Incidence rates of progressive childhood encephalopathy in Oslo, Norway: a population based study
© Stromme et al; licensee BioMed Central Ltd. 2007
Received: 27 January 2007
Accepted: 27 June 2007
Published: 27 June 2007
Progressive encephalopathy (PE) in children is a heterogeneous group of diseases mainly composed of metabolic diseases, but it consists also of neurodegenerative disorders where neither metabolic nor other causes are found. We wanted to estimate the incidence rate and aetiology of PE, as well as the age of onset of the disease.
We included PE cases born between 1985 and 2003, living in Oslo, and registered the number presenting annually between 1985 and 2004. Person-years at risk between 0 and 15 years were based on the number of live births during the observation period which was divided into four 5-year intervals. We calculated incidence rates according to age at onset which was classified as neonatal (0–4 weeks), infantile (1–12 months), late infantile (1–5 years), and juvenile (6–12 years).
We found 84 PE cases representing 28 diagnoses among 1,305,997 person years, giving an incidence rate of 6.43 per 100,000 person years. The age-specific incidence rates per 100,000 were: 79.89 (<1 year), 8.64 (1–2 years), 1.90 (2–5 years), and 0.65 (>5 years). 66% (55/84) of the cases were metabolic, 32% (27/54) were neurodegenerative, and 2% (2/84) had HIV encephalopathy. 71% (60/84) of the cases presented at < 1 year, 24% (20/84) were late infantile presentations, and 5% (4/84) were juvenile presentations. Neonatal onset was more common in the metabolic (46%) (25/55) compared to the neurodegenerative group (7%) (2/27). 20% (17/84) of all cases were classified as unspecified neurodegenerative disease.
The overall incidence rate of PE was 6.43 per 100,000 person years. There was a strong reduction in incidence rates with increasing age. Two-thirds of the cases were metabolic, of which almost half presented in the neonatal period.
Progressive neurological disease in children poses an important challenge to our health system in terms of diagnosis and management [1–3]. In the present study, we focused on children presenting with signs of progressive CNS disease associated with impairment of cognitive functioning, designated progressive encephalopathy (PE). In the literature, PE is often used interchangeably with neurodegenerative encephalopathy. Both terms lack a firm definition, but we preferred PE because it encompasses clinically progressive conditions without demonstrable neuronal loss as well as those with a demonstrable loss of neural tissue, most often detected by magnetic resonance imaging (MRI) examination.
Although the different diseases causing PE are individually rare, their cumulative incidence has been estimated to be 0.5 per 1000 live births , which is within the same range as other major neurological impairments, such as neural tube defects  or infantile hydrocephalus , and approximately half the incidence of cerebral palsy in full term children . PE is predominantly caused by inborn errors of metabolism, hereafter called metabolic diseases. PE also contains a relatively large mixed group of neurodegenerative disorders without an identifiable metabolic deficiency, hereafter designated neurodegenerative disease. Infectious, inflammatory or toxic aetiologies may also be considered as causes of PE. Epidemiological studies have most often focused on the cumulative incidence of known diagnoses associated with PE, particularly metabolic diseases. Cases with such diagnoses have either been discovered through screening programs for metabolic diseases or they have been registered after clinical presentation suggestive of metabolic deficiency [8–10]. The burden of disease may be heavily felt by patients and caregivers when the diagnosis remains unknown despite extensive investigation. It has been estimated that approximately one-third of all paediatric brain disorders without a known diagnosis, also called "anonymous" brain disorders, can be classified as PE . As epidemiological data are scarce, we aimed to estimate the overall incidence rate of PE with its different aetiologies and to determine the age of onset of symptoms of the disease.
In accordance with Uvebrant et al , PE was divided into metabolic, neurodegenerative, and infectious aetiology groups. The metabolic group was divided into disorders involved in metabolic processes related to subcellular organelles (lysosomes, mitochondrial respiratory chain, and peroxisomes) or defects of intermediate metabolism (organic acidurias, fatty acids oxidation disorders, urea cycle disorders, galactosemia, and unspecified intermediate metabolic defects). The latter group contained a few patients in whom specific management, such as a galactose free diet in galactosemia, protein restriction, and vitamin B12 supplementation in methylmalonic aciduria, and appropriate caloric supply in fatty acid oxidation defects, prevented them from developing clinical signs of disease progression.
