Case Report
Clinical and genetic characteristics of two patients with tyrosinemia type 1 in Slovenia – A novel fumarylacetoacetate hydrolase (FAH) intronic disease-causing variant

https://doi.org/10.1016/j.ymgmr.2021.100836Get rights and content
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open access

Highlights

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    Non-coding region variants of FAH gene can result in a symptomatic HT1.

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    Retrograde screening for HT1 is technically possible even three years after birth.

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    DBS are convenient for monitoring HT1 patients and are family-friendly.

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    Regular monitoring in HT1 patients can result in a favorable cognitive outcome.

Abstract

Tyrosinemia type 1 (HT1) is an inborn error of tyrosine catabolism that leads to severe liver, kidney, and neurological dysfunction. Newborn screening (NBS) can enable a timely diagnosis and early initiation of treatment.

We presented the follow up of the only two Slovenian patients diagnosed with HT1. Metabolic control was monitored by measuring tyrosine, phenylalanine and succinylacetone from dried blood spots (DBSs). Retrograde screening of HT1 was performed from DBSs taken at birth using tandem mass spectrometry.

First patient was diagnosed at the age of 6 months in the asymptomatic phase due to an abnormal liver echogenicity, the other presented at 2.5 months with an acute liver failure and needed a liver transplantation. The first was a compound heterozygote for a novel FAH intronic variant c.607-21A>G and c.192G>T whereas the second was homozygous for c.192G>T. At the non-transplanted patient, 66% of tyrosine and 79% of phenylalanine measurements were in strict reference ranges of 200–400 μmol/L and >30 μmol/L, respectively, which resulted in a favorable cognitive outcome at 3.6 years. On retrograde screening, both patients had elevated SA levels; on the other hand, tyrosine was elevated only at one.

We showed that non-coding regions should be analyzed when clinical and biochemical markers are characteristic of HT1. DBSs represent a convenient sample type for frequent amino acid monitoring. Retrograde diagnosis of HT1 was possible after more than three years of birth with SA as a primary marker, complemented by tyrosine.

Keywords

Tyrosinemia
Fumarylacetoacetate hydrolase
Nitisinone
Dried blood spot
Succinylacetone
Intronic variant

Abbreviations

AFP
alpha-fetoprotein
ALP
alkaline phosphatase
ALT
alanine transaminase
AST
aspartate transaminase
DBS
dried blood spot
FAH
fumarylacetoacetate hydrolase
GGT
gamma glutamyl transferase
HT1
tyrosinemia type 1
INR
international normalized ratio
MS/MS
tandem mass spectrometry
NBS
newborn screening
NTBC
nitisinone
PTT
partial thromboplastin time
RF
reference range
SA
succinylacetone

Cited by (0)

1

Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia (Permanent address); School of Medicine, Stanford University, California, USA (Present Address).

© 2021 The Authors. Published by Elsevier Inc.