Zellweger syndrome

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Zellweger syndrome
Other namesCerebrohepatorenal syndrome
Cerebro-Hepato-Renal Syndrome 2.jpg
Infant with Zellweger syndrome
Specialty Medical genetics   OOjs UI icon edit-ltr-progressive.svg
Complications pneumonia and respiratory distress.

Zellweger syndrome is a rare congenital disorder characterized by the reduction or absence of functional peroxisomes in the cells of an individual. [1] 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. [2] [3]

Contents

Signs and symptoms

Zellweger syndrome is one of three peroxisome biogenesis disorders which belong to the Zellweger spectrum of peroxisome biogenesis disorders (PBD-ZSD). [4] The other two disorders are neonatal adrenoleukodystrophy (NALD), and infantile Refsum disease (IRD). [5] [6] Although all have a similar molecular basis for disease, Zellweger syndrome is the most severe of these three disorders. [7]

Zellweger syndrome is associated with impaired neuronal migration, neuronal positioning, and brain development. [4] In addition, individuals with Zellweger syndrome 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, and in this regard, serves to insulate nerve fibers in the brain. Patients can also show postdevelopmental sensorineuronal degeneration that leads to a progressive loss of hearing and vision. [4]

Zellweger syndrome can also affect the function of many other organ systems. Patients can show craniofacial abnormalities (such as a high forehead, hypoplastic supraorbital ridges, epicanthal folds, midface hypoplasia, and a large fontanelle), hepatomegaly (enlarged liver), chondrodysplasia punctata (punctate calcification of the cartilage in specific regions of the body), eye abnormalities, and renal cysts. [4] Newborns may present with profound hypotonia (low muscle tone), seizures, apnea, and an inability to eat. [4] [7]

Cause

Autosomal recessive inheritance Autosomal recessive - en.svg
Autosomal recessive inheritance

Zellweger syndrome is an autosomal recessive disorder caused by mutations in genes that encode peroxins, proteins required for the normal assembly of peroxisomes. Most commonly, patients have mutations in the PEX1 , PEX2 , PEX3 , PEX5 , PEX6 , PEX10 , PEX12 , PEX13 , PEX14 , PEX16 , PEX19 , or PEX26 genes. [8] 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 above. In addition, these individuals can show deficient levels of plasmalogens, ether-phospholipids that are especially important for brain and lung function.[ citation needed ] Bile acid synthesis is defective due to lack of side chain modifications; for example, the last steps in the synthesis of chenodeoxycholic acid and cholic acid involve beta-oxidation of the branched side chains of dihydroxycholestanoic acid or trihydroxycholestanoic acid, respectively, by peroxisomal enzymes. [9]

Diagnosis

In addition to genetic tests involving the sequencing of PEX genes, [10] [11] biochemical tests have proven highly effective for the diagnosis of Zellweger syndrome and other peroxisomal disorders. Typically, Zellweger syndrome patients show elevated very long chain fatty acids in their blood plasma. Cultured primary 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. [4]

Treatment

The nutrient malabsorption resulting from a lack of bile acids has resulted in elemental formula being suggested for feeding. They are low in fat, with less than 3 per cent of calories being derived from long-chain triglycerides (LCT). However, reducing dietary very long chain fatty acids (VLCFA) has not been shown to reduce blood VLCFA levels, [12] [13] likely because humans can endogenously produce most VLCFA. Plasma VLCFA levels are decreased when dietary VLCFA is reduced in conjunction with supplementation of Lorenzo's oil (a 4:1 mixture of glyceryl trioleate and glyceryl trierucate) in X-ALD patients. [14] Since docosahexaenoic acid (DHA) synthesis is impaired [15] [59], DHA supplementation was recommended, but a placebo-controlled study has since shown no clinical efficacy. [16] Due to defective bile acid synthesis, fat-soluble supplements of vitamins A, D, E, and K are recommended.[ citation needed ]

Prognosis

Currently, no cure for Zellweger syndrome is known, nor is there a standard course of treatment. In November 2023, at five months old, Christopher Donald Miller was the first patient with Zellweger Syndrome in the United States to have a bone marrow transplant. He did pass away at seven months old of veno-occlusive disease. [17] Infections should be guarded against to prevent such complications as pneumonia and respiratory distress. Other treatment is symptomatic and supportive. Patients usually do not survive beyond one year of age. [4]

Related Research Articles

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

Adrenoleukodystrophy (ALD) is a disease linked to the X chromosome. It is a result of fatty acid buildup caused by failure of peroxisomal fatty acid beta oxidation which results in the accumulation of very long chain fatty acids in tissues throughout the body. The most severely affected tissues are the myelin in the central nervous system, the adrenal cortex, and the Leydig cells in the testes. The long chain fatty acid buildup causes damage to the myelin sheath of the neurons of the brain, resulting in seizures and hyperactivity. Other symptoms include problems in speaking, listening, and understanding verbal instructions.

