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Electronegative Electroretinogram in Mucolipidosis IV
Shan M. Pradhan;
La-Ongsri Atchaneeyasakul, MD;
Binoy Appukuttan, PhD;
Robert N. Mixon, MA;
Trevor J. McFarland;
Andrea M. Billingslea;
David J. Wilson, MD;
J. Timothy Stout, MD, PhD;
Richard G. Weleber, MD
Arch Ophthalmol. 2002;120:45-50.
ABSTRACT
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Objective To demonstrate the progression of electroretinographic (ERG) findings
in mucolipidosis IV.
Methods Two patients with mucolipidosis IV were examined clinically and their
condition was followed up for ophthalmic manifestations of the disease. Electroretinograms
were performed on both patients, and conjunctival biopsy specimens were analyzed
for characteristic ultrastructural inclusion bodies using light and electron
microscopy. Genomic DNA isolated from peripheral blood was screened for 2
major founder mutations in the ML4 gene using polymerase
chain reaction and restriction fragment length polymorphism analyses. Haplotypes
were confirmed by automated sequencing of polymerase chain reaction products.
Results In patient 1, an ERG obtained at 12 months of age showed mildly subnormal
amplitude of rod-mediated and cone-mediated responses and significantly prolonged
rod and cone b-wave implicit times. An ERG obtained when the patient was 6.6
years old disclosed marked progression with greater loss of b-wave than a-wave
responses to rod-and-cone–mediated activity. Scotopic ERG at the highest
intensity was electronegative in configuration. In patient 2, ERG showed minimal
rod-mediated responses, severely subnormal cone-mediated responses, and prolonged
cone b-wave implicit times. Again, electronegative configuration of the scotopic
bright flash response indicated greater disturbance of b-wave generators.
Conclusions Novel ERG findings in 2 cases of mucolipidosis IV are reported with
associated clinical courses, histopathologic abnormality, and genetic studies.
In both cases ERGs demonstrate an electronegative configuration, suggesting
that the primary retinal disturbance in mucolipidosis IV may occur at or proximal
to the photoreceptor terminals.
INTRODUCTION
MUCOLIPIDOSIS IV (MLIV) is an autosomal recessive lysosomal storage
disorder first described by Berman et al1 in
1974. Patients with MLIV usually are examined in the first year of life and
are found to have corneal opacities and severe psychomotor delays; often patients
are mistakenly diagnosed as having cerebral palsy. Other commonly associated
findings include strabismus, retinal degeneration, generalized hypotonia,
recurrent episodic ocular pain and tearing,2
and marked deceleration in physical growth by 2 to 3 years of age. Although
heterogeneity in the clinical features has been observed3
and cases of mild variants have been previously described,4-5
most patients are profoundly affected and exhibit significant neurologic impairment.
Most do not progress beyond a developmental age of 12 to 15 months. Older
patients may show skeletal dysplasia, kyphoscoliosis, and facial dysmorphism.
Organomegaly is absent.
The underlying biochemical defect in MLIV is accumulation of sphingolipids,
phospholipids, and acid mucopolysaccharides in virtually every cell type of
affected individuals. This abnormality, similar to that seen in other mucolipidoses,
appears histologically as intracytoplasmic inclusion bodies visible by transmission
electron microscopy.6-7 Identification
of characteristic fibrillogranular and multilamellar inclusions in conjunctival
biopsy specimens is considered diagnostic of MLIV, and detection in amniocytes
allows for prenatal testing.8
In contrast to what is seen in other lipid-storage disorders, lysosomal
hydrolases involved in the catabolism of the stored molecules are normal.
This finding, along with that of an alteration in movement of endocytic markers
along the lysosomal pathway,9 suggests that
the MLIV phenotype is due to a defect in membrane sorting and/or endocytosis,
rather than an enzyme deficiency.
