Biomedical subjects
Publications and source records attributed to B Hagberg.
In the absence of discriminatory laboratory tests for accurate diagnosis of the Rett syndrome, the authors have tried to give as precise clinical criteria as possible for use particularly for research purposes.
The prevalence of Rett's syndrome was studied in a part of southwestern Sweden comprising five counties and the city of Gothenburg. In a population of 315469 children and adolescents, 6-17 years of age, 10 cases were detected, all girls. The corresponding prevalence was 0.65/10 000 girls, i.e. about twice that of phenylketonuria (PKU) in the same area. As progressive brain disorders/metabolic diseases together constitute 5-6% (1.5-2.0/10 000 children) of the aetiologies among severely mentally retarded persons of this age group in central Sweden, it can be concluded that within this group Rett's syndrome should be considered as an aetiological factor to think of in females. This syndrome might well be responsible for one-fourth to one-third of such cases among girls.
The prevalence of the Rett syndrome was found to be approximately 1:15,000 in south-western Sweden. About 40 cases have now been traced in this country, the majority during the last 2 yrs. Experiences of over 20 yrs in efforts to obtain information on the etiology and pathogenesis are summarized. The neurobiological approach used in Gothenburg today to try to reveal the origin is described. A plea is made for developmental screening of deteriorating hand skill as a tool for early identification of potential cases of the Rett syndrome.
Tetrahydrobiopterin metabolism was studied in nine Swedish patients with the Rett disease. Normal values were found for the serum biopterin level, urine biopterins level and dihydropterine reductase activity. These findings suggest that a primary disturbance of tetrahydrobiopterin metabolism is unlikely.
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Ten autosomal recessive/sporadic cases of hereditary motor and sensory neuropathy type I (HMSN I), nine of which originated from the northern part of Sweden, were included in the study. Parents were free from neurologic symptoms. Motor and sensory conduction velocity was normal when recorded, i.e., in 19 and 17 parents, respectively. Sural nerve biopsies from the ten cases revealed a varying degree of onion bulb formation. In eight of the cases the onion bulbs consisted of abundant basement membranes, whereas the Schwann cells were few and sometimes lacking. There were in some cases considerable differences between separate fascicles as to the loss of myelinated nerve fibers. In the six biopsies in which teasing was performed signs of present and previous demyelination were noticed. Numerous internodal segments were abnormally thin with reference to their length. In many such segments there were marked local thickenings of the nerve fiber. In cross sections the probable counterparts to these thickenings were nerve fibers with unduly thick myelin sheaths and complex folding of the myelin. Ultrastructural axonal changes were seen in the majority of the cases. The pathogenetic and diagnostic implications of the present findings are discussed.
Neurological variants in clinical presentation of Krabbe's disease, the infantile and the late-onset (late infantile-juvenile) types are reviewed. The nosology of the infantile type is discussed on the basis of experiences from eighty Swedish cases in 1953-82 and a penetration of the literature. The classical irritative-hypertonic presentation with onset at three to five months of age is concluded to be the very predominant one (greater than 90%). Neonatal failure-to-thrive, infantile spasms, hemiplegic and prolonged floppy infant presentations are much more rare variants. The latter is believed to constitute a nosologic entity of its own, possibly more connected to the heterogeneous late-onset type (greater than or equal to eighteen months at onset), not observed in Sweden so far. Twenty-four late-onset cases from the literature and one personal Norwegian case are surveyed. It is concluded that the classical infantile type and the late-onset type (types) are different disease entities.
From a population-based series of 773 patients with cerebral palsy (CP) born in 1959-78, an analysis was made of the epidemiological trends over this period of 20 years, divided into five 4-year periods with emphasis on the last two. After a significantly decreasing incidence of CP in the first three periods (1959-70) from 1.9 to 1.4 per thousand, there was a significant increase in the last two periods, reaching 2.0 per thousand in the period 1975-78. Both the decreasing trend in the earlier periods and the increasing trend in the more recent ones were mainly referrable to spastic/ataxic diplegia in preterm CP, and to dyskinetic syndromes in CP infants born at term. With respect to pathogenesis, the corresponding changes in CP incidence were mainly accounted for by the group with potential perinatal risk factors. When analysed on the basis of surviving babies in birth-weight-specific groups, the incidence of CP in 1971-78 was found to have increased in all groups, but this was only statistically significant in the low birth weight group of 2 000-2 500 g. Changing trends in incidences ran parallel with a steadily progressive decline in perinatal mortality through all five periods. A considerable and cumulative net gain of surviving non-CP children was continuously achieved; this was also true for 1970-78, in spite of an increasing CP morbidity during these last two 4-year periods.
We studied two children who developed normally for the first 3-4 months of life and then displayed a failure-to-thrive syndrome, regression in psychomotor development, pronounced muscular hypotonia, and liver damage. At the age of about 1-2 years, optic atrophy and spastic parapareses were evident. One child died at the age of 2.5 years the other at an age of 4 years. Both children excreted 3-methylglutaconic acid, 0.1-0.4 mol/mol creatinine and 3-methylglutaric acid, 0.02-0.05 mol/mol creatinine. The excretion of 3-hydroxy-3-methylglutaric acid was not increased. One of the children was available for further biochemical studies. The activity of hydroxymethylglutaryl-CoA lyase (EC 4.1.3.4) was moderately reduced in leucocytes and fibroblasts. During a 21-h fast there was a normal formation of ketone bodies and we conclude that the cause of the syndrome is not a deficiency of hydroxymethylglutaryl-CoA lyase. Normal formation of 14CO2 from [1-14C]isovaleric acid and [2-14C]leucine in fibroblasts and leucocytes apparently excludes a deficiency of methylglutaconyl CoA-hydratase (EC 4.2.1.18).
