Peroxisomal disorders are a group of genetically heterogeneous metabolic diseases that share dysfunction of peroxisomes. The peroxisome is a cellular organelle measuring 0.5 µm in diameter that participates in important cellular functions, such as beta-oxidation of very-long-chain fatty acids (VLCFA), production of plasmalogen, and synthesis of bile acid.
Zellweger described the first case of peroxisomal disorder. Over the next 3 years, a number of case reports followed. The initial description of the peroxisome (originally termed the microbody) appeared in 1954 in a doctoral thesis about mouse kidneys, almost 10 years after the first case description of peroxisomal disease was published. Finally, in 1979, a study of initiating reactions in complex lipid syntheses in rat liver peroxisomes was conducted. Its results helped investigators to understand the role of these organelles in human disease.
Peroxisomes are ubiquitous components of the cytoplasm found in nearly all mammalian cells. Their function is indispensable in human metabolism and includes beta-oxidation of fatty acids, biosynthesis of ether phospholipids (including plasmalogen and platelet activating factor [PAF]), biosynthesis of cholesterol and other isoprenoids, detoxification of glycolate to glycine (The accumulation of glycolate leads to precipitation of calcium oxalate in various tissues with subsequent deleterious effects.), and oxidation of L-pipecolic acid (the function of which is incompletely understood).
Beta-oxidation of fatty acids
Whereas the mitochondria are responsible for the oxidation of the bulk of dietary fatty acid (palmitate, oleate and linolate), peroxisomes oxidize VLCFA in addition to pristanic acid (from the dietary phytanic acid) and dihydroxycholestanoic acid (DHCA) or trihydroxycholestanoic acid (THCA). These last 2 compounds lead to the formation of bile acids, cholic acid, and chenodeoxycholic acid from cholesterol in the liver. Another major function of the peroxisomal beta-oxidation system is related to the biosynthesis of polyunsaturated fatty acid (C22:6w3). Peroxisomes also work in conjunction with mitochondria to shorten fatty acid chains, which are in turn degraded to completion in the mitochondria. The end result is the formation of acetylcoenzyme A (acetyl-CoA) units, which are degraded in the Krebs cycle to produce energy (adenosine triphosphate [ATP]).
Abnormal accumulation of VLCFAs (C24, C26) is the hallmark of peroxisomal disorders. VLCFAs have deleterious effects on membrane structure and function, increasing microviscosity of RBC membranes and impairing the capacity of cultured adrenal cells to respond to adrenocorticotropic hormone (ACTH).
In the CNS, VLCFA accumulation may cause demyelination associated with an intense inflammatory response in the white matter, with increased levels of leukotrienes due to beta-oxidation deficiency. Accompanying this response is a perivascular infiltration by T cells, B cells, and macrophages in a pattern suggestive of an autoimmune response. Levels of tumor necrosis factor and alpha immunoreactivity in astrocytes and macrophages at the outermost edge of the demyelinating lesion are increased, suggesting a cytokine-mediated mechanism. Furthermore, VLCFAs are postulated to be components of gangliosides and cell-adhesion molecules in growing axons and radial glia, and hence contribute to the migrational defect in the CNS.
Biosynthesis of ether phospholipids (including plasmalogen and PAF)
Plasmalogen is essential in maintaining the integrity of cell membranes, especially those in the CNS. PAF deficiency impairs glutaminergic signaling and has been implicated in human lissencephaly and neuronal migration disorders.
One of the most challenging aspects in pathogenesis of these disorders is the mechanism responsible for neuronal migration defects. These defects are the most likely causes of the severe seizures and psychomotor retardation associated with many types of peroxisomal disorders. The severity of migrational defects is correlated with the elevation of VLCFAs, with depressed levels of ether-linked phospholipids, and with elevated levels of bile-acid intermediates.
Fatty acid alpha-oxidation
Fatty acid alpha-oxidation results in the conversion of phytanic acid into pristanic acid (removal of a 3-methyl group), which then undergoes beta-oxidation in peroxisomes. The product is shuttled to the mitochondria by means of carnitine ester for further degradation.
The combined incidence of peroxisomal disorders is in excess of 1 in 20,000 individuals. Patients hemizygous or heterozygous for adrenoleukodystrophy (ALD) that is X-linked (X-ALD) are by far the largest subset. Zellweger syndrome (ZWS) is the most common peroxisomal disorder to manifest itself in early infancy. Its incidence has been estimated to be 1 in 50,000-100,000. Baumgartner et al reported that peroxisomal disorders accounted for 2.7% of the 1000 patients with inborn errors of metabolism examined at the Hospital Necker-Enfants Malades between 1982 and publication of their report in 1998.
