Carbamyl phosphate synthetase 1 deficiency: A destructive encephalopathy

Carbamyl Phosphate Synthetase 1 Deficiency: A Destructive Encephalopathy Masanori Takeoka, MD, Teesta B. Soman, MD, Vivian E. Shih, MD, Verne S. Caviness, Jr., MD, DPhil, and Kalpathy S. Krishnamoorthy, MD Carbamyl phosphate synthetase I is a urea cycle enzyme. Severe deficiency of carbamyl phosphate synthetase I presents in the neonatal period as hyperammonemic encephalopathy with altered consciousness and occasional seizures after feeding begins. Episodes of altered consciousness with or without seizures and focal neurologic deficits are seen later with patients of partial carbamyl phosphate synthetase I deficiency. Fatal cerebral edema with brain herniation may develop on occasion. Three patients presenting with carbamyl phosphate synthetase I deficiency are reported with neuroimaging and pathologic findings illustrating the destructive encephalopathy with acute cerebral edema, followed by diffuse cerebral atrophy and occasional cystic encephalomalacia. The deterioration in carbamyl phosphate synthetase I deficiency occurs during the hyperammonemic crises. This deficiency may be difficult to treat despite the current advances in treatment strategies, especially in neonatal-onset patients with low carbamyl phosphate synthetase I activity. © 2001 by Elsevier Science Inc. All rights reserved.

athy in the neonatal period after feeding begins [2,3], with altered consciousness and occasional seizures. Partial CPS1 deficiency may present later in life, according to the residual activity of CPS1, with episodes of altered consciousness, seizures, or focal neurologic deficits [4]. CPS1 deficiency is inherited in an autosomal-recessive pattern, and the human CPS1 gene has been mapped to chromosome 2q35 [5]. The prevalence of the disease is estimated at approximately one in 800,000 to one in 1,000,000 [6] but is higher in areas with consanguinity. Although patients with CPS1 deficiency have been reported since 1969 [7], because of the relatively low prevalence the natural course of the disease has not been well demonstrated with findings that used recent technology, such as neuroimaging. Three patients with CPS1 deficiency are presented with neuroimaging and pathologic findings, which demonstrate the course of the destructive encephalopathy with CPS1 deficiency, are presented.

Takeoka M, Soman TB, Shih VE, Caviness VS Jr, Krishnamoorthy KS. Carbamyl phosphate synthetase 1 deficiency: A destructive encephalopathy. Pediatr Neurol 2001;24:193-199.

Patient 1

Introduction Carbamyl phosphate synthetase I (CPS1) is a urea cycle enzyme involved in the first committed step of urea synthesis. Ammonia and bicarbonate molecules are incorporated into carbamyl phosphate by CPS1. The nitrogen molecule from ammonia is transferred to ornithine in the next step by ornithine transcarbamylase [1]. Severe deficiency of CPS1 presents as hyperammonemic encephalop-

From the Department of Neurology; Massachusetts General Hospital and Harvard Medical School; Boston, Massachusetts.

© 2001 by Elsevier Science Inc. All rights reserved. PII S0887-8994(00)00259-9 ● 0887-8994/01/$—see front matter

Case Reports

Patients 1 and 2 were nonidentical twins of nonconsanguineous parents born at 36 weeks to a 34-year-old primigravida mother by twin gestation. Patient 1 began to manifest growth retardation on ultrasound at approximately 29 weeks. The twins were delivered by elective cesarean section. Apgar scores were six at 1 minute and seven at 5 minutes for Patient 1. Her birth weight was 1.53 kg (below the tenth percentile), and her head circumference was 30.5 cm (tenth percentile). On day 2, Patient 1 became progressively somnolent, with episodic apnea and bradycardia. She also had brief episodes of lip smacking and bicycling. Her general physical examination was unremarkable with no dysmorphic features. She was somnolent but arousable and mildly hypertonic in all four extremities. Her blood culture was positive for Group B Streptococcus but negative for other cultures. Routine laboratory tests on cerebrospinal fluid, including cell count, glucose, and total protein were unremarkable. She was treated with antibiotics for 14 days. She was also treated with phenobarbital for suspected seizure activity.

Communications should be addressed to: Dr. Takeoka; Child Neurology Service, Department of Pediatrics, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582 Japan. Received August 20, 2000; accepted November 13, 2000.

