To date, CKDu (MeN) causes remain undetermined and debatable; nevertheless the number of cases could lead to the application of a precautionary principles from a humanitarian perspective. Due to the fact that the Mesoamerican nephropathy is regarded as a multifactorial disease the experimental design of comparative study should take following logical setting into account.

Multifactorial problem. Assume that a disease is definitely caused by A,B,C. The disease will develop if at least 2 risk factors are present in a certain region.

- formula_1 no prevalence of disease in region 1

- A no prevalence of disease in region 2

- B no prevalence of disease in region 3

- C no prevalence of disease in region 4

- A,B prevalence of disease in region 5

- B,C prevalence of disease in region 6

- C,A prevalence of disease in region 7

- A,B,C prevalence of disease in region 8

Removing the risk factor A in the experimental group in comparison to control group will lead to changes in the outbreak of the disease in only 2 of 8 combinatorically possible regions, even if we define A as a relevant risk factor in this theoretical setting. The same is true if the experimental design adds in a comparative study the risk factor A to the regions in the experimental group in comparison to the control group.

If the difference in experimental and control are 2 risk factors (adding or removing two risk factor e.g. A,B in the control group), then 4 regions will show a differences in prevalence of the disease, with the disadvantage that the experimental design cannot clarify if one or both risk factors A and B are contributing to the progression and prevalence of the disease.

Beside this logical analysis of a multifactorial setting there is space for further investigation, e.g.: Leptospirosis has been suggested as a possible contributing factor and oceanic nephrotoxic algae or agents have also been brought to the chart of possibilities as a culprit for this unusual form of kidney damage..

Assessment of the mentioned risk factors and their possible synergism will depend on more and better research.

The TK2 related myopathic form results in muscle weakness, rapidly progresses, leading to respiratory failure and death within a few years of onset. The most common cause of death is pulmonary infection. Only a few people have survived to late childhood and adolescence.

SUCLA2 and RRM2B related forms result in deformities to the brain. A 2007 study based on 12 cases from the Faroe Islands (where there is a relatively high incidence due to a founder effect) suggested that the outcome is often poor with early lethality. More recent studies (2015) with 50 people with SUCLA2 mutations, with range of 16 different mutations, show a high variability in outcomes with a number of people surviving into adulthood (median survival was 20 years. There is significant evidence (p = 0.020) that people with missense mutations have longer survival rates, which might mean that some of the resulting protein has some residual enzyme activity.

RRM2B mutations have been reported in 16 infants with severe encephalomyopathic MDS that is associated with early-onset (neonatal or infantile), multi-organ presentation, and mortality during infancy.

Adding elements to the debate, another recent study from Sri Lanka, where a similar and apparently new form of CKDu has become a serious public health concern too, suggests chronic synergestic exposure to multiple pesticide residues and heavy metal could be the main causal factor. The authors hypothesize that “Agrochemicals are the essential factor for the disease“. Dr. Channa Jayasumana, a Sri Lankan researcher, member of the medical faculty of Rajarata University, has been a leading supporter of the pesticide hypothesis, always in connection to hard water consumption. He has said that research conducted by his university found that “pesticides and chemical fertilizers were responsible for the spike in kidney diseases”, Further he points out heat stress and dehydration is an important aggravating factor of the disease.

Wolcott–Rallison syndrome, WRS, is a rare, autosomal recessive disorder with infancy-onset diabetes mellitus, multiple epiphyseal dysplasia, osteopenia, mental retardation or developmental delay, and hepatic and renal dysfunction as main clinical findings. Patients with WRS have mutations in the EIF2AK3 gene, which encodes the pancreatic eukaryotic translation initiation factor 2-alpha kinase 3.

IPEX (immunodysregulation polyendocrinopathy enteropathy X-linked) syndrome is a rare disease linked to the dysfunction of the transcription factor FOXP3, widely considered to be the master regulator of the regulatory T cell lineage. It leads to the dysfunction of regulatory T-cells and the subsequent autoimmunity. The disorder manifests with autoimmune enteropathy, psoriasiform or eczematous dermatitis, nail dystrophy, autoimmune endocrinopathies, and autoimmune skin conditions such as alopecia universalis and bullous pemphigoid.

