SRD5A3-CDG | |
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Other names | CDG syndrome type Iq, CDG-Iq, CDG1Q or Congenital disorder of Glycosylation type 1q |
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SRD5A3 gene | |
Specialty | Medical genetics |
Causes | Mutation in the steroid 5 alpha reductase type 3 gene |
Frequency | Ultra rare |
SRD5A3-CDG (also known as CDG syndrome type Iq, CDG-Iq, CDG1Q or Congenital disorder of glycosylation type 1q) is a rare, non X-linked congenital disorder of glycosylation (CDG) [1] due to a mutation in the steroid 5 alpha reductase type 3 gene. It is one of over 150 documented types of Congenital disorders of Glycosylation. [2] Like many other CDGs, SRD5A3 is ultra-rare, with around 38 documented cases in the world. [3]
It is an inheritable autosomal recessive disorder that causes developmental delays and problems with vision. The gene is located at 4q12, which is the long (q) arm of chromosome 4 at position 12. [4]
SRD5A3-CDG is characterized by a highly variable phenotype. [5] Typical clinical manifestations include:
Less common manifestations may include:
The protein encoded by the SRD5A3 gene is involved in the production of androgen 5-alpha-dihydrotestosterone (DHT) from testosterone, and maintenance of the androgen-androgen receptor activation pathway. [7]
This protein is also necessary for the conversion of polyprenol into dolichol, which is required for the synthesis of dolichol-linked monosaccharides and the oligosaccharide precursor used for N-linked glycosylation of proteins. Dolichol is a key building block in the body's glycosylation process. [8] Typically, the dolichol generated is further modified into dolichol-linked oligosaccharide (DLO) by the addition of phosphates and sugars. Complex sugar molecules get added to DLO and are then transferred onto proteins. When insufficient DLO is produced in the body, many proteins are inadequately glycosylated.
Both glycosylation defects and an accumulation of polyprenol have been observed in SRD5A3-CDG patients and mouse models, and it is not currently known whether the disease is caused due to incorrect glycosylation, polyprenol accumulation, or a combination of the two.
Confirmation of clinical diagnosis for SRD5A3-CDG requires genetic testing and gene sequencing to identify deleterious mutations in the SRD5A3 gene. Other diagnostic tools include Isoelectrofocusing of Transferrin (TIEF), an assay from transferrin levels in blood, to screen for N-glycosylation defects [9] which occur in CDGs. A CDG blood analysis test using mass spectrometry technology is also available.
As SRD5A3-CDG is also an inheritable disorder, [10] parental genetic testing can indicate if one or both of the parents are carriers of the faulty gene. The gene is recessive in nature, so if both parents are carriers of the condition, there is a 25% chance that the offspring will have SRD5A3-CDG.
At present, there is no available treatment for SRD5A3-CDG. However, the disorder can be managed and some of the symptoms can be treated. [11] Some eye problems that manifest with SRD5A3-CDG can be surgically corrected and coagulation disorders may be treated.
The quality of life is mainly determined by the nature and the degree of the brain and eye involvement. Ongoing care and management for individuals with SRD5A3-CDG typically includes a combination of physical therapy (to alleviate issues pertaining to reduced muscle tone, mobility, etc.), occupational therapy (for vision and speech impairments) and palliative measures, where needed.
When a genetic risk or anomaly is identified, parents may have access to counselling to prepare them for any special needs their child may have and approaches on managing their condition as they grow.
SRD5A3-CDG is an ultra-rare disorder with a frequency of less than 1 in 10 million. [12] As of 2018, there were at least 38 reported cases of SRD5A3-CDG from 26 different families. While the exact number of patients worldwide is unknown, most recorded cases so far have been reported from Afghanistan, the Czech Republic, Iran, Pakistan, Poland, Puerto Rico and Turkey. [13]
SRD5A3-CDG is caused by a single-gene mutation, which makes it an attractive candidate for gene therapy. However, due to the extreme rarity of the disorder, research around it has been limited.
