Chronic axonal neuropathy with triosephosphate isomerase deficiency

doi:10.1016/S0887-8994(03)00423-5

Pediatric Neurology

Volume 30, Issue 2, February 2004, Pages 146-148

https://doi.org/10.1016/S0887-8994(03)00423-5 Get rights and content

Abstract

A patient with triosephosphate isomerase deficiency resulting from compound heterozygote mutation is described. Chronic axonal neuropathy was identified on clinical and neurophysiologic grounds and confirmed by sural nerve biopsy. This report describes the first biopsy-proven case confirming that peripheral neuropathy can occur with triosephosphate isomerase deficiency.

Introduction

Triosephosphate isomerase catalyzes the interconversion of glyceraldehyde phosphate and dihydroxyacetone phosphate in the glycolytic pathway [1]. Deficiency of the enzyme triosephosphate isomerase results in a triad of chronic nonspherocytic anemia, progressive neurologic dysfunction, and increased susceptibility to infection. Neurologic complications usually become evident by 2 years of age. They include dystonia, tremor, pyramidal tract signs, and spinal motor neuron involvement. Cognitive function is likely normal with developmental delay more related to motor dysfunction affecting mobility and speech [1].

Inheritance is by autosomal recessive transmission. A number of different DNA mutations have been identified causing varying degrees of disease severity [2], [3]. The commonest described mutation is a point mutation of the triosephosphate isomerase (TPI) gene at codon 104 changing Glu to Asp [4]. The heterozygous frequency is estimated at 1 to 5 per 1000 [5]. No cure is available but bone marrow transplantation and gene therapy are under evaluation [6], [7], [8].

Of the described cases, the peripheral motor findings are usually attributed to anterior horn cell damage [1]. Although histopathologic examination was described in detail in at least one case, the authors could not find any previous documentation of peripheral nerve biopsy being performed [9], [10].

We present a patient with triosephosphate isomerase deficiency and biopsy-proven peripheral neuropathy.

Section snippets

Case report

This male was born to healthy, unrelated parents. He was diagnosed with triosephosphate isomerase deficiency in the neonatal period after developing jaundice. His hematologic function remained stable apart from episodes of subtle jaundice during minor illnesses.

From 2 years of age neurologic involvement became evident. He had frequent falls, secondary to foot drop, with weakness of hip flexion and knee extension. Deep tendon reflexes were absent but with extensor plantar responses. He

Discussion

This report describes the first patient with clinical and biopsy evidence of peripheral neuropathy associated with triosephosphate isomerase deficiency. The sensory deficits were present at repeated examinations. Although the patient remained hematologically stable, he was progressively and markedly affected by his axonal neuropathy.

Peripheral neuropathy in triosephosphate isomerase deficiency has been described, but without histologic data [12]. Most patients in the literature were believed to

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Cited by (17)

