GAPO syndrome is a rare,

autosomal recessive In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...

disorder that causes severe growth retardation, and has been observed fewer than 30 times before 2011. GAPO is an acronym that encompasses the predominant traits of the disorder: growth retardation,

alopecia Hair loss, also known as alopecia or baldness, refers to a loss of hair from part of the head or body. Typically at least the head is involved. The severity of hair loss can vary from a small area to the entire body. Inflammation or scarri ...

, pseudoanodontia (teeth failing to emerge from the gums), and worsening

optic atrophy Optic neuropathy is damage to the optic nerve from any cause. The optic nerve is a bundle of millions of fibers in the retina that sends visual signals to the brain. Damage and death of these nerve cells, or neurons, leads to characteristic featu ...

in some subjects. Other common symptoms include

premature aging Progeroid syndromes (PS) are a group of rare genetic disorders that mimic physiological aging, making affected individuals appear to be older than they are. The term ''progeroid syndrome'' does not necessarily imply progeria (Hutchinson–Gilford ...

, large, prominent foreheads, and delayed bone aging. GAPO syndrome typically results in premature death around age 30–40, due to interstitial

fibrosis Fibrosis, also known as fibrotic scarring, is a pathological wound healing in which connective tissue replaces normal parenchymal tissue to the extent that it goes unchecked, leading to considerable tissue remodelling and the formation of perma ...

and

atherosclerosis Atherosclerosis is a pattern of the disease arteriosclerosis in which the wall of the artery develops abnormalities, called lesions. These lesions may lead to narrowing due to the buildup of atheroma, atheromatous plaque. At onset there are usu ...

Signs and symptoms

One of the principle symptoms of GAPO syndrome is growth retardation, caused by slow skeletal formation and results in individuals being below average height.

Alopecia Hair loss, also known as alopecia or baldness, refers to a loss of hair from part of the head or body. Typically at least the head is involved. The severity of hair loss can vary from a small area to the entire body. Inflammation or scarri ...

, or hair loss, is another key indication of GAPO syndrome. Their hair is typically thinly dispersed, and fragile, which often leads to baldness later in life. Similarly, tooth growth is stunted, with teeth failing to emerge form the gums or otherwise develop normally. Atrophy of the optic nerve occurs in approximately one third of individuals. This degradation leads to inhibited peripheral vision, and increased difficulty distinguishing colours. While not a defining feature, most individuals with GAPO syndrome have coarse facial features, and abnormal structure of the middle portion of their faces, typically coupled with a large forehead. Individuals with the disease tend to have depressed nose bridges, protruding ears, and abnormally thick lips, though these symptoms are not unique to this disorder. No direct correlation has been found between GAPO syndrome and mental retardation, though cases of individuals having both have been reported. Due to the severity of the phenotype, GAPO syndrome can be diagnosed very early on. Most cases can be diagnosed by 6 months of age, and most symptoms will be apparent by age 2.

Genetics

GAPO syndrome is caused by a deletion in both copies of the

ANTXR1 Anthrax toxin receptor 1 (ANTXR1 or also known asTEM8) is a protein that in humans is encoded by the ''ANTXR1'' gene. Its molecular weight is predicted as about 63kDa. The protein encoded by this gene is a type I transmembrane protein and is a t ...

gene, which encodes Anthrax Toxin Receptor 1. This gene is critical for the creation of

actin Actin is a family of globular multi-functional proteins that form microfilaments in the cytoskeleton, and the thin filaments in muscle fibrils. It is found in essentially all eukaryotic cells, where it may be present at a concentration of over ...

, and its disruption inhibits proper function of the actin network. As a result, individuals with GAPO syndrome have a buildup of

extracellular matrix In biology, the extracellular matrix (ECM), also called intercellular matrix, is a three-dimensional network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide stru ...

, and degraded

cell adhesion Cell adhesion is the process by which cells interact and attach to neighbouring cells through specialised molecules of the cell surface. This process can occur either through direct contact between cell surfaces such as cell junctions or indir ...

s. The alteration can occur in the form of

nonsense mutation In genetics, a nonsense mutation is a point mutation in a sequence of DNA that results in a premature stop codon, or a ''nonsense codon'' in the transcribed mRNA, and in leading to a truncated, incomplete, and usually nonfunctional protein produc ...

s or mutations which alter the splice sites, and result in alternative

RNA splicing RNA splicing is a process in molecular biology where a newly-made precursor messenger RNA (pre-mRNA) transcript is transformed into a mature messenger RNA (mRNA). It works by removing all the introns (non-coding regions of RNA) and ''splicing'' b ...

, leading to synthesis of a different or modified protein. In humans, the ANTXR1 gene is located on

Chromosome 2 Chromosome 2 is one of the twenty-three pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 2 is the second-largest human chromosome, spanning more than 242 million base pairs and representing almost e ...

and has 22

exons An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequence ...

. GAPO syndrome is inherited in an autosomal recessive fashion, and requires both parents to pass on the mutant genotype. Since this mutation is so rare, most confirmed cases have a history of ancestral inbreeding.

Diagnosis

APO syndrome is a very rare genetic disorder characterized by growth retardation, alopecia, pseudoanodontia and progressive optic atrophy (GAPO). To date, only 30 cases have been described worldwide. Recently, gene alterations in the ANTXR1 gene have been reported to be causative of this disorder, and an autosomal recessive pattern has been observed. This gene encodes a matrix-interacting protein that works as an adhesion molecule. In this report, we describe 2 homozygous siblings diagnosed with GAPO syndrome carrying a new missense mutation. This mutation produces the substitution of a glutamine in position 137 for a leucine (c.410A>T, p.Q137L).

Management

There is currently no cure for GAPO syndrome, but some options are available to reduce the symptoms.

Nearsightedness Near-sightedness, also known as myopia and short-sightedness, is an eye disease where light focuses in front of, instead of on, the retina. As a result, distant objects appear blurry while close objects appear normal. Other symptoms may include ...

, which affects some people with the disease, can be treated by

corrective lens A corrective lens is a lens (i.e. a transmissive optical device) that is typically worn in front of the eye to improve daily vision. The most common use is to treat refractive errors: myopia, hypermetropia, astigmatism, and presbyopia. Glass ...

es. Unfortunately, optic atrophy as a result of degradation of the optic nerve (common with GAPO syndrome) cannot be corrected.

Corticosteroid Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex of vertebrates, as well as the synthetic analogues of these hormones. Two main classes of corticosteroids, glucocorticoids and mineralocorticoids, are involv ...

s have been proposed as a treatment for optic nerve atrophy, but their effectiveness is disputed, and no steroid based treatments are currently available.

History

The first incidence of GAPO syndrome was reported by Anderson and Pindborg in 1947. Another case wasn't recorded until 1978 by Fuks ''et al.''

References

External links

* {{RareDiseases, 400, GAPO syndrome Autosomal recessive disorders Rare syndromes Syndromes affecting stature Genetic disorders with OMIM but no gene