Infantile Refsum disease
Encyclopedia
Infantile Refsum disease (IRD), also called infantile phytanic acid storage disease, is a rare autosomal
recessive congenital
peroxisomal biogenesis disorder
within the Zellweger spectrum. These are disorders of the peroxisome
s that are clinically similar to Zellweger syndrome
and associated with mutations in the PEX
family of genes. IRD is associated with deficient phytanic acid
catabolism
, as is Adult Refsum disease, but they are different disorders that should not be confused.
assembly. Most commonly, patients have mutations in the PEX1, PEX3, PEX6, PEX12, and PEX26 genes. In almost all cases, patients have mutations that inactivate or greatly reduce the activity of both the maternal and paternal copies of one these aforementioned PEX genes.
As a result of impaired peroxisome
function, an individual's tissues and cells can accumulate very long chain fatty acids (VLCFA) and branched chain fatty acids (BCFA) that are normally degraded in peroxisomes. The accumulation of these lipids can impair the normal function of multiple organ systems, as discussed below. In addition, these individuals can show deficient levels of plasmalogens, ether-phospholipids that are especially important for brain, lung, and heart functions.
(ZS) and neonatal adrenoleukodystrophy (NALD). Although they share a similar molecular basis for disease, Infantile Refsum disease is less severe than Zellweger syndrome
.
Infantile Refsum disease is an developmental brain disorder. In addition, patients can show a reduction in central nervous system
(CNS) myelin
(particularly cerebral), which is referred to as (hypomyelination). Myelin is critical for normal CNS functions. Patients can also show postdevelopmental sensorineuronal degeneration that leads to a progressive loss of hearing and vision.
Infantile Refsum disease can also affect the function of many other organ systems. Patients can show craniofacial abnormalities, hepatomegaly
(enlarged liver), and progressive adrenal dysfunction. Newborns may present with profound hypotonia
(low muscle tone), and a poor ability to feed. In some patients, a progressive leukodystrophy
has been observed that has a variable age of onset.
. Cultured primarily skin fibroblasts obtained from patients show elevated very long chain fatty acids, impaired very long chain fatty acid
beta-oxidation, phytanic acid
alpha-oxidation, pristanic acid
alpha-oxidation, and plasmalogen
biosynthesis.
and respiratory distress. Other treatment is symptomatic and supportive. Patients show variable lifespans with some individuals surviving until adulthood and into old age.
Autosome
An autosome is a chromosome that is not a sex chromosome, or allosome; that is to say, there is an equal number of copies of the chromosome in males and females. For example, in humans, there are 22 pairs of autosomes. In addition to autosomes, there are sex chromosomes, to be specific: X and Y...
recessive congenital
Congenital disorder
A congenital disorder, or congenital disease, is a condition existing at birth and often before birth, or that develops during the first month of life , regardless of causation...
peroxisomal biogenesis disorder
Peroxisomal disorder
Peroxisomal disorders represent a class of medical conditions caused by defects in peroxisome functions. This may be due to defects in single enzymes important for peroxisome function or in peroxins, proteins encoded by PEX genes that are critical for normal peroxisome assembly and...
within the Zellweger spectrum. These are disorders of the peroxisome
Peroxisome
Peroxisomes are organelles found in virtually all eukaryotic cells. They are involved in the catabolism of very long chain fatty acids, branched chain fatty acids, D-amino acids, polyamines, and biosynthesis of plasmalogens, etherphospholipids critical for the normal function of mammalian brains...
s that are clinically similar to Zellweger syndrome
Zellweger syndrome
Zellweger syndrome, also called cerebrohepatorenal syndrome is a rare, congenital disorder, characterized by the reduction or absence of functional peroxisomes in the cells of an individual. It is one of a family of disorders called leukodystrophies...
and associated with mutations in the PEX
PEX
Cross-linked polyethylene, commonly abbreviated PEX or XLPE, is a form of polyethylene with cross-links. It is formed into tubing, and is used predominantly in hydronic radiant heating systems, domestic water piping and insulation for high tension electrical cables...
family of genes. IRD is associated with deficient phytanic acid
Phytanic acid
Phytanic acid is a branched chain fatty acid that humans can obtain through the consumption of dairy products, ruminant animal fats, and certain fish. Western diets are estimated to provide 50-100 mg of phytanic acid per day...
catabolism
Catabolism
Catabolism is the set of metabolic pathways that break down molecules into smaller units and release energy. In catabolism, large molecules such as polysaccharides, lipids, nucleic acids and proteins are broken down into smaller units such as monosaccharides, fatty acids, nucleotides, and amino...
, as is Adult Refsum disease, but they are different disorders that should not be confused.
Molecular basis of disease
Infantile Refsum disease is an autosomal recessive disorder caused by mutations in genes that encode peroxins, proteins required for normal peroxisomePeroxisome
Peroxisomes are organelles found in virtually all eukaryotic cells. They are involved in the catabolism of very long chain fatty acids, branched chain fatty acids, D-amino acids, polyamines, and biosynthesis of plasmalogens, etherphospholipids critical for the normal function of mammalian brains...
assembly. Most commonly, patients have mutations in the PEX1, PEX3, PEX6, PEX12, and PEX26 genes. In almost all cases, patients have mutations that inactivate or greatly reduce the activity of both the maternal and paternal copies of one these aforementioned PEX genes.
