| Nestor-Guillermo progeria syndrome | |
|---|---|
| Other names | NGPS, PSCOO, Progeria syndrome childhood-onset with osteolysis [1] |
| Specialty | Medical genetics |
| Symptoms | premature aging |
| Causes | mutations in the BANF1 gene, in chromosome 11 |
Nestor-Guillermo progeria syndrome is an extremely rare autosomal-recessive progeroid disorder. This disorder is characterized by the same symptoms of other progeria syndromes, which are premature aging with accompanying aged physical appearance, osteolysis (destruction or loss of bone tissue), osteoporosis (disease that makes bones weak and brittle), scoliosis (abnormal lateral curvature of the spine) and lipoatrophy (loss of subcutaneous fat tissue), however, what makes this disorder unique from other progeroid syndromes is the absence of any atherosclerotic, cardiovascular, and metabolic symptoms/complications, this makes the life-span of a person with NGPS potentially longer than the average life-span of someone with progeria itself, although in place of the complications mentioned above, there's also additional symptoms, such as joint stiffness, growth retardation, facial dysmorphisms, wide cranial sutures, micrognathia (lower jaw is abnormally small), atrophic skin and a high risk of developing severe skeletal abnormalities [2] [3] [4]
In NGPS, hallmark features include: [5] [2]
This syndrome is caused by mutations in the BANF1 gene, in chromosome 11q13.1, and is inherited in an autosomal recessive pattern. [5] [6] [7] BANF1 encodes a small chromatin and nuclear enveloped-associated protein (BAF) that binds double-stranded DNA and interacts with nuclear envelope proteins. In NGPS, the A12 mutation (homozygous missense mutation) does not appear to destabilize the protein but it reduces its affinity for binding DNA. Recent data shows that the A12T mutation weakens the interaction between BAF and lamin A/C. This causes increased nuclear envelope fragility leading to more frequent re-reruptures despite repair still occurring. The nuclear envelope defects likely underlie the accelerated “aging” phenotype. Cells may accumulate damage more rapidly, fail to maintain nuclear structure, leading to downstream defects in the skeleton, connective tissues, etc. Because so few cases have been described, other variants may exist but to date the A12T is the only-well documented one. [8] [9]
Under the assumption of an autosomal recessive mode of inheritance, Puente conducted exon enrichment and massively parallel sequencing on DNA samples from the proband — the first individual in a family to be identified as having a genetic disorder or trait — and both parents in a Spanish family whose child had an atypical progeroid syndrome and tested negative for mutations in the LMNA and ZMPSTE24 genes. They discovered four variations, three of which were found in a lengthy, continuous region of homozygosity on chromosome 11q13, that were homozygous in the proband and heterozygous in the parents. [5]
Although the syndrome is classified as "chronic" and progresses more slowly than other types of progeria, it may have a longer lifespan. However, it is still a serious condition. [2]
This rare disorder was discovered when 2 seemingly healthy twin boys named Nestor and Guillermo were born in Spain, starting at the age of 2, they rapidly started aging, when they were 10 years old, they had lost their hair, their skin started wrinkling, their bones started weakening and their stature barely increased, it was clear they had progeria; however, their doctors couldn't find what type of progeria they had, since they didn't present cardiovascular abnormalities and they didn't have the known genetic mutations of the mentioned progeroid syndromes, that's when their shared genetic mutations (BANF1), which was not present in other known progeria syndromes, according to genetic testing, was discovered, and with that discovery came the revelation of a novel progeroid syndrome, by 2011, they were already 20–30 years old. [10] [11] Still, the phenotype of these NGPS patients is unique. They have no symptoms of hypertriglyceridemia (elevated levels of triglycerides [fats] in the bloodstream), diabetic mellitus, or cardiovascular damage at the ages of 32 and 24. Their quality of life is negatively impacted by severe skeletal abnormalities on the other hand.
Whereas A12T mutant BANF1 mRNA levels were comparable to those of wild type patients, BANF1 A12T protein was identified at a significantly lower level, according to Puente et al.[ citation needed ] Another study proposed that the A12T mutation was not unstable and that the reduced protein levels were only a consequence of changes in antigenicity to the BANF1 antibody. Therefore, the researchers reasoned that the NGPS phenotype might be explained by further effects of this mutation on protein function. [5] [9]
Nestor-Guillermo Progeria Syndrome (NGPS) differs from other progeroid syndromes in certain ways. NGPS is caused by autosomal recessive mutations in the BANF1 gene and does not include vascular issues, [5] in contrast to Hutchinson-Gilford Progeria Syndrome (HGPS), which is caused by LMNA mutations and results in severe heart and blood-vessel disease early in life. Instead, NGPS primarily impacts the skeleton, leading to severe bone disorders such scoliosis, osteolysis, and osteoporosis. These issues significantly restrict mobility, although they do not significantly reduce life expectancy like HGPS does. [2] Another difference is Werner syndrome, often known as "adult progeria," which appears later in life and is brought on by mutations in the WRN gene. Its symptoms include blindness, diabetes, and an increased risk of cancer. [12] Defects in DNA repair cause Cockayne syndrome, which results in neurological issues and excessive sun sensitivity. [13] These comparisons collectively show how separate genetic pathways cause premature-aging illnesses that impact different body sections. Understanding these differences amongst progeroid syndromes helps to explain the special difficulties that NGPS presents and highlights the need for treatment plans that are customized to its specific molecular and clinical characteristics.
There is currently no specific treatment for Nestor-Guillermo progeria syndrome (NGPS); care mainly focuses on relieving symptoms and maintaining mobility and bone health through orthopedic treatment, physiotherapy, and nutritional support (e.g., calcium and vitamin D). [14] One drug that has shown benefit in related progeroid disorders is lonafarnib, a type of medication known as a farnesyltransferase inhibitor (FTI). This therapy works by blocking an enzyme that adds a farnesyl group (a lipid attachment) to certain proteins, including defective forms of lamin A in Hutchinson-Gilford progeria syndrome (HGPS). In HGPS, this process prevents abnormal proteins from damaging the nuclear membrane, which helps cells function more normally. Clinical studies have shown that lonafarnib can improve blood vessel health, strengthen bones, and increase lifespan in children with HGPS. Although NGPS involves a different gene (BANF1) and lacks cardiovascular complications, lonafarnib’s mechanism offers insight into potential future therapies for NGPS by targeting similar cellular aging pathways. [2]
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