ACTA 0 PH T H A L M 0 L O G I C A 69 (19911 694-702

Autosomal dominant stationary night-blindness A large family rediscovered

Thomas Rosenberg, Marianne Hairn, Yoa Piczenik and Svend Erik Simonsen

National Eye Clinic for the Visually Impaired, Hellerup, Denmark

Abstract. In 1909, 2 years after the famous publication by Nettleship, a large family with congenital stationary night-blindness of the ‘Nougaret type’ was published by the Danish district surgeon, Sigurd Rambusch. In 1990 the ‘Rambusch family’, stiU resident in the original area, was sought out and rediscovered, at which time the rec- onstructed part of the pedigree comprised more than 200 affected persons in 11 generations. Dark adapto- metry and electroretinography were performed on a few affected family members, including a descendant with a uniocular affection. The pedigree is presented and recor- dings of dark adaptation courses and electroretinogra- phical responses from a few family members are demon- strated.

Key words: autosomal dominant night-blindness - CSNB - dark adaptation - eiectroretinography - hemeraiopia - nyctalopia - uniocular night-blindness.

Since the publication in 1838 by Cunier, night- blindness of the Nougaret type has been the para- digm of a Mendelian trait with autosomal domi- nant transmission.

In 1907, Nettleship and co-workers published an update of Cunier’s genealogy. The family at that time encompassed nine generations, and 135 night-blind persons were identified among des- cendants of the progenitor, Jean Nougaret of Ven- demian.

In 1909 the Danish district surgeon, Sigurd Ha- rald Alfr-ed Rambusch (1861-1919), published a ge- nealogical study of an eight generation family with congenital stationary night-blindness (CSNB). This paper was written in Danish. Only a short sum-

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mary appeared in the German language (R~nne 1910), and the work was never presented to the in- ternational scientific community, and therefore es- caped deserved attention.

The ancestor of the family studied by Rambusch was a farmer, Niels S~rensen, born about 1660 in the parish of Monsted, west of the city of Viborg in northern Jutland. According to family tradition, he joined the war against Sweden (Skkske krig 1675-1679) during which he suffered so much that he became night-blind for life. Niels S~rensen and his wife, Mette Kristensdatter, had 3 daughters, forebears to four lineages of night-blind des- cendants.

The work of Rambush is remarkable for that time due to its thorough genealogical analysis.He perceived that the night-blindness was inherited within an otherwise healthy family as an isolated and autosomal dominant trait according to Men- delian laws. The direct, continuous transmission with equal affection of both men and women was documented and statistically proven, based on 295 individuals, of whom 164 were night-blind. Ram- busch observed that this condition never appears in latent form and never skips a generation, and that consanguinity plays no role for the manifesta- tion of the trait. Apparently, Rambusch was famil- iar with the entire literature on the subject, al- though he emphasizes the lack of proof for the mode of inheritance at that time.

Rambusch had one of his patients examined by the Professor in Ophthalmology at the University of Copenhagen, Henning R0nne. The results of

I

II b.1688

Nybro

IV lineage

V

six VI-VIII generations

IX-x

b. 1728 Sjerup lineage

b.7,759 7 , I b.;763 7 I , @ t b. 1731

Laanum lineage

9NB in

five generations

0rum

lineage

24NB in

six

generations

Fig. 1. Schematic representation of the genealogy of Rambusch (1909). The original pedigree comprised four lineages (Nybro, Sjerup, Laanum and @rum) with 164 night-blind descendants after the progenitor born 1664. The numbers in boxes refer to the number of night-blind persons identified by Rambusch. The numbers in circles are night-blind descend- ants added with the present investigation, bringing the number of night-blind persons to 231. NB =night-blind, b. =born (year), filled-out squares =affected males, filled-out circles =affected females. The follow-up of this pedigree

was confined to the descendants of 3 persons of the Sjerup lineage born 1803, 1809, and 1810, respectively.

Renne’s pertinent experiments on visual thresh- olds to different objects, presented with various fo- veal eccentricities in dark adapted state, prove the correctness of Rambusch‘s diagnosis.

During the 20th century, knowledge of Ram- busch’s night-blind family gradually disappeared among Danish ophthalmologists, until they were completely forgotten. A review of the files at the National Eye Clinic for the Visually Impaired dis- closed no cases of autosomal dominant night- blindness (Haim 1986). The purpose of our investi- gation was to retrieve possible descendants of Rambusch’s family so that a genetic linkage ana- lysis could be carried out.

