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Improved neurologic prognosis for a patient with propionic acidemia who received early living donor liver transplantation
Molecular Genetics and Metabolism 108 (2013) 25–29
Contents lists available at SciVerse ScienceDirect
Molecular Genetics and Metabolism journal homepage: www.elsevier.com/locate/ymgme
Improved neurologic prognosis for a patient with propionic acidemia who received early living donor liver transplantation Masayoshi Nagao a,⁎, Toju Tanaka a, Mayuko Morii a, Shuji Wakai a, b, Reiko Horikawa c, Mureo Kasahara d a
Department of Pediatrics, National Hospital Organization, Hokkaido Medical Center, Sapporo, Japan Nakanoshima Clinic, Sapporo, Japan Department of Endocrinology and Metabolism, National Center for Child Health and Development, Tokyo, Japan d Department of Transplantation, National Center for Child Health and Development, Tokyo, Japan b c
a r t i c l e
i n f o
Article history: Received 18 September 2012 Received in revised form 24 October 2012 Accepted 24 October 2012 Available online 29 October 2012 Keywords: Propionic acidemia Living donor liver transplantation EEG findings Epilepsy Metabolic decompensation
a b s t r a c t Despite medical therapy, patients with propionic academia (PA) still display a tendency to develop epilepsy. Patients with neonatal-onset PA who have received early living donor liver transplantation (LDLT) are limited in number, and the effect on neurologic prognosis, including epilepsy, is not clear. We report a patient with PA whose EEG findings improved dramatically after undergoing LDLT at age 7 months. The patient's neurologic development and brain MRI findings were quite satisfactory at age 2 years and 3 months. LDLT is effective not only in preventing metabolic decompensation, but also in improving neurologic function to ensure better quality of life. © 2012 Elsevier Inc. All rights reserved.
1. Introduction Propionic acidemia (PA) is an autosomal recessive metabolic disorder with an incidence of 1:50000 in Japan [1]. It is caused by a deficiency in propionyl-CoA carboxylase (PCC) activity, leading to metabolic decompensation and mitochondrial dysfunction [2]. This occurs during the metabolism of amino acids, odd-numbered fatty acids, and intestinal bacteria. Many patients present with PA during the neonatal period. The mortality is quite high, with a survival rate of 41% despite intensive care [3]. Severe neurologic complications are frequent in survivors [4]. Recent advances in medical management have improved the prognosis of PA, but the long-term neurologic outcome is generally disappointing. In particular, EEG abnormalities and epileptic seizures are frequent findings, with long-term manifestations occurring at a rate of almost 100% [5]. The relationship between the development of metabolic failure and the occurrence of EEG abnormalities has not been well understood. Principal problems in management are unpredictable metabolic decompensation, elevated ammonia levels, and difficulties with dietary restriction. Liver transplantation (LT) has been proposed to minimize the risk of further metabolic decompensation and to improve the quality of life [6]. Recent case studies ⁎ Corresponding author at: Department of Pediatrics, National Hospital Organization, Hokkaido Medical Center, 5-7 Yamanote Nishi-ku, Sapporo, Hokkaido 063-0005, Japan. Fax: +81 11 611 5820. E-mail address: [email protected] (M. Nagao). 1096-7192/$ – see front matter © 2012 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ymgme.2012.10.022
have reported that supplementing the hepatic enzyme (PCC) by LT leads to clinical improvement, including better feeding and increased neurologic development, with fewer episodes of metabolic acidosis and decreased incidence of cardiomyopathies [7–10]. However, experience with LT for PA is still limited. In addition, the effect of LT on neurologic prognosis, including the role of LT in preventing the development of epilepsy in patients with PA, is not clear and remains controversial. We report a female patient with neonatal-onset PA who showed progressive EEG abnormalities in infancy, but dramatically improved without having any epileptic seizures after undergoing LT at age 7 months. 2. Case report A girl was born at term with normal delivery. Her body weight was 3243 g. She developed severe hyperammonemia (3170 μg/dl) and metabolic acidosis (venous blood pH of 7.02, HCO3− 7.2, base excess −17) at age 3 days. Metabolic encephalopathy was suspected, as evidenced by apnea and seizure. The patient was successfully rescued by continuous hemodiafiltration to decrease the levels of ammonia and organic acids. Ammonia levels normalized within 18 h after onset. Biochemical diagnosis was promptly performed. Acylcarnitine analysis revealed elevation of propionyl-carnitine (C3) to 12.7 nmol/ml (normal 2±0.8); the C3/C2 (C2: acetyl-carnitine) ratio was 0.90 (normalb 0.25). Urinary organic acid analysis gave typical findings compatible with propionic acidemia. Methylcitrate (100.2, normalb 3.3), 3OH-propionate (210, normalb 2.0)
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M. Nagao et al. / Molecular Genetics and Metabolism 108 (2013) 25–29
