Hypertryptophanemia

A number sign (#) is used with this entry because of evidence that hypertryptophanemia (HYPTRP) is caused by compound heterozygous mutation in the TDO2 gene (191070) on chromosome 4q32. One such patient has been reported.

Description

Congenital hypertryptophanemia, which is accompanied by hyperserotonemia, does not appear to have significant clinical consequences (Ferreira et al., 2017).

Clinical Features

Snedden et al. (1982, 1983) described a brother and sister with tryptophanuria as well as a marked increase in plasma tryptophan levels. Martin et al. (1995) provided additional details of these patients and also described abnormal urinary tryptophan metabolites in their mother and a half sib. The brother was a 23-year-old male, the offspring of a Micmac Indian mother and a French Canadian father, who was examined for evaluation of widespread joint pains, emotional lability, defective vision, and a stutter. He had developed normally until the age of 14 years when he began to complain of fleeting pains in his abdomen and joints, precipitated by exertion. At the same time he noticed increasing ulnar drift of the fingers and inability to extend the elbows fully. Generalized joint laxity was noted at the age of 18. A strabismus in the left eye which had almost no vision and high myopia in the right eye were other features. Psychiatric complaints had included aggressive outbursts. Physical examination showed ocular hypertelorism, marked correctable ulnar drift of all the fingers, adduction of the thumbs, and slight contractures of the distal interphalangeal joints of the fingers and intraphalangeal joints of the thumbs. Pes planus was present. The sister was evaluated at the age of 22 years. All her milestones had been delayed; she could not walk until the age of 3 and never acknowledged auditory stimuli or learned to talk. She was institutionalized where she showed hyperactive and aggressive behavior. The mother had had a fever and rash labeled as rubella in the fourth month of pregnancy; the auditory defect in the sister was probably the result of in utero exposure to rubella. Plasma tryptophan estimates were approximately 475 micromole/l in both sibs (normal 25-73). Tryptophanuria and massive excretion of indoleic acids in the urine were also found.

Cleary et al. (1998) reported on the growth, intellectual development, and general health of patients found to have elevated plasma tryptophan through a newborn screening program in Manchester, England, where 1-dimensional paper chromatography was used from 1961 to 1990. Hypertryptophanemia was detected in 12 of 1,196,913 infants screened, for an incidence of 1 in 99,743. Mean weight and growth were normal at all ages in 11 of the 12 children; 1 was overweight from the age of 6 years onward. One child exhibited head-banging at 6 years of age that was behavioral in origin; brain MRI was normal. Developmental scores and IQ scores were normal for all but 1 male infant who showed developmental delay at age 2 years. There were no trends apparent in Griffiths assessment subscores, and WISC testing scores were within the normal range. No correlation was found between intellectual performance and mean plasma tryptophan concentration at diagnosis or at age of assessment, and there were no apparent differences between the dieted and the non-dieted group. Cleary et al. (1998) concluded that there is no ill effect from elevated plasma tryptophan and no indication for dietary treatment, and that hypertryptophanemia should be regarded as a benign condition.

Ferreira et al. (2017) studied a 28-year-old woman who had been found to have hypertryptophanemia on newborn screening in Canada (McCoy and Ferreira, 1987). Serum serotonin was also high, and no unusual urinary indole metabolites were found. Despite a low-protein diet with supplementation using an amino acid mixture lacking tryptophan, her tryptophan level remained elevated, averaging 100 times the upper limit of normal, and serum serotonin was also elevated. However, because her growth, development, and general health were normal at age 2 years, the diet was relaxed then discontinued. Reevaluation at age 26 years, after the proband had completed a university education, showed elevated tryptophan and serotonin levels, a 24-hour urinary 5-HIAA in the high normal range, and a normal melatonin level. At age 28 years, because she was considering pregnancy, normalization of tryptophan and serotonin by dietary means was attempted, using various combinations of natural and medical protein ratios. On this regimen, in which natural protein was never lower than 0.3 g/kg/day, tryptophan could be normalized but not sustained at a normal level, and serotonin levels always remained elevated. An unrestricted diet was reinstituted, and she subsequently had 2 first trimester miscarriages, at 10 weeks' and 8 weeks' gestation. The proband's parents were unrelated and had completely normal tryptophan levels; her brother declined testing.

Molecular Genetics

In a 28-year-old woman with congenital hypertryptophanemia, Ferreira et al. (2017) sequenced the TDO2 gene and identified compound heterozygosity for a 1-bp duplication (191070.0001) and a missense mutation (M108I; 191070.0002). Her unaffected parents were each heterozygous for 1 of the mutations. The proband experienced 2 miscarriages; however, noting that the frequency of 2 consecutive first-trimester miscarriages in the general population was around 5%, and that Tdo, Ido, and Ido2 knockout mouse models had not shown any apparent adverse effect on fertility or ability to maintain pregnancy, the authors stated that no conclusion could be reached regarding the association of altered tryptophan metabolism and recurrent pregnancy loss. Ferreira et al. (2017) noted that unbiased ascertainment by newborn screening as in this case and the cases reported by Cleary et al. (1998) strongly suggested that TDO deficiency results in a benign biochemical phenotype of persistent hypertryptophanemia and hyperserotonemia with no clinical significance.