close

Вход

Забыли?

вход по аккаунту

?

Clinical approach to inherited peroxisomal disorders A series of 27 patients.

код для вставкиСкачать
ORIGINAL ARTICLES
Clinical Approach to Inherited Peroxisomal
Disorders: A Series of 27 Patients
M. R. Baumgartner, MD,* B. T . Poll-The, MD,? N. M. Verhoeven, PhD,$ C. Jakobs, PhD,$
M. Espeel, PhD,$ F. Roels, MD,5 D. Rabier, PhD,* T . Levade, MD,” M. 0. Rolland, PhD,S
M. Martinez, MD,# R. J. A. Wanders, PhD,** and J. M. Saudubray, MD*
To illustrate the clinical and biochemical heterogeneity of peroxisomal disorders, we report our experience with 27 patients
seen personally between 1982 and 1997. Twenty patients presented with a phenotype corresponding either to zellweger
syndrome, neonatal adrenoleukodystrophy, or infantile Refsum disease, 3 of whom had a peroxisomal disorder due to a
single enzyme defect. One patient had a mild form of rhizomelic chondrodysplasia punctata, 1 had classic Rebum disease.
Finally, 5 patients presented with clinical manifestations that were either unusually mild or completely atypical, and initially
did not arouse suspicion of a peroxisomal disorder. They showed multiple defects of peroxisomal functions with one or
several functions remaining intact, suggesting a peroxisome biogenesis disorder. The defect in peroxisome biogenesis was
further characterized by variable expression in different tissues and/or individual cells in 5 patients. Studies restricted to
fibroblasts failed to identify abnormalities in t h i s group. We demonstrate that clinical manifestations of peroxisomal disorders may be very mild or completely atypical, and therefore, peroxisomal disorders should be considered in a variety of
clinical settings. Furthermore, we suggest performing extensive peroxisomd investigations in every patient suspected of
suffering fiom a peroxisomal disorder, even when the clinical presentation is typical.
Baumgartner MR, Poll-The BT, Verhoeven NM, Jakobs C, Espeel M, Roels F, Rabier D, Levade T, Rolland MO,
Martinez M, Wanders RJA, Saudubray JM. Clinical approach to inherited peroxisomal disorders:
a series of 27 patients. Ann Neurol 1998;44:720-730
Twenty years after the first description of a human inherited peroxisomal disorder by Goldfischer and colleagues,
at least 20 disorders have been identified to be caused by
inherited peroxisomal dysfunctions, most of them involving neurological defects.2 By 1994, the nomenclature of
these disorders had something of an “inextricable puzzle”
as the amount of information rapidly expanded. This was
because most of the “new” disorders were denominated by
reference to the three main original clinical descriptions,
namely, Zellweger syndrome (2s),3 neonatal adrenoleukodystrophy (NALD)? and infantile Refsum disease
(IRD).5,6This is not surprising, as these three clinical
conditions correspond to the three main early-infantile
categories of clinical symptoms found in peroxisomal disorders-predominant polymalformative syndrome, as observed in classic ZS or in rhizomelic chondrodysplasia
punctata (RCDP),’ predominant neurological presentation, as in NALD, and predominant hepatodigestive
symptoms, as in IRD. Despite this rather simple clinical
classification of presenting signs, it became obvious that
there is no relationship between clinical and biochemical
phenotypes.
Similar clinical phenotypes may correspond to different biochemical lesions, as illustrated by RCDP,
which has been found to be associated either with
four biochemical abnormalities (unprocessed peroxisomal 3-oxoacyl-coenzyme A [3-oxoacyl-CoA] thiolase,
phytanoyl-CoA hydroxylase, dihydroxyacetone phosphate acyltransferase [DHAPAT] , and alkyldihydroxyacetone phosphate [alkyl-DHAP] synthase defects),*-”
or with an isolated enzyme defect (DHAPAT or alkylDHAP synthase deficiency).1 1 2 1 2 Conversely, the same
biochemical defect(s), or even the same genetic
complementation group, can be associated with very
dissimilar clinical phenotypes, as illustrated by classic
ZS and IRD.13,14 Given the diversity of clinical and
biochemical abnormalities and the rapidly advancing
knowledge about the normal function and biology of
the peroxisome, an arbitrary approach has been made
of classifying peroxisomal disorders into the following
From the *Departments of Pediatrics and Biochemistry, Hopital
Necker-Enfants Malades, Paris, “Department of Biochemistry, HOpital Rangueil, Toulouse, and SDepartment of Biochemistry, Hopital Debrousse, Lyon, France; ?Department of Metabolic Disorders,
Wilhelmina Kinderziekenhuis, Utrecht, and $Department of Clinical Chemistry, Metabolic Unit, Free University Hospital, and **Department of Pediatrics and Clinical Chemistry, University Hospital
Amsterdam, Academic Medical Center, Amsterdam, The Nether-
lands; §Department of Human Anatomy, Embryology and Histology, University of Gent, Gent, Belgium; and #Biomedical Research
Unit, Hospital Valle de Hebron, Barcelona, Spain.
’
720
Received
227 1997, and in revised form Apr 14, 1998. Accepted for publication Apr 14’ 1998’
Address correspondence to Dr Saudubray, Department of Pediatrics,
Hopital Necker-Enfana Malades, Paris Cedex 15, France.
Copyright 0 1998 by the American Neurological Association
three groups (Table 1): Group 1, peroxisome biogenesis disorders (PBDs) characterized by a complete absence of peroxisomes and the loss of many peroxisomal
functions (@-oxidation of very long chain fatty acids
[VLCFAs] and pristanic acid, synthesis of bile acids,
plasmalogens and polyunsaturated fatty acids, and metabolism of pipecolic acid and phytanic acid), ZS,
NALD, and IRD belonging to this group; Group 2,
PBDs characterized by a variable aspect of peroxisomes
and the loss of at least two peroxisomal functions, includes the “classic” type of RCDP (normal VLCFA oxidation) and yet unclassified PBDs with defects in at
least two peroxisomal functions other than plasmalogen
bio~ynthesis’~;
and Group 3, characterized by the loss
of a single peroxisomal function, consists at the present
time of at least 13 single enzyme deficiencies proven or
thought to be related to the peroxisome. This biochemical classification is not helpful for physicians who
are faced with clinical symptoms rather than biochemical phenotypes. Also, it bears little relation to what is
currently known about the nature of the disease processes. Thus, whatever the genetic defect might be, peroxisomal disorders should be considered in various
clinical conditions depending on the age of the patient
and the type and severity of symptoms.
We report our experience on 27 patients affected
with a peroxisomal disorder who have presented at the
Hopital Necker-Enfants Malades since 1982. In our
study, we briefly summarize the patients with classic
peroxisomal disorders and describe in detail those patients with atypical manifestations, showing the clinical, biochemical, and pathological heterogeneity.
