Treatment of THB deficiencies consists of THB supplementation (2–20 mg/kg per day) or diet to control blood phenylalanine concentration and replacement therapy with neurotransmitters precursors (L-DOPA and 5-HTP) and supplements of folinic acid in DHPR deficiency.

Tetrahydrobiopterin is available as a tablet for oral administration in the form of "tetrahydrobiopterin dihydrochloride" (BH4*2HCL). BH4*2HCL is FDA approved under the trade name Kuvan. The typical cost of treating a patient with Kuvan is $100,000 per year. BioMarin holds the patent for Kuvan until at least 2024, but Par Pharmaceutical has a right to produce a generic version by 2020. BH4*2HCL is indicated at least in tetrahydrobiopterin deficiency caused by GTPCH deficiency or PTPS deficiency.

The prognosis of this condition in childhood usually has a stable outcome, whereas in neonatal is almost always fatal, according to Jurecka, et al.

Treatment of adenylosuccinate lyase deficiency can be done via epilepsy management with anticonvulsive drugs.Additionally the following options include:

- D-ribose and uridine administration

- Ketogenic diet

- S-adenosyl-l-methionine

At this time there is no treatment for transaldolase deficiency.

There is currently research being done to find treatments for transaldolase deficiency. A study done in 2009 used orally administered N-acetylcysteine on transaldolase deficient mice and it prevented the symptoms associated with the disease. N-acetylcysteine is a precursor for reduced glutathione, which is decreased in transaldolase deficient patients.

This condition is very rare; approximately 600 cases have been reported worldwide. In most parts of the world, only 1% to 2% of all infants with high phenylalanine levels have this disorder. In Taiwan, about 30% of newborns with elevated levels of phenylalanine have a deficiency of THB.

For women with phenylketonuria, it is important for the health of their children to maintain low Phe levels before and during pregnancy. Though the developing fetus may only be a carrier of the PKU gene, the intrauterine environment can have very high levels of phenylalanine, which can cross the placenta. The child may develop congenital heart disease, growth retardation, microcephaly and intellectual disability as a result. PKU-affected women themselves are not at risk of additional complications during pregnancy.

In most countries, women with PKU who wish to have children are advised to lower their blood Phe levels (typically to between 2 and 6 mg/dL) before they become pregnant, and carefully control their levels throughout the pregnancy. This is achieved by performing regular blood tests and adhering very strictly to a diet, in general monitored on a day-to-day basis by a specialist metabolic dietitian. In many cases, as the fetus' liver begins to develop and produce PAH normally, the mother's blood Phe levels will drop, requiring an increased intake to remain within the safe range of 2–6 mg/dL. The mother's daily Phe intake may double or even triple by the end of the pregnancy, as a result. When maternal blood Phe levels fall below 2 mg/dL, anecdotal reports indicate that the mothers may suffer adverse effects, including headaches, nausea, hair loss, and general malaise. When low phenylalanine levels are maintained for the duration of pregnancy, there are no elevated levels of risk of birth defects compared with a baby born to a non-PKU mother.

Since biotin is in many foods at low concentrations, deficiency is rare except in locations where malnourishment is very common. Pregnancy, however, alters biotin catabolism and despite a regular biotin intake, half of the pregnant women in the U.S. are marginally biotin deficient.

Supplementary "protein substitute" formulas are typically prescribed for people PKU (starting in infancy) to provide the amino acids and other necessary nutrients that would otherwise be lacking in a low-phenylalanine diet. Tyrosine, which is normally derived from phenylalanine and which is necessary for normal brain function, is usually supplemented. Consumption of the protein substitute formulas can actually reduce phenylalanine levels, probably because it stops the process of protein catabolism from releasing Phe stored in the muscles and other tissues into the blood. Many PKU patients have their highest Phe levels after a period of fasting (such as overnight), because fasting triggers catabolism. A diet that is low in phenylalanine but does not include protein substitutes may also fail to lower blood Phe levels, since a nutritionally insufficient diet may also trigger catabolism. For all these reasons, the prescription formula is an important part of the treatment for patients with classic PKU.

