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Propionic Acidemia Revisited: A Workshop Report

Posted on: Friday, 17 December 2004, 03:00 CST

Summary: Propionic acidemia (PA) is one of the most frequent organic acidurias, but information on the outcome of individuals with PA is rather limited. We present data of 49 patients with PA, which were gathered from 18 metabolic centers throughout Central Europe on the occasion of an international workshop. All patients were identified by selective metabolic screening, and 86% of them were classified as having early-onset PA owing to their presentation with clinical symptoms within the first 90 days of life. Mortality rate was one third, and details of symptoms and treatment of the surviving patients are discussed. The great variation of phenotypic expression of the disease and different therapeutic strategies (especially in regard to the degree of protein restriction) used at the various institutions involved in this study imply the need for a registry of PA patients and for a multicenter prospective treatment study. Clin Pediatr. 2004;43:837-843

Introduction

Propionic acidemia (PA), an autosomal recessive disorder caused by isolated deficiency of the mitochondrial enzyme propionyl CoA carboxylase (PCC; EC 6.4.1.3),1 is one of the most frequent organic acidurias.

PCC converts propionyl-CoA (formed in the catabolism of isoleucine, valine, methionine, threonine, odd-chain fatty acids, cholesterol side chains, thymine, and uracil) to D-methylmalonyl CoA. The PCC apoenzyme is composed of nonidentical subunits alpha and beta, and the cofactor biotin is bound to the alpha subunit. Human PCC most likely is a hexamer of protomers each containing a single alpha and a single beta subunit. Isolated PCC deficiency can result from mutations in the PCCA gene or the PCCB gene, coding for the alpha and beta subunit, respectively, and corresponding to the complementation groups pccA (MIM 232000) and pccBC (MIM 232050).

In 1961 Childs et al2 described a patient with ketotic hyperglycinemia. A few years later the underlying defect was identified as deficiency of PCC.3,4

Most commonly, patients with propionic acidemia present with an acute metabolic crisis in the neonatal period. However, individuals with late-onset PA have also been reported. The clinical manifestation of the latter may comprise acute encephalopathy, episodic ketoacidosis, or even developmental retardation without metabolic decompensation.1 Until recently, the diagnosis of PA was usually made after onset of symptoms by analysis of urinary organic acids by gas chromatography.

Only 2 major reviews exist on greater groups of patients,5,6 and a few articles are available on (generally) smaller numbers of PA patients from single centers.7-10 Outcome and therapeutic strategies differ significantly among those descriptions. In general, outcome was poor in most of the reported patients.

In most metabolic centers the experience in treatment of propionic acidemia is limited to a few or single cases only. Following an international workshop, held in October 1998 at Salzburg, Austria, in order to compare current diagnostic and therapeutic approaches applied by 18 metabolic centers throughout Central Europe, we report cumulated experience of the participants and data collected by a questionnaire-based survey. These data are representative for a patient cohort in the prescreening era.

Patients

Data on 49 patients with PA were provided by 18 metabolic centers from Austria (11 questionnaires), Belgium (1), Czech Republic (2), Germany (26), The Netherlands (4), and Switzerland (5) during a study period between June 1998 and April 1999. Fortytwo of 49 patients presented with clinical symptoms within the first 90 days of life and were therefore classified as early-onset patients. An affected brother of an early-onset PA patient was excluded from the statistical analyses since he had been considered as potentially affected immediately after birth because of the family history, but not because of clinical symptoms. Therefore, data of the questionnaires of 42 early-onset patients of 41 mothers were used; 21 patients were female and 21 male. In 1 family, twins were affected and showed initial symptoms almost at the same time. Therefore, they were both included, whereas from 2 other families a questionnaire was available for 1 child only, although it was noted that a deceased sibling also had PA.

Individuals with onset of the disease after the 3rd month of life were classified as late-onset patients. Six questionnaires of late- onset patients were available. However, 1 was excluded from detailed analysis because the corresponding patient was diagnosed early, since PA was considered because of already known PA of his sister.

We focus our report on the early-onset patients, and statistical examinations refer to that subgroup, if not indicated otherwise.

