APA (Old Order Amish; Eastern Pennsylvania)
MEN (General Swiss-German Mennonite)
OOA (Old Order Amish)

Inheritance: autosomal recessive
Genes: ADA

SCID due to ADA deficiency
ADA-SCID
Partial ADA deficiency


Recurrent infection

Immunodeficiency

Hepatosplenomegaly

Adenopathy

Failure to thrive

Eosinophilia

Alymphocytosis

ADA deficiency

T cell negative

B cell negative

NK negative

Severe Combined Immunodeficiency (ADA deficiency)

CLINICAL CHARACTERISTICS:


General description (for patients):

This is actually a category of disease rather than a single disease, and much remains to be learned.  At least three specifically characterized types have been reported in plain people, with yet others incompletely studied.  The common denominator is reduced resistance to infection.   This may result in early death in infants or young children if unrecognized and untreated.  Such infants may often have chronic diarrhea and loss of fluids with failure to thrive.  Other signs are enlarged liver, spleen, and lymph glands.

Medical description: 

Severe combined immunodeficiency has been recognized around the world since the 1970s, and its familial nature was evident early.  It has been diagnosed in numerous sibships of plain people for about the same length of time and several specific types have been reported.  Unfortunately the mortality in such families is often high due to delayed diagnosis and the high cost of treatment.  The classic SCID disease is due to a deficiency of the enzyme adenosine deaminase gene (ADA deficiency type).  Patients are often T cell-negative (T-), B cell-negative (B-), and natural killer cell negative (NK-).  The common phenotypic feature is reduced cellular immunity but there is a wide range in degree of enzyme deficiency resulting in considerable variation in the amount of resistance to systemic infections.  Consequently, longevity is also variable.
Two forms of T-B+NK+ SCID have also been identified among plain people as well as a form of Omenn syndrome (T+B-NK+).  The latter characteristically presents with alopecia and markedly erythematous, scaly skin at birth, infiltrated with histiocytes and esosinophils.  As in other types of SCID, lymphadenopathy, hepatosplenomegaly, failure to thrive, severe diarrhea, and septicemia are often present.  Yet other varieties of SCID undoubtedly remain to be discovered.

Genetics: 

The locus for the ADA gene is located on chromosome 20 (20q13.11).  However, multiple mutations are responsible accounting for some of the phenotypic variability.  Mutations in the RAG1 and RAG2 genes on chromosome 11 (11p13) and the DCLRE1C gene on chromosome 10 (10p) have been associated with the Omenn syndrome.  All are recessive disorders.  Adenosine deaminase deficiency due to a c.648G>A mutation is responsible for alymphocytosis (T-B-NK-) found among Amish and Mennonites in Eastern Pennsylvania and elsewhere.

Treatment: 

Some forms of SCID are treatable, particularly those with ADA deficiency.  Replacement of normal ADA using transfusions of ADA positive red blood cells can be temporarily beneficial.  The use of polyethylene glycol-modified bovine intestinal ADA (PEG-ADA) can also improve lymphocyte numbers.  Longer survival is possible with bone marrow transplantation using HLA genotypically identical donors and it can be demonstrated that T and B-cell numbers increase following such treatment.  It has been suggested that the Omenn syndrome is curable with HLA-identical bone marrow transplantation following parenteral nutrition and immunosuppressive therapy.
ADA deficiency has become a model for the treatment of at least some genetic disorders.  Using retroviruses engineered to contain the gene for ADA, it has been possible to restore enzyme function in bone marrow CD34+ cells in a small number of patients.
PROGNOSIS:  Dependent upon prompt diagnosis and treatment as well as type of SCID.  Untreated, most die in infancy, but treated patients have lived into the second decade of life.

Ancillary treatments and support: 

Prevention of infections, appropriate and immediate antibiotic intervention, and close monitoring of the immune system are essential.
SPECIALISTS AND SPECIALTY CENTERS:  Immunologist, Infectious Disease Specialist, Pediatrician, Nutritionist.

References:

Strauss, K.A., Puffenberger, E.G., Bunin, N., Rider, N.L., Morton, M.C., Eastman III, J.T., and Morton, D.H.:  Clinical application of DNA microarrays: molecular diagnosis and HLA matching of an Amish child with severe combined immune deficiency.  Clin. Immun. 128: 31-38, 2008. PubMed ID: 18442948

Buckley, R. H.:  Molecular defects in human severe combined immunodeficiency and approaches to immune reconstitution.  Annu. Rev. Immun. 22: 625-655, 2004. PubMed ID: 15032591

Resources:

Immune Deficiency Foundation

Associated Graphics