Megaloblastic anaemia 1 (MGA1, OMIM 261100) is a rare, autosomal recessive disorder characterized by juvenile megaloblastic anaemia, as well as neurological symptoms that may be the only manifestations. At the cellular level, MGA1 is characterized by selective intestinal vitamin B12 (B12, cobalamin) malabsorption. MGA1 occurs worldwide, but its prevalence is higher in several Middle Eastern countries and Norway, and highest in Finland (0.8/100,000). We previously mapped the MGA1 locus by linkage analysis in Finnish and Norwegian families to a 6-cM region on chromosome 10p12.1 (ref. 8). A functional candidate gene encoding the intrinsic factor (IF)-B12 receptor, cubilin, was recently cloned; the human homologue, CUBN, was mapped to the same region. We have now refined the MGA1 region by linkage disequilibrium (LD) mapping, fine-mapped CUBN and identified two independent disease-specific CUBN mutations in 17 Finnish MGA1 families. Our genetic and molecular data indicate that mutations in CUBN cause MGA1.

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.

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.

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.

In a population-based study cerebral palsy (CP) was diagnosed in 110 cases (2.4 per 1000) among children live born with birth weight > or = 500 g (n = 45,976) during the 20-year-period 1970-89 (CP cases with a postneonatal etiology excluded). The CP-incidence showed a linear trend of decline from 2.8 per 1,000 in the first 5-year-cohort born 1970-74, to 2.0 per 1,000 in children born 1985-89 (p = 0.17). Birth weight specific CP-incidence showed a trend of decline in very low birth weight infants (500-1,499 g) and in infants > or = 2,500 g from the first 10-year-cohort born 1970-79 to the second born 1980-89. The same trend occurred for the incidence of spastic diplegia in total and in children born preterm. These trends of decline did not achieve statistical significance (p > 0.05). The CP-incidence was 36.7 and 11.3 times higher among infants with birth weight 500-1,499 g and 1,500-2,499 g respectively compared to infants > or = 2,500 g (p < 0.01). 15.9% of the decline in CP-incidence from the first to the second 10-year-cohort could be explained by a decreased low birth weight rate (500-2,499 g) in the population, from 4.2% 1970-79 to 3.8% 1980-89 (p < 0.05). The origin of CP was considered prenatal in 22 (20%), perinatal in 47 (42.7%), and undifferentiated in 41 (37.3%) of the cases. More CP-children born in the 10-year-period 1980-89 were treated with mechanical ventilation in the neonatal period (13/46; 28.3%) than those born in the 10-year-period 1970-79 (4/64; 6.3%) (p < 0.01). The neonatal mortality rate declined significantly from 7.2 per 1,000 in the first to 3.9 per 1,000 in the last 10-year-cohort respectively (p < 0.01). Birth weight-specific neonatal mortality rates declined more than 50% in all weight groups (p < 0.01). The results are contradictive to other investigations showing increased CP-incidence following improved survival rates in low birth weight infants, and may reflect a different pattern for development of perinatal care (organization, intensive care). The overall effect of mechanical ventilation may be improved survival and prevention of brain damage, though the percentage of ventilated CP-children increased. Preventing low birth weight should be a main strategy for preventing CP.