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She was maintained on IV hydration without protein, and her lethargy gradually improved over the next 4 days. She became somnolent again at 1 week when she resumed feeding. Her blood ammonia level was 640 ␮mol/L. She demonstrated low plasma citrulline and urine orotate, and was diagnosed with CPS1 deficiency on day 7. After receiving sodium benzoate, sodium phenylacetate, and peritoneal dialysis, she became alert. She was kept on a strict diet with protein restriction and sufficient calories and treated with sodium phenylbutyrate to enhance nitrogen waste excretion and to maintain ammonia levels within the normal range. She also received l-carnitine supplements. Her development was normal for gestational age when examined at 3 months. At 3 months of age, she presented with vomiting overnight, acute somnolence, and an increased ammonia level of 1200 ␮mol/L. Cerebral edema progressed even after the ammonia levels became normal with peritoneal dialysis and hemodialysis, and she died from diffuse cerebral edema and cerebral herniation despite peritoneal dialysis, hemodialysis, and aggressive measures to control intracranial pressure. Serum amino acids and plasma glutamine levels were monitored throughout the clinical course, including periods on dialysis. She did not require amino acid supplements during dialysis [8]. Mild elevations of 609-927 ␮mol/L (reference range: 243-822 [241-21 days], 475-746 [3 months-6 years]) in plasma glutamine correlated with increase in ammonia levels of 138-1080 ␮mol/L [9].

Patient 2 Patient 2, the nonidentical twin sister of Patient 1 and born by elective cesarean section, had Apgar scores of seven at 1 minute and eight at 5 minutes. Her birth weight was 2.09 kg (tenth to twenty-fifth percentile), and head circumference was 32 cm (twenty-fifth to fiftieth percentile). Like her twin sister, she developed similar episodes of apnea and bradycardia, lip smacking, and bicycling on day 3. Blood and cerebrospinal fluid cultures were negative. Routine laboratory tests of cerebrospinal fluid, including cell count, glucose, and total protein, were unremarkable. Episodes of lip smacking and bicycling resolved with phenobarbital treatment. Cranial computed tomography (CT) was normal. She had variable muscle tone, which increased at times and decreased on other occasions. She remained somnolent despite treatment with antibiotics. Her ammonia level was 900 ␮mol/L. She was diagnosed on day 7 with CPS1 deficiency from urine organic acid analysis, with low serum citrulline and normal urine orotate. She received sodium benzoate, sodium phenylacetate, and peritoneal dialysis, after which she became alert. She was also kept on a strict diet with protein restriction and sufficient calories and was treated with sodium phenylbutyrate and l-carnitine supplements to maintain her ammonia levels within normal range. Her development was normal for gestation at 3 months. At 4 months, an infection with respiratory syncytial virus was associated with hyperammonemic crisis with ammonia level of 360 ␮mol/L. She became systemically unstable with hypotension requiring dopamine, dobutamine, and epinephrine. She was somnolent and had diffuse cerebral edema. She underwent hemodialysis and peritoneal dialysis and was given mannitol for intracranial pressure management. Protein intake was restricted while she was given high calories and sodium benzoate/sodium phenylbutyrate to enhance waste nitrogen disposal. The cerebral edema progressed for 5 days despite normalized blood ammonia levels with the aggressive treatment to remove the ammonia from the body. After recovery she became developmentally delayed with microcephaly. She was unable to roll over or verbalize, only rarely reaching out with both hands, although she smiled responsively. She required a gastrotomy tube for feeding. After this episode, she experienced milder episodes of hyperammonemia, which were all controlled with adjustments in her diet and dosage of sodium phenylbutyrate. Patient 2 died at 12.5 months of age as a result of extensive superior vena cava thrombosis, causing pleural effusion and respiratory distress, which was attributed to the multiple surgical interventions she required for maintaining central venous access. As with her twin sister, Patient 2 also had monitoring of serum amino acids and plasma glutamine levels throughout the clinical course,

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including periods on dialysis. She required amino acid supplements for low levels in multiple amino acids during dialysis treatment when she had the acute crisis at 4 months [8]. Mild-to-moderate elevations of up to 766-1286 ␮mol/L in plasma glutamine levels correlated with an increase in ammonia levels of 74-900 ␮mol/L [9].

