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Biomedical subjects

S Rudnik-Schöneborn

Publications and source records attributed to S Rudnik-Schöneborn.

At least 19 recordsLinked to original sources
PubMed2006

Submicroscopic unbalanced translocation resulting in del10p/dup13q detected by subtelomere FISH.

Chromosomal rearrangements involving the (sub)telomeres are an important cause of human genetic diseases: with the development of advanced molecular cytogenetic methods they have been identified as a major cause of mental retardation and/or congenital malformation syndromes. We identified a cryptic unbalanced de novo translocation 10p/13q by subtelomere FISH in a boy with mental and growth retardation (karyotype: 46,XY,der(10)t(10;13)(p15.1;q34)(D10S2488-,D13S296+)). Craniofacial dysmorphisms included frontal bossing, epicanthal folds, long philtrum, thin upper lip, short nose, mild retrognathy and a flat midface. In addition the patient had ASDII, a pyloric stenosis, bilateral inguinal hernias and cryptorchidism. His psychomotor development was significantly delayed. Microsatellite typing revealed the paternal origin of the two chromosomes involved in the rearrangement. By comparing our case with previously published patients with similar aberrations we conclude that the congenital malformations in our case are associated with the partial 10p deletion. The craniofacial features might be attributed to the 13q duplication. The identification of a 10p/13q translocation in our case highlights the importance of searching for cryptic subtelomeric imbalances in mentally retarded patients and helps to further delineate genotype-phenotype correlations in rare chromosomal disturbances.

Abnormalities, Multiple↗
PubMed2006

Outcome and effect of pregnancy in myotonic dystrophy type 2.

The authors reviewed the obstetric histories of 42 women of 37 families with myotonic dystrophy type 2 (DM2). Nine women (21%) had the first symptoms during pregnancy and worsening in subsequent pregnancies. Of 96 pregnancies, 13% ended as early and 4% as late miscarriages. Preterm labor occurred in 50% of pregnancies resulting in 27% preterm deliveries in women with overt DM2 in pregnancy. There was no evidence of a congenital DM2.

Adult↗
PubMed2005

Mild Pelizaeus-Merzbacher disease caused by a point mutation affecting correct splicing of PLP1 mRNA.

We describe a 28-year-old male patient with a mild course of Pelizaeus-Merzbacher disease (PMD) who presented with developmental delay in his second year of life and was able to walk until 12 years of age. Several computed tomography scans in infancy and youth were normal, the diagnosis of PMD was eventually suggested by magnetic resonance imaging at the age of 24 years. Analysis of the proteolipid protein gene (PLP1) revealed a nucleotide exchange (c.762G>T) at the 3' border of exon 6, which did not entail an amino acid exchange but adversely affected splicing. PCR analysis of fibroblast cDNA showed that c.762G>T resulted in partial skipping of exon 6 in the PLP1 mRNA. Exclusion of exon 6 does not alter the reading frame but leads to absence of amino acids 232-253 that constitute a main part of the fourth transmembrane helix of the PLP protein. Remarkably, residual wild-type splicing was also detected in the patient's cultured fibroblasts. This might explain the mild phenotype in this case, as exon 6 skipping mutations resulted in a severe course of disease in other patients.

Adult↗
PubMed2004

Long-term observations of patients with infantile spinal muscular atrophy with respiratory distress type 1 (SMARD1).

We describe 6 unrelated patients affected by infantile spinal muscular atrophy with respiratory distress type 1 (SMARD1) with prolonged survival upon mechanical ventilation (4.5-11 years), which has not been reported before. Biallelic mutations in the IGHMBP2 gene proved the diagnosis of SMARD1 in all patients. Disease onset was in the first 2 months in the described patients, starting with generalised hypotonia, failure to thrive, and early breathing difficulties. Diaphragmatic palsy was diagnosed and permanent ventilation was initiated 2-8 months after onset. Within months a more distal muscular atrophy became evident associated with joint contractures (talipes), hand drops, and fatty finger pads. Motor development remained minimal, loss of function was observed within the first year after which no further progression was recorded. Voiding dysfunction with reflux nephropathy was observed in 3 patients and has not been reported before. Further evidence of autonomic nerve dysfunction resulting in cardiac arrhythmia, hypertension, and excessive sweating was given in 2 patients. Investigative results were largely compatible with those obtained in classic SMA. However, neurogenic atrophy muscle was more pronounced in distal muscles, if examined, and there was evidence of peripheral nerve involvement at least in some patients.

