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17:10: 964966 (1997)

SHORT COMMUNICATION

MUTATION ANALYSIS FOR PRENATAL


DIAGNOSIS OF HEREDITARY TYROSINAEMIA
TYPE 1
1*, 2, 3, . 4, 5
. . 1
1
Department of Clinical Genetics, Tampere University Hospital, SF-33520 Tampere, Finland
DNA Laboratory KGCU, Academisch Ziekenhuis Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands
3
Laboratory for Metabolic Disease, Wilhelmina Childrens Hospital, Utrecht, The Netherlands
4
Department of Paediatrics, Tampere University Hospital, SF-33520 Tampere, Finland
5
Department of Clinical Chemistry, University of Helsinki, SF-00290 Helsinki, Finland

Received 18 November 1996


Revised 17 March 1997
Accepted 21 March 1997

SUMMARY
Hereditary tyrosinaemia type 1 is a rare but serious metabolic disorder with an autosomal recessive mode of
inheritance. We describe the prenatal diagnosis of an affected fetus performed by DNA-mutation analysis and a
subsequent pregnancy with a healthy child in the same family. ? 1997 by John Wiley & Sons, Ltd.
Prenat. Diagn. 17: 964966, 1997
No. of Figures: 0. No. of Tables: 0.

No. of References: 15.

: prenatal diagnosis; tyrosinaemia; mutation analysis

INTRODUCTION
Hereditary tyrosinaemia type 1 (MIM 276700)
is an autosomal recessive disorder caused by
the deficiency of fumarylacetoacetase hydrolase
(FAH) (EC 3.7.1.2), the enzyme which takes part
in tyrosine metabolism (Goldsmith and Laberge,
1989). The disease has an acute and a chronic
form, the former presenting with severe hepatic
failure and the latter with tubulopathy, rickets,
and slowly progressive liver cirrhosis with a high
risk of hepatocellular carcinoma. An intermediate
phenotype also occurs as well as pseudodeficiency
*Correspondence to: Aki Mustonen, MD, Department of
Clinical Genetics, Tampere University Hospital, P.O. Box 2000,
SF-33520 Tampere, Finland.

CCC 01973851/97/10096403 $17.50


? 1997 by John Wiley & Sons, Ltd.

of the enzyme in persons presumed to be clinically


healthy (Rootwelt et al., 1994a).
The FAH gene is located on chromosome
15q2325 (Phaneuf et al., 1991). The cloned gene
has been characterized and 25 different mutations
have been reported (Phaneuf et al., 1992; Labelle
et al., 1993; Rootwelt et al., 1994b; Ploos van
Amstel et al., 1996). A founder effect with one
predominant mutation has been demonstrated in a
French-Canadian isolate with a remarkably high
frequency of the disease (Poudrier et al., 1996).
Also, in Finland one single mutation (W262X)
represents 88 per cent of all disease alleles (StLouis et al., 1994). The incidence of tyrosinaemia
type 1 in Finland is 1:63 000. We present a Finnish
family where prenatal diagnosis was performed in
two subsequent pregnancies based on the DNA
mutation analysis from chorionic villi.


CASE REPORT
The first child (a boy) of a Finnish family was
admitted to hospital at the age of 6 weeks because
of severe hepatic failure. High urinary excretion of
succinylacetone and reduced activity of FAH in
fibroblasts confirmed the diagnosis tyrosinaemia
type 1. A successful liver transplantation was performed at 45 months of age. His parents originate
from the same rural areacounty of Pohjanmaa
where the tyrosinaemia gene is known to exist
enriched. An extensive study of parish records
showed common ancestry of both parents 11
generations earliernot an uncommon finding in
this rural isolate.
After genetic counselling, the family asked for
prenatal examinations in the following pregnancy.
A sample of chorionic villi was taken at 12+4
weeks of pregnancy. It was analysed together with
the DNA specimens of both parents essentially as
described (St-Louis et al., 1994; Ploos van Amstel
et al., 1996).
The parents both showed heterozygosity for the
W262X mutation in exon 9 of the FAH gene. The
fetus was found to be homozygous for the mutation and the parents decided to terminate the
pregnancy. Post-mortem examination of the fetus
did not show structural anomalies. At the time of
termination (at 16+2 weeks) the succinylacetone
concentration in amniotic fluid, as measured
by mass fragmentography, was 063 mg/mmol
creatinine. The concentration of succinylacetone
in normal amniotic fluid samples analysed simultaneously was below the detection limit of the
method. Thus, we estimated that amniotic fluid
succinylacetone was at least 50 times higher than
normal, which confirmed the diagnosis of fetal
tyrosinaemia type 1.
In the next pregnancy, chorionic villus biopsy,
taken at the 13th week, showed the fetus to be
heterozygous for the W262X mutation and subsequently the mother gave birth to a healthy child.
DISCUSSION
Type 1 tyrosinaemia is a rare metabolic autosomal recessive disorder with a variable clinical
picture. The basic defect, deficiency of fumarylacetoacetase (FAH), causes accumulation of the
cytotoxic metabolites maleylacetoacetic acid and
fumarylacetoacetic acid, as well as the pathognomonic metabolite succinylacetone. These
? 1997 by John Wiley & Sons, Ltd.