As a result of impaired peroxisome
Peroxisome
Peroxisomes are organelles found in virtually all eukaryotic cells. They are involved in the catabolism of very long chain fatty acids, branched chain fatty acids, D-amino acids, polyamines, and biosynthesis of plasmalogens, etherphospholipids critical for the normal function of mammalian brains...
function, an individual's tissues and cells can accumulate very long chain fatty acids (VLCFA) and branched chain fatty acids (BCFA) that are normally degraded in peroxisomes. The accumulation of these lipids can impair the normal function of multiple organ systems, as discussed below. In addition, these individuals can show deficient levels of plasmalogens, ether-phospholipids that are especially important for brain, lung, and heart functions.
Clinical manifestations of disease
Infantile Refsum disease is one of three peroxisome biogenesis disorders which belong to the Zellweger spectrum of peroxisome biogenesis disorders (PBD-ZSD). The other two disorders are Zellweger syndromeZellweger syndrome
Zellweger syndrome, also called cerebrohepatorenal syndrome is a rare, congenital disorder, characterized by the reduction or absence of functional peroxisomes in the cells of an individual. It is one of a family of disorders called leukodystrophies...
(ZS) and neonatal adrenoleukodystrophy (NALD). Although they share a similar molecular basis for disease, Infantile Refsum disease is less severe than Zellweger syndrome
Zellweger syndrome
Zellweger syndrome, also called cerebrohepatorenal syndrome is a rare, congenital disorder, characterized by the reduction or absence of functional peroxisomes in the cells of an individual. It is one of a family of disorders called leukodystrophies...
.
Infantile Refsum disease is an developmental brain disorder. In addition, patients can show a reduction in central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
(CNS) myelin
Myelin
Myelin is a dielectric material that forms a layer, the myelin sheath, usually around only the axon of a neuron. It is essential for the proper functioning of the nervous system. Myelin is an outgrowth of a type of glial cell. The production of the myelin sheath is called myelination...
(particularly cerebral), which is referred to as (hypomyelination). Myelin is critical for normal CNS functions. Patients can also show postdevelopmental sensorineuronal degeneration that leads to a progressive loss of hearing and vision.
Infantile Refsum disease can also affect the function of many other organ systems. Patients can show craniofacial abnormalities, hepatomegaly
Hepatomegaly
Hepatomegaly is the condition of having an enlarged liver. It is a nonspecific medical sign having many causes, which can broadly be broken down into infection, direct toxicity, hepatic tumours, or metabolic disorder. Often, hepatomegaly will present as an abdominal mass...
(enlarged liver), and progressive adrenal dysfunction. Newborns may present with profound hypotonia
Hypotonia
Hypotonia is a state of low muscle tone , often involving reduced muscle strength. Hypotonia is not a specific medical disorder, but a potential manifestation of many different diseases and disorders that affect motor nerve control by the brain or muscle strength...
(low muscle tone), and a poor ability to feed. In some patients, a progressive leukodystrophy
Leukodystrophy
Leukodystrophy refers to a group of disorders characterized by dysfunction of the white matter of the brain. The leukodystrophies are caused by imperfect growth or development of the myelin sheath, the fatty covering that acts as an insulator around nerve fibers...
has been observed that has a variable age of onset.
Molecular diagnostics
In addition to genetic tests involving PEX genes, biochemical tests have proven highly effective for the diagnosis of infantile Refsum disease and other peroxisomal disorders. Typically, IRD patients show elevated very long chain fatty acids in their blood plasmaBlood plasma
Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...
. Cultured primarily skin fibroblasts obtained from patients show elevated very long chain fatty acids, impaired very long chain fatty acid
Very long chain fatty acid
A very long chain fatty acid is a fatty acid with aliphatic tails longer than 22 carbons.Unlike most fatty acids, VLCFAs are too long to be metabolized in the mitochondria, and must be metabolized in peroxisomes....
beta-oxidation, phytanic acid
Phytanic acid
Phytanic acid is a branched chain fatty acid that humans can obtain through the consumption of dairy products, ruminant animal fats, and certain fish. Western diets are estimated to provide 50-100 mg of phytanic acid per day...
alpha-oxidation, pristanic acid
Pristanic acid
Pristanic acid is a terpenoid acid present at micromolar concentrations in the blood plasma of healthy individuals. It is also found in the lipids from many sources such as freshwater sponges, krill, earthworms, whales, human milk fat, bovine depot fat, butterfat or Californian petroleum. It is...
alpha-oxidation, and plasmalogen
Plasmalogen
Plasmalogens are a type of ether phospholipid characterized by the presence of a vinyl ether linkage at the sn-1 position and an ester linkage at the sn-2 position . In mammals, the sn-1 position is typically derived from C16:0, C18:0, or C18:1 fatty alcohols while the sn-2 position is most...
biosynthesis.
Prognosis
Currently, there is no cure for infantile Refsum disease syndrome, nor is there a standard course of treatment. Infections should be guarded against to prevent such complications as pneumoniaPneumonia
Pneumonia is an inflammatory condition of the lung—especially affecting the microscopic air sacs —associated with fever, chest symptoms, and a lack of air space on a chest X-ray. Pneumonia is typically caused by an infection but there are a number of other causes...
and respiratory distress. Other treatment is symptomatic and supportive. Patients show variable lifespans with some individuals surviving until adulthood and into old age.
Additional resources for patients and families
- European Leukodystrophy Foundation
- March of Dimes Foundation
- The Global Foundation for Peroxisomal Disorders
- United Leukodystrophy Foundation
- Zellwegers Support Network