Evaluation of the facioscapulohumeral muscular dystrophy (FSHD1) phenotype in correlation to the concurrence of 4q35 and 10q26 fragments.

Probe p13E-11 (locus D4F104S1) detects two highly homologous polymorphic loci on chromosomes 4q35 and 10q26. Previous reports in the literature have described a correlation of shortened 4q35-specific fragments and facioscapulohumeral muscular dystrophy (FSHD1). We have identified 30 FSHDI families (46 patients) carrying one short 4q35 and one short 10q26 fragment. The clinical data of these patients were compared with those of 47 families (131 patients) showing a single short 4q35 fragment, in order to evaluate a potentially modifying influence of shortened 10q26 fragments on the phenotype. According to our results, the polymorphic locus on 10q26 does not modify the FSHDI phenotype. The normal population (14%) and our FSHDI population (13%) did not significantly differ in the overall frequency of short polymorphic 10q26 fragments. The specificity of the p13E-11/EcoRI-BlnI test for FSHD1 was 100%.

Different patterns of obstetric complications in myotonic dystrophy in relation to the disease status of the fetus.

The obstetric histories of 26 women with myotonic dystrophy (DM), who had a total of 67 gestations, were reviewed retrospectively comparing gestations with affected (DM-fetuses) and unaffected fetuses (UA-fetuses). Second, the influence of gestation on the disease course and the personal attitude towards family planning in DM was assessed. Miscarriages and terminations occurred in 11 pregnancies. Of the 56 infants carried to term, 29 had or most likely had inherited the gene for DM from their affected mothers at the time of investigation; 18 (61%) in this series were affected by the congenital form of DM. Perinatal loss rate was 11% and associated with congenital DM. The rate of obstetric complications was significantly increased in all women. However, preterm labor was a major problem in gestations with DM-fetuses (55 vs. 20%), as was polyhydramnios (21% vs. none). While forceps deliveries or vacuum extractions were required in 21% of deliveries with DM-fetuses and only 5% of UA-fetuses, the frequency of Cesarean sections was similar in both groups (24 and 25%). Obstetric problems were inversely correlated with age at onset of maternal DM, while no effect of age at delivery or birth order on gestational outcome was seen. DNA analysis confirmed the diagnosis in 19 patients by the presence of enlarged CTG repeats (EcoRI-expansions) on chromosome 19. Of the 17 patients whose CTG repeat length was known, 59% were classified as E2 (corresponding to 500-1000 repeats), 24% as E1 (<500 repeats), while larger expansions (E3; 1000-1500 repeats, or E4; >1500 repeats) were seen in three patients (17%). Obstetric complications or congenitally affected children occurred in all maternal phenotypes and CTG repeat classes. Eight (31%) patients experienced a worsening of symptoms that was temporary, weight related in three cases, and persistent in five. With the exception of three patients, most new mothers were able to care for their families. To conclude, pregnant women with DM need constant obstetric monitoring and should be advised to deliver in centres with perinatal facilities.

Increased risk for abnormal placentation in women affected by myotonic dystrophy.

The obstetric histories of 26 women with myotonic dystrophy, who had a total of 66 life births, were reviewed by means of questionnaires and medical reports. Six patients (23%) each had one pregnancy complicated by placenta praevia (affecting 9% of all completed pregnancies), pointing toward a susceptibility to abnormal placentation in this disorder. As involvement of the genitourinary tract is common in myotonic dystrophy, an increased risk for placenta praevia has to be considered in the antenatal care of these patients.

Obstetric aspects in women with facioscapulohumeral muscular dystrophy, limb-girdle muscular dystrophy, and congenital myopathies.

OBJECTIVE: To increase the knowledge about pregnancy and delivery in women with certain muscle diseases, which is important for obstetric management and family planning of affected women. DESIGN: The obstetric histories of patients with facioscapulohumeral (FSH) muscular dystrophy, limb-girdle (LG) muscular dystrophy, and congenital myopathies (CM) were retrospectively evaluated using questionnaires and medical reports. PATIENTS: The condition of 27 patients with different myopathies (FSH muscular dystrophy, n = 11; LG muscular dystrophy, n = 9; and CM, n = 7 [subdivided into 5 patients with central core disease, 1 patient with cytoplasmic bodies, and 1 patient with unspecified myopathy]) were ascertained from January 1, 1992, to December 31, 1994, through departments of neurology and human genetics, and the German self-support group for muscle diseases. Fifty-eight gestations resulting in 52 live births were reviewed. RESULTS: Miscarriages were reported in 3 of 26 gestations in 11 patients with FSH dystrophy, whereas 3 of 15 pregnancies in patients with LG dystrophy were terminated. Preterm births occurred in 2 patients with FSH dystrophy and in 3 patients with CM. Operative deliveries (vaginal operation or cesarean section) were performed in 6 of 23 gestations in patients with FSH dystrophy (1 emergency section), in 5 of 12 patients with LG dystrophy (2 emergency sections), and in 3 of 17 deliveries in patients with CM. Patients with FSH dystrophy generally coped well with their muscle disease in pregnancy and after delivery; however, 4 women were stated to have difficulties in caring for their families. The situation differed in LG dystrophy, where most women (5 of 9) experienced worsening of weakness in pregnancy and required assistance after delivery. In the patients with CM, 3 women experienced a deterioration during pregnancy, and 4 patients reported difficulties after delivery. CONCLUSIONS: No deleterious outcome of pregnancy and labor was observed in this series of patients with muscular dystrophy or CM, although operative deliveries were more frequent. A significant aggravation of symptoms in gestation is more likely to occur in patients with early-onset and progressive myopathy than in those with stable disease courses.