The neurodegenerative group consisted of patients with progressive loss of neural tissue, where a metabolic or other aetiology could not be detected. This group was subdivided into a group of patients with a specified or known diagnosis and a group of patients in whom an aetiological diagnosis had not been identified despite extensive work up. The degenerative course of the disease in the unspecified degenerative group was documented with repeated clinical assessments and MRI examination of the brain showing atrophy of brain tissue. We classified patients according to the part of the CNS that was predominantly affected by the degenerative process: cerebral cortex, cerebral white matter, basal ganglia, cerebellum, and brain stem. The infectious group consisted of patients with encephalopathy caused by infectious agents, for example human immunodeficiency virus (HIV). We recorded the age of onset of symptoms of the disorder and the age when an aetiological diagnosis was established. In the patients with unspecified neurodegenerative disease, we assigned the time of "diagnosis" as the age when a down-hill course in each case was recognized. The age of onset was defined as neonatal (0–4 weeks), infantile (1–12 months), late infantile (1–5 years), juvenile (6–12 years), or late juvenile (>12 years).
We excluded patients with spinocerebellar ataxia and spinal muscular atrophy and other neuromuscular disorders if not accompanied by signs of encephalopathy. We did not include children with multiple sclerosis, as they usually do not exhibit disturbances of cognitive functioning in the early years. Developmental disorders such as Rett syndrome and autism were excluded. In Rett syndrome, there is a period of regression in the early phase. However, mental capacity does not continue to deteriorate in this disorder . In autism, there may be a limited period of regression. However, autism spectrum disorders are not typically associated with progressive brain atrophy detected by MRI. The two diseases detected by the Norwegian newborn screening program, phenylketonuria and congenital hypothyroidism, were also excluded from the study, as affected individuals would not present with signs of encephalopathy.
ICD codes used in the search for cases of progressive encephalopathy in children born between 1985 and 2003
Inborn errors of metabolism
Sphingolipids and other lipid storage disorders
Purin and pyrimidine
Other aetiological diagnoses
Systemic atrophies primarily affecting CNS
Extrapyramidal and other movement disorders
Other CNS degenerative diseases
HIV with dementia
Unspecified metabolic disease
Other CNS disease
Incidence rates and cumulative incidences
In order to compare our results with other investigations, we also calculated cumulative incidences per 1000 live births. This was the number of cases divided by the total number of live births in Oslo during 1985 to 2003. The surveillance period for case registration in this study was between 1.1.2004 and 1.8.2006.
The Epi Info 6 statistical software was used for data entry and analysis of frequency distribution of variables. Population statistics for Oslo were provided by the Medical Birth Registry of Norway. The relative risk of PE according to time period and age at onset of disease was estimated with Poisson regression using STATA 9.0. Confidence intervals (CI) for incidence rates were calculated according to Greenland & Rothman , while CI for proportions were based on the Poisson distribution . Odds ratios (OR) were calculated using contingency tables, and p-values were calculated using Fisher's exact test. Differences between median values of age were calculated using the Mann-Whitney U test.
The Norwegian Social and Health Directorate and the Regional Ethics Committee approved the study.
Relative risks of progressive encephalopathy according to time period and age estimated as incidence rate ratios with 95% confidence intervals using Poisson regression
Incidence rate ratios
1.0 (reference value)
1.0 (reference value)
0.01 (0.00 – 0.02)
Aetiological classification and incidence rates in children with progressive encephalopathy
IR per 100,000 person yearsa
A. Subcellular organelles
B. Intermediate metabolism
Fatty acid oxidation defect
Urea cycle disorders
The overall cumulative incidence of PE among 138,550 live births was 0.60 per 1000 (95% CI 0.47–0.73). Other cumulative incidences were: metabolic diseases 0.40 (95% CI 0.30–0.50), lysosomal storage disorders 0.17 (95% CI 0.10–0.24), and organic acidurias combined with fatty acid oxidation defects 0.12 (95% CI 0.06–0.18), per 1000 live births.