and propionyl glycine (14.9, normalb 0.5) were increased greatly. The diagnosis of PA was finally confirmed by mutation analysis in the PCCA gene, which was compound heterozygous for 1196G>A and IVS18 + 1G > A. 1196G> A caused an R399Q amino acid substitution. This mutation also co-segregated with 1676G>T (W559L) on the same allele (maternal, in the present case), as reported by Yang et al. [11]. IVS18+ 1G> A caused skipping of exon 18. Homozygotes of each mutation were all symptomatic during the neonatal and infantile periods [11]. Propionyl-CoA carboxylase (PCC) activity in cultured fibroblasts was below 1% of control mean activity (5 pmol/min/mg protein; control value, 1345 ± 286 pmol/min/mg protein; n = 10). Patients with PCC activity levels below 5% of control levels had all shown neonatal onset in previous studies [12,13]. The patient recovered rapidly from metabolic failure through receiving a low protein diet using the special formula for PA and medication with L-carnitine and metronidazole. The post-newborn period was uneventful, and hyperammonemia and metabolic acidosis were well controlled. Her body weight and height were comparable to the control level. Head control was almost complete, but she remained slightly hypotonic in the lower limbs. Developmental quotient (DQ) at 3 months of age was 90. She experienced no seizures, but sometimes became inactive and lethargic. EEG showed a disturbance of background activity, as well as some epileptiform discharges at age 4 months (Fig. 1A). Diffuse irregular polyspike and spike-and-wave complexes from multifoci were clearly increased at 6 months, and further deteriorated to show hypsarrythmia and burst suppression (Fig. 1B). Administration of zonisamide was started for seizure prevention. Cerebrospinal fluid free carnitine, acethylcarnitine and propionylcarnitine were 32.9 nmol/ml (range 3.35±0.43), 9.7 nmol/ml (range 1.85±0.41), and 27.6 nmol/ml (range 0.04±0.005), respectively, which suggested the accumulation of organic acids in the central nervous system (CNS). She could not roll over, and was sometimes unresponsive to the voices of family members. DQ deteriorated to 77. The patient was referred for living donor liver transplantation (LDLT); the indication for LDLT was considered carefully through genetic counseling. The patient's pre-liver transplantation characteristics are listed in Table 1; most of the results were quite satisfactory. With parental concurrence, elective LT was thought to be a good option. LDLT (donated by the patient's father, a heterozygous carrier of IVS18 + 1G > A) was successfully performed at the National Center for Child Health and Development in Tokyo when the patient was 7 months old. She developed intestinal perforation on postoperative day 7, and experienced cytomegalovirus infection on day 48. Both events were well managed and her course has been uneventful since achieving normal graft function. After liver transplantation,
A
Table 1 Summary of the pre-LT evaluation. Age at presentation
3 days
Consanguinity UCGa ALT (U/L) Total Bilirubin (mg/dl) γGT (U/L) Ammonia (μg/dl) Protein restriction Nutrition Metabolic attack Indication for LT
N Normal 13–24 (normal 8–42) 0.15–0.73 (normal 0.3–1.2) 15–27 (normal 10–47) 53–92 (normal 18–75) 2 g/kg/day Bottle feeding None after the onset Elective
a
Ultrasound cardiography.
the EEG dramatically improved to show only sporadic paroxysms. At 9 months of age, only small spikes in the frontal lobe were observed, and the burst suppression pattern had completely disappeared (Fig. 2A). At age 2 years and 3 months, the EEG showed normal background activity without epileptic discharge (Fig. 2B). When the patient was 5 months of age, a magnetic resonance imaging (MRI) scan had revealed cortical atrophy, caused by neonatal metabolic failure and continuing exposure to propionate. After LT, when the patient was 10 months of age, dramatic improvement was observed in the brain mass, both in the grey and white matter. A recent MRI scan (at age 2 years and 3 months) showed myelination to be age-appropriate, and signal abnormalities in the basal ganglia were not observed (Fig. 3). She was able to walk around by herself and play with various toys. DQ had improved to 100. Although there was no apparent change in the elevated C3 level after LT, the C3/C2 ratio decreased to less than 1 (Fig. 4). This suggests that propionyl-CoA produced by extrahepatic tissues was more efficiently converted to acetyl-CoA in the transplanted liver. Urinary organic acid analysis also revealed a prominent decrease in propionate-related metabolites (methylcitrate 4.0–8.0, 3OH-propionateb 2.0). 3. Discussion Epileptic seizures and related EEG abnormalities have been described as major neurologic complications of inborn errors of metabolism [14]. Neuronal cells are very susceptible to the accumulation of toxic metabolites or deficiency in the energy supply in the central nervous system, which induces a burst suppression pattern in the EEG of an infant having progression of the disease. In reverse, such electrophysiological findings raise the suspicion of metabolic disorder
B Fp1- A1 Fp2- A2 F3- A1 F4- A2 C3- A1 C4- A2 P3- A1 P4- A2 O1- A1 O2- A2 F7- A1 F8- A2 T3- A1 T4- A2 T5- A1 T6- A2 Fz- A2 Cz- A2 Pz- A2 Fig. 1. EEG investigations before liver transplantation: (A) age 4 months; (B) age 6 months.
M. Nagao et al. / Molecular Genetics and Metabolism 108 (2013) 25–29
A
27
B Fp1 - A1 Fp2 - A2 F3 - A1 F4 - A2 C3 - A1 C4 - A2 P3 - A1 P4 - A2 O1 - A1 O2 - A2 F7 - A1 F8 - A2 T3 - A1 T4 - A2 T5 - A1 T6 - A2 Fz - A2 Cz - A2 Pz - A2 Fig. 2. EEG investigations after liver transplantation: (A) age 9 months; (B) age 2 years and 3 months.
