Wiskott-Aldrich Syndrome
| Classification according to ICD-10 | |
|---|---|
| D82.0 | Wiskott-Aldrich Syndrome
Immunodeficiency with thrombocytopenia and eczema |
| ICD-10 online (WHO version 2019) | |
The Wiskott-Aldrich syndrome ( WAS ) is an X-linked recessive inherited disease with insufficiency of blood coagulation and the immune system , which is characterized by the triad of symptoms - eczema (skin rash), thrombocytopenia (lack of blood platelets) and recurrent infections. The incidence in live male babies is approximately 1: 100,000 to 1: 250,000. Life expectancy is generally no more than ten years.
The syndrome is named after the German pediatrician Alfred Wiskott (1898–1978) and the American Robert Anderson Aldrich (1917–1998).
root cause
Mutations in the so-called Wiskott-Aldrich syndrome gene (abbreviation WAS gene, gene locus Xp11.23-p11.22) lead to impairment of cellular signal transmission. The actin polymerization is restricted, whereby the platelet enbildung from the megakaryocytes is reduced.
Symptoms
Shortly after birth, the first punctiform (petechial) bleeding occurs in the newborn as a result of thrombocytopenia , and gastrointestinal and intracranial bleeding occurs in later years. The typical eczema similar to atopic dermatitis also develops in the first days of life.
While T-cell immunity is still normal at the beginning, humoral immunity is already significantly reduced in the first year of life. The T-cell immunity decreases continuously over the next few years, which increases the susceptibility to infection. Recurrent, opportunistic infections such as pneumonia , otitis , septicemia and meningitis occur for the first time in the second year of life . Common pathogens are pneumococci , Haemophilus influenzae , meningococci and Pneumocystis jirovecii .
The young patients often suffer from autoimmune diseases such as vasculitis , arthritis and hemolytic anemia at the same time . Malignancies of the lymphoreticular system are found more frequently in Wiskott-Aldrich patients.
Diagnosis
The following characteristic changes lead the suspicion of Wiskott-Aldrich syndrome:
- The IgM - antibodies are lowered, the IgG antibodies normally high, IgA , IgD and IgE increased above the norm.
- The blood count typically shows severe thrombocytopenia with small blood platelets (low mean platelet volume = MPV).
- The vaccine antibodies are reduced.
- Severe lymphopenia first occurs after the age of six .
In Wiskott-Aldrich syndrome, the Wiskott-Aldrich protein (WASP) is not formed properly. WASP is needed for the organization of the cytoskeleton . If the protein in the hematopoietic stem cells is missing , T and B lymphocytes, macrophages , dendritic cells , NK cells and platelets are not fully functional. It can be used to confirm the diagnosis.
The diagnosis is confirmed by a molecular genetic examination using mutation analysis. A prenatal diagnosis is also possible.
therapy
Causal therapy
A functional immune system can be restored through a stem cell transplant . Gene therapy measures are used in controlled clinical studies . A first clinical study was started in 2006 at the Hannover Medical School . Initial results showed that hematopoietic stem cell transplantation through gene therapy (HSCT-GT for short) can restore the immune system in WAS patients with hematopoietic stem cell gene therapy using retrovirally modified stem cells. The children treated in this way showed a significant improvement in their symptoms over time or were symptom-free (no signs of bleeding, fewer infections, no eczema).
The healing successes achieved after a single HSCT-GT appeared after several weeks and months and could be observed over a long period of time (usually several years). While the sustainability and feasibility of HSCT-GT in WAS could be proven, there was an unacceptably high incidence of serious side effects (myelodysplastic syndromes and leukemia).
Due to these side effects, the gamma retroviral HSCT-GT can no longer be used to treat WAS. However, lentiviral HSCT-GT for the treatment of WAS are currently in clinical trials. The lentiviral HSCT-GT is assumed to have an improved safety profile.
In a scientific publication, the group headed by Christoph Klein , head of the study, reports that seven out of nine patients in whom gene therapy was successful have developed acute leukemia ; so far, eight out of nine patients have acute leukemia or myelodysplastic syndrome ill. Three of them died of the disease; to treat the leukemia, in addition to chemotherapy, an external donor market transplant was necessary in all cases . Further lentiviral HSCT-GT are in the follow-up phase; as described above, an improved safety profile is assumed here.
Symptomatic therapy
The affected patients must be given consistent antibiotic treatment at an early stage at the first sign of infection. Cotrimoxazole is used for pneumocystis prophylaxis, penicillin V for pneumococcal prophylaxis. The missing immunoglobulins can be replaced. If the bleeding is severe, platelet concentrates are transfused.
Individual evidence
- ↑ K. Boztug, M. Schmidt, A. Schwarzer, PP Banerjee, IA Díez, RA Dewey, M. Böhm, A. Nowrouzi, CR Ball, H. Glimm, S. Naundorf, K. Kühlcke, R. Blasczyk, I Kondatenko, L. Maródi, JS Orange, C. von Kalle, C. Klein : Stem-cell gene therapy for the Wiskott-Aldrich syndrome. In: N Engl J Med. 2010 Nov 11; 363 (20), pp. 1918-1927. PMID 21067383
- ^ A b Christian Jörg Braun, Kaan Boztug, Anna Paruzynski, Maximilian Witzel, Adrian Schwarzer: Gene Therapy for Wiskott-Aldrich Syndrome — Long-Term Efficacy and Genotoxicity . In: Science Translational Medicine . tape 6 , no. 227 , March 12, 2014, p. 227ra33 , doi : 10.1126 / scitranslmed.3007280 , PMID 24622513 .
- ↑ Alessandro Aiuti, Luca Biasco, Samantha Scaramuzza, Francesca Ferrua, Maria Pia Cicalese: Lentiviral hematopoietic stem cell gene therapy in patients with Wiskott-Aldrich syndrome . In: Science . tape 341 , no. 6148 , 23 August 2013, p. 1233151 , doi : 10.1126 / science.1233151 , PMID 23845947 , PMC 4375961 (free full text).