Patient 3 Patient 3 was born full term with a birth weight of 3.1 kg (twenty-fifth to fiftieth percentile) to parents of first-degree cousins in Kuwait. Otherwise her examination was unremarkable by report. She presented on the first day of age with somnolence and an ammonia level of 640 ␮mol/L. She received sodium benzoate and peritoneal dialysis in the neonatal period for hyperammonemia and was later maintained on nitrogen restriction, sodium phenylbutyrate, l-carnitine, and citrulline. After recovery she was microcephalic with significant developmental delay, unable to roll over or reach out for objects. She came to our institution for further management at 3 months of age. She was able to fix and follow objects visually and to respond to sound. She rarely smiled responsively and could not verbalize. She exhibited truncal hypotonia and mild spasticity in the extremities with sustained ankle clonus. She required a g-tube for feeding. She also had seizures, controlled with phenobarbital treatment. Shortly after she returned to Kuwait at 6 months of age, she died from systemic deterioration, and the details of her terminal state were not transmitted to us. Regarding the family history, the oldest brother died of hyperammonemia and had elevated 3-methylglutaconic acid in the urine. Two other brothers in the family are healthy. A cousin also has a urea cycle disorder, but the details are unknown. Of note, all three patients demonstrated elevated 3-methylglutaconic acid in the urine, which is of unknown significance.

CPS1 Enzyme Activity CPS1 enzyme activity was measured in liver tissue postmortem in Patient 1 (0.2 ␮mol/g liver/minute) and Patient 2 (0.3 ␮mol/g liver/ minute). These values were approximately 5% those of the cumulative controls (5.6 ⫾ 0.3 ␮mol/g liver/minute). Patient 3 underwent a needle liver biopsy before transferring to our institution, and the liver CPS1 activity was too low to be detected.

Neuroimaging Patient 1 had a normal magnetic resonance imaging (MRI) study of the brain at 1 month. At the time of the hyperammonemic crisis at 3 months, she had diffuse cerebral edema with loss of the gray-white junction and loss of cerebellar sulcations on cranial CT (Fig 1). Patient 2 had a normal cranial CT in the first week of life and a normal MRI of the brain at 1 month. When she had the hyperammonemic crisis at 4 months, she had diffuse cerebral edema with loss of contrast distinction of the gray-white matter junction, which progressed for the first 5 days (Fig 2). After the cerebral edema improved, she developed diffuse cerebral atrophy, as illustrated on cranial CT. MRI scanning of the brain at 5 months revealed the diffuse atrophy in the hemispheres with relatively less injury in the thalamus, cerebellum, and brainstem (Fig 3). The caudate nuclei appeared atrophic bilaterally, and the anterior horns of the lateral ventricles appeared enlarged. No neuroimaging study was available for Patient 3 during her hyperammonemic crisis. In the chronic phase the MRI scanning of the brain at 4 months demonstrated diffuse cerebral atrophy and cystic encephalomalacia (Fig 4). The basal ganglia appeared atrophic and were difficult to recognize on MRI. The bilateral thalami, brainstem, and cerebellum appeared relatively spared on MRI except for the abnormal T1 intensity in the thalami.

Figure 1. Cranial CT of Patient 1 during acute hyperammonemic crisis. Diffuse cerebral edema is seen with loss of gray-white junction in the cerebral hemispheres and loss of cerebellar sulcations indicating central herniation.

Pathology Pathology was obtained on Patient 1 after she died with diffuse cerebral edema. On gross pathologic examination, the brain appeared diffusely edematous. Microscopic examination with hematoxylin and

eosin staining was performed on the medial and lateral frontal cortex, occipital cortex, periventricular white matter and pulvinar, basal ganglia, brainstem, and cerebellum. Alzheimer type II astrocytes were distributed diffusely through the cerebral cortex and caudate nuclei (Fig 5). Evidence of ischemic insult, including pyknotic nuclei, eosinophilic cytoplasm,

Figure 2. Cranial CT of Patient 2 during acute hyperammonemic crisis. The sequence of acute progressive cerebral edema followed by atrophy is observed in the 15-day span during the hyperammonemic crisis. Diffuse cerebral edema is observed with loss of the gray-white matter junction in the cerebral hemispheres, progressing from day 1 to day 6 of the crisis. Cranial CT from day 15 reveals resolving cerebral edema and diffuse cerebral atrophy.

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Figure 3. MRI of the brain of Patient 2 (T2-weighted axial image: TR ⫽ 4200 ms, TE ⫽ 108 ms) after recovery from hyperammonemic crisis. Diffuse cerebral atrophy is seen with prominent sulci and increased subdural space, with atrophic caudate and enlarged lateral ventricles. The thalamus appears relatively spared in volume.

and even frank necrotic fragmentation, was observed in neurons of the same areas. The other structures, including the brainstem and cerebellum, were relatively spared of the ischemic injury from cerebral edema and the astrocytic changes.