Patients and Methods
Patients with Typical Characteristics
All 27 patients included in this study either had the phenotypic signs and symptoms described for the disorders of peroxisome assembly, or displayed biochemical abnormalities
characteristic of these disorders.’ They have presented at the
Hopital Necker-Enfants Malades since 1982. Twenty-six patients had been examined by us, whereas for 1 patient clinical information was kindly provided by the referring physician. As patients with X-linked adrenoleukodystrophy and
classic Refsum disease are usually not followed by us, only a
single patient with classic Refsum disease was included. The
patients were listed according to their age at the time of on-
Table I . Classification of Peroxisomal Disorders
Disorder
Peroxisome biogenesis disorder with loss
of multiple peroxisomal functions
Classic Zellweger syndrome
Neonatal adrenoleukodystrophy
Infantile Refsum disease
Peroxisome biogenesis disorder with loss
of at least 2 peroxisomal functions
Rhizomelic chondrodysplasia punctata
(classic and atypical phenotype)
Unclassified peroxisomal biogenesis
disorder
Loss of a single peroxisomal function
Rhizomelic chondrodysplasia punctata
X-linked adrenoleukodystrophy
Pseudo-NALD
Bifunctional enzyme deficiency
Pseudo-Zellweger syndrome
Trihydroxycholestanoic acidemia
Mevalonic aciduria
Classic Refsum disease
Glutaric aciduria type I11
Hyperoxaluria type I
Acatalasemia
Microscopy
Peroxisomes
Proposed Molecular Defect
References
Absent or mosaicism
PEXI: AAA protein (CG1)
PH.2: IPMP35 (CG10)
Pm5: receptor for PTSl (CG2)
PEX6 AAA ATPase (CG4)
P I X 1 2 IPMP40 (CG3)
Many others still unknown (at least 10 CGs)
45, 46
47
47
47
47
Enlarged
PEXZ receptor for PTS2 (CG11)
47
Present or absent
At least 2 peroxisomal functions other than
plasmalogen biosynthesis
15
Normal
Present
Enlarged
Abnormal
Enlarged
NA
NA
NA
Normal
Smaller
NA
Normal
Isolated DHAPAT or alkyl-DHAP synthase
ALD protein
Acyl-CoA oxidase
Bi(tri)functional enzyme deficiency
Peroxisomal 3-oxoacyl-CoA thiolase
Branched chain acyl-CoA oxidase
Mevalonate kinase
Phytanoyl-CoA hydroxylase
Peroxisomal glutaryl-CoA oxidase
Alanine:glyoxylate aminotransferase
Mistargeting
Catalase
11, 12, 48
49
16
34
50
51
52
53
54
33, 55
56
57
PEX = genes encoding peroxins (proteins involved in peroxisomal import, biogenesis, proliferation, and inheritance); CG = complementation
group; IPMP = integral peroxisomal membrane protein; PTS = peroxisomal targeting signal; DHAPAT = dihydroxyacetone phosphate
acyltransferase; DHAP = dihydroxyacetone phosphate; ALD = adrenoleukodystrophy; NALD = neonatal adrenoleukodystrophy; CoA =
coenzyme A; NA = information not available.
Baumgartner et al: Clinical Approach to Peroxisomal Disorders 721
set and subdivided into groups by use of the criteria described in Table 1. A summary of the predominant clinical
signs at the time of onset is given in Table 2. We provide
here a brief clinical summary for patients with clinical phenotypes consistent with those of the ZS, NALD, IRD, RCDP,
and Refsum disease categories. Five patients could not be assigned to a clinical phenotype and are described in detail.
PATIENTS 1 THROUGH 8. The clinical phenotype of these
patients conformed to the classic ZS category. It was dominated from birth by severe nervous system dysfunction and
facial dysmorphia, as well as by regressive symptoms, including cerebral white matter degeneration, chorioretinopathy
with extinguished electroretinogram (ERG), and liver fibrosis. At birth, the predominant symptom was often a severe
weakness and hypotonia. Craniofacial abnormalities included
large fontanelle, high forehead, epicanthus, broad nasal
bridge, abnormal ears, and high arched palate. Most patients
developed seizures, hepatomegaly, and feeding difficulties,
showed a failure to thrive, and usually died before the age of
6 months (range, 3 days to 11 months).
PATIENTS 9 THROUGH 12. The clinical picture of these 4
patients corresponded to the NALD category. Three of them
have been described in detail
They presented in
the first days of life with generalized neurological distress,
characterized by severe muscle hypotonia and seizures. Computed tomographic scan of the brain showed white matter
demyelination and cortical atrophy. There was no or only
mild facial dysmorphia. Psychomotor development was severely delayed and they showed progressive neurological regression with sensorineural hearing loss and abnormal ERG.
They died between 2.5 months and 5 years of age.
PATIENT 15. This girl with an unusually mild type of
RCDP has been described previously.’* She presented at 12
days of age with absence of movements of the upper limbs
and pain on passive movement of both shoulders. No other
clinical abnormalities were observed, except for a flattened
nasal bridge. Skeletal radiography revealed extensive stippled
calcifications at the epiphyses of both shoulders and knees,
but the long bones of the arms and legs were symmetrical
and only slightly shortened. At 7.5 months, bilateral cataracts
with normal optic fundi were noted. Between 18 and 24
months, moderately delayed psychomotor development became evident. However, the girl continued to make progress
and learned to speak her language fluently. She is now 8
years old, attends special schooling, and receives psychomotor and orthophonic reeducation.
PATIENTS 16 THROUGH 23. The clinical phenotype of
these 8 patients conformed to IRD and differed clearly from
that of the patients with ZS or NALD with respect to age at
onset and initial symptoms (see Table 2). Three of them
have been described in detail earlier,5,6including microscopic
studies.” None of our patients showed distinct abnormalities
in the neonatal period. First symptoms developed between
the age of 1 and 6 months and were nonspecific digestive
problems, osteoporosis, hepatomegaly, and hypocholesterolemia. Only minor facial dysplasia was noted. Subsequently,
regressive changes were noted, that is, chorioretinopathy,
sensorineuronal hearing loss, and a kink in development, followed by complete arrest and autistic behavior. However, all
but 1 were able to walk independently before the age of 3
years and explored objects bimanually. Only 1 patient died
(at the age of 2.5 years); all other patients are still alive, although severely handicapped (the oldest being 25 years old).
PATIENT 27. This patient had classic Refsum disease with
clinical onset at the age of 15 years. Symptoms included retinitis pigmentosa, minor sensorineural hearing loss, peripheral polyneuropathy, and cerebellar ataxia. At 45 years, she
worked regularly as a head nurse despite her significant motor and visual handicap.
Patients with Atypical Characteristics
PATIENT 13. This female child of consanguineous parents
was born at term after an uneventful pregnancy. Global hypotonia and moderate jaundice were noted. At 3 months she
Table 2. Summary of Predominant Clinical Signs at Onset
Patient No.
1-7
8
9
10
11, 12
13
14
15
16-23
24
25
26
27
Age at
Onset
Consanguinity (n)
Neonatal
Neonatal
Neonatal
Neonatal
Neonatal
Neonatal
Neonatal
Neonatal
1-6 mo
6 mo
10 yr
11 yr
15 yr
Yes (5)
No
Yes
Yes
Yes (2)
Yes
No
Yes
Yes (1)
No
No
No
No
n = number of patients with consanguinity;
= severe or almost constantly present.
722 Annals of Neurology Vol 44
Polymalformative Syndrome
and Dysmorphia
Neurological
Dysfunction
Hepatodigestive
Manifestations
+++
+++
+++
++
++
++
++
++
-
++
++
++
++
+
+
+-
++
+
-
-
+
-
-
+
-
= absent;
No 5
(+)
++
+
++
+
++/+++
++
-
-
+ = mild or occasionally present; ++ = moderate or frequently present; +++
November 1998
Table 3. Summa y of Laboratoy Finding?
Patient
No.
