Martin Renlund

No improvement in outcome of nationwide extremely low birth weight infant populations between 1996-1997 and 1999-2000

OBJECTIVE. Our goal was to investigate whether outcome in extremely low birth weight infants changes over time in Finland. PATIENTS AND METHODS. All infants with a birth weight <1000 g born in Finland in 1996–1997 and 1999–2000 were included in the study. Perinatal and follow-up data were collected in a national extremely low birth weight infant research register. Data concerning cerebral palsy and visual impairment were obtained from hospitals, the national discharge, and visual impairment registers. RESULTS. A total of 529 and 511 extremely low birth weight infants were born during 1996–1997 and 1999–2000. No changes were detected in prenatal, perinatal, neonatal, and postneonatal mortality rates between the periods. The survival rates including stillborn infants were 40% and 44%. The incidence of respiratory distress syndrome and septicemia increased from 1996–1997 to 1999–2000 (75% vs 83% and 23% vs 31%). The overall incidence of intraventricular hemorrhage increased (29% vs 37%), but the incidence of intraventricular hemorrhage grades 3 through 4 did not (16% vs 17%). The rates of oxygen dependency at the age corresponding with 36 gestational weeks, retinopathy of prematurity stages 3 to 5, cerebral palsy, and severe visual impairment did not change. Mortality remained higher in 1 university hospital area during both periods compared with the other 4 areas, but no regional differences in morbidity were detected during the later period. CONCLUSIONS. No significant changes were detected in birth or mortality rate in extremely low birth weight infants born in Finland during the late 1990s, but some neonatal morbidities seemed to increase. Regional differences in mortality were detected in both cohorts. Repeated long-term follow-up studies on geographically defined very preterm infant cohorts are needed for establishing reliable outcome data of current perinatal care. Regional differences warrant thorough audits to assess causalities.

Infantile form of neuronal ceroid lipofuscinosis (CLN1) maps to the short arm of chromosome 1

The neuronal ceroid lipofuscinoses (CLNs) are one of the most common progressive encephalopathies of childhood in Western countries. They are divided into three main types: infantile, late infantile, and juvenile. The inheritance of all forms is autosomal recessive, and the biochemical background is totally unknown. The infantile type (CLN1) demonstrates the earliest onset of symptoms and the most severe clinical course. CLN1 is enriched in the Finnish population with incidence of 1:20,000, and only about 50 cases have been reported from other parts of the world. We have collected 15 Finnish CLN1 families with one or two diseased children for a linkage analysis with polymorphic probes randomly localized on human chromosomes. After studying 42 polymorphic protein and DNA markers, we found definitive proof of linkage with three different probes on the short arm of chromosome 1, with maximum lod scores of 3.38 at theta = 0.00 (0.00-0.08) for D1S57 (pYNZ2), 3.56 at theta = 0.00 (0.00-0.09) for D1S7 (lambda MS1), and 3.56 at theta = 0.00 (0.00-0.11) for D1S79 (pCMM8). With the assignment of the CLN1 gene, our study demonstrates the power of multiallelic VNTR probes in the search for linkage of a rare recessive disorder using limited family material.

The auditory sensory memory trace decays rapidly in newborns.

The present study investigated the temporal dynamics of auditory sensory memory in newborns as reflected by the mismatch negativity (MMN), a preattentive electric change-detection response. MMN was obtained from 24 full-term healthy newborns who were either awake or asleep (quiet or active sleep) during the experiments. Stimuli were 1,000 Hz tones (standards) that were occasionally replaced by 1,100 Hz tones (deviants). The constant stimulus onset asynchrony (SOA) was, in separate blocks, either 450, 800, or 1,500 ms. A prominent MMN was obtained at the 800 ms SOA in all three sleep or waking states, whereas no MMN occurred at 450 and 1,500 ms SOAs. In view of the fact that in adults MMN is elicited even with a 10s SOA, these results imply that the time span of auditory memory is considerably shorter in neonates than in adults and 8-12-year-old children.

Salla disease: A new lysosomal storage disorder with disturbed sialic acid metabolism

Salla disease is a lysosomal storage disorder associated with increased urinary excretion of free sialic acid. The main clinical features in 34 patients were severe psychomotor retardation of early onset, ataxia, athetosis, rigidity, spasticity, and impaired speech. Growth retardation, thick calvarium, and exotropia were present in about half the patients. The amplitude of EEG decreased progressively with increasing age. Life span appears to be normal; the age range of the patients was 3 to 63 years. Genealogic studies suggest an autosomal mode of inheritance. A thin-layer method is described for the detection of increased urinary free sialic acid excretion. The basic defect is so far unknown.

