Transaldolase (TALDO) deficiency has a well-characterized phenotype. However, there are few large cohort studies, and little is known about the long term, including the need for organ transplantation. Our aim was to share a long multicenter experience in managing these patients. We retrospectively collected data on 16 patients followed for up to 20 years. Liver involvement was present in all patients, with six presenting liver failure at birth. During long-term follow-up, 10 patients developed cirrhosis and four underwent liver transplantation (LTx). Two patients died from severe liver failure in the first months of life; persistent weight below 4 kg precluded LTx. A third patient died from posttransplant complications at 6 months of life. Five patients developed chronic kidney failure, and in two of them kidney transplantation was considered after the age of 20 years. Patent foramen ovale (PFO) was the most frequent cardiac finding; cardiomyopathy or ventricular dysfunction was diagnosed in five patients. Twelve patients developed chronic cytopenia, all presenting with thrombocytopenia. Hypergonadotropic hypogonadism was found in seven patients; two others developed secondary adrenal cortisol insufficiency and primary hypothyroidism requiring replacement therapy. Mild neurocognitive delay was observed only in a few cases. We described different patterns of liver disease progression. Transplantation should be early considered if indicated for liver insufficiency; in the most severe patients with neonatal onset, achieving sufficient weight for transplantation may be challenging. Our preliminary data suggest that, in older patients, kidney involvement may also warrant consideration of kidney transplantation, which was not previously described for this disease.

Transaldolase deficiency is a rare metabolic disease caused by pathogenic variants in the TALDO1 gene. Transaldolase plays an important role in the ribose-5-phosphate production, maintaining the NADPH-dependent lipid biosynthesis and cellular redox homeostasis. A small number of patients, predominantly children, have been reported, with a wide range of phenotypic presentations, including liver and kidney disease, involvement of the hematopoietic and endocrine systems, as well as possible early death. We aim to provide further insight into the clinical progression of transaldolase deficiency in adolescence and adulthood. We report on three adult patients with genetically confirmed transaldolase deficiency, including two novel genetic variants in TALDO1. Although the patients have been symptomatic since newborn age, initially with hepatomegaly and cytopenias, they were only diagnosed during adolescence or adulthood. Genetic analysis was performed only at 17, 26, and 32 years, respectively, which, however, did not reveal any genetic variants that would be expected to cause a milder disease course. In adulthood, the dominant clinical features were hypergonadotropic hypogonadism, osteopenia, renal and hepatic involvement. In conclusion, when reporting three new adult cases and comparing them with 47 accessible cases from the literature, our findings suggest that, even if clinical manifestations begin in the neonatal period, the overall phenotype may remain relatively mild, with gradual progression. This means that patients presenting with otherwise unexplained progressive liver disease, kidney dysfunction, cytopenia, and hypergonadotropic hypogonadism should be tested for transaldolase deficiency. We recommend closely monitoring patients with known transaldolase deficiency regarding the above-mentioned problems.

Transaldolase deficiency is a rare autosomal recessive disease caused by biallelic mutations in the TALDO1 gene. This disorder is characterized by multisystem involvement, including liver disease. Here, we present 2 siblings with transaldolase deficiency and a novel homozygous mutation in the TALDO1 gene. The index case was presented with hepatosplenomegaly and elevated transaminases in infancy. The 11-year-old sibling, who was diagnosed through family screening, also had chronic liver disease with fibrotic changes, despite initially normal liver function tests. Both patients exhibited additional findings, including dysmorphic facial features, hypergonadotropic hypogonadism, proteinuria, and skeletal anomalies such as scoliosis. Liver biopsies revealed periportal and bridging fibrosis without necroinflammatory activity or malignant transformation. In the second case, a 6 mm T2-hyperintense nodular lesion detected on MRI prompted close monitoring for hepatocellular carcinoma. This report highlights the phenotypic variability of TALDO deficiency, the potential for progressive liver damage in asymptomatic patients, and the importance of liver biopsy and imaging in surveillance. Early diagnosis using genetic testing and family screening facilitates the timely management of complications. Given the multisystem nature of the disorder, multidisciplinary follow-up is essential.

Transaldolase deficiency (TALDO-D) is a rare autosomal recessive disorder of the pentose phosphate pathway, characterized by growth restriction, dysmorphism, cytopenia, with variable liver involvement. Herein, we report a rare case of TALDO-D who presented with primary amenorrhea, elevated gonadotrophins, and low/undetectable estradiol levels, consistent with premature ovarian insufficiency. Molecular genetic analysis identified a homozygous frameshift variant in TALDO1 (c.345dup), caused by a duplication. This case expands the clinical spectrum of TALDO-D by highlighting its association with premature ovarian insufficiency. Transaldolase deficiency should be kept in mind in the differential diagnosis of patients with premature ovarian insufficiency, mainly in the presence of hepatomegaly, cytopenia or other multisystem involvement.