Retinal Degeneration as Part of a Syndrome

The eye is a complex organ and vision loss is a common symptom of many complex diseases and syndromes which affect the human body

What is Refsum Disease?

Adult Refsum disease is a metabolic disorder caused by a number of faulty genes (principally PHYH) which affect the ability to metabolize phytanic acid, a type of fat found in certain foods. In humans, if phytanic acid is not degraded it accumulates in nerves, liver and fat.  Refsum disease can be life threatening if undiagnosed.

The diagnosis of Refsum disease is based on clinical findings and the finding of a raised blood phytanic acid level. Most people with Refsum disease have phytanic acid levels 10-100 fold above those found in the general population, though a few have lower but still abnormal levels. The diagnosis is typically confirmed through genetic (DNA) testing but in a few cases direct measurement of enzyme activities in skin biopsy samples may be required.

Symptoms

The most common symptoms of Refsum disease include:

  • Retinitis pigmentosa: Retinitis pigmentosa is an expression of degenerative eye disease as the visual receptors are lost in the retina and the background structure of the eye is exposed. It manifests as a failure of night vision and later decreased peripheral vision, and eventually can lead to low vision or blindness.
  • Anosmia: loss of the sense of smell and many aspects of the subtleties of taste
  • Peripheral polyneuropathy: Peripheral polyneuropathy is the term for dysfunction of the nerves outside of the spinal cord. Symptoms may include numbness, weakness, burning pain, and loss of reflexes occurring initially at the body extremes (feet or hands).
  • Deafness: loss of hearing
  • Cerebellar ataxia: Ataxia is a nerve-derived form of unsteadiness. Cerebellar ataxia refers to the fact that the defect is in a specific part of the brain (the cerebellum) that coordinates muscle functions. As a result the brain fails to regulate the body posture, as well as the strength and direction of movements.
  • Skeletal dysplasia: Bone abnormalities including shortening or deformity of the tubular bones in the hands and feet and abnormal growth plates (epiphyseal dysplasia) at the knees, elbows and shoulders may be found.
  • Ichthyosis: A distinct type of scaliness of the skin different in appearance from eczema or psoriasis. These symptoms can range anywhere from fish-like scaliness of the palms and soles of the feet to being present on the trunk of the body.
  • Pupillary abnormalities: The pupil of the eye is often small in Refsum disease and does not respond well to light or drugs used to ‘open’ the eye by optometrists.
  • Cataract: a clouding of the lens in the eye causing deterioration in vision often associated with starburst haloes around bright objects.
  • Nystagmus: rapid, involuntary, rhythmic eye movements
  • Cardiac Arrhythmia: Heart rhythm abnormalities are a rare but serious complication of very high phytanic acid levels and can be a cause of death in Refsum disease.
  • Weakness: significant slow-recovering weakness after illness is a feature of Refsum disease

The impact on an individual of these symptoms can increase based on their plasma phytanic acid level.  Higher levels will generally increase the severity of symptoms. Phytanic acid accumulates in the fat tissue of Refsum patients throughout their lives before their diagnosis.  This means that even with a strict diet low in phytanic acid an individual can still have higher levels of plasma phytanic acid throughout their lives due to release of phytanic acid from their fat cells into their blood.

Inheritance

Refsum disease is a familial (genetic) disorder that occurs in 1 in 1,000,000 people. Most cases are sporadic though the risks are increased if there is a history of consanguineous marriage in the family. It is classified as an autosomal recessive. This means that if both parents are carriers of the disease, each child has a 1 in 4 chance of developing Refsum disease.

When both parents are carriers of a specific mutated gene, such as those for Refsum disease, their children have a 25% chance of being affected by the disease, a 25% chance of neither being a carrier nor affected, and a 50% chance of being an unaffected carrier, just like their parents.

Treatments

There are currently two available treatment regimens for Refsum Disease.  The first treatment is a strict diet low in phytanic acid and is used for long-term management.  Dietary restriction of phytanic acid intake helps lessen or resolve ichthyosis, sensory neuropathy, and ataxia. A low phytanic acid diet is suspected to slow the progression of vision and hearing loss.

The second treatment is the direct removal from the blood stream of phytanic acid by a dialysis-type process (plasmapheresis or lipid apheresis) and is typically used in acute management of people hospitalized as a result of Refsum disease where it helps to resolve acute heart arrhythmias or extreme weakness. It may be done on a chronic regular basis in some patients whose phytanic acid levels do not fall sufficiently on diet.

In addition to the strict diet, patients with Refsum disease must try to minimize the acute release of stored phytanic acid from their fat cells.  Sickness, planned hospital procedures involving fasting (e.g. surgery) or rapid weight loss can mobilize fat as part of the body’s stress response which in turn can release phytanic acid from a patient’s liver or fat stores.  Patients should receive guidance from a trained dietician and physician on how to minimize risks of acute phytanic acid release and how to manage Refsum disease.

