Non-verbal deficits in young children with a genetic metabolic disorder: WPPSI-III performance in cystinosis.
ABSTRACT Cystinosis is a recessive genetic metabolic disorder in which the amino acid cystine accumulates in various organs of the body. Previous studies have demonstrated visuospatial dysfunction in children and adults with this disorder. It is not known whether this is a result of the genetic alteration or an accumulation of cystine in the brain over time. This study investigated patterns of performance in 20 young children with cystinosis (4-7 years) and 20 matched controls on the Wechsler Preschool and Primary Scale of Intelligence-Third Edition (WPPSI-III). The children with cystinosis had a mean Full Scale IQ at the low end of the average range. Their overall cognitive functioning was comprised of average verbal abilities, low average non-verbal abilities, and low average processing speed. Multivariate analyses indicated that the cystinosis and control groups were not significantly different on the verbal subtests. In contrast, the cystinosis group performed significantly more poorly than controls on the performance and processing speed subtests. Although overall intellectual function was in the normal range, young children with cystinosis demonstrated a discrepancy such that non-verbal abilities were poorer relative to verbal abilities. This pattern resembles the cognitive profile found previously in older individuals with cystinosis and indicates that the specific cognitive profile emerges early in development. These findings suggest that the cognitive dysfunction in cystinosis is not merely the result of cystine accumulation over time but may be related to differences in brain development as a consequence of alterations or deletions of the cystinosin gene.
- SourceAvailable from: cystinosis.org[show abstract] [hide abstract]
ABSTRACT: Infantile nephropathic cystinosis is a genetic metabolic disorder in which the amino acid cystine accumulates in various organs, including the kidney, cornea, thyroid, and brain. Despite normal intellect, individuals with cystinosis may have specific impairments in the processing of visual information. To examine further the specific types of deficits in visual processing found in individuals with cystinosis, we administered the Development Test of Visual-motor Integration to 26 children with cystinosis (4 to 16 yr. old) and 26 matched controls. The cystinosis group achieved a significantly lower standard score, raw score, and mean ceiling than did the control group. Qualitative analyses showed that in the cystinosis group, size within errors and rotation errors were more prevalent than in the control group. Correlational analyses showed that with advancing age, the cystinosis subjects tended to fall further behind their chronological age. Our data, together with the findings of previous studies, suggest that the visuospatial difficulties in children with cystinosis may be due to inadequate perception or processing of visually presented information. Furthermore, the increasing discrepancy with age may reflect a progressive cognitive impairment, possibly as a result of cystine accumulation in the brain over time.Perceptual and Motor Skills 03/1996; 82(1):67-75. · 0.49 Impact Factor
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ABSTRACT: The central nervous system has been considered to be uninvolved in nephropathic cystinosis. Survival into adulthood, following renal dialysis and transplantation, has brought attention to the sequelae of long-standing cystinosis. We examined 14 patients with cystinosis, 12 of whom had undergone renal transplantation. Two patients had neurologic symptoms. One patient had progressive bradykinesia, dementia, and spasticity with computed tomographic scan evidence of cerebral atrophy and multifocal mineralization in bilateral internal capsules and periventricular white matter. One patient had behavioral and, to a lesser extent, cognitive disturbance and computed tomographic scan evidence of marked, progressive cerebral atrophy. Although the remaining patients had normal results of neurologic examinations, 11 had roentgenographic evidence of generalized cerebral atrophy; 2 of these had abnormal electroencephalograms, 1 had borderline-deficient intellectual function, and 2 had computed tomographic scan evidence of multifocal, intracerebral mineralization. The patients with nervous system abnormalities were not distinguished by patterns of medication use, demographic or laboratory features, or the relative severity of cystinosis. Although the neurologic involvement in these patients suggests that cystinosis may eventually involve the central nervous system, the differential diagnosis must include other complications from renal failure, dialysis, and immunosuppression.JAMA Neurology 06/1989; 46(5):543-8. · 7.58 Impact Factor