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.

<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">ABCD1</span> Protein-coding gene in humans

ABCD1 is a protein that transfers fatty acids into peroxisomes.

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.

Infantile Refsum disease (IRD) is a rare autosomal recessive 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. IRD is associated with deficient phytanic acid catabolism, as is adult Refsum disease, but they are different disorders that should not be confused.

<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">PEX19</span> Protein-coding gene in the species Homo sapiens

Peroxisomal biogenesis factor 19 is a protein that in humans is encoded by the PEX19 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">ABCD2</span> Protein-coding gene in humans

ATP-binding cassette sub-family D member 2 is a membrane pump/transporter protein that in humans is encoded by the ABCD2 gene.

<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.

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.

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. ↑ Brul, S.; Westerveld, A.; Strijland, A.; Wanders, R.; Schram, A.; Heymans, H.; Schutgens, R.; Van Den Bosch, H.; Tager, J. (June 1988). "Genetic heterogeneity in the cerebrohepatorenal (Zellweger) syndrome and other inherited disorders with a generalized impairment of peroxisomal functions. A study using complementation analysis". Journal of Clinical Investigation (Free full text). 81 (6): 1710–1715. doi:10.1172/JCI113510. PMC   442615 . PMID   2454948.
  2. ↑ Zellweger's syndrome at Who Named It?
  3. ↑ Wiedemann, H. R. (1991). "Hans-Ulrich Zellweger (1909-1990)". European Journal of Pediatrics. 150 (7): 451. doi:10.1007/BF01958418. PMID   1915492. S2CID   34905299.
  4. 1 2 3 4 5 6 7 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.
  5. ↑ GeneReviews: Peroxisome Biogenesis Disorders, Zellweger Syndrome Spectrum
  6. ↑ 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.
  7. 1 2 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.
  8. ↑ Online Mendelian Inheritance in Man (OMIM): Zellweger syndrome; ZS - 214100
  9. ↑ Sundaram SS, Bove KE, Lovell MA, Sokol RJ (2008). "Mechanisms of Disease: inborn errors of bile acid synthesis". Nature Reviews Gastroenterology & Hepatology. 5 (8): 456–468. doi:10.1038/ncpgasthep1179. PMC   3888787 . PMID   18577977.
  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–E480. doi:10.1002/humu.20932. PMC   2649967 . PMID   19105186.
  12. ↑ Van Duyn, MA; Moser, AE; Brown FR, 3rd; et al. (August 1984). "The design of a diet restricted in saturated very long-chain fatty acids: therapeutic application in adrenoleukodystrophy". The American Journal of Clinical Nutrition. 40 (2): 277–84. doi: 10.1093/ajcn/40.2.277 . PMID   6465061.{{cite journal}}: CS1 maint: numeric names: authors list (link)
  13. ↑ Brown FR, 3rd; Van Duyn, MA; Moser, AB; et al. (October 1982). "Adrenoleukodystrophy: effects of dietary restriction of very long chain fatty acids and of administration of carnitine and clofibrate on clinical status and plasma fatty acids". The Johns Hopkins Medical Journal. 151 (4): 164–72. PMID   7120720.{{cite journal}}: CS1 maint: numeric names: authors list (link)
  14. ↑ Moser, AB; Borel, J; Odone, A; et al. (March 1987). "A new dietary therapy for adrenoleukodystrophy: biochemical and preliminary clinical results in 36 patients". Annals of Neurology. 21 (3): 240–9. doi:10.1002/ana.410210305. PMID   2440378. S2CID   29043456.
  15. ↑ Martinez, M (26 June 1992). "Abnormal profiles of polyunsaturated fatty acids in the brain, liver, kidney and retina of patients with peroxisomal disorders". Brain Research. 583 (1–2): 171–82. doi:10.1016/s0006-8993(10)80021-6. PMID   1504825. S2CID   20508763.
  16. ↑ Paker, AM; Sunness, JS; Brereton, NH; et al. (31 August 2010). "Docosahexaenoic acid therapy in peroxisomal diseases: results of a double-blind, randomized trial". Neurology. 75 (9): 826–30. doi:10.1212/WNL.0b013e3181f07061. PMC   3013498 . PMID   20805528.
  17. ↑ Missing reference
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