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Triose phosphate-isomerase deficiency
Triosephosphate isomerase (TPI) deficiency is a severe autosomal recessive inherited multisystem disorder of glycolytic metabolism characterized by hemolytic anemia and neurodegeneration.
ORPHA:868Classification level: Disorder
Prevalence of TPI deficiency is unknown and less than 50 cases have been reported in the literature. The frequency of heterozygosity was estimated at 0.4-1% among Caucasians and Asians, and 4% among African Americans. These high values suggest that homozygosity is often lethal in utero. Frequent miscarriages in the affected families support this view.
TPI deficiency is a congenital disease. Hemolytic anemia occurs with very few exceptions and manifests with jaundice in most cases. Reticulocytosis and hyperbilirubinemia are common. Patients have often recurrent bacterial infections, most frequently affecting the respiratory system. In the classical generalized form of the disease, manifestations of progressive neurologic dysfunction become evident usually after 6-24 months of age, with dystonia, tremor, dyskinesia, pyramidal tract signs, cardiomyopathy and spinal motor neuron involvement with progressive neuromuscular impairment (severe weakness and muscle wasting). Cognitive function is not or mildly/moderately influenced and developmental retardation is more related to motor dysfunction affecting mobility (e.g. walking ability) and speech. Chronic axonal neuropathy was proved by nerve biopsy and peripheral electrophysiologic studies. In one case, severe convulsive microcephalic encephalopathy was also reported. Cerebrospinal fluid has been normal when studied, as have CT brain scans and EEG in two cases.
TPI deficiency is due to mutations in the gene coding for the triosephosphate isomerase enzyme (TPI1, 12p13.31). The Glu104Asp substitution is the most frequent one, which accounts for approximately 80% of clinical TPI deficiency, and induces the most severe phenotype. However, many other mutations have been identified, mostly in compound heterozygotes coupled with the Glu104Asp mutation. These substitutions seems to result in a lack (Ile170Val, Phe240Leu) or delay (Cys41Tyr, Val231Met) of neurologic degeneration and an increased life expectancy.
Diagnosis is based on physical examination and laboratory findings revealing enzymatic activity deficiency (2-30% of the normal values) and 15 to 100-fold accumulation of the toxic substrate dihydroxyacetone phosphate (DHAP) in erythrocytes. Muscle biopsy shows myopathic changes; nerve biopsy can be indicative for chronic axonal neuropathy. Molecular genetics can confirm diagnosis. Identification of genotype is crucial because of the different life expectancies.
Antenatal diagnosis is feasible in the first trimester by chorionic villus DNA analysis or by analysis of fetal red cells.
As an autosomal recessive inherited disease, TPI deficiency as a 25% recurrence risk in the case of heterozygous parents.
Management and treatment
There is no curative treatment for TPI deficiency. Management is based on repetitive red blood cell transfusions. Supportive care, if needed, consists of respiratory assistance. Neurological management is the same as in other progressive neuromuscular diseases.
Prognosis of TPI deficiency is poor, especially for patients homozygous for Glu104Asp mutation or heterozygous for a TPI null allele and Glu104Asp. In these cases life expectancy is generally reduced to infancy or early childhood, while patients carrying other mutations show longer survival. The most frequent cause of death is respiratory failure and infection. Central nervous system degeneration and cardiac failure were also reported as causes of death.
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