Discussion The sequence of cerebral injury in hyperammonemic encephalopathy from CPS1 deficiency is demonstrated in the three patients. The complete sequence is illustrated in Figs 2 and 3 (both from Patient 2), revealing the progression of acute cerebral edema despite aggressive treatment and the lowering the ammonia levels to within normal limits and subsequent diffuse cerebral atrophy. The same sequence of injury is observed in Patient 1, with progressive cerebral edema despite normalized blood ammonia levels after aggressive treatment. Once developed, the cerebral edema may take additional time to resolve even with normalized blood ammonia levels. The distribution of injury demonstrated on the neuroimaging and pathology involved the cerebral cortex and white matter greater than the basal ganglia, with relative sparing of the thalamus, brainstem, and cerebellum. The reason for this anatomic distribution of injury is unknown, but it may be related to rate of metabolic activity. Type II astrocytes in the cerebral cortex and basal ganglia have been described in urea cycle disorders [10] but may not be specific. Type II astrocytes have also been reported in patients in hepatic disease [10], including Wilson’s disease [11] and galactosemia [12]. The similar neuropathology findings in these disorders may be secondary to hyperam-

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monemia from liver dysfunction, as these disorders primarily involve the liver. In galactosemia, which does not have neurologic involvement in isolation, similarities in clinical features to urea cycle disorders may also be accounted by the hyperammonemia. In Patient 3 the destruction was more severe compared with Patient 2. Diffuse atrophy was viewed in a similar anatomic distribution, with cystic encephalomalacia distributed throughout the gray-white junction of the bilateral cerebral hemispheres. The thalamus appeared relatively spared regarding volume loss but had increased T2-signal intensity, which may suggest injury to this area as well. Few published reports describe neuroimaging findings in CPS1, especially with MRI, compared with ornithine transcarbamylase deficiency. Most of the reports that include MRI findings are isolated case reports. Serial CT scans of a patient with adult onset CPS1 deficiency with valproate-induced coma have been reported by Verbiest et al. [13]. The CT scans in this study were taken over a longer time span, and only one scan was reported from during the acute crisis and coma, which revealed diffuse cerebral edema. A young child with CPS1 deficiency presenting with focal neurologic signs and MRI findings has been reported by Sperl et al. [4]. Regarding ornithine transcarbamylase deficiency, which is a more common urea cycle disorder, most of the recent reports describe focal neuroimaging findings that resemble ischemic strokes in late-onset cases [14,15]. No report in the past has demonstrated the acute progression of the disease process during an acute crisis by serial neuroimaging in

Figure 4. MRI of the brain of Patient 3, after recovery from hyperammonemic crisis. Diffuse cystic encephalomalacia is seen throughout the hemispheres with multiple round areas of hyperintensity on T2-weighted images (TR ⫽ 4200 ms, TE ⫽ 108 ms). The basal ganglia are difficult to recognize. The thalamus appears relatively spared in volume but has increase in signal intensity on T1-weighted images (TR ⫽ 500 ms, TE ⫽ 16 ms).

neonatal-onset CPS1 deficiency. The illustrations in our study demonstrate the rapid progression of tissue destruction from the hyperammonemic crisis. The diffuse cystic encephalomalacia from CPS1 has been described in the pathology literature, but such MRI findings in CPS1 have not been described previously. Regarding the pathophysiology in hyperammonemic crisis, the associated tissue destruction is considered to reflect a complex cascade of pathophysiologic mechanisms. Astrocytes respond to the increase in ammonia by incorporating the ammonia molecules into glutamate, forming glutamine [16]. The increased glutamine is hypothesized to cause edema in astrocytes by an osmolar effect. In fact, astrocytes are the main cells to manifest evidence of edema consequent to hyperammonemia. Furthermore, inhibiting glutamine synthesis has prevented the development of cerebral edema in animal models [17]. Once glutamine accumulates in astrocytes and develops cerebral edema, the edema may persist until the glutamine decreases, which may take time to resolve even after the blood ammonia level normalizes. Mild-to-moderate increase in plasma glutamine levels correlated well with increase in ammonia levels (Patients 1 and 2) but correlated less well with decreases in ammonia. The lag in normalization of plasma glutamine levels may support such a hypothesis. Regarding other mechanisms, neuronal and glial uptake of glutamate, altered cerebral energy metabolism, and stimulation of aromatic amino acid transport have been reported. Alterations in inhibitory and excitatory neuro-

