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Siegel GJ, Agranoff BW, Albers RW, et al., editors. Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6th edition. Philadelphia: Lippincott-Raven; 1999.

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Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6th edition.

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Peroxisomal Disease

and .

Correspondence to Kunihiko Suzuki, Departments of Neurology and Psychiatry, Neuroscience Center, CB 7250, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599.

This group comprises neurological disorders that occur as the result of defects in biogenesis of peroxisomes or, directly or indirectly, in enzymes that are normally localized in peroxisomes. For an overview of this rapidly evolving field, readers are referred to review articles [1,3,2427]. In the following, only representative disorders are described. Table 41-5 summarizes the main biochemical abnormalities and the known genetic defects in these diseases.

Table 41-5. Peroxisomal Diseasesa.

Table 41-5

Peroxisomal Diseasesa.

Disorders of function can result from genetic defects in factors that are critical for peroxisomal formation

These disorders form a clinically and genetically heterogeneous group of severe autosomal recessive diseases [26]. Consequently, peroxisomes are either absent or abnormal morphologically, and there is a general failure of all metabolic functions normally associated with the peroxisome.

Zellweger spectrum. The term Zellweger spectrum (ZS) has been given to a complex group of disorders with overlapping clinical features and common biochemical abnormalities [28]. Three major categories, ZS, neonatal adrenoleukodystrophy (NALD) and infantile Refsum's disease (IRD), are described here. However, it should be emphasized that this classification is based on clinical phenotypes but not on genetic causes. The metabolic abnormalities common among these disorders include accumulation of very long-chain fatty acids (VLCFA) and of phytanic acid, elevated bile acid intermediates and deficiency of plasmalogen biosynthesis. Peroxisomes are virtually absent in hepatocytes and fibroblasts, although peroxisomal membrane ghosts can be found. In spite of this common biochemical phenotype, genetic complementation analysis using cell hybridization has revealed the existence of at least nine different complementation groups (CGs), with no correlation to any given clinical phenotype. This clearly indicates the complexity of peroxisome biogenesis and of the genetic disorders that can result from abnormalities in any of the steps.

Zellweger syndrome. The prototype of the generalized peroxisomal disorder is ZS, or cerebro-hepato-renal syndrome, in which the seminal discovery of an apparent lack of peroxisomes in hepatocytes and renal tubules was made quite early. Patients show a combination of craniofacial dysmorphia; neurological abnormalities, including pronounced hypotonia, epileptic seizures and severe psychomotor retardation; ocular abnormalities; and liver involvement. They die before the end of the first year. The brain shows micropolygyria. The most characteristic neuropathological abnormality is an impaired neuronal migration and severe demyelination.

Neonatal adrenoleukodystrophy. The first described patient with this disorder showed central demyelination and adrenal atrophy, hence the denomination, together with abnormalities similar to those seen in ZS, although milder. Today, NALD is considered as a less severe form of ZS.

Infantile Refsum's disease. IRD patients show no distinct abnormalities in the neonatal period and only minor dysmorphia. The main clinical features are mental retardation, retinitis pigmentosa, neurosensory deafness and growth retardation. Several reported patients were still alive in their late teens.

Rhizomelic chondrodysplasia punctata (RCDP). The characteristic clinical features of this disorder are rhizomelia: severe symmetrical shortening of upper extremities, profound growth failure, flexion contractures, cataract, ichthyosis, some degree of craniofacial dysmorphism, variable neurological signs and widespread epiphyseal calcifications. Biochemical peroxisomal abnormalities consist of a severe deficiency of plasmalogens, with combined deficiency of dihydroxyacetone-phosphate acyl-transferase (DHAP-AT) and alkyl-DHAP synthetase. Deficient α-oxidation of phytanic acid is also present [27]. In spite of a defective import of peroxisomal thiolase, peroxisomal β oxidation does not seem to be compromised, as evidenced by normal plasma VLCFA. Peroxisomes are present but abnormal. Classic RCDP patients have been shown to belong to a common complementation group, CG11.

In disorders of peroxisomal biogenesis, an apparent lack of abnormal appearance of peroxisomes and mislocalization of several peroxisomal matrix proteins suggest a problem of protein import as the primary lesion. Considerable progress has been achieved in this field. Peroxisomal targeting signals, either C-terminal (PTS1, for most proteins) or N-terminal (PTS2, for thiolase and other yet unknown proteins) have been discovered and proteins involved in peroxisomal import, biogenesis, proliferation and inheritance isolated. The concerted action of such peroxisomal assembly proteins, peroxins, has been shown to govern import of matrix proteins into peroxisomes, and many of the corresponding PEX genes have been cloned, at least in yeast [29]. To date, defects in at least five PEX genes have been shown to cause human peroxisomal disorders. Mutations in PEX5, which encodes the PTS1 receptor, PEX2 and PEX12, which encode two zinc-binding integral membrane proteins; and PEX6, which encodes vesicle-associated cytosolic ATPase, cause a Zellweger spectrum phenotype, while mutated PEX7, which encodes the PTS2 receptor, is associated with a RCDP phenotype (Table 41-5).