VLCFA
Bile
Acids
Pipecolic
Acid
Phytanic
Acid
tt
N-t
8
tt
tt
9
10
tt
tt
t-t t
t
t
ND
11, 12
1
N
1-7
Tt
Tt
t
Microscopy
Liver
Peroxisomes
N
11
11
Absent
Clinicalb
Diagnosis
Molecular
Defect
Zellweger
syndrome
Zellweger
syndrome
NALD
NALD
?
1'1'
tt
ND
N
Absent
t
t
t
tt
N
t
ND
ND
11
N
N
Absent
Abnormal
N
N
ND
ND
ND
N
Enlarged
PseudoNALD
Absent
Present
Enlarged
PBD
PBD
Mild
RCDP
IRD
N
N
t
tt
(t)
tt
26
t
tt
Tt
27
N
N
N
t
tt
t
N-t
DHA
Plasmalogens
Pristanic/
Phytanic
N
24
25
(t)
t
Pristanic
Acid
(TI
N
N
N
N
11
t?
t
N
N
N
11
ND
N
Absent; and
Patients
18 and
23, mosaicism
Mosaicism
Abnormal
Abnormal,
mosaicism
Not done
?
?
Bifunctional
enzyme
deficiency
Acyl-CoA
oxidase
deficiency
?
?
Receptor for
PTS2
?
PBD
PBD
?
PBD
?
Refsum
disease
PhytanoylCoA hydroxylase
PhytanoylCoA hydroxylase
+?
"Detailed biochemical results for Patients 8, 10 through 15, and 24 through 26 are provided in Table 4.
bFirst clinical diagnosis based on clinical findings and preliminary biochemical results (usually VLCFA), before having results from fibroblasts or liver
studies.
VLCFA = very long chain fatty acids; DHA = docosahexaenoic acid; N = normal values; N D = not determined; NALD = neonatal adrenoleukodystrophy; CoA = coenzyme A; PBD = peroxisomal biogenesis disorder; RCDP = rhizomelic chondrodysplasia punctata; PTS = peroxisome
targeting signal; IRD = infantile Refsum disease;
= moderately elevated values; ( t ) = borderline values;
= highly elevated values; 1 = plasmalogen/
DHA synthesis moderately deficient; 1 1 = plasmalogen/DHA synthesis highly deficient or nearly extinguishedpristanidphytanic acid ratio extremely low.
t
tt
was admitted to the hospital because of major hypotonia and
hepatomegaly. She presented with severe, predominantly distal, muscular hypotonia, absence of tendon stretch reflexes
and lingual fasciculations, contrasting with a normal intellectual development-neurological symptoms very similar to
those observed in Werdnig-Hoffmann disease. Electromyographic (EMG) and nerve conduction velocity (NCV)
studies displayed neurogenic profiles compatible with an axonal process. However, muscle histology was normal and
Werdnig-Hoffmann disease was ruled out. Hepatomegaly
with elevated transaminases ( X lo), hypocholesterolemia (1.5
mmol/L), and bilateral cataract were present. No dysmorphia
was noted. A mitochondrial fatty acid oxidation defect was
initially considered and later ruled out. On amino acid chromatography, pipecolic acid was found to be elevated in urine
and plasma, which led to a complete peroxisomal investigation. Cerebral magnetic resonance imaging (MRI), electroencephalography (EEG), ERG, and visual evoked potential
(VEP) were normal at that time. Given the probable role of
docosahexaenoic acid (DHA) deficiency in the pathogenesis
of peroxisomal disorders,20a treatment with DHA (100 mg;
later, 200 mg/24 hr), to normalize plasma concentrations of
DHA, was started. Despite this treatment and a diet low in
phytanic acid, major hypotonia with severe amyotrophy persisted and progressive psychomotor retardation began. At 15
months, strabism and retinitis pigmentosa with abnormal
ERG were noted. Hearing remained normal. Skeletal radiography revealed severe osteoporosis. At 27 months, after DHA
treatment had been stopped, she suffered a severe gastrointestinal infection with dehydration and she deteriorated rapidly. After an initial recovery, she died suddenly without any
explanation. No autopsy was performed.
PATIENT 14. This female child of unrelated healthy parents
was born at term after a normal pregnancy. One older
brother had died at 10 days, presenting major hypotonia and
feeding difficulties. At 2 days of age, right-sided convulsions
occurred. Global hypotonia was noted and phenobarbital
treatment was introduced. The girl was then lost to followup. At the age of 1 year, she presented with major axial and
peripheral hypotonia, absence of deep tendon reflexes, and
bilateral positive signs of Babinski. She was unable to hold
her head and had no ocular contact. Craniofacial dysmorphia
Baumgartner et al: Clinical Approach to Peroxisomal Disorders
723
Myelination was normal for age. EMG and NCV studies
displayed sensorimotor polyneuropathy. Muscle histology
showed diffuse atrophy of type I1 fibers and moderate lipid
accumulation. Her ERG was extinguished and VEP response
to flash stimulation was absent. The patient died at the age
of 14 months.
Fig 1. In the liver biopsy of Patient 23, an isolated parenchyma1 cell (arrow) with peroxisomes, visualized as dzrk granules
after diaminobenzidine incubation for catalase activiy, was
found in between the rest of the parenchymal cells, which were
devoid of peroxisomes. Phase-contrast image of 2-mm section.
(Magnification, X 780; scale bar = 20 mm.)
Fig 2. Liver biopsy of Patient 23. Trilamellar inclusions (arrowheads) are a microscopic feature indicating a peroxisomdl
disorder. Together with the dense body (D), the trihmellar
inclusions make part of a lysosome in a parenchymal cell.
(MagniJication, X 64,800; scale bar = 0.2 mm.)
including high forehead, short philtrum and high arched palate, and mild hepatomegaly with cytolysis (transaminases,
X 5) and cholestasis (y-glutamyltranspeptidase, X20) were
present. Her EEG showed a severely abnormal ground activity with interpolated epileptiform discharges. Brain MRI revealed a very enlarged cisterne in the posterior fossa and
moderately dilated fourth, third, and lateral ventricles.
724 Annals of Neurology Vol 44 No 5
November 1998
PATIENT 24. This 6-year-old son of unrelated healthy parents was born at term after a normal pregnancy. He has been
described previously.21 At 6 months of age, severe axial hypotonia, psychomotor retardation, and moderate hepatic cytolysis were nored. Computed tomographic scan, EEG, ophthalmological examination, and skeletal radiography were
normal. Subsequently, he showed a failure to thrive due to
severe digestive problems (milk intolerance) with length,
weight, and head circumference decreasing from the 25th to
below the 10th percentile. At the age of 2 years, he presented
with severe mental retardation, major axial hypotonia, and
spastic hypertonia predominantly of the limbs, indicating
central motor involvement. He showed severe dystrophy and
microcephaly (measurements for weight, length, and head
circumference, <P3). Except for an epicanthus and a high
forehead, no dysmorphia was noted. An x-ray survey revealed
diffuse demineralization and retarded bone age. Brain MRI
showed a cortical and subcortical atrophy associated with
periventricular white matter anomalies. VEPs had somewhat
increased latency, but the child had eye contact and reacted
by smiling. ERG and fundoscopy were normal. EMG and
NCV were at rhe limit of the normal range, but both suggested an axonal process. At 5 years he had achieved little
further psychomotor progress and remained severly dystrophic (weight, 10.8 kg; length, 87 cm; head circumference,
45.5 cm; corresponding to a child of 18 months to 2 years).
However, eye contact had slightly improved, hearing was still
present, and he appeared to be well integrated in his family.
