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PEDIATRICS Vol. 110 No. 6 December 2002, pp. 1204-1211

Incidence and Short-Term Outcome of Children With Symptomatic Presentation of Organic Acid and Fatty Acid Oxidation Disorders in Germany

Daniela A. Klose, MD*, Stefan Kölker, MD*, Beate Heinrich, MA{ddagger}, Viola Prietsch, MD*, Ertan Mayatepek, MD*, Rüdiger von Kries, MD§ and Georg F. Hoffmann, MD*

Division of Metabolic and Endocrine Disorders, University Children’s Hospital, Heidelberg, Germany
ESPED Office, University Children’s Hospital, Düsseldorf, Germany
Institute of Social Pediatrics and Adolescent Medicine, Ludwig-Maximilians-University of Munich, Germany

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   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
Objective. To determine the incidence of symptomatic children with inherited organic acid disorders (OADs) and fatty acid oxidation disorders (FAODs) in Germany.

Methods. An active surveillance of symptomatic children with inherited OADs and FAODs was conducted during a time period of 24 months (1999–2000) in Germany. Monthly inquiries were sent to all Departments of Pediatrics by the German Pediatric Surveillance Unit (ESPED) and quarterly to all specialized metabolic laboratories. Newly diagnosed patients were added to the database, recording clinical and biochemical information via a standardized questionnaire.

Results. Prospective surveillance enrolling 844 575 children identified a total of 57 symptomatic children with newly diagnosed OADs or FAODs in states with conventional neonatal screening, resulting in an estimated cumulative incidence of 1:14 800. The most frequent diagnosis among these children was medium-chain acyl-CoA dehydrogenase deficiency (n = 20). The majority of symptomatic children revealed clinical symptoms during the first year of life (n = 36), frequently presenting with acute metabolic crises (n = 31). Eight children died during these crises. Notably, 47 of the symptomatic children suffered from diseases potentially detectable by expanded neonatal screening programs. This subgroup included 29 children presenting with metabolic crises and 7 of the 8 deaths.

Conclusions. Despite increased clinical awareness of OADs and FAODs, the mortality and morbidity for these children remains high, if they are diagnosed after manifestation of clinical disease. An introduction of nationwide neonatal screening programs would change the focus for organic acid analysis from patients presenting with acute metabolic crises to more chronic clinical presentations, especially the cerebral organic acid disorders.

Key Words: organic acid disorders • fatty acid oxidation disorders • epidemiology • ESPED • neonatal screening

Abbreviations: OAD, organic acid disorder • FAOD, fatty acid oxidation disorder • MS-MS, tandem mass spectrometry • CPT, carnitine palmitoyltransferase • MCAD, medium-chain acyl-CoA dehydrogenase • LCHAD, long-chain 3-hydroxyacyl-CoA dehydrogenase • VLCAD, very long-chain acyl-CoA dehydrogenase


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
Organic acids and fatty acids comprise a group of carbonic acids physiologically occurring as intermediates in a variety of intracellular metabolic pathways, such as catabolism of amino acids, ß-oxidation of fatty acids, tricarboxylic acid cycle, and neurotransmitters, as well as cholesterol biosynthesis. Organic acid disorders (OADs) and fatty acid oxidation disorders (FAODs) are caused by autosomal recessively inherited deficiencies of single enzymes in the outlined metabolic pathways. They are considered to be the most common, life-threatening inborn errors of metabolism.1–19 Variability in these diseases is remarkable, and epidemiologic data are sparse.

Because most of these disorders present with acute metabolic decompensation precipitated by periods of prolonged fasting and/or infectious diseases usually rapidly progress to organ failure and early death, there are often no specific early signs in these patients that would allow a timely diagnosis. Outcome in these diseases is related to the prevention of acute metabolic decompensation rather than to genotype or residual enzyme activity.6,14, 20 Thus, high frequency, high mortality, and high morbidity coupled with treatability in OADs and FAODs make these diseases good candidates for an implementation into expanded neonatal screening programs.21–25 At present, the following diseases are reliably detectable by tandem mass spectrometry (MS-MS)-based determination of acylcarnitine profiling in dried blood spots: Classical forms of methylmalonic acidurias (mut°, mut-), propionic aciduria, isovaleric aciduria, glutaric aciduria type I, maple syrup urine disease, malonic aciduria, carnitine palmitoyltransferase (CPT) I and II deficiency, carnitine translocase deficiency, medium-chain acyl-CoA dehydrogenases (MCAD) deficiency, long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency, 3-methylcrotonyl-CoA carboxylase, HMG-CoA lyase deficiency, and 2-methyl-3-hydroxybutyric aciduria (ß-ketothiolase).22–27 It is not yet clarified whether other inherited diseases, eg, very long-chain acyl-CoA dehydrogenase (VLCAD), carnitine transporter defect, and glutaric aciduria type II, are reliably detectable in newborns by MS-MS.23,28 In contrast to expanded neonatal screening, conventional screening in Germany only detects phenylketonuria, galactosemia, hypothyroidism, adrenogenital syndrome, and biotinidase deficiency.

