The spinocerebellar ataxias (SCAs) with autosomal dominant inheritance are a clinically and genetically heterogeneous group of neurodegenerative disorders. To date 27 different loci have been identified for these conditions. Recently, two deletions as well as one missense mutation in the beta-III spectrin gene (STBN2) were identified causing SCA5. To evaluate the clinical relevance of these mutations, we screened 310 familial and sporadic patients with ataxia. While none of the individuals tested had evidence for one of the known SCA5 mutations, additional sequencing of the coding region for 22 unrelated patients revealed three novel missense exchanges at evolutionary conserved amino acid positions. Even though each variation marks a unique genotype in 250 alleles, a disease causing capacity can be excluded with high probability. These results reflect the challenges for molecular analyses in SCA5.

Oculo-auriculo-vertebral spectrum (OMIM164210) is a phenotypically and probably also a genetically heterogeneous disorder, characterized by anomalies of the ear (mostly microtia), hemifacial microsomia, and defects of the vertebral column. Associated clinical findings include anomalies of the eye and brain, and developmental delay. We have evaluated the clinical data and photographs of 53 unrelated patients with OAVS, all presenting with either isolated microtia or preauricular tags in association with hemifacial microsomia as minimal diagnostic criteria; five had a positive family history for OAVS. Based on the main clinical findings and unilateral or bilateral involvement, we have developed a new classification system for OAVS, consisting of six subgroups. There is a statistically significant correlation between the subgroup and number of associated clinical findings, and a statistically significant difference regarding prognosis in uni- and bilaterally affected patients, suggesting that this classification is clinically relevant to the categorization of patients with OAVS. The newly developed scoring system (two points for each main clinical finding and one for each associated clinical finding) presented here, also aids prognosis, especially for delay of motor development and brain anomalies, and statistical analysis revealed significant clustering between different clinical findings of OAVS confirming the clinical impression previously published by several authors.

The Shprintzen–Goldberg syndrome (SGS) is a disorder of unknown cause comprising craniosynostosis, a marfanoid habitus and skeletal, neurological, cardiovascular, and connective‐tissue anomalies. There are no pathognomonic signs of SGS and diagnosis depends on recognition of a characteristic combination of anomalies. Here, we describe 14 persons with SGS and compare their clinical findings with those of 23 previously reported individuals, including two families with more than one affected individual. Our analysis suggests that there is a characteristic facial appearance, with more than two thirds of all individuals having hypertelorism, down‐slanting palpebral fissures, a high‐arched palate, micrognathia, and apparently low‐set and posteriorly rotated ears. Other commonly reported manifestations include hypotonia in at least the neonatal period, developmental delay, and inguinal or umbilical hernia. The degree of reported intellectual impairment ranges from mild to severe. The most common skeletal manifestations in SGS were arachnodactyly, pectus deformity, camptodactyly, scoliosis, and joint hypermobility. None of the skeletal signs alone is specific for SGS. Our study includes 14 mainly German individuals with SGS evaluated over a period of 10 years. Given that only 23 other persons with SGS have been reported to date worldwide, we suggest that SGS may be more common than previously assumed. © 2005 Wiley‐Liss, Inc.

