Infantile Refsum disease

Last updated
Infantile Refsum disease
Other namesInfantile phytanic acid storage disease' [1]
Phytanic acid.png
Phytanic acid

Infantile Refsum disease (IRD) is a rare autosomal recessive [2] congenital peroxisomal biogenesis disorder within the Zellweger spectrum. These are disorders of the peroxisomes that are clinically similar to Zellweger syndrome and associated with mutations in the PEX family of genes. [3] [4] IRD is associated with deficient phytanic acid catabolism, as is adult Refsum disease, but they are different disorders that should not be confused. [5]

Contents

Presentation

Infantile Refsum disease is one of three peroxisome biogenesis disorders which belong to the Zellweger spectrum of peroxisome biogenesis disorders (PBD-ZSD). [6] The other two disorders are Zellweger syndrome (ZS) and neonatal adrenoleukodystrophy (NALD). [7] [8] Although they share a similar molecular basis for disease, Infantile Refsum disease is less severe than Zellweger syndrome. [9]

Infantile Refsum disease is a developmental brain disorder. [6] 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. [6]

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. [6] [9] Newborns may present with profound hypotonia (low muscle tone), and a poor ability to feed. [6] [9] In some patients, a progressive leukodystrophy has been observed that has a variable age of onset. [9]

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. [1] 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.[ citation needed ]

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.[ citation needed ]

Diagnosis

In addition to genetic tests involving PEX genes, [10] [11] 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 plasma. 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. [6]

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 and respiratory distress. Other treatment is symptomatic and supportive. [9]

Prognosis

Patients show variable lifespans with some individuals surviving until adulthood and into old age. [9]

Related Research Articles

<span class="mw-page-title-main">Zellweger syndrome</span> Congenital disorder of nervous system

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 leukodystrophies. Zellweger syndrome is named after Hans Zellweger (1909–1990), a Swiss-American pediatrician, a professor of pediatrics and genetics at the University of Iowa who researched this disorder.

Phytol is an acyclic hydrogenated diterpene alcohol that is used as a precursor for the manufacture of synthetic forms of vitamin E and vitamin K1, as well as in the fragrance industry. Its other commercial uses include cosmetics, shampoos, toilet soaps, and detergents, as well as in some cannabis distillates as a diluent or for flavoring. Its worldwide use has been estimated to be approximately 0.1–1.0 metric tons per year.

Refsum disease is an autosomal recessive neurological disease that results in the over-accumulation of phytanic acid in cells and tissues. It is one of several disorders named after Norwegian neurologist Sigvald Bernhard Refsum (1907–1991). Refsum disease typically is adolescent onset and is diagnosed by above average levels of phytanic acid. Humans obtain the necessary phytanic acid primarily through diet. It is still unclear what function phytanic acid plays physiologically in humans, but has been found to regulate fatty acid metabolism in the liver of mice.

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. In a study conducted in Oxford, individuals who consumed meat had, on average, a 6.7-fold higher geometric mean plasma phytanic acid concentration than did vegans.

<span class="mw-page-title-main">Peroxisomal disorder</span> Medical condition

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 biogenesis.

<span class="mw-page-title-main">Rhizomelic chondrodysplasia punctata</span> Recessive genetic condition

Rhizomelic chondrodysplasia punctata is a rare developmental brain disorder characterized by abnormally short arms and legs (rhizomelia), seizures, recurrent respiratory tract infections and congenital cataracts.

<span class="mw-page-title-main">Pipecolic acidemia</span> Medical condition

Pipecolic acidemia is a very rare autosomal recessive metabolic disorder that is caused by a peroxisomal defect.

D-Bifunctional protein deficiency is an autosomal recessive peroxisomal fatty acid oxidation disorder. Peroxisomal disorders are usually caused by a combination of peroxisomal assembly defects or by deficiencies of specific peroxisomal enzymes. The peroxisome is an organelle in the cell similar to the lysosome that functions to detoxify the cell. Peroxisomes contain many different enzymes, such as catalase, and their main function is to neutralize free radicals and detoxify drugs. For this reason peroxisomes are ubiquitous in the liver and kidney. D-BP deficiency is the most severe peroxisomal disorder, often resembling Zellweger syndrome.

<span class="mw-page-title-main">Phytanoyl-CoA dioxygenase</span> Class of enzymes

In enzymology, a phytanoyl-CoA dioxygenase (EC 1.14.11.18) is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">PEX5</span> Protein-coding gene in the species Homo sapiens

Peroxisomal targeting signal 1 receptor (PTS1R) is a protein that in humans is encoded by the PEX5 gene.

<span class="mw-page-title-main">PEX1</span> Protein-coding gene in the species Homo sapiens

Peroxisome biogenesis factor 1, also known as PEX1, is a protein which in humans is encoded by the PEX1 gene.

<span class="mw-page-title-main">PEX14</span> Protein-coding gene in the species Homo sapiens

Peroxisomal membrane protein PEX14 is a protein that in humans is encoded by the PEX14 gene.