[15]. These findings suggest that metabolic disorders provoke EEG abnormalities, which can be improved by treatment of the underlying disease itself. Haberlandt et al. [5] reported that more than half of patients with PA suffered from epileptic seizures, in contrast to 0.5% to 1% of the general population. These authors evaluated EEG findings and the development of epilepsy in 17 PA patients. Changes of background activity and/or epileptiform activity were observed in most of the cases, leading to a high manifestation of clinical seizures. Several
reasons for EEG abnormalities are considered. One is repeated hyperammonemia with neuronal cell damage during metabolic decompensation. Another is continuous exposure to neurotoxic metabolites related to PA, such as methylcitrate and 3OH-propionate, which affect grey matter and cause focal cortical damage. The latter mechanism was possible in our patient. After the initial metabolic decompensation in the newborn period, ammonia levels were constantly kept below 92 μg/dl by medical therapy until LDLT at 7 months of age. However, levels of propionate-related metabolites remained
T1
FLAIR
5 mo
10 mo
2 yr 3 mo
Fig. 3. Brain MRI scans before and after LT (T1 and FLAIR imaging). Cortical atrophy was apparent (age 5 months). Brain mass improved after LT (age 10 months). Myelination was age-appropriate, and the basal ganglia were normal (age 2 years and 3 months).
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M. Nagao et al. / Molecular Genetics and Metabolism 108 (2013) 25–29
Age (years)
LT
Age (years)
LT Fig. 4. Changes in C3 and C3/C2 before and after LT. Elevation of C3 was unchanged (upper panel); however, C3/C2 decreased to less than 1 after LT (lower panel).
high and findings on EEG and brain imaging deteriorated at 6 months. The improvements on EEG and brain imaging after LDLT were thus clearly more closely associated with changes in propionate metabolism than with the resolution of severe hyperammonemia. In methylmalonic acidemia, an organic acidemia related to PA, Malfatti et al. [16] showed that activation of the N-methyl D-aspartate (NMDA) receptor and GABAergic mechanisms triggers the evolution of seizures. Rigo et al. [17] observed the induction of seizures in rats injected with propionic acid into the striatum; electrodischarges were detected in the EEG. These observations might explain the increased abnormalities in the EEGs of patients with PA of long duration. Complete seizure control is quite difficult in patients with PA in spite of various therapeutic interventions with anti-epileptics, although medications, including valproic acid, are well tolerated without affecting propionate metabolism [5]. We used zonisamide for anti-epileptic therapy without any complications. However, anti-epileptics alone cannot relieve the chronic toxicity of propionate-related intermediates in neuronal cells. Residual brain damage caused by every episode of metabolic failure will increase the possibility of epileptic discharges. Pathologic MRI findings have been frequently observed in PA patients with epilepsy [18]. An especially high frequency of metabolic decompensation was seen to be a dominating factor for aggravation. Basal ganglia are very sensitive to metabolic failure and mitochondrial dysfunction because they depend on a high energy supply [19]. Pathologic findings in basal ganglia can lead to thalamocortical spreading of epileptic discharges that cause generalized seizure. These observations support the idea that epilepsy and other neurologic abnormalities can be prevented if propionate is efficiently decreased without metabolic decompensation in early childhood. Considering the mechanism above, early LT is a treatment option.
Standard medical management for PA encompasses a low-protein diet and medications including metronidazole, carnitine, and ammonialowering drugs. Despite adherence to these treatments, neurologic and cardiac complications are frequently observed [20]. It is expected that accumulation of toxic metabolites is reduced and cellular energy stores increase after LT. In the central nervous system, LT enables normalization of morphologic changes of astrocytes and excitatory action through NMDA receptors [21]. However, PCC is also expressed in extrahepatic tissue. LT only partially corrects metabolic defects, and the production of variable amounts of propionate persists after surgery. Adequate protein restriction and L-carnitine administration should be maintained. Although in the present case, PA-related intermediates were greatly reduced after LT, care should be taken to avoid