Age Factors↗
PubMed2004

New options for prenatal diagnosis in autosomal recessive polycystic kidney disease by mutation analysis of the PKHD1 gene.

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.

Consanguinity↗
PubMed2003

Classical infantile spinal muscular atrophy with SMN deficiency causes sensory neuronopathy.

OBJECTIVE: Classic infantile spinal muscular atrophy (SMA) is believed to be a purely motor disorder, affecting neurons of the spinal anterior horn and nuclei of the lower cranial nerves. Other organ malformations or peripheral nerve involvement have been regarded as exclusion criteria for infantile SMA. Whether SMN protein deficiency can also lead to loss of sensory neurons has not been systematically addressed. METHODS: The authors evaluated the sural nerve biopsies of 19 patients with infantile SMA of varying severity. The diagnosis of SMA was confirmed by the presence of a homozygous deletion of the SMN1 gene in all patients. RESULTS: In seven unrelated infants with SMA type I, axonal degeneration of the sural nerve was noted. Five patients showed abnormal sensory conduction, thus prompting sural nerve biopsy. Sural nerves showed different degrees of axonal loss: fiber density ranged from 3.482 to 22.076/mm2 and was markedly reduced in four patients. There was no evidence of primary demyelination: the ratio of total myelinated fiber thickness to axon diameter (g-ratio) was normal in the patients examined. In seven patients with SMA II and five patients with SMA III, no sural nerve alterations were seen, and conduction velocity was normal. In addition to SMN1 gene deletions, homozygous NAIP gene deletions were detected in six out of seven infants with peripheral neuropathy, whereas there was no evidence of a large deletion including the multicopy markers C212 and Ag1-CA in two out of three families tested. CONCLUSIONS: In this series of patients with SMA I through III who underwent sural nerve biopsy, there was significant sensory nerve pathology in severely affected patients with SMA type I, whereas there were no sensory nerve alterations clinically or morphologically in patients with milder SMA type II or III.

Axons↗
PubMed2003

[Pathology and genetic hereditary kidney cysts].

The classification of cystic kidney diseases according to the pathologic-anatomic potter classification may be difficult. New molecular genetic findings are important to understand the underlying pathogenesis, but less useful to classify the hereditary diseases. An exact classification of polycystic kidney disease in fetus and children is very important for the human genetic consultation. Therefore, the investigation of pathological anatomy of kidney and liver, as well as the evaluation of additional malformations and family history is necessary. For clinical use the mode of inheritance (autosomal dominant and autosomal recessive) is used to differentiate hereditary polycystic kidney diseases.

Humans↗
PubMed2003

Behavioural problems in children and adolescents with spinal muscular atrophy and their siblings.

Spinal muscular atrophy (SMA) is a chronic illness characterized by loss of motor function. The aim of the study was to investigate behavioural adjustment in 96 children and adolescents with SMA (47 males, 49 females; mean age 11 years 2 months, range 6 to 18 years). Forty-five non-affected siblings (26 males, 19 females; mean age 11 years 6 months, range 6 to 18 years) and 59 normally developing children (33 males, 26 females; mean age 10 years 8 months, range 6 to 18 years) were recruited as control participants. Behavioural symptoms were measured with the Child Behaviour Checklist (CBCL) and disorders were assessed with a structured psychiatric interview (Kinder-DIPS). Of the patients with SMA, 12.5% fulfilled the criteria for an ICD-10 or DSM-IV diagnosis, with separation anxiety disorder being the most common diagnosis. The CBCL total score was in the clinical range for 11.5% of patients, 20% of the siblings, and 11.7% of the control children; the externalizing score rates were 2.1%, 22.2%, and 11.9% respectively; the internalizing score 18.9%, 24.4%, and 13.6% respectively. Comorbid psychopathology was not influenced by sex, IQ, nor severity of SMA, and only externalizing behaviour was correlated to age. In conclusion, children and adolescents with SMA are characterized by a low psychiatric comorbidity not different from control individuals. The group with the highest rate of behavioural problems and with the greatest need for intervention were the non-affected siblings who had a two- to threefold higher rate of behavioural problems than the normative population.

