John C. Bear

The Diagnosis and Prognosis of Autosomal Dominant Polycystic Kidney Disease

BACKGROUND Autosomal dominant polycystic kidney disease is usually caused by a mutant gene at the PKD1 locus on the short arm of chromosome 16, but in about 4 percent of families with the disorder it is caused by unknown mutations elsewhere in the genome. The natural course of the disease in both genetic forms is not well characterized. METHODS We studied 17 families with autosomal dominant polycystic kidney disease to compare presymptomatic diagnosis by ultrasonography with diagnosis by genetic-linkage studies and to relate clinical variation of the disease to whether the PKD1 mutation was implicated. RESULTS In 10 families the disorder was found to cosegregate with polymorphic DNA markers flanking the PKD1 locus, in 2 families it did not, and in 5 families linkage could not be determined. In the 10 families with the PKD1 mutation, 46 percent of the members less than 30 years old who had a 50 percent risk of inheriting a mutation had renal cysts, as compared with 11 percent of the members of the two families without linkage (P less than 0.001). In the PKD1 families, all 67 diagnoses made by ultrasonography were confirmed by determination of the genotype as inferred from linkage. Forty of 48 members (83 percent) less than 30 years old who inherited the PKD1 mutation had renal cysts. All 27 members 30 years old or older who inherited the mutation had renal cysts, suggesting that the probability of a false negative diagnosis did not exceed 0.13 in this age group (P less than 0.05). The mean (+/- SE) age at the onset of end-stage renal disease among members of the PKD1 families was 56.7 +/- 1.9 years, as compared with 69.4 +/- 1.7 years among members with cysts in the families without linkage (P = 0.0025). Hypertension and renal impairment were less frequent and occurred later in the families without the PKD1 mutation. CONCLUSIONS At present, in most persons with a 50 percent risk of autosomal dominant polycystic kidney disease, imaging techniques are the only mode of reaching a diagnosis before symptoms appear. In such persons a negative ultrasonographic study during early adult life indicates that the likelihood of inheriting a PKD1 mutation is small. In the few who inherit a non-PKD1 mutation for polycystic kidney disease, renal failure is likely to occur relatively late in life.

Refraction, nearwork and education. A population study in Newfoundland.

There is little information directly relating ocular refraction and nearwork habits in representative human populations. Ocular refraction (diopters), nearwork (hours per day), and education (years) were therefore measured for 957 persons comprising 80% of the population aged 5 years and above of 3 communities in western Newfoundland. Refraction was moderately, consistently and significantly correlated with nearwork from ages 5 to 60, and remained so after adjustments for the association of refraction and nearwork levels with age, sex and education. Multiple regression coefficients relating refraction to nearwork decreased from –0.43 D/h at ages 5–14 years to –0.22 D/h at ages 60 years and up. The magnitude of this association, and its consistency and persistence over a wide age range, suggest that large amounts of nearwork in childhood may contribute to the prevalence of clinical myopia.

Nearwork and familial resemblances in ocular refraction: A population study in Newfoundland

There is considerable epidemiological evidence that the nearwork associated with formal education can cause myopia. The potential for nearwork and education, as aspects of common familial environment, to inflate resemblances among nuclear family members in ocular refraction, was therefore investigated in a sample of 957 persons aged 5 years and over, comprising approximately 80 % of the population above that age in three communities on the west coast of Newfoundland. Refraction was evaluated using standard optometric methods, nearwork measured in hours/day as reported by each subject, education measured as last completed school grade in years. The effects of nearwork and education on refraction resemblances were evaluated by adjusting refraction for age and sex, then comparing correlations or regressions among relatives before and after further linear regression adjustment of refraction for nearwork and education. Reductions in sib‐sib correlations and offspring‐parent regressions were achieved in this way, suggesting that these environmental factors inflate familial resemblances in refraction. Patterns of resemblances among relatives after adjustment suggest that the effects of nearwork and education on refraction resemblances were not completely removed by the linear regression adjustment used.

Variant Multiple Endocrine Neoplasia I (MEN IBurin): Further Studies and Non-Linkage to HLA

We have extended our study of an incomplete variant of multiple endocrine neoplasia Type I (MEN IBurin). In this syndrome, primary hyperparathyroidism and prolactin-secreting adenoma are common, with hormone-secreting pancreatic tumors being rarely seen. The recent localization of the prolactin structural gene to chromosome 6 made further investigation of linkage to HLA of particular interest. Results in 2 multigeneration families exclude close linkage to HLA. We cannot at this time draw any inference regarding linkage of MEN IBurin to the prolactin structural gene.

The distribution of refraction in three isolated communities in Western Newfoundland.

Data were collected on refraction in three isolated communities in western Newfoundland. Altogether 971 persons, about 80% of the population, were refracted. Subjects were not visually selected. Females showed a greater range of refractions than males at most ages, generally had more negative refractions than males, in particular at younger ages, and showed negative age group means earlier than males. Persons under 30 had more negative mean refractions, and more formal education than persons over 30. The age distribution of refraction in this population is compared with that reported by several others, and arguments presented that exposure to formal education is associated with increased myopia.

Cylindrical refractive error: a population study in western Newfoundland.

ABSTRACT The distribution of cylindrical refractive error (right eye only) is presented for 957 persons, comprising approximately 80% of the population (aged 5 years and over) of three western Newfoundland communities. In 72% of males and 60% of females no cylindrical error was found; 12% of males and 19% of females had errors greater than 0.5 D. Cylindrical errors of 2 D or greater were found in 2.5% of females but only 0.5% of males, affecting females of all ages but males aged less than 15 years only. Persons aged 45 years and up had fewer cylindrical errors, more against‐the‐rule and less with‐the‐rule astigmatism than persons below that age. Cylindrical error and spherical error, and in particular against‐the‐rule error and myopia, commonly occurred together. Among persons aged 5 to 14 years an association of with‐the‐rule error with nearwork is suggested.

Additional data on spontaneous abortion and facial cleft malformations.

Examination of fetal wastage data for a large collection of CL ± P and CP sibships reported previously (Bear 1978) does not indicate the frequency of recognized abortion to be higher in the sibships of CL + P vs CL index cases, female vs male CL ± P index cases, bilateral vs unilateral CL ± P index cases, female bilateral CL ± P index cases vs male unilateral CL ± P index cases, or male vs female CP index cases. These observations fail to confirm those reported by Dronamraju (Dronamraju et al. 1982, Dronamraju & Bixler 1983a, b), and provide no evidence of a positive relation between degree of liability to facial cleft malformation and fetal mortality.