the insidious damage caused by propionate, even if the patient is under good metabolic control. This still leaves a risk (although much smaller) of potential metabolic, neurologic and cardiac problems after LT. Yorifuji et al. [8] reported metabolic decompensation 3 years after LT. In another case, metabolic stroke occurred in spite of normal graft function and biochemical levels. Scholl-Burgi et al. [18] showed that cerebral lactate and glutamine tended to remain at high levels even if children with PA were adequately treated. Brain MRI, and magnetic resonance spectroscopy (MRS) if possible, are necessary when any abnormalities are detected after LT. Our experience supports the performance of early LT for patients with neonatal-onset PA, because it appears that LT can reduce the risk for development of progressive cardiac/neurologic problems due to poor metabolic control [22]. Although the experience with LDLT in patients with propionic acidemia is limited, there have been no descriptions of mortality or morbidity related to the use of heterozygous donors [6–8]. The outcome is comparable to cadaveric grafts in general. A heterozygous individual is expected to have almost 50% of control
M. Nagao et al. / Molecular Genetics and Metabolism 108 (2013) 25–29
enzyme activity; this may be sufficient to ameliorate propionate metabolism and to prevent additional metabolic failures. Our patient underwent LDLT successfully, and no negativity from the use of a heterozygous carrier as a donor has been observed to date. Early LT for PA is expected not only to prevent metabolic decompensation, but also to improve EEG abnormalities and neurologic functioning to ensure better quality of life. For the present patient, the long-term effectiveness of LT will not be clear until she reaches adulthood, because late complications related to cardiac and neurologic symptoms could yet occur. Patients with PA should continue to be considered for early LT if the evidence shows benefit to long-term neurologic development. Acknowledgments This study was partly supported by a Research Grant from the National Hospital Organization. References [1] T. Yorifuji, M. Kawai, J. Muroi, M. Mamada, K. Kurosawa, Y. Shigematsu, S. Hirano, N. Sakura, I. Yoshida, T. Kuhara, F. Endo, Unexpectedly high prevalence of the mild form of propionic academia in Japan: presence of a common mutation and possible clinical implications, Hum. Genet. 111 (2002) 161–165. [2] L. Rosenberg, W. Fenton, Disorders of propionate and methylmalonate metabolism, in: C. Scriver, A. Beaudet, W. Sly, D. Valle (Eds.), The Metabolic and Molecular Basis of Inherited Disease, McGraw-Hill, New York, 2007, pp. 821–844. [3] S.B. Van der Meer, F. Poggi, M. Spada, J.P. Bonnefont, H. Ogier, P. Hubert, E. Depondt, D. Rapaport, D. Rabier, C. Charpentier, P. Parvy, J. Bardet, P. Kamoun, J.M. Saunubray, Clinical outcome and long-term management of 17 patients with propionic academia, Eur. J. Pediatr. 155 (1996) 205–210. [4] R.A.H. Surtees, E.E. Matthews, J.V. Leonard, Neurologic outcome of propionic acidemia, Pediatr. Neurol. 8 (1992) 333–337. [5] E. Haberlandt, C. Canestrini, M. Brunner-Krainz, D. Moslinger, K. Mussner, B. Plecko, S. Scholl-Burgi, W. Sperl, K. Rostasy, D. Karall, Epilepsy in patients with propionic acidemia, Neuropediatrics 40 (2009) 120–125. [6] D. Morioka, M. Kasahara, Y. Takada, J.P.G. Corrales, A. Yoshizawa, S. Sakamoto, K. Taira, E.Y. Yoshitoshi, H. Egawa, H. Shimada, K. Tanaka, Living donor liver transplantation for pediatric patients with inheritable metabolic disorders, Am. J. Transplant. 5 (2005) 2754–2763. [7] T. Yorifuji, J. Muroi, A. Uematsu, T. Nakahata, H. Egawa, K. Tanaka, Living-related liver transplantation for propionic academia, J. Pediatr. 137 (2000) 572–574. [8] T. Yorifuji, M. Kawai, M. Mamada, K. Kurokawa, H. Egawa, Y. Shigematsu, Y. Kohno, K. Tanaka, T. Nakahata, Living-donor liver transplantation for propionic academia, J. Inherit. Metab. Dis. 27 (2004) 205–210.
