The initial description of AGS suggested that the disease was always severe, and was associated with unremitting neurological decline, resulting in death in childhood. As more cases have been identified, it has become apparent that this is not necessarily the case, with many patients now considered to demonstrate an apparently stable clinical picture, alive in their 4th decade. Moreover, rare individuals with pathogenic mutations in the AGS-related genes can be minimally affected (perhaps only with chilblains) and are in mainstream education, and even affected siblings within a family can show marked differences in severity.

In about ten percent of cases, AGS presents at or soon after birth (i.e. in the neonatal period). This presentation of the disease is characterized by microcephaly, neonatal seizures, poor feeding, jitteriness, cerebral calcifications (accumulation of calcium deposits in the brain), white matter abnormalities, and cerebral atrophy; thus indicating that the disease process became active before birth i.e. "in utero". These infants can have hepatosplenomegaly and thrombocytopaenia, very much like cases of transplacental viral infection. About one third of such early presenting cases, most frequently in association with mutations in "TREX1", die in early childhood.

Otherwise the majority of AGS cases present in early infancy, sometimes after an apparently normal period of development. During the first few months after birth, these children develop features of an encephalopathy with irritability, persistent crying, feeding difficulties, an intermittent fever (without obvious infection), and abnormal neurology with disturbed tone, dystonia, an exaggerated startle response, and sometimes seizures.

Glaucoma can be present at birth, or develop later. Many children retain apparently normal vision, although a significant number are cortically blind. Hearing is almost invariably normal. Over time, up to 40% of patients develop so-called chilblain lesions, most typically on the toes and fingers and occasionally also involving the ears. They are usually worse in the winter.

It typically presents as a severe encephalopathy with myoclonic seizures, is rapidly progressive and eventually results in respiratory arrest.Standard evaluation for inborn errors of metabolism and other causes of this presentation does not reveal any abnormality (no acidosis, no hypoglycaemia, or hyperammonaemia and no other organ affected). Pronounced and sustained hiccups in an encephalopathic infant have been described as a typical observation in non-ketotic hyperglycinaemia.

The most common symptoms are intellectual disability and recurrent seizures developing in infancy or early childhood. Typically the seizures are resistant to treatment with anti-epileptic drugs. Other symptoms may include:

- Microcephaly

- Lymphedema

- Facial abnormalities

- Immune deficiencies

- Abnormalities of retina

- Slow growth

- Short stature

Aicardi–Goutières syndrome (AGS), which is completely distinct from the similarly named Aicardi syndrome, is a rare, usually early onset childhood, inflammatory disorder most typically affecting the brain and the skin (neurodevelopmental disorder). The majority of affected individuals experience significant intellectual and physical problems, although this is not always the case. The clinical features of AGS can mimic those of "in utero" acquired infection, and some characteristics of the condition also overlap with the autoimmune disease systemic lupus erythematosus (SLE). Following an original description of eight cases in 1984, the condition was first referred to as 'Aicardi–Goutières syndrome' (AGS) in 1992, and the first international meeting on AGS was held in Pavia, Italy, in 2001.

AGS can occur due to mutations in any one of a number of different genes, of which seven have been identified to date, namely: TREX1, RNASEH2A, RNASEH2B, RNASEH2C (which together encode the Ribonuclease H2 enzyme complex), SAMHD1, ADAR1, and IFIH1 (coding for MDA5). This neurological disease occurs in all populations worldwide, although it is almost certainly under-diagnosed. To date (2014) at least 400 cases of AGS are known.

There are several different forms of glycine encephalopathy, which can be distinguished by the age of onset, as well as the types and severity of symptoms. All forms of glycine encephalopathy present with only neurological symptoms, including mental retardation (IQ scores below 20 are common), hypotonia, apneic seizures, and brain malformations.

With the classical, or neonatal presentation of glycine encephalopathy, the infant is born after an unremarkable pregnancy, but presents with lethargy, hypotonia, apneic seizures and myoclonic jerks, which can progress to apnea requiring artificial ventilation, and often death. Apneic patients can regain spontaneous respiration in their second to third week of life. After recovery from the initial episode, patients have intractable seizures and profound mental retardation, remaining developmentally delayed. Some mothers comment retrospectively that they noticed fetal rhythmic "hiccuping" episodes during pregnancy, most likely reflecting seizure episodes in utero. Patients with the infantile form of glycine encephalopathy do not show lethargy and coma in the neonatal period, but often have a history of hypotonia. They often have seizures, which can range in severity and responsiveness to treatment, and they are typically developmentally delayed. Glycine encephalopathy can also present as a milder form with episodic seizures, ataxia, movement disorders, and gaze palsy during febrile illness. These patients are also developmentally delayed, to varying degrees. In the later onset form, patients typically have normal intellectual function, but present with spastic diplegia and optic atrophy.