The gene involved in MLIV has recently been identified10-11
and encodes an integral membrane protein termed "mucolipin." The function
of this protein, which shows homology to a family of calcium ion channels,
has yet to be fully elucidated. Two major founder mutations in the ML4 gene account for 95% of Ashkenazi MLIV
genotypes12: a 6432–base pair deletion
from the 5' end of the gene through exon 6 is the minor haplotype (23%
of Ashkenazi families) and an adenine to guanine transition at the splice-acceptor
site of intron 3 is the major haplotype (72% of Ashkenazi families).11 The splice-site transition in intron 3 introduces
a KpnI restriction site in genomic DNA, useful in
screening for this mutation. More than 80% of the patients with MLIV are of
Ashkenazi Jewish extraction.
An important ophthalmic feature of MLIV is progressive retinal degeneration.13-14 Electrophysiologic studies in affected
children have established the functional deterioration, with mildly subnormal
electroretinogram (ERG) recordings that become nearly flat, with indistinguishable
components, approximately a decade later.15
Thus, previous reports have described diffuse retinal impairment in patients
with MLIV.15 The present study documents an
ERG configuration that suggests the location of the primary retinal disturbance.
PATIENTS AND METHODS
We reviewed the medical records of and examined 2 patients, both referred
for evaluation of possible storage disease. The first patient was examined
at 12 months and 6.6 years of age; the second patient was examined at 7.9
years of age. Each patient was seen with a combination of medical history,
medical findings, and abnormal lysosomal function test results suggestive
of MLIV. Informed consent was obtained from parents or legal guardians of
the participating minors. Permission was given for the frontal face photograph
for patient 1.
HISTOPATHOLOGIC FEATURES
Conjunctival biopsy specimens were fixed in modified Karnovsky electron
microscope fixative and postfixed in osmium tetroxide. Specimens were en bloc
Kellenberger uranyl acetate stained, dehydrated in acetone and propylene oxide,
and embedded in Eponate 12–Araldite 502 (Ted Pella Inc, Redding, Calif)
resin. After 1-µm-thick light microscope sections were reviewed, blocks
were thin-sectioned, stained with uranyl acetate–lead citrate, and examined
on an electron microscope (CX2; JEOL, Tokyo, Japan) for the presence of characteristic
lysosomal inclusions.
ERG RECORDINGS
Electroretinograms were performed using either oral chloral hydrate
(100 mg/kg) or intravenous propofol sedation, using previously described techniques
that included responses conforming to the International Society for Clinical
Electrophysiology of Vision standard protocol.16-18
Additional responses were collected scotopically to a red light stimulus balanced
to the scotopic blue stimulus used to elicit rod responses. This allowed separation
of dark-adapted cone and rod–mediated function within the same flash.
The 30-Hz flicker responses were collected, with and without rod-suppressing
background illumination.
MOLECULAR METHODS
Genomic DNA was isolated from peripheral blood using a commercially
available blood mini kit (Qiaamp; Qiagen Inc, Valencia, Calif). Polymerase
chain reactions (PCRs) were carried out using primers previously listed by
Sun et al,19 and dimethylsulfoxide was added
to each reaction mix to a final concentration of 4%. Polymerase chain reaction
cycling conditions were as follows: 95°C for 5 minutes; 35 cycles with
1 minute at 95°C, 1 minute at 58°C, and 1 minute at 72°C; and
a final extension at 72°C for 10 minutes. Products were separated by size
and visualized using 1% agarose gel electrophoresis, and bands were excised
and purified using a commerically available gel extraction kit (Qiaquick;
Qiagen Inc). KpnI digestion was carried out at 37°C
for 3 hours followed by 2% agarose gel analysis. The PCR products were cycle
sequenced using dye terminator chemistry and an ABI 310 genetic analyzer (Perkin
Elmer Biosystems, Foster City, Calif). Sequences were aligned to wild-type
sequence using Sequence Navigator software (Perkin Elmer Biosystems).
RESULTS
PATIENT 1
This patient is the third-born female child of Ashkenazi Jewish parents.
Pregnancy and delivery were unremarkable; birth weight equaled 15.8 kg and
Apgar scores were normal. Some degree of hypoglycemia was present during the
neonate period. When the patient was 6 months old, hypotonia and delayed developmental
milestones were first noted, and at 9 months old the patient's mother observed
corneal haze. The patient was examined at age 12 months when her developmental
age was equal to 4.5 months. Length, weight, and head circumference were between
the 10th and 25th percentile, and epicanthal folds and corneal epithelial
haze were noted. Fundus detail could not be visualized owing to the corneal
opacity.