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ABSTRACT: Peroxidase-positive astrocytic inclusions, derived from effete, iron-laden mitochondria, accumulate in the rat hippocampus, striatum and other subcortical brain regions as a function of advancing age. The sulfhydryl agent, cysteamine (CSH), accelerates the appearance of this senescent glial phenotype both in primary astrocyte cultures and in the aging subcortical brain in situ. Earlier experiments have shown that short-term administration of CSH results in reversible depletion of brain somatostatin (SS) levels, cognitive deficits and decreases in locomotor activity. In the present study, we tested spatial learning/memory and motor functioning in rats at 4-5 weeks following cessation of chronic (6 week) CSH treatment to determine whether behavioral deficits may be associated with gliopathic changes within the dorsal hippocampus distinct from the behavioral abnormalities accruing to the immediate effects of the drug. CSH-treated rats displayed significantly impaired performance in the Morris water maze 4-5 weeks following termination of prolonged CSH treatment. In contrast, locomotor activity was not affected in this experimental paradigm. CSH-treated animals exhibited significantly higher numbers of peroxidase-positive astrocyte granules as well as total numbers of GFAP-positive astrocytes in the CA1 sector of the dorsal hippocampus relative to saline-treated controls. In the hilus of the dentate gyrus, numbers of both peroxidase-positive glial inclusions and astrocytes were unaffected by CSH exposure. At 5 weeks following cessation of CSH treatment, SS levels in the hippocampus and hypothalamus (but not cerebral cortex) were elevated relative to those of saline-treated controls. Our results indicate that chronic CSH exposure induces senescence-like changes in CA1 astrocytes which are associated with deficits in cognitive, but not locomotor, behavior and elevated levels of hippocampal and hypothalamic SS. Pathological glial-neuronal interactions within the hippocampus and other subcortical brain regions may play an important role in the cognitive decline observed during normal senescence and in aging-related neurodegenerative disorders.Brain Research 07/1997; 761(1):127-34. · 2.88 Impact Factor
American Journal of Medical Genetics Part B (Neuropsychiatric Genetics) 144B:444–447 (2007)
Non-Verbal Deficits in Young Children With a Genetic
Metabolic Disorder: WPPSI-III Performance in Cystinosis
Amy M. Spilkin,1* Angela O. Ballantyne,1Lynne R. Babchuck,1and Doris A. Trauner1,2
1Department of Neurosciences, School of Medicine, University of California, San Diego, La Jolla, California
2Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, California
disorder in which the amino acid cystine accu-
mulates in various organs of the body. Previous
studies have demonstrated visuospatial dysfunc-
tion in children and adults with this disorder.
It is not known whether this is a result of the
genetic alteration or an accumulation of cystine
in the brain over time. This study investigated
patterns of performance in 20 young children
with cystinosis (4–7 years) and 20 matched
controls on the Wechsler Preschool and Primary
Scale of Intelligence-Third Edition (WPPSI-III).
The children with cystinosis had a mean Full
Scale IQ at the low end of the average range.
Their overall cognitive functioning was com-
prised of average verbal abilities, low average
non-verbal abilities, and low average processing
the cystinosis and control groups were not
significantly different on the verbal subtests.
In contrast, the cystinosis group performed
significantly more poorly than controls on the
performance and processing speed subtests.
Although overall intellectual function was in
demonstrated a discrepancy such that non-
verbal abilities were poorer relative to verbal
abilities. This pattern resembles the cognitive
profile found previously in older individuals
with cystinosis and indicates that the specific
cognitive profile emerges early in development.
These findings suggest that the cognitive dys-
function in cystinosis is not merely the result
of cystine accumulation over time but may be
related to differences in brain development as
a consequence of alterations or deletions of the
? 2007 Wiley-Liss, Inc.
KEY WORDS:cystinosis; IQ; visuospatial; brain
Please cite this article as follows: Spilkin AM, Ballan-
tyne AO, Babchuck LR, Trauner DA. 2007. Non-Verbal
Deficits in Young Children With a Genetic Metabolic
Disorder: WPPSI-III Performance in Cystinosis. Am J
Med Genet Part B 144B:444–447.
Infantile nephropathic cystinosis is a rare autosomal
in the lysosomes. The organ affected most severely early in life
is the kidney, but most other organs are affected as well [Gahl
et al., 2001]. Neuroimaging and neuropathological studies of
system (CNS) involvement, including cerebral atrophy, white
matter necrosis, patchy demyelination, and brain cystine
accumulation [Ehrich et al., 1979; Levine and Paparo, 1982;
Ross et al., 1982; Cochat et al., 1986; Gahl and Kaiser-Kupfer,
1987; Jonas et al., 1987; Fink et al., 1989; Nichols et al., 1990;
Vogel et al., 1990].
Studies examining cognitive functioning in individuals with
cystinosis have shown overall intelligence within the normal
range as well as average performance in the areas of language
and auditory processing [Nichols et al., 1990]. In contrast,
individuals with cystinosis perform more poorly than controls
on tests of visual memory [Trauner et al., 1988] and visual-
motor integration [Scarvie et al., 1996]. Recent studies have
demonstrated specific deficits in visuospatial functioning,
whereas visual perceptual skills remain intact [Ballantyne
and Trauner, 2000].