Adolescent↗
PubMed2002

Intelligence and cognitive function in children and adolescents with spinal muscular atrophy.

Spinal muscular atrophy is a chronic disease characterised by loss of motor function. The aim of the study was to analyse cognitive functions in a large group of patients with spinal muscular atrophy. It was hypothesised that their intelligence is comparable to controls, but not above average as previously postulated. Ninety-six children and adolescents with spinal muscular atrophy I-III, aged 6.0-18.11 years, 45 non-affected siblings and 59 healthy, matched controls were examined with one- (CPM/SPM), as well as multi-dimensional intelligence tests (Kaufman-ABC; Wechsler tests). The mean IQ measured with the CPM/SPM tests was 109.6 for the spinal muscular atrophy group, 107.3 for the sibs and 104.1 for the healthy controls (no significant difference). In the older children and adolescents (SPM only) the mean IQ was significantly higher for the spinal muscular atrophy patients (109.6) than for the controls (95.4). The standard score in the 'mental processing composite' scale of the Kaufman-ABC was identical in the spinal muscular atrophy group and controls (103.8). The cognitive profile was relatively homogeneous. However, the older children and adolescents did have a significantly higher verbal IQ (113.8) than controls (104.6) in the Wechsler tests. There were no significant differences in any of the tests among different grades of severity (spinal muscular atrophy types I-III). It can be concluded that children and adolescents with spinal muscular atrophy have a general intelligence in the normal range. By adolescence, environmentally mediated aspects of intelligence are higher in patients with spinal muscular atrophy. It could be speculated that the development of cognitive skills and knowledge is a creative way to compensate the many restrictions due to their physical handicap.

Adolescent↗
PubMed2002

Extensor-tendon hypoplasia and multiple pterygia: Escobar syndrome in a 7-year-old boy.

Escobar syndrome is a rare condition with autosomal-recessive inheritance, characterised by multiple pterygia, kyphoscoliosis, multiple joint contractures and craniofacial dysmorphisms. A number of other abnormalities are also attributed to the syndrome. Here, we present a case of isolated extrinsic extensor-tendon hypoplasia of the right index finger in a 7-year-old patient with Escobar syndrome. To our knowledge, this has not been previously described in connection with this syndrome.

Abnormalities, Multiple↗
PubMed2002

Psychopathology and familial stress - comparison of boys with Fragile X syndrome and spinal muscular atrophy.

