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Clinical features of carbamyl phosphate synthetase-I deficiency in an adult.

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Clinical Features of
Carbamyl Phosphate
Synthetase-I Deficiency
in an Adult
Gregory Call, MD,* Alan R. Seay, MD,*
Richard Sherry, &ID,?and Ijaz A. Qureshi, PhDS
We describe a woman with CPS-I deficiency diagnosed at 33 years of age. In contrast to other patients
with this disorder, she has had mild, intermittent symptoms throughout life and has never experienced a severe, life-threatening encephalopathy. Results of cranial computed tomography (CT) and cerebral evoked
potential recordings in this patient suggest that longstanding hyperammonemia, o r perhaps other associated metabolic derangements, have adversely affected
central myelin.
Carbamyl phosphate synthetase-I (CPS-I) catalyzes the
first reaction required for the conversion of ammonia tu
urea through the urea cycle. Severe CPS-I deficiency
causes marked hyperammonemia with encephalopathy
in infancy and usually results in death within the first
few months of life. We describe a 33-year-old woman
whose CPS-I activity is less than 5% of normal. She has
had mild, intermittent symptoms throughout life but
has never experienced severe encephalopathy. Although
mildly retarded, she has no major neurological deficits.
Therapy with a low-protein diet, lactulose, and sodium
benzoate has prevented recurrence of hyperammonemia
and symptoms. Cranial computed tomographic scans
demonstrate prominent lucency of cerebral white matter, and cerebral evoked potential recordings indicate
slowed central conduction. These findings suggest that
the metabolic disturbances in this patient may have adversely affected central myelin formation or maintenance. This woman represents, to our knowledge, the
oldest reported patient with CPS-I deficiency, and the
case illustrates the need to consider urea cycle disorders
in the differential diagnosis of intermittent neurological
symptoms regardless of the patient’s age.
Call G, Seay AR, Sherry R, Qureshi IA: Clinical
features of carbamyl phosphate synthetase-I deficiency
in an adult. Ann Neurol 1690-93, 1984
Carbamyl phosphate synthetase-I (CPS-I) is the mitochondrial enzyme required for conversion of ammonia
to carbamyl phosphate, the first reaction in urea
biosynthesis [13]. Congenital deficiency of CPS-I has
been documented in 26 patients 1191, the majority of
whom developed hyperammonemia and severe encephalopathy in infancy. Survival has rarely extended
past 2 years of age.
From the “Departments of Pediatrics and Neurology, Division of
Pediatric Neurology, and the tDepartment of Radiology, University
of Utah School of Medicine, Salt Lake City, UT 84132, and the
$Department of Pediatrics, Hopital Sainte-Justine, University of
Montreal, Montreal, Quebec, H3T lCS, Canada.
Received Aug 23. 1983, and in revised form Dec 28. Accepted for
publication Dec 30, 1983.
Address reprint requests to Dr Call, University of Utah School of
Medicine, Department of Neurology, 30 N Medical Dr, Salt Lake
City, UT 84132.
Case Report and Methods
A 33-year-old woman was born on September 27, 1949,
after an uncomplicated pregnancy and delivery, and weighed
5 pounds 7 ounces at birth. Her neonatal course was uneventful. During the first two years of life, she was seen
frequently in the University of Utah Hospital outpatient department because of intermittent poor weight gain and brief,
self-limited episodes of irritability and vomiting. She did not
require hospitalization, and her illnesses were diagnosed as
mild viral respiratory or gastrointestinal infections. From infancy to adulthood the patient’s head circumference, height,
and weight increased at normal rates, between the 3rd and.
5th percentiles for age. She did not walk until 2 years and did
not talk until 4 years of age. When 13 years old she was
evaluated for mild mental retardation. The results of her
neurological examination were normal, and her EEG showed
slow dominant background rhythm. Her Full-Scale IQ was
At age 17 years she developed a generalized tonic-clonic
seizure disorder, weli controlled by phenytoin. From age 13
to 33 years, the patient experienced occasional episodes of
nausea, vomiting, gait ataxia, and somnolence, some of which
lasted for several days and were triggered by eating large
quantities of meat. The woman has cared for herself with
minimal supervision and has maintained steady employment
for more than 10 years.