The oral administration of tetrahydrobiopterin (or BH4) (a cofactor for the oxidation of phenylalanine) can reduce blood levels of this amino acid in some people. Most people, however, have little or no benefit.

Tentative evidence supports dietary supplementation with large neutral amino acids (LNAAs). The LNAAs (e.g. leu, tyr, trp, met, his, ile, val, thr) may compete with phe for specific carrier proteins that transport LNAAs across the intestinal mucosa into the blood and across the blood–brain barrier into the brain. It use is really only indicated in adults who will not follow an appropriate diet.

Another interesting treatment strategy for is casein glycomacropeptide (CGMP), which is a milk peptide naturally free of Phe in its pure form CGMP can substitute the main part of the free amino acids in the PKU diet and provides several beneficial nutritional effects compared to free amino acids. The fact that CGMP is a peptide ensures that the absorption rate of its amino acids is prolonged compared to free amino acids and thereby results in improved protein retention and increased satiety compared to free amino acids. Another important benefit of CGMP is that the taste is significantly improved when CGMP substitutes part of the free amino acids and this may help ensure improved compliance to the PKU diet.

Furthermore, CGMP contains a high amount of the phe lowering LNAAs, which constitutes about 41 g per 100 g protein and will therefore help maintain plasma phe levels in the target range.

No treatment is available for most of these disorders. Mannose supplementation relieves the symptoms in PMI-CDG (CDG-Ib) for the most part, even though the hepatic fibrosis may persist. Fucose supplementation has had a partial effect on some SLC35C1-CDG (CDG-IIc or LAD-II) patients.

In the United States, biotin supplements are readily available without a prescription in amounts ranging from 1,000 to 10,000 micrograms (30 micrograms is identified as Adequate Intake).

Transaldolase deficiency is recognized as a rare inherited pleiotropic metabolic disorder first recognized and described in 2001 that is autosomal recessive. There have been only a few cases that have been noted, as of 2012 there have been 9 patients recognized with this disease and one fetus.

Persons with the genotype for PKU are unaffected in utero, because maternal circulation prevents buildup of [phe]. After birth, PKU in newborns is treated by a special diet with highly restricted phenylalanine content. Persons with genetic predisposition to PKU have normal mental development on this diet. Previously, it was thought safe to withdraw from the diet in the late teens or early twenties, after the central nervous system was fully developed; recent studies suggest some degree of relapse, and a continued phenylalanine-restricted diet is now recommended.

PKU or hyperphenylalaninemia may also occur in persons without the PKU genotype. If the mother has the PKU genotype but has been treated so as to be asymptomatic, high levels of [phe] in the maternal blood circulation may affect the non-PKU fetus during gestation. Mothers successfully treated for PKU are advised to return to the [phe]-restricted diet during pregnancy.

A small subset of patients with hyperphenylalaninemia shows an appropriate reduction in plasma phenylalanine levels with dietary restriction of this amino acid; however, these patients still develop progressive neurologic symptoms and seizures and usually die within the first 2 years of life ("malignant" hyperphenylalaninemia). These infants exhibit normal phenylalanine hydroxylase (PAH) enzymatic activity but have a deficiency in dihydropteridine reductase (DHPR), an enzyme required for the regeneration of tetrahydrobiopterin (THB or BH), a cofactor of PAH.

Less frequently, DHPR activity is normal but a defect in the biosynthesis of THB exists. In either case, dietary therapy corrects the hyperphenylalaninemia. However, THB is also a cofactor for two other hydroxylation reactions required in the syntheses of neurotransmitters in the brain: the hydroxylation of tryptophan to 5-hydroxytryptophan and of tyrosine to L-dopa. It has been suggested that the resulting deficit in the CNS neurotransmitter activity is, at least in part, responsible for the neurologic manifestations and eventual death of these patients.

In the US, the Dietary Reference Intake for adults is 55 µg/day. In the UK it is 75 µg/day for adult males and 60 µg/day for adult females. 55 µg/day recommendation is based on full expression of plasma glutathione peroxidase. Selenoprotein P is a better indicator of selenium nutritional status, and full expression of it would require more than 66 µg/day.

