People with hypermethioninemia often do not show any symptoms. Some individuals with hypermethioninemia exhibit learning disabilities, mental retardation, and other neurological problems; delays in motor skills such as standing or walking; sluggishness; muscle weakness; liver problems; unusual facial features; and their breath, sweat, or urine may have a smell resembling boiled cabbage.

Hypermethioninemia can occur with other metabolic disorders, such as homocystinuria, tyrosinemia and galactosemia, which also involve the faulty breakdown of particular molecules. It can also result from liver disease or excessive dietary intake of methionine from consuming large amounts of protein or a methionine-enriched infant formula.

Hypermethioninemia is an excess of the amino acid methionine, in the blood. This condition can occur when methionine is not broken down properly in the body.

Defined as those seen in any macrocytic, megaloblastic anemia:

- Anemia: causing fatigue, conjuctival pallor, pale complexion, and in some cases, a mild icterus (yellowing of the eye).

- Glossitis ("shiny tongue"): shiny, glossy tongue.

- Cheilosis (stomatitis): Inflammation of the edges of the lips and the oral mucosa.

- Tabes dorsalis ("subacute combined degeneration of the spinal cord"): This involves the posterior section of the spinal cord and therefore involves proprioception (sense of position), touch, sense of vibration and in severe cases the lateral corticospinal tract, causing spastic paralysis of the limbs.

- Peripheral neuropathy: tingling sensation in the arms and legs.

- Pancytopenia: decreased number of blood cells of all lineages (RBCs, leucocytes, platelets), due to decreased bone marrow production.

- Methylmalonyl CoA-emia: defined as blood having an unusually high concentration of methylmalonyl CoA.

- Peripheral findings such as hypersegmented neutrophils and large RBCs on high field view of the blood smears.

- Laboratory findings indicating increased MCV (Mean Corpuscular Volume), decreased Hgb/Hct (indicating anemia), and decreased value of vitamin B in the blood.

- Proteinuria: protein found in the urine detected by analysis or by dipstick.

- Reversal of all symptoms except neurological symptoms, by IV injection of vitamin B.

- Schilling test indicating no radioactive vitamin B in the urine. (This test has dropped out of favor and should not be tried in patients with any form of renal failure).

Imerslund–Gräsbeck syndrome, is a rare autosomal recessive, familial form of vitamin B deficiency caused by malfunction of the ""Cubam"" receptor located in the terminal ileum. This receptor is composed of two proteins, amnionless (AMN), and cubilin. A defect in either of these protein components can cause this syndrome. This is a rare disease, with a prevalence about 1 in 200,000, and is usually seen in patients of European ancestry.

Vitamin B is an important vitamin needed for bone marrow functioning, the deficit of which causes decreased marrow output and anemia. Vitamin B has two forms, one of which, along with folate, is important in DNA synthesis. Vitamin B is sensitive to acid deformation in the stomach, so a molecule called haptocorrin (R-factor), protects it in the stomach. In the small bowel, a molecule named intrinsic factor (IF), allows vitamin B to be absorbed in the ileum. IGS is caused by a mutation in the receptors located in the terminal portion of ileum. This is a very rare, and unlikely cause of vitamin B deficiency but is a cause nonetheless.

Methylenetetrahydrofolate reductase (MTHFR) deficiency is the most common genetic cause of elevated serum levels of homocysteine (hyperhomocysteinemia). It is caused by genetic defects in MTHFR, which is an important enzyme in the methyl cycle.

Common variants of MTHFR deficiency are asymptomatic and have only minor effects on disease risk. Severe variants (from nonsense mutations) are vanishingly rare.

The common MTHFR deficiencies are usually asymptomatic, although the 677T variant can cause a mildly increased risk of some diseases.

For individuals homozygous in the 677T variant, there is a mildly elevated risk of thromboembolism (odds ratio 1.2), and stroke (odds ratio 1.26). There is also an elevated risk of neural tube defects among children of individuals with the C677T polymorphism (odds ratio 1.38).

For cardiovascular risk, common MTHFR deficiencies were once thought to be associated but meta-analyses indicate that correlation this was an artifact of publication bias.

Loss of appetite and weight loss can occur. Additional signs are weakness, sore tongue, headaches, heart palpitations, irritability, and behavioral disorders. In adults, anemia (macrocytic, megaloblastic anemia) can be a sign of advanced folate deficiency.

Women with folate deficiency who become pregnant are more likely to give birth to low birth weight premature infants, and infants with neural tube defects. In infants and children, folate deficiency can lead to failure to thrive or slow growth rate, diarrhea, oral ulcers, megaloblastic anemia, neurological deterioration. Microcephaly, irritability, developmental delay, seizures, blindness and cerebellar ataxia can also be observed.

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.

