It has recently been suggested that a substitution of glutamine for arginine at residue 3500 of apolipoprotein (apo) B-100 causes familial defective apo B-100 (FDB), an autosomal, dominantly inherited disorder, which leads to increased serum cholesterol levels. From a sample of 243 patients from Munich with type IIa hyperlipoproteinemia (HL), we have identified eight individuals with the apo B-100 arginine(3500)----glutamine mutation. In a group of 57 subjects with defective low density lipoprotein receptor (LDLR), no mutant apo B alleles were detected. The frequency of FDB in patients with type IIa HL was estimated to be 3%. In the kindreds of three of the probands, 10 additional carriers of the apo B mutation were identified. Clinical and biochemical data reveal a striking similarity between patients with FDB and those with a defect in the LDLR gene. Our data support previous findings that FDB is a serious disorder causing premature atherosclerosis.

Adult↗

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Results of microsurgical treatment of gliomas of the optic system and the hypothalamus in children.

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Adolescent↗

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[Indices of detection in integral radiophotographic examinations in rural areas].

Integral radiophotographic detection was carried out in the territories of 5 randomly selected village dispensaries in 5 different counties. The action was performed in strictly operational conditions, without external experimental interferences. Stress was laid on the strict following of the methodological letter concerning radiophotography. The performing of integral radiophotographic detection in strictly operational conditions in the rural environment demonstrated the utility of these examinations in the present stage. The output obtained can be considered as satisfactory; local variations can be noted and this indicates the possibility of differentiating the conduct in various geographical areas.

Humans↗

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Gene probes in diagnosis of familial hypercholesterolemia.

In the United Kingdom, about 5% of patients with familial hypercholesterolemia (FH) have a detectable deletion or rearrangement of part of the LDL-receptor gene, which results in the detection of shorter or abnormally sized fragments of the LDL-receptor gene in a Southern blot hybridization. This gene deletion can be used for following the inheritance of the defective gene and for diagnosis in the families of these individuals. In the families of the remaining patients, diagnosis may be possible using linked restriction fragment length polymorphisms (RFLPs) detected with the LDL-receptor probe. There are now 10 common RFLPs of the LDL-receptor gene, with variable sites in the 3' half of the gene. Over 80% of patients are heterozygous for at least one of these RFLPs, and, therefore, RFLPs are potentially informative for DNA diagnosis. For a fetus at risk of homozygous FH, antenatal diagnosis may also be possible using these methods. However, family studies require samples to be available from affected or unaffected relatives of the patient, and this limits the applicability of the tests. For some mutations, the base-pair change causing the defect in the LDL receptor itself creates or destroys a site for a restriction enzyme. Such "mutation-specific" RFLPs could be used for population screening, but, so far, such use has only been reported for the FH mutation common in Lebanon. In the future, it may be possible to develop mutation-specific oligonucleotide probes for the diagnosis of FH. These would be appropriate for screening populations or patients with hyperlipidemia. This information may also be useful if different mutations require different therapeutic strategies.

Cholesterol↗

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A xanthomatosis-susceptibility gene may exist in a Syrian family with familial hypercholesterolemia.

Familial hypercholesterolemia (FH) is an autosomal-dominant inherited disorder characterized by high serum low-density lipoprotein (LDL)-cholesterol concentrations, xanthoma formation, and premature atherosclerosis. Homozygous individuals die of vascular disease as children or young adults; heterozygous persons are at high risk for premature cardiovascular death. Mutations in the LDL-receptor gene are responsible for FH. We studied 49 members of a consanguineous Syrian kindred containing 6 homozygous individuals from the same pedigree. Half of the homozygotes had giant xanthomas, while half did not, even though their LDL-cholesterol concentrations were elevated to similar degrees (> 14 mmol/l). Heterozygous FH individuals from this family were also clearly distinguishable with respect to xanthoma size. We performed DNA analysis and were successful in identifying a hitherto not described mutation in this family's LDL receptor. DNA sequence analysis of the LDL-receptor gene revealed a T to C substitution at nucleotide 1,999 in codon 646 of exon 14. We next conducted a segregation analysis, which suggests that a susceptibility gene may explain the formation of giant xanthomas in this family. We raise the hypothesis that the appearance of giant xanthomas in this FH family is controlled by a second gene acting in an autosomal-dominant or recessive fashion. Elucidation of this 'xanthoma' gene may shed additional light on LDL-cholesterol deposition.

Adolescent↗