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K Zerres

Publications and source records attributed to K Zerres.

At least 55 records · Page 3Linked to original sources
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↗
PubMed2001

[Molecular biology of cystinuria].

Cystine stones belong to the kidney stones diseases which are difficult to manage due to the high rate of recidivation and the necessary surgical procedures. Cystinuria is an autosomal recessive defect of the transport of cystine and the dibasic amino acids in the proximal kidney tube. Recently, two subunits of a renal cystine transporter have been identified. Mutations in these genes have been shown to lead to the cystinuria phenotype. Genetic and functional analyses have helped to modify the classification of cystinuria which had previously been exclusively based on biochemical data. Furthermore, first steps towards a molecular genetic testing have been carried out replacing the so far diagnostic procedure which are stressing for the patients. The results of these testings make an individual therapy possible.

Cystinuria↗
PubMed2000

Syndrome of autosomal recessive polycystic kidneys with skeletal and facial anomalies is not linked to the ARPKD gene locus on chromosome 6p.

We report on two sibs, both males, one born at 37 the other at 24 weeks of gestation, both with a syndrome similar to that seen in three sets of sibs by Gillessen-Kaesbach et al. [1993: Am J Med Genet 45:511-518]. Both propositi had polycystic kidneys and hepatic fibrosis indistinguishable from that seen in autosomal recessive polycystic kidney disease (ARPKD), and skeletal and facial anomalies. Skeletal abnormalities included "butterfly" vertebrae, square shape of pelvis, and brachymelia. The facial anomalies included hypertelorism, epicanthic folds, and anteverted nares. Additional external findings were apparently low-set ears and a short neck. Histopathological examination of the kidneys showed radial orientation and cystic dilatation of the cortical and medullar tubules. The liver showed "congenital hepatic fibrosis." The hepatic findings in the second infant were less severe. Renal abnormalities were limited to focal tubular cystic changes. Linkage analysis with polymorphic markers of the region 6p21.1-p12, flanking the gene locus of ARPKD, showed different haplotypes in the sibs, thus excluding the ARPKD gene locus in this family and indicating genetic heterogeneity.

Abortion, Induced↗
PubMed2000

ADULT syndrome allelic to limb mammary syndrome (LMS)?

In 1993, we described an autosomal-dominant syndrome in a German family characterized by ectrodactyly/syndactyly, dysplasia of nails, lacrimal duct atresia, hypodontia, hypoplastic breasts and nipples, intensive freckling (ADULT syndrome, acro-dermato-ungual-lacrimal-tooth syndrome, MIM 103285). In 1996 a large Dutch family with an autosomal-dominant syndrome ("limb mammary syndrome", LMS, MIM *603543) characterized by hypoplasia/aplasia of mammary glands and nipples, ectrodactyly, other hand/foot anomalies, lacrimal-duct atresia, nail dysplasia, hypohidrosis, cleft palate/bifid uvula, hypodontia was reported. In this family the disease locus was recently mapped to the chromosomal region 3q27 through a genome-wide linkage screen. Given the similarity of manifestations we hypothesized that the two syndromes might be allelic. We genotyped 21 members of the ADULT family with 19 polymorphic markers from the chromosomal region 3q27 and obtained a maximal lod score of 4.82 at straight theta = 0.00 with marker D3S1288. Our results place the ADULT locus to the same chromosomal region where LMS was mapped, suggesting that these two conditions are allelic.

Abnormalities, Multiple↗
PubMed2000

Genomic structure of the gene for the human P1 protein (MCM3) and its exclusion as a candidate for autosomal recessive polycystic kidney disease.

The locus PKHD1 (polycystic kidney and hepatic disease 1) has been linked to all typical forms of the autosomal recessive polycystic kidney disease (ARPKD) and maps to chromosome 6p21.1-p12. We previously defined its genetic interval by the flanking markers D6S1714 and D6S1024. In our current work, we have fine-mapped the gene for the human P1 protein (MCM3), thought to be involved in the DNA replication process, to this critical region. We have also established its genomic structure. Mutation analyses using SSCP were performed in ARPKD patients' cDNA samples, leading to the exclusion of this gene as a candidate for this disorder. We also identified two intragenic polymorphisms that allowed families with critical recombination events to be evaluated. Although neither marker was informative in these individuals, they are the closest yet described for PKHD1 and may help to refine the candidate region.

Cell Cycle Proteins↗
PubMed2000

An essential SMN interacting protein (SIP1) is not involved in the phenotypic variability of spinal muscular atrophy (SMA).