PATIENT 25. This female patient was born at term after an
uneventful pregnancy. At 10 years as she entered special
schooling, because mild developmental delay, cranial asymmetry, retrognathism and dental dysharmony, distal osseous
abnormalities, and a systolic murmur were noted. It was only
by chance that 2 years later a chromatography of plasma
amino acids was performed, revealing elevated plasma pipecolic acid. At the time of admittance to our hospital at the
age of 12 years she was in excellent general health. Except for
a systolic murmur, her examination was normal. A psychomotor evaluation showed mild developmental delay with
language difficulties and partial alexia. Echocardiography revealed a mitral prolapse with mild m i d insufficiency and
minimal aortic insufficiency. No other visceral abnormalities
were found. Skeletal radiography showed shortened fourth
and fifth metacarpals predominantly on the left side, but no
anomalies of long bones, no calcifications, and no osteoporosis. Brain MEU, EEG, ophthalmological examination,
ERG, and VEP were normal.
PATIENT 26. This 23-year-old woman has been presented
earlier.'' She developed normally until 11 years of age when
she began to present with ataxia and minor gait difficulties.
At 13 years, she was seen by neurologists because of motor
defect, hypotonia, and areflexia of the lower extremities associated with ataxia. EMG and NCV displayed zonal sensorimotor polyneuropathy. Slight elevation of phytanic acid
was found in the plasma and a diagnosis of adult Refsum
disease was considered. However, ocular and cutaneous
symptoms were absent. The patient received physiotherapy
and a low phytanic acid diet for 3 years. Phytanic acid levels
remained normal after discontinuation of the diet. The girl
suffered a slow deterioration of symptoms. Pes cavus and
scoliosis were noted and a diagnosis of Charcot-Marie-Tooth
disease type 2 was established despite absence of familial history. Her I Q was normal and she attended university. From
21 to 23 years, her condition worsened; she lost the ability to
walk and became wheelchair bound. Severe distal amyotrophy was noted. Cerebellar ataxia, dysarthria, pyramidal signs,
mild cognitive impairment, and pseudobulbar palsy progressively appeared. T2-weighted cerebral MRI displayed leukoencephalopathy involving the corpus callosum, the posterior part
of the centrum semiovale and pyramidal tract in brainstem
and internal capsule. VLCFAs were found to be elevated and
X-linked adrenoleukodystrophy in its heterozygous form was
considered. Finally, 10 years after the initially suspected diagnosis of Refsum disease, the old plasma sample was rechecked,
and it became evident that this patient had accumulation of
not only phytanic but also pristanic and pipecolic acids, suggesting a more generalized peroxisomal disorder.
Methods
VLCFAs, phytanic, pristanic, and pipecolic acids, and bile
acid intermediates were measured in plasma according to
previously described methods.23 Polyunsaturated fatty acids
and plasmalogens were measured by capillary column gas
chromatography after direct transesterification of plasma and
erythrocytes, as specified elsewhere.24325
Liver and skin biopsies were performed for diagnostic purposes, after informed consent was obtained from the parents.
Peroxisomal functions were determined in cultured fibroblasts by assaying peroxisomal P-oxidation, dihydroxyacetonephosphate acyltransferase activity, de novo plasmalogen
synthesis, and concentrations of VLCFAs as described in the
Immunological material cross-reactive to the
peroxisomal p-oxidation enzymes acyl-CoA oxidase and
3-oxoacyl-CoA thiolase in fibroblasts was examined by the
immunoblotting procedure of Wanders and colleag~es.~'
Peroxisomes were made visible in the liver for light and
electron microscopy by staining for catalase a~tivity,~'
and by
protein A-colloid gold immunolocalization of the matrix
proteins catalase, acyl-CoA oxidase, 3-ketoacyl-CoA thiolase,
and alanineglyoxylate amin~transferase,~'
and 43-kd peroxisomal membrane protein.32 Morphometry of peroxisomes
was performed on random electron micrographs with a semiautomated device.33
Statistical analysis to compare consanguinity of the parents
with severity of disease in our patients was done by using the
x2 test. According to Table 2, disease was considered severe
in Patients 1 through 14 and less severe in Patients 15
through 27.
Results
Table 3 lists a summary of biochemical findings. As
shown by making use of the criteria described in the
introductory section (see Table I), of the 2 0 patients
initially listed in the ZS/NALD/IRD categories (Patients 1-12 and 16-23), 3 (Patients 10-12) had a single enzyme deficiency and 1 (Patient 8) fit into group
2 disorders. Sixteen patients (Patients 1-7, 9, and 1623) were identified as suffering from a generalized peroxisomal disorder. Their clinical phenotype most commonly conformed to the ZS/NALD/IRD categories.
Liver peroxisomes were absent in all but 2 patients. In
1 (Patient 18) abnormal catalase-deficient organelles
were frequent in some cells, representing only 47% of
normal number. 19,33 T h e second patient (Patient 23)
showed hepatic mosaicism with absence of peroxisomes
in more than 99% of hepatocytes, contrasting with less
than 1% of cells containing peroxisomes with catalase
and alanine/glyoxylate aminotransferase antigen activity
(Figs 1 and 2).
Patients 10, 11, 12, and 27 were diagnosed as having a peroxisomal disorder due to a single enzyme deficiency bi[tri]-functional enzyme, acyl-CoA oxidase,
phytanoyl-CoA hydroxylase, respectively). Detailed
biochemical findings for Patients 10, 11, and 1 2 are
provided in Table 4. As previously reported,'"'* the
clinical manifestations of acyl-CoA oxidase and bi- or
trifunctional enzyme deficiency resembled those of
NALD. However, liver biopsy showed abnormally enlarged peroxisomes in the 2 patients with acyl-CoA deficiency" and round but also elongated peroxisomes
in the patient with bi(tri)-hnctional enzyme deficiency" (Patient 3).
Patient 15 with an unusually mild RCDP phenotype
was Characterized by the classic tetrad of biochemical
abnormalities9,' O , l S including a deficiency of DHAPAT,
alkyl-DHAP synthase, and phytanoyl-CoA hydroxylase
(see Tables 3 and 4), and a failure to process the peroxisomal 3-oxoacyl-CoA thiolase (results not shown).
This patient belongs to the same complementation
group as the "classic" R C D P patients (results not
shown). Ultrastructural studies showed absence of peroxisomes in most hepatocytes, whereas some liver cells
displayed a markedly decreased number of abnormally
shaped peroxisomes."