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[9] N.R. Barshes, J.M. Vanatta, A.J. Patel, B.A. Carter, C.A. O'Mahony, S.J. Karpen, J.A. Goss, Evaluation and management of patients with propionic acidemia undergoing liver transplantation: a comprehensive review, Pediatr. Transplant. 10 (2006) 773–781. [10] S. Romano, V. Valayannopoulos, J.P. Jais, D. Rabier, Y. de Keyzer, D. Bonnet, P. de Lonlay, Cardiomyopathies in propionic aciduria are reversible after liver transplantation, J. Pediatr. 156 (2010) 128–134. [11] X. Yang, O. Sakamoto, Y. Matsubara, S. Kure, Y. Suzuki, Y. Aoki, S. Yamaguchi, T. Nishikubo, C. Kawaguchi, A. Yoshioka, T. Kimura, K. Hayasaka, Y. Kohno, K. Iinuma, T. Ohura, Mutation spectrum of the PCCA and PCCB genes in Japanese patients with propionic academia, Mol. Genet. Metab. 81 (2004) 335–342. [12] C. Perez-Cerda, B. Merinero, M. Marti, J.C. Cabrera, L. Pena, M.J. Garcia, J. Gangoiti, P. Sanz, P. Roudriguez-Pombo, J. Hoenicha, S. Muro, M. Ugarte, An usual late-onset case of propionic acidemia: biochemical investigations, neuroradiological findings and mutation analysis, Eur. J. Pediatr. 157 (1998) 50–52. [13] C. Perez-Cerda, B. Merinero, P. Rodriguez-Pombo, B. Perez, L.R. Desviat, S. Muro, E. Richard, M.J. Garcia, J. Gangoiti, P. Ruiz Sala, P. Sanz, P. Briones, A. Ribes, M. Martinez-Pardo, J. Campistol, M. Perez, R. Lama, M.L. Murga, T. Lema-Garrett, A. Verdu, M. Ugarte, Potential relationship between genotype and clinical outcome in propionic acidaemia patients, Eur. J. Hum. Genet. 8 (2000) 187–194. [14] N.I. Wolf, T. Bast, R. Surtees, Epilepsy in inborn errors of metabolism, Epileptic Disord. 7 (2005) 67–81. [15] M. Garcia-Alvarez, D.R. Nordli, D.C. De Vivo, Inherited Metabolic Disease, in: J. Engel Jr., T.A. Pedley (Eds.), Epilepsy: A Comprehensive Textbook, Lippincott-Raven Publishers, Philadelphia, 1997, pp. 2547–2562. [16] C.R. Malfatti, M.L. Perry, I.D. Schweigert, A.P. Mullaer, L. Paquetti, F.K. Rigo, M.R. Fighera, E.R. Garrido-Sanabria, C.F. Mello, Convulsions induced by methylmalonic acid are associated with glutamic acid decarboxylase inhibition in rats: a role for GABA in the seizures presented by methylmalonic acidemia patients? Neuroscience 146 (2007) 1879–1887. [17] F.K. Rigo, L. Pasqutti, C.R. Malfatti, M.R. Fighera, R.C. Coelho, C.Z. Petri, C.F. Mello, Propionic acid induces convulsions and protein carbonylation in rats, Neurosci. Lett. 13 (408) (2006) 151–154. [18] S. Scholl-Burgi, E. Haberlabdt, T. Gotwald, U. Albrecht, S. Baumgartner Sigl, M. Rauchenzauner, K. Rostasy, D. Karall, Stroke-like episode in propionic acidemia caused by central focal metabolic decompensation, Neuropediatrics 40 (2009) 76–81. [19] A. Broomfield, R. Gunny, P. Prabhakar, S. Grunewald, Spontaneous rapid resolution of acute basal ganglia changes in an unrelated infant with propionic acidemia: a clue to pathogenesis? Neuropediatrics 41 (2010) 256–260. [20] G. Touati, V. Valayannopoulos, K. Mention, P. de Lonlay, P. Jouvet, E. Depondt, M. Assoun, J.C. Souberbielle, D. Rabier, H. Ogier de Bauiny, J.M. Saudubray, Methylmalonic and propionic acidurias; management without or with a few supplements of specific amino acid mixtures, J. Inherit. Metab. Dis. 29 (2006) 288–298. [21] R.F. Butterworth, Pathophysiology of hepatic encephalopathy: the concept of synergism, Hepatol. Res. 38 (2008) S116–S121. [22] R. Vara, C. Turner, H. Mundy, N.D. Heaton, M. Rela, G. Mieli-Vergani, M. Champion, N. Hadzic, Liver transplantation for propionic acidemia in children, Liver Transpl. 17 (2011) 661–667.
Contents lists available at SciVerse ScienceDirect
Molecular Genetics and Metabolism journal homepage: www.elsevier.com/locate/ymgme
Improved neurologic prognosis for a patient with propionic acidemia who received early living donor liver transplantation Masayoshi Nagao a,⁎, Toju Tanaka a, Mayuko Morii a, Shuji Wakai a, b, Reiko Horikawa c, Mureo Kasahara d a
Department of Pediatrics, National Hospital Organization, Hokkaido Medical Center, Sapporo, Japan Nakanoshima Clinic, Sapporo, Japan Department of Endocrinology and Metabolism, National Center for Child Health and Development, Tokyo, Japan d Department of Transplantation, National Center for Child Health and Development, Tokyo, Japan b c
a r t i c l e
i n f o
Article history: Received 18 September 2012 Received in revised form 24 October 2012 Accepted 24 October 2012 Available online 29 October 2012 Keywords: Propionic acidemia Living donor liver transplantation EEG findings Epilepsy Metabolic decompensation
a b s t r a c t Despite medical therapy, patients with propionic academia (PA) still display a tendency to develop epilepsy. Patients with neonatal-onset PA who have received early living donor liver transplantation (LDLT) are limited in number, and the effect on neurologic prognosis, including epilepsy, is not clear. We report a patient with PA whose EEG findings improved dramatically after undergoing LDLT at age 7 months. The patient's neurologic development and brain MRI findings were quite satisfactory at age 2 years and 3 months. LDLT is effective not only in preventing metabolic decompensation, but also in improving neurologic function to ensure better quality of life. © 2012 Elsevier Inc. All rights reserved.