Age at the onset of symptoms of disease in children with progressive encephalopathy
Diagnoses in 84 children with progressive encephalopathy
I cell disease (1), alpha-Mannosidosis (1), MLD (3), MPS1 (4), MPS2 (1), MPS3 (1), NCL congenital  (3), NCL3 (4), NPC (3), Salla disease (1), Sandhoff disease (1)
Leigh disease (3)
Adrenoleukodystrophy X-linked (2)
2-methylbutyryl CoA dehydrogenase deficiency a (1), glutaric aciduria (1), L2 hydroxy glutaric aciduria (2), methyl malonic aciduriab (2), multiple carboxylase deficiency (2), propionic aciduria (3)
Fatty acid beta oxidation
MTP (2), MCAD (2), VLCAD (1), unspecified (1)
CPS1 (3), OCT (1)
Galactosemia (4), Unspecified intermediate metabolism (2)
Ataxia teleangiectasia (1), Cockayne syndrome (2), megaloencephalic leukoencephalopathy with subcortical cysts (1), microphthalmia brain atrophy disease  (3), pontocerebellar hypoplasia-infantile spinal muscular atrophy  (1), Schinzel Gideon syndrome (2)
Mainly affecting: basal ganglia (1), cerebellum (8), cerebellum and basal ganglia (1), cerebellum and brain stem (1), cerebral cortex (3), cerebral white matter (3)
HIV encephalopathy (2)
Our investigation showed that 6.0 to 6.5 per 100,000 children between 0 and 15 years of age presented with signs of PE annually. From 1999 on the population was complete and included all person years between 0 and 15 years at risk for getting PE. However, the incidence rates from 2003 and 2004 may be underestimated, as the observation time for children born in 2003 was short. Thus, the most representative part of the observation period was between 1999 and 2002 with an average incidence rate of 6.13 per 100,000 person years (see Figure 2). There was a strong tendency for PE to present early in life, as 32.1% of the cases presented before 4 weeks and 39.3% presented between 1 and 12 months of age (see Table 4). This corresponded to an incidence rate of almost 80 per 100,000 person years below 1 year, approximately 13 times more common than the mean incidence rate in the total childhood population. The male to female ratio of 2 could not be explained by known X-linked inherited disorders, which occurred in only four boys in our study. However, males outnumber females with regards to several types of neurological handicaps, such as mental retardation  and autism .
Incidence rates expressed per person years have not been used as a measure of frequency of PE by other investigators. Consequently, the frequency of known diagnoses in our study was not directly comparable with similarly designed epidemiological studies. However, the cumulative incidence of 0.60 per 1000 live births was close to that of 0.58 per 1000 live births in West Sweden . For metabolic diseases, the cumulative incidence of 0.40 per 1000 (95% CI 0.30–0.50) was somewhat higher than 0.27 per 1000 live births (95% CI 0.269–0.271) in a large-scale Italian study comprising 200 diseases . We did not include phenylketonuria, which has a cumulative incidence of 7.5 per 100,000 live births in Norway . The cumulative incidence of mitochondrial encephalopathy in our study was as low as 2.2 per 100,000 live births, approximately one-third of the cumulative incidence found in Sweden . With a historic cohort design, we were dependent on the information given in the medical charts and may therefore have missed some accuracy regarding diagnoses, particularly for the early years of the observation period. Mitochondrial disorders may have been inadequately diagnosed in Norway. The cumulative incidence of lysosomal storage diseases of 0.17 per 1000 (95% CI 0.10–0.24) in our study was comparable to 0.13 per 1000 in Western Australia  and 0.25 per 1000 in Portugal , while the combination of organic acidurias and fatty acid oxidation defects of 0.12 per 1000 (95% CI 0.06–0.18) in our study was similar to that of 0.13 per 1000 live births in Germany . There was a trend towards identifying an exact molecular cause in patients with known diseases. The potentially increased incidence rate of PE in the non-western immigration population, associated with higher proportion of consanguineous marriages, will be addressed in a separate study.
