++
The clinical consequences of the PBD can be organized into two
broad phenotypic spectra. The largest of these, the Zellweger spectrum, accounts
for about 80% of PBD patients and includes at least three
phenotypes originally thought to represent discrete disorders but which
are now recognized as segments of a continuous spectrum.1,4,8 Listed
from the most to the least severe, these three disorders are Zellweger
syndrome (ZS), neonatal adrenoleukodystrophy (NALD), and infantile
Refsum disease (IRD). The second PBD phenotypic spectrum, accounting
for about 20% of PBD patients, is rhizomelic chondrodysplasia
punctata (RCDP). The phenotype of most RCDP patients is severe and
relatively uniform, but milder variants have been described.
++
Zellweger syndrome, a metabolic disorder with dysmorphic features
(see Table 176-1), represents the severe
end of the Zellweger spectrum. These infants have a characteristic facial
appearance, with a high forehead, epicanthal folds, a small nose
with a broad nasal bridge, anteverted nares, and micrognathia (Fig. 162-1A and B).
The anterior fontanelle is large. Cataracts and a pigmentary retinopathy are
common. There is profound hypotonia, feeding problems, and growth
failure. Most have neonatal seizures. Liver function is abnormal,
with conjugated hyperbilirubinemia. Radiological examination reveals
punctate calcifications (“calcific stippling”)
in the patella and epiphyses of the long bones. Multiple small renal
cysts are common but may not be detected by ultrasound examination.
Abnormalities in neuronal migration (neocortical dysplasia and cerebral/cerebellar
white matter disease) are common. Infants with ZS rarely live to
be 1 year of age.
++
++
Neonatal adrenoleukodystrophy (NALD) is similar to, but less
severe than, ZS. Dysmorphic facial features are less severe or may
even be absent (Fig. 162-1C). Hypotonia and
seizures are common. Because of their flat facial features and hypotonia,
NALD patients are sometimes thought to have Down syndrome. Survival
ranges from several months to several years. The older patients
have profound mental retardation often accompanied by sensorineural
hearing loss and retinopathy.
++
Infantile Refsum disease (IRD) patients have mild dysmorphic
features and hypotonia (Fig. 162-1D). The
predominant manifestations may be hepatomegaly, cholestasis, osteoporosis,
and failure to thrive in early infancy. As they get older, virtually
all IRD patients develop sensorineural hearing loss and pigmentary
retinopathy. They usually learn to walk but have severe mental retardation.
Patients with IRD may live into adulthood.
++
Milder variants of the Zellweger spectrum with normal development
and appearance may present in adult life with sensorineural hearing
loss and pigmentary retinopathy.
+++
Rhizomelic Chondrodysplasia Punctata
Spectrum (Rcpd)
++
Patients with classic RCDP (see Table 176-1) have
severe skeletal involvement at birth that distinguishes them from
those in the Zellweger spectrum (Fig. 162-2).
There is rhizomelia (shortening of the proximal limbs) and limited
range of movement of the large joints of the extremities. Radiological
examination shows extensive calcific stippling that involves the
epiphyses of long bones; it is most prominent in the knees, elbows,
hips, and shoulders. Coronal clefts of the vertebral bodies are
apparent on lateral spine films. RCDP patients also have a flat
face with frontal bossing. Cataracts are common, and an ichthyotic skin
rash may develop after birth. Severe psychomotor retardation is
present, and most die before 2 years of age. In addition to this
classic RCDP phenotype, mildly affected patients with little or
no rhizomelia have been described; some have mild intellectual defects
as their only manifestation. Classic RCDP is a PBD caused by mutations
in PEX7, the gene encoding the receptor for PTS2 proteins. A few
patients with the classic RCDP phenotype (< 10% of the
total number of patients) have single-function defect in PTS2-targeted
peroxisomal matrix enzymes necessary for normal synthesis of plasmalogen.
++
++
Over the last two decades, research in model organisms and PBD
patients has identified a set of genes and their protein products,
termed PEXgenes and peroxins,
respectively, that are necessary for peroxisome assembly.1,4 Most
of these are involved in the targeting and uptake of matrix proteins
into the organelle. All of the PBD complementation groups so far
defined are explained by mutations in these PEX genes, one particular
gene for each complementation group. The number of PEX genes is
greater than the number of complementation groups, suggesting there
are new groups to recognize. See Weller et al for a review of this
topic.4
++
Peroxisome matrix proteins are synthesized on free cytosolic
ribosomes and directed to the organelle by targeting sequences of
two types (Fig. 162-3). Peroxisome-targeting
signal 1 (PTS1), a C-terminal tripeptide (-SKL or conservative variants
thereof), is utilized by more than 90% of the matrix proteins.
PTS2, located 5 to 10 residues from the N-terminus, is utilized
by a few peroxisomal matrix proteins, including one involved in β-oxidation
(peroxisomal thiolase 1), one involved in α-oxidation,
and one involved in plasmalogen synthesis. The PTS1 or PTS2 motifs
are bound by specific cytosolic receptors encoded by PEX5 and PEX7,
respectively. Docking of the receptor and its bound cargo on the
peroxisome membrane is mediated by binding to specific peroxisomal
membrane proteins (PEX13, PEX14, PEX17). With the action of additional
peroxisomal membrane proteins (PEX2, PEX8, PEX10, PEX12), the newly
synthesized matrix proteins are translocated into the organelle,
and the receptors are recycled to the cytosol. Recycling of PEX5
requires an unusual monoubiquitination on a conserved cysteine near
the N-terminus of the protein.9 The recycling process
is facilitated by the action of PEX1, PEX6, PEX22, PEX4, and PEX26.