Material and Methods

The Rambusch family first came to our attention in 1984 due to a quotation by the Norwegian oph- thalmologist, Syversen (1974). According to Ram- busch (1909) the genealogical material had been deposited at The provincial Archives of Jutland (Landsarkivet i Viborg). We had assistance from Rambusch’s grandson, Sigurd Rambusch, who happened to be a Senior Registrar at The National Archives (Rigsarkivet) in Copenhagen, but the search proved fruitless.

In 1986 inquiries were sent to all Danish ophthal- mologists, eye departments, genetic institutes, and military medical boards. The great majority of re- plies were negative, but two colleagues in private practice were able to recall a patient. A personal contact by one of us (MH) was arranged and turned out to be most informative. Now a reconstuction of the pedigree followed with good help from some of the family members. A preliminary report was presented by MH at the EPOG meeting in Briigge, October 20-22, 1989. During 1990 one of us (YP) continued the family reconstruction and collected blood samples for linkage analysis.

Finally, a copy of the original genealogical ma- terial was found in the archives of a former An- thropological Committee, kept at the Genetic In- stitute, University of Copenhagen.

The retrieval of affected family members was ac- complished simply by asking the individuals if they were night-blind or not. In accordance with Rambusch (1909), family members were quite cer- tain about their state of affection. Three persons expressed some doubt after previous appraisals had failed to substantiate their subjective percep- tion of being night-blind. The uncertain cases ware verified by examination. In a few instances infor- mations on state of affection were received from family members. Most members of the family were

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Autosomal Dominant Congenital Stationary Night Blindness Rambusch’s genealogy updated 1990

0 Affected 0 0 Unaffected

0 Unilateral case # Deceased

I II

111

IV

V VI VII

Vlll

IX

XI Fig. 2.

The reconstructed pedigree. Only a smaller part of the original genealogy of Rambusch (1909) is shown (cf Fig. 1). 67 night-blind descendants born 1909 or later were discovered. Only offspring of night-blind persons are shown. Still births were excluded. The letters N, 0, S, and L designates the progenitors of the four lineages: Nybro, arum, Sjmup, and Laanum. Examined persons are marked with an X. Persons from whom blood samples were obtained are marked

with a hatched line.

positive on whether their relatives were affected or not.

Blood samples were obtained from 81 descend- ants and we examined 7 persons, including a uni- lateral case described below. The 6 bilaterally af- fected family members consisted of 4 women and 2 men, aged 32 to 56 years, with a median age of 40 years. Physical examinations comprised a routine ophthalmological examination, including slit- lamp examination and ophthalmoscopy in artifi- cial cycloplegia. In addition we performed dark adaptation measured with Goldmann-Weekers in- tegral technique and electroretinography under dark adapted conditions using a Ganzfeld flash

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stimulator. Methods and normal values have been published earlier (Rosenberg et al. 1990).

We also examined a young woman who claimed to be night-blind in her right eye only.

Case report

A 21-year-old healthy woman had complaints from her right eye. She had finished high school success- fully, and she enjoyed sports, being a member of the Danish national bowling team. Her mother was affected by night-blindness, belonging to the youn- gest generation of the pedigree described by Ram-

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- Binocular dark adaptation curves obtained with Goldmann-Weekers integral technique. The tracings from 6 night- blind persons from Rambusch's genealogy are shown. Horizontal axis: time (min), vertical axis: stimulus threshold

(cd/m2) logarithmic scale. M=male, F=female. The numbers indicate the age of the persons.

busch. Her only sib, an older sister, was not af- fected.

Her symptoms had been present as long as she could remember. During daylight she could detect no difference between her two eyes, but in twilight it became totally dark for her right eye, the only visual sensation being described as two grayish- white splotches, one on either side of the central part of the visual field. In the dark her vision with the right eye was described as completely abol- ished, and she even claimed to be unable to see an artificial light with this eye. The condition was un- affected by prolonged stay in the dark. She experi- enced some glare at night and wore dark sun- glasses while driving a car in the dark. The oph- thalmological examination demonstrated emme- tropia, and visual acuity was 1.6 in both eyes. Slit- lamp examination and ophthalmoscopy revealed no abnormality or asymmetry. Photopic perimetry with a Goldmann perimeter, target II/4e was nor- mal and symmetrical in the two eyes. Nevertheless, dark adaptation and electroretinography showed significant abnormalities of the right eye (see below).