transmission, glutamate receptor function, cholinergic parameters, and GABAergic parameters also have been reported [10]. None of the hypothesized mechanisms provides a clear explanation for the focal cerebral involvement in late-onset cases of CPS1 and ornithine transcarbamylase deficiencies. Reviewing these mechanisms may help in considering roles of neuroprotective strategies. The neurologic sequelae of the hyperammonemic encephalopathy for patients who survive the cerebral edema may involve significant developmental delay and seizures from the diffuse neuronal injury and subsequent gliosis. Because of the atrophy the risk of cerebral herniation may decrease, but the patients theoretically remain at risk for further episodes of hyperammonemic encephalopathy and cerebral edema. Currently the treatment for CPS1 deficiency is similar to treatment for other urea cycle disorders [18] except that the administration of arginine may not decrease the ammonia levels in CPS1. Acute treatment for hyperammonemic encephalopathy involves nitrogen restriction, high-calorie intake for suppressing amino acid catabolism, and enhancement of nitrogen excretion using sodium benzoate, phenylacetate, or phenylbutyrate [19]. Hemodialysis would be indicated if the above treatments do not improve the patient’s condition [1]. Hemodialysis is preferred over peritoneal dialysis because acute lowering of the ammonia level is essential. Supportive treatment, such as aggressive mea-

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Figure 5. Alzheimer type II astrocytes in acute hyperammonemic encephalopathy from CPS1 deficiency (Patient 1, hematoxylin and eosin staining). Diffuse Alzheimer type II astrocytes (arrows) are seen in the cerebral cortex (hematoxylin and eosin staining). The type II astrocytes have large pale vesicular nuclei and little visible cytoplasm, referred to as naked nuclei [11].

sures to control intracranial pressure, is also crucial to avoid cerebral herniation. In the chronic phase of the disease, nitrogen restriction, sufficient caloric intake, and chronic treatment with sodium phenylbutyrate are necessary to control the blood ammonia levels. Arginine and citrulline supplements are essential because arginine is supplied through the urea cycle [1]. Carnitine supplements may also be necessary in some patients [20], as it was in our three patients. Avoiding systemic stress, such as infection, is another important element in the prevention of hyperammonemic crises. Antiepileptic drugs provide prophylaxis against seizures, which potentially are an additional systemic stress that may increase ammonia production. Despite all the various treatment options, progression of the disease is difficult to prevent in the neonatal patients [3] with the low CPS1 activity, which was the case in our patients. Because Patients 1 and 2 had normal neurologic examinations before the deterioration at 3 and 4 months the cerebral injury and neurologic deterioration appear to occur with hyperammonemic crises. Thus prevention and immediate intervention of hyperammonemic crises should improve prognosis in CPS1 deficiency when applied before the cerebral edema and injury develops. In patients with partial CPS1 deficiency, [21] the residual CPS1 activity will be higher, and the prognosis may be better with early and aggressive treatment. Patients 1 and 2 did not develop significant cerebral edema during the first week of life, which is an interesting finding. Because the MRI findings were normal in both

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patients during that period, the mechanisms for astrocyte swelling may not have been mature enough to produce significant edema at this age. These patients demonstrate that even if acute cerebral edema is not observed in the neonatal period, the acute edema may develop with the next hyperammonemic crisis. It has been proposed that urea cycle disorders be included in the expanded newborn screening program. Tandem mass spectroscopy enables more efficient screening for multiple newborn errors of metabolism compared with the traditional methods [22]. The urea cycle disorders that accompany increased plasma citrulline levels can be detected by this method (argininosuccinate synthetase deficiency, argininosuccinate lyase deficiency, and arginase deficiency). Ornithine transcarbamylase and CPS1 deficiency are accompanied by decreased citrulline and would not be detected by the current methods. The detection of increased urine orotate for ornithine transcarbamylase deficiency may not be ideal for screening purposes because the compound is not easily detected and induction with allopurinol may be necessary. The allopurinol test also has many false-positive results [23]. Prenatal DNA testing is performed on patients with positive family histories and not for screening the general public [24]. For the three types of urea cycle disorders with increased citrulline, newborn screening will help identify patients and initiate early treatment, but such methods are currently not available for ornithine transcarbamylase or CPS1 deficiency. Currently the immediate detection of hyperammonemic crises and expediting appropriate investiga-

tions appear to be the prudent approach for rapid diagnosis of CPS1 deficiency. Conclusion Despite the current understanding of the biochemical, genetic, and clinical aspects of CPS1 deficiency, treatment of this disease remains greatly problematic, especially in neonatal patients with low CPS1 activity. The hyperammonemic encephalopathy may result in severe brain destruction and severe neurologic outcome. As observed on neuroimaging in our patients, brain destruction occurs predominantly with hyperammonemic crises. Prompt diagnosis, treatment, and prevention of the crises are crucial in improving the prognosis of this potentially treatable disease. The authors thank Dr. Mendel Tuchman at the Biochemical Genetics and Metabolism Laboratory, Department of Pediatrics and Laboratory Medicine and Pathology at the University of Minnesota Medical School for the CPS1 enzyme activity assay.

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