Folate deficiency is a low level of folic acid and derivatives in the body. Also known as vitamin B9, folate is involved in adenosine, guanine, and thymidine synthesis (part of DNA synthesis). Signs of folate deficiency are often subtle. Anemia is a late finding in folate deficiency and folate deficiency anemia is the term given for this medical condition. It is characterized by the appearance of large-sized, abnormal red blood cells (megaloblasts), which form when there are inadequate stores of folic acid within the body.

Vitamin B deficiency can also cause symptoms of mania and psychosis, fatigue, memory impairment, irritability, depression, ataxia, and personality changes. In infants symptoms include irritability, failure to thrive, apathy, anorexia, and developmental regression.

Vitamin B deficiency can lead to anemia and neurologic dysfunction. A mild deficiency may not cause any discernible symptoms, but as the deficiency becomes more significant, symptoms of anemia may result, such as weakness, fatigue, light-headedness, rapid heartbeat, rapid breathing and pale color to the skin. It may also cause easy bruising or bleeding, including bleeding gums. GI side effects including sore tongue, stomach upset, weight loss, and diarrhea or constipation. If the deficiency is not corrected, nerve cell damage can result. If this happens, vitamin B deficiency may result in tingling or numbness to the fingers and toes, difficulty walking, mood changes, depression, memory loss, disorientation and, in severe cases, dementia.

The main syndrome of vitamin B deficiency is pernicious anemia. It is characterized by a triad of symptoms:

1. Anemia with bone marrow promegaloblastosis (megaloblastic anemia). This is due to the inhibition of DNA synthesis (specifically purines and thymidine)

2. Gastrointestinal symptoms: alteration in bowel motility, such as mild diarrhea or constipation, and loss of bladder or bowel control. These are thought to be due to defective DNA synthesis inhibiting replication in a site with a high turnover of cells. This may also be due to the autoimmune attack on the parietal cells of the stomach in pernicious anemia. There is an association with GAVE syndrome (commonly called watermelon stomach) and pernicious anemia.

3. Neurological symptoms: Sensory or motor deficiencies (absent reflexes, diminished vibration or soft touch sensation), subacute combined degeneration of spinal cord, seizures, or even symptoms of dementia and or other psychiatric symptoms may be present. Deficiency symptoms in children include developmental delay, regression, irritability, involuntary movements and hypotonia.

The presence of peripheral sensory-motor symptoms or subacute combined degeneration of spinal cord strongly suggests the presence of a B deficiency instead of folate deficiency. Methylmalonic acid, if not properly handled by B, remains in the myelin sheath, causing fragility. Dementia and depression have been associated with this deficiency as well, possibly from the under-production of methionine because of the inability to convert homocysteine into this product. Methionine is a necessary cofactor in the production of several neurotransmitters.

Each of those symptoms can occur either alone or along with others. The neurological complex, defined as "myelosis funicularis", consists of the following symptoms:

1. Impaired perception of deep touch, pressure and vibration, loss of sense of touch, very annoying and persistent paresthesias

2. Ataxia of dorsal chord type

3. Decrease or loss of deep muscle-tendon reflexes

4. Pathological reflexes — Babinski, Rossolimo and others, also severe paresis

Vitamin B deficiency can cause severe and irreversible damage, especially to the brain and nervous system. These symptoms of neuronal damage may not reverse after correction of hematological abnormalities, and the chance of complete reversal decreases with the length of time the neurological symptoms have been present.

Tinnitus may be associated with vitamin B deficiency.

Hyperhomocysteinemia or hyperhomocysteinaemia is a medical condition characterized by an abnormally high level of homocysteine in the blood, conventionally described as above 15 µmol/L.

As a consequence of the biochemical reactions in which homocysteine is involved, deficiencies of

vitamin B, folic acid (vitamin B), and vitamin B can lead to high homocysteine levels.

Hyperhomocysteinemia is typically managed with vitamin B6, vitamin B9 and vitamin B12 supplementation. Supplements of these vitamins; however, do not change outcomes.

X-linked intellectual disability (previously known as X-linked mental retardation) refers to forms of intellectual disability which are specifically associated with X-linked recessive inheritance.

As with most X-linked disorders, males are more heavily affected than females. Females with one affected X chromosome and one normal X chromosome tend to have milder symptoms.

Unlike many other types of intellectual disability, the genetics of these conditions are relatively well understood. It has been estimated there are ~200 genes involved in this syndrome; of these ~100 have been identified.

X-linked intellectual disability accounts for ~16% of all cases of intellectual disability in males.

Elevated levels of homocysteine have been associated with a number of disease states.

Several X-linked syndromes include intellectual disability as part of the presentation. These include:

- Coffin–Lowry syndrome

- MASA syndrome

- MECP2 duplication syndrome

- X-linked alpha thalassemia mental retardation syndrome

- mental retardation and microcephaly with pontine and cerebellar hypoplasia

A triplex tetra-primer ARMS-PCR method was developed for the simultaneous detection of C677T and A1298C polymorphisms with the A66G MTRR polymorphism in a single PCR reaction.

