Peroxisome Biogenesis Disorder 1b

A number sign (#) is used with this entry because this form of peroxisome biogenesis disorder (PBD1B) is caused by homozygous or compound heterozygous mutation in the PEX1 gene (602136) on chromosome 7q21. Mutations in the PEX1 gene also cause Zellweger syndrome (PBD1A; 214100).

Description

Peroxisome biogenesis disorder-1B (PBD1B) is characterized by the overlapping phenotypes of neonatal adrenoleukodystrophy (NALD) and infantile Refsum disease (IRD), which represent the milder manifestations of the Zellweger syndrome spectrum (ZSS) of peroxisome biogenesis disorders (PBDs). Initial presentation and natural history varies, with many children presenting as newborns, whereas others do not come to attention until later. Most affected children have hypotonia, but unlike Zellweger syndrome (see PBD1A, 214100) there is a degree of psychomotor development, and some patients achieve head control, sit unsupported, and may even walk independently. Many can communicate, and although language is rare, there have been children who have near normal language for age. Craniofacial anomalies are similar to but less pronounced than in Zellweger syndrome. In some individuals a leukodystrophy develops, with degeneration of myelin, loss of previously acquired skills, and development of spasticity; this may stabilize, or progress and be fatal. In PBD1B, the most common manifestations that are less apparent in ZS are sensorineural hearing loss and retinitis pigmentosa (summary by Steinberg et al., 2006). While Zellweger syndrome usually results in death in the first year of life, children with the NALD presentation may reach their teens, and those with the IRD presentation may reach adulthood (summary by Waterham and Ebberink, 2012).

Individuals with mutations in the PEX1 gene have cells of complementation group 1 (CG1, equivalent to CGE). For information on the history of PBD complementation groups, see 214100.

Genetic Heterogeneity of Peroxisome Biogenesis Disorder NALD/IRD

The phenotypic spectrum of NALD/IRD peroxisome biogenesis disorders can be caused by mutation in members of the peroxin (PEX) gene family. The PEX genes encode proteins essential for the assembly of functional peroxisomes (summary by Distel et al., 1996). PBD1B is caused by mutation in the PEX1 gene on chromosome 7q21; PBD2B (202370) is caused by mutation in the PEX5 gene (600414) on chromosome 12p13.3; PBD3B (266510) is caused by mutation in the PEX12 gene (601758) on chromosome 17; PBD4B (614863) is caused by mutation in the PEX6 gene (601498) on chromosome 6p21.1; PBD5B (614867) is caused by mutation in the PEX2 gene (170993) on chromosome 8q21.1; PBD6B (614871) is caused by mutation in the PEX10 gene (602859) on chromosome 1p36.32; PBD7B (614873)is caused by mutation in the PEX26 gene (608666) on chromosome 22q11.21; PBD8B (614877) is caused by mutation in the PEX16 gene (603360) on chromosome 11p11; PBD10B (617370) is caused by mutation in the PEX3 gene (603164) on chromosome 6q24; and PBD11B (614885) is caused by mutation in the PEX13 gene (601789) on chromosome 2p15.

See PBD1A (214100) for a phenotypic description and a discussion of genetic heterogeneity of Zellweger syndrome, which is also caused by mutation in peroxin genes. The rhizomelic chondrodysplasia subtype of PBD (RCDP1, PBD9; 215100), and a mild PBD without rhizomelia (PBD9B; 614879), are caused by mutation in the PEX7 gene (601757) on chromosome 6q23.

Clinical Features

Benke et al. (1981) reported brother and sister with similar facial features, seizures from birth, delayed neurologic development which began to deteriorate at age 1 year, and sudden death, associated with respiratory infections, before the age of 3 years. Tanning of the skin was noted 2 months before death of the first child; in the second child, blood cortisol levels failed to increase after intravenous ACTH administration. At autopsy, both patients showed adrenal atrophy and degenerative changes of the white matter throughout the neuroaxis. One of the infants had polar cataracts at birth. The characteristic craniofacial changes were dolichocephaly, prominent and high forehead, esotropia, epicanthic folds, broad nasal bridge, high-arched palate, low-set ears, and anteverted nostrils. The female was as severely affected as the male, making X-linked inheritance unlikely.