Submicroscopic or subtle aneusomies at the chromosome ends, typically diagnosed by subtelomere fluorescence in situ hybridization (FISH), are a significant cause of idiopathic mental retardation (MR). Some 20 subtelomere studies, including more than 2,500 subjects, have been reported. The studies are not directly comparable because different techniques and patient ascertainment criteria were used, but an analysis of 14 studies showed that aberrations were detected in 97 out of 1,718 patients (5.8%, range 2–29%; 95% confidence interval (CI) 4.60–6.84%). We performed a subtelomere FISH study of 50 unrelated children ascertained by a checklist that evaluates MR or developmental delay, dysmorphism, growth defect, and abnormal pedigree and found 10 bona fide causal rearrangements (detection rate 20%, 95% CI 10–33.7%). The findings included five unbalanced familial translocations or inversions, two unbalanced de novo translocations, and two de novo deletions. Patient 5 showed multiple anomalies (large head, vision defect, omphalocele, heart defect, enlarged kidneys, moderate MR, speech defect, mild transient homocysteinemia) and a de novo balanced translocation of chromosomes 17p13.3 and 20q13.33. The report of a subtelomeric balanced rearrangement associated with a disease phenotype is a novel one. FISH mapping using panels of overlapping BAC clones identified a number of candidate genes at or near his breakpoints, including ASPA , TRPV3 , TRPV1 , and CTNS at 17p13.3, and three genes of unknown function at 20q13.33. Only the homocysteinemia could be speculatively linked to one of these genes ( CTNS , the gene for cystinosis). Three within the subset of 16 children (18.8%) with mild (IQ, 50–69) or unspecified degree of MR tested positive, suggesting that the checklist approach could be especially useful within this group of patients. © 2004 Wiley‐Liss, Inc.

We report on a rare additional numerical chromosomal aberration in a child with Down syndrome due to free trisomy 21. The karyotype showed 48,XY,+21,+mar after GTG banding, with the marker present in 80% of cells. The supernumerary marker chromosome (SMC) was as small as approximately one-third of 18p, and with the recently developed centromere-specific multi-color fluorescence in situ hybridization (cenM-FISH) technique, it was shown that the SMC was a derivative chromosome 4. The SMC was not specifically stained by arm-specific probes for chromosome 4; thus, it has been described as der(4)(:p11 --> q11:). Microsatellite analysis resulted in a partial maternal uniparental isodisomy (UPD) for chromosome 4p15-16 and a maternal origin for two chromosomes 21. Until now only two similar cases have been described in the literature, but without clarifying the origin of the SMC and without looking for an additional UPD. This is the only reported case of a UPD 4p in a liveborn child.

Recently mutations in the gene ZFHX1B (SIP1) were shown in patients with "syndromic Hirschsprung disease" with mental retardation (MR) and multiple congenital anomalies (MCA), but it was unclear if Hirschsprung disease is an obligate symptom of these mutations and if the distinct facial phenotype delineated by Mowat et al. [1998: J Med Genet 35: 617-623] is specific for ZFHX1B mutations. In order to address these open questions we analyzed the ZFHX1B gene in five patients, three of whom had "syndromic Hirschsprung disease" two with and one without the facial phenotype described by Mowat et al. [1998], and two of whom had the distinct facial gestalt without Hirschsprung disease. Analyses of microsatellite markers and newly identified SNPs, and/or FISH with BACs from the ZFHX1B region excluded large deletions in all five patients. Direct sequencing demonstrated truncating ZFHX1B mutations in all four patients with the characteristic facial phenotype, but not in the patient with syndromic Hirschsprung disease without the distinct facial appearance. We demonstrate that there is a specific clinical entity with a recognizable facial gestalt, mental retardation and variable MCAs which we propose be called the "Mowat-Wilson syndrome."

We report on the incidental prenatal detection of an interstitial X-chromosomal deletion in a male fetus and his mother by fetal sexing with a primer pair recognizing an X-Y homologous locus (DXYS19), formerly unassigned on the X chromosome. The proband asked for prenatal diagnosis because of her elevated age and risk of Duchenne muscular dystrophy (DMD). Prior to molecular genetic testing for DMD, fetal sexing was carried out on DNA prepared from cultured amniocytes. PCR analysis revealed the expected Y-chromosomal product, but did not show the constitutive X-chromosomal fragment. The absence of the X-chromosomal fragment in the fetus and on one X chromosome of the mother was confirmed by Southern hybridization of HindIII restricted DNA with probe pJA1165 (DXYS19). DXYS19X was mapped to Xp22.3 by combining several approaches, including: (1) analysis of somatic cell hybrid lines containing different fragments of the human X chromosome; (2) Southern hybridization of a yeast artificial chromosome (YAC)-filter panel provided by the Resource Center/Primary Database (RZPD); (3) FISH analysis; and (4) re-evaluation of two patients with interstitial deletions in Xp22.3. The extent of the deletion in the fetus was estimated by further markers from Xp22.3 and found to include the STS gene. Mental retardation could not be excluded since some mentally retarded patients exhibited overlapping deletions. Copyright (C) 2000 John Wiley & Sons, Ltd.

