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We have observed a 49 bp tandem duplication adjacent to the triplet repeat of the FMR1 gene and have shown it to occur as a variant in Finland. It affects the primers commonly used in molecular analysis of fragile X syndrome by polymerase chain reaction (PCR) methods. One concern is that females with the full mutation and variant alleles might be missed because of the two PCR products generated by the variant. We suggest that the duplication has arisen by a misalignment of the proximal end of the repeat tract and the non-adjacent GGCGGCGGCGG-sequence located 37 bp upstream and may indicate a mutation hot spot. The discovery of this duplication and the previous observations on deletions associated with full mutations in FMR1 indicate that realignment between the repeat tract and dispersed non-adjacent homologous repetitive sequences may also play a role in repeat instability in fragile X.

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Due to the poor prognosis of severe autosomal recessive polycystic kidney disease (ARPKD), there is a strong demand for prenatal diagnosis (PD). Reliable PD testing is possible by molecular genetic analysis only. Although haplotype-based analysis is feasible in most cases, it is associated with a risk of misdiagnosis in families without pathoanatomically proven diagnosis. Linkage analysis is impossible in families where DNA of the index patient is not available. Direct mutation analysis of the recently identified polycystic kidney and hepatic disease 1 gene opens new options in families to whom a reliable PD cannot be offered on the basis of linkage analysis. We for the first time report two cases with PD based on mutation detection, illustrating the new options for PD in ARPKD.

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UNLABELLED: The case is reported of a seriously affected newborn with homozygous protein C deficiency who developed neonatal purpura fulminans. Foetal ultrasound at 33 wk of gestation revealed ventriculomegaly. The first lesions appeared on the scalp 48 h after birth. She was initially treated with fresh-frozen plasma and, after the diagnosis was confirmed, with purified protein C concentrate. After skin necrosis had healed, therapy was continued with oral warfarin. The infant was homozygous for protein C W380G mutation. Diagnosis at the DNA level gave the parents an option of reliable prenatal diagnosis in their subsequent pregnancy. CONCLUSION: Difficulties in reaching an accurate diagnosis are discussed since early diagnosis and urgent therapy with protein C replacement are crucial to avoid further damage after delivery.

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The aim of the present study was to evaluate the rate of intrahepatic cholestasis of pregnancy in first-degree relatives of index patients. Index patients (n=65) with singleton pregnancies complicated by intrahepatic cholestasis were identified among the women (n=11 984) who gave birth at Kuopio University Hospital in 1994-1998. The pregnancy histories of relatives of 56 index patients were reviewed and the rate of cholestasis in first-degree relatives was compared with that in the general obstetric population. Obstetric cholestasis was experienced by 9% of the parous sisters and 11% of the mothers of the index patients. The risk per delivery was 6% in the first-degree relatives. The rate in the general obstetric population was 0.54%. The odds ratios and 95% confidence intervals were 12.6 (5.6-28.1) for the sisters and 12.2 (6.2-24.2) for the mothers. Obstetric cholestasis clusters within some families and is under strong genetic influence, although the precise genetic pattern remains obscure. The sisters of index patients are at an increased risk of the disorder and may benefit from close obstetric care.

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PURPOSE: This study presents data on cumulative risk of seizures, cause, comorbidity, and remission of epilepsy among mentally retarded (MR) children followed until the age of 22 years. METHODS: A total of 151 MR children were identified at the age of 8 or 9 years by screening four birth cohorts of 12,882 children born from 1969 to 1972 in the Finnish province of Kuopio. Information about epilepsy was gathered longitudinally when children were 9 to 10, 17, and 22 years old. The guidelines for epidemiological studies on epilepsy proposed by the International League Against Epilepsy were followed. RESULTS: By the age of 10 years, 29 of the 151 MR children (19%) had epilepsy. The cumulative risk for epilepsy at 22 years was 21%. The probability of developing epilepsy was increased fivefold in severely MR children compared with mildly MR children, i.e., in 27 of the 77 severely MR children (35%) versus 5 of the 74 mildly MR children (7%). Postnatal causes of mental retardation or association with cerebral palsy increased the risk for epilepsy, especially in the mildly MR children. When these risk factors were not present, the mildly MR children exhibited only a 3% risk for epilepsy, whereas the respective risk was about 10-fold in severe mental retardation. The cumulative probability of epilepsy being in remission for 5 years by the age of 22 was 32%. CONCLUSIONS: The cumulative risk of epilepsy varies according to the severity and the cause of the retardation as well as the presence of additional disabilities. The cumulative probability of epilepsy remission tended to increase with age.

