Stargardt disease (STGD) is a common autosomal recessive maculopathy of early and young-adult onset and is caused by alterations in the gene encoding the photoreceptor-specific ATP-binding cassette (ABC) transporter (ABCA4). We have studied 144 patients with STGD and 220 unaffected individuals ascertained from the German population, to complete a comprehensive, population-specific survey of the sequence variation in the ABCA4 gene. In addition, we have assessed the proposed role for ABCA4 in age-related macular degeneration (AMD), a common cause of late-onset blindness, by studying 200 affected individuals with late-stage disease. Using a screening strategy based primarily on denaturing gradient gel electrophoresis, we have identified in the three study groups a total of 127 unique alterations, of which 90 have not been previously reported, and have classified 72 as probable pathogenic mutations. Of the 288 STGD chromosomes studied, mutations were identified in 166, resulting in a detection rate of approximately 58%. Eight different alleles account for 61% of the identified disease alleles, and at least one of these, the L541P-A1038V complex allele, appears to be a founder mutation in the German population. When the group with AMD and the control group were analyzed with the same methodology, 18 patients with AMD and 12 controls were found to harbor possible disease-associated alterations. This represents no significant difference between the two groups; however, for detection of modest effects of rare alleles in complex diseases, the analysis of larger cohorts of patients may be required.

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Muscle sodium-channel disorders cover a spectrum of rare myotonic diseases. In a German family with 17 affected individuals in four generations, we identified a heterozygous missense mutation in exon 24 A1481D (c.4442 C>A) of the voltage-gated sodium channel gene (SCN4A) alpha subunit. Phenotypes of 12 family members were characterized by a mild myotonia with cold sensitivity but without paramyotonia. The index patient presented with fluctuating cold- and exercise-induced stiffness of ocular, facial, and distal muscles. The myotonia became more severe at the age of 22 years. His father had had cold- and exercise-induced periodic weakness with fluctuating myotonia since age 10. Later he developed a more severe, purely exercise- and cold-aggravated myotonia of arms, hands, and facial muscles. The father's mother presented with cold-induced myotonia until age 65, when progressive weakness of proximal limb muscles developed. Her muscle biopsies revealed considerable myopathic changes with a variety of fine structural alterations. This study presents a family with cold-aggravated myotonia and progression of myopathic changes in the muscle biopsy with increasing age. In older patients, sodium channelopathies may mimic the phenotypic features of myotonic dystrophy type 2.

Background-Autosomal recessive Stargardt's disease is a macular degeneration characterised by a juvenile onset and a rapidly progressive course resulting in an atrophic macular area typically surrounded by yeliowish retinal flecks. Method-The disease locus has previously been assigned to markers from chromosome 1p21-pl3 by genetic linkage analysis in eight multiplex Stargardt's disease families.Results-In an extended analysis, the assignment to chromosome lp was confirmed in the majority of the 21 families with Stargardt's disease who were studied. In addition, a series of recombinant chromosomes further narrowed the Stargardt's disease region to an approximately 3 cM interval between markers at D1S424 and DlS497. Conclusion-Multipoint linkage analysis most probably excludes this locus in three of these families suggesting non-allelic heterogeneity with at least one additional minor Stargardt's disease locus. (BrJ Ophthalmol 1996;80:745-749 Here, we report our results on the genetic linkage analysis in 21 Stargardt's disease families. We confirm linkage of the disease locus to chromosome lp21-p13 in the majority of our families. In addition, this study has identified a series of recombinant Stargardt's disease chromosomes which together refine the previous localisation of the disease gene to a small interval on chromosome lp between markers at D1S424 and D1S497. In three out of our 21 Stargardt's disease families we found evidence for non-allelic heterogeneity of this condition suggesting the occurrence of at least one additional minor Stargardt's disease locus. Patients and methods CLINICAL STUDIESForty four affected and 28 non-affected at risk individuals belonging to 21 Stargardt's disease families were recruited from the Eye Care Center Vancouver (Canada) and the Eye Clinic Tubingen (Germany) (Fig 1). At least one patient per family was seen by one of the authors (DW or AE), Dr W Macrae (Toronto) (family 15), or Dr CC Ewing (Saskatoon) (family 13). All families were of white origin except family 1 which originated from China. All affected family members were diagnosed with having typical features of Stargardt's disease including the following criteria: (1) the Weber, Sander, Kopp, Walker, Eckstein, Wissinger, Zrenner, Grimm initial presence of fundus flavimaculatus with yellow 'flecks' in the macular and paramacular areas when patients were seen at younger age; (2) a normal appearance of the optic disc, blood vessels, and peripheral retina; (3) the presence of the typical dark choroid on fluorescein angiography; (4) normal to subnormal electro-oculogram (EOG), normal electroretinogram (ERG) for rods and cones in early stages, and abnormal dark adapted amplitudes of the ERG recordings in advanced cases; (5) mottled pigmentation of the macula; and (6)

Familial central diabetes insipidus is an inherited disease of predominant autosomal dominant trait characterized by a deficiency of arginine vasopressin. The arginine vasopressin-neurophysin II ( AVP-NPII) gene consists of three exons and is located on chromosome 20p13 encoding for the precursor protein of AVP. We investigated two Caucasian families with a typical autosomal dominant trait of familial central diabetes insipidus, defined by deficiency of arginine vasopressin. After PCR amplification of exon 1 and exon 2/3, fragments were pooled and purified. Nucleotide sequencing was performed with the Taq DyeDeoxy-terminator cycle sequencing method using nested primers. Two mutations in the coding region of NPII were identified. In family C we found a heterozygous G ==> C missense mutation (AA61) in exon 2 leading to the substitution of cystein with serine. In family D a novel heterozygous nonsense mutation in exon 3 (AA 83, GAG ==> TAG) was indentified, leading to a stop codon instead of glutamine. Both mutations were confirmed by restriction analysis and were found in all affected but not in healthy family members or control subjects. We therefore have identified a missense mutation of the AVP-NPII gene and a novel mutation predicting a truncated protein.

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X-linked lymphoproliferative disease (XLP) is a rare worldwide occurring inherited immunodeficiency which is triggered by Epstein-Barr virus infection. Clinical phenotypes in 21 affected males from 5 German families with XLP ranged from severe and fatal infectious mononucleosis (57%) to acquired hypogammaglobulinaemia (28%), malignant lymphoma (28%), aplastic anaemia (19%) and hypergammaglobulinaemia M (19%). Molecular genetic studies with various polymorphic X-chromosomal DNA markers in 14 XLP families mapped the XLP gene locus to Xq25-q26. Haplotype analysis enables detection of XLP-positive and XLP-negative males already before EBV-infection as well as diagnosis of healthy female carriers within XLP families.

Germ cell mosaics were demonstrated in Duchenne's and Becker's muscular dystrophy by molecular genetic methods. These findings affect risk estimates in these x-chromosomal muscular diseases. The mutation-selection equilibrium for x-chromosomally lethal inheritance for determining the a priori probability for risk estimate according to the Bayes theorem must therefore be redefined to take the germ cell mosaic problem into account. Taking Duchenne's and Becker's progressive muscular dystrophy as an example, the article explains how the estimation of the heterozygote risk in women seeking advice changes in different family situations.