosis

lists selected genes known to be associated with typical severe combined immunodeficiency (SCID). Note: Other genes (not included in ) have been associated with SCID-like phenotypes in rare instances. Table 3. Typical Severe Combined Immunodeficiency (SCID): Genetic Causes

Management Guidelines

Consensus recommendations for managing severe combined immunodeficiency (SCID) due to adenosine deaminase (ADA) deficiency have been published . These guidelines focus on correction of the ADA deficiency and the restoration of immune function. No recommendations or guidelines have been developed for the management of systemic (non-immunologic) abnormalities associated with ADA deficiency, which varies among medical centers and practitioners.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with ADA deficiency, the following evaluations are recommended, some of which may have been performed as part of the diagnostic evaluation. The frequency and timing of testing may vary by the treating practitioner and the individual's clinical presentation.

Source: GeneReviews — "Adenosine Deaminase Deficiency"

Clinical Guidance

To ensure the safety of the infant or older individual with ADA-SCID or ADA-CID pending definitive treatment to achieve immunocompetence, parents and other care providers need to avoid the following:

• Breastfeeding and breast milk, until maternal cytomegalovirus (CMV) status is established by CMV serologies. CMV is a chronic infection, and intermittent viral shedding in various bodily fluids occurs unpredictably. If maternal CMV serology is negative, breast milk may be considered safe for feeding.

Note: Use of pasteurized breast milk while the infant is being prepared for HSCT remains controversial given the severe negative effects of CMV infection in the outcome of HSCT.

• Exposure to young children, sick contacts, or individuals with cold sores in order to decrease the risk of transmission of disease to the infant

• Crowded enclosed spaces due to risk of infectious exposure

• Live viral vaccines for the infant as well as household contacts until after immunocompetence is restored following HSCT

• Transfusion of non-irradiated blood products .

Source: GeneReviews — "Adenosine Deaminase Deficiency"

Therapies Under Investigation

Hematopoietic stem cell gene therapy (HSC-GT). An experimental approach to HSC-GT for ADA-SCID employing a self-inactivating lentiviral vector has been investigated at the University of California, Los Angeles, and Great Ormond Street Hospital, London. Several studies (NCT01852071, NCT02999984, NCT01380990) have demonstrated safety and efficacy, and no leukemic transformations have been described in ADA HSC-GT recipients treated with lentiviral vectors. This approach has resulted in survival and safety comparable to that of HSCT . Investigation of this promising form of gene therapy was interrupted by the COVID-19 pandemic and other factors , but a new study at the University of California, Los Angeles, is under way (NCT05432310).

Source: GeneReviews — "Adenosine Deaminase Deficiency"

Surveillance Guidelines

Response to targeted therapy. To monitor the individual's response to targeted treatment, the following evaluations are recommended.

• Immune function. Frequent evaluation of lymphocyte counts, serum immunoglobulin levels, and various in vitro tests of cellular and humoral immune function should be performed during ERT and following allogenic HSCT and HSC-GT .

• Biochemical monitoring. If the individual continues to receive ERT for more than one year, periodic monitoring of plasma ADA activity (due to Revcovi®) and red blood cell dAXP levels should be performed. The monitoring interval may be extended to every three to four months in the second year of treatment, and twice yearly thereafter .

Source: GeneReviews — "Adenosine Deaminase Deficiency"