BACKGROUND: Chronic illness and mental retardation are both associated with an increased rate of behavioural problems in children and with considerable emotional strain in families. The aim of the study was to analyse and compare the specific effects of two exemplary conditions on familial stress and coping. METHODS: Forty-nine boys with Fragile X syndrome (FXS) were compared with 46 boys with Spinal Muscular Atrophy (SMA) and 32 male controls. Intelligence was measured with the RAVEN or K-ABC tests. Psychopathology was assessed with the CBCL questionnaire and a structured psychiatric interview (Kinder-DIPS), parental stress with the QRS, coping with the F-COPES and social support with the F-SOZU questionnaires. RESULTS: The mean age of the FXS boys was 8.6, of the SMA boys 12.7 and of the controls 11.2 years. The mean IQ was 47 for the FXS, 112 for the SMA and 103 for the control groups. According to the CBCL, 89.8% of the FXS boys, 21.7% of the SMA and 15.7% of the controls had a total score in the borderline or clinical range. The rates were 63.3%, 34.8% and 21.9% for internalising and 67.3%, 10.9% and 18.8% for externalising behaviour, respectively. 81.6% of the FXS and 10.9% of the SMA patients had a DSM-IV or ICD-10 psychiatric diagnosis. The most common were ADHD (FXS: 36) and Separation Anxiety Disorder (SMA: 4). In total, parental stress was significantly higher in the FXS than in the SMA families (and in both compared to controls). There were no major inter-group differences regarding social support and familial coping. CONCLUSIONS: Children with FXS are severely mentally retarded and have a high rate of mainly externalising disorders. Despite good coping abilities and social support, this is associated with high familial stress. The SMA boys, with an intelligence in the upper normal range, are no more deviant than their healthy controls. Parental stress is lower in the SMA families with good coping abilities. In conclusion, families with mentally retarded children are in even greater need of help than those of children with severe chronic illness/physical handicap.

Adaptation, Psychological↗
PubMed2001

Phenotypic variation of a novel nonsense mutation in the P0 intracellular domain.

Mutations in the gene for the peripheral myelin protein zero (P0, MPZ) cause type 1B of Charcot-Marie-Tooth sensorimotor neuropathy (CMT1B). Here we report a German family with a novel heterozygous P0 nonsense mutation (G206X) that supposedly removes four-fifths of the amino acid residues constituting the P0 intracellular domain. The 12-year-old propositus had childhood-onset CMT1B associated with bilateral pes cavus, moderate lower limb weakness, and mildly reduced sensory qualities in the distal legs. The electrophysiology was consistent with a demyelinating neuropathy. He inherited the mutation from his mother who had no complaints but slight pes cavus deformity and slow nerve conduction velocities (NCV). Conclusively, truncating mutations within the P0 intracellular domain do not necessarily cause a severe phenotype such as Dejerine-Sottas syndrome (DSS) or congenital hypomyelinating neuropathy (CHN), but can result in mild or moderate CMT1B with intrafamilial clinical variability.

Adult↗
PubMed2001

A point mutation in the human connexin32 promoter P2 does not correlate with X-linked dominant Charcot-Marie-Tooth neuropathy in Germany.

The sensorimotor neuropathy Charcot-Marie-Tooth disease (CMT) is the most common hereditary disorder of the peripheral nervous system. The X-linked dominant form of CMT (CMTX) is associated with mutations in the connexin32 gene (Cx32). The majority of CMTX cases harbour mutations in the coding region while a few cases have been reported to result from mutations in the promoter region. We found a G-713A transition of the nerve specific Cx32 promoter P2 in the Caucasian German population. The allele frequency reached 50%, both in CMT patients and in healthy control individuals. In contrast, in an earlier contribution to this journal [Brain Res. Mol. Brain Res.78 (2000) 146], the same base transition was reported to cause CMTX in a Taiwanese family. These divergent results are important for genetic counselling and require careful consideration of ethnic backgrounds and of diagnostic and experimental pitfalls.

Charcot-Marie-Tooth Disease↗
PubMed2001

Mutations in the gene encoding immunoglobulin mu-binding protein 2 cause spinal muscular atrophy with respiratory distress type 1.

Classic spinal muscular atrophy (SMA) is caused by mutations in the telomeric copy of SMN1. Its product is involved in various cellular processes, including cytoplasmic assembly of spliceosomal small nuclear ribonucleoproteins, pre-mRNA processing and activation of transcription. Spinal muscular atrophy with respiratory distress (SMARD) is clinically and genetically distinct from SMA. Here we demonstrate that SMARD type 1 (SMARD1) results from mutations in the gene encoding immunoglobulin micro-binding protein 2 (IGHMBP2; on chromosome 11q13.2-q13.4). In six SMARD1 families, we detected three recessive missense mutations (exons 5, 11 and 12), two nonsense mutations (exons 2 and 5), one frameshift deletion (exon 5) and one splice donor-site mutation (intron 13). Mutations in mouse Ighmbp2 (ref. 14) have been shown to be responsible for spinal muscular atrophy in the neuromuscular degeneration (nmd) mouse, whose phenotype resembles the SMARD1 phenotype. Like the SMN1 product, IGHMBP2 colocalizes with the RNA-processing machinery in both the cytoplasm and the nucleus. Our results show that IGHMBP2 is the second gene found to be defective in spinal muscular atrophy, and indicate that IGHMBP2 and SMN share common functions important for motor neuron maintenance and integrity in mammals.

