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Age of Onset and Evolution of Fabry's Disease

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AGE OF ONSET AND EVOLUTION OF FABRY'S DISEASE

ALBERT Th. FRANCESCHETTI

Department of Ophthalmology, University of Geneva, Switzerland

Personal examination of 39 cases of Fabry's disease, with special respect to a chronogenetical

analysis, revealed interesting temporal features both in the age of onset and the age of death.

Reviewing the literature on Fabry's disease, we found the description of 470 cases. Of

these we personally examined 39 (Franceschetti 1973). Although the purpose of our study

was not a chronogenetical analysis, we obtained some interesting temporal features.

The genetical analysis of our material produced a series of evidences on the sex-linked

genetical transmission of Fabry's disease, namely:

1. The ratio, affected males/affected females, is compatible with the theoretical

ra-tio 1 : 2.

2. In 120 cases the gene was transmitted from mother to son.

3. Transmission from father to son was never firmly proved.

4. Sons of hemizygotes are normal.

5. Heterozygotes inherit their gene more frequently from the mother than from the

father (ratio compatible with the theoretical ratio 1: 3).

6. If one of the parents marries twice, children of both marriages follow the expected

pattern.

7. Linkage data support a sex-linked inheritance.

8. Chromosomal examinations are normal.

AGE OF ONSET

The cornea verticillata and the angiokeratomes are the two most constant features of

Fabry's disease. But patients become aware of their ophthalmological lesions only late in the

disease, when hypertensive lesions also appear.

We tabulated the age at which cutaneous lesions were first noted and, despite the biases

of these data, we fit a gaussian curve (Fig. 1). To do this, we disregarded patients with onset

before 7. In fact, the high number of onsets reported at the age of 6 is, in our opinion, due

only to the fact that the lesions were detected when the subjects went to school. We also had

to exclude the cases with late onset. The mean age is 13.982. Only 3 cases reported showed

no cutaneous lesions (Jensen 1966, Kemp 1967, and Nakao et al. 1967).

A close analysis of the genealogical trees reveals the following chronogenetical facts:

1. In some families the age of onset is approximatively the same for each member; e.g.:

family I of Christensen Lou et al. (1970), where case IV/10 had his first symptoms at age 10

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10 IS 20 25 30

Fig. 1. Age of onset of Fabry's disease.

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O = female

1 9 = Angiokeratoma corporis diffusum (Fabry) x = examined

io y = age of onset

+ 32 = age at death

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AGE OF ONSET AND EVOLUTION OF FABRY'S DISEASE 295

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LZI = male O = female B = Fabry's disease ® = Carrier

<§> = 4 children

00 = dead al lime of investigation

A = miscarriage x = examined i7y = age of onset

Fig. 3. Fabry's disease. [Iowa kindred of von Gemmingen et al. 1965].

and IV/11 at age 12; and for two step brothers examined by A. Denden and myself onset

was at 16 (Denden and Franceschetti 1968).

2. In other families, the disease starts earlier in subsequent members; this could be

explained by a progressive decay of the gametal ergon of the affected gene. In two families,

we observed a gradual chronon reduction not only within a generation but also from one

generation to the other (Figs. 3 and 4).

Unfortunately, there are few cases were both age of onset and age of death are reported.

Therefore, nothing precise can be said on the length of the disease.

Renal transplants can halt the disease. This was observed by Philippart et al. (1972) and

by Desnick et al. (1972). The suggested chronogenetical explanation is that the transplanted

kidney is able to compensate the genes deficiency, when these exhaust their informational

capacity.

AGE OF DEATH

Fig. 5 shows the age of death of 39 patients affected by Fabry's disease. Age ranges from

26 to 67 years.

In one family, 4 brothers died at about the same age (Fig. 6). In three families, death struck

earlier in the second generation, in particular:

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1960 1961 1962 1963 L J = male O = female [ 1 3 = Cornea verticil lata

died of nephrosclerosis or vascular disease (cornea not examined) 0 0 = bio logically affected

131 = Cornea verticillata, angiokeratoma corporis diffusum (Fabry) © = Carrier

A = s t i l l - b i r t h

x = Slitlamp examination 20» = age of onset

Genealogical free of cornea verMcillara(published by GRUBER.1946,family 2) | completed by A Th FRANCESCHETTI 1967

Fig. 4

$5 67 age at death Fig. 5. Age at death of 39 cases of Fabry's disease.

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AGE OF ONSET AND EVOLUTION OF FABRY'S DISEASE 297

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9 = probable Fabry's disease

O = Female ^ ^ = possible Fabry's disease

<3> = 7 children +37 = age at death

Fig. 6. Fabry's disease. [Family II of Christensen Lou 1967].

— 52 and 43 years of age (HI/6 and IV/15) for one of the families we observed in 1967

(Fig. 4);

— 54 and 32 (III/2 and IV/10) for family I of Christensen Lou et al. (1970, Fig. 2).

This seems to hold true also for females, as III/3 died at 63 and IV/14 at 48 years in the

family we observed (Fig. 4).

In conclusion, chronogenetical analysis revealed interesting time relations in Fabry's

disease. It is to be hoped that future studies on angiokeratoma corporis diffusum will pay

due attention to chronogenetical factors.

BIBLIOGRAPHY Christensen Lou H.O. 1967. Fabry's disease. A

clin-ical study with emphasis on neurologclin-ical symp-toms and signs. Second Int. Congr. Neuro-Oph-thalmol., Montreal. Progress in Neuro-Ophthal-mology. [pp. 363-376]. Amsterdam 1969: Excerpta Medica.

Christensen Lou H.O., Heidensleben E., Larsen H.W. 1970. The value of ocular findings in the diagnosis of angiokeratoma corporis diffusum (Fabry's disease). Acta Ophthalmol. (Kbh.), 48: 1185-1194.

derson. Ber. Dtsch. Ophthalmol. Ges., 69:145-148. Desnick R.J., Simmons R.L., Allen K.Y., Woods

J.E., Anderson C.F., Najarian J.S., Krivit W. 1972. Correction of enzymatic deficiencies by renal transplantation. Fabry's disease. Surgery, 72: 203-211.

Franceschetti A.Th. 1967. La cornea verticillata et ses relations avec la maladie de Fabry (angio-keratoma corporis diffusum). Soc. Suisse Ophtal-mol., Flims. Ophthalmologica, 156: 232-238, 1968.

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Jensen E. 1966. On the pathology of angiokeratoma corporis diffsum (Fabry). Acta Pathol. Micro-biol. Scand., 68: 313-331.

Kemp G.L. 1967. Fabry's disease involving the myo-cardium and coronary arteries. Without skin

disease) by kidney transplanatation. Ann. Intern. Med., 77: 195-200.

Wise D. 1960. Angiokeratoma corporis diffusum. Cambridge: Thesis.

Figure

Fig. 2. Fabry's disease. [Family I of Christensen Lou et al. 1970].
Fig. 3. Fabry's disease. [Iowa kindred of von Gemmingen et al. 1965].
Fig. 6. Fabry's disease. [Family II of Christensen Lou 1967].

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