Transient neonatal hyperglycinemia has been described in a very small number of cases. Initially, these patients present with the same symptoms and laboratory results that are seen in the classical presentation. However, levels of glycine in plasma and cerebrospinal fluid typically normalize within eight weeks, and in five of six cases there were no neurological issues detected at follow-up times up to thirteen years. A single patient was severely retarded at nine months. The suspected cause of transient neonatal hyperglicinemia is attributed to low activity of the glycine cleavage system in the immature brain and liver of the neonate.

Males show more serious symptoms than females affected by this disorder.

The symptoms for males are:

1. Profound sensorineural hearing loss i.e, a complete or almost complete loss of hearing caused by abnormalities in the inner ear.

2. Weak muscle tone - Hypotonia.

3. Impaired muscle coordination - Ataxia.

4. Developmental delay.

5. Intellecual disability.

6. Vision loss caused by optic nerve atrophy in early childhood.

7. Peripheral neuropathy.

8. Recurrent infections, especially in the respiratory system.

9. Muscle weakness caused by recurrent infections.

Symptoms for females:

Very rarely seen hearing loss that begins in adulthood (age > 20 years) combined with ataxia and neuropathy. Optic atrophy and retinitis pigmentosa observed in some cases too.

Symptoms for Alström syndrome generally appear during infancy with great variability in age. Some of the symptoms include:

- Heart failure (Dilated cardiomyopathy) in over 60% of cases, usually within the first few weeks after birth, but sometimes the onset is in adolescence or adulthood.

- Light sensitivity and vision problems (Cone-rod dystrophy) in all cases, usually within 15 months of birth and progressively worsening until about 20 years of age

- Delays in early, developmental milestones in 50% of cases, learning disabilities in about 30% of cases

- Obesity in 100% of cases, apparent by 5 years of age, but often apparent in infancy (Alström infants usually have normal birth weights, and by adolescence, weights tend to be in the high-normal to normal range)

- Nystagmus (usually affects the children) one of the first symptoms to occur which causes involuntary rapid eye movement.

- Heart failure (Dilated cardiomyopathy) in over 60% of cases, usually within the first few weeks after birth, but sometimes the onset is in adolescence or adulthood.(chronic)

- Mild to moderate bilateral sensorineural hearing loss.

- Type 2 diabetes usually occurs in early childhood.

- Hyperinsulinemia/ insulin resistance—development of high level of insulin in blood.

- Steatosis (fatty liver) and elevated transaminases (liver enzymes) often develop in childhood and can progress in some patients to cirrhosis and liver failure.

- Endocrine dysfunctions may occur where the patient may experience an under or over active thyroid gland, weak growth hormone, increased androgen in females, and low testosterone in males.

- Slowly progressive kidney failure can occur in the second to fourth decade of life.

Arts syndrome is a rare metabolic disorder that causes serious neurological problems in males due to a malfunction of the PRPP synthetase 1 enzyme. Arts Syndrome is part of a spectrum of PRPS-1 related disorders with reduced activity of the enzyme that includes Charcot–Marie–Tooth disease and X-linked non-syndromic sensorineural deafness.

Neurologic signs and symptoms include progressively delayed development, weak muscle tone (hypotonia), seizures, and abnormal movements. The body's network of blood vessels is also affected. Children with this disorder may experience rashes of tiny red spots (petechiae) caused by bleeding under the skin and blue discoloration in the hands and feet due to reduced oxygen in the blood (acrocyanosis). Chronic diarrhea is another common feature of ethylmalonic encephalopathy. EE is often identified by urine organic acid analysis, the excretion of ethylmalonic acid, methylsuccinic acid, isobutyrylglycine and isovalerylglucine. Patients will also often have elevated thiosulphate concentration in their urine.

The signs and symptoms of ethylmalonic encephalopathy are apparent at birth or begin in the first few months of life. Problems with the nervous system typically worsen over time, and most affected individuals survive only into early childhood. A few children with a milder, chronic form of this disorder have been reported, and there can be considerable phenotypic variation, even within families. The life expectancy of individuals with EE is less than ten years.