Amino Acid Sequence↗
PubMed2001

Enuresis and urinary incontinence in children and adolescents with spinal muscular atrophy.

OBJECTIVE: To assess the rate and type of urinary incontinence in a large sample of children and adolescents with spinal muscular atrophy (SMA), a genetic disorder characterized by loss of motor function caused by anterior horn degeneration. PATIENTS, SUBJECTS AND METHODS: The study included 96 severely incapacitated patients with SMA (aged 6.0-18.11 years) who were examined in detail, including a structured interview (Kinder-DIPS), the Child Behaviour Checklist (CBCL) and a specific questionnaire for urinary incontinence. They were compared with two control groups of unaffected siblings and normal children. RESULTS: In all, 29% of the patients were wet at night and/or during the day; mostly younger children with SMA types I and II only were affected. The results of the interview were more reliable than the CBCL. The specific questionnaire revealed a variety of possible functional and neurogenic forms of wetting, including nocturnal enuresis, voiding postponement, dysfunctional voiding, stress, symptomatic (urinary tract infections, UTIs) and neurogenic incontinence. Many patients were constipated, soiled or had UTIs. The rate of behavioural problems was twice as high (32%) as normal (15%; CBCL). CONCLUSION: Children with SMA have a high rate of urinary incontinence which is often overlooked, and not diagnosed and treated adequately. These problems should be addressed routinely by paediatricians in children referred to paediatric urological specialists.

Adolescent↗
PubMed2001

The predictive value of achieved motor milestones assessed in 441 patients with infantile spinal muscular atrophy types II and III.

Proximal spinal muscular atrophy (SMA) is classified into three main subtypes (I-III), defined by age at onset and achieved motor milestones. As age at onset can be very early in SMA II and III (IIIa, onset < 3 years) and does not necessarily correlate with prognosis, the question arises whether the child can be correctly assigned to a specific SMA type at the time of presentation based on the assessment of motor function. Therefore we studied the motor milestones in 175 SMA type II and 266 SMA type III patients. In SMA II, 73% of the patients sat within the normal age range (up to 9 months), the remainder learned to do so at ages between 10 and 30 months. In SMA III, the walking milestone was passed with delay (given an upper normal limit of 18 months) in 10% of all and 16% of SMA IIIa patients (median age 13 months, range 9-53 months). There was a correlation between late sitting and walking in SMA III, since those who sat after 9 months were responsible for the majority of delayed walkers. The median age when becoming chairbound did not differ between early-onset SMA III patients who walked with delay and those who walked within the normal age range (10.2 versus 10.5 years). In conclusion, a significant proportion of patients with early-onset SMA classified as SMA II on the basis of achieved motor function turned out to be SMA III at later follow-up. It is important to reassess a child in the first 2-4 years, to determine whether walking can be achieved with or without aids, as children who start to walk late have a similar favourable outcome for ambulation compared to earlier walkers.

Adolescent↗
PubMed2001

DNA diagnosis in hereditary nephropathies.

Increasing knowledge regarding the genetic basis of hereditary nephropathies has contributed much to the understanding of their pathogenesis. In addition, localization and identification of genes have offered new tools for the classification and diagnostics of hereditary nephropathies. The diagnosis at the DNA level, however, differs from classical diagnostic procedures in many respects. The current status of DNA diagnostics in hereditary nephropathies is summarized in this review, which includes a discussion of the major principles and limitations.

Chromosome Mapping↗