The signs and symptoms of "activated PI3K Delta Syndrome" are consistent with the following:

- Immunodeficiency

- Lymphadenopathy

- Sinopulmonary infections

- Bronchiectasis

Symptoms range widely in their onset and severity. The onset of the most severe form, type III, begins within the first months of life and includes a quick progression of intellectual disability, liver and spleen enlargement (splenomegaly), hearing loss, respiratory infections and skeletal abnormalities. Often the appearance of an affected individual includes the following facial features: protruding forehead, leveled nasal bridge, small nose and wide mouth. Muscular weakness or spinal abnormalities can occur due to the buildup of storage materials in the muscle. A milder form of alpha-mannosidosis involves mild to moderate intellectual disability which develops during childhood or adolescence.

Activated PI3K delta syndrome is a primary immunodeficiency disease caused by activating gain of function mutations in the PIK3CD gene. Which encodes the p110δ catalytic subunit of PI3Kδ, APDS-2 (PASLI-R1) is caused by exon-skipping mutations in PIK3R1 which encodes for the regulatory subunit p85α. APDS and APDS-2 affected individuals present with similar symptoms, which include increased susceptibility to airway infections, bronchiectasis and lymphoproliferation.

Developmental toxicity is any structural or functional alteration, reversible or irreversible, which interferes with homeostasis, normal growth, differentiation, development or behavior, and which is caused by environmental insult (including drugs, lifestyle factors such as alcohol, diet, and environmental toxic chemicals or physical factors). It is the study of adverse effects on the development of the organism resulting from exposure to toxic agents before conception (either parent), during prenatal development, or post-natally until puberty. The substance that causes developmental toxicity from embryonic stage to birth is called teratogens. The effect of the developmental toxicants depends on the type of substance, dose and duration and time of exposure.

Certain Pathogens are also included since the toxins they secrete are known to cause adverse effects on the development of the organism when the mother or fetus is infected. Developmental toxicology is a science studying adverse developmental outcomes. This term has widely replaced the early term for the study of primarily structural congenital abnormalities, teratology, to enable inclusion of a more diverse spectrum of congenital disorders. Typical factors causing developmental toxicity are radiation, infections (e.g. rubella), maternal metabolic imbalances (e.g. alcoholism, diabetes, folic acid deficiency), drugs (e.g. anticancer drugs, tetracyclines, many hormones, thalidomide), and environmental chemicals (e.g. mercury, lead, dioxins, PBDEs, HBCD, tobacco smoke). The first-trimester exposure is considered the most potential for developmental toxicity.

Once fertilization has taken place, the toxicants in the environment can pass through the mother to the developing embryo or fetus across the placental barrier. The fetus is at greatest risk during the first 14th to 60th day of the pregnancy when the major organs are being formed. However, depending on the type of toxicant and amount of exposure, a fetus can be exposed toxicant at any time during pregnancy. For example, exposure to a particular toxicant at one time in the pregnancy may result in organ damage and at another time in the pregnancy could cause death of the fetus and miscarriage. There are a number of chemicals, biological agents (such as bacteria and viruses), and physical agents (such as radiation) used in a variety of workplaces that are known to cause developmental disorders. Developmental disorders can include a wide range of physical abnormalities, such as bone or organ deformities, or behavioral and learning problems, such as a mental retardation. Exposures to some chemicals during pregnancy can lead to the development of cancer later in the life of the child and are called transgenerational carcinogens. Exposure to toxicants during the second and the third trimester of a pregnancy can lead to slow fetal grown and result in low birth weight.

A defective alpha-mannosidase enzyme, which normally helps to break down complex sugars derived from glycoproteins in the lysosome, causes sugar build up and impairs cell function. Complete absence of functionality in this enzyme leads to death during early childhood due to deterioration of the central nervous system. Enzymes with low residual activity lead to a milder type of the disease, with symptoms like reduced hearing, mental disabilities, susceptibility to bacterial infections, and skeletal deformities. The course of the disease is progressive.

Alpha-mannosidosis is classified into types I through III based on severity and age of onset. In contrast to the usual classifications scheme of these disorders, type III is the most severe.

Copper toxicity, also called copperiedus, refers to the consequences of an excess of copper in the body. Copperiedus can occur from eating acid foods cooked in uncoated copper cookware, or from exposure to excess copper in drinking water or other environmental sources.

ICD-9-CM code 985.8 "Toxic effect of other specified metals" includes acute & chronic copper poisoning (or other toxic effect) whether intentional, accidental, industrial etc.

- In addition, it includes poisoning and toxic effects of other metals including tin, selenium nickel, iron, heavy metals, thallium, silver, lithium, cobalt, aluminum and bismuth. Some poisonings, e.g. zinc phosphide, would/could also be included as well as under 989.4 Poisoning due to other pesticides, etc.