Townes-Brocks syndrome (TBS) is an autosomal dominantly inherited malformation syndrome characterized by anal, renal, limb, and ear anomalies. Recently, we showed that mutations in the putative zinc finger transcription factor gene SALL1 cause TBS. To determine the spectrum of SALL1 mutations and to investigate the genotype-phenotype correlations in TBS, we examined 23 additional families with TBS or similar phenotypes for SALL1 mutations. In 9 of these families mutations were identified. None of the mutations has previously been described. Two of these mutations are nonsense mutations, one of which occurred in three unrelated families. Five of the mutations are short deletions. All of the mutations are located 5' of the first double zinc finger (DZF) encoding region and are therefore predicted to result in putative prematurely terminated proteins lacking all DZF domains. This suggests that only SALL1 mutations that remove the DZF domains result in TBS. We also present evidence that in rare cases SALL1 mutations can lead to phenotypes similar to Goldenhar syndrome. However, phenotypic differences in TBS do not seem to depend on the site of mutation.

It has previously been shown that, in the heterozygous state, mutations in the SOX9 gene cause campomelic dysplasia (CD) and the often associated autosomal XY sex reversal. In 12 CD patients, 10 novel mutations and one recurrent mutation were characterized in one SOX9 allele each, and in one case, no mutation was found. Four missense mutations are all located within the high mobility group (HMG) domain. They either reduce or abolish the DNA-binding ability of the mutant SOX9 proteins. Among the five nonsense and three frameshift mutations identified, two leave the C-terminal transactivation (TA) domain encompassing residues 402-509 of SOX9 partly or almost completely intact. When tested in cell transfection experiments, the recurrent nonsense mutation Y440X, found in two patients who survived for four and more than 9 years, respectively, exhibits some residual transactivation ability. In contrast, a frameshift mutation extending the protein by 70 residues at codon 507, found in a patient who died shortly after birth, showed no transactivation. This is apparently due to instability of the mutant SOX9 protein as demonstrated by Western blotting. Amino acid substitutions and nonsense mutations are found in patients with and without XY sex reversal, indicating that sex reversal in CD is subject to variable penetrance. Finally, none of 18 female patients with XY gonadal dysgenesis (Swyer syndrome) showed an altered SOX9 banding pattern in SSCP assays, providing evidence that SOX9 mutations do not usually result in XY sex reversal without skeletal malformations.

Duplications in Xp including the DSS (dosage sensitive sex reversal) region cause male to female sex reversal. We investigated two patients from families with Xp duplications. The first case was one of two sisters with karyotype 46,XY, der(22), t(X;22)(p11.3;p11)mat and unambiguous female genitalia. The living sister was developmentally retarded, and showed multiple dysmorphic features and an acrocallosal syndrome. The second case was a boy with a maternally inherited direct duplication of Xp21.3-pter with the breakpoint close to the DSS locus. He had multiple abnormalities and micropenis, but otherwise unambiguous male genitalia. We performed quantitative Southern blot analysis with probes from Xp22.13 to p21.2 to define the duplicated region. Clinical, cytogenetic, and molecular data from both patients were compared with those of previously reported related cases. A comparison of the extragenital symptoms revealed no differences between patients with or without sex reversal. In both cases, the symptoms were non-specific. Among 22 patients with a duplication in Xp, nine had unambiguous female genitalia and a well-documented duplication of the DSS region. Two patients with duplication of DSS showed ambiguous external genitalia. From these data, we conclude that induction of testicular tissue may start in these patients, but that the type of genitalia depends on the degree of subsequent degeneration by a gene in DSS.

This study presents the most extensive epidemiological data on chronic forms of spinal muscular atrophy in childhood (CSMA) in West-Thüringen in Germany. The incidence of CSMA was calculated to be 1 in 9,420 live births. The prevalence was 1.624 in 100,000 of the general population (as of 31 December 1980).