The patient’s father died in 1962 at age 42 years of an
undiagnosed central nervous system disorder. Review of his
hospital records suggests that he had viral encephalitis. Serum
levels of ammonia were never measured. The patient‘s
mother had diabetes and died at age 52. In addition, the
patient has a 34-year-old brother who is described as a “siow
learner,” a 16-year-old half-sister (same mother) who is retarded, and a paternal first cousin (male) who is retarded and
institutionalized. These individuals and their medical records
have not been available for evaluation.
Five days before admission, the patient developed
anorexia, nausea, gait ataxia, and lethargy. Physical examination showed normal vital signs. Her weight was 56 kg, height
156 cm, and head circumference 53.5 cm. There were no
dysmorphic features. Cranial nerve, cerebellar, sensory, and
motor functions were normal except for slow rapidalternating movements and a poorly coordinated tandem gait.
Muscle stretch reflexes were 2 + and 3 + throughout, and
plantar reflexes were flexor, bilaterally. The Full-Scale IQ was
The results of the following tests and assays were normal:
complete blood count with differential, platelet count, erythrocyte sedimentation rate, N a + , K + , Cl-, COz, Ca+ +,glu-
In Vitro Activity of Carbamyl Phosphate Synthetase-I
and Ornithine Transcarbamylase
Enzyme Activity
(pmol producdmg proteidhr)
Simultaneous control
Laboratory controls
1.11 0.26
0.59- 1.63
CPS-I = carbamyl phosphate synthetase-I; OTC
ornithine trans-
cose, creatinine, hepatocellular enzymes, bilirubin, albumin,
total protein, prothrombin time, partial thromboplastin
time, carnitine (5.4 p,moYL; normal, 2.3 to 7.0 p,mol/L),
and urinalysis. The blood urea nitrogen level was consistently
low ( 1 to 7 mg/dl). Orotic acid and other organic acids were
not detected in two separate urine samples. The serum level
of ammonia was elevated to 256 pmol/L (normal, 0 to 64
p,mol/L) 1171. Serum amino acid chromatography showed
the following levels: glutamic acid, 663 pmoYL (normal,
1 to 85 pmol/L); alanine, 807 pmol/L (normal, 136 to 440
p,moVL); citrulline, trace (normal, 10 to 30 pmoYL); arginine, trace (normal, 15 to 1 1 5 pmol/L). The remainder of the
amino acid profile was normal.
Six weeks after admission and while the patient was asymptomatic, a percutaneous needle biopsy of the liver was performed. Informed consent was obtained from the patient and
the patient’s sister. The only histopathological change consisted of multiple intracellular vacuoles throughout the tissue
sample, which probably contained fat. CPS-I activity in the
liver biopsy specimen was measured by a modification of the
technique described by Nuzum and Snodgrass { 101 in which
500 units of purified ornithine transcarbamylase (OTC) from
Streptococcus faecalis (Sigma Chemical Co, St. Louis, MO) was
added to each tube to couple the CPS-I reaction to produce
citrulline. OTC activity was determined by the colorimetric
technique of Ceriotti [ 4 ] using a barbital sodium acetate buffer, p H 7.7. Liver protein was assayed by the method of
Lowry and colleagues {8], and enzyme activities were expressed as micromoles of citrulline per milligram of protein
per hour. Livers examined postmortem with known enzyme
activity were used as controls. The Table shows the patient’s
CPS-I and OTC activity levels compared with those in a
simultaneously run control and with the range of normal
enzyme activities measured by the diagnostic laboratory at
Montreal. T h e patient’s O T C activity was normal, but her
CPS-I activity was less than 5% of normal. Because of the
limited amount of tissue, activity of other urea cycle enzymes
could not be measured.
