Peroxisome biogenesis disorders in the Zellweger spectrum: An overview of current diagnosis, clinical manifestations, and treatment guidelines.

Peroxisome biogenesis disorders in the Zellweger spectrum (PBD-ZSD) are a heterogeneous group of genetic disorders caused by mutations in PEX genes responsible for normal peroxisome assembly and functions. As a result of impaired peroxisomal activities, individuals with PBD-ZSD can manifest a complex spectrum of clinical phenotypes that typically result in shortened life spans. The extreme variability in disease manifestation ranging from onset of profound neurologic symptoms in newborns to progressive degenerative disease in adults presents practical challenges in disease diagnosis and medical management. Recent advances in biochemical methods for newborn screening and genetic testing have provided unprecedented opportunities for identifying patients at the earliest possible time and defining the molecular bases for their diseases. Here, we provide an overview of current clinical approaches for the diagnosis of PBD-ZSD and provide broad guidelines for the treatment of disease in its wide variety of forms. Although we anticipate future progress in the development of more effective targeted interventions, the current guidelines are meant to provide a starting point for the management of these complex conditions in the context of personalized health care.

The Δ4-desaturation pathway for DHA biosynthesis is operative in the human species: differences between normal controls and children with the Zellweger syndrome.

BACKGROUND: Docosahexaenoic acid (DHA, 22:6ω3) is a fundamental component of cell membranes, especially in the brain and retina. In the experimental animal, DHA deficiency leads to suboptimal neurological performance and visual deficiencies. Children with the Zellweger syndrome (ZS) have a profound DHA deficiency and symptoms that can be attributed to their extremely low DHA levels. These children seem to have a metabolic defect in DHA biosynthesis, which has never been totally elucidated. Treatment with DHA ethyl ester greatly improves these patients, but if we could normalize their endogenous DHA production we could get additional benefits. We examined whether DHA biosynthesis by Δ4-desaturation could be enhanced in the human species by transfecting the enzyme, and if this could normalize the DHA levels in cells from ZS patients. RESULTS: We showed that the Δ4-desaturase gene (Fad4) from Thraustochytrium sp, which can be expressed by heterologous transfection in other plant and yeast cells, can also be transfected into human lymphocytes, and that it expresses the enzyme (FAD4, Δ4-desaturase) by producing DHA from direct Δ4-desaturation of 22:5ω3. We also found that the other substrate for Δ4-desaturase, 22:4ω6, was parallely desaturated to 22:5ω6. CONCLUSIONS: The present "in vitro" study demonstrates that Δ4-desaturase can be transfected into human cells and synthesize DHA (as well as 22:5ω6, DPA) from 22:5ω3 and 22:4ω6, respectively, by putative Δ4-desaturation. Even if this pathway may not be the physiological route for DHA biosynthesis "in vivo", the present study opens new perspectives for the treatment of patients within the ZS spectrum.

Blenderized Tube Feeding: Health Outcomes and Review of Homemade and Commercially Prepared Products.

The popularity of homemade blenderized tube feeding (HBTF) continues to increase among enteral nutrition (EN) consumers and healthcare providers alike, citing improved feeding tolerance over standard commercial enteral formulas, among other health outcomes. Within the past 5-10 years, there has been a surge in the development of commercial blenderized tube feeding (CBTF) products. CBTF products promote similar benefits from whole foods like those used in HBTF while being a nutritionally-consistent, easy to use, and shelf-stable option for EN consumers. Research is improving but is still limited for HBTF and virtually nonexistent for CBTF products. This review aims to summarize current health outcomes of HBTF, compare HBTF with CBTF, evaluate CBTF products, and provide considerations for future research and practices.

Zellweger spectrum disorders: clinical overview and management approach.

Zellweger spectrum disorders (ZSDs) represent the major subgroup within the peroxisomal biogenesis disorders caused by defects in PEX genes. The Zellweger spectrum is a clinical and biochemical continuum which can roughly be divided into three clinical phenotypes. Patients can present in the neonatal period with severe symptoms or later in life during adolescence or adulthood with only minor features. A defect of functional peroxisomes results in several metabolic abnormalities, which in most cases can be detected in blood and urine. There is currently no curative therapy, but supportive care is available. This review focuses on the management of patients with a ZSD and provides recommendations for supportive therapeutic options for all those involved in the care for ZSD patients.

[Intrahepatic cholestasis due to biochemical errors of bile acids. II. Clinical and therapeutic aspects]. / Colestasi intraepatiche da errori biochimici degli acidi biliari. Parte II--Aspetti clinici e terapeutici.