In all patients diagnosis has been achieved with the help of gas chromatography-mass spectrometry analysis of urinary organic acids (or was at least confirmed by that method after analysis by gas chromatography alone). Except for 2 cases (patients born in 1998 and 1999) for whom additional acylcarnitine analyses were performed, the acylcarnitine pattern did not contribute to the diagnosis in the patients described here.

In 83% of the early-onset patients and in all patients with late- onset disease confirmatory enzyme analysis was performed in cultivated fibroblasts and/or isolated lymphocytes. Mutation analysis (by the group of Professor Ugarte, Madrid, Spain) was performed in 13% of the early-onset patients and in 1 of the 5 individuals with late-onset PA.

Family History and Perinatal Anamnesis

In 10 of 40 families (25%) unexplained death of siblings was reported. In 2 of those families and in 2 others, siblings are known to be also affected by PA. Prenatal diagnosis was documented 5 times (in 3 families), resulting in 4 children without PA and in 1 termination of pregnancy. For a third of the parents (12/36) consanguinity was revealed; 92% (36/39) of the early-onset PA patients were born at term, with unremarkable APGAR scores for 27/ 29 (93%).

Initial Manifestation of PA

Of the 42 individuals with early-onset PA, almost three quarters (74%) presented with clinical symptoms within the first 8 days of life, and the remaining 26%, between days 11 and 90. Based on the 38 patients with detailed information available, median day of onset was 4.0 days (range 1.0-90.0 days). The diagnosis of PA was obtained at the age of 13.5 days (= median; range: 4-195). One patient was excluded from these calculations who had presented with neonatal- onset PA in 1960 (before the first description of the disease), but was diagnosed with PA only 24 years later.11 As shown in Table 1, muscular hypotonia, inappetency, and somnolence/lethargy were the most prominent findings. Notably, 32 of 38 newborns (84%) presented with blood ammonia concentrations exceeding 150 mol/L, thus once more underlining the value of this widely available parameter in the diagnosis of inborn errors of metabolism. Median ammonia values in the initial crisis were 459 mol/L (range 86-2,450 mol/L).

Table 1

MOST FREQUENTLY REPORTED (>20%) INITIAL CLINICAL FINDINGS IN PATIENTS WITH EARLY ONSET PA

Clinical Course Including Metabolic Crises and Hospitalizations

Regarding the number of metabolic crises and hospitalizations, data were available for 35 and 39 patients, respectively. Eleven patients were reported to have had no metabolic decompensation at all, 10 with 1, 5 with 2 or 3, and 9 with more than 3. Three patients did not need any hospitalization, 6 had 1,14 had 2 or 3, and 16 had more than 3.

However, median age of living patients (n=28) at the time of data collection was only 3.50 years (range 0.25-38.0 years). One third of the patients (n=14) included in the study had already died at the time of data collection. Usually death occurred within the first year of life (median age of death 0.58 year; range 0.02-14.67 years).

Management of Metabolic Crises and Long-Term Therapeutic Approaches

Duration of total protein restriction during management of the initial crisis has been reported for 23 patients and reached a median value of 48 hours (range 12-192 hours).

For 15 patients detoxification by methods such as hemofiltration (n=5), peritoneal dialysis (n = 7), and-in 1 case-blood exchange transfusion was reported, and in 2 patients both peritoneal dialysis and exchange transfusion were performed. In a 16th patient continuous arteriovenous hemofiltration was tried without success. The patient died.

Regarding management of the initial crisis, information on fluid and energy intake has been given for 19 and 23 patients, respectively. Median values were 150 mL/kg/day (range 12-200) and 114 kcal/kg/day (range 45-133), respectively. Insulin was administered to 17 patients (median dose 0.075 IU/kg/hr; range 0.01- 0.20), and for 15 patients it was reported that they did not receive any insulin.

Carnitine was given from the 1980s on only, but then to most patients. Doses were between 17.2 and 300 mg/kg/day, and usually at least 100 mg/kg/day were given. For long-term treatment, most patients received between 50 and 300 mg/kg/day. Antibiotic treatment (e.g., with metronidazole) in order to achieve a reduction of the gut bacterial population as an important source of propionic acid,12 has been reported for \13 patients but was denied for 21.