Venous blood samples were obtained and ana- lysed at the Institute of Forensic Genetics at the University of Copenhagen with the purpose of throwing light on a possible chimerian condition.

This study complies with the Helsinki Declara- tion 11.

Results

The genealogical tree is presented in Figs. 1 and 2. It appears that the family today encompasses 11 generations, including the progenitor. The case with a unilateral affection is marked by a separate signature (generation X,42) in Fig. 2. Until now we have only succeeded in a partial retrieval of one of the four lineages mentioned by Rambusch (1909). During our work a family with autosomal domi- nant CSNB in 8 generations, six smaller pedigrees and a few single cases have come to our attention. Further genealogical work, indeed, is needed to unravel any connection with the presented family.

The night-blind persons gave rather uniform descriptions of their symptoms. None of them seemed to consider the abnormality a major prob-

697

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3 x 10-6 0 5 10 15 20

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Monocular dark adaptation curves in the uniocular night-blind case. OD = right eye (affected), 0s =left eye (normal).

lem. Most of them had a driver’s license, but a few had been imposed by restrictions not to drive at night. Many of the men were rejected from military duties. Nevertheless, some of them did their mili- tary services. They all considered the condition to be completely stationary. Except for minor refrac- tive errors routine ophthalmological examination revealed no abnormalities or other visual symp- tom in any of the 7 persons, including the unilat- eral case, other than night-blindness. The 6 bilat- erally afEected persons presented normal visual acuities (6/6 Snellen) and no fimdus abnormality was found.

Dark adaptation The dark adaptation courses in the 6 bilaterally af- fected persons confirmed their subjective impress- ions of being night-blind (Fig. 3). The final thre- sholds were elevated by 2.5-3.0 logarithmic units compared to normal. Slightly elevated cone pla- teaus were reached within 3-4 min, and in 4 no fur- ther sensitivity gain occurred. In the remaining 2, aged 54 and 33 years, a second phase appeared after a break point at 4-5 min. This observation might be interpreted as a sign of rod activity, yet abnormal, as the addition threshold was only de- pressed by 0.5 log units below the initial cone pla- teau.

The uniocular case (Fig. 4) showed a completely normal curve in her left eye: A rapid cone phase spanning 2.5 log units was succeeded by a second (rod) phase after 4 min. A later break after 11 min was seen. This is often found in normal individ- uals, indicating that three adaptational mechan-

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isms might be involved under the circumstances employed during test conditions.

In the right eye, claimed to be night-blind, the threshold after 20 min of dark adaptation was elev- ated by 2 log units. But the most obvious departure from normal was a defective cone phase starting with a delay of 1 min and shortened by 1.5 log units compared to the left eye. A h t deflection oc- curred after 3 min followed by a second deflection after 9 min. Even if the first breakpoint is inter- preted as an artefact it might be concluded that the dark adaptation curve from the right eye expresses a cone dysfunction as well as a rod deficiency.

Electroretinography Rod responses elicited by a blue flash stimulus (Ganzfeld) were non recordable in the 6 bilaterally affected family members (Fig. 5). The dark adapted cone responses to 32 Hz white flickering light dem- onstrated either normal or slightly reduced ampli- tudes and normal implicit times. With a strong, white standard flash a mixed rod-cone response was obtained (Fig. 5). Compared to normal (top tracing), moderate a-wave depressions and even more pronounced b-wave depressions were seen.

In the uniocular case a completely normal ERG was recorded from the left eye (Fig. 6). In compari- son, tracings from the right eye exhibited reduced b-wave amplitudes by 33% (rod response) and 54% (cone response), while the mixed rod-cone re- sponse was reduced by 30%. The implicit times (28.0 msec) of the flicker responses were identical in the two eyes.

Five oscillations (OP1-OP5) were readily distin-

N,40

F,56 M,54 F,41

F,38

M,33

F.32

Rod-Cone response Rod response Cone response

2oopv L 40ms

Fig. 5. - Dark adapted electroretinograms in a normal person, aged 40 (top), and 6 night-blind persons, aged 32-56. F = female, M=male. 1. column: mixed rod-cone response to a white standard single flash stimulus (SF), 2. column: rod response to a blue single flash stimulus (-1.5 log SF), 3. column: cone response to a white 32 Hz standard flicker stimulus.

guished (Fig. 6) from the normal eye of the uniocu- lar case. On the affected right eye the oscillations had reduced amplitudes with normal latencies.