Before expanded neonatal screening programs for OADs and FAODs can be widely advocated, data are needed on incidence, clinical presentation, and outcome of symptomatic children diagnosed after clinical presentation. Therefore, we have prospectively investigated the frequencies, clinical presentation, and outcome of symptomatic children with OADs and FAODs in Germany during a 2-year interval.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
Active Surveillance of Symptomatic Children With OADs and FAODs From 1999 Through 2000
Symptomatic, newly diagnosed children with OADs and FAODs were included in the nationwide surveillance by the Erhebungseinheit für seltene pädiatrische Erkrankungen in Deutschland29 between January 1, 1999, and December 31, 2000 (24 months), in Germany. Inquiries were sent monthly to all Departments of Pediatrics (source A) and quarterly to all specialized metabolic laboratories (source B). Newly diagnosed patients were included into a database via a standardized anonymous questionnaire, evaluating presumed diagnosis and the dates of birth, first clinical presentation, suspicion of diagnosis, and the beginning of specific treatment, as well as laboratory findings and methods used for confirmation of the diagnosis, eg, loading tests, involvement of enzyme activity, and molecular analyses.

False-positive and double reports were excluded from the primary data sets. Furthermore, those children born in German states with already established expanded MS-MS-based neonatal screening programs (Baden-Württemberg, Bavaria, Lower Saxonia) were excluded from the study to avoid underestimation of disease frequencies. Period prevalence of definite cases with OADs and FAODs was estimated from the number of births in states with conventional neonatal screening during the surveillance period (n = 844 575 neonates). Cases reported in 1999 and 2000 could be born before 1999 and could therefore belong to earlier birth cohorts, whereas children from the 1999 and 2000 birth cohorts might still have been presymptomatic during the surveillance period. These period prevalence data can be assumed to reflect the expected disease-related outcome of the children born in 1999–2000, because the birth rates in Germany have not changed essentially since 1995 and the probability of being diagnosed after presentation with symptoms is likely to have also remained similar.

Capture-Recapture Analysis
After completing the surveillance and elimination of false-positive and double reports, we used capture-recapture methods to evaluate the completeness of reported OADs and FAODs in Germany. The capture-recapture methodology was designed to estimate population sizes on the basis of the proportion of subjects (re)captured by 2 or more sources. Capture-recapture has been applied to a wide range of epidemiologic fields.30 It relies on the basic assumptions that 1) the population should not change in composition during times of capture, 2) sufficient information should allow to match subjects from different sources in a unique manner, 3) the sources should be independent, and 4) each subject should have an equal likelihood of capture.31 These assumptions are fulfilled in our study, because capture-recapture analysis was only performed in definite cases of OADs and FAODs after finishing the prospective surveillance. The 2 independent data sources (Pediatrics departments and specialized metabolic laboratories) were linked on the patients’ diagnosis, date of birth, initials of first prename and surname, and postal code. We computed Chapman estimates of the true number of cases of symptomatic OADs and FAODs by pairwise matching of the sources.30 na denotes the number of cases captured in data source A, nb denotes the number of cases captured in data source B, and nab denotes the number of cases captured in both sources. The Chapman estimate of the true number of cases is then calculated as

All data are anonymous. The study has been approved by the local ethics committee.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 CONCLUSION
 REFERENCES
 
Active Surveillance of Symptomatic Children With OADs and FAODs
A total of 325 initial notifications were received in the 2 prospective surveillance systems from 1999–2000. One hundred forty children were recorded from German Departments of Pediatrics and another 185 children were from the German metabolic laboratories. After elimination of false-positive reports, double reports, and children from states with already established MS-MS-based neonatal screening programs (Baden-Württemberg, Bavaria, Lower Saxonia), there were 64 incident cases with confirmed diagnosis of OADs and FAODs during this time period in a population of 844 575 children from states with conventional screening only (Table 1). From these children, 7 asymptomatic siblings of previously diagnosed children with OADs and FAODs were further excluded from the study, resulting in 57 symptomatic children (Fig 1). Forty-seven children suffered from diseases detectable by MS-MS-based expanded neonatal screening, 41 of those becoming symptomatic after the age of 7 days, thus suggesting that they would have had potential benefit from early detection (Fig 1).