This study contains the largest body of epidemiological data on Werdnig-Hoffmann disease (acute infantile spinal muscular atrophy; ASMA) in West-Thüringen in Germany. The incidence of ASMA was calculated to be 1 in 10202 live births. The prevalence was 1 in 595362 of the general population (as of 31 December 1987). The study gives an unexpectedly high incidence rate confirming the suggestion that ASMA in Central and Eastern Europe might be more frequent than in Western Europe. However, we consider that this high incidence rate in West-Thüringen is a result of the almost complete ascertainment made possible because of the well-organised and centralised health system existing in Thüringen over the last few decades.

Journal of Inherited Metabolic DiseaseVolume 13, Issue 3 p. 371-374 Short Communication First prenatal diagnosis of acyl-CoA oxidase deficiency R. J. A. Wanders, R. J. A. Wanders Department of Paediatrics, University Hospital Amsterdam, Meibergdreef 9, Amsterdam, 1105 AZ The NetherlandsSearch for more papers by this authorA. Schelen, A. Schelen Department of Paediatrics, University Hospital Amsterdam, Meibergdreef 9, Amsterdam, 1105 AZ The NetherlandsSearch for more papers by this authorN. Feller, N. Feller Department of Paediatrics, University Hospital Amsterdam, Meibergdreef 9, Amsterdam, 1105 AZ The NetherlandsSearch for more papers by this authorR. B. H. Schutgens, R. B. H. Schutgens Department of Paediatrics, University Hospital Amsterdam, Meibergdreef 9, Amsterdam, 1105 AZ The NetherlandsSearch for more papers by this authorF. Stellaard, F. Stellaard Department of Paediatrics, Free University of Amsterdam, De Boelelaan 1117, Amsterdam, 1007 MB The NetherlandsSearch for more papers by this authorC. Jakobs, C. Jakobs Department of Paediatrics, Free University of Amsterdam, De Boelelaan 1117, Amsterdam, 1007 MB The NetherlandsSearch for more papers by this authorB. Mitulla, B. Mitulla Bezirkkrankenhaus Suhl, Suhl, German Democratic RepublicSearch for more papers by this authorG. Seidlitz, G. Seidlitz Ernst-Moritz-Arndt Universität, Greifswald, German Democratic RepublicSearch for more papers by this author R. J. A. Wanders, R. J. A. Wanders Department of Paediatrics, University Hospital Amsterdam, Meibergdreef 9, Amsterdam, 1105 AZ The NetherlandsSearch for more papers by this authorA. Schelen, A. Schelen Department of Paediatrics, University Hospital Amsterdam, Meibergdreef 9, Amsterdam, 1105 AZ The NetherlandsSearch for more papers by this authorN. Feller, N. Feller Department of Paediatrics, University Hospital Amsterdam, Meibergdreef 9, Amsterdam, 1105 AZ The NetherlandsSearch for more papers by this authorR. B. H. Schutgens, R. B. H. Schutgens Department of Paediatrics, University Hospital Amsterdam, Meibergdreef 9, Amsterdam, 1105 AZ The NetherlandsSearch for more papers by this authorF. Stellaard, F. Stellaard Department of Paediatrics, Free University of Amsterdam, De Boelelaan 1117, Amsterdam, 1007 MB The NetherlandsSearch for more papers by this authorC. Jakobs, C. Jakobs Department of Paediatrics, Free University of Amsterdam, De Boelelaan 1117, Amsterdam, 1007 MB The NetherlandsSearch for more papers by this authorB. Mitulla, B. Mitulla Bezirkkrankenhaus Suhl, Suhl, German Democratic RepublicSearch for more papers by this authorG. Seidlitz, G. Seidlitz Ernst-Moritz-Arndt Universität, Greifswald, German Democratic RepublicSearch for more papers by this author First published: 01 May 1990 https://doi.org/10.1007/BF01799398Citations: 33AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume13, Issue3May 1990Pages 371-374 RelatedInformation