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Title: Autosomal dominant Kufs` disease: Clinical heterogeneity in nine families, and exclusion of linkage to CLN1 and CLN3 markers in a large American kindred

Abstract

Most forms of neuronal ceroid lipofuscinosis (NCL) are autosomal recessive, and three genes have already been mapped: the infantile form (CLN 1); the juvenile form (CLN 3); and the early juvenile variant (CLN 5) on chromosomes 1, 16 and 13, respectively. Kufs` disease or adolescent-adult onset NCL is usually inherited as an autosomal recessive trait, and presents as three distinct clinical syndromes: progressive myoclonus epilepsy (PME) with onset in the early teens or around age 30; and onset of dementia with motor disability in the 30s. We have studied three families originating from different parts of the USA manifesting dominantly inherited Kufs` disease. Granular osmophilic deposits (GROD) were found in brain, but storage in skin was not an obligatory feature. Six dominantly inherited PME families have been ascertained from three different regions of Spain. No storage was found in skin or muscle in any of these families. The mean age of onset in the American families is earlier, the clinical manifestations more severe, and the progression much more rapid that in the Spanish families. These findings would suggest the possibility of genetic heterogeneity involving two or more loci, or different mutations at the same gene locus. Genetic linkage studies havemore » been carried out in a six-generation New Jersey family in an attempt to characterize the gene(s) responsible for this disorder. The infantile NCL locus on chromosome 1p (CLN1) and the juvenile NCL locus on chromosome 16p (CLN 3) have been excluded in this family. Further clinical, pathological and molecular genetic studies should lead to the clarification of the diagnostic approaches in this disorder.« less

Authors:
; ;  [1]
  1. and others
Publication Date:
OSTI Identifier:
134675
Report Number(s):
CONF-941009-
Journal ID: AJHGAG; ISSN 0002-9297; TRN: 95:005313-1412
Resource Type:
Journal Article
Resource Relation:
Journal Name: American Journal of Human Genetics; Journal Volume: 55; Journal Issue: Suppl.3; Conference: 44. annual meeting of the American Society of Human Genetics, Montreal (Canada), 18-22 Oct 1994; Other Information: PBD: Sep 1994
Country of Publication:
United States
Language:
English
Subject:
55 BIOLOGY AND MEDICINE, BASIC STUDIES; PATIENTS; HEREDITARY DISEASES; PHENOTYPE; NERVOUS SYSTEM DISEASES; MENTAL DISORDERS; EPILEPSY; GENES; GENE MUTATIONS; GENETIC MAPPING; SPAIN; USA; AGE DEPENDENCE; DIAGNOSIS; HUMAN CHROMOSOMES; DOMINANT MUTATIONS; BIOLOGICAL MARKERS; GENETICS; STATISTICS

Citation Formats

Andermann, F., Andermann, E., and Carpenter, S.. Autosomal dominant Kufs` disease: Clinical heterogeneity in nine families, and exclusion of linkage to CLN1 and CLN3 markers in a large American kindred. United States: N. p., 1994. Web.
Andermann, F., Andermann, E., & Carpenter, S.. Autosomal dominant Kufs` disease: Clinical heterogeneity in nine families, and exclusion of linkage to CLN1 and CLN3 markers in a large American kindred. United States.
Andermann, F., Andermann, E., and Carpenter, S.. 1994. "Autosomal dominant Kufs` disease: Clinical heterogeneity in nine families, and exclusion of linkage to CLN1 and CLN3 markers in a large American kindred". United States. doi:.
@article{osti_134675,
title = {Autosomal dominant Kufs` disease: Clinical heterogeneity in nine families, and exclusion of linkage to CLN1 and CLN3 markers in a large American kindred},
author = {Andermann, F. and Andermann, E. and Carpenter, S.},
abstractNote = {Most forms of neuronal ceroid lipofuscinosis (NCL) are autosomal recessive, and three genes have already been mapped: the infantile form (CLN 1); the juvenile form (CLN 3); and the early juvenile variant (CLN 5) on chromosomes 1, 16 and 13, respectively. Kufs` disease or adolescent-adult onset NCL is usually inherited as an autosomal recessive trait, and presents as three distinct clinical syndromes: progressive myoclonus epilepsy (PME) with onset in the early teens or around age 30; and onset of dementia with motor disability in the 30s. We have studied three families originating from different parts of the USA manifesting dominantly inherited Kufs` disease. Granular osmophilic deposits (GROD) were found in brain, but storage in skin was not an obligatory feature. Six dominantly inherited PME families have been ascertained from three different regions of Spain. No storage was found in skin or muscle in any of these families. The mean age of onset in the American families is earlier, the clinical manifestations more severe, and the progression much more rapid that in the Spanish families. These findings would suggest the possibility of genetic heterogeneity involving two or more loci, or different mutations at the same gene locus. Genetic linkage studies have been carried out in a six-generation New Jersey family in an attempt to characterize the gene(s) responsible for this disorder. The infantile NCL locus on chromosome 1p (CLN1) and the juvenile NCL locus on chromosome 16p (CLN 3) have been excluded in this family. Further clinical, pathological and molecular genetic studies should lead to the clarification of the diagnostic approaches in this disorder.},
doi = {},
journal = {American Journal of Human Genetics},
number = Suppl.3,
volume = 55,
place = {United States},
year = 1994,
month = 9
}
  • The split hand/split foot anomaly (SHSF) is a developmental defect of the distal limbs, specifically involving the central digital rays. Such a defect is usually inherited as an autosomal trait, although most cases occur sporadically. Penetrance of SHSF is extremely variable, ranging from apparent excess of affected offspring in some families to very low penetrance in others. One explanation for this variability is that of locus heterogeneity. More recently, we ascertained a family with normal chromosomes and a highly penetrant type of SHSF, segregating as an autosomal dominant trait, and investigated whether it could also be due to the putativemore » limb-development mutant gene at the 7q locus. For this purpose, we studied linkage between the defect and highly polymorphic DNA markers from the 7q22 region. The results demonstrate that, in the highly penetrant family, autosomal dominant SHSF is caused by a mutant gene not linked with the putative locus in 7q22.1. Our data is in agreement with the findings of other groups and provide further evidence for genetic heterogeneity of autosomal dominant SHSF. 12 refs., 2 figs., 1 tab.« less
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  • ADPKD results from mutations in at least two genetically distinct loci. Most of the cases (ADPKD-1) are due to mutations in the locus PKD1, on the short arm of chromosome 16. ADPKD-2 accounts for 15% of ADPKD in Spanish population. Previous linkage studies have localized the gene for ADPKD-2 (PKD2) in the chromosome region 4q13-q23, and the distance between the flanking markers, D4S231 and D4S423/D4S414, was 7 cM. We have analyzed seven unrelated families with ADPKD not linked to PKD1 by using eight microsatellite markers that map within the candidate region. All the families did show linkage to any ofmore » the markers for which they were informative. Pairwise linkage analysis revealed that loci D4S414 and D4S423 are tightly linked to the disease with lod scores of 3.12 and 6.50, respectively, at a recombination fraction of 0.00. Multilocus linkage analysis indicates that the most likely location for PKD2 is distal to D4S1542, with odds of 1000:1 over the location proximal to D4S1542. Two recombination events involving PKD2 chromosomes have been identified in our seven families. These results provide a proximal boundary for the PKD2 locus and, considering previous studies, its localization is further refined to a 3 cM interval flanked by markers D4S1542 and D4S414/D4S423.« less
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