| Zellweger syndrome | |
|---|---|
| Other names | Cerebrohepatorenal syndrome |
 | |
| Infant with Zellweger syndrome | |
| Specialty | Medical genetics  |
| Complications | pneumonia and respiratory distress. |
Zellweger syndrome is a rarecongenital disorder characterized by the reduction or absence of functionalperoxisomes in the cells of an individual.[1] It is one of a family of disorders calledZellweger spectrum disorders which areleukodystrophies. Zellweger syndrome is named afterHans Zellweger (1909–1990), a Swiss-American pediatrician, a professor ofpediatrics andgenetics at theUniversity of Iowa who researched thisdisorder.[2][3]
Zellweger syndrome is one of threeperoxisome biogenesis disorders that belong to the Zellweger spectrum of peroxisome biogenesis disorders (PBD-ZSD).[4] The other two disorders areneonatal adrenoleukodystrophy (NALD), andinfantile 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, andbrain development.[4] In addition, individuals with Zellweger syndrome can show a reduction incentral nervous system (CNS)myelin (particularly cerebral), which is referred to ashypomyelination. Myelin is critical for normal CNS functions, and in this regard, serves to insulate nerve fibers in the brain. Patients can also show postdevelopmental sensorineural 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, andrenal cysts.[4] Newborns may present with profoundhypotonia (low muscle tone), seizures, apnea, and an inability to eat.[4][7]
Zellweger syndrome is anautosomal recessive disorder caused by mutations in genes that encodeperoxins, proteins required for the normal assembly ofperoxisomes. Most commonly, patients have mutations in thePEX1,PEX2,PEX3,PEX5,PEX6,PEX10,PEX12,PEX13,PEX14,PEX16,PEX19, orPEX26 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 aforementionedPEX genes.[citation needed]
As a result of impaired peroxisome function, an individual's tissues and cells can accumulatevery 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 ofplasmalogens, 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 involvebeta-oxidation of the branched side chains of dihydroxycholestanoic acid or trihydroxycholestanoic acid, respectively, by peroxisomal enzymes.[9]
In addition to genetic tests involving the sequencing ofPEX genes,[10][11] biochemical tests have proven highly effective for the diagnosis of Zellweger syndrome and other peroxisomal disorders. Typically, Zellweger syndrome patients show elevatedvery long chain fatty acids in theirblood plasma. Cultured primary skin fibroblasts obtained from patients show elevated very long chain fatty acids, impaired very long chain fatty acidbeta-oxidation,phytanic acidalpha-oxidation,pristanic acid alpha-oxidation, and plasmalogen biosynthesis.[4]
The nutrient malabsorption resulting from a lack of bile acids has resulted inelemental formula being suggested for feeding. They are low in fat, with less than 3 percent of calories being derived fromlong-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 ofLorenzo's oil (a 4:1 mixture ofglyceryl 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]
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 ofveno-occlusive disease.[17]Infections should be guarded against to prevent such complications aspneumonia and respiratory distress. Other treatment is symptomatic and supportive. Patients usually do not survive beyond one year of age.[4]
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