Etiology of cerebral palsy.

AIMS: To register the prevalence of cerebral palsy (CP) and determine etiological factors for the condition. METHODS: Population based study with registration of CP-cases in children born during the 30-year period 1970-99. Cases with postneonatal etiology were excluded. RESULTS: 166 CP-cases were registered among 70 824 children, a prevalence of 2.3 per 1000 live born infants. The prevalence did not change significantly during the period. 66 (40%) were low birthweight infants (LBWIs; <2500 g), and 100 (60%) normal birthweight infants (NBWIs; > or = 2500 g). The origin was classified as prenatal in 37 (22%), perinatal/neonatal in 78 (47%) and unclassifiable in 51 (31 %). In LBWIs 39/66 (59%) had a perinatal/neonatal etiology, most frequently intra- or periventricular hemorrhages (IVH/PVH) and/or periventricular leukomalacia (PVL) or cerebral infarctions (CI) (17; 44%). In NBWIs 39/100 (39%) had a perinatal etiology, most frequently hypoxic-ischemic encephalopathy (HIE) (31; 79%). CONCLUSIONS: In a substantial percentage of CP-cases perinatal/neonatal brain injury was classified as the cause. Among these IVH/PVH/PVL/CI dominated in LBWIs, while HIE dominated in NBWIs. Our data may point to preventability of a larger part of CP than earlier suggested.

Genetically heterogeneous selective intestinal malabsorption of vitamin B12: founder effects, consanguinity, and high clinical awareness explain aggregations in Scandinavia and the Middle East.

Selective intestinal malabsorption of vitamin B(12) causing juvenile megaloblastic anemia (MGA; MIM# 261100) is a recessively inherited disorder that is believed to be rare except for notable clusters of cases in Finland, Norway, and the Eastern Mediterranean region. The disease can be caused by mutations in either the cubilin (CUBN; MGA1; MIM# 602997) or the amnionless (AMN; MIM# 605799) gene. To explain the peculiar geographical distribution, we hypothesized that mutations in one of the genes would mainly be responsible for the disease in Scandinavia, and mutations in the other gene in the Mediterranean region. We studied 42 sibships and found all cases in Finland to be due to CUBN (three different mutations) and all cases in Norway to be due to AMN (two different mutations), while in Turkey, Israel, and Saudi Arabia, there were two different AMN mutations and three different CUBN mutations. Haplotype evidence excluded both CUBN and AMN conclusively in five families and tentatively in three families, suggesting the presence of at least one more gene locus that can cause MGA. We conclude that the Scandinavian cases are typical examples of enrichment by founder effects, while in the Mediterranean region high degrees of consanguinity expose rare mutations in both genes. We suggest that in both regions, physician awareness of this disease causes it to be more readily diagnosed than elsewhere; thus, it may well be more common worldwide than previously thought.

Amnionless, essential for mouse gastrulation, is mutated in recessive hereditary megaloblastic anemia.

The amnionless gene, Amn, on mouse chromosome 12 encodes a type I transmembrane protein that is expressed in the extraembryonic visceral layer during gastrulation. Mice homozygous with respect to the amn mutation generated by a transgene insertion have no amnion. The embryos are severely compromised, surviving to the tenth day of gestation but seem to lack the mesodermal layers that normally produce the trunk. The Amn protein has one transmembrane domain separating a larger, N-terminal extracellular region and a smaller, C-terminal cytoplasmic region. The extracellular region harbors a cysteine-rich domain resembling those occurring in Chordin, found in Xenopus laevis embryos, and Sog, found in Drosophila melanogaster. As these cysteine-rich domains bind bone morphogenetic proteins (Bmps), it has been speculated that the cysteine-rich domain in Amn also binds Bmps. We show that homozygous mutations affecting exons 1-4 of human AMN lead to selective malabsorption of vitamin B12 (a phenotype associated with megaloblastic anemia 1, MGA1; OMIM 261100; refs. 5,6) in otherwise normal individuals, suggesting that the 5' end of AMN is dispensable for embryonic development but necessary for absorption of vitamin B12. When the 5' end of AMN is truncated by mutations, translation is initiated from alternative downstream start codons.