Prenatal prediction in families with autosomal recessive proximal spinal muscular atrophy (5q11.2-q13.3): molecular genetics and clinical experience in 109 cases.

Prenatal prediction in families at risk for autosomal recessive proximal spinal muscular atrophy (SMA) mainly of type I is often requested due to the high incidence and the fetal outcome of the disease. So far, only indirect genotype analysis can be performed in SMA families, since the gene has not yet been identified. We present our experience of 109 prenatal diagnoses obtained in 91 families by use of single- and multi-locus polymorphic microsatellites of the region 5q11.2-q13.3. The marker combinations and specific features of the closest microsatellites are described in detail. From 137 requests for prenatal prediction of SMA between October 1991 and August 1994, 28 families were excluded, mostly because the clinical diagnosis was uncertain or doubtful. Others had to be classified as 'SMA-variants' or showed autosomal dominant transmission of SMA. Of the 109 prenatal diagnoses performed, 29 fetuses were diagnosed to be at high risk (> 99 per cent) of developing the disease, while in seven additional pregnancies no exact prediction could be made due to a recombination event in one parental haplotype. Altogether, recombinations between closely flanking markers were observed in 14 cases. In 35 cases, the parents decided to terminate the pregnancy. Of the remaining pregnancies, 32 could be followed beyond term. All infants were reported to develop normally without signs of SMA. Two children were born with transverse reduction defects of one hand, which was most likely related to early chorionic villus sampling at 9 and 10 weeks' gestation. No further abnormalities could be detected. The limits of indirect genotype analysis and the problems of diagnostic accuracy and heterogeneity of proximal SMA are discussed.

Exclusion of the gene locus for spinal muscular atrophy on chromosome 5q in a family with infantile olivopontocerebellar atrophy (OPCA) and anterior horn cell degeneration.

Two sisters with infantile OPCA plus spinal muscular atrophy (SMA) are reported. Both showed severe hypotonia and psychomotor delay from birth, and in addition, nystagmoid eye movements and vision impairment were evident. Cerebellar hypoplasia with cystic dilatation was seen by neuro-imaging methods. Pathoanatomically, a marked cerebellar hypoplasia and neuronal loss in the basal ganglia, brainstem and anterior horns were found in the deceased girl. Linkage studies with polymorphic markers of the region 5q11.2-q13.3 flanking the gene locus for infantile SMA showed identical parental haplotypes in the patients and their older healthy sister. It can be concluded that the gene locus for infantile SMA on chromosome 5q is not responsible for infantile OPCA plus anterior horn cell degeneration in the described family which might apply to this disorder in general.

Autosomal recessive proximal spinal muscular atrophy in 101 sibs out of 48 families: clinical picture, influence of gender, and genetic implications.

We analysed the clinical picture of 101 sibs (43 sib pairs, 5 triplets) with autosomal recessive proximal spinal muscular atrophy (SMA). Linkage data of 20 sibships, which were available for analysis, were in agreement with chromosome 5q linkage. The patients were classified according to the motor development into SMA I (never sat), SMA II (sitting without support), and SMA III (walking without aids). Three sibs with adult onset (> 30 years = SMA IV) were discussed as a separate entity. Age-of-onset of the 101 patients showed a wide spectrum (prenatal to 47 years). Among sib pairs with SMA I and SMA II the ages-of-onset appeared to be very similar except of one atypically discordant sib pair. With regard to SMA III, 3 out of 13 sibships (23%) showed a marked variation in age-of-onset ranging from 5-15 years within a family. Concerning acquired motor development (ability to sit and walk), 7 sibships (15%) belonged to different SMA types. Ages of death in 29 sib pairs in whom at least one sib had died before the age of 20 years were strikingly discordant. Neither the degree of disability nor the respiratory deficits are reliable predictors of life expectancy. Although a predominance of males can be observed, no significant effect of gender has been established in familial cases. The existence of multiple allelism seems to be the most suitable explanation for the high interfamilial variability considering the clinical concordance in most affected sib pairs.