The ERG obtained when the patient was 12 months old (Figure 1A) showed mildly subnormal rod and cone–mediated b-wave
responses with prolonged b-wave implicit times. Compared with age-adjusted
mean normal values for 0.6- to 1.9-year-olds (n = 10), the rod b-wave amplitude
was 66% of normal values (171 µV vs 260 µV, respectively). For
the bright white stimulus, the scotopic a wave was normal (188 µV vs
178 µV [normal mean, 178 µV]), but the b wave was mildly subnormal
at 68% of normal mean (270 µV vs 394 µV). The photoreceptor a-wave
amplitudes mediated by cones were normal for dark-adapted cone-mediated responses
(40 µV vs 38 µV [normal mean, 38 µV]) and light-adapted
cone-mediated responses (35 µV vs 41 µV [normal mean, 41 µV]).
The scotopic cone x wave to red flash was subnormal at 42% of normal mean
(80 µV vs 192 µV) and the photopic cone b wave was subnormal at
52% of normal mean (71 µV vs 136 µV). Rod and cone b-wave implicit
times were markedly prolonged. Cone flicker timing without background was
significantly prolonged. These findings were characterized as consistent with
either early retinal dystrophy or developmental delay, with responses that
would have been normal at the age of 2 to 3 months. Abundant granular and
multimembranous cytoplasmic inclusions, typical of MLIV, were seen using transmission
electron microscopy (Figure 2A).
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Figure 1. A, Electroretinogram (ERG) for
patient 1 at 12 months of age compared with the ERG of a child whose amplitudes
are strongly normal for early childhood (see the "Patient 1" subsection of
the "Results" section for comparison to age-adjusted means). The responses
for the patient are mildly to moderately subnormal for corneal positive peaks
with prolonged rod and cone b-wave implicit times and markedly subnormal oscillatory
potentials. The study was initially interpreted as consistent with either
early retinal dystrophy or delayed retinal development. OPs indicates oscillatory
potentials; cd candela. B, An ERG for patient 1 at 6.6 years and patient 2
(see the "Patient 2" subsection of the "Results" section for comparison to
age-adjusted means) at 7.9 years compared with an age-matched healthy child
with normal responses. Note subnormal cone flash and flicker ERGs with prolonged
b-wave implicit times, severe loss of oscillatory potentials, electronegative
configuration of scotopic bright flash response, minimal response of dark-adapted
rods to blue light stimuli, and severely subnormal response of dark-adapted
cones to red light stimuli.
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Figure 2. Conjunctival biopsy specimens.
A, Patient 1. Electron micrograph demonstrating characteristic granular (asterisks)
and multilamellar inclusions (arrows) (original magnification x21 000).
B, Patient 2. Light microscopy showing multiple large vacuoles (arrow) within
conjunctival epithelium. C, Patient 2. Transmission electron microscopy shows
abundant intracytoplasmic multilamellar inclusion bodies (arrows) lying beneath
the basal body (original magnification x42 000).
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On follow-up examination, the patient had had recurrent episodes of
eye pain and redness thought to be due to corneal erosion. No fluorescein
staining was visible on a second ophthalmic examination. Visual acuity by
Teller cards at the age of 16 months was 20/200 OD and 20/150 OS. At the age
of 2.5 years visual acuity was 20/300 OD and 20/200 OS. The examiner (R.G.W.)
noted that visual acuity was better than that anticipated based on the obscured
fundal view. At the age of 5.5 years visual acuity was 20/190 OD and 20/470
OS.
