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ADENOSINE DEAMINASE

(ADA) DEFICIENCY CAUSING


SEVERE COMBINED
IMMUNODEFICIENCY
SYNDROME (SCID)
SECTION A2 – GROUP 10

PESANTE, RAMON JR. B.


Members:
PILAPIL, JANNELA RACHEL
Padilla, George E.
Payoyo, Joy
Rivera, Danecee PILAPIL, JUNFELLE AYE M.
Objectives:
1. To describe and explain the cause of Severe
Combined Immunodeficiency (SCID)

1. To enumerate different kinds of SCID

1. To describe the clinical features of each kind of SCID

1. To discuss how adenosine deaminase (ADA) affects


the immune system

1. To explain diagnostic test procedures for confirmation


of SCID

1. To discuss the treatments of SCID


SEVERE COMBINED
IMMUNODEFICIENCY (SCID)
AND ITS TYPES & CLINICAL
FEATURES

PESANTE, RAMON JR. B.


Severe Combined Immune
Deficiency (SCID)
- defects in different genes involved in the development
and function of infection-fighting immune cells.

-recurrent infections:
○Pneumonia
○Chronic Diarrhea
○Thrush infections of the mouth and skin
○Many other types of infections, including severe viral
and invasive bacterial or fungal infections
Severe Combined Immune
deficiency (SCID)
• often called “bubble boy disease”
ETIOLOGY OF SEVERE
COMBINED
IMMUNODEFICIENCY
(SCID)

PESANTE, RAMON JR. B.


Etiology of SCID
• Mutations in different genes whose
products are crucial for the development
and function of both T and B cells.

➢X-LINKED RECESSIVE INHERITANCE


➢AUTOSOMAL RECESSIVE INHERITANCE
Definition of Terms

Autosomal Recessive Inheritance


- appears only in individuals who have received two copies of an
altered gene, one copy from each parent.
- their parents, each with a single copy of the altered gene, appear
normal.
X – Linked Recessive Inheritance
- gene alteration on the X chromosome
- males affected almost exclusively
- the gene alteration can be transmitted from female carriers to sons
- affected males cannot transmit the condition to their sons
AUTOSOMAL SCID
X - Linked SCID
Types of SCID

X – SCID
Gene Involved: IL2RG gene
Mode of Inheritance: X – Linked Recessive
cell involve: T (-) B (+) NK (-) / T (-) B (+) NK (+)
*IL2RG gene
- codes for a protein called common gamma chain
- common to receptors for IL- 2, 4, 7, 9, 15, and 21
• Normal signaling cannot occur in cells with defective receptors, hence
halting natural maturation
Clinical Manifestation ● failure to thrive
● oral/diaper candidiasis
● recurrent infections
● absence of tonsils and
lymph nodes
Types of SCID

JAK3 – SCID
Gene Involved: JAK3 gene
Mode of Inheritance: Autosomal Recessive
cell involve: T (-) B (+) NK (-)
*JAK3 gene
- 19p13.11 location
- codes for a tyrosine kinase
- lack of JAK3 kinase means that lymphocytes are unable to transmit
signals from IL-2 and IL-4 for maturation of T – Lymphocytes and NK Cells.
- JAK3-deficient SCID have few or no T cells and natural killer cells and a normal
number of poorly functioning B cells.
Clinical Manifestations:
• chronic diarrhea
• failure to thrive
• recurrent respiratory infection and/or generalized infections from opportunistic
pathogens
Types of SCID

RAG Deficient SCID


Gene Involved: RAG1 gene
Mode of Inheritance: Autosomal Recessive
cell involve: T (-) B (-) NK (+)
*RAG1 gene
- Recombinant Activating Genes
- mediate the initial step of somatic recombination of genes encoding (V), (D),
and (J) segments to generate variable types of immunoglobulins and
T-cell receptors.
- Failure of the recombination machinery leads to arrest of both T- and B-cell
development, resulting in SCID
Clinical Manifestations:
• Persistent diarrhea
• Candidiasis
• Lung infections
• Fever
• Opportunistic infections
Types of SCID

SCID Athabaskan(artemis)
Gene Involved: DCLRE1C gene
Mode of Inheritance: Autosomal Recessive
cell involve: T (-) B (-) NK (+)
*DCLRE1C gene
- DNA Cross-Link Repair 1C
- found among Athabascan-speaking Native Americans
- null mutations in the DCLRE1C gene which leads to a defect in the VDJ
combination
- leads to an early arrest of both B and T cell maturation
Clinical Manifestations:
• Failure to thrive
• Severe infections (pneumonia, GI infections, sepsis)
• Recurrent or persistent thrush
• Chronic diarrhea
Types of SCID