Nutritional data of our retrospective work-up were rather heterogeneous, thus reflecting the individual therapeutic approaches in mostly single or very few cases per center. Treatment strategies to reduce the precursor substrates of PCC were different. Protein restriction to the minimum safe recommended protein intake per age was attempted in almost all patients after diagnosis. This goal was achieved in some centers by just restricting natural protein intake in a subgroup of mildly affected patients. More severely affected patients usually were restricted to around two thirds of their minimum safe protein intake by natural protein and the lacking third was supplemented by using a precursor-free amino acid mixture. We could verify no differences regarding outcome of the patients on different degrees of protein restriction.

Follow-up and Outcome

The frequency of controls in the outpatients' departments varied greatly and depended especially on the ages of the patients. Most of the time, patients were seen every 3 or 6 months. None of the patients underwent an organ transplantation.

There was a tendency toward decreased body length (standard deviation score [SDS] -1.191.32 [n=14]) and head circumference (- 0.84 1.59 [n=8]), whereas the SDS score of the body mass index was not decreased (0.69 1.81 [n=14]).

Cognitive and neurologic development was at least mildly impaired in most cases, although the majority of the .early-onset patients included in this study was rather young (median age of the patients being alive at time of data collection: 3.5 years). Normal development was documented for 2 children in kindergarten age only. For 15 patients occupational therapy or special educational support was reported.

EEG appeared normal for 17 patients, moderately abnormal for 9, and (clearly) abnormal for 6. Cerebral magnetic resonance imaging/ computed tomography appeared normal in 8 cases, moderately abnormal in 7, and (clearly) abnormal in 2. However, the clinical presentation of the patients varied considerably. Notably, as indicated above, 1 of the patients had presented with neonatal- onset PA in 1960 but was not diagnosed with PA until 24 years later, after she had not become pregnant. She has never received any treatment, later became pregnant, delivered a child, and is working. She has an IQ of approximately 80 and is living in an independent household together with her husband.

Two patients had metabolic strokes leading to death. Indications for increased bone fracture have been reported in the questionnaires for 4 individuals. Only a few patients were systematically evaluated for osteopenia or osteoporosis. For 11 of 36 patients (31%) with a corresponding response, signs of bone marrow depression were stated, which, however, in 4 cases were rather nonspecific (only isolated anemia). Impaired kidney function or indications for hypertonia, which are both known from methylmalonic acidemia,13 have not been recognized for any patient.

Notably, cardiomyopathy was reported for 2 of 34 patients for whom the corresponding question in the questionnaire was filled in.

Lale-Onset Propionic Addenda

Questionnaires were used from 5 individuals (4 females, 1 male) with late-onset propionic acidemia on average manifesting at the age of 16 months (=median; range 11-69 months). In those patients no more than 1 metabolic crisis was noted, except for 1 girl with 2 crises.

At the time of data collection the late-onset patients were all alive (median age 11 years, range 1.75-33), 2 were considered slightly retarded, and the others were thought to have normal neurologic development. Dietary restrictions appeared to be less strict; propionyl-GoA precursor-free amino acid preparations were not taken by all patients, and if prescribed, were not taken as regularly as in most early-onset cases.

Discussion

Our report extends the information on patients with PA given in earlier reports6,8-10 to more recently born patients (median year of birth 1993-1994), who in addition to restriction of natural protein were mostly supplemented with propionyl-CoA precursor-free amino acid mixtures. However, all patients were identified by selective metabolic screening after onset of symptoms.

Since data were contributed by 18 centers throughout Central Europe, we expect a more comprehensive view than that provided in the past. Our results allow a more positive view (especially on the early-onset PA patients) compared with the outcomes reported by Surtees and the London group in 1992.9 They reported no survival of patients with an onset within the first week of life, and recorded death of those 2 of 9 patients born after the first 6 weeks who were born in the 1960s or 1970s. In addition, Surtees et al9 found mental retardation with an IQ≤ 60 in all early-onset patients. Those patients were usually on a low-protein diet; unfortunately, no details on the protein intake were given.

