13 Rare Genetic Disorders And How They Are Inherited

A genetic disorder, in layman’s terms, is a serious medical condition triggered by irregularities in the genome (gene) which can either be hereditary (inherited from parents) or caused by new alterations to the DNA.

They can be divided into two broad classes; single-gene and multiple gene disorder. In a single-gene disorder, also known as monogenic, only a particular gene is mutated or permanently altered. Most metabolic disorders are caused by single-gene defects. On the other hand, multi-gene disorders are more complex and include more than one faulty gene. They are generally difficult to predict and are largely influenced by environmental factors.

While not all genetic disorders are fatal or directly lead to death, there are currently no known remedies to cure such diseases. Below, we have compiled a list of rare genetic disorders known to us. We have also mentioned the manner in which each of these genetic disorder is inherited.

13. DiGeorge Syndrome

DiGeorge syndromeAn infant with DiGeorge Syndrome   Image courtesy: National Center for Biotechnology Information

Inheritance Pattern: Autosomal dominant (only one affected parent)

22q11.2 deletion syndrome, more commonly known as DiGeorge syndrome is a relatively rare genetic disorder caused by defective chromosome 22. Basically, a small section of chromosome 22 containing about 30 genes is deleted from the DNA.

Symptoms include facial deformities, congenital heart defects (present from birth), along with kidney problems and hearing loss. Patients suffering from this anomaly are likely to have at least one autoimmune disorder and a higher risk of developing Parkinson’s and Schizophrenia.

It was first discovered and documented by physician Angelo DiGeorge in 1968. Its genetic component, however, was not studied until 1981. DiGeorge syndrome affects roughly about 1 in every 4000 people worldwide though it might be more common.

12. Tuberous Sclerosis Complex

Inheritance Pattern: Autosomal dominant

Tuberous Sclerosis Complex (TSC for short) is a single-gene disorder that causes non-cancerous tumors (benign) to develop in multiple organs including liver, lungs, brain, kidneys, skin, and heart. This rare condition is caused by mutations in any one of the two tumor suppressors genes namely TSC1 and TSC2. Don’t confuse it with Tuberculosis (TB).

Most common symptoms of tuberous sclerosis include severe neurological problems such as seizures, intellectual disability, autism, and other neurodevelopmental disorders along with different types of tumors in the aforementioned organs. In rare cases, it can also mess with pancreas causing pancreatic neuroendocrine tumors.

Most of the TSC cases result from random genetic mutations rather than inheritance. TSC is generally difficult to diagnose since it affects almost all major human organs and has no clear symptoms.

11. Ehlers–Danlos Syndromes

Ehlers–Danlos syndromesImage Courtesy: Piotr Dołżonek 

Inheritance pattern: Autosomal dominant/recessive

Ehlers-Danlos syndromes (EDS) are a group of well-documented genetic disorders associated with connective tissue. The most common symptoms, which are consistent with EDS are stretchy skin, abnormally flexible joints (hypermobility) and scars. Other medical conditions such as scoliosis and early-onset osteoarthritis may also arise.

This genetic condition can be triggered by a mutation in one of nearly a dozen genes. So far, about 13 different sub-types of EDS’ have been recognized. Out of those 13, only two, namely Arthrochalasia EDS and Dermatosparaxis EDS are considered to be extremely rare with just 30 and 10 reported cases respectively.

Patients suffering from Arthrochalasia EDS usually experience congenital hip dysplasia, joint hypermobility, scoliosis, bone loss, and skin problems. Ehlers-Danlos syndromes can either be inherited or caused by new mutations.

10. Hereditary Coproporphyria

Inheritance Pattern: Autosomal dominant

Hereditary coproporphyria (HCP) belongs to a group of acute porphyrias which primarily affects the central nervous system. Individuals suffering from hereditary coproporphyria experience acute episodic attacks involving seizures, severe abdominal pain, high blood pressure, and an abnormal heart rate. Other symptoms include nausea, fragile skin, and scarring.

These attacks are triggered by alcohol, hormonal and lifestyle changes, and can also be chemically induced. Without any triggers, many affected individuals may even go asymptomatic (without signs).

HCP is caused by a deficiency of an enzyme known as coproporphyrinogen oxidase which is caused by mutations in the CPOX gene. In general, porphyrias are rare and have an estimated rate of occurrence (all forms) of about 1 in 20,000.

