Refsum disease is an inherited condition that causes vision loss, absence of the sense of smell (anosmia), and a variety of other signs and symptoms.

The vision loss associated with Refsum disease is caused by an eye disorder called retinitis pigmentosa. This disorder affects the retina, the light-sensitive layer at the back of the eye. Vision loss occurs as the light-sensing cells of the retina gradually deteriorate. The first sign of retinitis pigmentosa is usually a loss of night vision, which often becomes apparent in childhood. Over a period of years, the disease disrupts side (peripheral) vision and may eventually lead to blindness.

Vision loss and anosmia are seen in almost everyone with Refsum disease, but other signs and symptoms vary. About one-third of affected individuals are born with bone abnormalities of the hands and feet. Features that appear later in life can include progressive muscle weakness and wasting; poor balance and coordination (ataxia); hearing loss; and dry, scaly skin (ichthyosis). Additionally, some people with Refsum disease develop an abnormal heart rhythm (arrhythmia) and related heart problems that can be life-threatening.

Adult Refsum disease (ARD) is a rare genetic disease that causes weakness or numbness of the hands and feet (peripheral neuropathy). Due to a genetic abnormality, people with ARD disease lack the enzyme in peroxisomes that break down phytanic acid, a type of fat found in certain foods. As a result, toxic levels of phytanic acid build up in the brain, blood, and other tissues.

The disease usually begins in late childhood or early adulthood with increasing night blindness due to degeneration of the retina (retinitis pigmentosa). If the disease progresses, other symptoms may include:

• Deafness
• Loss of the sense of smell (anosmia)
• Problems with balance and coordination (ataxia)
• Dry and scaly skin (ichthyosis)
• Heartbeat abnormalities (cardiac arrhythmias)

Some individuals will have shortened bones in their fingers or toes, or a visibly shortened fourth toe. Although the disease usually appears in early childhood, some people will not develop symptoms until their 40s or 50s.

ARD is treatable because phytanic acid is not produced by the body but is only found in foods. With treatment, muscle weakness, numbness, and dry and scaly skin generally disappear. However, vision and hearing problems may persist, and the sense of smell may not return. Untreated, ARD can lead to sudden death caused by heartbeat abnormalities.

Infantile Refsum disease (IRD) is the mildest of a group of disorders known as peroxisome biogenesis disorders, Zellweger syndrome spectrum (PBD-ZSS). PBD-ZSS is a group of inherited genetic disorders that damage the white matter of the brain and affect motor movements. Peroxisome biogenesis disorders, in turn, are part of a larger group of disorders called leukodystrophies.

IRD can cause low muscle tone (hypotonia), retinitis pigmentosa (a visual impairment that can lead to blindness), developmental delay, sensorineural hearing loss, and liver dysfunction. IRD usually presents at birth or in infancy. Most individuals with IRD can achieve motor milestones, though they may be delayed, and most individuals can communicate with a few words or signs. Leukodystrophy with loss of acquired skills can occur at any age and may stabilize or progress. Peroxisome biogenesis disorders are caused by genetic changes in one of the PEX genes and are inherited in an autosomal recessive manner.

Adult Refsum disease and infantile refsum disease are separate disorders caused by different genetic defects.

More than 90 percent of all cases of Refsum disease result from mutations in the PHYH gene. The remaining cases are caused by mutations in a gene called PEX7.

The signs and symptoms of Refsum disease result from the abnormal buildup of a type of fatty acid called phytanic acid. This substance is obtained from the diet, particularly from beef and dairy products. It is normally broken down through a process called alpha-oxidation, which occurs in cell structures called peroxisomes. These sac-like compartments contain enzymes that process many different substances, such as fatty acids and certain toxic compounds.

Mutations in either the PHYH or PEX7 gene disrupt the usual functions of peroxisomes, including the breakdown of phytanic acid. As a result, this substance builds up in the body's tissues. The accumulation of phytanic acid is toxic to cells, although it is unclear how an excess of this substance affects vision and smell and causes the other specific features of Refsum disease.

Normal Function

The PHYH gene provides instructions for making an enzyme called phytanoyl-CoA hydroxylase. This enzyme is critical for the normal function of cell structures called peroxisomes. These sac-like compartments contain enzymes needed to break down many different substances, including fatty acids and certain toxic compounds.

One substance that is broken down in peroxisomes is phytanic acid, a type of fatty acid obtained from the diet (particularly from beef and dairy products). Phytanoyl-CoA hydroxylase is responsible for one of the first steps in breaking down phytanic acid as part of a process known as alpha-oxidation. In subsequent steps, additional enzymes in peroxisomes and other parts of the cell further process this compound into smaller molecules that the body can use for energy.