At age 6.6 years the patient was reexamined. Medications at this time
included carbamazepine for possible seizures and benztropine mesylate for
drooling. Her cognitive function was at the 11.5-month age level, gross motor
function at the 7-month age level, and fine motor function at the 9-month
age level. She was able to make some sounds and somewhat able to express her
feelings but said no words. The patient exhibited hypotonia of the facial
musculature (Figure 3A), alternate
exotropia, poor muscle tone, ataxia, and had been fed by gastrostomy tube
for 3 years. Fixation was central and steady in each eye. Pupils responded
normally. Intraocular pressures were 16 to 20 mm Hg OD and 20 mm Hg OS. Biomicroscopy
revealed generalized corneal cloudiness (Figure 3B) with a ground-glass appearance and clear anterior chambers
and lenses. The fundus view was obscured bilaterally and only blurred optic
discs and posterior poles were seen. An ERG done under propofol sedation showed
marked further loss of responses to rod and cone–mediated activity (Figure 1B). Compared with age-adjusted normal
values for 10-year-olds, the rod b-wave amplitude was 2% of normal (9 µV
vs 465 µV). The scotopic ERG at the highest intensity was electronegative
in configuration. The scotopic a wave to the bright white stimulus was 18%
of the normal mean (57 µV vs 314 µV), but the b wave was only
3% of the normal mean (19 µV vs 652 µV). The photoreceptor responses
mediated by cones, as represented by the a waves, were 30% of the normal mean
(17 µV vs 56 µV) for dark-adapted cone-mediated responses and
81% of normal mean (38 µV vs 48 µV) for light-adapted cone-mediated
responses. The scotopic cone x wave to red flash was 6% of normal mean (20
µV vs 310 µV) and the photopic cone b wave was 17% of normal mean
(45 µV vs 263 µV). Implicit times were markedly prolonged. Thus,
the ERG documented progressive loss of retinal function, predominantly involving
loss of the b wave, suggesting the retinal insult responsible for this finding
may be at the photoreceptor terminals, bipolar cells, or Müller cells.
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Figure 3. Patient 1, aged 6.6 years old.
A, Facial appearance showing hypotonia and cloudy cornea. B, Cornea showing
cloudiness.
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Polymerase chain reaction and restriction fragment length polymorphism
analyses generated DNA fragments of the size expected with the splice-acceptor
site mutation within intron 3 of the ML4 gene (Figure 4A). Sequencing of PCR products confirmed
the presence of the adenine to guanine transition resulting in the introduction
of a KpnI site and, hence, the presence of the major
haplotype in this individual (Figure 4B).
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Figure 4. Determination of the presence
of the major haplotype in patient 1. A, KpnI digest
of a 571–base pair (bp) polymerase chain reaction fragment encompassing
exons 3 and 4 of the ML4 gene for patient 1 (individual
III) and immediate family members. After digestion, the parents show 571-bp,
360-bp, and 211-bp bands indicating that they are heterozygous for the acceptor
splice-site mutation, as is the case for the siblings of the patient. The
patient is homozygous for the mutation. B, Sequencing confirmation of the
splice site adenine to guanine transition.
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PATIENT 2
This patient is the female child of Mexican-American first cousins.
She is severely developmentally delayed and has cerebral palsy with quadriparesis.
Physical growth is delayed. Visual impairment was first noted when the patient
was 3 years old and her condition has worsened since she was 6 years old.
She is partially deaf.
On physical examination at the age of 7.9 years, the patient could briefly
fix, but not follow, a light. Esotropia was noted; the patient did not alternate
and fixated with the left eye. Dilated pupil red reflex was dull. On biomicroscopy,
the anterior one fifth of each cornea was markedly cloudy and lenses appeared
minimally cataractous. A view of the fundus commensurate with 20/100 visual
acuity was present bilaterally and showed pink discs, attenuated vessels,
and fine pigment granularity peripherally.
An ERG showed minimal rod-mediated responses and severely subnormal
cone-mediated responses with prolonged cone b-wave implicit times (Figure 1B). Electronegative configuration
of the scotopic bright flash response indicated greater disturbance of b-wave
than a-wave responses, though both were significantly abnormal. Thus, the
ERG predominately documented loss of the b wave, suggesting the retinal insult
may be at the photoreceptor terminals, bipolar cells, or Müller cells.