- ZWS is the most severe type of peroxisomal disorder. This disorder is apparent at birth and results in death within the first year of life.
- The childhood cerebral form of ALD leads to total disability during the first decade and death soon thereafter.
- Survival in other patients may extend into the second and third decade.
- Adrenomyeloneuropathy (AMN) is compatible with survival to the eighth decade.
Four-group classification by clinical criteria
Peroxisomal disorders also can be classified into 4 groups based on clinical criteria. Group 1 includes disorders of peroxisome biogenesis (PBD) that share the ZWS phenotype, such as ZWS, a subgroup sharing with ZWS a general loss of all peroxisomal enzymes (ie, NALD, infantile Refsum disease [IRD], hyperpipecolic academia [HPA]); disorders displaying the ZWS phenotype in which peroxisomes are present; those with a deficiency of only 1 enzyme of peroxisomal beta-oxidation (eg, pseudo–NALD, pseudo-ZWS, bifunctional protein insufficiency); and disorders displaying the ZWS phenotype characterized by the loss of several enzymes and a normal amount of peroxisomes. In ZWS-like syndrome, enzymes for peroxisomal beta-oxidation are still unidentified.
Group 2 contains the RCDPs and related bone dysplasias. RCDP types II and III are due to plasmalogen deficiency.
Group 3 includes the X-ALD and phenotypic variants.
Group 4 comprises hyperoxaluria, acatalasemia, Refsum disease, mevalonate kinase deficiency, glutaryl-CoA oxidase deficiency, and dihydroxy or trihydroxy cholestanoic acidemia (enzyme unknown).
Two-group classification based on organelle structure and deficiencies
Although different classifications have been proposed, the growing consensus supports a classification in which 2 groups of disorders are distinguished: (1) disorders of peroxisomal biogenesis (PBD) in which the organelle is abnormally formed and missing several functions and (2) single-enzyme deficiencies with intact peroxisomal structure.
The second group includes at least 10 disorders in which the defect involves a single peroxisomal protein but the structure of the peroxisome is intact. This category includes ALD (ie, VLCFA synthesis deficiency), AMN, pseudo–neonatal ALD (ie, NALD, or acyl-CoA oxidase deficiency), metabolic kinase deficiency, hyperoxaluria type I (ie, alanine glyoxylate aminotransferase deficiency), bifunctional enzyme deficiency, pseudo-ZWS (ie, peroxisome thiolase deficiency), acatalasemia (ie, catalase deficiency), dihydroxy acetone phosphate (DHAP) acyltransferase (AT) deficiency (ie, DHAP-AT deficiency, or type II rhizomelic chondrodysplasia punctata [RCPD]), alkyl-DHAP synthase deficiency (ie, type III RCDP), glutaric aciduria type III, and classic Refsum disease (ie, phytanoyl-CoA hydroxylase deficiency).
- PDBs are due to mutation or mutations in the PEX genes that normally encode for peroxin proteins and whose proper expression is required for peroxisome biogenesis. Fourteen distinct PEX genes have been described.
- Zellweger syndrome
- ZWS is considered to be the prototype of the PBD group, which includes NALD, IRD, and HPA. Bowen et al first described ZWS in 1964. Passarge and McAdams introduced the name cerebrohepatorenal syndrome.
- ZWS causes multiple congenital anomalies dominated by a typical craniofacial dysmorphism, including a high forehead, a large anterior fontanelle, hypoplastic supraorbital ridges, broad nasal bridge, micrognathia, deformed ear lobes, and redundant nuchal skin folds.
- The neurologic picture comprises severe psychomotor retardation, profound hypotonia with depressed deep tendon reflexes (DTRs), neonatal seizures, and impaired hearing. Brain anomalies include cortical dysplasia with pachygyria and neuronal heterotopia; regressive changes related to storage with subsequent cell death may be seen. Dysmyelination rather than demyelination is observed.
- Ocular findings include congenital cataract, glaucoma and retinal degeneration with an absent electroretinogram (ERG).
- Other abnormalities are calcific stippling of the epiphyses, small renal cysts, and liver cirrhosis.
- Patients with ZWS have a decreased number of hepatic peroxisomes, impaired plasmalogen synthesis (especially in RBCs) and increased levels of VLCFA, bile acids, pipecolic, and phytanic acids. These findings suggest the involvement of different peroxisomal pathways.
- Patients with NALD and IRD have less severe disease and longer survival rates than those of patients with ZWS. Sensorineural hearing loss and pigmentary retinal degeneration is invariably present. Leukodystrophy may develop in the mild phenotypes; however, migration defects are not common, and seizures are usually absent in IRD but not in NALD, which involves exclusive atrophy of the adrenal cortex. Likewise, renal cysts and chondrodysplasia punctata are not typically present. However, short stature and delayed eruption of teeth are noted.