Thirty-five patients, exclusively girls, from three countries had a uniform and striking progressive encephalopathy. After normal general and psychomotor development up to the age of 7 to 18 months, developmental stagnation occurred, followed by rapid deterioration of higher brain functions. Within one-and-a-half years this deterioration led to severe dementia, autism, loss of purposeful use of the hands, jerky truncal ataxia, and acquired microcephaly. The destructive stage was followed by apparent stability lasting through decades. Additional insidious neurological abnormalities supervened, mainly spastic parapareses, vasomotor disturbances of the lower limbs, and epilepsy. Prior extensive laboratory investigations have not revealed the cause. The condition is similar to a virtually overlooked syndrome described by Rett in the German literature. The exclusive involvement of females, correlated with findings in family data analyses, suggests a dominant mutation on one X chromosome that results in affected girls and nonviable male hemizygous conceptuses.
ecent epidemiological studies in Swedish school age children revealed a prevalence of severe mental retardation (SMR = IQ less than 50) of 0.3% and of mild mental retardation (MMR = IQ 50-70) around 0.4%. In SMR prenatal causes were found in 55%, perinatal in 15-20%, no traceable brain pathology in 18%. Corresponding figures for MMR were 23%, 18% and 55%, respectively. Down syndrome was the largest single cause of SMR and polygenic subcapacity considered to be that of MMR. Chromosomal errors were detected among 29% SMR and 4% MMR school children. Fragile X accounted for 4% SMR and 10% MMR in boys. Fetal alcohol syndromes constituted 8% of urban MMR. The contribution of inborn errors of metabolism was 4-5% and less than 1%, in SMR and MMR, respectively. Perinatal (28th prenatal week-28th postnatal day) brain damage was implicated in 15% of SMR and 18% of MMR. Pathogenetic data are considered for potential preventive measures.
An unselected series of 93 Swedish diplegic children born in 1969-1976 and subgrouped into 49 term (TDC) and 44 preterm (PDC) cases were analyzed for differences in reduced optimality in pre- and perinatal conditions, these also being related to degree of handicap, associated neurology and conventional pathogenetic grouping. Comparisons of the reduced optimality with those of a dyskinetic and a control series were also made. TDC were shown to have more severe handicaps and more additional neurologic abnormalities than PDC. The profile of reduced optimality was weighted in TDC to items pointing to fetal maladjustment/deprivation and birth asphyxia and in PDC to items accompanying preterm birth and to postpartal items. The optimality of diplegics was in general more reduced than in controls and less than in dyskinetics. This was especially true for TDC. Differences in the background mechanisms of the diplegia between TDC and PDC were indicated from dissimilarities in the combined patterns of reduced optimality and conventional pathogenetic grouping. Postpartal complications predominated among PDC. A prepartal factor as the only cause of the diplegia was likely in 41% of TDC, and as a contributory cause in another 24%. Birth asphyxia, present in 31% of the TDC, was never the only risk factor among infants born at term.
103 consecutive childhood cases of genetic peripheral neuropathies of heredodegenerative background were collected from Gothenburg from 1973 to 1980. From this series, 63 hereditary motor and sensory neuropathies (HMSN) were distinguished: 31 cases of demyelinating and remyelinating HMSN (HMSN I), 21 (18 families) with an autosomal dominant and 10 with sporadic mode of inheritance and unaffected parents; and 32 cases of neuronal-axonal types (HMSN II), 27 of whom (25 families) had at least one affected, if asymptomatic, parent. In one family, both parents were neurologically and neurophysiologically completely normal. Three cases of uncharacteristic HSN were diagnosed. Among 37 cases with a combined degenerative encephalopathy/myelopathy and a peripheral neuropathy, nine had hereditary spastic paraplegia, six had heredoataxias (three of the Friedreich type), nine had lysosomal storage diseases (five of the Krabbe type), seven had other known inborn metabolic errors and six had biochemically undefined disorders. Progressive neuropathies are important manifestations of a large variety of genetically determined heredodegenerative neurological disorders of infancy and childhood. For classification of HMSN, clinical and neurophysiological examinations are necessary for the index case and for both parents as well.
The prevalence of hereditary motor and sensory neuropathies (HMSN) and their distribution according to the severity of the disability were studied in a population-based series of Swedish children 2-15 years old. The prevalence per 100 000 of total peroneal muscle atrophies was 21.6 and of all clinical HMSN 19.0 Among HMSN, de- and remyelinating types (HMSN I) constituted 8 per 100000 and neuronal-axonal types (HMSN II) 11. Eighteen of the 21 HMSN I cases and 26 of the 29 HMSN II were considered to represent an autosomal dominant mode of inheritance. Ten per cent of all children were severely, 70% moderately and 20% mildly disabled. All the severely affected children belonged to the HMSN I group and 9 of the 10 mildly affected to HMSN II.
Clinical, neurophysiological and certain other laboratory data are given for 10 children considered to represent sporadic cases of de- and remyelinating hereditary motor and sensory neuropathies (HMSN). In all 10 families the parents had been found to be non-affected and said to be non-consanguineous. Nine of the 10 families originated from the two most northerly Swedish counties, but none from the Gothenburg area. The median age at clinical onset was 3 years. Gait abnormalities and/or foot deformities were common reasons for referral. Scoliosis developed in all 10 and hand atrophies in 7 children. In the majority there was neurological deterioration through childhood. Nerve conduction velocities, both motor and sensory, were consistently and markedly reduced. The protein level in cerebrospinal fluid (medium 657 mg/l) was slightly to moderately raised in 7 of 9 examined children and greater than or equal to 1 500 mg/l in the remaining two. The fatty acid pattern of serum lecithin was consistently normal in all 10.
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