Mild to moderate intellectual impairment was also reported by North et al8 for 6 Bostonian patients with early-onset PA.8 All of them received gastrostomy tube feeding. Compared with the recommendations outlined in Table 2, their intake of natural protein was rather low. Tube feeding was also applied in three quarters of the early-onset patients of van der Meer et al.10 As also discussed by those authors, the low-protein intake (6.3 1.5 g/day, which corresponds to approximately 0.6-0.8 g/kg/day) in these French patients, may (for instance) have been a cause of the short stature of the individuals (mean SDS for height: -2). Five of the 12 early- on-set patients (42%) had died (and 2 of 5 late-onset individuals), 4 of them within the first year of life.

Table 2

RECOMMENDATIONS FOR PROTEIN INTAKE FOR THE LONG-TERM TREATMENT OF PA PATIENTS

Of the early-onset patients described in the present report, two thirds were still alive at the time of data collection as were all the late-onset patients. Although the low age of many of the patients may prevent the drawing of hard conclusions, our data indicate that a relatively higher protein intake than reported earlier has no negative effect on survival and outcome of patients or may even be beneficial. Notably, tube feeding could generally be avoided during the study period but had to be introduced later in a few cases.

The recommendations for protein intake (Table 2) have been delineated from the authors' experience during long-term management of PA with continuous follow-up, but they lack confirmation in a larger study population. They are, however, well in agreement with the recently reported experience of the group from Valparaso.7

Besides changes in protein intake, other factors that may lead to improved outcome comprise, e.g., earlier diagnosis (shorter time between clinical onset and diagnosis), especially because of increased awareness of organoacidopathies and widely available selective screening procedures. Optimized therapeutic strategies (as previously outlined in reference 5), including early intervention and hospitalization, may also contribute to a better outcome. Our list of most frequent initial findings in PA is well in agreement with the corresponding tables by Wolf et al6 and Lehnert et al.5 Notably, the median ammonia value in the initial crisis was 459 mol/ L with an upper range of 2,450 mol/L, which indicates that even very high ammonia levels alone do not allow the distinguishing of propionic acidemia from a urea cycle defect.

It is remarkable that skin lesions, which were observed in 53% of the patients described by Lehnert et al,5 were only rarely reported in the current study (5/35; i.e., 14%). Although it may be tempting to speculate that this could be due to an improved/ more nearly adequate intake of protein following the wider dissemination of special amino acid supplements, it must be considered that, unfortunately, our questionnaire did not ask clearly for skin lesions during the course of the disease (after the time of onset).

Cardiomyopathy was reported for 2 early-onset patients but was denied for 32 others. This finding is in agreement with earlier observations of cardiomyopathy in PA14 and underlines that it may be an important complication in PA in the long run. Recently, after the data collection for this report had been completed, prolonged QT intervals were found in several of the patients examined in this regard.15

Monitoring of PA patients depends very much on the clinical picture, laboratory parameters reflect a present metabolic decompensation but give only little notice in advance.

Thus far, there is no established and generally accepted laboratory parameter for the long-term monitoring in PA, although odd-numbered long-chain fatty acids and acylcarnitines have been studied in this regard.16-19 Residual activity of PCC neither is a marker for the severity of the disease nor provides information on the outcome.5 Similarly, although some mutations are known that are associated with certain courses of PA,20 no general association has been found between the time of onset and severity of the disease and certain genotypes. Notably, there may even exist a great difference in the severity of the disease between affected siblings.21

During the 5 years since the workshop has taken place, no real progress in PA has been achieved, neither in therapeutic recommendations (e.g., the optimum amount of protein intake) nor regarding optimal parameters for long-term monitoring of PA patients.

The introduction of tandem mass spectrometry into general newborn screening should lead to earlier diagnosis. It remains to be demonstrated that this will lead to a better outcome in PA patients. It certainly should help to minimize the initial insult caused by the acute metabolic decompensation of neonates and to decrease mortality as well as the variability in neurologic outcome. Our data from the prescreening era could become useful to demon\strate the impact of unselective newborn screening on PA. In view of the great variations between the treatment and monitoring protocols used at the various institutions involved in the follow-up of single or few PA patients, a registry of PA patients and a prospective multicenter- based study on PA are warranted to provide evidence for rational patient care in the future.