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  		TABLE 1. Symptomatic Children With Newly Diagnosed OADs and FAODs During 1999–2000

 


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  		Fig 1. Identification of the definite study population. Initially, a total of 325 notifications were independently achieved from Pediatric departments (source A) and specialized metabolic laboratories (source B) via the standardized prospective surveillance from 1999–2000 in Germany. Only reports from states without MS-MS-based expanded neonatal screening programs were included into the study. After removal of false-positive and double reports, as well as asymptomatic children, 57 symptomatic children with confirmed diagnosis of OADs and FAODs were identified. Forty-seven of these children suffered from diseases that are detectable by expanded neonatal screening, with 41 presenting after the first postnatal week.

 
Among the symptomatic children, 30 patients suffered from OADs and 27 patients from FAODs (Table 1). MCAD deficiency was the most frequent disease diagnosed (n = 20; 74% of reported FAODs; estimated incidence: 1 in 42 200 newborns; capture-recapture analysis: 1 in 35 200 newborns). Sex ratio was balanced in FAODs but revealed a higher frequency of symptomatic males than females in OADs (Table 1).

Estimation of Incidences and Capture-Recapture Analysis
Seven cases (12%) were only identified by Pediatrics departments, whereas 28 (49%) children were only detected by specialized metabolic laboratories. Another 22 patients (39%) were independently identified by both sources. Capture-recapture calculations revealed a total of 66 children (Table 2), estimating 9 symptomatic children to be missed by the 2-year surveillance. Based on these calculations, the cumulative incidence for symptomatic OADs and FAODs in German states with conventional neonatal screening was estimated to 1 in 14 800 births by active surveillance and to 1 in 12 800 births by capture-recapture analysis (Table 3). The incidence of OADs and FAODs detectable by expanded neonatal screening programs was 1 in 18 000 and 1 in 16 600 births, respectively, after capture-recapture analysis (Table 3).


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  		TABLE 2. Capture-Recapture Analysis

 

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  		TABLE 3. Estimation of Symptomatic Children With Confirmed Diagnosis of OADs and FAODs

 
Clinical Presentation and Outcome
The majority of newly diagnosed children became symptomatic during the first year of life (n = 36; 65%; Fig 2A). Diagnosis was suspected with a median age of 180 days (10th to 90th percentile [P10-P90]: 6–2153 days). A comparison of symptomatic children with OADs or FAODs revealed that OADs (median age: 90 days; P10-P90: 4–2035 days) presented earlier than FAODs (median age: 381 days; P10-P90: 53–2607 days; Fig 2B). A comparison between diseases detectable or not by expanded neonatal screening revealed no relevant differences between the 2 groups (Fig 2C).



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  		Fig 2. Age of patients at their first episode diagnosed with or suspected of having OADs or FAODs. A, Age distribution of the complete group of symptomatic children with OADs and FAODs. Fatal episodes are marked by asterisks (*). B, OADs were detected earlier and revealed a wider time frame of clinical manifestation than FAODs. C, Age distribution of diseases detectable by expanded neonatal screening was similar to those not detectable.

