Comparison with clinical subclassification

The phenotype found to be associated with the chromosome 19q locus is an early onset, severe, progressive cone-rod dystrophy with first central then peripheral areas o f corresponding rod and cone deficits and other areas where rod and cone function appeared relatively normal. Macular abnormalities from the earliest age and later onset bone spicule peripheral intraretinal pigmentation with upper pseudoaltitudinal field defects and nyctalopia were characteristically seen and are known features o f some types o f CRD. Dominant conditions are classically described as “ mild ”. This was not the case in this condition.

No systemic disorder or other ocular abnormality was found to segregate with the retinal dystrophy although such associations do occur (Heckenlively JR et al, 1981; Gorgone G et al, 1986; Heckenlively JR et al, 1988a; Bjork A et al, 1956; Jalili IK,

1989; Jalili IK et al, 1988; Mantyjarvi M et al, 1989; Samra D et al, 1988).

The phenotype associated with the chromosome 18q locus is different from that seen in this study. A more profound disorder with early optic and peripapillary atrophy, a pale tigroid fundus and no abnormal retinal pigmentation from early childhood has been described suggestive o f a stationary disorder (Warburg M et al, 1991). The patient described with the chromosome 17q-CRD locus (Kylstra JA et al, 1993) had macular pigmentation and atrophy similar to that seen in some individuals in this study however other features such as a fine pendular nystagmus and lack o f peripheral retinal

pigmentation were not seen. Both o f these localisations are based on individual case reports. Mutations o f the chromosome 19q-CRD locus or elsewhere in the genome were not specifically excluded, and the chromosomal and disease associations identified may have been coincidental. However such associations have been successful in identifying other gene loci. The localisation o f the G6PD deficiency gene was aided by linkage, in certain families, with colour blindness known to map to chromosome Xq28 (Adam A et al, 1966). The association between retinitis pigmentosa and Duchenne muscular dystrophy helped to localise an X-linked retinitis pigmentosa gene (RP3) to Xp21 (Franke U et al, 1985). Also, the identification o f the retinoblastoma gene was aided by the association o f the condition with chromosome 13 deletions (Friend SH et al, 1986).

Two studies have been undertaken to subclassify the CRD phenotype into groups that may be genetically homogeneous. Yagasaki and Jacobson (Yagasaki K et al, 1989) tested 14 autosomal recessive and simplex CRD cases using full field electroretinograms, dark adaptometry and modified perimetric techniques and suggested that a sub-classification could be based on three distinct patterns o f visual field loss. Type 1 cases had central rod/cone scotomas, eccentric fixation, mild peripheral photoreceptor dysfunction and slow progression. Type 2 was described as more severe with a central rod/cone scotoma, eccentric fixation, more cone than rod dysfunction in the periphery and relatively normal mid-peripheral fields. Subjects classified as type 3 had central fixation, no measurable cone function and patchy rod function loss. The family studied here would best fit their type 2 classification although regional, quantitative differences between cone and rod responses were not as great as

is said to be typical o f type 2. Szlyk and co-workers (Szlyk JP et al, 1993) in a prospective study o f 33 CRD patients and a review o f the records o f a further 150, identified four functionally distinct subtypes. Subjects were subdivided into type 1 (less rod than cone dysfunction) and type 2 (equal cone and rod dysfunction) on the basis o f quantitative eletroretinographic responses. These groups were further subdivided into type “ a ” (cone thresholds more elevated centrally, rod thresholds more peripherally) or type “ b ” (matching areas o f cone and rod threshold elevation, mostly peripherally) on the basis o f pattern o f field loss and threshold elevation. The 19q-linked phenotype would best fit into their type lb subgroup, although the central scotoma identified in all younger affected individuals is more analogous to type la and the preferential loss o f cone and rod function in the peripheral retina was also not seen.

With the molecular genetic information that is available, different CRD-phenotypes may correspond to different genotypes. The CRD-19q phenotype does not seem to fit well with the subclassifications o f clinical phenotype that have been described to date suggesting that more work on this will be needed if clinical investigative techniques are to be o f value in identifying CRD-genotypes.

4.1.2 M eiotic drive

A statistically significant variation in the numbers o f affected individuals from that which would have been expected in an autosomal dominant pedigree was seen in this family. Other influences superimposed upon simple autosomal dominant, recessive and X-linked inheritance are well established in genetics. Genomic imprinting (e.g. Angelman's/Prader-Willi syndrome, Magenis RE et al, 1990) and anticipation (e.g.

fragile-X syndrome, Richards RI et al, 1992) are two well known examples. Meiotic drive (Lyttle TW, 1991) is the term used to describe another type where the gender o f the affected parent influences the probability o f offspring being affected and would explain the variation from expected seen in this extended pedigree.

Meiotic drive is said to occur when a member o f a pair o f heterozygous alleles or heteromorphic chromosomes is transmitted to progeny in excess o f expected proportions. The driving influence may work via an asymmetry in oogenesis in the female or by influencing spermatogenesis in males. This phenomenon is well established in non-human genetics e.g. in Drosophila melanogaster (Hiraizumi Y et al, 1979) and the t alleles o f the mouse (Bennett D and Dunn LC, 1971). It has rarely been documented in human disease. Such a phenomena has been described in North Carolina macular dystrophy which has been mapped to chromosome 6q (Small KW, 1993). Also, segregation distortion has been found in the distribution o f cystic fibrosis and normal alleles in human spermatozoa (Williams C et al, 1993). However, this has yet to be shown to result in a disease bias in an extended cystic fibrosis pedigree. Meiotic drive is thought to occur in myotonic dystrophy (Carey N et al, 1994) where it has been suggested that it may be a direct consequence o f trinucleotide repeat expansion or be due to the influence o f the larger repeats on a nearby segregation distorting locus. This putative segregation distortion locus on chromosome 19q may also be the source o f the phenomena in chromosome 19q CRD. Such a bias would be potentially useful in genetic counselling o f a family, but the evidence for meiotic drive in this CRD pedigree is only suggestive and awaits confirmation.