Finally, 6 patients (Patients 8, 13, 14, and 24-26)
were found to have multiple defects of peroxisomal
functions, with one or several functions remaining intact. Clinically, 1 patient could be attributed to the ZS
phenotype, but the others presented clinical manifestations that initially did not arouse suspicion of peroxisomal disease. Detailed biochemical findings for these
patients are provided in Table 4. Five of them (Patients
8, 13, 14, 24, and 26) were characterized by impaired
peroxisomal P-oxidation and elevated plasma pipecolic
acid but normal plasmalogen synthesis. Patient 25 differed from all other patients showing the unusual combination of highly elevated phytanic acid concentration
due to deficient phytanoyl-CoA hydroxylase, as seen in
Baurngartner et al: Clinical Approach to Peroxisomal Disorders 725
Table 4. Biochemical Findings in Plasma and Eytbroytes of Atypical Patients
Plasma
Pipecolic
Acid
Patients (pmol/L)
~~
~
I’hytanic Pristanic
C26:O
C26:0/C22:0 DHCA THCA
Acid
Acid
(r*.mol/L) (I*.mol/L) (pnol/L) Ratio
(FmollL) (pnol/L) DHA (pmol/L)
C16:O
Plasmalogen
C18:O
Plasmalogen
~
Control 0.542.46 0.01-9.88 0.01-2.98 0.22-1.31
8
10
11
12
13
14
15
24
25
26
Erythrocytes”
9.22
0
1.66
0
280
4.12
4.1
21
62.1
60.86
5.46
50.3
6.4
0
34.8
6.4
197
9.75
274
34.8
27.6
68.6
ND
ND
24.8
16.1
0.61
4.24
1.01
51.96
7.9
18.4
7.2
ND
6.7
4.71
1.33
1.21
1.30
2.37
0.003-0.021
0.27
0.68
0.076
0.16
0.45
0.105
0.023
0.056
0.018
0.054
0-0.012 0-0.035
5.71
1.15
ND
ND
ND
0
ND
0
7.03
1.04
0.029
0.036
0.013
0.005
0.078
0.319
0
0
3.812
4.5
162.43 ? 120.92 0.103 2 0.011 0.222 2 0.015
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
0.079
0.171
20.66
ND
ND
ND
0.088
0.039
135.43
0.082
0.225
122.36
0.097
0.252
160.3
0.08
0.204
144.7
”Plasmalogen content in erythrocytes. The values represent the ratios of the C16 or C18 dimethylacetal to methylester derivatives. A low ratio indicates
a plasmalogen deficiency.
boxidation of C24:O instead of C26:O in indicated cases.
DHCA = dihydroxycholestanoicacid; THCA = trihydroxycholestanoic acid; DHA = docosahexaenoic acid; pPE = plasmalogen phosphatidylethanolamine; PE = total phospharidylethanolamine; DHAPAT = dihydroxyacetone phosphate acyltransferase; ND = not determined; 0 = not detectable;
CoA = coenzyme A.
classic Refsum disease, plus hyperpipecolatemia. Liver
peroxisomes were not visualized by catalase staining,
but all other enzymes were present in the peroxisomes,
indicating an isolated catalase import defect. Ultrastructural studies displayed the presence of unusually
large peroxisomes with membrane in vagina ti on^.^^
In 3 of the atypical patients (Patients 13, 24, and
26), the defect in peroxisome biogenesis was further
characterized by variable expression in different tissues
(Patients 13, 24, and 26) (liver vs fibroblasts) or within
individual cells (Patients 24 and 26) (mosaicism). Patient 13 showed absence of liver peroxisomes with presence of trilamellar inclusions in the parenchymal cells,
and in immunoblot studies missing acyl-CoA oxidase
and 3-oxoacyl-CoA thiolase (result not shown) contrasting with partly normal peroxisomal functions and
normal immunoblot pattern in cultured skin fibroblasts. Remarkably, virtually all catalase was cytoplasmic (such as in liver) indicating that the peroxisomal
defect was definitely expressed in fibroblasts. Patient 24
showed normal peroxisomal functions in fibroblasts as
well as liver mosaicism. Peroxisomes were absent in
about 90% of the biopsy specimen after visualization
of catalase activity by enzyme cytochemistry. In the remaining 10% of cells, typical peroxisomes containing
all enzymes were seen by light and electron microscopy, as reported by Espeel and associates21 (Patient
1). In Patient 26, liver peroxisomes were not visible
after catalase staining, which was localized in the cyroplasm. In fibroblasts, however, incubation with antibodies against human adrenoleukodystrophy (ALD)
protein showed a colocalization of ALD protein and
726 Annals of Neurology
Vol 44
No 5
November 1998
catalase within peroxisomes in 80 to 90% of fibroblasts, whereas in 10 to 20% of the cells only ALD
protein was present in the peroxisomes, catalase remaining cytosolic, thus confirming fibroblast mosaicism (results not shown). In the liver, organelles resembling peroxisomes were frequent in some cells and
labeled for peroxisomal thiolase; very few cells contained acyl-CoA oxidase. Many hepatocytes lacked
these organelles, suggesting a peculiar type of mosaic
(results from this patient to be published separately).
Discussion
Peroxisomal disorders are a recently recognized group
of inborn errors of metabolism with severe dysfunction
of multiple organs and poor prognosis. Individual disorders are relatively rare, but many clinical phenotypes
are present. 2 At the Hopital Necker-Enfants Malades,
since 1982, we have seen 27 patients affected by peroxisomal disorders, excluding X-ALD. This is a small
number of cases compared with about 1,000 seen with
other inborn errors of metabolism at our hospital during the same time. Sixteen patients presented with a
clinical phenotype and biochemical findings corresponding to the ZS/NALD/IRD categories. These are
now thought to represent a continuous spectrum of
disease severity, ZS being the most severe, IRD the least
severe, and NALD of intermediate severity; biochemistry
and microscopic pathology are nearly identicaL2
The prototype of peroxisomal disorders is represented by classic ZS, characterized by the association of
errors of morphogenesis, severe neurological dyshnction, neurosensory defects, regressive changes, hepato-
Fibroblasts
De Novo
Plasmalogen
Biosynthesis
(%pPE in PE)
DHAPAT
(% of Control)
C26:0/C22:0
Ratio
C26:Ob
Pristanic Acid
Phytanic Acid
@-Oxidation
@-Oxidation
a-Oxidation
Immunoblot @-Oxidation
(% of Control) (% of Control) (% of Control) Proteins
64.5-85.7
86.6
82.2
74.9
74.5
88.3
67.7
9.0
88.9
90.3
79.1
88
38
82
100
94
95.3
25
79
145
97.6
0.02-0.05
0.5
1.58
1.577
1.047
0.07
0.41
0.03
0.03
0.03
ND
7.3b
10
6.2
4.1
38
15
ND
71.6
107
101.Gb
ND
<1
130
134
5.4
2.3
ND
133
109
ND
digestive involvement with failure to thrive, usually
early death, and absence of recognizable liver peroxisomes. NALD clinically appears as a milder form of ZS
with often more impressive cerebral demyelination but
milder or absent craniofaciai dysmorphia. Although
IRD patients also share some clinical features with ZS,
they differ from ZS with respect to age at onset, initial
symptoms, degree of dysfunction, and survival.6 The
reason for the different clinical course remains poorly
understood. It is noteworthy that there is a clear correlation between severity of disease and consanguinity
in the parents of our patients ( p < 0.001). This may
be due to a higher frequency of homozygous defects in
patients with consanguineous parents versus compound
heterozygocity in less severely affected patients. However, it must be stressed that most of our patients with
consanguineous parents are of North African origin
where more severe genetic defects may be prevalent. It
has been suggested that the severity of disease correlates
with the degree of C26:O accumulation and with the
amount of impairment of de novo plasmalogen synthesis in ZS, NALD, and IRD, and in RCDP.2,28 However, no correlation regarding other parameters was
found, and an absolute correlation between biochemical and clinical phenotype is lacking.
A list of clinical symptoms related to age and their
differential diagnosis, which were hypothesized in
many of our patients, is provided in Table 5. Presenting symptoms may include polymalformative syndrome
with craniofacial dysmorphism or severe neurological
dysfunction in neonates; hepatomegaly and failure to
thrive, resembling malabsorption syndrome, during the
first 6 months of life; psychomotor retardation, hearing
loss, and ocular abnormalities between 6 months and 4
years; and behavioral changes, intellectual deterioration, and peripheral neuropathy beyond 4 years.