A high-protein diet can overcome the deficient transport of neutral amino acids in most patients. Poor nutrition leads to more frequent and more severe attacks of the disease, which is otherwise asymptomatic. All patients who are symptomatic are advised to use physical and chemical protection from sunlight: avoid excessive exposure to sunlight, wear protective clothing, and use chemical sunscreens with a SPF of 15 or greater. Patients also should avoid other aggravating factors, such as photosensitizing drugs, as much as possible. In patients with niacin deficiency and symptomatic disease, daily supplementation with nicotinic acid or nicotinamide reduces both the number and severity of attacks. Neurologic and psychiatric treatment is needed in patients with severe central nervous system involvement.

Methylene tetrahydrofolate reductase (MTHFR) is the rate-limiting enzyme in the methyl cycle, and it is encoded by the "MTHFR" gene. Methylenetetrahydrofolate reductase catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a cosubstrate for homocysteine remethylation to methionine. Natural variation in this gene is common in healthy people. Although some variants have been reported to influence susceptibility to occlusive vascular disease, neural tube defects, Alzheimer's disease and other forms of dementia, colon cancer, and acute leukemia, findings from small early studies have not been reproduced. Some mutations in this gene are associated with methylenetetrahydrofolate reductase deficiency.

6-Pyruvoyltetrahydropterin synthase deficiency is an autosomal recessive disorder that causes malignant hyperphenylalaninemia due to tetrahydrobiopterin deficiency.

It belongs to the rare diseases. It is a recessive disorder that is accompanied by hyperphenylalaninemia. Commonly reported symptoms are initial truncal hypotonia, subsequent appendicular hypertonia, bradykinesia, cogwheel rigidity, generalized dystonia, and marked diurnal fluctuation. Other reported clinical features include difficulty in swallowing, oculogyric crises, somnolence, irritability, hyperthermia, and seizures. Chorea, athetosis, hypersalivation, rash with eczema, and sudden death have also been reported. Patients with mild phenotypes may deteriorate if given folate antagonists such as methotrexate, which can interfere with a salvage pathway through which dihydrobiopterin is converted into tetrahydrobiopterin via dihydrofolate reductase. Treatment options include substitution with neurotransmitter precursors (levodopa, 5-hydroxytryptophan), monoamine oxidase inhibitors, and tetrahydrobiopterin. Response to treatment is variable and the long-term and functional outcome is unknown. To provide a basis for improving the understanding of the epidemiology, genotype/phenotype correlation and outcome of these diseases their impact on the quality of life of patients, and for evaluating diagnostic and therapeutic strategies a patient registry was established by the noncommercial International Working Group on Neurotransmitter Related Disorders (iNTD).

These diseases are most common in certain parts of China where the intake is low because the soil is extremely deficient in selenium. Studies in Jiangsu Province of China have indicated a reduction in the prevalence of these diseases by taking selenium supplements. In Finland, selenium salts are added to chemical fertilizers, as a way to increase selenium in soils. Dietary supplements may utilize sodium selenite, L-selenomethionine or selenium-enriched yeast.

Inhibitors of MTHFR and antisense knockdown of the expression of the enzyme have been proposed as treatments for cancer. The active form of folate, L-methylfolate, may be appropriate to target for conditions affected by MTHFR polymorphisms.

One 10-year-old girl with Crigler–Najjar syndrome type I was successfully treated by liver cell transplantation.

The homozygous Gunn rat, which lacks the enzyme uridine diphosphate glucuronyltransferase (UDPGT), is an animal model for the study of Crigler–Najjar syndrome. Since only one enzyme is working improperly, gene therapy for Crigler-Najjar is a theoretical option which is being investigated.

Currently, there is no cure for laminopathies and treatment is largely symptomatic and supportive. Physical therapy and/or corrective orthopedic surgery may be helpful for patients with muscular dystrophies. Cardiac problems that occur with some laminopathies may require a pacemaker. Treatment for neuropathies may include medication for seizures and spasticity.