The survival motor neuron (SMN) protein and the SMN interacting protein 1 (SIP1) are part of a 300 kD protein complex with a crucial role in snRNP biogenesis and pre-mRNA splicing. Both proteins are colocalised in nuclear structures called gems and in the cytoplasm. Approximately 96% of patients with autosomal recessive spinal muscular atrophy (SMA) show mutations in the SMN1 gene, while about 4% fail to show any mutation, despite a typical SMA phenotype. Additionally, sibs with identical 5q13 homologs and homozygous absence of SMN1 can show variable phenotypes which suggest that SMA is modified by other, yet unknown factors. Since both genes, SMN1 and SIP1, belong to the same pathway and are part of the same protein complex, it is obvious to ask whether mutations within SIP1 are responsible for both the phenotypic variability and the appearance of non-SMN mutated SMA patients. First, we identified the chromosomal location of SIP1 and assigned it to chromosomal region 14q13-q21 by fluorescence in situ hybridisation. No SMA related disorder has yet been assigned to this chromosomal region. Next, we determined the exon-intron structure of the SIP1 gene which encompasses 10 exons and identified five transcription isoforms. We sequenced either RT-PCR products or genomic DNA covering the complete coding region from 23 typical SMA patients who had failed to show any SMN1 mutation. No mutation and no polymorphism was found within SIP1. Additionally, we sequenced RT-PCR products or genomic fragments of the entire SIP1 coding region from 26 sibs of 11 SMA families with identical genotypes (delta7SMN/delta7SMN or delta7SMN/other mutation) but different phenotypes and again no mutation was found. Finally, we performed quantitative analysis of RT-PCR products from the same 26 sibs. No difference in expression level of the five isoforms among phenotypically variable sibs was observed. Based on these data, we suggest that neither the phenotypic variability nor the 5q-unlinked SMA are caused by mutations within SIP1.

Alternative Splicing↗
PubMed1999

A 1-Mb BAC/PAC-based physical map of the autosomal recessive polycystic kidney disease gene (PKHD1) region on chromosome 6.

The PKHD1 (polycystic kidney and hepatic disease 1) gene responsible for autosomal recessive polycystic kidney disease has been mapped to 6p21.1-p12 to an approximately 1-cM interval flanked by the markers D6S1714/D6S243 and D6S1024. We have developed a sequence-ready BAC/PAC-based contig map of this region as the next step for the positional cloning of PKHD1. This contig comprising 52 clones spanning approximately 1 Mb was established by content mapping of 44 BAC/PAC-end-derived STSs, 3 known genetic markers, 5 YAC-end-derived STSs, 3 random STSs, 1 previously mapped gene, and 1 EST. The average depth per marker is 6.3 clones, and the average STS density is 20 kb. The genomic clone overlaps were confirmed by restriction fragment fingerprint analysis. A high-resolution BAC/PAC-based contig map is essential to the ultimate goal of identifying the PKHD1 gene.

Chromosomes, Human, Pair 6↗
PubMed1999

Congenital hydrocephalus internus and aqueduct stenosis: aetiology and implications for genetic counselling.

UNLABELLED: Genetic counselling in families with congenital hydrocephalus internus (CHI) in combination with aqueduct stenosis (AS) is often difficult due to an uncertain aetiology. We present a series of 35 patients with CHI and AS focusing on the aetiology and presumed recurrence risk for siblings. In 13 patients (37.1%) a genetic aetiology was identified with an increased recurrence risk for siblings. The relative frequency of patients with X-linked hydrocephalus in our sample was in accordance with the literature (2/35), but was more frequent in other diseases with Mendelian inheritance. CONCLUSION: In addition to the well-known X-linked and autosomal recessive forms of aqueduct stenosis with hydrocephalus, this malformation can occur in other diseases with Mendelian inheritance. This finding is of considerable importance for genetic counselling and prognosis.

Cerebral Aqueduct↗
PubMed1999

Quantitative analysis of survival motor neuron copies: identification of subtle SMN1 mutations in patients with spinal muscular atrophy, genotype-phenotype correlation, and implications for genetic counseling.

Problems with diagnosis and genetic counseling occur for patients with autosomal recessive proximal spinal muscular atrophy (SMA) who do not show the most common mutation: homozygous absence of at least exon 7 of the telomeric survival motor neuron gene (SMN1). Here we present molecular genetic data for 42 independent nondeleted SMA patients. A nonradioactive quantitative PCR test showed one SMN1 copy in 19 patients (45%). By sequencing cloned reverse-transcription (RT) PCR products or genomic fragments of SMN1, we identified nine different mutations in 18 of the 19 patients, six described for the first time: three missense mutations (Y272C, T274I, S262I), three frameshift mutations in exons 2a, 2b, and 4 (124insT, 241-242ins4, 591delA), one nonsense mutation in exon 1 (Q15X), one Alu-mediated deletion from intron 4 to intron 6, and one donor splice site mutation in intron 7 (c.922+6T-->G). The most frequent mutation, Y272C, was found in 6 (33%) of 18 patients. Each intragenic mutation found in at least two patients occurred on the same haplotype background, indicating founder mutations. Genotype-phenotype correlation allowed inference of the effect of each mutation on the function of the SMN1 protein and the role of the SMN2 copy number in modulating the SMA phenotype. In 14 of 23 SMA patients with two SMN1 copies, at least one intact SMN1 copy was sequenced, which excludes a 5q-SMA and suggests the existence of further gene(s) responsible for approximately 4%-5% of phenotypes indistinguishable from SMA. We determined the validity of the test, and we discuss its practical implications and limitations.

