Triosephosphate Isomerase Deficiency

A number sign (#) is used with this entry because triosephosphate isomerase deficiency (TPID) is caused by homozygous or compound heterozygous mutation in the TPI1 gene (190450) on chromosome 12p13.

Description

Triosephosphate isomerase deficiency is an autosomal recessive multisystem disorder characterized by congenital hemolytic anemia, and progressive neuromuscular dysfunction beginning in early childhood. Many patients die from respiratory failure in childhood. The neurologic syndrome is variable, but usually includes lower motor neuron dysfunction with hypotonia, muscle weakness and atrophy, and hyporeflexia. Some patients may show additional signs such as dystonic posturing and/or spasticity. Laboratory studies show intracellular accumulation of dihydroxyacetone phosphate (DHAP), particularly in red blood cells (summary by Fermo et al., 2010).

Clinical Features

A form of nonspherocytic hemolytic anemia of Dacie's type II (in vitro autohemolysis is not corrected by added glucose) has been found to have a deficiency of red cell triosephosphate isomerase (Schneider et al., 1965). Association with recurrent infection, causing death in some, and a progressive neurologic disorder characterized by spasticity was noted. The homozygotes showed 6% of normal TPI activity in red cells and 20% in white cells. Heterozygotes showed about 50%. Schneider et al. (1965) raised the 'intriguing possibility that the marked reduction in leukocyte triosephosphate isomerase functionally impairs the activity of these cells.'

Clay et al. (1982) reported a 12-year-old girl who died of TPI deficiency. Clinically, she had developmental and motor delay and muscular weakness, followed by cerebellar dysfunction and spasticity with hyperreflexia. Neuropathology showed abnormal hyaline cell bodies and axonal spheroids in the hypothalamus and cerebellar cortex, severe neuronal loss in the dentate and olivary nuclei, and partial loss of cerebellar Purkinje cells (olivocerebellar atrophy).

Rosa et al. (1985) detected 7 homozygotes for TPI deficiency in 5 unrelated families. All showed hemolytic anemia, apparent soon after birth, and progressive neuromuscular symptoms.

Poll-The et al. (1985) reported a Bulgarian sister and brother with TPI deficiency. The patients, aged 7 and 4 years at the time of the report, developed hemolytic anemia in early infancy, followed by a progressive neuromuscular syndrome beginning at about age 2 years. They were easily fatigued and had muscle weakness and progressive gait abnormalities resulting in a loss of independent ambulation after a few years. The girl had a scissoring gait, areflexia of the legs, and extensor plantar responses, as well as generalized hypotonia, muscle atrophy, intention tremor, and jerky movements of the proximal muscles. The boy was unable to walk, even with support, and showed upper limb weakness, dystonic posturing of the hands, intention tremor, and abnormal jerks of the proximal arms and legs. Both had pallor of the optic discs. EMG in both patients suggested anterior horn cell impairment. Intelligence was preserved. Laboratory studies showed significantly decreased TPI activity.

Bellingham et al. (1989) reported a family in which a child with triosephosphate isomerase deficiency died at the age of 13 months because of early central nervous system degeneration and cardiac failure. Death usually occurs in this disorder before the age of 15 years.

Eber et al. (1991) described the disorder in an 8-year-old Turkish girl who had chronic hemolytic anemia, myopathy, and developmental retardation since early infancy. The concentration of enzyme substrate dihydroxyacetone phosphate (DHAP) was elevated. They concluded that low TPI activity leads to a metabolic block of the glycolytic pathway and hence to a generalized impairment of cellular energy supply. They referred to the variant as TPI Hamm for the city where the child was hospitalized. Accelerated enzyme deamidation, the first step in the normal catabolism of TPI during aging of the erythrocyte, was a characteristic of this variant and was apparently responsible for the altered electrophoretic pattern.

Hollan et al. (1993) and Chang et al. (1993) reported a Hungarian family in which 2 brothers had TPI deficiency. The older brother, a 23-year-old amateur wrestler, had congenital hemolytic anemia but no neurologic symptoms, whereas his 13-year-old brother had congenital hemolytic anemia and hyperkinetic torsion dyskinesia. Both had less than 10% TPI activity and a greatly increased DHAP level in their red blood cells. Their TPI had a slow electrophoretic mobility and was heat unstable. Both parents and a third brother were healthy heterozygotes. The older brother represented a unique phenotype since all published homozygotes had severe neurologic alterations from infancy or early childhood except 1 infant who died at 11 months, probably too young for neurologic symptoms to be noted. Furthermore, in contrast to the 2 affected Hungarian brothers, all but 1 homozygote had died before the age of 6 years.

Pekrun et al. (1995) reported a 2-year-old girl, born of consanguineous Turkish parents, with TPI deficiency. She presented with hemolytic anemia shortly after birth, and later developed neuromuscular problems, including progressive hypotonia and loss of reflexes. She had recurrent respiratory infections and developed respiratory failure requiring intermittent mechanical ventilation. TPI activity in red cells was reduced to about 20% of normal. Heat stability of the enzyme was strongly reduced; concentration of the physiologic substrate, DHAP, was increased 20-fold due to the metabolic block. During a second pregnancy, examination of a cord blood sample obtained at 19 weeks' gestation showed that the infant was homozygous wildtype, and an unaffected, healthy newborn was delivered.