Within the "primary" cholestasis we can discriminate "essential" forms due to an endogenous biochemical error of bile acid metabolism and/or secretion and "conditioned" forms, in which a known precipitating factor is required to elicit the functional disorder responsible for cholestasis. Among the essential forms of cholestasis must be included benign recurrent intrahepatic cholestasis or Summerskill-Walshe disease, Aagenaes disease, progressive familial intrahepatic cholestasis or Byler's disease, and forms due to disorders of the peroxisomes. Benign recurrent intrahepatic cholestasis, the best known form, is characterized by recurrent episodes of itching and jaundice with an acute onset separated by symptom-free intervals, which shows no tendency to progress to liver failure. The conditioned cholestasis group comprises cholestasis of pregnancy and drug-induced cholestasis. Benign recurrent cholestasis of pregnancy is a form induced "by" pregnancy and not a form occurring "in" pregnancy, such as cholestasis due to hepatitis, to primary biliary cirrhosis, to cholelithiasis. Drug-induced cholestasis is a chapter of great clinical relevance: forms due to steroid hormones and due to phenothiazines are discussed.

Zellweger syndrome: report of one case.

Zellweger syndrome is a fatal autosomal-recessive hereditary disease characterized by the absence of peroxisomes in liver and kidneys. The absence of peroxisomes results in impairment of many metabolic pathways, especially beta-oxidation of very long chain fatty acids (VLCFAs). We report a case of a three-month-old male infant with facial dysmorphism, hypotonia, psychomotor retardation, and hepatomegaly. He had an elder brother with the same facial features and hypotonia who died of hepatic failure at four months of age. Biochemical studies revealed elevation of blood pipecolic acid and VLCFAs, compatible with peroxisomal disorder. Electron microscopy of liver biopsy revealed absence of peroxisomes. Zellweger syndrome was diagnosed. Because this syndrome is usually fatal in early life, genetic counseling and prenatal diagnosis are crucial.

[Zellweger syndrome--a peroxisomal disease]. / Zellwegers syndrom--en peroxisomal sygdom.

Zellweger syndrome is a fatal recessively inherited disease with disturbed function of many organs. The disease is caused by a defect of peroxisomes, subcellular organelles, which are absent in these patients. Several genes are necessary for the formation and function of the peroxisomes. The clinical picture of Zellweger syndrome can be caused by defects in a number of genes. On the other hand, clinically different diseases such as neonatal adrenoleucodystrophy and infantile Refsum disease have been shown to be allelic to Zellweger syndrome. We describe a typical Zellweger patient belonging to complementation group 1, which is by far the largest group containing more than half of the Zellweger patients.

Zellweger syndrome and associated phenotypes.

Until recently, the peroxisome was considered a "reactor chamber" for H2O2 producing oxidases, and it is now recognised as a versatile organelle performing complex catabolic and biosynthetic roles in the cell. Zellweger syndrome (ZS), the paradigm of human peroxisomal disorders, is characterised by neonatal hypotonia, severe neuro-developmental delay, hepatomegaly, renal cysts, senorineural deafness, retinal dysfunction, and facial dysmorphism. It is now clear that ZS is at the severe end of a phenotypic spectrum of Zellweger-like syndromes which may present for diagnosis later in childhood and even in adult life. It is important that clinical geneticists are aware of these milder clinical variants as the availability of sensitive and specific biochemical assays of peroxisomal function (for example, serum VLCFA ratios, platelet DHAP-AT activity) makes their diagnosis relatively straightforward.

Correction by gene expression of biochemical abnormalities in fibroblasts from Zellweger patients.

Zellweger syndrome is a prototype of peroxisomal biogenesis disorders and a fatal autosomal recessive disease with no effective therapy. We identified nine genetic complementation groups of these disorders, and mutations in peroxisome assembly factor-1 (PAF-1) and the 70-kD peroxisomal membrane protein (PMP70) genes have been detected by our group F and Roscher's group 1, respectively. We now describe permanent recovery from generalized peroxisomal abnormalities in fibroblasts of a Zellweger patient from group F, such as biochemical defects of peroxisomal beta-oxidation, plasmalogen biosynthesis, and morphologic absence of peroxisomes, by stable transfection of human cDNA encoding PAF-1. In the light of these observations, we designed a gene expression system using fibroblasts from patients with peroxisomal biogenesis disorders. In Zellweger fibroblasts obtained from Roscher's group 1 and transfected with human cDNA encoding PMP70, peroxisomes were not morphologically identifiable, and peroxisomal function did not normalize.

Peroxisomal disorders. Neurodevelopmental and biochemical aspects.

The peroxisomal disorders represent a group of inherited metabolic disorders that derive from defects of peroxisomal biogenesis and/or from dysfunction of single or multiple peroxisomal enzymes. Because peroxisomes are involved in the metabolism of lipids critical to the functioning of the nervous system, many of the peroxisomal disorders manifest with significant degrees of progressive psychomotor dysfunction. These disorders should be considered in the differential diagnosis of the infant with hypotonia and psychomotor delay (especially if accompanied by facial dysmorphisms, hepatomegaly, cataracts and/or retinitis, calcific stippling, short limbs, or combinations of these features), in the school-aged child with progressive neurologic dysfunction, and in adults with slowly progressive motor dysfunction. Current knowledge of peroxisomal biochemical and enzymatic processes permits precise identification of particular disorders within the peroxisomal disorder grouping. An effort should be made to identify the specific peroxisomal disorder to provide a precise explanation for neurodevelopmental deficits, to potentially prevent recurrence through genetic counseling, and to provide appropriate therapies when available.