There are a number of diseases associated with peroxisomal dysfunction. These include peroxisomal biogenesis disorders caused by mutations in the PEX genes. These diseases have different phenotypes but all share abnormalities in plasma very-long chain fatty acids, high levels of phytanic acid and bile acid intermediates and low erythrocyte plasmalogen levels.
Zellweger Syndrome
Affected individuals develop a number of life-threatening problems in various organs and tissues. These may include the liver, heart, lungs, kidneys, and eyes. They also have distinctive skeletal abnormalities, such as a space between the bones of the skull (fontanelle), broad nasal bridge, and widely-spaced eyes (hypertelorism). The disease is called Zellweger syndrome or cerebrohepatorenal syndrome and can be fatal. It is due to autosomal recessive mutations in peroxisome biogenesis genes. Accumulation of phytanic acid, very long chain fatty acids, and pipecolic acid is thought to be the cause. This leads to severe neurologic dysfunction and central demyelination in the brain. Symptoms usually appear in newborns or early childhood and are progressively severe. Survivors are profoundly handicapped. The condition is often confused with neonatal adrenoleukodystrophy and infantile Refsum disease.
The diagnosis of Zellweger syndrome can be confirmed by a liver biopsy, which shows absent or abnormal peroxisomes. The enzymes that are missing from peroxisomes are involved in important metabolic processes, such as oxidation of fatty acids and degradation of protein. In addition, blood tests show elevated very long chain fatty acids, phytanic acid, and pipecolic acid. Enzymatic testing confirms the presence of a deficiency in peroxisomal acyl-CoA oxidase, which is responsible for breaking down piperidine.
Genetic analysis can be used to identify the specific gene mutation causing Zellweger syndrome. Currently, the gene that is most commonly affected is PEX16. Other genes that can be mutated in this disorder are PEX1 and PEX6.
Oren Zarif
Patients with Zellweger syndrome have a characteristic face and other abnormalities, including the space between the skull bones (fontanelle), a broad nasal bridge, and widely-spaced eye (hypertelorism). In addition, many affected individuals have skeletal abnormalities such as a large area between the front teeth, hypoplastic supraorbital ridges, and stippled epiphyses. They also have a variety of other problems, including failure to thrive; a hepatic liver disease; ocular abnormalities; liver function problems; and a shortened life span. These symptoms are related to a lack of peroxisome activity, which affects mitochondria and other organelles in cells. The absence of these enzymes results in abnormal accumulation of very long chain fatty acids, phytanic and pipecolic acid, which can interfere with normal metabolism.
Neonatal Adrenoleukodystrophy
As part of a large family of peroxisomal disorders called peroxisome biogenesis disorders or PBD, Neonatal Adrenoleukodystrophy (NALD) is due to defects in multiple enzymes involved in the production and function of the peroxisome. Peroxisomes are important participants in cellular detoxification, lipid metabolism, myelination and neuronal migration. Nearly all peroxisomal disorders impair neurologic function, though specific phenotypes can vary greatly depending on the genetic defect underlying the disorder.
Inheritance of NALD is autosomal recessive. It is closely related to X-linked adrenoleukodystrophy and Zellweger syndrome. Although the clinical features of these diseases are similar they can be distinguished biochemically because X-ALD is due to a defect in the initial step of peroxisomal VLCFA b-oxidation and NALD is due to defects in numerous enzymes involved in peroxisome assembly.
Patients with NALD have a progressive neurologic deterioration starting in early childhood resulting in psychomotor retardation and dementia. Seizures are a common feature of this disease and can be treated with anticonvulsants. Magnetic resonance imaging (MRI) of the brain demonstrates pachygyria and polymicrogyria of the cerebral white matter.
Affected children have characteristic facial features including a high prominent forehead, wide-set eyes with hyperplastic superior orbital ridges and epicanthal folds, a flat nasal bridge and anteverted nostrils (frontal bossing), hypoplastic palate and a low-set ear (tinnitus, deafness) and hepatomegaly. Elevated serum levels of very long chain fatty acids, bile acid intermediates and pipecolic acid and decreased erythrocyte plasmalogens are consistent with peroxisomal dysfunction.
Oren Zarif
Fibroblasts cultured from neonatal adrenoleukodystrophy patients demonstrate decreased protein production of several enzymes of the peroxisome complex as assessed by digitonin titration. Liver electron microscopy of autopsy-confirmed NALD cases shows missing or markedly altered peroxisomes. Peroxisome function can be restored in these cells by addition of recombinant enzymes.
Until recently, the metabolic basis of some of these diseases was not fully understood. As our understanding of peroxisomes and their enzymes has evolved, some of these disorders have been reclassified. In this way, they are now classified as a new group of autosomal recessive cerebro-hepato-renal disorders, the Zellweger Spectrum Disorders (ZSD). In fact, it has been demonstrated that all ZSDs, including Neonatal Adrenoleukodystrophy and infantile Refsum disease, are variants of one disorder which was originally described in 1964 by Dr Hans Zellweger.