In 5 patients, increased levels of VLCFAs and bile
28.7
71
121
132
15
54
1.6
ND
8
ND
Normal
Normal
Acyl-CoA deficiency
Acyl-CoA deficiency
Normal
Normal
Unprocessed peroxisomal thiolase
Normal
Normal
ND
acid intermediates combined with an elevated pristaniclphytanic acid ratio and normal plasmalogen synthesis suggested a defect in peroxisomal @-oxidation.
Clinically, 1 patient could be attributed to the ZS phenotype. However, the remaining patients presented
clinical manifestations that were either unusually mild
or completely atypical, and therefore initially did not
arouse suspicion of peroxisomal disease. Diagnosis such
as Werdnig-Hoffmann disease, adult Refsum disease,
Charcot-Marie-Tooth type 2 disease, and X-linked adrenoleukodystrophy were considered before peroxisomal involvement was demonstrated by biochemistry as
well as liver pathology. The gap between onset of
symptoms and correct diagnosis was more than 10
years in 1 patient, and in another patient with mild
psychomotor retardation, diagnosis of peroxisomal disorder was made only accidentally by detecting elevated
pipecolic acid in routine chromatography of plasma
amino acids.
In 4 patients suspected to have a defect in peroxisoma1 f3-oxidation, immunoblot studies in fibroblasts to
further characterize the peroxisomal P-oxidation enzyme proteins were found to be normal, indicating that
the import of P-oxidation enzymes into peroxisomal
structures did occur. In the last years, an increasing
number of patients have been described with a defect
in peroxisomal P-oxidation of unknown cause and detectable enzyme protein^.^"'^ However, contrary to
these reports, our patients with impaired p-oxidation
but normal plasmalogen synthesis had elevated plasma
pipecolic acid, which suggests a defect in peroxisome
biogenesis rather than an isolated defect of peroxisomal
P-oxidation. According to our data, we can distinguish
three subgroups in Group I1 of the classification shown
in Table 1: (1) RCDP showing the classic four biochemical abnormalities including plasmalogen biosynthesis deficiency9”’; (2) PBDs, the molecular defect(s)
Baumgartner et al: Clinical Approach to Peroxisomal Disorders 727
Table 5. Clinical Symptoms of Peroxisomal Disorders Rekzted to Age and Dzfferential Diagnosis
Differential Diagnosis
Symptoms
Neonatal period
Hypotonia, areactivity
Encephalopathy, seizures
Craniofacial dysmorphia, dysmorphic features
Skeletal abnormalities (calcific stippling, short
ened proximal limbs)
First 6 months
Failure to thrive
Digestive problems, hypocholesterolemia
Hepatomegaly, prolonged jaundice, liver failure
Osteoporosis
Visual abnormalities (retinopathy, cataract, optic
nerve dysplasia, abnormal ERG/VEPs)
6 months to 4 years
Neurological presentation
Psychomotor retardation
Visual and hearing impairment (ERG, BAEP)
Failure to thrive
Osteoporosis
Beyond 4 years of age
Behavior changes, intellectual deterioration
White matter demyelination
Visual and hearing impairment
Peripheral neuropathy, gait abnormalities
Carbohydrate-deficient glycoprotein syndrome
Respiratory chain defects
Fatty acid oxidation disorders
Werdnig-Hoffmann disease, other neuromuscular disorders
Chromosomal aberrations
Inborn errors of metabolism with hypotonia/seizures, but without
evident biochemical abnormalities by routine metabolic screening
Malabsorption syndromes, hypobetalipoproteinemia, celiac disease,
cow's milk intolerance
Reye's syndrome, vitamin E deficiency, inborn errors of bile acid
metabolism, Niemann-Pick type C
Carbohydrate-deficient glycoprotein syndrome
Respiratory chain defects, LCHAD
Autosomal recessive syndromes with retinitis pigmentosa and devel
opmental delay
Inborn errors of metabolism with retinitis pigmentosa (abetalipoproteinemia, vitamin E deficiency, ceroid lipofuscinosis, abnormal
purine metabolism)
Carbohydrate-deficient glycoprotein syndrome
Respiratory chain defects, LCHAD
Sanfilippo, Niemann-Pick type C, metachromatic leukodystrophy,
Wilson, juvenile GM2 gangliosidosis, multiple sclerosis, SSPE,
juvenile nile ceroid lipofuscinosis and neuroaxonal dystrophy
Atypical Charcot-Marie-Tooth disease, other peripheral neuropathies
ERG = electroretinogram; VEPs = visual evoked potentials; LCHAD = long chain 3-hydroxyacyl-coenzymeA dehydrogenase deficiency; BAEP =
brain auditory evoked potentials; SSPE = subacute sclerosing panencephalitis.
of which is still unexplained, with accumulation of
VLCFAs, bile acids, phytanic and pipecolic acids; and
( 3 ) PBDs with deficiency of phytanoyl-CoA hydroxylase and pipecolic acidemia.'
In 5 patients (3 with atypical phenotype and 2 with
IRD), the defect in peroxisome biogenesis was characterized by variable expression in different tissues (liver
vs fibroblasts) and/or within individual cells in the
same tissue (liver or fibroblast mosaicism). The application of advanced immunocytochemical and electron
microscopic method^^^,^',^^ may reveal that tissue heterogeneity is not a rare phenomenon, because at least 7
cases with hepatic mosaicism have been
In 4 of our patients, data from liver and cultured fibroblasts differ clearly, and studies restricted to fibroblasts failed to identify the disease. Other examples of
disagreement between liver and cultured fibroblasts
have been r e p ~ r t e d . ~ ' -The
~ ~ variable expression in
different tissues could at least in part explain the mild
clinical course in some of our patients, and mosaicism
may explain the phenotypic variation between patients
whose fibroblasts belong to the same complementation
gro~p.~~,~*
The rapid expansion of the clinical spectrum of
peroxisome-related diseases constitutes a widening di-
728
Annals of Neurology
Vol 44
No 5
November 1998
agnostic ~ h a l l e n g e ' ~ , ' ~and
, ~ ' indicates the need to reexamine the clinical settings in which tests for these
disorders are recommended. According to our experience, biochemical investigation for peroxisomal function as well as microscopy and immunocytochemistry
of liver should be considered in patients showing one
or more of the symptoms listed in Table 5. The clinician must be aware that not all peroxisomal disorder
patients will fulfill these criteria and that others may
display features that have not been hitherto considered
as indicative. The manifestations may initially be very
mild, but early diagnosis is crucial for genetic counseling.
Independently of the clinical symptoms and age at
onset, most peroxisomal disorders described so far can
be screened by the recordings of ERG, VEP, and brain
auditory evoked potential, which are almost always abnormal. Only urinary pipecolic acid excretion, hyperoxaluria, and mevalonic aciduria can be detected by a
general metabolic screening. The clinical presentations
of the typical phenotype of RCDP and classic Refsum
disease are distinct from the other disorders and should
not cause difficulties in their diagnosis. Because most
of the peroxisomal disorders with neurological involvement are associated with an accumulation of VLCFAs,
assay of plasma VLCFAs is generally regarded as a
Table 6 Diagnostic Assays in Peroxisomal Disorder5
Material
Type of Assay
Plasma
VLCFAs, including C26:0/C22:0 and C26:llC22:O ratios; phytanic and pristanic acids, including pristaniclphytanic acid ratio; THCA and DHCA, including THCNCA and
DHCAlCDCA ratios; pipecolic acid, plasmalogens, and PUFAs including DHA
Organic acids, and pipecolic acid
Plasmalogens, and PUFAs including DHA
Plasmalogen biosynthesis, DHAPAT, and alkyl-DHAP synthase; particle-bound catalase;
VLCFAs, P-oxidation, and phytanic acid oxidation; immunoblotting P-oxidation proteins
Cytochemical localization of peroxisomal proteins, trilamellar inclusions, and insoluble lipid
Urine
Red blood cells
Fibroblasts
Liver
VLCFAs = very long chain fatty acids; THCA = trihydroxycholestanoic acid; DHCA = dihydroxycholestanoic acid; CA = cholic acid; CDCA =
chenodeoxycholic acid; DHAPAT = dihydroxyacetone phosphate acyltransferase; DHAP = dihydroxyacetone phosphate: PUFAs = polyunsaturated
fatty acids; DHA = docosahexaenoic acid.
good screening method for peroxisomal disorders.