Management for immunodysregulation polyendocrinopathy enteropathy X-linked syndrome has seen limited success in treating the syndrome by bone marrow transplantation.

The severity and prognosis vary with the type of mutation involved.

GSE can result in high risk pregnancies and infertility. Some infertile women have GSE and iron deficiency anemia others have zinc deficiency and birth defects may be attributed to folic acid deficiencies.

It has also been found to be a rare cause of amenorrhea.

Immunodysregulation polyendocrinopathy enteropathy X-linked syndrome is inherited in males via an x-linked recessive manner. Apparently the FOXP3 gene, whose cytogenetic location is Xp11.23, is involved in the mechanism of this condition.

The main focus for this autosomal recessive disease is mutations to the EIF2AK3 gene. This gene is located on chromosome 2 p11.2. In unrelated families, different mutations have been observed in the EIF2AK3 gene, including missense and nonsense mutations. For some cases for unrelated families, identical mutations were observed, although these cases are rare.

The EIKF2AK3 gene codes for PERK (pancreatic endoplasmic reticulum kinase), an explanation for the spectrum symptoms. PERK is associated with the activity of beta cells in the pancreas. Beta cells are needed for the proper release of insulin into the blood stream after an increase in blood glucose. This kinase is needed for the control of protein levels in the endoplasmic reticulum and is linked to ribosome activity. The endoplasmic reticulum is a major protein sorting and processing center in every cell of the body. A broad range of bodily systems is affected because of the lack of post-translational modifications of to proteins. These proteins are coming from the endoplasmic reticulum can be in the cells of the various organ systems effected, such as urinary and central nervous system. EIKF2AK3 is also involved in bone cells. This is part of the reason why patients suffer from multiple epiphyseal dysplasia and osteopenia.

Fibromyalgia was found in 9% of adult patients relative to 0.03% in the general population with a link common to IBD. Concurrent IBS is found in 30% to 70%. Small intestinal bacterial overgrowth is associated is common with a transient response to antimicrobial therapy.

This syndrome is characterized by an increased susceptibility to disseminated nontuberculous mycobacterial infections, viral infections, especially with human papillomaviruses, and fungal infections, primarily histoplasmosis, and molds. There is profound monocytopenia, B lymphocytopenia and NK lymphocytopenia. Patients have an increased chance of developing malignancies, including: myelodysplasia/leukemia vulvar carcinoma, metastatic melanoma, cervical carcinoma, Bowen disease of the vulva, and multiple Epstein-Barr virus(+) leiomyosarcoma. Patients may also develop pulmonary alveolar proteinosis without mutations in the granulocyte-macrophage colony-stimulating factor receptor or anti-granulocyte-macrophage colony-stimulating factor autoantibodies. Last, patients may develop autoimmune phenomena, including lupus like syndromes, primary biliary cirrhosis or aggressive multiple sclerosis.

Of the 26, now 28, patients probably afflicted by this syndrome, 48% died of causes ranging from cancer to myelodysplasia with a mean age at death of 34.7 years and median age of 36.5 years.

The exact incidence of MELAS is unknown. It is one of the more common conditions in a group known as mitochondrial diseases. Together, mitochondrial diseases occur in about 1 in 4,000 people.

An average clinical profile from published studies shows that the median onset age for HDLS patients is 44.3 years with a mean disease duration of 5.8 years and mean age of death at 53.2 years. As of 2012, there have been around 15 cases identified with at least 11 sporadic cases of HDLS. HDLS cases have been located in Germany, Norway, Sweden, and the United States, showing an international distribution focusing between Northern Europe and the United States.

Through the study of numerous kindred, it was found that the disease did not occur among just males or females, but rather was evenly distributed indicative of an autosomal rather than a sex-linked genetic disorder. It was also observed that the HDLS cases did not skip generations as it would occur with a recessive inheritance, and as such has been labeled autosomal dominant.

Toxic optic neuropathy refers to the ingestion of a toxin or an adverse drug reaction that results in vision loss from optic nerve damage. Patients may report either a sudden loss of vision in both eyes, in the setting of an acute intoxication, or an insidious asymmetric loss of vision from an adverse drug reaction. The most important aspect of treatment is recognition and drug withdrawal.