Clinical neurophysiological tests were performed when the
patient was asymptomatic and had a serum ammonia level of
less than 200 p,moUL. The electroencephalogram showed an
abnormally slow dominant rhythm of 6 Hz without focal or
lateralized abnormalities. Nerve conduction velocities (left
median and left peroneal nerves), as well as visual evoked
Contrast-enhanced computed tomographic scan through the lateral ventricles, showing abnormal lucency of the subcortical white
matter (Hounsjield units, 18; normal, 30). The ventricular size,
sulcalpattern, and gray matter density were normal.
potentials (EPs) and brainstem auditory EPs, were normal.
Somatosensory EP recordings produced by stimulation of left
and right median nerves at the wrists showed prolonged interwave latencies between Erb‘s point and the contralateral
parietal area bilaterally (left, 11.6 ms; right, 11.4 ms; normal,
less than 10.7 ms). This finding suggested abnormally slow
central conduction velocities.
A contrast-enhanced C T scan showed diffuse lucency of
the subcortical white matter of both cerebral hemispheres
(Figure). The cortical and deep gray matter, ventricular size,
and sulcal pattern were normal. A follow-up enhanced CT
scan two months after initiation of treatment showed no
change .
The patient’s serum levels of ammonia in the hospital
varied between 100 and 420 pmoYL. When her serum ammonia level reached 200 pmoVL, she developed ataxia,
slurred speech, and giddiness. At higher levels she fell frequently and became somnolent. A low-protein diet (0.75 gmi
kg a day), administration of lactulose (40 mi three times a
day), and intermittent administration of L-arginine hydrochloride ( 5 gm intravenously over one hour) successfully lowered her serum levels of ammonia and prevented symptoms.
After the diagnosis of CPS-I deficiency was confirmed,
sodium benzoate therapy (410 mg/kg a day) was started. The
patient also received oral supplementation with L-arginine
free-base powder (10 gm a day), folate (0.5 mg a day), and
pyridoxine (5.0 mg a day). For the ensuing nine months
Case Report: Call et al: CPS-I Deficiency
on this regimen, the patient has been asymptomatic, with
her serum ammonia levels stabilized between 70 and 100
This patient evidenced symptoms typical of urea cycle
disorders, and the combination of high serum levels of
ammonia, low serum levels of citrulline, and nondetectable urine levels of orotic acid suggested a defect
in carbamyl phosphate synthesis. Assay of urea cycle
enzymes in liver tissue verified CPS-I deficiency.
Compared with previously reported patients with severe CPS-I deficiency, this patient appears unique in
her clinical course and longevity. The vast majority of
patients with CPS-I activity less than 10% of normal
are profoundly affected, with hyperammonemic coma,
recurrent seizures, and secondary ischemic insults to
the brain [6, 12); 80% of these patients die by age 15
months [19]. Survival beyond the first decade has occurred in three other cases [2, 11). One girl, aged 13
years, had severe retardation and neurological deficits
{Z), whereas two sisters evaluated at ages 12 and 18
years had no neurological deficits and Full-scale IQs of
67 [9, 11). These two patients, along with ours, illustrate that mild, intermittent symptoms may exist despite markedly reduced CPS-I activity in vitro. This
disparity suggests that biochemical variants of CPS-I
that possess different in vivo activity may correlate with
the variable clinical expressions that have been observed.
Therapy directed at lowering ammonia load and at
enhancing ammonia excretion as hippurate by administration of sodium benzoate [l] has succeeded in preventing recurrent hyperammonemia and symptoms
without causing any adverse side effects.
CT scan findings in patients with CPS-I deficiency
have ranged from normal to abnormally enlarged ventricles, widened sulci, and diffuse edema [IS}. Some of
these changes probably represent ischemic or hypoxic
lesions caused by cardiorespiratory insufficiency that
occurred during acute episodes of encephalopathy.