- Excluded are toxic effects of mercury, arsenic, manganese, beryllium, antimony, cadmium, and chromium.

Symptoms of BNS gradually progress over the span of a week or even a month, and there is typically a delay in diagnosis after the initial symptoms arise. Although BNS arises due to complications from WM, some individuals may experience symptoms of BNS without having a past history of WM.

Given that BNS is so rare, the symptoms are diverse and nonspecific. Symptoms range in severity from nausea to seizures and are characterized by how they interfere with the function of the CNS. Where certain symptoms are present depends on which branch of the CNS is being affected by plasma B-cells. People diagnosed with BNS experience some sensory symptoms as well. Some sensory symptoms include a pin and needles sensation experienced in the lower limbs, the hands, and in the arms, along with pain and extreme numbness.

MODY 6 is a form of maturity onset diabetes of the young.

MODY 6 arises from mutations of the gene for the transcription factor referred to as neurogenic differentiation 1. The gene is on chromosome 2 in a region of the p arm known as IDDM7 because it includes genes affecting susceptibility to type 1 diabetes. NeuroD1 promotes transcription of the insulin gene as well as some genes involved in formation of beta cells and parts of the nervous system.

This is also one of the rarer forms of MODY. Only 3 kindreds with mutations causing MODY6 have been identified so far. In both, some of the members had more typical type 2 diabetes rather than MODY, and the reasons for the difference of expression have not been worked out. Most of the family members with diabetes were diagnosed after age 40, but a few required insulin for blood sugar control.

Fetal alcohol spectrum disorders (FASD) is a term that constitutes the set of conditions that can occur in a person whose mother drank alcohol during the course of pregnancy. These effects can include physical and cognitive problems. FASD patient usually has a combination of these problems. Extent of effect depends on exposure frequency, dose and rate of ethanol elimination from amniotic fluid. FAS disrupts normal development of the fetus, which may cause certain developmental stages to be delayed, skipped, or immaturely developed. Since alcohol elimination is slow in a fetus than in an adult and the fact that they do not have a developed liver to metabolize the alcohol, alcohol levels tend to remain high and stay in the fetus longer. Birth defects associated with prenatal exposure to alcohol can occur in the first three to eight weeks of pregnancy before a woman even knows that she is pregnant.

Acute TM is rarer than chronic TM and symptoms appear within days of onset. Acute TM degrades muscle fibers rapidly. Due to the rapid degradation of muscle fibers patients usually cite severe muscle cramps and muscle pain. Some acute TM patients may present symptoms of blurred vision and bulging eyes due to eye muscle degradation and inflammation, but documented cases are rare. Acute TM patients usually have very weak respiratory muscles and often severe respiratory failure occurs.

Bing–Neel syndrome (BNS) is an extremely rare neurologic complication of Waldenström macroglobulinemia (WM), which is a chronic lymphoproliferative disorder.

There's no clear definition of BNS but what is known so far is that unlike WM, It involves the central nervous system (CNS), infiltrated by differentiated malignant B cells and by having hyperglobulinemia. This infiltration increases blood viscosity, which impairs blood circulation through small blood vessels of the brain and the eye. Some scientists proposed that a person diagnosed with BNS is typically classified into Group A and Group B depending on whether or not plasma cells are present within the brain parenchyma, leptomeninges, dura, and/or the cerebral spinal fluid (CSF). Symptoms are diverse and nonspecific, and they can vary depending on which aspect of the CNS is being affected. Symptoms can include a range of severity of nausea and seizures. Since the symptoms vary, there are multiple treatment options to treat the symptoms for this non-curable disease. Although there is no specific set of diagnosis for BNS, different combinations of diagnostic tools are used to narrow down and conclude the presence of BNS.

Organic acidemias are usually diagnosed in infancy, characterized by urinary excretion of abnormal amounts or types of organic acids. The diagnosis is usually made by detecting an abnormal pattern of organic acids in a urine sample by gas chromatography-mass spectrometry. In some conditions, the urine is always abnormal, in others the characteristic substances are only present intermittently. Many of the organic acidemias are detectable by newborn screening with tandem mass spectrometry.

These disorders vary in their prognosis, from manageable to fatal, and usually affect more than one organ system, especially the central nervous system.

Neurological damage and developmental delay are common factors in diagnosis, with associated symptoms ranging from poor feeding to slow growth, lethargy, vomiting,

dehydration, malnutrition, hypoglycemia, hypotonia, metabolic acidosis, ketoacidosis, hyperammonemia, and if left untreated, death.