Researchers suspect that phytanoyl-CoA hydroxylase may have other functions in addition to its role in breaking down phytanic acid. For example, this enzyme appears to help determine the number of peroxisomes within cells and is involved in regulating their activity.

Health Conditions Related to Genetic Changes

Refsum disease

Mutations in the PHYH gene have been found to cause more than 90 percent of all cases of Refsum disease. About 30 mutations in this gene have been identified. These mutations alter the structure or production of phytanoyl-CoA hydroxylase, which reduces the enzyme's activity. A shortage of this enzyme disrupts the breakdown of phytanic acid in peroxisomes. As a result, phytanic acid and related compounds build up in the body's tissues. The accumulation of phytanic acid is toxic to cells, although it is unclear how an excess of this substance affects vision and smell and causes the other specific features of Refsum disease.

Other Names for This Gene

• LN1
• LNAP1
• PAHX
• PAHX_HUMAN
• PHYH1
• phytanic acid oxidase
• phytanoil-CoA alpha hydroxylase
• phytanoyl-CoA 2 oxoglutarate dioxygenase
• phytanoyl-CoA alpha-hydroxylase
• phytanoyl-CoA dioxygenase, peroxisomal

Genomic Location

Normal Function

The PEX7 gene provides instructions for making a protein called peroxisomal biogenesis factor 7, which is part of a group known as the peroxisomal assembly (PEX) proteins. Within cells, PEX proteins are responsible for importing certain enzymes into structures called peroxisomes. The enzymes in these sac-like compartments break down many different substances, including fatty acids and certain toxic compounds. They are also important for the production (synthesis) of fats (lipids) used in digestion and in the nervous system.

Peroxisomal biogenesis factor 7 transports several enzymes that are essential for the normal assembly and function of peroxisomes. The most important of these enzymes is alkylglycerone phosphate synthase (produced from the AGPS gene). This enzyme is required for the synthesis of specialized lipid molecules called plasmalogens, which are present in cell membranes throughout the body. Peroxisomal biogenesis factor 7 also transports the enzyme phytanoyl-CoA hydroxylase (produced from the PHYH gene). This enzyme helps process a type of fatty acid called phytanic acid, which is obtained from the diet. Phytanic acid is broken down through a multistep process into smaller molecules that the body can use for energy.

Health Conditions Related to Genetic Changes

Refsum disease

Mutations in the PEX7 gene cause a small percentage of all cases of Refsum disease. The three mutations known to be responsible for this condition reduce the activity of peroxisomal biogenesis factor 7, which disrupts the import of several critical enzymes (including phytanoyl-CoA hydroxylase) into peroxisomes. Without enough of these enzymes, peroxisomes cannot break down fatty acids and other substances effectively.

In people with Refsum disease, a shortage of phytanoyl-CoA hydroxylase prevents peroxisomes from breaking down phytanic acid. Instead, this substance gradually builds up in the body's tissues. Over time, the accumulation of phytanic acid becomes toxic to cells. It is unclear, however, how an excess of this substance affects vision and smell and causes the other specific features of Refsum disease.

Rhizomelic chondrodysplasia punctata

More than three dozen mutations in the PEX7 gene have been found to cause rhizomelic chondrodysplasia punctata type 1 (RCDP1). These mutations tend to be more severe than the mutations that cause Refsum disease. The genetic changes associated with RCDP1 often lead to a completely nonfunctional version of peroxisomal biogenesis factor 7 or prevent cells from making any of this protein. The most common mutation responsible for RCDP1 replaces the amino acid leucine at protein position 292 with a premature stop signal in the instructions for making peroxisomal biogenesis factor 7 (written as Leu292Ter or L292X). This mutation leads to a nonfunctional version of the protein.

The PEX7 gene mutations responsible for RCDP1 prevent peroxisomal biogenesis factor 7 from transporting critical enzymes, particularly alkylglycerone phosphate synthase, into peroxisomes. A shortage of alkylglycerone phosphate synthase prevents the synthesis of plasmalogens. Problems with the production of these lipid molecules appear to cause the signs and symptoms of RCDP1. However, researchers are still working to determine how a lack of plasmalogens leads to skeletal abnormalities, intellectual disability, and the other features of this condition.

Other Names for This Gene

• peroxin-7
• peroxisomal PTS2 receptor
• peroxisome targeting signal 2 receptor
• PEX7_HUMAN
• PTS2R

Genomic Location

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

The prevalence of Refsum disease is unknown, although the condition is thought to be uncommon.