Research and Clinical Trials

Past research in this area clarified the clinical features of Refsum disease, helped devise a dietary intervention and identified responses to fasting. Before the establishment of the diet and plasmapheresis, patients with the disease had a shortened life expectancy. Basic science clarified the pathways involved in degrading phytanic acid and also the genetic defects that cause the condition. All of these contributed to the understanding of Refsum disease which established the treatments that are currently available.

Research has slowed in the more recent years due to funding challenges.  Global DARE Foundation was established in 2019 to help drive research and find better therapies to improve the quality of life of Refsum patients.

The Global DARE Foundation is starting a research project to test more foods for their phytanic acid content and to update the previous measurements as dietary habits, farming practices and food manufacturing processes have changed dramatically in the last 30 years.  To date only 150 foods have been tested which limits the foods that Refsum patients can eat.  The foundation is also in early conversations on a proof of concept study for gene therapy in this inherited disorder.

To learn more about the Global DARE Foundation mission and priorities, visit their website at https://www.defeatadultrefsumeverywhere.org/

Bardet-Biedl syndrome (BBS) is a rare and genetically inherited disorder which causes a wide range of symptoms in the body. Bardet-Biedl can occur due to mutations in at least 14 genes (BBS genes) which are important in the development of cilia; finger-like projections which protrude out from many cell-types. Cilia are very important for facilitating cell-movement, in addition to being required for sensory perception (vision, hearing, smell).

Mutations in the BBS genes causes these cilia to develop incorrectly and malfunction, which has a major effect on many chemical signalling pathways and impact our senses.

There are a wide variety of symptoms which develop as a result of Bardet-Biedl syndrome, particularly vision loss due to deterioration of the retina and blind spots developing in peripheral vision, obesity and the excessive growth of fingers and toes (polydactyly). Other common signs of Bardet-Biedl syndrome include impaired speech, poor motor control which affects walking and infertility.

Alström syndrome is a rare and complex genetic disorder which is inherited in an autosomal recessive manner, where an affected individual has two copies of the ALMS1 gene.

It generally begins in early childhood and impacts a number of systems in the body, with vision loss due to cone-rod dystrophy a common feature of the condition. Progressive hearing loss, type-2 diabetes and heart disease are other symptoms which are frequently recognised in people living with Alström syndrome.

Wolfram syndrome is a condition which affects many body systems and exists in two forms, Wolfram syndrome type 1 and Wolfram syndrome type 2. Wolfram syndrome type 1 is caused by mutations in the WFS1 gene, while wolfram syndrome type 2 arises due to mutations in the CISD2 gene and share common symptoms, such as cell death in the optic nerve to eventually cause blindness, hearing loss caused by changes to the inner ear and neurological disorders.

People living with Wolfram syndrome type 2 also experience stomach ulcers. The severe health complications associated with Wolfram syndrome makes it a fatal disease, often by mid-adulthood.

Joubert syndrome is an inherited ciliopathy, meaning it is a condition caused by poorly structured and developed cilia, arising due to mutations in a wide number of genes, all of which have not yet been identified. Joubert syndrome is inherited in an autosomal recessive manner, and so two faulty gene copies must be present for the condition to develop.

Joubert syndrome is a developmental brain disorder and is characterised by an underdeveloped cerebellar vermis; the part of the brain responsible for coordination. As a result, many people living with Joubert syndrome have difficulty with controlling body movements (ataxia), with uncontrolled eye movements a very common feature and difficulty moving eyes for peripheral vision challenging (oculomotor ataxia).

Mainzer-Saldino syndrome is a genetic and rare ciliopathy, which means that it develops due to mutations in genes which have a fundamental role in cilia development. Mainzer-Saldino syndrome is caused by mutations in the IFT140 gene, which produces a protein that is involved in cilia formation and maintenance.

This condition is characterised by a deterioration in visual acuity, kidney problems and abnormal skeletal structures. Degeneration of the light-sensitive tissue at the back of the eye, called the retina occurs because the rod and cone photoreceptors which perceive light, contain cilia which have not developed correctly. Therefore, vision loss is a primary feature of this condition and can vary in time of onset, from infancy to childhood. The manner of this vision loss is also similar to that of Leber Congenital Amaurosis (LCA) and Rod-Cone dystrophies, although the pigment deposits evident in these dystrophies, for example, Retinitis Pigmentosa, are not present in Mainzer-Saldino syndrome.

Stickler syndrome is an inherited condition, which has two distinct forms, caused by mutations in the COL2A1 gene and COL11A1 gene respectively. These genes provide instructions to make collagen, which provides structure to the connective tissue of the body.

Therefore, people living with Stickler syndrome have a distinct flattened face because of undeveloped bone structures. Nearsightedness (myopia) and retinal detachment are other common symptoms, and may result in serious visual impairment and blindness for some people living with Stickler syndrome.

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