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X-linked diseases, understanding them and examples.

Writer's picture: Roberto CastilloRoberto Castillo

Luis as you are aware from my past articles has a rare x-linked illness caused by a sporadic mutation. It made me question what other rare x-linked illnesses exist, are they similar and do they affect males and females equally or do they predominantly affect one gender, and how are they passed on?


I did some digging below to find answers to share with you about x-linked diseases.


X-linked diseases, how are they passed on?

X-linked inheritance relates to the genes that are passed on via the X chromosome. An X-

A generated example of DNA

linked condition occurs when a pathogenic (viruses, bacteria,) variant in a gene on the X chromosome leads to disease.


Women have two X chromosomes (XX) and men have one X and one Y chromosome (XY). When considering X-linked inheritance, this difference between the sexes is important. As males only have one copy of each X chromosome gene, if they carry the variant then they will be affected by the condition themselves. Fathers will always pass their X chromosome to their daughters and their Y chromosome to their sons.


Because females have two X chromosomes, carriers have a second non-pathogenic (or ‘wild type’) copy of the gene. This means that female carriers are usually not affected by X-linked recessive conditions, or affected only mildly. They may pass either X chromosome to their children.


X-linked dominant inheritance

X-linked dominant inheritance is a way a genetic trait or condition can be passed down from parent to child through mutations (changes) in a gene on a single X chromosome. In females (who have two X chromosomes), a mutation in a gene on one of the X chromosomes is enough to cause the condition. In males (who only have one X chromosome), a mutation in the copy of the gene on the single X chromosome causes the condition. Fathers cannot pass X-linked dominant conditions to their sons, but all daughters of affected fathers will be affected with the condition and can pass it on to their children.


  • Male and female both are affected, but females are affected in excess and less severely.


X-linked recessive inheritance

X-linked recessive inheritance is a way a genetic trait or condition can be passed down from parent to child through mutations (changes) in a gene on the X chromosome. In males a mutation in the copy of the gene on the single X chromosome causes the condition. Females must have a mutation on both X chromosomes in order to be affected with the condition. If only the father or the mother has the mutated X-linked gene, the daughters are usually not affected and are called carriers because one of their X chromosomes has the mutation but the other one is normal. Sons will be affected if they inherit the mutated X-linked gene from their mother. Fathers cannot pass X-linked recessive conditions to their sons.


  • Generally, it manifests only in males.


Sporadic or spontaneous mutation

A researcher who is looking through her microscope

Spontaneous mutations do occur, and the disorder may occur without any family history in some patients. They are not passed on to their children as they may occur for different reasons like damaged DNA when copying cells to create new ones.


There can also be external factors such as being exposed to radiation or chemicals.


Rare x-linked diseases examples


X-linked hypophosphatemia is a rare disorder affecting 1 in 20,000 individuals, XLH occurs when levels of the mineral phosphorus are low in the blood and phosphorus is excreted in urine.


This “wasting” can cause low phosphorus levels in blood called hypophosphatemia. XLH may lead to bone abnormalities and defects that may impair mobility, including bone fractures, hearing loss, ligament and bone pains, and increased risk of infections such as spontaneous dental abscesses. 


XLH may affect individuals at any age. Adults may develop calcification of the tendons, ligaments, and joint capsules, also known as enthesopathies. In the past, XLH was called “hypophosphatemic rickets" or “vitamin D-resistant rickets,” because it resembles the bone problems of vitamin D deficiency but doesn’t respond to vitamin D supplementation. However, there is now a different disorder with this name, caused by problems of vitamin D action. XLH also has been referred to as “phosphate diabetes,” due to the urinary wasting of phosphorus. 


Incontinentia pigmenti (IP) is a rare X-linked dominant genetic disorder that affects the skin, hair, teeth, nails and central nervous system. It is named from its appearance under a microscope.


The disease is characterized by skin abnormalities that begin in childhood, usually a blistering rash which heals, followed by the development of harder skin growths. The skin may develop grey or brown patches which fade with time. Other symptoms can include hair loss, dental abnormalities, eye abnormalities that can lead to vision loss and lined or pitted fingernails and toenails. Associated problems can include delayed development, intellectual disability, seizures and other neurological problems.


The disease occurs, almost exclusively, in females, and is usually fatal in utero (the womb) for males and, therefore, ends in abortion.


X-linked adrenoleukodystrophy is a genetic disorder that mainly affects the nervous system and the adrenal glands, which are located on top of each kidney.


In this disorder, the fatty covering (myelin) that insulates nerves in the brain and spinal cord tends to deteriorate (a condition called demyelination). The loss of myelin reduces the ability of the nerves to relay information to the brain. In addition, damage to the outer layer of the adrenal glands (adrenal cortex) causes a shortage of certain hormones (adrenocortical insufficiency). Adrenocortical insufficiency may cause weakness, weight loss, skin changes, vomiting, and coma.


There are four distinct types of X-linked adrenoleukodystrophy: a childhood cerebral form, an adrenomyeloneuropathy type, an adrenal insufficiency only form, and a type called asymptomatic.


The childhood cerebral form of X-linked adrenoleukodystrophy typically occurs in boys. Girls are rarely affected with this type. If not treated, affected boys experience learning and behavioural problems that usually begin between the ages of 4 and 10.


Over time the symptoms can worsen, and children may have difficulty reading, writing, understanding speech, and comprehending written material. Additional signs and symptoms of the cerebral form include aggressive behaviour, vision problems, difficulty swallowing, poor coordination, and impaired adrenal gland function. The rate at which this disorder progresses is variable but can be extremely rapid, often leading to total disability within a few years.


Learnings

These of course are only a handful of rare x-linked illnesses. What is apparent with more digging is each illness can affect males or females differently and can lean more towards affecting one of the sexes more than the other.


Some of the illnesses have more recorded cases whereas other may have less and only medically recorded information as a guide for patients. That being said in most instances these disorders seldom or almost never affect any two people the same way.



References:

X-linked inheritance — Knowledge Hub


X-linked adrenoleukodystrophy: MedlinePlus Genetics


Orphanet: an online rare disease and orphan drug data base. Copyright, INSERM 1999. Available on https://www.orpha.net. Accessed (27/11/2024).


X-linked dominant inheritance - https://www.cancer.gov/publications/dictionaries/genetics-dictionary/def/x-linked-dominant-inheritance


X-linked recessive inheritance -

https://www.cancer.gov/publications/dictionaries/genetics-dictionary/def/x-linked-recessive-inheritance

 

Marina Basta; Ashish M. Pandya. National Library of Medicine

https://www.ncbi.nlm.nih.gov/books/NBK557383/#:~:text=Because%20of%20the%20availability%20of,Go%20to


Endocrine Society."X-Linked Hypophosphatemia (XLH) | Endocrine Society." Endocrine.org, Endocrine Society, 17 December 2024, https://www.endocrine.org/patient-engagement/endocrine-library/x-linked-hypophosphatemia


https://en.wikipedia.org/wiki/Incontinentia_pigmenti


https://pmc.ncbi.nlm.nih.gov/articles/PMC10722245/

Vaghani UP, Qadree AK, Mehta S, Chaudhary NS, Sharma K, Chaudhary SM, Kelechi AE, Bano K. Bloch-Sulzberger Syndrome: A Rare X-Linked Dominant Genetic Disorder in a Newborn. Cureus. 2023 Nov 15;15(11):e48823. doi: 10.7759/cureus.48823. PMID: 38106755; PMCID: PMC10722245.





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