Among the many causes of TON, the top 10 toxins include:

- Medications

- Ethambutol, rifampin, isoniazid, streptomycin (tuberculosis treatment)

- Linezolid (taken for bacterial infections, including pneumonia)

- Chloramphenicol (taken for serious infections not helped by other antibiotics)

- Isoretinoin (taken for severe acne that fails to respond to other treatments)

- Ciclosporin (widely used immunosuppressant)

- Acute Toxins

- Methanol (component of some moonshine, and some cleaning products)

- Ethylene glycol (present in anti-freeze and hydraulic brake fluid)

Metabolic disorders may also cause this version of disease. Systemic problems such as diabetes mellitus, kidney failure, and thyroid disease can cause optic neuropathy, which is likely through buildup of toxic substances within the body. In most cases, the cause of the toxic neuropathy impairs the tissue’s vascular supply or metabolism. It remains unknown as to why certain agents are toxic to the optic nerve while others are not and why particularly the papillomacular bundle gets affected.

Long-term nonprogressors (LTNPs), sometimes also called "elite controllers", are individuals infected with HIV, who maintain a CD4 count greater than 500 without antiretroviral therapy with a detectable viral load. Many of these patients have been HIV positive for 30 years without progressing to the point of needing to take medication in order not to develop AIDS. They have been the subject of a great deal of research, since an understanding of their ability to control HIV infection may lead to the development of immune therapies or a therapeutic vaccine. The classification "Long-term non-progressor" is not permanent, because some patients in this category have gone on to develop AIDS.

Long-term nonprogressors typically have viral loads under 10,000 copies RNA/ml blood, do not take antiretrovirals, and have CD4+ counts within the normal range. Most people with HIV not on medication have viral loads which are much higher.

It is estimated that around 1 in 300 people with HIV are long-term nonprogressors. Without the symptoms of AIDS, many LTNP patients may not know they are infected.

Genetic traits that confer greater resistance or more robust immune response to HIV are thought to explain why LTNP patients are able to live much longer with HIV than patients who are not LTNP. Some LTNP are infected with a weakened or inactive form of HIV, but it is now known that many LTNP patients carry a fully virulent form of the virus. Genetic traits that may affect progression include:

- Gene mutation. A mutation in the FUT2 gene affects the progression of HIV-1 infection. 20% of Europeans who have that mutation are called "non secretor" because of their absence of a certain type of antigen that also provides strong resistance against norovirus.

- Mitochondrial DNA. Different mitochondrial DNA haplotypes in humans may increase or decrease rates of AIDS progression. Haplotypes associated with more loosely coupled mitochondrial respiration, with reduced ATP and ROS generation, have been associated with faster progression and vice versa.

- Receptor mutations. A low percentage of long-term nonprogressors have been shown to have inherited mutations of the CCR5 receptor of T cell lymphocytes. HIV uses CCR5 to enter these cells. It is believed that the Δ32 (delta 32) variant of CCR5 impairs HIV ability to infect cells and cause disease. An understanding of this mechanism led to the development of a class of HIV medicines, the entry inhibitors. The presence of this mutation, however, is not a unifying theme among LTNPs and is observed in an exceedingly small number of these patients.

- HLA type has also been correlated with long-term non-progressor cohorts. In particular, strong correlations have been found between possessing the class 1 HLA-B*5701, HLA-B*5703, and/or HLA-B*2705 alleles and ability to exert control over HIV.

- Antibody production. All individuals with HIV make antibodies against the virus. In most patients, broadly neutralizing antibodies do not emerge until approximately 2–4 years after the initial infection. At this point, the latent reservoir has already been established and the presence of broadly neutralizing antibodies is not enough to prevent disease progression. In some rare patients, these antibodies emerge earlier and can result in a delayed disease course. These patients, however, are not typically classified as LTNPs, but rather as slow progressors, who will eventually develop AIDS. Induction of broadly neutralizing antibodies in healthy individuals is a potential strategy for a preventive HIV vaccine, as is the elicitation of these antibodies through rationally designed immunogens. Direct production of these antibodies in somatic tissue through plasmid transfection also pose a viable method for making these antibodies available in a large number of humans.