However, VLCFA elevation can be very moderate and
easily missed in some mild variant patients. In addition, RCDP, Refsum disease, and isolated bile acid disorders do not involve peroxisomal fatty acid oxidation.
For this reason, we suggest performing extensive peroxisomal investigations in every patient suspected of
suffering from a peroxisomal disorder, even when the
clinical phenotype is very typical. Table 6 lists a variety
of diagnostic assays that we consider to be indispensable for the diagnostic workup of a patient in whom
either clinical or biochemical findings warrant investigation for peroxisomal disorder. We want to emphasize
the diagnostic usefulness of pipecolic acid measured on
routine amino acid chromatography, which led to suspicion of peroxisomal disorder in 5 of our patients.
This study was supported by grants from the M. & W. Lichtenstein
Stiftung, the Freie Akademische Gesellschaft, Basel, Switzerland (to
M.B.); and the BIOMED 2 program “Concerted Action on Peroxisomal Leukodystrophy,” BMH 4-CT 96.162 1 .
We are grateful to Profs Lacombe (Bordeaux), Bonneau (Poitiers),
Joannard (Grenoble), Hautecoeur (Lille), and Nuyts (Lille), all in
France, for referring their patients to our center.
References
1 . Goldfischer SL, Moore CL, Johnson AB, et al. Peroxisomal and
mitochondrial defects in the cerebro-hepato-renal syndrome.
Science 1973;182:62-64
2. Lazarow PB, Moser HW. Disorders of peroxisomal biogenesis.
In: Scriver CR, Beaudet AL, Sly WS, Valle DE, eds. The metabolic and molecular basis of inherited disease, 7th ed. New
York: McGraw-Hill, 1995:2287-2324
3. Opitz JM, Zu Rhein GM, Vitale L, et al. The Zellweger syndrome (cerebrohepatorenal syndrome). Birth Defects 1969;5:
144-158
4. Kelley RI, Datta NS, Dobyns WB, et al. Neonatal
adrenoleukodystrophy: new cases, biochemical studies and differentiation from Zellweger and related polydystrophy syndromes. Am J Med Genet 1986;23:869-901
5. Scotto JM, Hadchouel M, Odihvre M, et al. Infantile phyranic
acid storage disease, a possible variant of Refsum’s disease: three
cases, including ultrastructural studies of liver. J Inherit Metab
Dis 1982;5:83-90
6. Poll-The BT, Saudubray JM, Ogier HAM, et al. Infantile Refsum disease: an inherited peroxisomal disorder. Comparison
with Zellweger syndrome and neonatal adrenoleukodystrophy.
Eur J Pediatr 1987;146:477-483
7 . Heymans HSA, Oorthuys JWE, Nelck G, et al. Rhizomelic
chondrodysplasia punctata: another peroxisomal disorder.
N Engl J Med 1985;313:187-188
8. Heikoop JC, Wanders RJA, Strijland A, et al. Genetic and biochemical heterogeneity in patients with the rhizomelic form of
chondrodysplasia punctata-a
complementation study. Hum
Genet 1992;89:439-444
9. Hoefler G, Hoefler S, Watkins PA, et al. Biochemical abnormalities in rhizomelic chondrodysplasia punctata. J Pediatr
1988;1 12:726-733
10. Jansen GA, Mihalik SJ, Watkins PA, et al. Phytanoyl-CoA hydroxylase is not only deficient in classical Refsum disease but
also in rhizomelic chondrodysplasia punctata. J Inherit Metab
Dis 1997;20:444-446
1 1 . Wanders RJA, Schuhmacher H, Heikoop J, et al. Human dihydroxyaceronephosphate acyltransferase deficiency: a new peroxisomal disorder. J Inherit Metab Dis 1992;15:389-391
12. Wanders RJA, Decker C, Hovarth VAP, et al. Human alkyldihydroxyacetonephosphatesynthase deficiency: a new peroxisomal disorder. J Inherit Metab Dis 1994;17:315-318
13. Shimozawa N, Suzuki Y, Orii T , et al. Standardization of
complementation grouping of peroxisome-deficient disorders
and the second Zellweger patient with peroxisome assembly
factor-I (PAF-I) defect. Am J Hum Genet 1993;52:843-844
14. Moser AB, Rasmussen M, Naidu S, et al. Phenotype
. _ of -patients
with peroxisomal disorders subdivided into sixteen complementation groups. J Pediatr 1995;127:13-22
15. Tranchant C, Aubourg P, Mohr M, et al. A new peroxisomal
disease with impaired phytanic and pipecolic acid oxidation.
Neurology 1993;43:2044-2048
16. Poll-The BT, Roels F, Ogier H, et al. A new peroxisomal disorder with enlarged peroxisomes and a specific deficiency of
acyl-CoA oxidase (pseudo-neonatal adrenoleukodystrophy).
Am J Hum Genet 1988;42:422-434
17. Roels F, Pauwels M, Poll-The BT, et al. Hepatic peroxisomes
in adrenoleukodystrophy and related syndromes: cytochemical
and morphometric data. Virchows Arch 1988;413:275-285
18. Poll-The BT, Maroteaux P, Narcy C, et al. A new type of
chondrodysplasia puncrata associated with peroxisomal dysfunction. J Inherit Metab Dis 1991;14:361-363
19. Rods F, Cornelis A, Poll-The BT, et al. Hepatic peroxisomes
are deficient in infantile Refsum disease: a cytochemical study
of 4 cases. Am J Med Genet 1986;25:257-271
20. Martinez M, Vasquez E. MRI evidence that docosahexaenoic
Baumgartner et al: Clinical Approach to Peroxisomal Disorders 729
acid ethyl ester improves myelination in generalized peroxisoma1 disorders. Neurology 1998;51:26-32
21. Espeel M, Mandel H, Poggi F, et al. Peroxisome mosaicism in
the livers of peroxisomal deficiency patients. Hepatology 1995;
22:497-504
22. Saudubray JM, Hautecoeur P, Krystkowiak P, et al. A new peroxisomal assembly defect presenting as pseudo Charcot Marie
Tooth disease. Abstracts of the 35th SSIEM symposium. J Inherit Metab Dis 1997;2O(Suppl 1):70 (Abstract)
23. Verhoeven NM, Kulik W, van den Heuvel CMM, Jakobs C.
Pre- and postnatal diagnosis of peroxisomal disorders using
stable-isotope dilution gas chromatography-mass spectrometry.
