Hereditary hemolytic anemia with triosephosphate isomerase deficiency

Valentine, William N.; Schneider, Arthur S.; Baughan, Marjorie A.; Paglia, Donald E.; Heins, Henry L.

doi:10.1016/0002-9343(66)90004-0

Cited by 150 publications

(10 citation statements)

References 12 publications

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“…The underlying pathogenesis of these diseases remains poorly understood. Triose phosphate isomerase (TPI) deficiency is a severe glycolytic enzymopathy caused by specific missense mutations in the TPI gene that are associated with hemolytic anemia, progressive neuromuscular degeneration, increased susceptibility to infection, and premature death (Schneider et al 1965;Valentine 1966). The TPI protein exists as a homodimer of $26.5-kDa monomers that functions to convert dihydroxyacetone phosphate (DHAP) to glyceraldehyde-3-phosphate (G3P) in glycolysis (Rieder and Rose 1959;Mande et al 1994).…”

mentioning

confidence: 99%

Degradation of Functional Triose Phosphate Isomerase Protein UnderliessugarkillPathology

Seigle

Celotto²,

Palladino

2008

Genetics

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Triose phosphate isomerase (TPI) deficiency glycolytic enzymopathy is a progressive neurodegenerative condition that remains poorly understood. The disease is caused exclusively by specific missense mutations affecting the TPI protein and clinically features hemolytic anemia, adult-onset neurological impairment, degeneration, and reduced longevity. TPI has a well-characterized role in glycolysis, catalyzing the isomerization of dihydroxyacetone phosphate (DHAP) to glyceraldehyde-3-phosphate (G3P); however, little is known mechanistically about the pathogenesis associated with specific recessive mutations that cause progressive neurodegeneration. Here, we describe key aspects of TPI pathogenesis identified using the TPI sugarkill mutation, a Drosophila model of human TPI deficiency. Specifically, we demonstrate that the mutant protein is expressed, capable of forming a homodimer, and is functional. However, the mutant protein is degraded by the 20S proteasome core leading to loss-of-function pathogenesis.

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mentioning

confidence: 99%

Degradation of Functional Triose Phosphate Isomerase Protein UnderliessugarkillPathology

Seigle

Celotto²,

Palladino

2008

Genetics

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“…Glycolytic enzymopathies result from a disturbance in anaerobic metabolism; however, these diseases remain poorly understood. Familial triosephosphate isomerase (TPI) deficiency, an autosomal recessive disorder, has been reported in numerous pedigrees and results in anemia, neuromuscular wasting, and reduced longevity (Schneider et al 1965;Valentine 1966). The relationship of anemia, neuromuscular degeneration, and glycolytic flux to disease pathogenesis is not clear, and an animal model that captures salient features of TPI deficiency has not been reported.…”

mentioning

confidence: 99%

Drosophila Model of Human Inherited Triosephosphate Isomerase Deficiency Glycolytic Enzymopathy

Celotto

Frank²,

Seigle

et al. 2006

Genetics

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Heritable mutations, known as inborn errors of metabolism, cause numerous devastating human diseases, typically as a result of a deficiency in essential metabolic products or the accumulation of toxic intermediates. We have isolated a missense mutation in the Drosophila sugarkill (sgk) gene that causes phenotypes analogous to symptoms of triosephosphate isomerase (TPI) deficiency, a human familial disease, characterized by anaerobic metabolic dysfunction resulting from pathological missense mutations affecting the encoded TPI protein. In Drosophila, the sgk gene encodes the glycolytic enzyme TPI. Our analysis of sgk mutants revealed TPI impairment associated with reduced longevity, progressive locomotor deficiency, and neural degeneration. Biochemical studies demonstrate that mutation of this glycolytic enzyme gene does not result in a bioenergetic deficit, suggesting an alternate cause of enzymopathy associated with TPI impairment.

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“…No neuroradiological studies have been performed in previously reported patients. Cerebrospinal fluid findings have been normal in all studied cases including ours 19, 11, 121 and EEG has not shown specific abnormalities 14, 9,12). The neurological involvement is clearly not the consequence of the generally moderate degree of hemolytic anemia.…”

Section: Discussionmentioning

confidence: 52%

“…The neurological picture found in our patients of lower motor neuron involvement combined with dystonic and dyskinetic features of central origin is seen frequently enough in reported cases to be considered an integral part of the disease. Lower motor neuron disease, which is responsible for weakness, amyotrophy, loss of tendon reflexes 14, 6,111, and, at least in part, hypotonia, has been documented by EMG in only five patients 14, 11 The one article that gives enough detail 141 clearly indicates that motor rather than mental retardation was predominant. Involvement of the optic nerves, as seen in the patients reported here, has not been recorded.…”

Section: Discussionmentioning

confidence: 99%

Nuerological finding in triosephosphate isomerase deficiency

Poll-Thé

Aicardi

Girot

et al. 1985

Annals of Neurology

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Two siblings with hemolytic anemia caused by triosephosphate isomerase deficiency developed a progressive neurological syndrome featuring dystonic movements, tremor, pyramidal tract signs, and evidence of spinal motor neuron involvement. Intelligence was unaffected. The findings in these patients and in 14 previously published cases indicate that neurological manifestations are an integral part of the disorder and suggest that specific structures in the basal ganglia, brainstem, and spinal cord bear the brunt of the pathological process, which does not affect the cerebral cortex.

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Hereditary hemolytic anemia with triosephosphate isomerase deficiency

Cited by 150 publications

References 12 publications

Degradation of Functional Triose Phosphate Isomerase Protein UnderliessugarkillPathology

Degradation of Functional Triose Phosphate Isomerase Protein UnderliessugarkillPathology

Drosophila Model of Human Inherited Triosephosphate Isomerase Deficiency Glycolytic Enzymopathy

Nuerological finding in triosephosphate isomerase deficiency

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