Genetic defects in this subset of PEX genes are responsible for
nine PBD complementation groups that are characterized at the cellular
level by mislocalization of matrix proteins to the cytosol.
++
++
The mechanism and signals involved in targeting peroxisomal membrane
proteins to the organelle are less well understood, although PEX genes
encoding proteins that function in this process have been identified
(PEX3, PEX16, PEX19).4 Not surprisingly, genetic
defects in this subset of peroxins are responsible for the three
PBD complementation groups characterized by lack of detectable peroxisomes.
++
Recently, an infant with metabolic features consistent with abnormal
peroxisome and mitochondrial function has been described and represents
a different type of PBD.10 In this patient’s
cells, there was a defect of organellar fission of both peroxisomes
and mitochondria caused by a dominant negative mutation in the dynamin-like
protein 1 gene DLP1. This observation, together with studies in
model systems, indicates that normal DLP1 function is required for
the division of two different subcellular organelles.
+++
Laboratory Diagnosis of
PBD
++
The most frequently utilized diagnostic laboratory tests for
PBD detect abnormalities of peroxisomal metabolic processes, including
very-long-chain fatty acid (VLCFA) β-oxidation,
phytanic acid β-oxidation, and plasmalogen synthesis.1,2,4Plasma
VLCFA (C26:0 and C26:1) are abnormally increased in Zellweger spectrum
patients to an extent roughly correlating with clinical severity.
Compared to control levels (C26:0 = 0.22 ± 0.08; C26:1 = 0.12
± 0.05 μg/mL), VLCFA are elevated about
tenfold in ZS, about fivefold in neonatal adrenoleukodystrophy (NALD),
and about threefold in IRD. Similarly, plasma phytanic acid (normal = 0.8
± 0.4 μg/mL) is increased ten- to a hundredfold
in Zellweger spectrum patients who are old enough to ingest dietary
precursors of this compound. Red cell plasmalogens (expressed as
a ratio of dimethylacetyl derivatized plasmalogens to fatty acids
of the same chain length; normal range of C16:0 DMA/C16:0
fatty acids = 0.051 – 0.90; C18:0 DMA/C18:0
fatty acids = 0.137 – 0.255) are reduced by tenfold
or more. Other laboratory abnormalities in Zellweger spectrum patients
include increased urinary excretion of medium- and long-chain dicarboxylic acids
and pipecolic acid and reduced levels of plasma bile acids.
++
In RCDP, plasma VLCFA levels are normal, possibly because peroxisomal
thiolase 2 (sterol carrier protein X) substitutes for the lack of
the PTS2-targeted peroxisomal thiolase 1. RBC plasmalogens are reduced
in RCDP to an extent similar to that in Zellweger spectrum patients.
In RCDP patients ingesting foods containing phytanic acid precursors,
the levels of phytanic acid in plasma are usually higher than in
Zellweger spectrum patients.
++
Confirmation of diagnoses made on the basis of clinical phenotype
and the above metabolite assays should be confirmed by studies of
peroxisomal β-oxidation and plasmalogen synthesis
in cultured skin fibroblasts. These are available at reference labs
(see www.genetests.org or www.peroxisome.org)
and can be supplemented by immunohistochemical studies localizing
PTS1- and PTS2-targeted matrix proteins and peroxisomal membrane
proteins. Complementation analysis is a useful preliminary test
for molecular studies to identify the responsible PEX gene; however,
this has little prognostic value, since patients representing different
segments of the Zellweger spectrum have been identified in most
complementation groups. Progress in identifying the PEX genes and
the relative frequency of disease-causing mutations has led to an
efficient hierarchical plan for molecular diagnosis by gene sequencing.8
++
The pathophysiology of the PBDs is complex and often begins in
utero. For these reasons, treatment of patients with the severe
forms of these disorders is largely supportive. Feeding difficulties
are frequent, and placement of a gastrostomy tube is often indicated
to improve nutrition and to facilitate care. Anticonvulsant medications
are indicated to control seizures. In older individuals, plasma
phytanic acid concentrations should be measured repeatedly and dietary
phytanic acid and its precursors (phytol) limited. The consequences
of the severe skeletal involvement should be carefully assessed
in RCDP patients. For example, moderate cervical spine stenosis
has been described in RCDP.
++
Age at demise is often listed as one of the criteria used to
categorize phenotypic severity in the Zellweger spectrum (ZS). At
the time of diagnosis, however, the phenotypic features of ZS, NALD,
and IRD overlap; thus, in most cases, it is unwise to make precise
survival predictions.
++
All known PBD are inherited as autosomal recessive traits, with
a 25% recurrence risk for each subsequent pregnancy of
couples who have had one PBD infant. Prenatal diagnosis is possible
by biochemical methods and is provided by several reference labs
(see Web sites above). If the molecular basis of the index case is
known, similar studies can be used for prenatal diagnosis in subsequent
pregnancies.