Peroxisome biogenesis disorders are genetically heterogeneous diseases with an autosomal recessive mode of inheritance. They include Zellweger syndrome (ZS, also called cerebrohepatorenal syndrome), neonatal adrenoleuko dystrophy (NALD), and infantile Refsum disease (IRD). The clinical pictures of these disorders show similarities, but an important difference is a difference in severity, the clinical course being most severe in ZS and mildest in IRD. Exceptional patients present with a still milder phenotype.
After birth children with ZS show profound muscular hypotonia. Most patients lie motionless with weak or absent Moro reflex, tendon reflexes, and sucking and swallowing reflexes. Tube feeding is necessary. Typically, the children have craniofacial dys-morphism with a high and bulging forehead, flat occiput, upslanting palpebral fissures, puffy eyelids, hypoplastic supraorbital ridges, and a low and broad nasal bridge with hypertelorism and epicanthus folds, giving them a mongoloid appearance. In addition, Brushfield spots, peripheral pigmentary retinopathy, optic nerve dysplasia or hypoplasia, glaucoma, corneal clouding, cataracts, low-set malformed ears, high arched palate, micrognathia, and widely patent sutures and fontanels are present. Macrocephaly may be present. Some children have a cleft soft palate. The children have a severe visual and hearing deficit. Nystagmus is often present. Hepatomegaly, prolonged neonatal or later-onset icterus, and hemorrhages due to hypoprothrombine-mia are common. Limb anomalies include cubitus valgus, camptodactyly, single transverse palmar creases, and talipes equinovarus. Failure to thrive and severe psychomotor retardation are conspicuous. Seizures are frequent. Cardiac defects are not frequent, but ventricular septum defect, patent ductus arteriosus, and patent foramen ovale may occur. Cryptorchidism is frequently observed in boys, cli-toromegaly and labial hypoplasia in girls. About 90% of the patients die within the first year of life, death occurring in the majority within the first few months.
Most children with NALD have neurological abnormalities at birth, but some are initially near-normal. Hypotonia is moderate to severe, reflexes are hy-poactive. Craniofacial dysmorphism is milder than in
ZS. Widely patent fontanels are uncommon. The affected children show feeding problems, failure to thrive, hepatomegaly, and sometimes jaundice. Furthermore, the disease is characterized by seizures, sensorineural hearing loss, decreased vision with nystagmus, optic atrophy or dysplasia, and pigmentary retinal degeneration. The posterior eye segment abnormalities are identical to those of ZS, but anterior segment abnormalities are lacking. Macrocephaly may be present. Within the first year of life severe developmental retardation becomes apparent, although most infants reach some milestones before neurological deterioration occurs. The age at which regression begins varies from 12 months to more than 7 years. Progressive neurological dysfunction is characterized by cerebellar ataxia, spasticity of the arms and legs with truncal hypotonia, increased deep tendon reflexes, extensor plantar reflexes, and sensory defects. If not present from birth onwards, seizures usually occur in this period. Visual dysfunction progresses to blindness. Adrenal insufficiency is rarely clinically manifest. Exceptional patients are initially entirely normal or close to normal with onset of rapid neurological deterioration in the second year of life. The course of disease is more protracted in NALD than in ZS, death occurring between the ages of 1.5 and more than 10 years.
IRD is the mildest variant of the three mentioned disorders. The disease is usually not manifest at birth but presents itself within the first 6 months of life with psychomotor retardation, minor facial dysmor-phism, mild hypotonia, sensorineural deafness, and visual impairment with retinal pigmentary degeneration, optic dysplasia, and nystagmus. Hepatomegaly and failure to thrive with growth retardation are common. Seizures occur but epilepsy is not as severe as in ZS. Many patients are able to sit and walk independently after several years, whereas others never acquire these abilities. The gait is usually ataxic and broad-based, and cognitive function in the severely retarded range. Life expectancy is considerably longer than in ZS and NALD, up to more than 2 decades.