1. Introduction Propionic acidemia (PA) is an autosomal recessive metabolic disorder with an incidence of 1:50000 in Japan [1]. It is caused by a deficiency in propionyl-CoA carboxylase (PCC) activity, leading to metabolic decompensation and mitochondrial dysfunction [2]. This occurs during the metabolism of amino acids, odd-numbered fatty acids, and intestinal bacteria. Many patients present with PA during the neonatal period. The mortality is quite high, with a survival rate of 41% despite intensive care [3]. Severe neurologic complications are frequent in survivors [4]. Recent advances in medical management have improved the prognosis of PA, but the long-term neurologic outcome is generally disappointing. In particular, EEG abnormalities and epileptic seizures are frequent findings, with long-term manifestations occurring at a rate of almost 100% [5]. The relationship between the development of metabolic failure and the occurrence of EEG abnormalities has not been well understood. Principal problems in management are unpredictable metabolic decompensation, elevated ammonia levels, and difficulties with dietary restriction. Liver transplantation (LT) has been proposed to minimize the risk of further metabolic decompensation and to improve the quality of life [6]. Recent case studies ⁎ Corresponding author at: Department of Pediatrics, National Hospital Organization, Hokkaido Medical Center, 5-7 Yamanote Nishi-ku, Sapporo, Hokkaido 063-0005, Japan. Fax: +81 11 611 5820. E-mail address: [email protected] (M. Nagao). 1096-7192/$ – see front matter © 2012 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ymgme.2012.10.022
have reported that supplementing the hepatic enzyme (PCC) by LT leads to clinical improvement, including better feeding and increased neurologic development, with fewer episodes of metabolic acidosis and decreased incidence of cardiomyopathies [7–10]. However, experience with LT for PA is still limited. In addition, the effect of LT on neurologic prognosis, including the role of LT in preventing the development of epilepsy in patients with PA, is not clear and remains controversial. We report a female patient with neonatal-onset PA who showed progressive EEG abnormalities in infancy, but dramatically improved without having any epileptic seizures after undergoing LT at age 7 months. 2. Case report A girl was born at term with normal delivery. Her body weight was 3243 g. She developed severe hyperammonemia (3170 μg/dl) and metabolic acidosis (venous blood pH of 7.02, HCO3− 7.2, base excess −17) at age 3 days. Metabolic encephalopathy was suspected, as evidenced by apnea and seizure. The patient was successfully rescued by continuous hemodiafiltration to decrease the levels of ammonia and organic acids. Ammonia levels normalized within 18 h after onset. Biochemical diagnosis was promptly performed. Acylcarnitine analysis revealed elevation of propionyl-carnitine (C3) to 12.7 nmol/ml (normal 2±0.8); the C3/C2 (C2: acetyl-carnitine) ratio was 0.90 (normalb 0.25). Urinary organic acid analysis gave typical findings compatible with propionic acidemia. Methylcitrate (100.2, normalb 3.3), 3OH-propionate (210, normalb 2.0)
26
M. Nagao et al. / Molecular Genetics and Metabolism 108 (2013) 25–29
and propionyl glycine (14.9, normalb 0.5) were increased greatly. The diagnosis of PA was finally confirmed by mutation analysis in the PCCA gene, which was compound heterozygous for 1196G>A and IVS18 + 1G > A. 1196G> A caused an R399Q amino acid substitution. This mutation also co-segregated with 1676G>T (W559L) on the same allele (maternal, in the present case), as reported by Yang et al. [11]. IVS18+ 1G> A caused skipping of exon 18. Homozygotes of each mutation were all symptomatic during the neonatal and infantile periods [11]. Propionyl-CoA carboxylase (PCC) activity in cultured fibroblasts was below 1% of control mean activity (5 pmol/min/mg protein; control value, 1345 ± 286 pmol/min/mg protein; n = 10). Patients with PCC activity levels below 5% of control levels had all shown neonatal onset in previous studies [12,13]. The patient recovered rapidly from metabolic failure through receiving a low protein diet using the special formula for PA and medication with L-carnitine and metronidazole. The post-newborn period was uneventful, and hyperammonemia and metabolic acidosis were well controlled. Her body weight and height were comparable to the control level. Head control was almost complete, but she remained slightly hypotonic in the lower limbs. Developmental quotient (DQ) at 3 months of age was 90. She experienced no seizures, but sometimes became inactive and lethargic. EEG showed a disturbance of background activity, as well as some epileptiform discharges at age 4 months (Fig. 1A). Diffuse irregular polyspike and spike-and-wave complexes from multifoci were clearly increased at 6 months, and further deteriorated to show hypsarrythmia and burst suppression (Fig. 1B). Administration of zonisamide was started for seizure prevention. Cerebrospinal fluid free carnitine, acethylcarnitine and propionylcarnitine were 32.9 nmol/ml (range 3.35±0.43), 9.7 nmol/ml (range 1.85±0.41), and 27.6 nmol/ml (range 0.04±0.005), respectively, which suggested the accumulation of organic acids in the central nervous system (CNS). She could not roll over, and was sometimes unresponsive to the voices of family members. DQ deteriorated to 77. The patient was referred for living donor liver transplantation (LDLT); the indication for LDLT was considered carefully through genetic counseling. The patient's pre-liver transplantation characteristics are listed in Table 1; most of the results were quite satisfactory. With parental concurrence, elective LT was thought to be a good option. LDLT (donated by the patient's father, a heterozygous carrier of IVS18 + 1G > A) was successfully performed at the National Center for Child Health and Development in Tokyo when the patient was 7 months old. She developed intestinal perforation on postoperative day 7, and experienced cytomegalovirus infection on day 48. Both events were well managed and her course has been uneventful since achieving normal graft function. After liver transplantation,
A
Table 1 Summary of the pre-LT evaluation. Age at presentation
3 days
Consanguinity UCGa ALT (U/L) Total Bilirubin (mg/dl) γGT (U/L) Ammonia (μg/dl) Protein restriction Nutrition Metabolic attack Indication for LT
N Normal 13–24 (normal 8–42) 0.15–0.73 (normal 0.3–1.2) 15–27 (normal 10–47) 53–92 (normal 18–75) 2 g/kg/day Bottle feeding None after the onset Elective
a
Ultrasound cardiography.