Like other mitochrondrial diseases, "MNGIE is a multisystem disorder". MNGIE primarily affects the gastrointestinal and neurological systems. Gastrointestinal symptoms may include gastrointestinal dysmotility, due to inefficient peristalsis, which may result in pseudo-obstruction and cause malabsorption of nutrients. Additionally, gastrointestinal symptoms such as borborygmi, early satiety, diarrhea, constipation, gastroparesis, nausea, vomiting, weight loss, and diverticulitis may be present in MNGIE patients. Neurological symptoms may include diffuse leukoencephalopathy, peripheral neuropathy, and myopathy. Ocular symptoms may include retinal degeneration, ophthalmoplegia, and ptosis. Those with MNGIE are often thin and experience continuous weight loss. The characteristic thinness of MNGIE patients is caused by multiple factors including inadequate caloric intake due to gastrointestinal symptoms and discomfort, malabsorption of food from bacterial overgrowth due to decreased motility, as well as an increased metabolic demand due to inefficient production of ATP by the mitochondria.

Infants with this disorder appear normal at birth but usually develop signs and symptoms during the first year of life or in early childhood. The characteristic features of this condition, which can range from mild to life-threatening, include feeding difficulties, recurrent episodes of vomiting and diarrhea, excessive tiredness (lethargy), and weak muscle tone (hypotonia). If untreated, this disorder can lead to delayed development, seizures, and coma. Early detection and lifelong management (following a low-protein diet and using appropriate supplements) may prevent many of these complications. In some cases, people with gene mutations that cause 3-methylcrotonyl-CoA carboxylase deficiency never experience any signs or symptoms of the disorder.

The characteristic features of this condition are similar to those of Reye syndrome, a severe disorder that develops in children while they appear to be recovering from viral infections such as chicken pox or flu. Most cases of Reye syndrome are associated with the use of aspirin during these viral infections.

Ring chromosome 14 syndrome is a very rare human chromosome abnormality. It occurs when one or both of the telomeres that mark the ends of chromosome 14 are lost allowing the now uncapped ends to fuse together forming a ring chromosome. It causes a number of serious health issues.

Alström syndrome, also called Alstrom-Halgren syndrome, is a rare genetic disorder caused by mutations in the gene ALMS1. It is among the rarest genetic disorders in the world, as currently it has only 266 reported cases in medical literature and over 501 known cases in 47 countries. It was first described by Carl-Henry Alström in Sweden in 1959. Alstrom syndrome is sometimes confused with Bardet-Biedl syndrome, which has similar symptoms. Bardet-Biedl syndrome tends to have later onset in its symptoms. The likelihood of two carrier parents both passing the gene and therefore having a child affected by the syndrome is 25% with each pregnancy. The likelihood of having a child who is only a carrier of the gene is 50% with each pregnancy. The likelihood of a child receiving normal genes from both parents and being considered to be "genetically" normal is 25%. The risk for carrying the gene is equivalent for both males and females.

"Alström syndrome (AS) is a rare autosomal recessive disease characterized by multiorgan dysfunction. The key features are childhood obesity, blindness due to congenital retinal dystrophy, and sensorineural hearing loss. Associated endocrinologic features include hyperinsulinemia, early-onset type 2 diabetes, and hypertriglyceridemia."

Thus, AS shares several features with the common metabolic syndrome, namely obesity, hyperinsulinemia, and hypertriglyceridemia. Mutations in the ALMS1 gene have been found to be causative for AS with a total of 79 disease-causing mutations having been described." Prevalence estimates have ranged from 1 in 10,000 to fewer than 1 in 1,000,000 individuals in the general population.

Mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE) is a rare autosomal recessive mitochondrial disease. It has been previously referred to as polyneuropathy, ophthalmoplegia, leukoencephalopathy, and POLIP syndrome. The disease presents in childhood, but often goes unnoticed for decades. Unlike typical mitochondrial diseases caused by mitochondrial DNA (mtDNA) mutations, MNGIE is caused by mutations in the TYMP gene, which encodes the enzyme thymidine phosphorylase. Mutations in this gene result in impaired mitochondrial function, leading to intestinal symptoms as well as neuro-ophthalmologic abnormalities. "A secondary form of MNGIE, called MNGIE without leukoencephalopathy, can be caused by mutations in the POLG gene".

Ethylmalonic encephalopathy (EE) is a rare autosomal recessive inborn error of metabolism. Patients affected with EE are typically identified shortly after birth, with symptoms including diarrhea, petechiae and seizures. The genetic defect in EE is thought to involve an impairment in the degradation of sulfide intermediates in the body. Hydrogen sulfide then builds up to toxic levels. EE was initially described in 1994. Most cases of EE have been described in individuals of Mediterranean or Arabic origin.

Neonatal encephalopathy (NE), also known as neonatal hypoxic-ischemic encephalopathy (neonatal HIE or NHIE), is defined by signs and symptoms of abnormal neurological function in the first few days of life in an infant born at term. In this condition there is difficulty initiating and maintaining respirations, a subnormal level of consciousness, and associated depression of tone, reflexes, and possibly seizures. Encephalopathy is a nonspecific response of the brain to injury which may occur via multiple methods, but is commonly caused by birth asphyxia.