The neurodegenerative group comprised 32.1% (95% CI 22.4–43.2%) (see Table 3) of all cases, which is comparable to the proportion (28%) in West Sweden . However, we did not include Rett syndrome in our study. The proportion of cases with unspecified neurodegenerative diagnosis of 20.2% (95% CI 12.3–30.4) occurred at an incidence rate of 1.3 per 100,000 person years. The incidence rate of this heterogeneous group has not previously been reported in the literature. Despite extensive investigation, this group may contain patients with rare metabolic diseases or metabolic deficiencies with an unusual presentation. For example, one patient initially classified as having an unspecified neurodegenerative disorder with cerebellar atrophy was eventually diagnosed with juvenile Sandhoff disease  at the age of 15 years. The cerebellum and the basal ganglia are frequently targeted by metabolic deficiency or other genetically determined disorders. The majority of our unspecified neurodegenerative cases demonstrated neural loss in these particular areas.
The clinical course in the neurodegenerative group, both known and unspecified, appeared generally less aggressive than for those in the metabolic group. The proportion with neonatal onset was significantly less compared to the metabolic group. Also, the median age of diagnosis was considerably increasesed in the neurodegenerative compared to the metabolic group. On the other hand, the prospect of therapeutic measures is almost non-existent relative to the increasing number of metabolic diseases which have become amenable to treatment, such as lysosomal storage disorders .
The incidence rate of PE in children was estimated to be between 6.0 and 6.5 per 100,000 person years, while the cumulative incidence was 0.6 per 1000 live births. Almost two-thirds of the cases were metabolic disorders, and one-third other neurodegenerative diseases. Unspecified neurodegenerative diseases accounted for one-fifth of all cases. There was a strong reduction in the risk of PE with increasing age. This trend was most noticeable in the metabolic group, in which less than half had neonatal presentation. The neurodegenerative group was characterized by a later onset of symptoms and a markedly older age at the time of diagnosis.
electronic registry of diagnoses
international classification of disease
magnetic resonance imaging
Sven Ove Samuelsen, Faculty of Mathematics, University of Oslo, assisted in the calculation of confidence intervals of incidence rates. Håkon K Gjessing, The Norwegian Institute of Public Health, assisted in calculating the relative risks from Poisson regression. Petter Mowinckel, Department of Pediatrics, Ullevål University Hospital, assisted in creating the figures. Arpad Matlary, Joseph Soosai, Sverre Halvorsen, and Hilde Dahl (Department of Paediatrics), Chantal Tallaksen (Department of Neurology), Ullevål University Hospital, Ola H Skjeldal, Department of Pediatrics, Rikshospitalet-Radium Hospitalet Medical Center, Oslo, Norway, Marjo S. van der Knaap, Department of Child Neurology, VU University Medical Center, Amsterdam, The Netherlands, and Marie T Vanier, Lyon-Sud University Hospital, Lyon, France assisted in the diagnostic evaluation of cases. Jan-Eric Månsson, Institute of Clinical Neuroscience, Sahlgrenska University Hospital, Mölndal, Sweden, was responsible for the enzymatic assays in fibroblasts diagnosing lysosomal storage disorders. Monica Haakonsen and Andres Server, Department of Radiology, Ullevål University Hospital, were the principal MRI investigators. Paul Uvebrant, Department of Pediatrics, Sahlgrenska University Hospital Gøteborg, Sweden, reviewed the manuscript.