Disorders of the peroxisomal β-oxidation pathway result in a loss of peroxisomal function

A number of patients with clinical features mimicking those of the Zellweger spectrum but showing only an accumulation of VLCFA and possibly some abnormalities of bile acid intermediates have also been reported under the descriptive names of “pseudo-neonatal adrenoleukodystrophy” or “pseudo-Zellweger syndrome” [26]. Detailed investigations of the peroxisomal β-oxidation pathway revealed a single loss of peroxisomal function in these patients, either an acyl-CoA oxidase deficiency (pseudo-NALD), bifunctional enzyme deficiency or thiolase deficiency (pseudo-ZS).

X-Linked adrenoleukodystrophy (ALD) and adrenomyeloneuropathy (AMN). The name adrenoleukodystrophy was coined based on the features of a progressive genetic demyelinating disease associated with adrenal insufficiency manifesting in boys aged 5 to 13 years. This X-linked recessive disease, with an estimated frequency of 1/20,000 men, presents in a variety of phenotypes [24]. Different phenotypes are commonly observed in the same family or the same kindred. In the most severe late infantile or juvenile cerebral form, which has a mean age of onset of about 7 years and constitutes 40 to 50% of the cases, neurological symptoms predominate. Initial behavioral and school problems are followed by gait disturbances, visual and hearing impairment, varying alterations of cognitive functions with progressive dementia and a devastating downhill course toward an apparent vegetative state in 3 to 5 years. Adrenal insufficiency can be demonstrated in 90% of cases. Most patients die in adolescence. Severe and confluent demyelinating lesions involving the parieto-occipital region are observed most characteristically, but magnetic resonance imaging (MRI) studies have shown other topographic localizations, especially at an early stage of the disease. Correlations between the initial localization of demyelinating lesions and progression of the disease have been reported. A rare adult-onset cerebral form has been described. The second most frequent clinical variant, AMN, which accounts for 30 to 40% of cases, occurs in older individuals, with a mean age of onset of about 27 years. This form involves predominantly the spinal cord and peripheral nerves with the main clinical symptoms of spastic paraplegia and adrenal insufficiency, and the disease progresses slowly over decades. Some degree of cerebral involvement may occur in one-third to one-half of patients, as judged by brain MRI and cognitive functions. Approximately 10% of patients present only with symptoms characteristic of Addison's disease for a long time. A significant proportion of female carriers show varying degrees of clinical signs of the disease.

The most prominent biochemical finding is increased concentrations of VLCFA (>C22) in the brain, adrenal, plasma, red cells and cultured fibroblasts. These fatty acids are present mostly in the forms of cholesterol esters, cerebrosides, gangliosides and sphingomyelin. There are no indications of other peroxisomal dysfunctions. The biochemical pathogenesis that leads to the massive demyelination is unclear because, even though the relative increase is large, the net concentrations of VLCFA in the tissue remain very low. Accumulation of VLCFA appears to be due to impaired activation of VLCFA-CoA, a reaction catalyzed by the peroxisomal enzyme VLCFA-CoA synthase. The gene responsible for X-linked ALD has been cloned and shown to be an ABC transporter protein (Chap. 5) [30]. To date, the substrate transported by the ALD protein and the relationship between its transport function and VLCFA-CoA synthase activation are unknown. Elucidation of its precise physiological function should provide insight into the pathogenetic mechanism of this disorder. More than 150 disease-causing mutations have been described. Interestingly, many of them, including 60% of mis-sense mutations, lead to undetectable levels of ALD protein by either Western blot or immunofluorescence [24]. A murine model has been generated [31].

Adult Refsum's disease. The classic form of Refsum's disease occurs in adults of both sexes, with hypertrophic polyneuropathy as the most prominent manifestation [25]. There is an abnormal elevation of a methylated fatty acid, phytanic acid, which is exogenously derived from chlorophyll in the food. There is no indication of other peroxisomal dysfunction. Peroxisomes appear morphologically normal in size and number. Since phytanic acid is exclusively exogenous in origin, chlorophyll-free dietary treatment can be quite effective in alleviating the disease. As indicated above, the so-called infantile Refsum's disease is genetically distinct from the classic adult Refsum's disease.

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Copyright © 1999, American Society for Neurochemistry.
Bookshelf ID: NBK28022


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