Acknowledgments

The following physicians and scientists are gratefully acknowledged for participating in the Salzburg Workshop on Propionic Acidemia and/or contribution of patient data: S. Albers (Mnster, Germany), K. Baerlocher (St. Gallen, Switzerland), H. D. Bakker (Amsterdam, The Netherlands), R. Baumgartner (Basel, Switzerland), A. Burlina (Padova, Italy), F. Eyskens (Antwerp, Belgium), P. Freisinger (Mnchen, Germany), J. Herwig (Frankfurt, Germany), G. de Jong (Rotterdam, The Netherlands), A. Kamper (Salzburg, Austria), J. B. G. de Klerk (Rotterdam, The Netherlands), H. G. Koch (Mnster, Germany), C. Korenke (Gttingen/ Oldenburg, Germany), W. Lehnert (Freiburg, Germany), R. Mallmann (Bonn/Bochum, Germany), E. Mnch (Berlin, Germany), D. Mslinger (Wien, Austria), A. Muntau-Heger (Mnchen, Germany), H. Niederhoff (Freiburg, Gemany), E. Plchl (Salzburg, Austria), R. Puttinger (Salzburg, Austria), W. Roschinger (Mnchen, Germany), A. A. Roscher (Mnchen, Germany), S. Scheibenreiter (Wien, Austria), H. Schmidt (Heidelberg, Germany), K. O. Schwab (Freiburg, Germany), G. P. A. Smit (Groningen, The Netherlands), R. Steinfeld (Hamburg/ Gttingen, Germany), S. Stckler- Ipsiroglu (Wien, Austria), D. Sobetzko (Zrich, Switzerland), A. Superti-Furga (Zrich/Lausanne, Switzerland), B. Szczerbak (Friedrichsdorf, Germany), F. K. Trefz (Reutlingen, Germany), U. Wendel (Dsseldorf, Germany), V. Veitl (Puch, Austria), H. Wick (Basel, Switzerland), and J. Zeman (Praha, Czech Republic).

We especially thank Dr. B. Szczerbak (Milupa GmbH; Friedrichsdorf, Germany) for her input in the preparation of this report and continuous encouragement.

REFERENCES

1. Fenton WA, Gravel WA, Rosenblatt DS. Disorders of propionate and methylmalonate metabolism. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Diseases. New York: McGraw-Hill; 2001:2165-2193.

2. Childs B, Nyhan WL, Borden M, et al. Idiopathic hyperglycinemia and hyperglycinuria: a new disorder of amino acid metabolism. Pediatrics. 1961;27:522-538.

3. Hsia YE, Scully KJ, Rosenberg LE. Defective propionate carboxylation in ketotic hyperglycinaemia. Lancet. 1969;1:757-758.

4. Hsia YE, Scully KJ, Rosenberg LE. Inherited propionyl-CoA carboxylase deficiency in 'ketotic hyperglycinemia.' J Clin Invest. 1971;50:127-130.

5. Lehnert W, Sperl W, Suormala T, Baumgartner ER. Propionic acidemia: clinical, biochemical and therapeutic aspects. Experience in 30 patients. Eur J Pediatr. 1994;153(Suppl 1):68-80.

6. Wolf B, Hsia E, Sweetman L, et al. Propionic acidemia: a clinical update. J Pediatr. 1981;99:835-846.

7. Cornejo V, Colombo M, Duran G, et al. Diagnostico y seguimento de 23 ninos con acidurias orgnicas. Rev Md Chile. 2002;130:259-266.

8. North KN, Korson MS, Gopal YR, et al. Neonatal-onset propionic acidemia: neurologic and developmental profiles, and implications for management. J Pediatr. 1995;126:916-922.