- Davies H: Living with dying: families coping with a child who has a neurodegenerative genetic disorder. Axone. 1996, 18: 38-44.PubMedGoogle Scholar
- Gravelle AM: Caring for a child with a progressive illness during the complex chronic phase: parents' experience of facing adversity. J Adv Nurs. 1997, 25: 738-745. 10.1046/j.1365-2648.1997.1997025738.x.View ArticlePubMedGoogle Scholar
- Davidson EJ, Silva TJ, Sofis LA, Ganz ML, Palfrey JS: The doctor's dilemma: challenges for the primary care physician caring for the child with special health care needs. Ambul Pediatr. 2002, 2: 218-223. 10.1367/1539-4409(2002)002<0218:TDSDCF>2.0.CO;2.View ArticlePubMedGoogle Scholar
- Surtees R: Understanding neurodegenerative disorders. Currr Paediatr. 2006Google Scholar
- Lary JM, Edmonds LD: Prevalence of spina bifida at birth--United States, 1983-1990: a comparison of two surveillance systems. MMWR CDC Surveill Summ. 1996, 45: 15-26.PubMedGoogle Scholar
- Persson EK, Hagberg G, Uvebrant P: Hydrocephalus prevalence and outcome in a population-based cohort of children born in 1989-1998. Acta Paediatr. 2005, 94: 726-732. 10.1080/08035250510027336.View ArticlePubMedGoogle Scholar
- Himmelmann K, Hagberg G, Beckung E, Hagberg B, Uvebrant P: The changing panorama of cerebral palsy in Sweden. IX. Prevalence and origin in the birth-year period 1995-1998. Acta Paediatr. 2005, 94: 287-294.View ArticlePubMedGoogle Scholar
- Klose DA, Kolker S, Heinrich B, Prietsch V, Mayatepek E, von KR, Hoffmann GF: Incidence and short-term outcome of children with symptomatic presentation of organic acid and fatty acid oxidation disorders in Germany. Pediatrics. 2002, 110: 1204-1211. 10.1542/peds.110.6.1204.View ArticlePubMedGoogle Scholar
- Nelson J, Crowhurst J, Carey B, Greed L: Incidence of the mucopolysaccharidoses in Western Australia. Am J Med Genet A. 2003, 123: 310-313. 10.1002/ajmg.a.20314.View ArticleGoogle Scholar
- Pinto R, Caseiro C, Lemos M, Lopes L, Fontes A, Ribeiro H, Pinto E, Silva E, Rocha S, Marcao A, Ribeiro I, Lacerda L, Ribeiro G, Amaral O, Sa Miranda MC: Prevalence of lysosomal storage diseases in Portugal. Eur J Hum Genet. 2004, 12: 87-92. 10.1038/sj.ejhg.5201044.View ArticlePubMedGoogle Scholar
- Hagberg B: 'Anonymous'--an organization for families of children with undiagnosed brain diseases. Eur J Paediatr Neurol. 1998, 2: 285-286. 10.1016/S1090-3798(98)80002-0.View ArticlePubMedGoogle Scholar
- Uvebrant P, Lanneskog K, Hagberg B: The epidemiology of progressive encephalopathies in childhood. I. Live birth prevalence in west Sweden. Neuropediatrics. 1992, 23: 209-211.View ArticlePubMedGoogle Scholar
- Hagberg B: Rett syndrome: long-term clinical follow-up experiences over four decades. J Child Neurol. 2005, 20: 722-727.View ArticlePubMedGoogle Scholar
- Organization WH: Manual of the international statistical classification of diseases, injuries, and causes of death. 1967, GenevaGoogle Scholar
- Klassifikasjon av sykdommer, skader og dødsårsaker: norsk utgave av International Classification of Diseases, ninth revision (ICD-9). 1986, Oslo: Statistisk sentralbyrå
- Organization WH: ICD-10International statistical classification of diseases and related health problems : tenth revision. 2004, Geneva, World Health Organization, 2nd ed,Google Scholar
- Greenland S, Rothman DL: Introduction to categorical statistics. Modern Epidemiology. Edited by: Rothman KJ and Greenland S. 1998, Lippincott-Raven, 14: 231-252. 2ndGoogle Scholar
- Altman DG: Practical statistics for medical research. 2006Google Scholar
- Siintola E, Partanen S, Stromme P, Haapanen A, Haltia M, Maehlen J, Lehesjoki AE, Tyynela J: Cathepsin D deficiency underlies congenital human neuronal ceroid-lipofuscinosis. Brain. 2006, 129: 1438-1445. 10.1093/brain/awl107.View ArticlePubMedGoogle Scholar