 
The most frequent clinical presentation in FAODs (n = 17; 63%) and OADs (n = 14; 47%) was acute metabolic decompensation precipitated by febrile illness, or in 1 child by scheduled surgery (Fig 3A). In OADs, acute metabolic decompensation occurred earlier and revealed a wider time window of manifestation (median age: 61 days; P10-P90: 4–2200 days) than in FAODs (median age: 330 days; P10-P90: 53–750 days; Fig 3B). Eight children (26%) died during acute metabolic decompensation because of MCAD deficiency (n = 2), LCHAD deficiency (n = 2), CPT II deficiency, glutaric aciduria type I and II, and fumaric aciduria (each n = 1; Fig 3A, Table 1). Additional clinical presentations included psychomotor retardation (OADs: n = 7, 23%; FAODs: n = 4, 15%), failure to thrive (OADs: n = 7, 23%; FAODs: n = 1, 4%), and others (cardiomyopathy, hemolytic anemia, seizures, macrocephalus, and facial dysmorphism). In 5 children (9%), no sufficient clinical information could be obtained through the questionnaire (Fig 3A). A comparison of symptomatic children with diseases detectable or not by expanded neonatal screening programs revealed a marked difference in the clinical presentation (Fig 3C). Acute metabolic decompensation was predominantly found in children with diseases detectable by expanded neonatal screening (n = 29; 62%) but was relatively rare in those not detectable by expanded neonatal screening (n = 2; 20%). In the latter group, psychomotor retardation was the most frequent presentation (n = 7; 70%), whereas it was relatively rare in those diseases detectable by expanded neonatal screening (n = 4; 9%; Fig 3C). Notably, diagnosis was suggested much earlier in children presenting with acute metabolic crises (median age: 210 days) than those presenting with psychomotor retardation (median age: 1183 days; Fig 3D).



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  		Fig 3. Clinical presentation in symptomatic children with OADs (n = 30) and FAODs (n = 27). A, Comparison of clinical presentation between symptomatic children with OADs and FAODs. B, Age distribution of metabolic crises in OADs and FAODs. C, Comparison of clinical presentation of children with diseases detectable or not by expanded neonatal screening programs. D, Diagnosis was suggested earlier in children presenting with acute metabolic crises and those presenting with psychomotor retardation.

 
Short-term outcome of symptomatic children revealed the following distribution: Eight children died (14%; n = 2: MCAD and LCHAD deficiency; n = 1: CPT II deficiency, isovaleric aciduria, fumaric aciduria, glutaric aciduria type II), 16 children suffered from residual defects or showed progressive neurologic impairment (28%; n = 4: MCAD deficiency; n = 3: glutaric aciduria type I; n = 2: Canavan disease; n = 1: VLCAD and short-chain acyl-CoA dehydrogenase deficiency, Barth disease, 4-hydroxybutyric, malonic, 2-methyl-3-hydroxybutyric acidurias), 15 children revealed an unaffected development or completely recovered from metabolic crises (26%; n = 8: MCAD deficiency; n = 2: methylmalonic and propionic acidurias; n = 1: 2-hydroxyglutaric and isovaleric acidurias, maple syrup urine disease), and in 15 children short-term outcome was questionable or not reported (26%; n = 6: MCAD deficiency; n = 2: propionic aciduria; n = 1: LCHAD and VLCAD deficiency, isovaleric, methylmalonic and malonic acidurias, Canavan disease, maple syrup urine disease). Two children suffered from repeated metabolic crises after introduction of dietary treatment (n = 1: propionic aciduria, maple syrup urine disease). Although the definite outcome of these children can not be precisely predicted because of the short follow-up, our data demonstrate that OADs and FAODs cause a high frequency of mortality and morbidity in affected children. It can be suggested that long-term outcome will identify additional children with sequelae becoming obvious at a later time point of development.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
CONCLUSION
 REFERENCES
 
OADs and FAODs are suggested to be the most common, life-threatening inborn errors of metabolism.1–19 The frequency, high mortality, and high morbidity coupled with a treatability in OADs and FAODs make these diseases good candidates for an implementation into expanded neonatal screening programs. In the present study, enrolling 844 575 children from German states with conventional neonatal screening, we identified a total number of 57 children with OADs and FAODs during 1999–2000, resulting in an estimated incidence of 1 in 14 800 births (capture-recapture analysis: 1 in 12 800 births).

Incidence estimates for rare inborn errors of metabolism represent an essential prerequisite for decisions regarding the inclusion of these conditions in screening programs. If these estimates are based on figures from expanded neonatal screening programs only, the estimates may be too high, whereas estimates from detection after presentation with symptoms (like in the present study) indicate the minimal number of clinically relevant cases. Surveillance of symptomatic children may lead to an underestimation of definite cases, because it cannot provide information on the proportion of children who remain undiagnosed (eg, sudden infant death syndrome) or asymptomatic. For MCAD deficiency, the most frequent single disease in the present study (n = 20 children), there exists some estimates for the rate of cases detectable in expanded neonatal screening programs from the United States (United States: 1 in 15 000 births)16 and United Kingdom populations (United Kingdom: 1 in 12 600 births).20 These data are very similar to the first data from expanded neonatal screening programs for the German population, ie, 1 in 10 600 births.33 Notably, the incidence of symptomatic children with MCAD deficiency was 1 in 42 200 births (capture-recapture analysis: 1 in 35 200) in the present study, revealing a remarkable underestimation of incidence by this approach. This finding is in line with previous studies from the United States as well as the United Kingdom, estimating an incidence of 1 in 30 000, respectively, and 34 000 births for symptomatic MCAD deficiency.11,20

