Infantile Refsum disease (IRD) is a rare

autosomal An autosome is any chromosome that is not a sex chromosome. The members of an autosome pair in a diploid cell have the same morphology, unlike those in allosomal (sex chromosome) pairs, which may have different structures. The DNA in autosom ...

recessive In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...

congenital peroxisomal biogenesis disorder within the Zellweger spectrum. These are disorders of the peroxisomes that are clinically similar to

Zellweger syndrome Zellweger 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 Zellweger spectrum disorders which are leukodystrophie ...

and associated with mutations in the ''PEX'' family of genes. IRD is associated with deficient

phytanic acid Phytanic acid (or 3,7,11,15-tetramethyl hexadecanoic 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&nbs ...

catabolism, as is adult Refsum disease, but they are different disorders that should not be confused.

Presentation

Infantile Refsum disease is one of three

peroxisome biogenesis disorders 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 cri ...

which belong to the Zellweger spectrum of peroxisome biogenesis disorders (PBD-ZSD). The other two disorders are

(ZS) and

neonatal adrenoleukodystrophy Neonatal adrenoleukodystrophy is an inborn error of peroxisome biogenesis. It is part of the Zellweger spectrum. It has been linked with multiple genes (at least five) associated with peroxisome biogenesis, and has an autosomal recessive pa ...

(NALD).GeneReviews: Peroxisome Biogenesis Disorders, Zellweger Syndrome Spectrum
/ref> Although they share a similar molecular basis for disease, Infantile Refsum disease is less severe than Zellweger syndrome. Infantile Refsum disease is a developmental brain disorder. In addition, patients can show a reduction in

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all p ...

(CNS)

myelin Myelin is a lipid-rich material that surrounds nerve cell axons (the nervous system's "wires") to insulate them and increase the rate at which electrical impulses (called action potentials) are passed along the axon. The myelinated axon can be ...

(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 is the condition of having an enlarged liver. It is a non-specific medical sign having many causes, which can broadly be broken down into infection, hepatic tumours, or metabolic disorder. Often, hepatomegaly will present as an abdo ...

(enlarged liver), and progressive adrenal dysfunction. Newborns may present with profound

hypotonia Hypotonia is a state of low muscle tone (the amount of tension or resistance to stretch in a muscle), often involving reduced muscle strength. Hypotonia is not a specific medical disorder, but a potential manifestation of many different diseases ...

(low muscle tone), and a poor ability to feed. In some patients, a progressive

leukodystrophy Leukodystrophies are a group of usually inherited disorders characterized by degeneration of the white matter in the brain. The word ''leukodystrophy'' comes from the Greek roots ''leuko'', "white", ''dys'', "abnormal" and ''troph'', "growth". Th ...

has been observed that has a variable age of onset.

Molecular mechanism

Infantile Refsum disease is an autosomal recessive disorder caused by mutations in genes that encode peroxins, proteins required for normal peroxisome 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 Glycerophospholipids of biochemical relevance are divided into three subclasses based on the substitution present at the sn-1 position of the glycerol backbone: acyl, alkyl and alkenyl. Of these, the alkyl and alkenyl moiety in each case form an ...

, ether-phospholipids that are especially important for brain, lung, and heart functions.

Diagnosis

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 A very-long-chain fatty acid (VLCFA) is a fatty acid with 22 or more carbons. Their biosynthesis occurs in the endoplasmic reticulum. VLCFA's can represent up to a few percent of the total fatty acid content of a cell. Unlike most fatty acids, VL ...

in their

blood plasma Blood plasma is a light amber-colored liquid component of blood in which blood cells are absent, but contains proteins and other constituents of whole blood in suspension. It makes up about 55% of the body's total blood volume. It is the intr ...

. Cultured primarily skin fibroblasts obtained from patients show elevated very long chain fatty acids, impaired

very long chain fatty acid A very-long-chain fatty acid (VLCFA) is a fatty acid with 22 or more carbons. Their biosynthesis occurs in the endoplasmic reticulum. VLCFA's can represent up to a few percent of the total fatty acid content of a cell. Unlike most fatty acids, VL ...

beta-oxidation,

alpha-oxidation,

pristanic acid Pristanic acid (2,6,10,14-tetramethylpentadecanoic 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, earthw ...

alpha-oxidation, and

plasmalogen Glycerophospholipids of biochemical relevance are divided into three subclasses based on the substitution present at the sn-1 position of the glycerol backbone: acyl, alkyl and alkenyl. Of these, the alkyl and alkenyl moiety in each case form an ...

biosynthesis.

Management

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

pneumonia Pneumonia is an inflammatory condition of the lung primarily affecting the small air sacs known as alveoli. Symptoms typically include some combination of productive or dry cough, chest pain, fever, and difficulty breathing. The severity ...

and respiratory distress. Other treatment is symptomatic and supportive.

Prognosis

Patients show variable lifespans with some individuals surviving until adulthood and into old age.

References

External links

{{DEFAULTSORT:Infantile Refsum disease Peroxisomal disorders Autosomal recessive disorders Rare diseases Genodermatoses Neurodegenerative disorders