Primary Trimethylaminuria

CLINICAL CHARACTERISTICS

Primary trimethylaminuria is characterized by a fishy odor resembling that of rotten or decaying fish that results from excess excretion of trimethylamine in the urine, breath, sweat, and reproductive fluids. No physical symptoms are associated with trimethylaminuria. Affected individuals appear normal and healthy; however, the unpleasant odor often results in social and psychological problems. Symptoms are usually present from birth and may worsen during puberty. In females, symptoms are more severe just before and during menstruation, after taking oral contraceptives, and around the time of menopause.

DIAGNOSIS/TESTING: The diagnosis of primary trimethylaminuria is established in a proband who: Excretes (under normal dietary conditions) in the urine more than 10% of total trimethylamine (TMA) as the free amine; and Has biallelic (homozygous or compound heterozygous), known loss-of-function pathogenic variants in on molecular genetic testing.

MANAGEMENT

Dietary restriction of: Trimethylamine (present in milk obtained from wheat-fed cows) and its precursors including choline (present in eggs, liver, kidney, peas, beans, peanuts, soya products, and brassicas [Brussels sprouts, broccoli, cabbage, cauliflower]), lecithin and lecithin-containing fish oil supplements; Trimethylamine -oxide (present in seafood [fish, cephalopods, and crustaceans]); Inhibitors of FMO3 enzyme activity such as indoles (found in brassicas). Note: Planning and monitoring of diet to ensure that the daily intake of choline and folate meets recommendations for age and sex; no restriction of dietary choline during pregnancy and lactation. Use of: Acid soaps and body lotions to remove secreted trimethylamine by washing; Activated charcoal and copper chlorophyllin to sequester trimethylamine produced in the gut; Antibiotics (metronidazole, amoxicillin, and neomycin) to suppress production of trimethylamine by reducing bacteria in the gut; Riboflavin supplements to enhance residual FMO3 enzyme activity. : Foods with a high content of precursors of trimethylamine or inhibitors of FMO3 enzyme activity (seafoods: fish, cephalopods, and crustaceans), eggs, offal, legumes, brassicas, and soya products; food supplements and "health" foods that contain high doses of choline and lecithin; drugs metabolized by the enzyme FMO3; circumstances that promote sweating (e.g., exercise, stress, emotional upsets). : Biochemical testing of sibs to identify those who are affected and will benefit from management to reduce production of trimethylamine.

GENETIC COUNSELING

Primary trimethylaminuria is inherited in an autosomal recessive manner. The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one pathogenic variant based on family history). If both parents are known to be heterozygous for an pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.