The genetic typing of the uniocular case gave the following results:

A, MNS+ C+D+E+c+ Le(a-b+) Hp 2H-1S Gc2-IS Tf 1-1 Gm(a+x-b-f-) Inv-PGM 2s-1F SP BC GPT 2-2 EsD 1-1 GLO 2-2. In addition, the fol- lowing highly polymorphic DNA-probes were tested: MSl (DlS7), MS31 (D7S21), MS43A (D12Sll), and YNH24 (DZS44). The findings did not support a suspicion of mosaicism.

Discussion CSBN is a heterogenous group of disorders which have a genetic background and an impaired dark adaptation in common. Among the forms with normal fundi (Carr 1974) three distinctive hered- itary groups are encountered. Besides this genetic heterogeneity a considerable clinical heterogene- ity exists. Clinical subclassifications have been pro- posed according to electroretinographic charac- teristics into a Schubert-Bornschein type and a Riggs type (Auerbach et al. 1969). Keunen et al. (1988), using densitometric measurements, have demonstrated a group of CSNB with normal rho-

dopsin kinetics (type I) and a group with impaired rhodopsin kinetics (type 11). Miyake et al. (1986) proposed a subclassification into a complete CSNB type and an incomplete CSNB type. Attempts to correlate the different clinical types with the Men- delian modes of transmission have failed. From a clinical point of view CSNB with normal fundi falls into a group with reduced visual acuity, nystagmus, and myopia, to which the cases with X-linked and autosomal recessive heredity belong. It is not known whether heterogeneity exists within the autosomal dominant variety, which is charac- terized by a normal visual acuity and the absence of significant refractive errors. Autosomal domi- nant CSNB is an uncommon disorder. In the monumental work by Julia Bell (1922) 9 out of a total of 33 pedigrees with CSNB (including Cu- nier’s and Nettleship’s case) might be referred to the autosomal dominant form. When male-to- male transmission is demanded as certainty for autosomal dominant inheritance, only a few do- cumented families are mentioned in literature from the last five decades: the Nougaret family of Vendkmian, France (Dejean & Gassenc 1949; Fran- cois et al. 1956), a family from North America (Car- roll & Haig 1952; Riggs 1954), a family from Sardi- nia (Latte 1957), and finally, a Sicilian family (Ponte et al. 1974). In the present state of confusion re-

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Left

Right

Rod-Cone response

Rod response Cone response Oscillatory potentials

2004-

40ms

2 0 0 p I 40ms

Fig 6 Electroretinographical tracings in the uniocular night-blind case, dark adapted state. Column 1-3: stimulus para-

meters as in Fig. 5 . Column 4: oscillatory potentials. Top: left eye (normal). Bottom: right eye.

garding classification it is necessary that claims for a certain mode of inheritance are substantiated by exposition of complete genealogical evidence.

With this presentation we draw attention to the early and remarkable work by Rambusch (1909) describing a pedigree of congenital stationary night-blindness inherited through 9” generations. An inquiry among Danish ophthalmologists showed that the majority of our colleagues, repre- senting hundreds of practice years and millions of consultations, did not recall having ever met a pa- tient with CSNB. On the other hand, our investiga- tion showed that approximately 70 affected per- sons from this family, and a further 70 affected per- sons without known connection to the Rambusch family are prevalent in the Danish population. This seemingly contradictive situation may be ex- plained by the relatively benign character of the af- fection and the high degree of knowledge among family members, typical for a disorder with domi- nant transmission, and implies that night-blind- ness in a modern, urban life i s much less incapacit- ing than it might have been around the beginning of this century, when Rambusch made his observa- tions.

We did not intend to construct a complete ge-

* Rambusch numbered his genealogy starting with the offspring of the progenitor, attaining 8 generations. In- cluding the progenitor the pedigree comprised 9 generations.

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nealogy, but merely to find a number of descend- ants sufficient for a linkage analysis.

Inquiries among family members confirmed the observation by Rambusch that autosomal domi- nant CSNB is a strictly monosymptomatic condi- tion, which either is present or not. Some persons, uncertain of being affected, were shown to be as night-blind as their cognizant family members. No single case of a skipped generation was reported.

Two of the 6 examined persons demonstrated dark adaptation courses in which a second mech- anism besides cone adaptation seemed to be ac- tive. This might reflect a variable expressivity of the underlying mutation.