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Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is a recessively inherited defect in the mitochondrial beta-oxidation of fatty acids. A single nucleotide change, the A985 --> G transition, in the MCAD gene accounts for approximately 90% of all the disease-causing mutations in the patients. We have used PCR to amplify a segment of the human MCAD gene and typed the allelic sequence variation at base 985 by a colorimetric oligonucleotide ligation assay (OLA). PCR/OLA provides a technique that permits differentiation of the homozygotes, heterozygotes, and normals for the A985 --> G allele in the MCAD gene. Genotyping of 1908 random Finnish DNA samples by OLA identified 10 carriers of the mutant allele, but no homozygotes were found. The calculated carrier frequency for the A985 --> G mutation was 1:191 (95% confidence limits, 1:118-1:501), and the calculated frequency for the A985 --> G homozygotes was 1:147,000 (95% confidence limits, 1:56,000-1:1,004,000).

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Anteroposterior translation of the knee joint was measured with a Knee Signature System device on 12 women and 14 men with a unilateral, chronic, isolated, anterior cruciate ligament (ACL) tear. A control group with stable knees consisted of 10 women and 10 men. Anterior translation at 178 N load of the uninjured knees was 8.0 mm (+/-2.2 mm) and in knees with an ACL tear, 14.2 mm (+/-4.2 mm). Corresponding values for anteroposterior translation were 12.1 mm (+/-2.5 mm) and 19.3 mm (+/-4.9 mm), respectively. A difference of 3 mm or more in anteroposterior translation at 178 N load between injured and uninjured knees indicated an ACL tear with 85% specificity and 88% sensitivity.

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The effect of a single intraoperative injection of hyaluronan on intraocular pressure (IOP) and postsurgical tissue healing was evaluated on 18 rabbits with an aqueous drainage implant. During the follow-up period IOP was recorded and analysed. Furthermore, inflammatory reaction and appearance of the fibrous tissue around the implants were studied in histological sections. In both the hyaluronan and control groups the operation lowered the average IOP statistically significantly for the whole follow-up period when compared with preoperative values. From days 7 to 60 the mean IOP values of the hyaluronan injected eyes stayed at a lower level than in the control eyes, but with no statistical difference between the 2 groups. The connective tissue layer around the implants appeared less dense during the first 17 postoperative days in the sodium-hyaluronate group; in addition, the inflammatory cell reaction showed a tendency to remain acute longer.

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The causes of mental retardation (MR) were studied as part of a multidisciplinary epidemiological case-control study in 151 mentally retarded patients identified by screening four age cohorts (12,882 children) at 8-9 years of age in the province of Kuopio, Finland. The causes of MR in 77 severely retarded (SD < or = -3 SD) and 74 mildly retarded (-2 > SD > -3) children were divided into pre-, peri-, postnatal and unknown groups according to the probable time of onset. The causes were pre-, peri-, postnatal and unknown in 60%, 9%, 8% and 23%, and 22%, 1%, 3% and 74%, in the two populations, respectively. Genetic causes were found in 28% of all 151 cases; the three most common subgroups were trisomy 21, fragile X syndrome and aspartylglycosaminuria (13%, 4% and 2% respectively). The study design used provided reliable information on the causes of MR and also demonstrated those forms of genetic metabolic diseases typical of Finnish inheritance.

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Serum, plasma, and lymphocytes from aspartylglycosaminuria (AGU) patients and carriers and from normal controls were incubated with a fluorescent glycosylasparaginase substrate, L-aspartic acid beta-(7-amido-4-methylcoumarin), and the release of 7-amino-4-methylcoumarin was measured fluorometrically after incubation for 1-4 h. The mean glycosylasparaginase (EC 3.5.1.26) activity in normal serum, plasma, and lymphocytes was 20.2 (SD 5.0) mU/L (n = 24), 17.5 (SD 5.0) mU/L (n = 24), and 242 (SD 108) mU/g protein (n = 17), respectively. The corresponding values in the Finnish AGU patients were 0.7 (SD 0.4) mU/L (n = 10), 0.3 (SD 0.3) mU/L (n = 10), and 6.0 (SD 4.6) mU/g protein (n = 7). No overlapping values were obtained between the AGU patients and the carriers in any of the samples, but the values between the carriers and controls were overlapping in 28 of 29 serum, 22 of 29 plasma, and 4 of 21 lymphocyte samples. Thus, the fluorometric glycosylasparaginase assay in various blood samples allows specific detection of the enzyme defect in AGU, but cannot be used for reliable detection of carriers of the disease.