<span class="mw-page-title-main">ABCD3</span> Protein-coding gene in the species Homo sapiens

ATP-binding cassette sub-family D member 3 is a protein that in humans is encoded by the ABCD3 gene.

<span class="mw-page-title-main">Peroxisomal biogenesis factor 2</span> Protein found in humans

Peroxisomal biogenesis factor 2 is a protein that in humans is encoded by the PEX2 gene.

<span class="mw-page-title-main">PEX12</span> Protein-coding gene in humans

Peroxisome assembly protein 12 is a protein that in humans is encoded by the PEX12 gene.

<span class="mw-page-title-main">PEX6</span> Protein-coding gene in the species Homo sapiens

Peroxisome assembly factor 2 is a protein that in humans is encoded by the PEX6 gene. PEX6 is an AAA ATPase that localizes to the peroxisome. PEX6 forms a hexamer with PEX1 and is recruited to the membrane by PEX26.

<span class="mw-page-title-main">PEX10</span> Protein-coding gene in the species Homo sapiens

Peroxisome biogenesis factor 10 is a protein that in humans is encoded by the PEX10 gene. Alternative splicing results in two transcript variants encoding different isoforms.

<span class="mw-page-title-main">PEX16</span> Protein-coding gene in the species Homo sapiens

Peroxisomal membrane protein PEX16 is a protein that in humans is encoded by the PEX16 gene.

<span class="mw-page-title-main">PEX26</span> Protein-coding gene in the species Homo sapiens

Peroxisome assembly protein 26 is a protein that in humans is encoded by the PEX26 gene.

Zellweger spectrum disorders are a group of rare disorders that create the same disease process. The subdivisions of this spectrum are hyperpipecolic acidemia, infantile Refsum disease, neonatal adrenoleukodystrophy, and Zellweger syndrome. It can also be referred to as peroxisomal biogenesis disorders, Zellweger syndrome spectrum, NALD, cerebrohepatorenal syndrome, and ZSS. It can affect many body organs, including the kidneys, eyes, and hearing. It is named after Hans Zellweger.

References

  1. 1 2 Online Mendelian Inheritance in Man (OMIM): Refsum Disease, Infantile form - 266510
  2. ↑ Choksi, V; Hoeffner, E; Karaarslan, E; Yalcinkaya, C; Cakirer, S (2003). "Infantile refsum disease: case report". AJNR. American Journal of Neuroradiology. 24 (10): 2082–4. PMC   8148918 . PMID   14625237.
  3. ↑ Steinberg SJ, Raymond GV, Braverman NE, et al. (2020). Adam MP, Ardinger HH, Pagon RA, et al. (eds.). "Zellweger Spectrum Disorder". GeneReviews® [Internet]. University of Washington. PMID   20301621. NBK1448.
  4. ↑ Krause, C.; Rosewich, H.; Gärtner, J. (2009). "Rational diagnostic strategy for Zellweger syndrome spectrum patients". European Journal of Human Genetics. 17 (6): 741–8. doi:10.1038/ejhg.2008.252. PMC   2947092 . PMID   19142205.
  5. ↑ Online Mendelian Inheritance in Man (OMIM): Refsum Disease, Classic - 266500
  6. 1 2 3 4 5 6 Steinberg, S.; Dodt, G.; Raymond, G.; Braverman, N.; Moser, A.; Moser, H. (2006). "Peroxisome biogenesis disorders". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1763 (12): 1733–48. doi:10.1016/j.bbamcr.2006.09.010. PMID   17055079.
  7. ↑ GeneReviews: Peroxisome Biogenesis Disorders, Zellweger Syndrome Spectrum
  8. ↑ Krause, C.; Rosewich, H.; Thanos, M.; Gärtner, J. (2006). "Identification of novel mutations in PEX2, PEX6, PEX10, PEX12, and PEX13 in Zellweger spectrum patients". Human Mutation. 27 (11): 1157. doi:10.1002/humu.9462. PMID   17041890. S2CID   9905589.
  9. 1 2 3 4 5 6 Raymond, G. V.; Watkins, P.; Steinberg, S.; Powers, J. (2009). "Peroxisomal Disorders". Handbook of Neurochemistry and Molecular Neurobiology. pp. 631–670. doi:10.1007/978-0-387-30378-9_26. ISBN   978-0-387-30345-1.
  10. ↑ Steinberg, S.; Chen, L.; Wei, L.; Moser, A.; Moser, H.; Cutting, G.; Braverman, N. (2004). "The PEX Gene Screen: molecular diagnosis of peroxisome biogenesis disorders in the Zellweger syndrome spectrum". Molecular Genetics and Metabolism. 83 (3): 252–263. doi:10.1016/j.ymgme.2004.08.008. PMID   15542397.
  11. ↑ Yik, W. Y.; Steinberg, S. J.; Moser, A. B.; Moser, H. W.; Hacia, J. G. (2009). "Identification of novel mutations and sequence variation in the Zellweger syndrome spectrum of peroxisome biogenesis disorders". Human Mutation. 30 (3): E467–80. doi:10.1002/humu.20932. PMC   2649967 . PMID   19105186.

Further reading

This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.