- HPA is considered to belong to the PBD group; however, isolated HPA is rare and not well understood.
- Zellweger syndrome
- Rhizomelic chondrodysplasia punctata 1
- RCDP type 1 is a heterogenous group of disorders that is clinically distinct from the ZWS.
- Various forms of inheritance with autosomal or X-linked, dominant, or recessive patterns have been described.
- Peroxisomal abnormalities are found in only the rhizomelic autosomal recessive variant. Patients with these abnormalities have short stature, with spasticity and contractures, dysmorphic facies, and severe mental retardation. Shortening mainly involves the proximal parts of the limbs. Patients suffer mostly from severe scoliosis and chronic chest infection. Skeletal radiography typically reveals bone dysplasia with epiphyseal stippling. Death occurs in the first decade of life. Plasmalogen deficiency is a consistent feature and highly reliable for diagnosis.
- Single-enzyme deficiencies with intact peroxisomal structure include disorders of peroxisomal beta-oxidation (POD), disorders of ether-phospholipid biosynthesis, and disorders of fatty acid alpha-oxidation.
- Disorders of peroxisomal beta-oxidation - X-ALD
- These disorders, seen only in males, are due to mutation of a gene that encodes for ABC, a transporter molecule involved in the uptake of VLCFA across peroxisomal membranes. This mutation results in the accumulation of VLCFA due to lack of peroxisomal oxidation. Clinical presentations are diverse, ranging from the lethal cerebral childhood form to an isolated Addison-like disease with no neurologic involvement. Phenotypes in the same pedigree are markedly heterogeneous, a phenomenon attributed to the action of a modifier gene.
- Approximately 20% of women who are heterozygous for the ALD locus develop neurologic disability that is milder and later in onset than that observed in affected men. Deficits vary from mild hyperreflexia and vibratory sense impairment to paraparesis causing patients to use a wheelchair. Signs of dementia are rare. The implicated gene is subject to X-inactivation.
- In the cerebral form of X-ALD, early development is entirely normal, and the first neurologic manifestations most commonly occur at 4-8 years of age. Early manifestations are often mistaken for attention-deficit/hyperactivity disorder. Characteristic neurologic manifestations, such as impaired auditory discrimination, visual disturbances, spatial disorientation, poor coordination, and seizures supervene late in the disease, which may then progress rapidly. Progression leads to a vegetative state in 2 years and death at various times thereafter. Relatively uncommon adolescent and adult cerebral forms can occur. An inflammatory response is seen in the cerebral form.
- AMN, another variant of X-ALD, causes slowly progressive paraparesis and sphincter disturbances and is often misdiagnosed as multiple sclerosis. Symptoms typically start at 28 ± 9 years. Forms include pure AMN and AMN-cerebral. Patients with pure AMN present with only spinal cord and peripheral nerve involvement and sparing of higher cognitive functions. However, neuropsychological testing may show subtle deficits in psychomotor speed and visual memory. This variant has a prognosis better than that of other forms. AMN-cerebral is used to describe increased impairment of neuropsychological function. Patients have various degrees of brain MRI abnormalities.
- Progressive cerebellar disorder resembling olivopontocerebellar degeneration is described.
- The Addison-like phenotype is distinguished from Addison disease by high levels of serum VLCFA.
- Patients with acyl-CoA oxidase deficiency, or pseudo-NALD, have a ZWS phenotype but no dysmorphic features. Symptoms consist of hypotonia, psychomotor regression, seizures, deafness and retinopathy with hypodensity of the cerebral white matter in addition to adrenocortical insufficiency. However, all peroxisomal metabolites, for the exception of VLCFA, are normal.
- D-Bifunctional protein deficiency results in a phenotype similar to that of ZWS, with dysmorphic facies and cerebral migrational defects. Levels of both VLCFA and bile-acid intermediates are abnormally elevated. However, peroxisomes appear normal on liver biopsy.
- Peroxisomal thiolase deficiency, or pseudo-ZWS, is believed to be a subgroup of D-bifunctional protein deficiency.
- Peroxisomal 2-methylacyl-CoA racemase deficiency (AMACR) is characterized by a defect in beta-oxidation of branched-chain fatty acids. Clinical manifestations consist of adult-onset sensory-motor neuropathy, a symptom also reported in Refsum disease and in the ALD variant. However, phytanic acid and VLCFA levels are normal, though levels of 2-methyl branched-chain fatty acid, pristanic acid, and DHCA and/or THCA are abnormally elevated. Symptoms may vary, and patients may have isolated liver disease without neurologic involvement.