Although global intellectual function is within the normal
range [Fink et al., 1989], IQ is lower than would be predicted
Academically, individuals with cystinosis exhibit poorer
performance than comparison groups on arithmetic and
spelling [Williams et al., 1994; Ballantyne et al., 1997].
There are at least two potential mechanisms that might
explain the previously observed cognitive profile. The under-
lying gene mutation might exert an adverse effect on early
brain development, resulting in neural changes that could
account for differences in cognitive functioning. In this
instance, one would expect the cognitive deficits to be present
progressive accumulation of cystine within the brain during
childhood could lead to cognitive impairments. If this hypoth-
esis were correct, one would anticipate that these children
would demonstrate no or mild cognitive differences early in
life, with progressive worsening over time.
To begin to elucidate the potential mechanism of cognitive
impairment in cystinosis, the current study examined cogni-
tive functioning in a very young group of children. The aim of
the current study was to determine whether the cognitive
profile previously found in school-age children and adults
with cystinosis is present in young children. We examined
results from the Wechsler Preschool and Primary Scale of
Grant sponsor: National Institutes of Health; Grant number:
*Correspondence to: Amy M. Spilkin, Ph.D., Department of
Neurosciences, University of California, San Diego, 9500 Gilman
Dr., #0935, La Jolla, CA 92093-0935.
Received 19 May 2006; Accepted 28 August 2006
? 2007 Wiley-Liss, Inc.
Intelligence-Third Edition (WPPSI-III) [Wechsler, 2002]. It
was hypothesized that children with cystinosis would exhibit
verbal and overall intellectual abilities (VIQ and FSIQ) in the
normal range, with relative deficits in performance IQ (PIQ)
because many of the non-verbal tasks on the PIQ scale involve
Participants were 20 children with cystinosis (mean age
5 years 0 months, range 4-0 to 7-0) and 20 typically developing
control subjects (mean age 5 years 5 months, range 4-0 to 7-1).
Participants with cystinosis were diagnosed by a nephrologist
or metabolic disorders specialist based on clinical history
and laboratory confirmation (i.e., elevated leukocyte cystine
levels). Individuals with cystinosis were excluded from the
study if they had impaired vision, had uncorrected thyroid
problems, or were in renal failure. All children in the study
were taking cysteamine (Cystagon) at the time of testing. The
dose range reported was 50–60 mg/kg/day in four equally
supplements as well. In addition, there were a number of
medications reportedly being taken by some of the children in
3); esomephrazole (Nexium; 3); metoclopramide (Reglan; 3);
lansoprazole (Prevacid; 2); growth hormone replacement
therapy (2); indomethacin (1); Singulair (1); lisinopril (1);
chlorothiazide (1); and dihydrotachysterol (DHT; 1). We were
unable to obtain laboratory testing on all of the children in the
study. Parents reported, however, that their children had
good balance based on their physicians’ communications with
them. No child was ill or known to have significant renal or
other metabolic dysfunction at the time of the study.
histories and were recruited from the community through
advertisements and physician referrals. All participants were
part of a larger longitudinal study examining brain structure
and cognition in children with cystinosis. Informed consent
was obtained in accordance with UCSD Institutional Review
The WPPSI-III is a commonly used measure of intelligence
in young children ages 2–6 to 7–3 years. It consists of subtests
speed, as well as composite scores that represent Verbal IQ
(VIQ), Performance IQ (PIQ), a Processing Speed Quotient
(PSQ), and Full Scale IQ (FSIQ). The Core subtests of the
WPPSI-III for children ages 4-0 to 7-3 years are: Information,
Matrix Reasoning, and Picture Concepts (Performance Scale),
and Coding (Processing Speed Quotient). Although not a core
subtest for FSIQ, Symbol Search was also administered
allowing the computation of the Processing Speed Quotient.
Each subtest has a mean score of 10?3, and the composite
scores of VIQ, PIQ, PSQ, and FSIQ have a mean of 100?15.
Between-group (cystinosis vs. control) analyses of VIQ, PIQ,
PSQ, and FSIQ were conducted using independent samples
t-tests. To compare subtest scores between the groups, a
multivariate framework was used. Multivariate Analyses
of Variance (MANOVAs) for the Verbal, Performance, and
Processing Speed subtests were conducted separately. To
further characterize the pattern of performance by the
cystinosis group, all WPPSI-III Composite Scores and subtest
scores were compared to the normative means using one-
Comparison of Cystinosis and Control Groups
Cystinosis and control children were not significantly
orageat testing.Compared toage-andSES-matched controls,
the cystinosis group performed significantly more poorly on
VIQ, PIQ, PSQ, and FSIQ (see Table I). Qualitatively, the
cystinosis group performed in the Average range on VIQ and
FSIQ and in the Low Average range on PIQ and PSQ, whereas
the control group performed in the Average range across all
Multivariate analyses indicated that the cystinosis and
control groups were not significantly different on the WPPSI-
III verbal subtests (Table II). In contrast, the cystinosis group
performedsignificantly morepoorly thandidthecontrolgroup
Follow-up analyses revealed that on the subtests of Block
Design, Matrix Reasoning, Symbol Search, and Coding, the
cystinosis group performed significantly more poorly than
the control group. The cystinosis group performed in the
Average range on the verbal subtests and in the Low Average
range on the performance and processing speed subtests (with
the exception of Picture Concepts).