Microscopic examination of 1-µm-thick plastic sections of the
biopsy specimen revealed large vacuoles within epithelial cells (Figure 2B). Transmission electron microscopy
of the conjunctival biopsy specimen revealed abundant multilamellar inclusions,
typical of MLIV (Figure 2C). Inclusions
were noted in endothelial and epithelial cells.
COMMENT
There have been few reports to date characterizing the retinal changes
associated with MLIV. Histopathologic studies have demonstrated disorganized
and severely atrophic retina with marked loss of photoreceptors and ganglion
cells.13 The ERGs described5, 14-15
have shown diffuse retinal disease or progressive rod-cone impairment similar
to that seen in more common forms of retinal dystrophy, with initially subnormal
responses that later become undetectable. In the present study, ERGs for patients
1 and 2 showed electronegative responses to the scotopic bright light flash,
indicating greater disturbance of photoreceptor inner segments and middle
retinal neurons than photoreceptor outer segments. The ERGs for patient 1
also demonstrated progressive disturbance at or proximal to the photoreceptor
terminals. These findings differ from the configuration seen in most nonsyndromal
retinal dystrophies that show primary involvement of photoreceptor outer segments.
However, rarely retinitis pigmentosa will show an electronegative ERG configuration
suggesting dysfunction not only at the level of the photoreceptor outer segment
but also at or proximal to the photoreceptor terminal region.20
The ERG recordings are helpful in confirming the diagnosis of and monitoring
the progression of many disorders involving the retina, including metabolic
diseases such as the mucopolysaccharidoses and various forms of lipopigment-storage
disorders.21 In mucopolysaccharidoses such
as Hurler, Sanfilippo, and Scheie syndromes, ERG amplitudes can vary from
subnormal to nondetectable. Other systemic disorders with retinal and neurologic
degeneration feature electronegative ERGs, suggesting greater involvement
of proximal photoreceptors, bipolar cells, or other middle retinal neurons.
Infantile Refsum disease, a disorder of peroxisomal biogenesis, is associated
with an electronegative ERG.22-23
The neuronal ceroid lipofuscinoses, particularly infantile neuronal ceroid
lipofuscinosis and juvenile neuronal ceroid lipofuscinosis, also show electronegative
ERGs.24 Thus, MLIV can be added to the growing
list of disorders associated with an electronegative ERG configuration.25
CONCLUSIONS
This article demonstrates electronegative ERG responses to the scotopic
bright flash in patients with MLIV, suggesting that the primary retinal disturbance
resides within proximal photoreceptors, bipolar cells, or other middle retinal
neurons. Suggestions for the function of the ML4
gene product include involvement in sorting and/or transport along the late
endocytic pathway and a role as a novel ion channel protein; thus, the presumed
defect could interfere with vesicular transport or other functions necessary
for the integrity and maintenance of photoreceptor inner segment–bipolar
cell synaptic connections.
AUTHOR INFORMATION
Accepted for publication September 19, 2001.
This work was supported in part by a center grant from the Foundation
Fighting Blindness, Hunt Valley, Md (Dr Weleber and Ms Billingslea); the Clayton
Foundation for Research and the Casey Eye Institute (Dr Stout); and by unrestricted
funds from Research to Prevent Blindness Inc, New York, NY (Drs Weleber and
Wilson).
Mr Pradhan and Dr Atchaneeyasakul contributed equally to this work.
Corresponding author: Richard G. Weleber MD, Casey Eye Institute,
Oregon Health & Science University, 3375 SW Terwilliger Blvd, Portland,
OR 97201-4197 (e-mail: weleberr{at}ohsu.edu).
From the Keck School of Medicine, University of Southern California,
Los Angeles (Ms Pradhan); the Department of Ophthalmology, Siriraj Hospital,
Mahidol University, Bangkok, Thailand (Dr Atchaneeyasakul); Department of
Molecular and Medical Genetics, Oregon Health & Science University (Drs
Stout and Weleber); and the Department of Ophthlmology, Case Eye Institute,
Oregon Health & Science University (Drs Appukuttan, Wilson, Stout, and
Weleber, Messrs Mixon and McFarland, and Ms Billingslea), Portland.
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