Our patient’s CT scan showed no abnormalities of the
ventricles, sulci, or gray matter but demonstrated
prominent lucency of central white matter. Similar
changes in cerebral white matter have been seen in
other disorders of amino acid metabolism [7, 16) and
may reflect nonspecific, spongy degeneration of white
matter found on neuropathological examination [3, 5,
13- 151.
Results of the CT scan and cerebral evoked potential
recordings in this patient, who had never suffered increased intracranial pressure, hypoxia, or ischemia, suggest that metabolic derangements resulting from CPS-I
deficiency may have adversely affected central myelin
formation or maintenance. In CPS-I deficiency and
92 Annals of Neurology Vol 16 No 1 July 1984
other disorders associated with hyperammonemia,
levels of substances other than ammonia, such as glutamate, are elevated and may interfere with central myelination [181.
This patient’s very low enzyme activity level, mild
clinical course, longevity, CT scan and evoked potential results, and therapeutic response represent an unusual constellation of features not recorded previously
in severe CPS-I deficiency. These features extend the
spectrum of involvement that can occur in this disorder
and emphasize that urea cycle defects, generally considered disorders of infants and children, should be
considered in the differential diagnosis of intermittent
neurological symptoms regardless of the patient’s age.
Supported in part by Research Grant 1392-A-1 from the Multiple
Sclerosis Society, New York, NY; Grant MA 7394 from the Canadian Research Council; a grant from the Fitch Foundation, Salt Lake
City, U T and a grant from Foundation Justine Iacoste Beaubien,
Montreal, Quebec, Canada. Dr Seay is recipient of TeacherInvestigator Award 5K07-NS-00458 from the National Institute of
Neurological and Communicative Disorders and Stroke, National
Institutes of Health, Bethesda, MD.
The authors thank Dr Alvin Wirthlin for referring the patient to the
University of Utah, and Dr Mark L. Batshaw for consultations regarding the patient’s amino acid chromatography and management.
Urine organic acid chromatography was done by Dr Stephen I.
Goodman, University of Colorado Health Sciences Center, Denver,
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errors of urea synthesis. N Engl J Med 306:1387-1392, 198.2
2. Batshaw M, Brusilow S, Walrer M: Treatment of carbamyl phosphate synthetase deficiency with keto analogues of essential
amino acids. N Engl J Med 292:1085-1090, 1975
3. Burton CJ, Corsellis J, Russel A: Hereditary hyperammonernia.
Brain 93:423-434, 1970
4. Ceriotti G: Optimal conditions for ornithine carbamyl transferase determination: a simple micromethod with deproteinization.
Clin Chim Acta 4797-100, 1973
5. Donohue W L Lesions in the cerebral nervous system associated
with inborn errors of amino acid metabolism. Acta Pediatr Scand
56~116-117, 1967
6. Ebels EJ: Neuropathological observations in a patienr with carbamyl-phosphate synthetase deficiency and in two sibs. Arch Dis
Child 47:47-51, 1972
7. Kendall BE, Kingsley DPE, Leonard JV, et al: Neurological
features and computed tomography of the brain in children with
ornithine carbamyl transferase deficiency. J Neurol Neurosurg
Psychiatry 46:28-34, 1983
8. Lowry OH, Rosebrough NJ, Farr AL, et al: Protein measurement with the Folin-phenol reagent. J Biol Chem 193265-275,
9. McReynolds JW,
Crowley B, Mahoney MJ, et al: Autosomal
recessive inheritance of human mitochondrial carbamyl phosphate synthetase deficiency. Am J Hum Genet 33:345-353,
10. Nuzum CT, Snodgrass PJ: Multiple assays of the five urea cycle
enzymes in human liver homogenates. In Grisolia S, Baguena R,
Mayor F (eds): The Urea Cycle. New York, Wiley, 1976, pp
Sassaman EA, Zartler AS, Mulick JA: Cognitive functioning in
two sisters with carbamyl phosphate synthetase I deficiency. J
Pediatr Psycho1 6171-175, 1981
Shih V: Congenital hyperammonemic syndromes. Clin Perinatol 3:3-14, 1976
Shih V: Hereditary urea-cycle disorders. In Grisolia S, Baguena
R, Mayor F (eds): The Urea Cycle. New York, Wiley, 1976, pp
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in nonketotic hyperglycinemia. Comput Tomogr 5:265-270,
Van Anken HC, Schiphorst ME: A kinetic determination of
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Van Gelder NM: Intracerebral p H regulation and ammonia
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New York, McGraw-Hill, 1983, pp 402-438
Abnormahties in
Tourette’s Syndrome
Gabor Barabas, MD, Wendy S. Matthews, PhD,
and Mary Holowinsky
Krumholz and colleagues [2) reported a comprehensive electrophysiological investigation of Tourette’s syndrome (TS).