Comparison of Cystinosis Group to Normative Mean
In the cystinosis group, VIQ was not significantly different
from the normative mean, whereas PIQ, PSQ, and FSIQ fell
significantly below the mean. Similarly, children with cysti-
nosis did not score significantly below the normative mean on
anyofthe verbal subtests, but didscore significantly below the
mean on all of the non-verbal and processing speed subtests,
with the exception of Picture Concepts.
functioning in a young group of children with cystinosis in
TABLE I. Mean WPPSI-III Verbal IQ, Performance IQ, Processing Speed Quotient, and Full Scale IQ, Significance Values, and
Qualitative Descriptions for the Cystinosis and Control Groups
Processing Speed Quotient
Full Scale IQ
Non-Verbal Deficits in Cystinosis 445
order to help define the mechanism of impairment previously
observed in older children and adults with cystinosis. Our
(ages 4–7 years) have a mean IQ at the low end of the average
range, which is lower than would be expected compared to
age- and SES-matched controls. This result is a composite of
average verbal abilities, low average non-verbal abilities, and
low average processing speed. The lower than expected Full
ScaleIQislargely theresult oflowPerformance IQ,indicating
that there is a dissociation between verbal and non-verbal
abilities. This pattern replicates, in a much younger group
of children, findings from older children and adults with
cystinosis on other tests of intellectual and cognitive function-
ing [Trauner et al., 1988; Williams et al., 1994; Scarvie et al.,
1996; Ballantyne and Trauner, 2000].
Examination of the WPPSI-III subtests revealed that on the
verbal scale subtests, the cystinosis group performed similarly
to the control group. In contrast, on the subtests that comprise
the performance and processing speed scales, the cystinosis
group performed at a significantly lower level than did
controls, and predominantly in the low average range. The
one performance subtest on which the cystinosis and control
groups performed similarly was Picture Concepts. Examina-
tion of the normative data for the WPPSI-III, however,
demonstrates that Picture Concepts loads more highly on the
verbal factor (factor loading¼0.34) than on the performance
factor (factor loading¼0.22), suggesting a strong verbal
component to the Picture Concepts subtest [Sattler and
Dumont, 2004]. Given the intact verbal abilities of our
cystinosis subjects, one would expect average performance on
To our knowledge, this is the first study of cognitive
performance in such a young group of children with cystinosis.
Our data indicate that even early in life, individuals with
cystinosis are demonstrating the aberrant cognitive profile of
non-verbal deficits against a background of average verbal
on cognitive abilities, and thus possibly on the developing
nervoussystem. Theneurologic basisofthe observed cognitive
profile is unknown, although several possibilities exist. First,
the underlying gene mutation might cause a difference in the
way the brain develops in utero, resulting in differences
in neural or cerebral organization for particular structures
and/or functions. Alternatively, progressive accumulation of
cystine within the brain during infancy and childhood could
lead to the observed cognitive impairments. The results of the
current study suggest that the first hypothesis may be more
cystine-depleting agent, at the time of testing, reducing the
likelihood of significant cystine accumulation in the brain.
Longitudinal studies of cognition in children with cystinosis
will help to further define the likely mechanisms of cognitive
impairment in nephropathic cystinosis. If the cognitive
differences are caused by early changes in brain development,
wewouldexpect the cognitivedifference tobestable overtime.
On the other hand, if the cognitive dysfunction is caused by
accumulation of cystine in the brain, we would expect the
cognitive deficits to worsen over time. These longitudinal
studies are in progress.
There are other factors that might explain the observed
deficits. One is the medications that the children with
cystinosis are taking. All of the children were taking cystea-
mine. Studies have shown that rats injected with cysteamine
show visual memory and locomotor deficits [Fitzgerald and
across many years, however, indicates that individuals with
cystinosis who were never treated with cysteamine show the
et al., 1988]. This argues against cysteamine as the sole cause
of the impairments. The only other consistent therapies were
those involving electrolyte replacements. Most of the other
medications listed were taken by a small percentage of
the children. Thus it is unlikely that the cognitive results
we observed could be caused by one of these medications.
