Hereditary adenosine deaminase deficiency

Classification according to ICD-10
D81.3	Adenosine deaminase [ADA] deficiency
ICD-10 online (WHO version 2019)

The Hereditary adenosine deaminase deficiency is a very rare congenital to the severe combined immunodeficiencies associated (SCID) immune deficiency disease (ADA-SCID) with the features marked lymphopenia and very low immunoglobulin -Spiegeln and repeated serious infections .

Synonyms are: chondrodysplasia, metaphyseal with thymolymphopenia; ADA deficiency; Adenosine deaminase deficiency, severe combined immunodeficiency due to adenosine deaminase (ADA) deficiency; ADA-deficient SCID; Lymphoplasmocytic hereditary dysgenesis; English Adenosine deaminase deficient SCID; Adenosine deaminase deficient, severe combined immunodeficiency

The first description comes from the year 1961 by the Swiss pediatrician WH Hitzig and H. Willi.

distribution

The frequency is given as 1–9 in 1,000,000, inheritance is autosomal - recessive . Both sexes are affected; around 10–15% of SCID diseases have an adenosine deaminase deficiency.

root cause

The lack are mutations in the ADA - gene on chromosome 20 locus q13.12 basis that for the enzyme adenosine deaminase coded. With this enzyme deficiency, the synthesis of dADP, dGDP, dUDP and dCDP is disturbed due to an indirect inhibition of ribonucleotide reductase . Adenosine deaminase deaminates adenosine to inosine and deoxyadenosine to deoxyinosine. In the case of an enzyme deficiency, deoxyadenosine is enriched and increasingly phosphorylated to dATP . Increased concentrations of dATP inhibit ribonucleotide reductase, which inhibits the synthesis of the other deoxyribonucleotides . As a result, there is a disruption of DNA synthesis, which mainly hinders the proliferation of lymphocytes , which causes a severe immune deficiency. The ADA deficiency also leads to toxic levels of purine metabolites .

Classification

Depending on the appearance of the first signs of the disease (and the extent of the enzyme inhibition), the following clinical forms are distinguished:

Early onset (classic ADA deficiency), (in 80%): predominant manifestation in the first 3 months of life. ADA activity <0.01%, additionally with malformations or disorders of the skeleton , kidneys and nervous system as well as hearing loss .
Delayed onset (in 15%): manifestation in 1.-2, LJ; ADA activity 1-2%
Late onset (in 5%): manifestation in the 3rd-15th LJ. ADA activity at 3-5%; Recurrent or persistent herpes simplex infections, bacterial infections of the paranasal sinuses and bronchi , autoimmune diseases
Partial ADA deficiency (rare): manifestation between the 4th year of life and adulthood; ADA activity 5 to 80%

Infections are less severe with higher enzyme activity.

Clinical manifestations

Clinical criteria are:

Manifestation in infancy, at the time of the newborn
Combined cellular and humoral immunodeficiency with decreased immunoglobulins , impaired function of B-lymphocytes and T-lymphocytes
Failure to thrive , chronic diarrhea, short stature , chronic candidiasis
Missing thymus in the sonography , also missing thymus shadow on the chest X-ray
Image of a metaphyseal chondrodysplasia with a square pelvis, short tubular bones distended in the metaphysis , and short ribs

diagnosis

The diagnosis is based on the measurement of the ADA enzyme activity in erythrocytes and can be confirmed by increased dATP levels in the blood plasma and increased deoxy-adenosine in the urine .

In prenatal diagnosis , evidence can be obtained from amniotic or trophoblast cultures.

Differential diagnosis

Other forms of SCID must be distinguished.

therapy

Treatment options include allotransplantation of haematopoietic stem cells , enzyme replacement therapy with pegylated adenosine deaminase, or gene therapy with transformed bone marrow cells .