Chronic poisoning usually presents with symptoms affecting multiple systems, but is associated with three main types of symptoms: gastrointestinal, neuromuscular, and neurological. Central nervous system and neuromuscular symptoms usually result from intense exposure, while gastrointestinal symptoms usually result from exposure over longer periods. Signs of chronic exposure include loss of short-term memory or concentration, depression, nausea, abdominal pain, loss of coordination, and numbness and tingling in the extremities. Fatigue, problems with sleep, headaches, stupor, slurred speech, and anemia are also found in chronic lead poisoning. A "lead hue" of the skin with pallor and/or lividity is another feature. A blue line along the gum with bluish black edging to the teeth, known as a Burton line, is another indication of chronic lead poisoning. Children with chronic poisoning may refuse to play or may have hyperkinetic or aggressive behavior disorders. Visual disturbance may present with gradually progressing blurred vision as a result of central scotoma, caused by toxic optic neuritis.

Symptoms of chronic TM arise slowly. Patients usually cite decreased exercise tolerance, increased fatigue, and difficulty completing certain tasks after six months of onset. If chronic TM goes untreated worse symptoms may develop including difficulty swallowing and respiratory distress. These occurrences are rare since diagnosis of chronic TM usually occurs during the early stages of onset, before these symptoms develop.

The olfactory system is the system related to the sense of smell (olfaction). Many fish activities are dependent on olfaction, such as: mating, discriminating kin, avoiding predators, locating food, contaminant avoidance, imprinting and homing. These activities are referred to as “olfactory-mediated.” Impairment of the olfactory system threatens survival and has been used as an ecologically relevant sub-lethal toxicological endpoint for fish within studies. Olfactory information is received by sensory neurons, like the olfactory nerve, that are in a covered cavity separated from the aquatic environment by mucus. Since they are in almost direct contact with the surrounding environment, these neurons are vulnerable to environmental changes. Fish can detect natural chemical cues in aquatic environments at concentrations as low as parts per billion (ppb) or parts per trillion (ppt).

Studies have shown that exposures to metals, pesticides, or surfactants can disrupt fish olfaction, which can impact their survival and reproductive success. Many studies have indicated copper as a source of olfactory toxicity in fishes, among other common substances. Olfactory toxicity can occur by multiple, complex Modes of Toxic Action.

In acute poisoning, typical neurological signs are pain, muscle weakness, numbness and tingling, and, rarely, symptoms associated with inflammation of the brain. Abdominal pain, nausea, vomiting, diarrhea, and constipation are other acute symptoms. Lead's effects on the mouth include astringency and a metallic taste. Gastrointestinal problems, such as constipation, diarrhea, poor appetite, or weight loss, are common in acute poisoning. Absorption of large amounts of lead over a short time can cause shock (insufficient fluid in the circulatory system) due to loss of water from the gastrointestinal tract. Hemolysis (the rupture of red blood cells) due to acute poisoning can cause anemia and hemoglobin in the urine. Damage to kidneys can cause changes in urination such as decreased urine output. People who survive acute poisoning often go on to display symptoms of chronic poisoning.

The symptoms of Leigh syndrome are classically described as beginning in infancy and leading to death within a span of several years; however, as more cases are recognized, it is apparent that symptoms can emerge at any age—including adolescence or adulthood—and patients can survive for many years following diagnosis. Symptoms are often first seen after a triggering event that taxes the body's energy production, such as an infection or surgery. The general course of Leigh syndrome is one of episodic developmental regression during times of metabolic stress. Some patients have long periods without disease progression while others develop progressive decline.

Infants with the syndrome have symptoms that include diarrhea, vomiting, and dysphagia (trouble swallowing or sucking), leading to a failure to thrive. Children with early Leigh disease also may appear irritable and cry much more than usual. Seizures are often seen. Excess lactate may be seen in the urine, cerebrospinal fluid, and blood of a person with Leigh syndrome.

As the disease progresses, the muscular system is debilitated throughout the body, as the brain cannot control the contraction of muscles. Hypotonia (low muscle tone and strength), dystonia (involuntary, sustained muscle contraction), and ataxia (lack of control over movement) are often seen in people with Leigh disease. The eyes are particularly affected; the muscles that control the eyes become weak, paralyzed, or uncontrollable in conditions called ophthalmoparesis (weakness or paralysis) and nystagmus (involuntary eye movements). Slow saccades are also sometimes seen. The heart and lungs can also fail as a result of Leigh disease. Hypertrophic cardiomyopathy (thickening of part of the heart muscle) is also sometimes found and can cause death; asymmetric septal hypertrophy has also been associated with Leigh syndrome. In children with Leigh-syndrome associated ventricular septal defects, caused by pyruvate dehydrogenase deficiency, high forehead and large ears are seen; facial abnormalities are not typical of Leigh syndrome.

However, respiratory failure is the most common cause of death in people with Leigh syndrome. Other neurological symptoms include peripheral neuropathy, loss of sensation in extremities caused by damage to the peripheral nervous system.

Hypertrichosis is seen in Leigh syndrome caused by mutations in the nuclear gene SURF1.