Fermo et al. (2010) reported 2 unrelated children with TPI deficiency. The first was an Italian girl born of nonconsanguineous parents. The pregnancy was complicated by oligohydramnios and reduced fetal growth. At birth, she had jaundice and macrocytic anemia, eventually requiring blood transfusions. Neuromuscular complications, including hypotonia and severe difficulty breathing, occurred at 2 months of age. Brain MRI at 9 months showed cerebral atrophy with myelination defects. She had recurrent infections and progressive neuromuscular impairment, resulting in death from respiratory failure at age 6 years. The second child was a male infant born of unrelated parents of Turkish and English origin. Soon after birth he developed hemolytic anemia, jaundice, and respiratory distress. He later developed recurrent infections and showed decreased muscle tone with abnormal posturing; he died from respiratory failure at age 10 weeks.

Diagnosis

Prenatal Diagnosis

Bellingham et al. (1989) made a prenatal diagnosis of the heterozygous state by analysis of fetal red cells obtained by cordocentesis at 19 weeks' gestation. Bellingham et al. (1989) recognized that study of chorion villus biopsy material is a more satisfactory approach to prenatal diagnosis. Bellingham and Lestas (1990) suggested that there are reasons to be cautious about the use of enzyme activity in amniocytes or trophoblastic material because of the likelihood that nucleated cells will metabolize the marker material through the presence of an alternative enzyme. They suggested that reliance be placed on assay of red cells in the second trimester pending availability of DNA diagnosis.

Inheritance

The transmission pattern of TPI deficiency in the families reported by Chang et al. (1993) was consistent with autosomal recessive inheritance.

Molecular Genetics

Daar et al. (1986) and Pekrun et al. (1995) identified homozygosity for a missense mutation in the TPI1 gene (E104D; 190450.0001) in patients with triosephosphate isomerase deficiency.

Arya et al. (1997) found that the E104D mutation accounted for 11 (79%) of 14 mutant alleles among 7 unrelated families of northern European origin with TPI deficiency. Haplotype analysis supported a founder effect.

In 2 Hungarian brothers with TPI deficiency, Chang et al. (1993) and Orosz et al. (2001) identified compound heterozygous mutations in the TPI1 gene (F240L, 190450.0003 and E145X, 190450.0006).

In 2 unrelated children with TPI deficiency, Fermo et al. (2010) identified compound heterozygous mutations in the TPI gene. Each patient carried the E104D mutation on 1 allele and a different mutation on the other allele (190450.0007 and 190450.0008).

Clinical Management

Ationu et al. (1999) noted that the metabolic defect of TPI deficiency can be corrected in vitro in deficient primary skeletal muscle myoblasts and lymphoblastoid cells cultured in the presence of exogenous TPI. They reported a trial of red cell transfusion for replacing enzyme in a 4-year-old child homozygous for the common glu104-to-asp (E104D) mutation. The patient had typical features of TPI deficiency, including chronic hemolytic anemia, and severe generalized muscle weakness with hypotonia and dystonia. TPI deficiency is the most severe of the red cell enzymopathies; most reported patients die before 6 years of age. The data obtained in this trial showed a significant increase in lymphocyte TPI activity accompanied by a reduction of DHAP levels following red cell transfusion. The transient nature of the biochemical changes suggested that sustained reversal of the metabolic effects of TPI deficiency would require continuous delivery of active enzyme.

Pathogenesis

In a review of TPI deficiency, Orosz et al. (2006) noted that some evidence suggests that accumulated DHAP may decompose to form advanced glycation end products that are toxic to cells and/or that presence of the mutant protein may result in the formation of toxic protein aggregates; both may result in neurodegeneration in addition to the enzymatic defect that primarily affects red cell survival.

Population Genetics

Mohrenweiser (1981) studied the frequency of enzyme deficiency variants in 675 newborn infants and about 200 adults. Seven children were observed with heterozygous TPI deficiency. In each case one parent was also an apparent heterozygote. In Germany, Eber et al. (1984) found a frequency of heterozygotes of 3.7 per 1000.

Watanabe et al. (1996) reviewed briefly the frequency of the reduced TPI trait. Direct determination enzymatic activity in erythrocytes of unselected Caucasians and Japanese indicated that approximately 4.8 per 1,000 individuals had a level of TPI activity that was 50% of normal. The frequency of heterozygosity was estimated as 9 in 1,713 among Caucasians and 7 in 168 among African Americans. Genetic transmission of the trait was confirmed in all families. The high frequency of the presumptive deficiency allele is not consistent with the rarity of clinically identified TPI deficiency in humans and suggests, as has been reported in studies of TPI-deficient mice (Merkle and Pretsch, 1989), that complete TPI deficiency is an embryo-lethal condition.