Healing prospects

The prognosis is determined by the severity of the disease. With early treatment, high survival rates can be achieved.

literature

E. South, E. Cox, N. Meader, N. Woolacott, S. Griffin: Strimvelis for Treating Severe Combined Immunodeficiency Caused by Adenosine Deaminase Deficiency: An Evidence Review Group Perspective of a NICE Highly Specialized Technology Evaluation. In: PharmacoEconomics - open. Volume 3, Number 2, June 2019, pp. 151–161, doi: 10.1007 / s41669-018-0102-3 , PMID 30334168 , PMC 6533345 (free full text) (review).
DB Kohn, MS Hershfield, JM Puck, A. Aiuti, A. Blincoe, HB Gaspar, LD Notarangelo, E. Grunebaum: Consensus approach for the management of severe combined immune deficiency caused by adenosine deaminase deficiency. In: The Journal of allergy and clinical immunology. Volume 143, number 3, March 2019, pp. 852–863, doi: 10.1016 / j.jaci.2018.08.024 , PMID 30194989 , PMC 6688493 (free full text).
AM Flinn, AR Gennery: Adenosine deaminase deficiency: a review. In: Orphanet Journal of Rare Diseases. Volume 13, number 1, 04 2018, p. 65, doi: 10.1186 / s13023-018-0807-5 , PMID 29690908 , PMC 5916829 (free full text) (review).

Individual evidence

↑ ^a ^b Bernfried Leiber (founder): The clinical syndromes. Syndromes, sequences and symptom complexes . Ed .: G. Burg, J. Kunze, D. Pongratz, PG Scheurlen, A. Schinzel, J. Spranger. 7., completely reworked. Edition. tape 2 : symptoms . Urban & Schwarzenberg, Munich et al. 1990, ISBN 3-541-01727-9 .
↑ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j Immunodeficiency, combined severe, due to adenosine deaminase deficiency. In: Orphanet (Rare Disease Database).
↑ ^a ^b Encyclopedia Dermatology
↑ WH Hitzig, H. Willi: Hereditary lymphoplasmocytic dysgenesis (Alymphocytose with Agammaglobulinämia). In: Schweizerische Medizinische Wochenschrift 1961, Vol. 91, pp. 1625–1633
^ Severe combined immunodeficiency due to ADA deficiency. In: Online Mendelian Inheritance in Man . (English)
↑ FX Arredondo-Vega, I. Santisteban, E. Richard, P. Bali, M. Koleilat, M. Loubser, A. Al-Ghonaium, M. Al-Helali, MS Hershfield: Adenosine deaminase deficiency with mosaicism for a "second - site suppressor "of a splicing mutation: decline in revertant T lymphocytes during enzyme replacement therapy. In: Blood. Volume 99, Number 3, February 2002, pp. 1005-1013, doi: 10.1182 / blood.v99.3.1005 , PMID 11807006 .

Web links

[Leiber-1] Bernfried Leiber (founder): The clinical syndromes. Syndromes, sequences and symptom complexes . Ed .: G. Burg, J. Kunze, D. Pongratz, PG Scheurlen, A. Schinzel, J. Spranger. 7., completely reworked. Edition. tape 2 : symptoms . Urban & Schwarzenberg, Munich et al. 1990, ISBN 3-541-01727-9 .

[Orpha-2] ↑ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j Immunodeficiency, combined severe, due to adenosine deaminase deficiency. In: Orphanet (Rare Disease Database).

[Altmeyer-3] Encyclopedia Dermatology

[4] WH Hitzig, H. Willi: Hereditary lymphoplasmocytic dysgenesis (Alymphocytose with Agammaglobulinämia). In: Schweizerische Medizinische Wochenschrift 1961, Vol. 91, pp. 1625–1633

[5] Severe combined immunodeficiency due to ADA deficiency. In: Online Mendelian Inheritance in Man . (English)

[6] FX Arredondo-Vega, I. Santisteban, E. Richard, P. Bali, M. Koleilat, M. Loubser, A. Al-Ghonaium, M. Al-Helali, MS Hershfield: Adenosine deaminase deficiency with mosaicism for a "second - site suppressor "of a splicing mutation: decline in revertant T lymphocytes during enzyme replacement therapy. In: Blood. Volume 99, Number 3, February 2002, pp. 1005-1013, doi: 10.1182 / blood.v99.3.1005 , PMID 11807006 .