Research has predominantly been focused on two types of research models: Cell-based models and model organisms. [14]
Common cell-based models include patient cells such as fibroblast cells derived from skin samples (patient-derived fibroblasts [PDFs]), induced pluripotent stem cells (iPSCs) created by reprogramming fibroblasts, and specialized cells, such as neurons derived from stem cell differentiation. Patient-derived cell models are important preclinical model systems as they contain the same genome and mutation(s) as the patient, allowing researchers to assess potential therapies for individual patients early on in the drug development process. For SRD5A3-CDG, patient-derived cell models could be crucial in understanding the impact of polyprenol reductase enzyme deficiency and be used to investigate various treatment options such as dietary supplementation, novel or repurposed drugs and gene therapy.
Model organisms like worms, zebrafish and mice have been genetically modified to study the impact of several mutations, including those in the SRD5A3 gene. Researchers in the United States and France have been working on genetically modified mice that have SRD5A3 mutations limited to the cerebellum region of their brain. [15] These mice are viable, show CDG symptoms in the brain, and are part of planned studies for new experimental treatments.
A congenital disorder of glycosylation is one of several rare inborn errors of metabolism in which glycosylation of a variety of tissue proteins and/or lipids is deficient or defective. Congenital disorders of glycosylation are sometimes known as CDG syndromes. They often cause serious, sometimes fatal, malfunction of several different organ systems in affected infants. The most common sub-type is PMM2-CDG where the genetic defect leads to the loss of phosphomannomutase 2 (PMM2), the enzyme responsible for the conversion of mannose-6-phosphate into mannose-1-phosphate
Fukuyama congenital muscular dystrophy (FCMD) is a rare, autosomal recessive form of muscular dystrophy (weakness and breakdown of muscular tissue) mainly described in Japan but also identified in Turkish and Ashkenazi Jewish patients; fifteen cases were first described on 1960 by Dr. Yukio Fukuyama.
Congenital muscular dystrophies are autosomal recessively-inherited muscle diseases. They are a group of heterogeneous disorders characterized by muscle weakness which is present at birth and the different changes on muscle biopsy that ranges from myopathic to overtly dystrophic due to the age at which the biopsy takes place.
Dolichyl pyrophosphate Man9GlcNAc2 alpha-1,3-glucosyltransferase is an enzyme that in humans is encoded by the ALG6 gene.
UDP-N-acetylglucosamine—dolichyl-phosphate N-acetylglucosaminephosphotransferase is an enzyme that in humans is encoded by the DPAGT1 gene.
Alpha-1,3/1,6-mannosyltransferase ALG2 is an enzyme that is encoded by the ALG2 gene. Mutations in the human gene are associated with congenital defects in glycosylation The protein encoded by the ALG2 gene belongs to two classes of enzymes: GDP-Man:Man1GlcNAc2-PP-dolichol alpha-1,3-mannosyltransferase and GDP-Man:Man2GlcNAc2-PP-dolichol alpha-1,6-mannosyltransferase.
Beta-1,4-galactosyltransferase 7 also known as galactosyltransferase I is an enzyme that in humans is encoded by the B4GALT7 gene. Galactosyltransferase I catalyzes the synthesis of the glycosaminoglycan-protein linkage in proteoglycans. Proteoglycans in turn are structural components of the extracellular matrix that is found between cells in connective tissues.
Dolichol-phosphate mannosyltransferase is an enzyme that in humans is encoded by the DPM1 gene.
Dolichyl-P-Man:Man(7)GlcNAc(2)-PP-dolichyl-alpha-1,6-mannosyltransferase is an enzyme that in humans is encoded by the ALG12 gene.
Dolichyl-P-Man:Man(5)GlcNAc(2)-PP-dolichyl mannosyltransferase is an enzyme that, in humans, is encoded by the ALG3 gene.
Dehydrodolichyl diphosphate synthase is an enzyme that in humans is encoded by the DHDDS gene.
Wrinkly skin syndrome(WSS) is a rare genetic condition characterized by sagging, wrinkled skin, low skin elasticity, and delayed fontanel (soft spot) closure along with a range of other symptoms. The disorder exhibits an autosomal recessive inheritance pattern with mutations in the ATP6V0A2 gene, leading to abnormal glycosylation events. There are only about 30 known cases of WSS as of 2010. Given its rarity and symptom overlap to other dermatological conditions, reaching an accurate diagnosis is difficult and requires specialized dermatological testing. Limited treatment options are available but long-term prognosis is variable from patient-to-patient, on the basis of individual case studies. Some skin symptoms recede with increasing age while progressive neurological advancement of the disorder causes seizures and mental deterioration later in life for some patients.