965

compounds cause renal tubular dysfunction and


hepatic damage.
The highest incidence of the disease reported so
far is among the French-Canadian population
(estimated heterozygous incidence as high as 1 in
22 persons) in the Saguenay-Lac-St-Jean area (De
Braekeleer and Larochelle, 1990). In Finland, the
total incidence of the disease among neonates is 1
in 63 000, but in the western county of Pohjanmaa,
the incidence is much higher1 in 5000 (Salo,
1992).
The different consequences of different mutations of the FAH gene can explain some of the
heterogeneity of the clinical picture of the disease.
However, external genetic and non-genetic factors
may also have an effect on the clinical course.
Earlier studies have shown a total lack of FAH
immunoreactivity in the acute form, while patients
with the chronic form have had diminished
amounts of immunoreactive enzyme protein
(Tanguay et al., 1990).
However, the disease is always serious, the
acute form leading to early death and the chronic
form to tubulopathy, rickets, progressive hepatic
cirrhosis, and hepatocellular carcinoma if liver
transplantation is not performed. The new pharmacological therapy with NTBC has improved
substantially the success of conservative treatment
(Lindstedt et al., 1992) but an open question is
whether it will replace the need for liver transplantation. Thus, the need for reliable prenatal
diagnosis of FAH deficiency is indisputable.
Formerly, prenatal diagnosis was performed by
measuring the concentration of succinylacetone in
amniotic fluid and by determining the activity of
FAH in cultured amniocytes or chorionic villi
(Jakobs et al., 1985; McCormack et al., 1992).
However, the occurrence of presumed pseudodeficiency alleles in the populations studied can lead
to a false interpretation. False-negative prenatal
diagnosis by succinylacetone measurements as well
as false-positive ones by immunoreactive enzyme
analyses are extremely rare but possible. Direct
DNA analysis of the mutated alleles is feasible in
populations and families where these mutations
have been characterized. This technique can be
especially utilized in isolates, where a single predominant mutation exists, but is less successful in
mixed populations where several unrelated causative mutations are causing the disease. In Finland,
a single mutation (W262Xa G to A transversion
in nucleotide 262 of exon 9) has been found to
account for more than 80 per cent of cases. The
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966

localization of the majority of tyrosinaemia cases


to a rural area where less than 5 per cent of
the total Finnish population live makes prenatal
diagnosis, and even carrier screening, feasible.
REFERENCES
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Saguenay-Lac-St-Jean, Am. J. Hum. Genet., 47, 302
307.
Goldsmith, L.A., Laberge, C. (1989). Tyrosinemia and
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Sly, W.S., Valle, D. (Eds). The Metabolic Basis of
Inherited Disease, New York: McGraw-Hill, 547562.
Jakobs, C., Kvittingen, E.A., Berger, R., Haagen, A.,
Kleijer, W., Niermeijer, M. (1985). Prenatal diagnosis
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mass spectrometry, Eur. J. Pediatr., 144, 209210.
Labelle, Y., Phaneuf, D., Leclerc, B., Tanguay, R.M.
(1993). Characterization of the human fumarylacetoacetate hydrolase gene and identification of a missense
mutation abolishing enzymatic activity, Hum. Mol.
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J.R., Green, A. (1992). Fumarylacetoacetase activity
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chromosome 15, Am. J. Hum. Genet., 48, 525535.
Phaneuf, D., Lambert, M., Laframboise, R., Mitchell,
G., Lettre, F., Tanguay, R.M. (1992). Type 1 hereditary tyrosinemia. Evidence for molecular hetero-

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? 1997 by John Wiley & Sons, Ltd.

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