9. Myoclonic Epilepsy with Ragged Red Fibers

Ragged Red Fibersragged red fibers in muscle fibers (MERRF syndrome)

Inheritance Pattern: Mitochondrial inheritance (maternal)

Mitochondrial DNA is an essential part of the human genome. They are located inside mitochondria, which, as you may know, are practically the powerhouses of individual cells. Any abnormality in cells can trigger one of many mitochondrial diseases which are mostly inherited and often manifest themselves in various metabolic and neurological disorders.

One such mitochondrial disease is myoclonic epilepsy with ragged red fibers or MERRF for short which is extremely rare. This condition has severe effects on the nervous system and muscles, though it affects most of the body. Most often a person with MERRF show involuntary twitching (myoclonus) as the first symptom, then present with seizures and ataxia (when the brain starts to lose control of the body).

As with other genetic disorders, the actual mechanism behind MERRF is not properly understood but the mutation to the mitochondrial genomes (mitochondrial DNA or Nuclear DNA) is understood to be central to this. A distinct physical characteristic of the MERRF is ragged red fibers (dead mitochondria) that accumulate in muscle fiber and are visible on muscle biopsy.

8. Chronic Granulomatous Disease

GranulomaMicroscopic view of granuloma

Inheritance Pattern: Autosomal recessive, X-linked

Chronic granulomatous disease (CGD) is a genetic condition in which the immune system is unable to fend-off invading pathogen completely, making the affected individual vulnerable to all sorts of bacterial and fungal infections. The disease basically interferes with white blood cell’s ability to produce oxygen compounds necessary for killing harmful organisms. Instead, the immune system forms granulomata (plural for granuloma) in different parts of the body to wall off the bacteria.

CGD is most likely to be caused by mutations on the X chromosome, but alterations on chromosome 7 (CYBA gene) and 16 (NCF1 gene) have also been linked to the genetic condition. In a handful of cases, a CGD patient may also carry another extremely rare genetic disease known as McLeod syndrome. This is due to the close proximity of genes associated with the two conditions.

Read: 26 Intriguing Facts About DNA You Probably Didn’t Know

7. Von Hippel–Lindau Disease

Inheritance Pattern: Autosomal dominant

von Hipple-Lindau syndrome (VHL) is a rare genetic disorder which affects multiple organ systems in our body. A person suffering from this condition usually presents with cysts and benign tumors (with the potential to transform into malignant form) in various body parts, including the nervous system (hemangioblastomas), kidneys, uterus, and pancreas. Visible symptoms include headaches, weakness, vision problems, and high blood pressure.

This condition is triggered by mutations in a particular tumor suppressor gene (located in chromosome 3) bearing an identical name. About 80% of VHL cases are inherited, while the rest are caused by ‘new’ mutations.

Globally, the incidence rate of von Hippel-Lindau syndrome is about 1 in 36,000 live births. Back in 2007, researchers at the Vanderbilt university stipulated that VHL may have played a significant role in the legendary Hatfield-McCoy rivalry after some members of the McCoy blood-line have been diagnosed with von Hipple-Lindau. Pheochromocytomas (tumor in the adrenal gland), which is caused by VHL could explain their short temper, rage and violent outbursts.

6. Cryopyrin-associated Periodic Syndrome

Inheritance Pattern: Autosomal dominant

Cryopyrin-associated periodic syndrome (CAPS for short) is a group of clinically overlapping autoinflammatory disease (faulty innate immune system) including the Muckle-Wells syndrome, neonatal-onset multisystem inflammatory disease, and familial cold autoinflammatory syndrome, all of which share the same pathology and triggered by mutations in a particular gene.

Fever is the most common symptom among CAPS patients along with fatigue, mood swings, rash, and depression. It can also cause visual and hearing impairment along with various musculoskeletal problems including arthritis and bone deformity. In extremely rare cases, CAPS can cause abnormal proteins to build in multiple organ tissues (AA amyloidosis).

Mutations in the NLRP3 gene (located in chromosome 3) is known to be the root cause of CAPS. The particular gene is responsible for encoding cryopyrin protein, an essential component of the innate immune system responsible for recognizing the pathogen-associated molecular pattern.