9. Surtees RAH, Matthews EE, Leonard JV. Neurologic outcome of propionic acidemia. Pediatr Neurol. 1992;8:333-337.

10. Van der Meer SB, Poggi F, Spada M, et al. Clinical outcome and long-term managment of 17 patients with propionic acidemia. Eur J Pediatr. 1996;155: 205-210.

11. Van Gennip AH, Bakker HD, Droog RP, et al. Complete deficiency of propionyl CoA carboxylase in an adult with "atypical propionic acidemia." Abstracts of Communications, 24th Annual Symposium of the SSIEM 1986, Amersfoort, The Netherlands, p41.

12. Thompson GN, Chalmers RA, Walter JH, et al. The use of raetronidazole in management of methylmalonic and propionic acidaemias. Eur J Pediatr. 1990;149:792-796.

13. Van Calcar SC, Harding CO, Lyne P, et al. Renal transplantation in a patient with methylmalonic acidaemia. J Inherit Metab Dis. 1998;21:729-737.

14. Massoud AF, Leonard JV. Cardiomyopathy in propionic acidaemia. Eur J Pedialr. 1993;152:441-445.

15. Skladal D, Baumgartner D, Konstanlopoulou V, et al. Prolonged QT intervals in propionic acidemia. J Inherit Metab Dis. 2002;25(Suppl 1):49, abstract 097-P.

16. Divry P, Vianey-Saban C, Guffon N, Mathieu M. Odd-numbered long-chain fatty acids (OLCFA) in patients with propionic (PA) and methylmalonic (MMA) acidurias: a follow-up. J Inherit Metab Dis. 1998;21 (Suppl 2):43, abstract A86.

17. Sperl W, Murr C, Skladal D, et al. Odd-numbered long-chain fatty acids in propionic acidaemia. Eur J Pediatr. 2000;159:54-58.

18. Wendel U, Baumgartner R, van der Meer SB, Spaapen LJM. Accumulation of odd-numbered long-chain fatty acids in fetuses and neonates with inherited disorders of propionate metabolism. Pediatr Res. 1991:25:403-405.

19. Skladal D, Rschinger W, Roscher AA, Sass JO. The role of propionyl carniline in the management of patients with propionic acidemia. Annual Meeting, Society of Inherited Metabolic Disorders, Miami, FL, March 2001, poster.

20. Perez-Cerda C, Merinero B, Rodriguez-Pombo P, et al. Potential relationship between genotype and clinical outcome in propionic acidaemia patients. Eur J Hum Genet. 2000;8:187-194.

21. Wolf B, Paulscn EP, Hsia YE. Asymptomatic propionyl CoA carboxylase deficiency in a 13-year-old girl. J Pediatr. 1979;95:563- 565.

J. O. Sass, Dr rer nat1

M. Hofmann, Dr med univ2

D. Skladal, Dr med univ3

E. Mayatepek, Prof Dr med univ4

B. Schwahn, Dr med univ4

W. Sperl, Prof Dr med univ2

1 Stoffwechsellabor, Zentrum fr Kinderheilkunde und Jugendmedizin, Universittsklinikum Freiburg, Freiburg, Germany; 2 Universittsklinik fr Kinder-und Jugendheilkunde, Paracelsus Medizinische Privatuniversitt, Salzburg, Austria; 3 Universittsklinik fr Kinder-und Jugendheilkunde, Innsbruck, Austria; 4 Klinik fr Allgemeine Pdiatrie, Zentrum fr Kinder-und Jugendmedizin, Heinrich-Heine-Universitt Dsseldorf, Germany.

The Salzburg Workshop on Propionic Acidemia (Oct. 9-11, 1998) was financially and organizationally supported by Milupa GmbH & Co KG, Friedrichsdorf, Germany.

Reprint requests and correspondence to: Dr. Jrn Oliver Sass, Stoffwechsellabor, Zentrum fr Kinderheilkunde und Jugendmedizin, Universittsklinikum Freiburg, Mathildenstr. 1, D-79106 Freiburg, Germany.

2004 Westminster Publications, Inc., 708 Glen Cove Avenue, Glen Head, NY 11545, U.S.A.

Copyright Westminster Publications, Inc. Nov/Dec 2004

Source: Clinical Pediatrics

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