The electrophysiological tracings from the six dark adapted autosomal dominant cases show non-recordable rod-responses (Fig. 5, middle), and cone-responses within the normal range (Fig. 5, last column). The responses to a high intensity- flash (Fig. 5, first column) show a normal to moder- ately reduced a-wave. The b-waves exhibit pro- nounced reduction in amplitude.

The existing evidence concerning ERGS in auto- somal dominant CSNB is scarce and partly con- flicting. Francois et al. (1956) examined two mem- bers from the Nougaret family electrophysiologi- cally and reported a non-recordable scotopic b-wave. The photopic b-wave (named X-wave) and the a-wave were normal. In an American pedigree with autosomal dominant CSNB (Carroll & Haig 1952) two cases were studied electrophysiologically

by L. A. Riggs. The presented curves exhibited nor- mal a-waves and no increment of the b-waves dur- ing dark adaptation was encountered. Carr et al. (1966) in a single case (P.M.) from a family with dominant transmission also noticed an absent sco- topic component from the dark adapted response to a high luminance flash. In their subject the a-wave was signrficantly reduced, and the flicker responses were clearly depressed.

Sharp et al. (1990) published a detailed clinical analysis of i.a. 4 patients from a Sardinian family with autosomal dominant SCNB: The dark adapted electroretinograms demonstrated unrec- ordable b-waves to weak blue flashes. 30 Hz flicker stimulus elicited cone responses with peak times similar to normal and slightly reduced amplitudes. Intense white flashes produced subnormal a-waves and b-waves (not illustrated) with increased b:a- wave ratio.

Different techniques of stimulation, amplifica- tion, and recording troubles the comparisons be- tween different reports. Yet, we conclude that ERG‘s from night-blind persons belonging to the Rambusch family seem to be similar to ERG’s from night-blind persons from other well-documented cases of autosomal dominant transmission. Some pedigrees with dominantly transmitted CSNB from which electroretinographical data are pub- lished, are characterized by sole maternal trans- mission, raising the suspicion that some of these cases might constitute examples of mitochondrial dysfunction (Francois et al. 1965; Keunen et al. 1988; Noble et al. 1990). This interpretation is con- sistent with our knowledge of the key role held by mitochondrial enzyme systems in energy metabol- ism. It might be added that a mitochondria1 muta- tion recently was described in a family with i.a. ‘classical’ retinitis pigmentosa (Holt et al. 1990).

The uniocular case remains a puzzle to us. Examination confirmed that her left eye was nor- mal in every respect. Her right eye demonstrated gross functional abnormalities, ruling out a possible psychological explanation for her symp- toms. On the other hand, it was obvious that neither dark adaptation nor electrophysiology of the affected eye were in agreement with the night- blind cases. The most prominent difference no- ticed was a reduced cone function under dark adapted conditions.

Cases with reduced cone sensitivity under dark adapted conditions have recently been described

by Arden & Hogg (1985). Yet, in these cases dark adapted rod thresholds were normal.

In incomplete CSNB (Miyake et al. 1986) the electrical cone characteristics are depressed, espe- cially in the dark adapted state (Miyake et al. 1987). Dark adaptation curves with similar diphasic ap- pearance in night-blind individuals are presented, among others, by Keunen et al. (1988). These cases, indeed, were presumed to be autosomal recessive types and incomplete types of CSNB. The question of whether a mixture of normally and abnormally functioning rods could be responsible for the ob- servations in our uniocular case cannot be an- swered without further examination including electrical recordings during different adaptational levels.

Uniocular night-blindness has been reported by Kelsey & Arden (1971), Ayaki et al. (1984), Arden (1985), Arden & Hogg (1985) and Jacobson et al. (1986). These cases daered from the present one by being acquired and temporary.

Acknowledgments

The genetic analysis of the uniocular case was carried out by Hans Giirtler, MD and S ~ r e n Nmby, MD.

We are indepted to several family members for their participation in examinations, for help with the recon- struction of the family tree and for hospitality during our visits to their homes.

The study was supported by grants from The Danish Eye Research Foundation (ajenfonden) and from Cykel- handler P. Th. Rasmussen og Hustru Alma Rasmussens Mindelegat.

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Received on June 18th, 1991.

Author’s address:

Thomas Rosenberg, MD, National Eye Clinic for the Visually Impaired, 1 Rymarksvej, DK-2900 Hellerup.

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