Missense variant in TPI1 (Arg189Gln) causes neurologic deficits through structural changes in the triosephosphate isomerase catalytic site and reduced enzyme levels in vivo
2019, Biochimica et Biophysica Acta - Molecular Basis of Disease
Citation Excerpt :
These disorders are caused by dysfunction of various proteins within the glycolytic pathway and typically lead to hemolytic anemia; however, TPI deficiency has also been shown to lead to neurologic symptoms [2–5]. A common pathogenic mutation has been identified in patients with TPI deficiency (TPIE104D), while TPIC41Y, TPIA62D, TPII170V, TPIV231M, and TPIF240L have also been associated with the disease [6–11]. TPI mutations produce a spectrum of clinical symptoms in patients, raising questions about penetrance and expressivity.
Mutations in the gene triosephosphate isomerase (TPI) lead to a severe multisystem condition that is characterized by hemolytic anemia, a weakened immune system, and significant neurologic symptoms such as seizures, distal neuropathy, and intellectual disability. No effective therapy is available. Here we report a compound heterozygous patient with a novel TPI pathogenic variant (NM_000365.5:c.569G>A:p.(Arg189Gln)) in combination with the common (NM_000365.5:c.315G>C:p.(Glu104Asp)) allele. We characterized the novel variant by mutating the homologous Arg in Drosophila using a genomic engineering system, demonstrating that missense mutations at this position cause a strong loss of function. Compound heterozygote animals were generated and exhibit motor behavioural deficits and markedly reduced protein levels. Furthermore, examinations of the TPI^Arg189Gln/TPI^Glu104Asp patient fibroblasts confirmed the reduction of TPI levels, suggesting that Arg189Gln may also affect the stability of the protein. The Arg189 residue participates in two salt bridges on the backside of the TPI enzyme dimer, and we reveal that a mutation at this position alters the coordination of the substrate-binding site and important catalytic residues. Collectively, these data reveal a new human pathogenic variant associated with TPI deficiency, identify the Arg189 salt bridge as critical for organizing the catalytic site of the TPI enzyme, and demonstrates that reduced TPI levels are associated with human TPI deficiency. These findings advance our understanding of the molecular pathogenesis of the disease, and suggest new therapeutic avenues for pre-clinical trials.
Differential effects on enzyme stability and kinetic parameters of mutants related to human triosephosphate isomerase deficiency
2018, Biochimica et Biophysica Acta - General Subjects
Citation Excerpt :
Chronic axonal neuropathy. The damage became evident at the age of 2 years [27]. In a yeast model with the deleted endogenous gene tim, this mutant showed the same activity as the WT enzyme [28].
Human triosephosphate isomerase (TIM) deficiency is a very rare disease, but there are several mutations reported to be causing the illness. In this work, we produced nine recombinant human triosephosphate isomerases which have the mutations reported to produce TIM deficiency. These enzymes were characterized biophysically and biochemically to determine their kinetic and stability parameters, and also to substitute TIM activity in supporting the growth of an Escherichia coli strain lacking the tim gene. Our results allowed us to rate the deleteriousness of the human TIM mutants based on the type and severity of the alterations observed, to classify four “unknown severity mutants” with altered residues in positions 62, 72, 122 and 154 and to explain in structural terms the mutation V231M, the most affected mutant from the kinetic point of view and the only homozygous mutation reported besides E104D.
In silico prediction of the effects of mutations in the human triose phosphate isomerase gene: Towards a predictive framework for TPI deficiency
2017, European Journal of Medical Genetics
Citation Excerpt :
Two variants (Cys41Tyr and Val231Met) were classified as “pathological (intermediate)” as they exhibited many of the stereotypical clinical phenotypes of TPI deficiency including haemolytic anaemia and neuromuscular impairment but patients with these variants survived longer than the typical TPI deficiency patient. In contrast to the more severe TPI deficiency cases, three of these patients were eight years of age and one was aged 15 at the time their cases were described in the literature (Arya et al., 1997; Bardosi et al., 1990; Orosz et al., 2006; Serdaroglu et al., 2011; Wilmshurst et al., 2004). Finally a group of variants (Ala62Asp, Gly72Ala, Val154Met, Gly122Arg (TPI Manchester)) were classified as “unknown severity” (Manco and Ribeiro, 2007; Perry and Mohrenweiser, 1992; Watanabe et al., 1996).
Triose phosphate isomerase (TPI) deficiency is a rare, but highly debilitating, inherited metabolic disease. Almost all patients suffer severe neurological effects and the most severely affected are unlikely to live beyond early childhood. Here, we describe an in silico study into well-characterised variants which are associated with the disease alongside an investigation into 79 currently uncharacterised TPI variants which are known to occur in the human population. The majority of the disease-associated mutations affected amino acid residues close to the dimer interface or the active site. However, the location of the altered amino acid residue did not predict the severity of the resulting disease. Prediction of the effect on protein stability using a range of different programs suggested a relationship between the degree of instability caused by the sequence variation and the severity of the resulting disease. Disease-associated variations tended to affect well-conserved residues in the protein's sequence. However, the degree of conservation of the residue was not predictive of disease severity. The majority of the 79 uncharacterised variants are potentially associated with disease since they were predicted to destabilise the protein and often occur in well-conserved residues. We predict that individuals homozygous for the corresponding mutations would be likely to suffer from TPI deficiency.
Triosephosphate isomerase deficiency: A patient with Val231Met mutation
2011, Pediatric Neurology
Citation Excerpt :
They identified severe neuronal loss in the dentate and olivary nuclei, as well as small fibers and prominent nuclei with no fibrosis and fatty replacement [10]. Wilmshurst et al. reported on the first biopsy-proven case of peripheral neuropathy resulting from a triosephosphate isomerase deficiency [9]. The mother exhibited a Glu104Asp mutation, and the father exhibited a Cys41Tyr mutation.
Triosephosphate isomerase deficiency constitutes a rare autosomal recessive disorder, characterized by hemolytic anemia, neurodegeneration, and recurrent bacterial infections. It is the most severe glycolytic enzyme defect associated with progressive neurologic dysfunction. Patients with various inherited triosephosphate isomerase deficiency gene mutations were identified. The most frequent is a Glu104Asp mutation, manifested in homozygous and compound heterozygous states. The mutation Val231Met is very rare. We describe a second triosephosphate isomerase-deficient patient homozygous for the Val231Met mutation, with different phenotypic characteristics from the previous case.
Disorders of glycolysis and the pentose phosphate pathway
2022, Inborn Metabolic Diseases: Diagnosis and Treatment
Movement Disorders in Childhood, Third Edition
2022, Movement Disorders in Childhood, Third Edition

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Chronic axonal neuropathy with triosephosphate isomerase deficiency

Abstract

Introduction

Section snippets

Case report

Discussion

Lancet

Blood

J Pediatr

Blood Cells Mol Dis

Neurological findings in triosephosphate isomerase deficiency

Ann Neurol

Evidence for founder effect of the Glu104Asp substitution of new mutations in triosephosphate isomerase deficiency

Human Mutation

Human triosephosphate isomerase deficiency resulting from mutation of Phe-240

Am J Hum Genet

Triosephosphate isomerase deficiencyRepetitive occurrence of point mutation in amino acid 104 in multiple apparently unrelated families

Am J Hematol