- APOBEC3G protein production. In a small number of people infected with HIV, the virus is naturally suppressed without medical treatment. These people may carry high quantities of a protein called APOBEC3G that disrupts viral replication in cells. APOBEC3G, or "A3" for short, is a protein that sabotages reverse transcription, the process HIV relies on for its replication. This process involves the virus transcribing its singe-stranded RNA genome into double-stranded DNA that is incorporated into the cell's genome. A3 usually stops dormant viruses in the human genome, called endogenous retroviruses, from reawakening and causing infections.

TAA is an old term for a constellation of elements that can lead to a mitochondrial optic neuropathy. The classic patient is a man with a history of heavy alcohol and tobacco consumption. Respectively, this combines nutritional mitochondrial impairment, from vitamin deficiencies (folate and B-12) classically seen in alcoholics, with tobacco-derived products, such as cyanide and ROS. It has been suggested that the additive effect of the cyanide toxicity, ROS, and deficiencies of thiamine, riboflavin, pyridoxine, and b12 result in TAA.

On the other hand, there is evidence that HIV-1 infection on its own contributes to the development of the lipodystrophic phenotype by interfering with some key genes of adipocyte differentiation and mitochondrial function on patients which have not received antiretroviral treatment.

Kearns–Sayre syndrome occurs spontaneously in the majority of cases. In some cases it has been shown to be inherited through mitochondrial, autosomal dominant, or autosomal recessive inheritance. There is no predilection for race or sex, and there are no known risk factors. As of 1992 there were only 226 cases reported in published literature.

The exact mechanism of HIV-associated lipodystrophy is not fully elucidated. There is evidence indicating both that it can be caused by anti-retroviral medications and that it can be caused by HIV infection in the absence of anti-retroviral medication.

About 1 in 4,000 children in the United States will develop mitochondrial disease by the age of 10 years. Up to 4,000 children per year in the US are born with a type of mitochondrial disease. Because mitochondrial disorders contain many variations and subsets, some particular mitochondrial disorders are very rare.

The average number of births per year among women at risk for transmitting mtDNA disease is estimated to approximately 150 in the United Kingdom and 800 in the United States.

The various mutations may be responsible for the untimely initiation of apoptosis in myelocytes, producing their premature destruction. There may be, in addition, other underlying molecular/genetic changes producing DNA mutations and genome instability, which contribute to initiation and progression of this disease.

Infants with SCN have frequent infections: 50% have a significant infection within 1 month, most others by 6 months. Their etiology is usually bacterial, especially staphylococcal, and they commonly involve abscesses, both cutaneous and of internal organs, pneumonia, mastoiditis (inflammation of the mastoid process), and sepsis. All of these are life-threatening for infants.

Different genetic causes and types of Leigh syndrome have different prognoses, though all are poor. The most severe forms of the disease, caused by a full deficiency in one of the affected proteins, cause death at a few years of age. If the deficiency is not complete, the prognosis is somewhat better and an affected child is expected to survive 6–7 years, and in rare cases, to their teenage years.

In Northern European populations about one in 9000 people carry one of the three primary LHON mutations.

The LHON ND4 G11778A mutation dominates as the primary mutation in most of the world

with 70% of Northern European cases and 90% of Asian cases. Due to a Founder effect, the LHON ND6 T14484C mutation accounts for 86% of LHON cases in Quebec, Canada.

More than 50 percent of males with a mutation and more than 85 percent of females with a mutation never experience vision loss or related medical problems. The particular mutation type may predict the likelihood of penetrance, severity of illness and probability of vision recovery in the affected. As a rule of thumb, a woman who harbors a homoplasmic primary LHON mutation has a ~40% risk of having an affected son and a ~10% risk of having an affected daughter.

Additional factors may determine whether a person develops the signs and symptoms of this disorder. Environmental factors such as smoking and alcohol use may be involved, although studies of these factors have produced conflicting results. Researchers are also investigating whether changes in additional genes, particularly genes on the X chromosome,