Moser (1981) suspected that the neonatal form of adrenoleukodystrophy is inherited as an autosomal recessive: the incidence and degree of affection are comparable in boys and girls. The neonatal form of ALD is clearly separate from the X-linked forms of childhood and adult ALD/AMN and also from Zellweger syndrome (214100) to which it bears many clinical and biochemical similarities including the accumulation of very long chain fatty acids (VLCFA), particularly hexacosanoic acid (C26:0). Levels are normal in parents whereas in the X-linked form they are intermediate in the heterozygous female. It also bears similarities to hyperpipecolic acidemia (239400). All are apparently disorders of the peroxisomes, which are lacking in both Zellweger syndrome and neonatal ALD and which are the main site of oxidation of very long chain fatty acids. Since 40 enzymes have been localized to the peroxisome (Tolbert, 1981), there is adequate opportunity for genetic heterogeneity among disorders with phenotypic overlap (cf., the mucopolysaccharidoses).

Kelley and Moser (1984) showed that serum pipecolic acid is elevated, often markedly, in patients with NALD but in none of those with X-linked ALD or adrenomyeloneuropathy, or in normal adults and children, or children with cirrhosis or other neurodegenerative disorders. This finding can be added to that of elevated very long chain fatty acids to support a generalized peroxisomal dysfunction and relationship to the Zellweger syndrome. Cystic changes in the kidneys and skeletal changes (very large fontanels and cartilaginous calcifications) occur in Zellweger syndrome but not in NALD. Differentiation is confused by the fact that cases of NALD have been found to have no hepatic peroxisomes (Partin and McAdams, 1982), a finding considered virtually pathognomonic of Zellweger syndrome, whereas 2 sibs with many classic features of Zellweger syndrome and elevated VLCFA and pipecolic acid have normal hepatic peroxisomes (Burton et al., 1981).

Kelley et al. (1986) presented 8 new cases and contrasted the findings with those of Zellweger syndrome. See 300100 for a discussion of the usual form of adrenoleukodystrophy. Chen et al. (1987) found that despite the absence of the bifunctional enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase, its mRNA could be demonstrated in neonatal ALD fibroblasts. This suggested to them that the protein was rapidly degraded in the cytoplasm before its entry into peroxisomes. In Zellweger syndrome, acyl-CoA oxidase and beta-ketothiolase are also deficient. All 3 enzymes are synthesized on free polyribosomes and then transported into peroxisomes.

Patients with the infantile form of phytanic acid storage disease show both clinical and biochemical differences from patients with the classic form of Refsum disease (266500). Features include early onset, mental retardation, minor facial dysmorphism, retinitis pigmentosa, sensorineural hearing deficit, hepatomegaly, osteoporosis, failure to thrive, and hypocholesterolemia. The biochemical abnormalities are not restricted to phytanic acid but also include accumulation of very long chain fatty acids (VLCFA), di- and trihydroxycholestanoic acid and pipecolic acid. Deficiency of peroxisomes in hepatocytes and cultured skin fibroblasts is demonstrable (Wanders et al., 1990).

A relationship between the infantile form of Refsum disease and Zellweger syndrome (ZWS) was suggested by the observations of Poulos et al. (1984) in 2 patients. In the infantile form of Refsum disease, as in Zellweger syndrome, peroxisomes are deficient and peroxisomal functions are impaired (Schram et al., 1986). Clinically, infantile Refsum disease, ZWS, and adrenoleukodystrophy (300100) have several overlapping features. Biochemically, IRD patients show accumulation of phytanic acid as in the classic form of Refsum disease but in addition they show defective bile acid metabolism as in ZWS (Stokke et al., 1984). In IRD, manifestations date from birth. Features in addition to those of Refsum disease include some seen in Zellweger syndrome: delayed development, mental retardation, hepatomegaly, and skeletal changes. The levels of VLCFAs are elevated in ZWS and IRD but not in classic Refsum disease.

In infantile Refsum disease, Zellweger disease, and the rhizomelic form of chondrodysplasia punctata (RCDP1; 215100), also a peroxisomal disorder, the activity of the peroxisomal enzyme acyl-CoA-dehydroxyacetonephosphate acyltransferase is low in platelets and fibroblasts, plasmalogens are deficient, and the plasma phytanic acid levels are usually elevated in patients over the age of 5 months. Wanders et al. (1986) found restoration of acyltransferase activity when RCDP cells and infantile Refsum cells were fused. When infantile Refsum cells and Zellweger cells were fused, restoration of enzyme activity was not observed. Wanders et al. (1986) felt that this did not necessarily indicate that these are allelic disorders.

In 4 cases of infantile Refsum disease, Roels et al. (1986) could visualize no peroxisomes by light microscopy after cytochemical staining for catalase, a marker enzyme for this organelle. Absence of peroxisomes was confirmed by electron microscopy in 3 patients and, in the fourth, organelles of peculiar size and shape, with minimal catalase activity, were seen. Birefringent macrophages containing PAS-positive material, on light microscopy, was considered another useful finding.