Many organ systems are affected by triploidy, but the central nervous system and skeleton are the most severely affected. Common central nervous system defects seen in triploidy include holoprosencephaly, hydrocephalus (increased amount of cerebrospinal fluid within the brain), ventriculomegaly, Arnold-Chiari malformation, agenesis of the corpus callosum, and neural tube defects. Skeletal manifestations include cleft lip/palate, hypertelorism, club foot, and syndactyly of fingers three and four. Congenital heart defects, hydronephrosis, omphalocele, and meningocele (spina bifida) are also common. Cystic hygromas occur but are uncommon. Triploid fetuses have intrauterine growth restriction beginning early in the pregnancy, as early as 12 weeks, and does not affect the head as severely as the body. Oligohydramnios, low levels of amniotic fluid, is common in triploid pregnancies.

Placental abnormalities are common in triploidy. Most frequently, the placenta is enlarged and may have cysts within. In some cases, the placenta may be unusually small, having ceased to grow.

Leigh syndrome (also called Leigh disease and subacute necrotizing encephalomyelopathy) is an under-recognized inherited neurometabolic disorder that affects the central nervous system. It is named after Archibald Denis Leigh, a British neuropsychiatrist who first described the condition in 1951.

Symptoms typically begin in childhood and are progressive, often resulting in death by early adulthood. Symptoms of PKAN begin before middle childhood, and most often are noticed before ten years of age. Symptoms include:

- dystonia (repetitive uncontrollable muscle contractions that may cause jerking or twisting of certain muscle groups)

- dysphagia & dysarthria due to muscle groups involved in speech being involved

- rigidity/stiffness of limbs

- tremor

- writhing movements

- dementia

- spasticity

- weakness

- seizures (rare)

- toe walking

- retinitis pigmentosa, another degenerative disease that affects the individual’s retina, often causing alteration of retinal color and progressive deterioration of the retina at first causing night blindness and later resulting in a complete loss of vision.

25% of individuals experience an uncharacteristic form of PKAN that develops post-10 years of age and follows a slower, more gradual pace of deterioration than those pre-10 years of age. These individuals face significant speech deficits as well as psychiatric and behavioral disturbances.

Being a progressive, degenerative nerve illness, PKAN leads to early immobility and often death by early adulthood. Death occurs prematurely due to infections such as pneumonia, and the disease in itself is technically not life limiting.

Triploid syndrome, also called triploidy, is an extremely rare chromosomal disorder, in which a fetus has three copies of every chromosome instead of the normal two. If this occurs in only some cells, it is called mosaic triploidy, and is less severe.

Pantothenate kinase-associated neurodegeneration (PKAN), also known as neurodegeneration with brain iron accumulation 1 (NBIA1), also called Hallervorden–Spatz syndrome, is a degenerative disease of the brain that can lead to parkinsonism, dystonia, dementia, and ultimately death. Neurodegeneration in PKAN is accompanied by an excess of iron that progressively builds up in the brain.

As the grinding components cause metal flakes to shed from the system, the implant wears down. Metallosis results in numerous additional side effects:

- Confusion;

- Feelings of malaise;

- Gastrointestinal problems;

- Emotional disturbance;

- Recurring infections;

- Dizziness;

- Headaches;

- Problems in the nervous system (feelings of burning, tingling, or numbness of the extremities); and

- Cobalt poisoning (skin rashes, cardiomyopathy, problems with hearing, sight or cognition, tremors, and hypothyroidism).

Neurocutaneous melanosis is associated with the presence of either giant congenital melanocytic nevi or non-giant nevi of the skin. It is estimated that neurocutaneous melanosis is present in 2% to 45% of patients with giant congenital melanocytic nevi. Patients with non-giant congenital melanocytic nevi seem to have a much lower, but undefined risk. Of these patients, only a small number are symptomatic, usually displaying symptoms before the age of 2.

These symptoms are the result of melanocytic lesions being present in the leptomeninges of the central nervous system.

Symptoms can include:

- Papilledema

- Cranial palsies

- Headache

- Vomiting

- Seizures

Others symptoms may also exist that are related to an increase in intracranial pressure. These symptoms seem to be present regardless of the malignancy of the melanin deposits within the central nervous system.

Approximately 10% of patient with neurocutaneous melanosis also present the Dandy–Walker syndrome and associated Dandy-Walker malformation. This malformation involves an enlargement of the posterior fossae and fourth ventricle along with agenesis of the cerebellar vermis. The abnormalities of the leptomeninges during fetal development due to neurocutaneous melanosis may be the cause of this increased incidence of the Dandy-Walker malformation. The development of hydrocephalus is the most common symptom associated with a combination of neurocutaneous melanosis and a Dandy-Walker malformation, occurring in about two out of three patients.