J Inherit Metab Dis 1995;18(Suppl 1):45-60
24. Martinez M, Mougan I, Roig M, Ballabriga A. Blood polyunsaturated fatty acids in patients with peroxisomal fatty acid disorders. A multicenter study. Lipids 1994;29:273-280
25. Lepage G, Roy CC. Direct transesterification of all classes of
lipids in one reaction. J Lipid Res 1986;27:114-120
26. Wanders RJA, Denis R, Ruiter JPN, et al. Measurement of peroxisomal fatty acid P-oxidation in cultured human skin fibroblasts. J Inherit Metab Dis 1995;18(Suppl 1):113-124
27. Wanders RJA, Ofman R, Romeijn GJ, et al. Measurement of
dihydroxyacetonephosphate acyltransferase (DHAPAT) in chorionic villous samples, blood cells and cultured cells. J Inherit
Metab Dis 1995;18(Suppl 1):90-100
28. Schrakamp G, Schalkwiik CG, Schutgens RBH, et al. Plasmalogen biosynthesis in peroxisomal disorders: fatty alcohol
versus alkylglycerol precursors. J Lipid Res 1988;29:325-334
29. Wanders RJA, Dekker C, Ofman R, et al. Immunoblot analysis
of peroxisomal proteins in liver and fibroblasts from patients.
J Inherit Metab Dis 1995;18(Suppl 1):lOl-112
30. Roels F, de Prest B, de Pestel G. Liver and chorion cytochemistry. J Inherit Metab Dis 1995;18(Suppl 1):155-171
31. Espeel M, van Limbergen G. Immunocytochemical localization
of peroxisomal proteins in liver and kidney. J Inherit Metab Dis
1995;18(Suppl 1):135-1 54
32. Espeel M, Roels F, Giros M, et al. Immunolocalization of a
43kDa peroxisomal membrane protein in the liver of patients
with generalized peroxisomal disorders. Eur J Cell Biol 1995;
67:319-327
33. Kerckaert I, de Craemer D, van Limbergen G. Practical guide
for morphometry of human peroxisomes on electron micrographs. J Inherit Metab Dis 1995;18(Suppl 1):172-180
34. Watkins PA, Chen WN, Harris CJ, et al. Peroxisomal bifunctional enzyme deficiency. J Clin Invest 1989;83:771-777
35. Roels F, Espeel M, Poggi F, et al. Human liver pathology in
peroxisomal diseases: a review including novel data. Biochimie
1993;75:281-292
36. Naidu S, Hoefler G, Watkins PA, et al. Neonatal seizures and
retardation in a girl with biochemical features of X-linked
adrenoleukodystrophy: a possible new peroxisomal disease entity. Neurology 1988;38:1100-1107
37. Mandel H, Berant M, Aizin A, et al. Zellweger-like phenotype
in two siblings: a defect in peroxisomal @-oxidation with elevated very-long-chain fatty acids but normal bile acids. J Inherit
Metab Dis 1992;15:381-384
38. Christensen E, Anker Pedersen S, Leth H, et al. A new peroxisomal P-oxidation disorder in twin neonates: defective oxidation of both cerotic and pristanic acids. J Inherit Metab Dis
1997;20:658 - 664
39. Roels F, Tytgat T , Beken S, et al. Peroxisome mosaics in the
liver of patients and the regulation of peroxisome expression in
rat hepatocyte cultures. Ann NY Acad Sci 1996;804:502-5 15
I
730 Annals of Neurology Vol 44
No 5
November 1998
40. Schutgens RBH, Wanders RJA, Jakobs C, et al. A new variant
of Zellweger syndrome with normal peroxisomal functions in
cultured fibroblasts. J Inherit Metab Dis 1994;17:319-322
41. Mandel H, Espeel M, Roels F, et al. A new type of peroxisomd
disorder with variable expression in liver and fibroblasts. J Pediatr 1994;125:549-555
42. Aubourg P, Kremser K, Rolland MO, et al. Pseudo infantile
Refsum’s disease: catalase-deficient peroxisomal particles with
partial deficiency of plasmalogen synthesis and oxidation of
fatty acids. Pediatr Res 1993;34:270-276
43. Yajima S, Suzuki Y, Shimozawa N, et al. Complementation
study of peroxisome-deficient disorders by immuno-fluorescence staining and characterization of fused cells. Hum Genet
1992;88:49 1-499
44. Wiemer EA, Out M, Schelen A, et al. Phenotypic heterogeneity
in cultured skin fibroblasts from patients with disorders of peroxisome biogenesis belonging to the same complementation
group. Biochim Biophys Acta 1991;1097:232-237
45. Reuber BE, Germain-Lee E, Collins CS, et al. Mutations in
PEXl are the most common cause of peroxisome biogenesis disorders. Nat Genet 1997;17:445-448
46. Portsteffen H, Beyer A, Becker E, et al. Human PEXl is mutated in complementation group 1 of the peroxisome biogenesis
disorders. Nat Genet 1997;17:449-452
47. Subramani S. Pex genes on the rise. Nat Genet 1997;15:331333
48. Hebestreit H, Wanders RJA, Schutgens RBH, et al. Isolated
dihydroxyacetonephosphate-acyl-transferase deficiency in rhizomelic chondrodysplasia punctata: clinical presentation, metabolic and histological findings. Eur J Pediatr 1996;155:10351039
49. Moser HW, Smith KD, Moser AB. X-linked adrenoleukodystrophy. In: Scriver CR, Beaudet AL, Sly WS, Valle DE, eds.
The metabolic and molecular basis of inherited disease. 7th ed.
New York: McGraw-Hill, 1995:2325-2349
50. Schram AW, Goldfischer S, van Roermund CWT, et al. Human peroxisomal 3-oxoacyl-coenzyme A thiolase deficiency.
Proc Natl Acad Sci USA 1987;84:2494-2496
51. Ten Brink HJ, Wanders RJA, Christensen E, et al. Heterogeneity in di/trihydroxycholestanoicaciduria. Ann Clin Biochem
199431:195-197
52. Hgffmann G, Gibson KM, Brandt IK, et al. Mevalonic aciduria-an inborn error of cholesterol and nonsterol isoprene biosynthesis. N Engl J Med 1986;314:1610-1614
53. Jansen GA, Wanders RJA, Watkins PA, Mihalik SJ. Phytanoylcoenzyme A hydroxylase deficiency-the enzyme defect in Refsum’s disease. N Engl J Med 1997;337:133-134
54. Bennett MJ, Pollitt RJ, Goodman SI, et al. Atypical riboflavinresponsive glutaric aciduria, and deficient peroxisomal glutarylCoA oxidase activity: a new peroxisomal disorder. J Inherit
Metab Dis 1991;14: 165-173
55. Danpure CJ, Jennings PR. Deficiency of peroxisomal alanine:
glyoxylate aminotransferase in primary hyperoxaluria type 1.
FEBS Lett 1986;201:20-24
56. Danpure CJ, Copper PJ, Wise PJ, Jennings PR. An enzyme
trafficking defect in two patients with primary hyperoxaluria
type 1: peroxisomal a1anine:glyoxylate aminotransferase rerouted to mitochondria. J Cell Biol 1989;108:1345-1352
57. Eaton JW, Ma M. Acatalasemia. In: Scriver CR, Beaudet AL,
Sly WS, Valle DE, eds. The metabolic and molecular basis of
inherited disease. 7th ed. New York: McGraw-Hill, 1995:
2371-2383
Документ
Категория
Без категории
Просмотров
5
Размер файла
1 465 Кб
Теги
patients, approach, series, clinical, disorder, peroxisomal, inherited
1/--страниц
Пожаловаться на содержимое документа