The precise symptoms of a primary immunodeficiency depend on the type of defect. Generally, the symptoms and signs that lead to the diagnosis of an immunodeficiency include recurrent or persistent infections or developmental delay as a result of infection. Particular organ problems (e.g. diseases involving the skin, heart, facial development and skeletal system) may be present in certain conditions. Others predispose to autoimmune disease, where the immune system attacks the body's own tissues, or tumours (sometimes specific forms of cancer, such as lymphoma). The nature of the infections, as well as the additional features, may provide clues as to the exact nature of the immune defect.

All types of Griscelli syndrome have distinctive skin and hair coloring.

Type 1 is associated with eurological abnormalities. These include delayed development, intellectual disability, seizures, hypotonia and eye abnormalities.

Type 2 - unlike type 1 - is not associated primary neurological disease but is associated with an uncontrolled T lymphocyte expansion and macrophage activation syndrome. It is often associated with the hemophagocytic syndrome. This latter condition may be fatal in the absence of bone marrow transplantation.

Persons with type 3 have the typical light skin and hair coloring but are otherwise normal.

About 50% of all cancer patients suffer from cachexia. Those with upper gastrointestinal and pancreatic cancers have the highest frequency of developing a cachexic symptom. This figure rises to 80% in terminal cancer patients. In addition to increasing morbidity and mortality, aggravating the side effects of chemotherapy, and reducing quality of life, cachexia is considered the immediate cause of death of a large proportion of cancer patients, ranging from 22% to 40% of the patients.

Symptoms of cancer cachexia include progressive weight loss and depletion of host reserves of adipose tissue and skeletal muscle. Cachexia should be suspected if involuntary weight loss of greater than 5% of premorbid weight occurs within a six-month period. Traditional treatment approaches, such as appetite stimulants, 5-HT antagonists, nutrient supplementation, and COX-2 inhibitor, have failed to demonstrate success in reversing the metabolic abnormalities seen in cancer cachexia.

Primary immunodeficiencies are disorders in which part of the body's immune system is missing or does not function normally. To be considered a "primary" immunodeficiency, the cause of the immune deficiency must not be secondary in nature (i.e., caused by other disease, drug treatment, or environmental exposure to toxins). Most primary immunodeficiencies are genetic disorders; the majority are diagnosed in children under the age of one, although milder forms may not be recognized until adulthood. While there are over 100 recognized PIDs, most are very rare. About 1 in 500 people in the United States are born with a primary immunodeficiency. Immune deficiencies can result in persistent or recurring infections, autoinflammatory disorders, tumors, and disorders of various organs. There are currently no cures for these conditions; treatment is palliative and consists of managing infections and boosting the immune system.

The onset of the disease is usually before age 2, but patients have been diagnosed with PFIC even into adolescence. Of the three entities, PFIC-3 usually presents earliest. Patients usually present in early childhood with cholestasis, jaundice, and failure to thrive. Intense pruritus is characteristic; in patients who present in adolescence, it has been linked with suicide. Patients may have fat malabsorption, leading to fat soluble vitamin deficiency, and complications, including osteopenia.

Cachexia is often seen in end-stage cancer, and in that context is called "cancer cachexia". Patients with congestive heart failure can have a cachectic syndrome. Also, a cachexia comorbidity is seen in patients who have any of the range of illnesses classified as chronic obstructive pulmonary disease. Cachexia is also associated with advanced stages of chronic kidney disease, cystic fibrosis, multiple sclerosis, motor neuron disease, Parkinson's disease, dementia, HIV/AIDS and other progressive illnesses.

Progressive familial intrahepatic cholestasis (PFIC) is a group of familial cholestatic conditions caused by defects in biliary epithelial transporters. The clinical presentation usually occurs first in childhood with progressive cholestasis. This usually leads to failure to thrive, cirrhosis, and the need for liver transplantation.

Griscelli syndrome type 2 (also known as "partial albinism with immunodeficiency") is a rare autosomal recessive syndrome characterized by variable pigmentary dilution, hair with silvery metallic sheen, frequent pyogenic infections, neutropenia, and thrombocytopenia.

Symptoms of M2DS include infantile hypotonia and failure to thrive, delayed psychomotor development, impaired speech, abnormal or absent gait, epilepsy, spasticity, gastrointestinal motility problems, recurrent infections, and genitourinary abnormalities. Many of those affected by M2DS also fit diagnostic criteria for autism. M2DS can be associated with syndromic facies, namely an abnormally flat back of the head, underdevelopment of the midface, ear anomalies, deep-set eyes, prominent chin, pointed nose, and a flat nasal bridge.