[Spinal muscular atrophy in childhood. Possibilities and limits of clinical and molecular genetic diagnosis]. / Spinale Muskelatrophien des Kindesalters. Möglichkeiten und Grenzen der klinischen und molekulargenetischen Diagnostik.

The proximal spinal muscular atrophies (SMA) are a clinically and genetically heterogeneous group of neuromuscular disorders which are characterized by selective degeneration of motor neurons in the spine and brainstem. The clinical features resemble other muscle diseases, the diagnostic criteria of proximal SMA have recently been defined by the International SMA Consortium. The classification of the clinical picture in different subgroups is still a focus of discussion. At present it seems likely that childhood onset SMA represents a broad spectrum of various ages of onset and different degrees of disability. Apart from different modes of inheritance, there is further evidence of heterogeneity in proximal SMA. The autosomal recessive forms represent the second frequent recessive disorder after cystic fibrosis, whereas autosomal dominant inheritance is an exception in childhood onset SMA. There are no convincing reports of X-linked SMA hitherto. With mapping of acute and chronic forms of childhood SMA to chromosome 5q11.2-13.3 diagnosis by use of DNA markers in affected families has become available. The current possibilities but also problems and limitations of genotype analysis are discussed, with special regard to the application of prenatal diagnosis. We report on the first experiences with prenatal diagnosis in 37 SMA families.

Pregnancy and delivery in Charcot-Marie-Tooth disease type 1.

We report the obstetric complications and the influence of pregnancy and delivery in 21 Charcot-Marie-Tooth disease type 1 (CMT 1) patients with 45 gestations. Sixteen patients had subjective disabilities from childhood or youth, and five with late onset had subclinical CMT when they became pregnant. The rate of obstetric complications in the study group was in accordance with that of the normal population, and there was no deleterious effect on fetal outcome. Of the 21 participants, 38% (8 of 21) reported an exacerbation of CMT in at least one pregnancy. These patients noted increasing weakness in 81% (17 of 21) of their gestations. A temporary worsening occurred in 35% (6 of 17) of these pregnancies, and neurologic disabilities persisted after 65% of the deliveries (11 of 17). Patients who had pregnancy-associated progression in the first gestation (7 of 21) experienced similar deterioration in subsequent pregnancies (10 of 11), ie, there is a high risk for recurrence of exacerbations. Four women (19%) stated that their last deliveries were responsible for either an exacerbation or the onset of the neuropathy. The remaining nine patients (43%) denied any effect of their gestations on the progression of the neuropathy. Among the patients who had subjective disabilities from childhood or youth, the risk of a noticeable exacerbation in at least one pregnancy was 50% (8 of 16) and affected 81% of their gestations (17 of 21), whereas there was no influence of pregnancy in the five patients with adult onset of CMT, although the first symptoms were noticed postpartum in two of them.(ABSTRACT TRUNCATED AT 250 WORDS)

Fine mapping and narrowing of the genetic interval of the spinal muscular atrophy region by linkage studies.

The gene for autosomal recessive proximal spinal muscular atrophy (SMA) has recently been mapped to chromosome 5q12.2-q13, within a genetic distance of about 6 cM, and is proximally flanked by the locus D5S6 and distally by D5S112. Here, we report linkage analyses in 64 SMA families with nine polymorphic markers closely linked to the SMA gene, which allowed us to narrow the SMA region to about 4 cM and to define a new proximal genetic border by the locus D5S125 (EF(TG/AG)n. Based on haplotype analysis and specific recombination events, the following order of the loci was determined: 5cen-D5S76-D5S6-D5S125-SMA-(5'MAP-1B-3'MAP- 1B)/D5S112-JK53CA1/2-(D5S39-D5S127)-5qter. The location of the SMA gene between D5S125 and MAP-1B is further supported by multipoint linkage analysis.

[Amino acid metabolism in post-stress metabolism]. / Untersuchungen zum Aminosäurenmetabolismus im Postaggressionsstoffwechsel.

During the first four days after cholecystectomy 5 patients were nourished totally parenterally with the amino acid solution INFESOL 40 and carbohydrates. The utilization of the applied amino acids were observed by nitrogen balances, amino acid pattern in plasma and urine and other data. It was achieved a positive nitrogen balance at the 3rd postoperative day. The utilization of the amino acids typically was influenced by postaggression metabolism. For the application of INFESOL 40 in the postoperative period (posttraumatic period) some modifications of the amino acid pattern were recommended.