Peroxisomes are cellular organelles that carry out important functions such as lipid metabolism and metabolic oxidations. A group of genetic disorders, known as peroxisome biogenesis disorders (PBD), affect the membrane biogenesis and fission of the peroxisomes, thereby resulting in mild to severe phenotypic defects. Zellweger Syndrome is the most severe of these PBDs. Unfortunately, it is also the most common of the PBDs occurring in early infancy. Infants born with ZS present with generalized hypotonia, hepatomegaly, hepatic dysfunction, and neurological abnormalities, including seizures. Since the peroxisomes play a vital role in clearing the cells' toxic metabolites, most of the above mentioned clinical features result from a reduction or elimination of peroxisomes causing very high build up of iron and copper in the body tissues. The most characteristic feature of ZS is the typical facies of infants with this condition. These facial deformities include a high forehead, deformed earlobes, underdeveloped ridges of the eyebrows, large anterior fontanelle, and a flat looking face. In some cases, infants may even be born with glaucoma, impaired hearing, and/or chondrodysplasia punctata.
The distinctive facial features are one of the first signs to suspect ZS in an infant. However, confirmation of the diagnosis is based upon a series of biochemical tests. The most important of these tests is the assay of plasma levels of very-long-chain fatty acids (VLCFA), especially the C26:0 and C26:1 levels, and the ratio of levels of C24/C22 and C26/C22. A number of genes are involved in the proper peroxisome biogenesis and genetic testing is available for seven of these genes. Like most genetic disorders, no cure is available at present for ZS. Treatment is symptomatic and focuses on vitamin supplementation, controlling the seizures, cataract removal, and using hearing aids. Physical and occupational therapy has an important role to play. Most infants born with ZS do not survive beyond the first six months of their life. Those that do are plagued by complications, such as retinal dystrophy, sensorineural hearing loss, developmental delays, and liver dysfunction. A regular monitoring of their condition is critical.
The process of peroxisomal biogenesis and protein import into the organelle is not very clearly known. However, it is understood that at least 29 different genes are involved in these processes. Mutations in at least 12 of these genes have been shown to result in ZS; three of them (PEX3, PEX16, and PEX9) interfering with membrane biogenesis and the remaining nine (PEX1, PEX2, PEX5, PEX6, PEX10, PEX12, PEX13, PEX14, and PEX26) expected to play some part in the protein import. Of these, PEX1 gene is the most common gene to be mutated in ZS, having been found mutated in about 68% of affected individuals. In addition, almost 90% of affected individuals have mutation in one of PEX1, PEX6, PEX26, PEX10, or PEX12 genes.
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Joshi et al. (2002) carried out a retrospective analysis of all patients born with inborn errors of metabolism in Oman between 1998 and 2000. Among the 82 patients, one was diagnosed with Zellweger Syndrome.
Rajab et al. (2005) in a study to estimate the prevalence of commonly diagnosed autosomal recessive diseases in Oman from a hospital-based register in the year 1993 to 2002, found that Zellweger Syndrome was diagnosed in 19 patients, with an observed incidence of 1 in 20,000 births.
Al-Essa et al. (1999) reported the clinical and laboratory findings of Zellweger syndrome (ZS) patients diagnosed at King Faisal Specialist Hospital and Research Center over a period of 10 years. Eleven patients (nine females and two males) from 2 to 4 months old were referred for evaluation of hypotonia, seizures, and dysmorphic features. The common clinical findings included high forehead, large fontanel, shallow orbit ridges, micrognathia, upslanting palebral fissures, epicanthal folds, severe hypotonia, hyporeflexia, pigmentary retinopathy, optic nerve atrophy, complete or partial agenesis of corpus callosum, and failure to thrive. Interestingly, no Brushfield spots were observed in this study and certain symptoms, such as renal and brain cysts and adrenal insufficiency, were also absent. Some unique clinical findings were the presence of gallstones, club feet, or bilateral knee or hip dislocation in some patients. All patients had markedly elevated plasma levels of very long chain fatty acids (VLCFA). Electron microscopy performed on liver biopsies of two patients revealed absence of peroxisomes. Biochemical studies of dermal fibroblasts from three patients showed deficient beta-oxidation of lignoceric acid and dihydroxyacetone phosphate acyltransferase (DHAPATase) activity. Al-Essa et al. (1999) noted the observation that 10 of the 11 parents in their study were first-degree relatives and, except for families 1 and 3, each family had at least another baby who died of the same disease. Al-Essa et al. (1999) further suggested that the incidence of ZS in Saudi Arabia may actually be higher than currently reported. They have also suggested that the clinical differences between their study and studies in other populations may indicate a different underlying mutation/s and mechanisms of pathogenesis.
In 2007, Al-Sayed and colleagues reported on the first live birth of a normal child after performance of preimplantation genetic diagnosis (PGD) for Zellweger syndrome (ZS). The child was born to a family with four children diagnosed with ZS, who were all born at term and who expired around 4 months of age. After PGD, two genotypically normal embryos were transferred back to the mother. Pregnancy ensued, and a healthy baby girl was delivered in week 40 of pregnancy. The baby was confirmed as genotypically wild-type and free of any sign of ZS. This could be the first successful PGD for ZS caused by mutation in PEX26 gene, with the subsequent delivery of a homozygous normal baby.
Moammar et al. (2010) reviewed all patients diagnosed with inborn errors of metabolism (IEM) from 1983 to 2008 at Saudi Aramco medical facilities in the Eastern province of Saudi Arabia. During the study period, 165530 Saudi infants were born, of whom a total of 248 newborns were diagnosed with 55 IEM. Affected patients were evaluated based on clinical manifestations or family history of similar illness and/or unexplained neonatal deaths. Almost all patients were born to consanguineous parents. Organelle disorders were 18 out of 248 of diagnosed subjects. Among them, 8 cases from 6 families were found to have Zellweger syndrome, with an estimated incidence of 5 per 100,000 live births. The authors concluded that data obtained from this study underestimate the true figures of various IEM in the region. Therefore, there is an urgent need for centralized newborn screening program that utilizes tandem mass spectrometry, and offers genetic counseling for these families.
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