Similarly, the children were in good health with no evidence
of renal failure or severe metabolic dysfunction, making it
unlikely that these might be the explanation for the observed
This study has implications for a greater understanding of
the mechanism of cognitive dysfunction observed in these
individuals. The pattern of cognitive impairment observed in
young children with cystinosis suggests that cystinosis may
have a deleterious neurodevelopmental effect on the brain,
such that even very young children with the disease show the
characteristic cognitive profile. Hence, the timing of the CNS
may reflect some abnormality in brain development, rather
than a long-term cumulative process.
We thank Ms. Jenny Williams for her assistance in the
completion of this project.
TABLE II. WPPSI-III Overall Verbal, Performance, and Processing Speed MANOVA Results, Individual Subtest Means and Standard
Deviations, Significance Values, and Qualitative Descriptions
Multivariate Tests and
Cystinosis (n¼20)Control (n¼20) Cystinosis (n¼20)Control (n¼20)
Processing Speed MANOVA
—, represent subtests for which follow-up analyses were not applicable because the multivariate test was not significant.
446 Spilkin et al.
Ballantyne AO, Trauner DA. 2000. Neurobehavioral consequences of a
genetic metabolic disorder: Visual processing in infantile nephropathic
cystinosis. Neuropsychiatry Neuropsychol Behav Neurol 13(4):254–263.
Ballantyne AO, Scarvie KM, Trauner DA. 1997. Academic achievement in
individuals with infantile nephropathic cystinosis. Am J Med Genet
Cochat P, Drachman R, Gagnadoux M-F, Pariente D, Broyer M. 1986.
Cerebral atrophy and nephropathic cystinosis. Arch Dis Child 61:401–
Ehrich JHH, Stoeppler L, Offner G, Brodehl J. 1979. Evidence for cerebral
involvement in nephropathic cystinosis. Neuropadiatric 10(2):128–137.
Fivush V, Gahl WA. 1989. Neurological complications in long-standing
nephropathic cystinosis. Arch Neurol 46:543–548.
Fitzgerald LW, Dokla CPJ. 1989. Morris water task impairment and
hypoactivity following cysteamine-induced reductions of somatostatin-
like immunoreactivity. Brain Res 505:246–250.
after renal failure. Pediatr Nephrol 1:260–268.
Gahl WA, Thoene JG, Schneider JA. 2001. Cystinosis: A disorder of
lysosomal membrane transport. In: Scriver CR, Beaudet AL, Sly WS,
Valle D, editors. The metabolic and molecular bases of inherited
diseases, 8th edition. New York: McGraw-Hill. pp 5085–5108.
Jonas AJ, Conley SB, Marshall R, Johnson RA, Marks M, Rosenberg H.
1987. Nephropathic cystinosis with central nervous system involve-
ment. Am J Med 83:966–970.
Justino L, Welner SA, Tannenbaum GS, Schipper HM. 1997. Long-term
effects of cysteamine on cognitive and locomotor behavior in rats:
Relationship to hippocampal glial pathology and somatostatin levels.
Brain Res 761:127–134.
Levine S, Paparo G. 1982. Brain lesions in a case of cystinosis. Acta
Nichols S,Press GA, Schneider JA, Trauner DA. 1990. Cortical atrophy and
cognitive performance in infantile nephropathic cystinosis. Pediatr
Ross DL, Strife F, Towbin R, Bove KE. 1982. Nonabsorptive hydro-
cephalus associated with nephropathic cystinosis. Neurology 32:1330–
III Supplement. San Diego, CA: Jerome M. Sattler.
Scarvie KM, Ballantyne AO,Trauner DA.1996. Visuomotorperformance in
children with infantile nephropathic cystinosis. Percept Mot Skills
Trauner DA, Chase C, Scheller J, Katz B, Schneider JA. 1988. Neurological
and cognitive deficits in children with cystinosis. J Pediatr 112(6):912–
Vogel DG, Malekzedah MH, Cornford ME, Schneider JA, Shields WD,
VintersHV. 1990. Central nervoussystem involvement innephropathic
cystinosis. J Neuropathol Exp Neurol 49:591–599.
Wechsler D. 2002. Wechsler Preschool and Primary Scale of Intelligence,
3rd edition (WPPSI-III). San Antonio, TX: Psychological Corporation.
Williams BLH, Schneider JA, Trauner DA.1994. Globalintellectualdeficits
in cystinosis. Am J Med Genet 49:83–87.
Non-Verbal Deficits in Cystinosis447