The onset of symptoms tends to be fairly gradual and to occur over 1–7 days.

Symptoms of Hashimoto's encephalopathy may include:

- personality changes

- aggression

- delusional behavior

- concentration and memory problems

- coma

- disorientation

- headaches

- jerks in the muscles (myoclonus – 65% cases)

- lack of coordination (ataxia – 65% cases)

- partial paralysis on the right side

- psychosis

- seizures (60% cases)

- sleep abnormalities (55% cases)

- speech problems (transient aphasia – 80% cases)

- status epilepticus (20% cases)

- tremors (80% cases)

In neonates born at or beyond 35 weeks, neonatal encephalopathy may present itself as the following symptoms:

- Reduced level of consciousness

- Seizures (which peak at 48 hours)

- Difficulty initiating and maintaining respiration

- Depression of tone and reflexes

Typical symptoms of PRES, listed according to prevalence, include: altered mental status (encephalopathy), seizure, and headache. Less commonly there may be visual disturbances, focal neurologic signs, and status epilepticus.

3-Methylcrotonyl-CoA carboxylase deficiency (3MCC deficiency), also known as 3-Methylcrotonylglycinuria or BMCC deficiency is an inherited disorder in which the body is unable to process certain proteins properly. People with this disorder have inadequate levels of an enzyme that helps break down proteins containing the amino acid leucine. This condition affects an estimated 1 in 50,000 individuals worldwide.

Clinically, TRIANGLE disease is characterized combined immunodeficiency, severe autoimmunity, and developmental delay. Patients typically present in early childhood with recurrent bacterial and viral infections of the middle ear and respiratory tract. Additionally, patients develop severe, difficult to treat autoimmunity. This autoimmunity includes auto-antibody mediated destruction of red blood cells, neutrophils, and platelets; central nervous system lupus erythematous with stroke; and hepatitis. Patients also have mild to moderate developmental delay.

Reversible cerebral vasoconstriction syndrome (RCVS, sometimes called Call-Fleming syndrome) is a disease characterized by a weeks-long course of thunderclap headaches, sometimes focal neurologic signs, and occasionally seizures. Symptoms are thought to arise from transient abnormalities in the blood vessels of the brain. In some cases, it may be associated with childbirth, vasoactive or illicit drug use, or complications of pregnancy.

For the vast majority of patients, all symptoms disappear on their own within three weeks. Deficits persist in a small minority of patients, with severe complications or death being very rare. Because symptoms resemble a variety of life-threatening conditions, differential diagnosis is necessary.

TRIANGLE disease is a rare genetic disorder of the immune system. TRIANGLE stands for “TPPII-related immunodeficiency, autoimmunity, and neurodevelopmental delay with impaired glycolysis and lysosomal expansion” where "TPP2" is the causative gene. This disease manifests as recurrent infection, autoimmunity, and neurodevelopmental delay. TRIANGLE disease was first described in a collaborative study by Dr. Helen C. Su from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, and Dr. Sophie Hambleton from the University of Newcastle and their collaborators in 2014. The disease was also described by the group of Ehl et al.

A relapsing encephalopathy occurring in association with Hashimoto's thyroiditis, with high titers of anti-thyroid antibodies. Clinically, the condition may present one or more symptoms.

Onset is often gradual and may go unnoticed by the patient and close associates to the patients.

Symptoms sometimes resolve themselves within days to weeks, leaving a patient undiagnosed. For many other patients, the condition may result in ongoing problems with a variety of manifestations, often confusing clinicians due to the diffuse nature of symptoms.

The key symptom of RCVS is recurrent thunderclap headaches, which over 95% of patients experience. In two-thirds of cases, it is the only symptom. These headaches are typically bilateral, very severe and peak in intensity within a minute. They may last from minutes to days, and may be accompanied by nausea, photophobia, phonophobia or vomiting. Some patients experience only one headache, but on average there are four attacks over a period of one to four weeks. A milder, residual headache persists between severe attacks for half of patients.

1–17% of patients experience seizures. 8–43% of patients show neurologic problems, especially visual disturbances, but also hemiplegia, ataxia, dysarthria, aphasia, and numbness. These neurologic issues typically disappear within minutes or a few hours; more persistent symptoms may indicate a stroke. Posterior reversible encephalopathy syndrome is present in a small minority of patients.

This condition features the unique property that the patient's cerebral arteries can spontaneously constrict and relax back and forth over a period of time without intervention and without clinical findings. Vasospasm is common post subarachnoid hemorrhage and cerebral aneurysm, but in RCVS only 25% of patients have symptoms post subarachnoid hemorrhage.