the EEG dramatically improved to show only sporadic paroxysms. At 9 months of age, only small spikes in the frontal lobe were observed, and the burst suppression pattern had completely disappeared (Fig. 2A). At age 2 years and 3 months, the EEG showed normal background activity without epileptic discharge (Fig. 2B). When the patient was 5 months of age, a magnetic resonance imaging (MRI) scan had revealed cortical atrophy, caused by neonatal metabolic failure and continuing exposure to propionate. After LT, when the patient was 10 months of age, dramatic improvement was observed in the brain mass, both in the grey and white matter. A recent MRI scan (at age 2 years and 3 months) showed myelination to be age-appropriate, and signal abnormalities in the basal ganglia were not observed (Fig. 3). She was able to walk around by herself and play with various toys. DQ had improved to 100. Although there was no apparent change in the elevated C3 level after LT, the C3/C2 ratio decreased to less than 1 (Fig. 4). This suggests that propionyl-CoA produced by extrahepatic tissues was more efficiently converted to acetyl-CoA in the transplanted liver. Urinary organic acid analysis also revealed a prominent decrease in propionate-related metabolites (methylcitrate 4.0–8.0, 3OH-propionateb 2.0). 3. Discussion Epileptic seizures and related EEG abnormalities have been described as major neurologic complications of inborn errors of metabolism [14]. Neuronal cells are very susceptible to the accumulation of toxic metabolites or deficiency in the energy supply in the central nervous system, which induces a burst suppression pattern in the EEG of an infant having progression of the disease. In reverse, such electrophysiological findings raise the suspicion of metabolic disorder
B Fp1- A1 Fp2- A2 F3- A1 F4- A2 C3- A1 C4- A2 P3- A1 P4- A2 O1- A1 O2- A2 F7- A1 F8- A2 T3- A1 T4- A2 T5- A1 T6- A2 Fz- A2 Cz- A2 Pz- A2 Fig. 1. EEG investigations before liver transplantation: (A) age 4 months; (B) age 6 months.
M. Nagao et al. / Molecular Genetics and Metabolism 108 (2013) 25–29
A
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B Fp1 - A1 Fp2 - A2 F3 - A1 F4 - A2 C3 - A1 C4 - A2 P3 - A1 P4 - A2 O1 - A1 O2 - A2 F7 - A1 F8 - A2 T3 - A1 T4 - A2 T5 - A1 T6 - A2 Fz - A2 Cz - A2 Pz - A2 Fig. 2. EEG investigations after liver transplantation: (A) age 9 months; (B) age 2 years and 3 months.
[15]. These findings suggest that metabolic disorders provoke EEG abnormalities, which can be improved by treatment of the underlying disease itself. Haberlandt et al. [5] reported that more than half of patients with PA suffered from epileptic seizures, in contrast to 0.5% to 1% of the general population. These authors evaluated EEG findings and the development of epilepsy in 17 PA patients. Changes of background activity and/or epileptiform activity were observed in most of the cases, leading to a high manifestation of clinical seizures. Several
reasons for EEG abnormalities are considered. One is repeated hyperammonemia with neuronal cell damage during metabolic decompensation. Another is continuous exposure to neurotoxic metabolites related to PA, such as methylcitrate and 3OH-propionate, which affect grey matter and cause focal cortical damage. The latter mechanism was possible in our patient. After the initial metabolic decompensation in the newborn period, ammonia levels were constantly kept below 92 μg/dl by medical therapy until LDLT at 7 months of age. However, levels of propionate-related metabolites remained
T1
FLAIR
5 mo
10 mo
2 yr 3 mo
Fig. 3. Brain MRI scans before and after LT (T1 and FLAIR imaging). Cortical atrophy was apparent (age 5 months). Brain mass improved after LT (age 10 months). Myelination was age-appropriate, and the basal ganglia were normal (age 2 years and 3 months).
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M. Nagao et al. / Molecular Genetics and Metabolism 108 (2013) 25–29
Age (years)
LT
Age (years)
LT Fig. 4. Changes in C3 and C3/C2 before and after LT. Elevation of C3 was unchanged (upper panel); however, C3/C2 decreased to less than 1 after LT (lower panel).
high and findings on EEG and brain imaging deteriorated at 6 months. The improvements on EEG and brain imaging after LDLT were thus clearly more closely associated with changes in propionate metabolism than with the resolution of severe hyperammonemia. In methylmalonic acidemia, an organic acidemia related to PA, Malfatti et al. [16] showed that activation of the N-methyl D-aspartate (NMDA) receptor and GABAergic mechanisms triggers the evolution of seizures. Rigo et al. [17] observed the induction of seizures in rats injected with propionic acid into the striatum; electrodischarges were detected in the EEG. These observations might explain the increased abnormalities in the EEGs of patients with PA of long duration. Complete seizure control is quite difficult in patients with PA in spite of various therapeutic interventions with anti-epileptics, although medications, including valproic acid, are well tolerated without affecting propionate metabolism [5]. We used zonisamide for anti-epileptic therapy without any complications. However, anti-epileptics alone cannot relieve the chronic toxicity of propionate-related intermediates in neuronal cells. Residual brain damage caused by every episode of metabolic failure will increase the possibility of epileptic discharges. Pathologic MRI findings have been frequently observed in PA patients with epilepsy [18]. An especially high frequency of metabolic decompensation was seen to be a dominating factor for aggravation. Basal ganglia are very sensitive to metabolic failure and mitochondrial dysfunction because they depend on a high energy supply [19]. Pathologic findings in basal ganglia can lead to thalamocortical spreading of epileptic discharges that cause generalized seizure. These observations support the idea that epilepsy and other neurologic abnormalities can be prevented if propionate is efficiently decreased without metabolic decompensation in early childhood. Considering the mechanism above, early LT is a treatment option.