Reticular Dysgenesis
Gene Involved: AK2 gene
Mode of Inheritance: Autosomal Recessive
cell involve: T (-) B (-) NK (-)
*AK2 gene
- mutation in the Adenylate Kinase 2 gene
- In bone marrow of individuals with reticular dysgenesis, myeloid differentiation is
blocked at the promyelocytic stage
- absent cellular and humoral immunity functions
Clinical Manifestations:
• Sepsis
• diarrhea
• Failure to thrive
• Fever
• Recurrent infections
• Oral candidiasis
• Perianal infections
Types of SCID

TCR Deficiency SCID


Gene Involved: CD3D, CD3E, CD247 gene
Mode of Inheritance: Autosomal Recessive
cell involve: T (-/low) B (+) NK (+)
*TCR
- T – Cell Receptor
- severe or leaky mutations in the genes encoding for TCR complex
chains
- characterized by a selective TCR complex expression defect frequently
associated with peripheral blood T, but not B or natural killer (NK),
lymphocytopenia
Clinical Manifestations:
• Recurrent respiratory infections
• Chronic diarrhea
• Failure to thrive
Types of Classic Severe Combined
Immunodeficiency
Lymphocyte Phenotype
Disorder Gene(s) MOI
T B NK
X-SCID IL2RG XLR
– + –
JAK3-SCID JAK3 AR
Adenosine
Deaminase ADA – – – AR
Deficiency
RAG1 – – +
RAG-deficient AR
RAG2 – – +
SCID
DCLRE1C – – + AR
Athabaskan
CD3D, CD3E,
TCR deficiency –/Low + + AR
CD247
Reticular
AK2 – – – AR
dysgenesis
Adenosine Deaminase
(ADA) Deficiency

PILAPIL, JUNFELLE AYE M.


Purine Metabolism
Adenosine Deaminase

• Essential enzyme involved in purine metabolism


• Molecular weight of 41kDa
• The gene is on chromosome 20q13.11

DEOXYADENOSINE

ADENOSINE
Types of SCID

Adenosine Deaminase Deficiency


Gene Involved: ADA gene
Mode of Inheritance: Autosomal Recessive
Lymphocyte phenotype: T (-) B (-) NK (-)
*ADA gene
- codes for the enzyme adenosine deaminase
- high concentration in lymphocytes
- protects the cell from the toxic substance deoxyadenosine
Clinical Manifestations:
• Pneumonia
• Chronic diarrhea
• Widespread skin rashes
Adenosine deaminase is first enzyme
in the breakdown of adenosine
nucleotide causes Severe Combined
Immunodeficiency, probably by
blocking ribonucleotide redutase via
excess dATP
DIAGNOSTIC
PROCEDURES

PILAPIL, JUNFELLE AYE M.


• Blood Testing
- lymphopenia
- low serum immunoglobulins
- elevated level of dATP
- very low activity of adenosine deaminase

● DNA testing
- if the SCID or gene defect in SCID is known or present in the
other sibling or other members of the family
• Newborn Screening
– T cell receptor excision circles (TRECs)

• Flow Cytometry
- enumeration of T cell, B cell and even NK cells

• Chest Radiography
- classic SCID show a small or absent thymus
TREATMENTS
FOR
SCID

PILAPIL, JANNELA RACHEL. E.


TREATMENTS

▪ Enzyme Replacement Therapy


▪ Immunoglobulin Replacement Therapy
▪ Hematopoietic Stem Cell Therapy
▪ Gene Therapy
TREATMENTS
✓Enzyme Replacement Therapy

- the administration of an
enzyme for the purpose of
improving a disorder caused
by the lack of a specific
enzyme activity

Example: Adagen
(Pegademase Bovine)
TREATMENTS
✓Immunoglobulin Replacement
Therapy

- replace antibodies to help


rebuild immune system
TREATMENTS

✓Hematopoietic Stem Cell Therapy


- also known as Bone Marrow Transplant
- gold standard treatment
TREATMENTS
✓Gene therapy
- repair of a genetic deficiency through
introduction of a functional recombinant
version of the gene
GENE THERAPY
Newborn Screening
for SCID

PILAPIL, JANNELA RACHEL E.


NEWBORN SCREENING
● important preventive public
health program to assist families
in obtaining early diagnoses,
medical interventions and
services for newborns affected
with rare congenital conditions

1. T-cell receptor excision circles


(TREC) Test
2. Tandem Mass Spectrometry
(TMS)
NEWBORN SCREENING
Severe combined immune deficiency (SCID) is important to be
included in Newborn Screening because:

● SCID can be detected before clinical signs and symptoms are


present.

● Proper management may be given to prevent consequences of


untreated conditions

● Bone marrow transplants are at higher success rate if SCID is


detected early.
THANK YOU
:)