Expanding screening for rare metabolic disease in the newborn: An analysis of costs, effect and ethical consequences for decision‐making in Finland

AIM Currently, the only metabolic disorder that newborns are screened for in Finland is congenital hypothyroidism. A proposal to start a pilot study on screening for other rare metabolic diseases using tandem mass spectrometry prompted a health technology assessment project on the effect and costs of expanded newborn screening programme options. METHOD A modelling study using data from current published studies, healthcare registers and expert opinion. RESULTS The annual running cost of screening 56,000 newborns for the chosen five disorders (congenital adrenal hyperplasia, medium-chain acyl-CoA dehydrogenase deficiency [MCADD], long chain 3-hydroxyacyl-CoA dehydrogenase deficiency [LCHADD], phenylketonuria [PKU] and glutaric aciduria type 1 [GA 1]) was estimated to be euros 2.5 million or euros 45 per newborn when starting costs were included. The costs per quality-adjusted life year (QALY) gained are a maximum of euros 25,500. Prevention of severe handicap in one newborn would reduce the costs to a maximum of euros 18,000 per QALY gained. CONCLUSIONS Expanding the Finnish neonatal screening programme would require a new organization. The cost-effectiveness, resources, ethics and equity need to be considered when deciding in favour of or against starting a new screening programme.

The mismatch negativity to changes in speech sounds at the age of three months

This study shows that an infrequent vowel (deviant) presented among frequent vowels (standard) elicits in awake 3‐month‐old infants a negativity in the auditory event‐related potential resembling the mismatch negativity elicited by the same stimuli in previous studies in adults (Aaltonen, Niemi, Nyrke, &Tuhkanen, 1987) and newborns (Cheour‐Luhtanen et al., 1995). The mismatch negativity amplitude for the deviant vowels was larger and the event‐related potentials to standard stimuli were in general more positive in 3‐month‐old infants than in newborns, which might reflect increased maturation of their nervous system relative to that of newborns.

Phenotypic spectrum of Salla disease, a free sialic acid storage disorder

Salla disease (MIM 269920) represents the mildest phenotype among recessively inherited lysosomal-free sialic acid storage disorders. Although the vast majority of Salla disease patients in Finland share the same founder mutation, R39C in the SLC17A5 gene, there still is a wide clinical variation among mentally retarded, ataxic patients. We evaluated neurologic and neurocognitive findings of Salla disease in a cross-sectional study of 41 Finnish patients who were 11 months to 63 years of age (median = 19.5 years). The phenotype of Salla disease could be classified into two main categories. The majority of patients (90%) had so-called conventional phenotype, including a subgroup of seven patients with relatively mild symptoms. All but two patients with conventional phenotype were homozygous for the Finnish founder mutation. Four severely disabled, profoundly mentally retarded patients, 15-28 years of age, clearly could be clinically delineated as a separate group, likely reflecting the underlying compound heterozygous genotype. A typical developmental pattern could be outlined in the conventional type of the disease, emphasizing a strong motor handicap in Salla disease. The cognitive profile consisted of better verbal ability, especially speech comprehension, compared with nonverbal functioning in all patients. Our results indicate a partial genotype-phenotype correlation, although factors other than the molecular background are also involved in the phenotypic manifestation of Salla disease.

Sialic Acid Storage Disorders: Observations on Clinical and Biochemical Variation

Lysosomal accumulation of free sialic acid results in two phenotypically distinct inherited metabolic disorders, Salla disease and infantile sialic acid storage disease. Clinical and biochemical findings in both diseases are reviewed. Recent studies indicate that sialic acid storage is a consequence of defective function of a lysosomal membrane transport system specific for sialic acid and some other acidic monosaccharides.

Confirmation of the chromosomal localization of human lamp genes and their exclusion as candidate genes for Salla disease

SummarySalla disease is an inherited lysosomal storage disorder caused by accumulation of free sialic acid in the lysosomes. Lamp genes, lamp A and lamp B (lysosome associated membrane proteins), are the first known genes encoding for human lysosomal membrane proteins. Absence of linkage in a large group of families shows that lamp genes are not involved in Salla disease. The lamp genes were localized, using Southern hybridization in hamster — human hybrid cell panels, to chromosomes 13 (lamp A) and X (lamp B).

Expanding screening for rare metabolic disease in the newborn: An analysis of costs, effect and ethical consequences for decision-making in Finland: Newborn screening

Aim: Currently, the only metabolic disorder that newborns are screened for in Finland is congenital hypothyroidism. A proposal to start a pilot study on screening for other rare metabolic diseases using tandem mass spectrometry prompted a health technology assessment project on the effect and costs of expanded newborn screening programme options. Method: A modelling study using data from current published studies, healthcare registers and expert opinion. Results: The annual running cost of screening 56 000 newborns for the chosen five disorders (congenital adrenal hyperplasia, medium‐chain acyl‐CoA dehydrogenase deficiency [MCADD], long chain 3‐hydroxyacyl‐CoA dehydrogenase deficiency [LCHADD], phenylketonuria [PKU] and glutaric aciduria type 1 [GA 1]) was estimated to be €2.5 million or €45 per newborn when starting costs were included. The costs per quality‐adjusted life year (QALY) gained are a maximum of €25 500. Prevention of severe handicap in one newborn would reduce the costs to a maximum of €18 000 per QALY gained.