Milder variants of peroxisome biogenesis defects with later onset and more protracted disease course have been described. One of the mildest variants reported concerns a family in whom adults with a normal or borderline intelligence only demonstrate sensorineural hearing loss and retinitis pigmentosa, leading to a diagnosis of Usher syndrome (RaasRothschild et al. 2002).
In ZS, laboratory investigations may reveal many different, in themselves nonspecific biochemical abnormalities, such as hyperbilirubinemia, elevated liver enzymes,hypoprothrombinemia, reduced albumin level, hypocarnitinemia, hypocholesterolemia, generalized amino aciduria, and elevated CSF protein. These abnormalities are not necessarily all present. Elevated serum iron, iron saturation, and transferrin may be found, but these findings are inconsistent and transient. As a rule, an abnormally low cortisol response to ACTH stimulation is found despite normal basal cortisol level. More specific abnormalities are directly related to generalized deficiency of peroxisomal function. Plasma levels of very long-chain fatty acids are increased with an elevation of the C26:C22 and C24:C22 fatty acid ratio. Saturated as well as mo-nounsaturated and polyunsaturated very-long-chain fatty acids are increased. Plasma pipecolic acid and phytanic acid may be normal initially but increase with age. Plasma dicarboxylic acids are raised.Abnor-mal bile acids such as dihydroxycholestanoic acid and trihydroxycholestanoic acid are elevated. In urine elevated levels of dicarboxylic acids, dihydroxyc-holestanoic acid, and trihydroxycholestanoic acid are present. In platelets and red blood cells a deficiency of the peroxisomal enzyme dihydroxyacetone phosphate acyltransferase can be shown. The plasmalogen content of red blood cells is decreased in the first few months of life. The plasmalogen level of the red blood cells increases with age and may be normal in patients who are 4 months or older. The synthesis of platelet activating factor by leukocytes is deficient. The activity of dihydroxyacetone phosphate acyl-transferase can be shown to be deficient in leukocytes and thrombocytes. In cultured fibroblasts a decreased content of plasmalogen and increased levels of very-long-chain fatty acids can be demonstrated. The b-oxidation of very-long-chain fatty acids, the de novo biosynthesis of plasmalogens, and the activity of dihydroxyacetone phosphate acyltransferase, alkyl dihydroxyacetone phosphate synthase, and phytanic acid oxidation can be shown to be deficient in fibro-blasts. Finally, in fibroblasts catalase activity is not found in organelles, but in the cellular cytoplasm.
Laboratory abnormalities are essentially the same in NALD and IRD, but milder than in ZS. In ZS the accumulation of very-long-chain fatty acids includes the saturated and monounsaturated C26 fatty acid and is associated with a decrease in the C22 saturated fatty acid concentration. In NALD the rise in very-long-chain fatty acids is not associated with an increase in monounsaturated C26 fatty acid and the C22 fatty acid is on average higher than normal. In NALD, mild adrenal insufficiency and low cortisol response in ACTH stimulation is usually found, although appar ently normal adrenal function is not incompatible with the diagnosis. In IRD adrenal function is normal.
X-ray examinations in ZS often reveal calcific stippling of bony epiphyses. Stippled, irregular calcification of particularly the patellae, greater trochanters, triradiate cartilages, acetabulum, scapula, and sternum is seen in 50-70 % of the ZS patients. Ultrasound may detect multiple small renal cortical cysts, but they are often difficult to find. In NALD and IRD no calcific stippling of bony epiphyses is present. No renal cysts are found. ERG is extinguished at a very early age in ZS and the EEG is highly abnormal with epileptic discharges. BAEP shows reduced responses. In NALD and IRD the ERG becomes extinguished and BAEP is abnormal. Nerve conduction velocity may be decreased in NALD; it is normal in IRD.
Prenatal diagnosis can be performed with the help of various biochemical investigations in cultured chorionic villus cells and amniocytes. DNA techniques can be applied in families with known mutations.
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