The recent progress in uncovering the molecular mechanisms of toxic progerin formation in laminopathies leading to premature aging has opened up the potential for the development of targeted treatment. The farnesylation of prelamin A and its pathological form progerin is carried out by the enzyme farnesyl transferase. Farnesyl transferase inhibitors (FTIs) can be used effectively to reduce symptoms in two mouse model systems for progeria and to revert the abnormal nuclear morphology in progeroid cell cultures. Two oral FTIs, lonafarnib and tipifarnib, are already in use as anti-tumor medication in humans and may become avenues of treatment for children suffering from laminopathic progeria. Nitrogen-containing bisphosphate drugs used in the treatment of osteoporosis reduce farnesyldiphosphate production and thus prelamin A farnesylation. Testing of these drugs may prove them to be useful in treating progeria as well. The use of antisense oligonucleotides to inhibit progerin synthesis in affected cells is another avenue of current research into the development of anti-progerin drugs.

There is some evidence that zinc may have an effect on cancer and further study is recommended.

Hartnup disease (also known as "pellagra-like dermatosis" and "Hartnup disorder") is an autosomal recessive metabolic disorder affecting the absorption of nonpolar amino acids (particularly tryptophan that can be, in turn, converted into serotonin, melatonin, and niacin). Niacin is a precursor to nicotinamide, a necessary component of NAD+.

The causative gene, "SLC6A19", is located on chromosome 5.

The treatment consists of identification of comorbid conditions, preventive measures to reduce the risk of infection, and prompt and effective treatment of infections. Infections in an IgA-deficient person are treated as usual (i.e., with antibiotics). There is no treatment for the underlying disorder.

There is a historical popularity in using intravenous immunoglobulin (IVIG) to treat SIGAD, but the consensus is that there is no evidence that IVIG treats this condition. In cases where a patient presents SIGAD and another condition which is treatable with IVIG, then a physician may treat the other condition with IVIG. The use of IVIG to treat SIGAD without first demonstrating an impairment of specific antibody formation is extremely controversial.

Adverse effects have been documented from vitamin B supplements, but never from food sources. Damage to the dorsal root ganglia is documented in human cases of overdose of pyridoxine. Although it is a water-soluble vitamin and is excreted in the urine, doses of pyridoxine in excess of the dietary upper limit (UL) over long periods cause painful and ultimately irreversible neurological problems. The primary symptoms are pain and numbness of the extremities. In severe cases, motor neuropathy may occur with "slowing of motor conduction velocities, prolonged F wave latencies, and prolonged sensory latencies in both lower extremities", causing difficulty in walking. Sensory neuropathy typically develops at doses of pyridoxine in excess of 1,000 mg per day, but adverse effects can occur with much less, so doses over 200 mg are not considered safe. Symptoms among women taking lower doses have been reported.

Existing authorizations and valuations vary considerably worldwide. As noted, the U.S. Institute of Medicine set an adult UL at 100 mg/day. The European Community Scientific Committee on Food defined intakes of 50 mg of vitamin B per day as harmful and established a UL of 25 mg/day. The nutrient reference values in Australia and New Zealand recommend an upper limit of 50 mg/day in adults. "The same figure was set for pregnancy and lactation as there is no evidence of teratogenicity at this level. The UL was set based on metabolic body size and growth considerations for all other ages and life stages except infancy. It was not possible to set a UL for infants, so intake is recommended in the form of food, milk or formula." The ULs were set using results of studies involving long-term oral administration of pyridoxine at doses of less than 1 g/day. "A no-observed-adverse-effect level (NOAEL) of 200 mg/day was identified from the studies of Bernstein & Lobitz (1988) and Del Tredici "et al" (1985). These studies involved subjects who had generally been on the supplements for five to six months or less. The study of Dalton and Dalton (1987), however, suggested the symptoms might take substantially longer than this to appear. In this latter retrospective survey, subjects who reported symptoms had been on supplements for 2.9 years, on average. Those reporting no symptoms had taken supplements for 1.9 years."