The findings led the investigators to conclude that there was
“no notable diagnostic or therapeutic value” for routine electroencephalographic or evoked response studies in the management of patients with TS. Our own work in this area
suggests that this conclusion may be premature.
Krumholz and colleagues studied 40 patients, 16 of whom
were receiving medication (haloperidol, 11; fluphenazine, 1;
clonidine, 1; thioridazine, 1; levodopdcarbidopa, 1; diazepam, 1). The mean age was 14.8 years, with a range of 7 to
50 years. Electroencephalograms (EEGs) were obtained from
all 40 patients, and evoked response studies were performed
in a subgroup of 17 patients: 12.5% (5 of the 40 patients) had
abnormal EEGs. Of these 5 patients, 4 had a positive family
history of tics, versus 14 of the 35 patients with normal
EEGs. (Neither age, sex, age at onset, nor duration and severity of tics differentiated individuals with normal and abnormal
EEGs.) Three of the 5 patients with abnormal EEGs were
receiving haloperidol. In each of these patients the abnormalities noted were related to slowing of background activity.
In the 2 patients receiving 1.5 and 2 mg of haloperidol, respectively, the slowing was described as “mild,” whereas in
the patient receiving 13 mg daily, the slowing was “moderate.” Of the 2 patients with abnormal EEGs who were not
receiving medication, 1 had mild slow activity anteriorly and
the other had “sporadic bilateral central-parietal spikes and
sharp waves.”
We agree with the authors that their finding of a 12.5%
incidence of abnormal EEGs is similar to that in the general
population and that these findings suggest that routine electroencephalography has no utility in the diagnosis or management of TS. O f our 35 unselected patients with TS (mean
age, 10.3 years; range, 5.7 to 16.4 years), 7 (20%) had abnormal EEGs. Unlike the patients of Krumholz and colleagues,
none of our children were receiving medication; the EEGs
were obtained at the time of diagnosis, prior to pharmacological intervention. Of our patients, 11% showed paroxysmal
abnormalities and 9% showed nonfocal slowing. We found
that these abnormalities were unrelated to the patient’s sex,
age at onset, duration of symptoms, or handedness. However, having recently found that there is an increased incidence of migraine in children with TS (26%) El], we
speculated that this may identify clinical subgroups in TS in
which differential findings might be expected. Examining the
EEG results according to the presence or absence of migraine
in the patient, we found a 29.2% incidence (7 of 24 patients)
of EEG abnormalities in the group of patients who did not
have migraine and virtually no incidence of EEG abnormalities among the 11 patients with migraine.
The statistical significance of the observation of a differential incidence of EEG abnormalities in the presence or absence of migraine among patients with TS is not established,
but the finding may indicate that the suggestion that there is
no utility in EEG studies in patients with TS must await
further study.
Department of Pediatrics
Univwsity 4 Medicine and Dentistty of New Jersey
Rutgers Medical School
New Brunswick, NJ 08903
1. Barabas G, Matthews W, Ferrari M: Tourette syndrome and
childhood migraine. Arch Neurol (in press)
2. Krumholz A, Singer HS, Niedermeyer E, er al: Electrophysiological studies in Tourette’s syndrome. Ann Neurol 14:638-641,
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adults, features, phosphate, clinical, deficiency, carbamyl, synthetase
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