- Disorders of ether-phospholipid biosynthesis
- In most patients with RCDP type I, the primary defect involves the PEX-7 gene, which encodes for the peroxisomal targeting sequence (PTS-2) receptor. This receptor helps to target cytosolic proteins to the peroxisome. As a result, multiple peroxisomal enzymes that depend on PTS-2 signaling (eg, peroxisomal thiolase, alkyl DHAP synthase, phytanoyl-CoA hydroxylase, DHAP-AT (are affected).
- RCDP types II and III are characterized by variable severity of clinical manifestations and by disproportionately short stature that primarily affects the proximal parts of the extremities, a typical facial appearance, congenital contractures, cataracts, and mental retardation similar to that of RCDP type I. However, bone stippling is not present. In RCDP types II and III, the PEX-7 protein is normal, and a mutation occurs in the structural gene encoding for their specific enzymes, PHAP-AT and alkyl DHAP synthase, respectively. Plasmalogen is deficient but, unlike RCDP type I, phytanic acid and other peroxisomal metabolites are normal (unlike in RCDP type I).
- A single case of glutaric aciduria type III has been described and included failure to thrive, vomiting, and severe glutaric aciduria. Serum glutaryl-CoA oxidase activity was not detectable. DNA studies were not performed.
- Mevalonate kinase is implicated in the biosynthesis of isoprenoids. Its deficiency leads to elevated levels of mevalonic acid in the urine. Clinical manifestations include developmental delay, cataracts, hepatosplenomegaly, and lymphadenopathy with early death. Similar symptoms have been observed in patients with hypergammaglobulinemia type D and periodic fever syndrome in addition to skin rash and arthralgias.
- Acatalasemia is a rare disease variably associated with ulcerating oral lesions but no other disabilities. It has been described in Japan and in Switzerland.
- Mulibrey nanism, also known as muscle-liver-brain-eye syndrome, has been described in Finnish people and consists of muscle weakness, constrictive pericarditis, hepatomegaly, and J -shaped sella turcica with enlarged cerebral ventricles. Yellowish dots are noted on funduscopic examination. Patients have severe growth retardation but normal psychomotor development. Plasma VLCFA and liver peroxisomes are normal. The protein involved is strongly suspected but not yet confirmed to be a peroxisomal factor.
- Patients with hyperoxaluria type I have calcium oxalate urolithiasis and nephrocalcinosis that leads to progressive renal failure at various ages. In addition, they may have myocarditis, neuropathy, osteosclerosis, and retinopathy as a result of oxalate deposits in various organs. Urine excretion of glyoxylic and glycolic acid is increased. The enzyme is present only in the liver, and liver biopsy is usually needed for diagnosis. This disorder is also notable for the absence of neurologic dysfunction and dysmorphic features.
- Disorders of fatty acid alpha-oxidation: Refsum disease is the only known type in this group. It is characterized by retinitis pigmentosa with progressive deterioration of night vision, sensory-motor polyneuropathy, cerebellar ataxia, and elevated cerebrospinal fluid protein levels without pleocytosis. Inconstant features include sensory-neural hearing loss, anosmia, ichthyosis, skeletal malformation and cardiac abnormalities. No cognitive decline or dysmorphism is associated with this condition. Symptoms begin in adolescence. Accumulation of phytanic acid is the only known abnormality. The causative gene has been identified.
- Disorders of peroxisomal beta-oxidation - X-ALD
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disorders of peroxisomal biogenesis, PBD, disorders of peroxisomal beta-oxidation, POD, metabolic disorders, metabolic diseases, peroxisome disorders, peroxisome diseases, adrenoleukodystrophy, ALD, neonatal adrenoleukodystrophy, NALD, adrenomyeloneuropathy, infantile Refsum disease, IRD, hyperpipecolic acidemia, rhizomelic chondrodysplasia punctata, RCPD, pseudo–neonatal adrenoleukodystrophy, acyl CoA oxidase deficiency, metabolic kinase deficiency, hyperoxaluria type I, alanine glyoxylate aminotransferase deficiency, bifunctional enzyme deficiency, pseudo-Zellweger syndrome, peroxisome thiolase deficiency, acatalasemia, catalase deficiency, dihydroxy acetone phosphate acyltransferase deficiency, DHAP-AT, alkyl-DHAP synthase deficiency, glutaric aciduria, adult Refsum disease, ARD, classic Refsum disease, phytanoyl CoA hydroxylase deficiency, Zellweger syndrome, ZWS, microbody, microbodies, hyperpipecolic academia, HPA, cerebrohepatorenal syndrome, peroxisomal 2-methylacyl-CoA racemasedeficiency,AMACR, Lorenzo's oil