Poll-The et al. (1987) compared IRD with neonatal adrenoleukodystrophy (NALD) and Zellweger syndrome. The studies of Brul et al. (1988) suggested that one form of Zellweger syndrome, the infantile form of Refsum syndrome, and hyperpipecolic acidemia (239400) are allelic; they failed to show complementation after somatic cell fusion.

Goez et al. (1995) described 2 IRD infants who had neonatal cholestatic jaundice as the sole initial clinical presentation of their disorder and no accompanying clinical features that would indicate peroxisomal disease. Parental consanguinity was present in both cases. The correct diagnosis was made by evaluation of plasma VLCFAs. Both families were Israeli-Arabs. The 2 parental couples met by chance in the hospital corridor and realized for the first time that all 4 were relatives.

Bader et al. (2000) reported 4 Amish sibs from a consanguineous (second-cousin) marriage with clinical and biochemical findings of IRD. At least 3 of the 4 had characteristic poorly formed yellow-orange teeth. In addition, the 2 affected females had a pronounced behavior/mood problem which was most apparent after puberty.

Jansen et al. (2004) pointed out that infantile Refsum disease was called such because at the time it was first described, Refsum disease was the only known disorder characterized by the accumulation of phytanic acid. Subsequent studies showed that these patients had metabolite patterns typical of generalized peroxisomal biogenesis disorders and, indeed, morphologic studies of liver showed a strong deficiency of peroxisomes. Jansen et al. (2004) concluded that infantile Refsum disease is an unfortunate name for this peroxisome biogenesis disorder, and suggested that the term be discarded.

Paul et al. (1993) described affected male and female infant offspring of first-cousin Egyptian parents who presented with manifestations suggesting infantile progressive spinal muscular atrophy (253300).

Moser et al. (1995) found that among the 61 patients in complementation group 1 (corresponding to Netherlands group 2 and Japan group E), 56% had the Zellweger syndrome phenotype (ZS; 214100), 26% had the phenotype of neonatal adrenoleukodystrophy (NALD), 11% had the phenotype of infantile Refsum disease (see 601539), and 43 patients (25%) had phenotype of rhizomelic chondrodysplasia (RCDP; 215100). A variant phenotype was observed in 7% of patients.

One of the variant cases described by Moser et al. (1995) was a 40-year-old woman with severe hearing impairment and visual disturbances associated with pigmentary degeneration of the retina detected in early childhood. The patient received special education services, learned to read and write, became a good athlete, and in her twenties functioned well as a special education assistant. In her mid-thirties, gradually increasing impulsive and compulsive behavior developed, and by the age of 40 she had become mute and incontinent. This deterioration was attributed to an extensive and progressive leukodystrophy first demonstrated by magnetic resonance imaging (MRI) at age 37 years. The patient illustrated the wide range of both severity and clinical features in peroxisome biogenesis defects, even of the same complementation group. Of the whole group of 173 patients reported by Moser et al. (1995), 10 had unusually mild clinical manifestations, including survival to the fifth decade or deficits limited to congenital cataracts.

Using systematic clinical and biochemical investigations, Poll-The et al. (2004) delineated the natural history of 31 patients with PBDs, aged 1.2 to 24 years. They excluded classic Zellweger syndrome from the study and included all patients with biochemically confirmed generalized PBD over 1 year of age. Common to all patients were cognitive and motor dysfunction, retinopathy, sensorineural hearing impairment, and hepatic involvement. Many patients showed postnatal growth failure. Hyperoxaluria was present in 10 patients, of whom 4 had renal stones. Motor skills ranged from sitting with support to normal gait. Speech development ranged from nonverbal expression to grammatical speech and comprehensive reading. The neurodevelopmental course was variable with stable course, rapid decline with leukodystrophy, spinocerebellar syndrome, and slow decline over a wide range of faculties.

Molecular Genetics

Reuber et al. (1997) identified a homozygous gly843-to-asp mutation of the PEX1 gene (G843D; 602136.0001) in at least 1 patient with neonatal adrenoleukodystrophy (NALD) and in several cases of infantile Refsum disease (IRD).

Waterham and Ebberink (2012) stated that by far the most common mutation in PEX1 is the G843D mutation and that the effect of this mutation is relatively mild.

Reviews

Subramani (1997) summarized the progress in identifying PEX genes responsible for human genetic diseases. Waterham and Cregg (1997) reviewed the current understanding of peroxisome biogenesis.