Congenital disorder of glycosylation type IIc or Leukocyte adhesion deficiency-2 (LAD2) is a type of leukocyte adhesion deficiency attributable to the absence of neutrophil sialyl-LewisX, a ligand of P- and E-selectin on vascular endothelium. It is associated with SLC35C1.
Steroid 5-alpha-reductase 3, also known as 3-oxo-5-alpha-steroid 4-dehydrogenase 3, is an enzyme that in humans is encoded by the SRD5A3 gene. It is one of three forms of 5α-reductase.
Polyprenol reductase (EC 1.3.1.94, SRD5A3 (gene), DFG10 (gene)) is an enzyme with systematic name ditrans,polycis-dolichol:NADP+ 2,3-oxidoreductase. This enzyme catalyses the following chemical reaction
PGM3 deficiency is a rare genetic disorder of the immune system associated with diminished phosphoglucomutase 3 function. PGM3 is an enzyme which in humans is encoded by gene PGM3. This disorder manifests as severe atopy, immune deficiency, autoimmunity, intellectual disability, and hypomyelination. In 2014, Investigators Atfa Sassi at the Pasteur Institute of Tunis, Sandra Lazaroski at the University Medical Center Freiburg, and Gang Wu at the Imperial College London, identified PGM3 mutations in nine patients from four consanguineous families. In the same year, a researchers from the laboratories of Joshua Milner and Helen Su at the National Institute of Allergy and Infectious Disease at the U.S. National Institutes of Health described PGM3 deficiency in eight additional patients from two families.
WNT4 deficiency is a rare genetic disorder that affects females and it results in the underdevelopment and sometimes absence of the uterus and vagina. WNT4 deficiency is caused by mutations of the WNT4 gene. Abnormally high androgen levels are found in the blood and can initiate and promote the development of male sex characteristics. This is seen as male pattern of hair growth on the chest and face. Those with this genetic defect develop breasts but do not have their period. Mayer–Rokitansky–Küster–Hauser syndrome is a related but distinct syndrome. Some women who have an initial diagnosis of MRKH have later been found to have WNT4 deficiency. Most women with MRKH syndrome do not have genetic mutations of the WNT4 gene. The failure to begin the menstrual cycle may be the initial clinical sign of WNT4 deficiency. WNT4 deficiency can cause significant psychological challenges and counseling is recommended.
PMM2 deficiency or PMM2-CDG is a very rare genetic disorder caused by mutations in PMM2. It is an autosomal recessive disorder. A defective copy of the PMM2 gene is the most common cause of a disease called “congenital disorders of glycosylation” or “PMM2-CDG”. PMM2-CDG is the most common of a growing family of more than 130 extremely rare inherited metabolic disorders. Only about 1000 children and adults have been reported worldwide.
ALG1-CDG is an autosomal recessive congenital disorder of glycosylation caused by biallelic pathogenic variants in ALG1. The first cases of ALG1-CDG were described in 2004, and the causative gene was identified at the same time. This disorder was originally designated CDG-IK, under earlier nomenclature for congenital disorders of glycosylation. Clinically, individuals with ALG1-CDG have developmental delay, hypotonia, seizures and microcephaly. Fewer than 60 cases of ALG1-CDG have been confirmed in published literature. ALG1-CDG can be suspected based on clinical findings, and abnormal serum transferrin glycosylation test results. Confirmation of the diagnosis can be performed based on sequence analysis of ALG1. The analysis of ALG1 is complicated by the presence of a pseudogene. There are no specific treatments for ALG1-CDG, and most care consists of managing symptoms.
SLC35A1-CDG is a rare inherited disorder that mainly affects the vascular systems of the body. It forms part of a large group of disorders called congenital disorders of glycosylation. It is caused by mutations in the SLC35A1 gene, located in the sixth chromosome.