Cyclic AMP Response Element-Binding Protein↗
PubMed1999

Mutations in the SLC3A1 gene in cystinuric patients: frequencies and identification of a novel mutation.

Cystinuria is a frequent autosomal recessive transport disorder characterized by defective renal resorption of cystine and other dibasic amino acids. Biochemically, three types of cystinuria can be defined. Here we present our results of screening for mutations in the SLC3A1 gene, which codes for a dibasic amino acid transporter protein and appears to be involved in the pathogenesis of cystinuria type I. Our study population consists of 5 Italian cystinuria type I patients and 10 cystinuric patients as yet unclassified as to clinical type. The latter were of different ethnic origin. In total, we found 13 point mutations and 8 genomic rearrangements in 15 cystinuric patients, i.e., our detection rate was 70% (23/30 chromosomes). Remarkably, in patients known to be suffering from cystinuria type I, the mutation detection rate was only 50%, whereas in patients unselected as to cystinuria type, we found 80% of mutations. Additionally, our results, as with those published in the literature, indicate a possible population specific distribution of mutations: Each of the 4 Greek patients analyzed here showed homozygosity for mutation T216M in exon 3. Analysis of a Yugoslavian patient showed homozygosity for a novel mutation, R365L, in exon 6 (nt1094G > T). Findings from molecular genetic studies, as well as physiological investigations, suggest that there are further genes that play a role in the etiology of cystinuria. Nevertheless, our results show that screening for mutations in the SLC3A1 gene can be a meaningful step toward molecular genetic diagnosis of cystinuria in patients without biochemical classification. As with cystic fibrosis, the finding of specific mutations in particular ethnic populations, suggest that the diagnostic approach should take into consideration a patient's ethnic origins.

Amino Acid Transport Systems, Basic↗
PubMed1999

Multiple intracranial aneurysms in a patient with autosomal recessive polycystic kidney disease.

Autosomal recessive polycystic kidney disease (ARPKD) is usually characterized by early onset chronic renal failure due to innumerable dilated collecting ducts. Hepatic fibrosis is an obligate sign. Here, for the first time, we report a 31-year-old female with ARPKD who was diagnosed with symptomatic multiple intracranial aneurysms, a manifestation previously only known to be associated with autosomal dominant polycystic kidney disease (ADPKD).

Adult↗
PubMed1999

Growth retardation in Turner syndrome: aneuploidy, rather than specific gene loss, may explain growth failure.

The etiology of short stature (SST) in Turner syndrome (TS) is still a subject of speculation. A variety of hypotheses have been put forward, from SST as a result of increased intrauterine tissue pressure after fetal lymphedema to haploinsufficiency of a specific growth gene(s). These hypotheses have various statistical-auxological implications on the growth distribution in TS. Empirical research has provided no clear evidence for any of these theories, but the well known correlation between patients' and midparental height (MPH) could be established. The influence of undetected mosaic status has often been cited as a major problem in the investigation of growth in TS. However, an assessment of mosaic status (simultaneous analysis of karyotype and phenotype) and its effect on growth with inclusion of MPH has been not yet carried out for a large sample. The aim of this study was to evaluate growth and its complex relationship to mosaic status and MPH in TS. In a mixed cross-sectional and longitudinal study we retrospectively analyzed the auxological and clinical data of 447 patients with a pure loss of X-chromosomal material (n = 381 with 45,X0; n = 66 mosaics). The 447 patients were selected from a series of 609 consecutive patients with TS. To assess the effect of mosaic status on growth, we computed a bifactorial analysis of variance (phenotype, karyotype), including MPH as a covariate. In line with the mosaic hypothesis, we found a correlation between individual loss of X-chromosomal material and phenotypical expressivity. In contrast, no correlation was found with respect to growth. With respect to MPH, we found growth retardation (GR) even in those patients with "normal" height above the third percentile (-2 or more SD score). The interindividual variance of GR in TS (comparable to growth variance in the normal population) seems to be unrelated to other TS-specific factors (e.g. mosaic status or single gene loss). Instead, both interindividual variance and the global growth shift distribution are best explained by the presence of an unspecific aneuploidic effect. Furthermore, consideration of patient height in relation to MPH should lead to a better understanding of the nature of GR in TS than the commonly used, strictly qualitative definition of SST.

Adolescent↗