- Andresen BS, Christensen E, Corydon TJ, Bross P, Pilgaard B, Wanders RJ, Ruiter JP, Simonsen H, Winter V, Knudsen I, Schroeder LD, Gregersen N, Skovby F: Isolated 2-methylbutyrylglycinuria caused by short/branched-chain acyl-CoA dehydrogenase deficiency: identification of a new enzyme defect, resolution of its molecular basis, and evidence for distinct acyl-CoA dehydrogenases in isoleucine and valine metabolism. Am J Hum Genet. 2000, 67: 1095-1103. 10.1086/303105.View ArticlePubMedPubMed CentralGoogle Scholar
- Kleppa L, Kanavin OJ, Klungland A, Stromme P: A novel splice site mutation in the Cockayne syndrome group A gene in two siblings with Cockayne syndrome. Neuroscience. 2006Google Scholar
- Kanavin OJ, Haakonsen M, Server A, Bajwa TJ, van der Knaap MS, Stromme P: Microphthalmia and brain atrophy: a novel neurodegenerative disease. Ann Neurol. 2006, 59: 719-723. 10.1002/ana.20827.View ArticlePubMedGoogle Scholar
- Rudnik-Schoneborn S, Sztriha L, Aithala GR, Houge G, Laegreid LM, Seeger J, Huppke M, Wirth B, Zerres K: Extended phenotype of pontocerebellar hypoplasia with infantile spinal muscular atrophy. Am J Med Genet A. 2003, 117: 10-17. 10.1002/ajmg.a.10863.View ArticleGoogle Scholar
- Stromme P, Maehlen J, Strom EH, Torvik A: [The carbohydrate deficient glycoprotein syndrome]. Tidsskr Nor Laegeforen. 1991, 111: 1236-1237.PubMedGoogle Scholar
- Chelly J, Khelfaoui M, Francis F, Cherif B, Bienvenu T: Genetics and pathophysiology of mental retardation. Eur J Hum Genet. 2006, 14: 701-713. 10.1038/sj.ejhg.5201595.View ArticlePubMedGoogle Scholar
- Posserud MB, Lundervold AJ, Gillberg C: Autistic features in a total population of 7-9-year-old children assessed by the ASSQ (Autism Spectrum Screening Questionnaire). J Child Psychol Psychiatry. 2006, 47: 167-175. 10.1111/j.1469-7610.2005.01462.x.View ArticlePubMedGoogle Scholar
- Dionisi-Vici C, Rizzo C, Burlina AB, Caruso U, Sabetta G, Uziel G, Abeni D: Inborn errors of metabolism in the Italian pediatric population: a national retrospective survey. J Pediatr. 2002, 140: 321-327. 10.1067/mpd.2002.122394.View ArticlePubMedGoogle Scholar
- Pettersen RD, Saugstad OD, Heyerdahl S, Motzfeldt K, Lie SO: [Screening of newborn infants in Norway for severe metabolic disease]. Tidsskr Nor Laegeforen. 1995, 115: 584-587.PubMedGoogle Scholar
- Darin N, Oldfors A, Moslemi AR, Holme E, Tulinius M: The incidence of mitochondrial encephalomyopathies in childhood: clinical features and morphological, biochemical, and DNA anbormalities. Ann Neurol. 2001, 49: 377-383. 10.1002/ana.75.View ArticlePubMedGoogle Scholar
- Meikle PJ, Hopwood JJ, Clague AE, Carey WF: Prevalence of lysosomal storage disorders. JAMA. 1999, 281: 249-254. 10.1001/jama.281.3.249.View ArticlePubMedGoogle Scholar
- Hoffmann GF, von KR, Klose D, Lindner M, Schulze A, Muntau AC, Roschinger W, Liebl B, Mayatepek E, Roscher AA: Frequencies of inherited organic acidurias and disorders of mitochondrial fatty acid transport and oxidation in Germany. Eur J Pediatr. 2004, 163: 76-80. 10.1007/s00431-003-1246-3.View ArticlePubMedGoogle Scholar
- Hendriksz CJ, Corry PC, Wraith JE, Besley GT, Cooper A, Ferrie CD: Juvenile Sandhoff disease--nine new cases and a review of the literature. J Inherit Metab Dis. 2004, 27: 241-249. 10.1023/B:BOLI.0000028777.38551.5a.View ArticlePubMedGoogle Scholar
- Hoffmann B, Mayatepek E: Neurological manifestations in lysosomal storage disorders - from pathology to first therapeutic possibilities. Neuropediatrics. 2005, 36: 285-289. 10.1055/s-2005-872810.View ArticlePubMedGoogle Scholar
- The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2431/7/25/prepub
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