5. Wiskott–Aldrich Syndrome

Inheritance Pattern: X-linked recessive (both parents must be a carrier)

Wiskott-Aldrich syndrome (WAS) is a rare x-linked recessive condition which usually affects only males. The most common symptoms are small red spots on the skin (broken blood vessels) and easy bruising due to low platelet counts, dermatitis, and bloody diarrhea. Most WAS patients are likely to develop at least one autoimmune disorder and blood-related cancer.

This condition is caused by mutations in WAS gene located on X chromosome. A couple of other rare genetic disorders have also been linked to mutations in the aforementioned gene.

Treatments for WAS are currently symptom(s) based i.e treating symptoms as they arise. Regular intravenous immunoglobulins (IVIG) and blood transfusion can help patients. In the United States, this genetic condition affects 1 in about 250,000 live births.

4. Harlequin-type ichthyosis

Harlequin fetusHarlequin fetus

Inheritance Pattern: Autosomal recessive

Harlequin-type ichthyosis or simply Harlequin ichthyosis is a life-threatening genetic condition in which infants are born with hard, diamond-shaped skin plates that are separated by large cracks. A healthy skin basically acts like a protective barrier that stops hostile microbes from entering our body while keeping important fluids inside.

The extreme skin condition in harlequin ichthyosis, however, disrupt this balance, making affected individuals to maintain body temperature, water and susceptible to infections. It also limits the movement of the limbs and legs. Restricted movement of the chest can lead to breathing difficulties. Infants affected with Harlequin-type ichthyosis are likely to die within one month of their birth.

Harlequin ichthyosis is extremely rare and though its exact occurrence rate is not known, it’s estimated to affect about 1 in every 300,000 live births.

Read: Babies Born To Older Fathers Have Higher Risk of Adverse Birth Outcomes

3. Tay–Sachs Disease

Inheritance Pattern: Autosomal recessive

Tay-Sachs is a fatal (in most cases) genetic disorder in which nerve cells present in the spinal cord and the brain are rapidly destroyed. This extremely rare genetic anomaly is caused by mutations in the HEXA gene located on chromosome 15.

Based on its time of onset, the disease can be classified into three types, the most common and perhaps the most lethal being infantile Tay–Sachs disease which usually starts showing signs in infants six months after their birth. Symptoms include a rapid decline in physical and mental abilities, blindness and muscle stiffness. The other two forms of Tay-Sachs are rarer and are not life-threatening.

In the United States, Tay-Sachs disease affects nearly about 1 in 320,000 individuals. However, it has an exceptionally high incidence rate among Ashkenazi Jews which is around 1 in every 3,500 live births.

2. Proteus Syndrome

Proteus syndromeLeft to right: A kid with Proteus syndrome; graphical illustration of the condition

Proteus syndrome is an extremely rare genetic condition which involves abnormal growth of bones, skin, blood vessels and fatty tissues. It’s progressive in nature means a person is normally born without any visible deformities. Proteus syndrome patients generally develop bone and skin tumors and have unique skeletal malformations including inconsistency in limb length and spinal deformity.

According to a study conducted in 2011, alterations in AKT1 gene (located in chromosome 14) can trigger this condition. There are just over 200 confirmed cases of Proteus syndrome worldwide, however, the number doesn’t include people who go undiagnosed.

1. Fibrodysplasia ossificans progressiva

Inheritance Pattern: Autosomal dominant

Fibrodysplasia ossificans progressiva (FOP) is perhaps one of the rarest known diseases that affect humans. It messes up body’s skeletal repair mechanism and puts it into overdrive. The disorder causes muscles, ligaments, and tendons to slowly turn into bone (ossification). Formation of extra-skeletal bone trigger gradual loss of mobility which can lead to further complications.

People suffering from FOP are born with malformed big toes (for unknown reasons) and may also have abnormally short thumbs. The usual onset is before age of 10 when lumps started to become visible around the neck, shoulders and then spread throughout the body.

Read: 12 Weird Diseases That Science Failed To Explain

Muscle injuries, trauma or surgical attempts to remove a bone overgrowth are more likely to aggravate the situation by triggering more rapid ossification in the affected area. Due to its extreme rarity and muscle involvement, Fibrodysplasia ossificans progressiva is often misdiagnosed either as cancer or fibrosis.

Almost all known cases of FOP are caused by new mutations and are not genetically inherited. Alterations in the gene ACVR1 is understood to be the root cause of this disease.

Leave a reply