Standard medical management for PA encompasses a low-protein diet and medications including metronidazole, carnitine, and ammonialowering drugs. Despite adherence to these treatments, neurologic and cardiac complications are frequently observed [20]. It is expected that accumulation of toxic metabolites is reduced and cellular energy stores increase after LT. In the central nervous system, LT enables normalization of morphologic changes of astrocytes and excitatory action through NMDA receptors [21]. However, PCC is also expressed in extrahepatic tissue. LT only partially corrects metabolic defects, and the production of variable amounts of propionate persists after surgery. Adequate protein restriction and L-carnitine administration should be maintained. Although in the present case, PA-related intermediates were greatly reduced after LT, care should be taken to avoid the insidious damage caused by propionate, even if the patient is under good metabolic control. This still leaves a risk (although much smaller) of potential metabolic, neurologic and cardiac problems after LT. Yorifuji et al. [8] reported metabolic decompensation 3 years after LT. In another case, metabolic stroke occurred in spite of normal graft function and biochemical levels. Scholl-Burgi et al. [18] showed that cerebral lactate and glutamine tended to remain at high levels even if children with PA were adequately treated. Brain MRI, and magnetic resonance spectroscopy (MRS) if possible, are necessary when any abnormalities are detected after LT. Our experience supports the performance of early LT for patients with neonatal-onset PA, because it appears that LT can reduce the risk for development of progressive cardiac/neurologic problems due to poor metabolic control [22]. Although the experience with LDLT in patients with propionic acidemia is limited, there have been no descriptions of mortality or morbidity related to the use of heterozygous donors [6–8]. The outcome is comparable to cadaveric grafts in general. A heterozygous individual is expected to have almost 50% of control
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enzyme activity; this may be sufficient to ameliorate propionate metabolism and to prevent additional metabolic failures. Our patient underwent LDLT successfully, and no negativity from the use of a heterozygous carrier as a donor has been observed to date. Early LT for PA is expected not only to prevent metabolic decompensation, but also to improve EEG abnormalities and neurologic functioning to ensure better quality of life. For the present patient, the long-term effectiveness of LT will not be clear until she reaches adulthood, because late complications related to cardiac and neurologic symptoms could yet occur. Patients with PA should continue to be considered for early LT if the evidence shows benefit to long-term neurologic development. Acknowledgments This study was partly supported by a Research Grant from the National Hospital Organization. References [1] T. Yorifuji, M. Kawai, J. Muroi, M. Mamada, K. Kurosawa, Y. Shigematsu, S. Hirano, N. Sakura, I. Yoshida, T. Kuhara, F. Endo, Unexpectedly high prevalence of the mild form of propionic academia in Japan: presence of a common mutation and possible clinical implications, Hum. Genet. 111 (2002) 161–165. [2] L. Rosenberg, W. Fenton, Disorders of propionate and methylmalonate metabolism, in: C. Scriver, A. Beaudet, W. Sly, D. Valle (Eds.), The Metabolic and Molecular Basis of Inherited Disease, McGraw-Hill, New York, 2007, pp. 821–844. [3] S.B. Van der Meer, F. Poggi, M. Spada, J.P. Bonnefont, H. Ogier, P. Hubert, E. Depondt, D. Rapaport, D. Rabier, C. Charpentier, P. Parvy, J. Bardet, P. Kamoun, J.M. Saunubray, Clinical outcome and long-term management of 17 patients with propionic academia, Eur. J. Pediatr. 155 (1996) 205–210. [4] R.A.H. Surtees, E.E. Matthews, J.V. Leonard, Neurologic outcome of propionic acidemia, Pediatr. Neurol. 8 (1992) 333–337. [5] E. Haberlandt, C. Canestrini, M. Brunner-Krainz, D. Moslinger, K. Mussner, B. Plecko, S. Scholl-Burgi, W. Sperl, K. Rostasy, D. Karall, Epilepsy in patients with propionic acidemia, Neuropediatrics 40 (2009) 120–125. [6] D. Morioka, M. Kasahara, Y. Takada, J.P.G. Corrales, A. Yoshizawa, S. Sakamoto, K. Taira, E.Y. Yoshitoshi, H. Egawa, H. Shimada, K. Tanaka, Living donor liver transplantation for pediatric patients with inheritable metabolic disorders, Am. J. Transplant. 5 (2005) 2754–2763. [7] T. Yorifuji, J. Muroi, A. Uematsu, T. Nakahata, H. Egawa, K. Tanaka, Living-related liver transplantation for propionic academia, J. Pediatr. 137 (2000) 572–574. [8] T. Yorifuji, M. Kawai, M. Mamada, K. Kurokawa, H. Egawa, Y. Shigematsu, Y. Kohno, K. Tanaka, T. Nakahata, Living-donor liver transplantation for propionic academia, J. Inherit. Metab. Dis. 27 (2004) 205–210.
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