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Human glycoasparaginase (N4-(beta-N-acetyl-D-glucosaminyl)-L-asparaginase, EC 3.5.1.26) hydrolyzes a series of compounds that contain L-asparagine residue with free alpha-amino and alpha-carboxyl groups. Substrates include high mannose and complex type glycoasparagines as well as those that lack the di-N-acetylchitobiose moiety, L-aspartic acid beta-methyl ester and L-aspartic acid beta-hydroxamate. The enzyme is inactive toward L-asparagine and L-glutamine and glycoasparagines containing substituted alpha-amino and/or alpha-carboxyl groups. In the presence of the acyl acceptor hydroxylamine, glycoasparaginase catalyzes the synthesis of L-aspartic acid beta-hydroxamate from aspartyl-glucosamine, L-aspartic acid beta-methyl ester, and L-aspartic acid. 13C NMR studies using 18O-labeled L-aspartic acid demonstrate that glycoasparaginase catalyzes an oxygen exchange between water and the carboxyl group at C-4 of L-aspartic acid. These results indicate that glycoasparaginase reacts as an exo-hydrolase toward the L-asparagine moiety of the substrates and the free alpha-amino and alpha-carboxyl groups are required for the enzyme reaction. The results are consistent with an L-asparaginase-like reaction pathway which involves a beta-aspartyl enzyme intermediate. Since glycoasparaginase is active toward a series of structurally different glycoasparagines, we suggest the revised systematic name of N4-(beta-glycosyl)-L-asparaginase for the enzyme.

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We report on 2 male propositi, their mothers, and a maternal aunt with a new skeletal dysplasia associated with a unique pattern of digital malformation, variable mild short stature, and mild bowleg with proximal overgrowth of the fibula. The digital malformations comprise a pattern of brachydactyly which includes short, abducted thumbs, short index fingers, and markedly short, abducted great toes. The radiographic findings include hypoplastic thumbs and great toes with short first metacarpals and first metatarsals, absent distal phalanges of the index fingers and second toes, and coalescence of the carpal and tarsal bones. Radiographs of the long bones show mild metaphyseal and epiphyseal irregularity, tibial spurs, and relative elongation of the fibulae. The males are very similarly affected whereas the females show phenotypic variation and are generally less severely affected. The family histories from 2 fairly extensive pedigrees suggest X-linked dominant inheritance.

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Aspartylglycosaminuria is a lysosomal storage disease caused by deficient activity of glycoasparaginase (EC 3.5.1.26), and it occurs with a high frequency among Finns. We have recently shown that the molecular defect in all Finnish aspartylglycosaminuria patients examined to date consists of two single base changes in the heavy chain of glycoasparaginase (Mononen, I., Heisterkamp, N., Kaartinen, V., Williams, J. C., Yates, J. R., III, Griffin, P. R., Hood, L. E., and Groffen, J. (1991) Proc. Natl. Acad. Sci U.S.A. 88, 2941-2945). This is the first report on the identification of the molecular defect causing aspartylglycosaminuria in a patient of non-Finnish origin. Total RNA from fibroblasts of a black American aspartylglycosaminuria patient was isolated, first-strand cDNA was synthesized, and the cDNA encoding glycoasparaginase was amplified by the polymerase chain reaction. The patient's mRNA nucleotide sequence was different from the normal sequence by a deletion of 134 nucleotides at positions 807-940. Nucleotide sequence analysis of the normal glycoasparaginase gene demonstrated that the deletion corresponded precisely to a 134-base pair exon. Moreover, analysis of the splice sites demonstrated a single base change, G to T, that altered the donor splice site of the exon deleted in the patient's mRNA. This change led to an exon-skipping event resulting in a frame shift and generation of a stop codon.

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A one-piece silicone filtration implant for glaucoma surgery was evaluated in 18 normotensive rabbits. During the follow-up period of 60 days the function of the implant and the effect of the implant on intraocular pressure (IOP) and local reaction in operated eyes were examined. Mean IOP in operated eyes during the whole follow-up period stayed in a level that was statistically significantly (p < 0.001) lower than the preoperative starting value. Despite of a slight inflammatory reaction in the immediate postoperative period the implants were well tolerated. No marked foreign body reaction were noted around the implants in histological sections. In 3 eyes the implants had to be removed due to complications caused by surgical technique.

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A high prevalence of the lysosomal storage disease aspartylglycosaminuria was found in a study of four birth cohorts of 12882 children in eastern Finland. Using school achievement tests and registers of mentally retarded individuals, 178 mentally retarded children were identified. Randomized urine samples from 151 of the 178 retarded children and from 101 healthy children were analyzed quantitatively for aspartylglucosamine by high-performance liquid chromatography. The results identified three affected individuals in the retarded group indicating an exceptionally high prevalence of aspartylglycosaminuria (1:3643) in the study population, consistent with a carrier frequency of 1:30. The 95% confidence limits for the prevalence are 1:4 352-1:16389. This is the highest prevalence described for any glycoproteinosis in any population and comparable to the incidence figures of the most common lysosomal storage diseases, Gaucher disease type I and Tay-Sachs disease among Ashkenazi Jews. In the study group, aspartylglycosaminuria was, after trisomy 21 (n = 19) and the fragile X syndrome (n = 6), the most common genetic cause for mental retardation.

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