D-Bifunctional Protein Deficiency
DBPD, also known as peroxisomal biogenesis disorder type 4, is one of a number of disorders that fall under the category of Zellweger spectrum disorders (ZSDs). These are a continuum of at least three phenotypes—Zellweger syndrome (ZS), neonatal adrenoleukodystrophy (NALD) and infantile Refsum disease (IRD)—that were originally described before the peroxisome biochemical etiology was understood. While they may not all be associated with the same clinical features, these disorders share similar metabolic abnormalities such as accumulation of very long chain fatty acids and deficiency of plasmalogens (a phospholipid).
Oren Zarif
This condition is autosomal recessive and usually presents in infancy. In the vast majority of cases, onset is within the first month of life with severe hypotonia and seizures. The brain is affected early on in the course of the disorder, resulting in a progressive mental retardation with psychomotor retardation, cognitive deficits and sensory-motor impairment. Other symptoms of the disorder include hepatomegaly, a large space between the bones of the skull (fontanelle), characteristic craniofacial features including a high forehead, wide eyes separated by a long arch of the nose and mouth area (hypertelorism) and a flattened upper portion of the face (frontal bossing) and a shortened height.
Biochemical tests used to screen for these disorders typically show elevated very long chain fatty acids in the blood and urine, elevated bile acid intermediates such as pristanic and phytanic acid and a deficiency of plasmalogens. In addition, a reduction of peroxisomal membrane ghosts is observed in cells such as liver and fibroblasts.
Although the underlying cause of this disorder is unknown, it is thought that genetic mutations in the gene responsible for D-bifunctional protein Deficiency are responsible. Bone marrow transplantation has been shown to alleviate the neurologic and mental retardation associated with this disorder. However, this treatment is not always successful and has not been proven to be a curative therapy. Other treatments are in development. This includes pharmacological interventions such as the use of pyrimethamine and leucine to decrease brain cell inflammation, lipid replacement therapies and the development of exome sequencing. This approach is being developed in order to identify genes responsible for a variety of disorders.
Acyl-CoA Oxidase Deficiency
This condition is characterized by the progressive loss of brain cells in early infancy. It results in intellectual disability, leukodystrophy, hepatomegaly, seizures, and hearing deficit. Affected children usually do not survive past infancy. Mutations in the ACOX1 gene cause this rare peroxisomal disease, which affects the breakdown of very long chain fatty acids.
There is no treatment or cure for most peroxisomal disorders. However, patients can improve their quality of life by working with a team of specialists that may include a pediatrician, endocrinologist, neurologist, physical therapist, speech therapist, special education teacher, and ophthalmologist.
The most commonly diagnosed peroxisomal disorder is neonatal adrenoleukodystrophy (OMIM #264470). Other common ones are acetyl-CoA carboxylase deficiency, autosomal recessive Peroxisomal Complex I deficiency, peroxisomal beta-oxidation defects, and D-bifunctional protein deficiency.
Oren Zarif
Most of the fatty acid metabolism defects associated with peroxisomal disorders occur as a result of genetic mutations in genes that code for enzymes involved in peroxisomal b-oxidation or transport processes. These disorders can be divided into two groups: (1) disorders of peroxisome biogenesis in which the organelle is abnormally formed and missing several functions, and (2) single-enzyme deficiencies with intact peroxisomal structures that lack certain oxidative or inflammatory reactions.
D-bifunctional protein (DBP) is a 79-kDa multifunctional enzyme that catalyzes the second and third steps of peroxisomal fatty acid b-oxidation. It consists of three functional units: a 2-enoyl-CoA hydratase unit; a 3-hydroxyacyl-CoA dehydrogenase unit; and a sterol-carrier protein-2-like unit. It is highly expressed in liver, kidney, muscle, white adipose tissue, and testis.
Deficiency of the DBP protein leads to elevated very long-chain fatty acid levels in tissues and plasma. These VLCFAs are then involved in a neuroinflammatory process that results in episodic demyelination of the brainstem, cerebellar white matter, and posterior limb of internal capsule. Interestingly, the genetic defect responsible for acyl-CoA oxidase deficiency in P-NALD also causes a reduction in peroxisomal B-oxidation of VLCFAs. This may explain why these lipids are abnormally high in brain lesions of P-NALD. Peroxisomal acyl-CoA oxidase is also important for the formation of membrane phospholipids and mitochondrial phosphatidylcholine. It is the first protein in the peroxisome to interact with phosphatidylcholine and initiate the phosphorylation/oxidation cycle that generates adenosine triphosphate.