Early diagnosis and treatment is the conditio sine qua non for survival and a good outcome in OADs and FAODs.3,6–8 In the present study, morbidity and mortality in symptomatic children still proved to be high despite increased awareness and knowledge of pediatricians as well as unrestricted access to metabolic testing. Most frequently, children presented with acute metabolic crises (n = 31; 54%), leading to death in 8 children (26% of children suffering metabolic crises).

Because acute metabolic crises are related to death and severe sequelae in affected children, those OADs and FAODs detectable by expanded neonatal screening programs are likely to benefit the most from early diagnosis and treatment. In the present study, we identified 47 children with screenable diseases, 29 children of whom presented with metabolic crises. Six children revealed acute crises during the first days of life and, thus, developed metabolic decompensation too early to really benefit from expanded neonatal screening. However, the remaining 41 children (ie, 71% of all cases with OADs and FAODs) would have been detectable by expanded neonatal screening and would have likely benefitted from early diagnosis and treatment.

Introduction of nationwide MS-MS-based expanded neonatal screening programs would change the focus for organic acid analysis from patients presenting with acute metabolic crises to more chronic clinical presentation. In the present study, we demonstrated a remarkable difference in the clinical presentation of OADs and FAODs detectable by expanded neonatal screening to those that are not. Diseases detectable by expanded neonatal screening revealed a higher frequency of acute metabolic crises (n = 29; 62%) and death (n = 7; 15%) than those not detectable by expanded neonatal screening (metabolic crises: n = 2, 20%; death: n = 1, 10%). The latter group showed psychomotor retardation (n = 7; 70%) as the most frequent clinical presentation. These differences may be explained by the high proportion of cerebral OADs (n = 8; 80%) in this group—including Canavan disease (n = 3), L-2-hydroxyglutaric aciduria (n = 2), 4-hydroxybutyric aciduria (n = 1), and mevalonic aciduria (n = 1). Clinically, cerebral OADs present with (progressive) neurologic features but without characteristic symptoms like hypoglycemia, metabolic acidosis, or lactic acidosis often present in classic OADs (eg, methylmalonic and propionic acidurias).5 Acute decompensation may present as encephalopathic crises in this disease group, in particular in glutaric aciduria type I and severe variants of D-2-hydroxyglutaric aciduria. Glutaric aciduria type I is screenable by expanded neonatal screening, whereas D-2-hydroxyglutaric aciduria is extremely rare.13


   CONCLUSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
REFERENCES
 
These are the first data estimating potentially treatable metabolic disorders that might benefit from MS-MS-based expanded neonatal screening, identified after presentation with symptoms from a population of considerable size. It is clearly demonstrated that morbidity and mortality are still high in these inborn errors of metabolism. The cumulative incidence is high enough to justify an implementation in expanded neonatal screening. Definite decision-making regarding the expansion of expanded neonatal screening programs also requires information on the potential achievements of early treatment of these conditions. An introduction of nationwide neonatal screening would change the spectrum of diagnoses ascertained by organic acid analysis from patients presenting with acute metabolic crises to more chronic clinical presentations, especially the cerebral organic acid disorders.


   ACKNOWLEDGMENTS
 
This study was supported by APS (Arbeitsgemeinschaft für Pädiatrische Stoffwechselstörungen, Germany) and the SHS company (Heilbronn, Germany).

We thank all German Departments of Pediatrics and metabolic laboratories for contributing to the study and for their cooperation.


   FOOTNOTES
 
Received for publication Feb 22, 2002; Accepted Jul 8, 2002.

Reprint requests to (G.F.H.) Department of General Pediatrics, Im Neuenheimer Feld 150, D-69120 Heidelberg, Federal Republic of Germany. E-mail: georg_hoffmann{at}med.uni-heidelberg.de


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 

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PEDIATRICS (ISSN 1098-4275). ©2002 by the American Academy of Pediatrics




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