There is a deficiency of malate in patients because fumarase enzyme can't convert fumarate into it therefore treatment is with oral malic acid which will allow the krebs cycle to continue, and eventually make ATP.

The prognosis is very poor. Two studies reported typical age of deaths in infancy or early childhood, with the first reporting a median age of death of 2.6 for boys and less than 1 month for girls.

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.

Treatment centers on limiting intake of ammonia and increasing its excretion. Dietary protein, a metabolic source of ammonium, is restricted and caloric intake is provided by glucose and fat. Intravenous arginine (argininosuccinase deficiency) sodium phenylbutyrate and sodium benzoate (ornithine transcarbamoylase deficiency) are pharmacologic agents commonly used as adjunctive therapy to treat hyperammonemia in patients with urea cycle enzyme deficiencies. Sodium phenylbutyrate and sodium benzoate can serve as alternatives to urea for the excretion of waste nitrogen. Phenylbutyrate, which is the product of phenylacetate, conjugates with glutamine to form phenylacetylglutamine, which is excreted by the kidneys. Similarly, sodium benzoate reduces ammonia content in the blood by conjugating with glycine to form hippuric acid, which is rapidly excreted by the kidneys. A preparation containing sodium phenylacetate and sodium benzoate is available under the trade name Ammonul.

Acidification of the intestinal lumen using lactulose can decrease ammonia levels by protonating ammonia and trapping it in the stool. This is a treatment for hepatic encephalopathy.

Treatment of severe hyperammonemia (serum ammonia levels greater than 1000 μmol/L) should begin with hemodialysis if it is otherwise medically appropriate and tolerated.

Fumarase deficiency is extremely rare - until around 1990 there had only been 13 diagnosed and identified cases worldwide.

A cluster of 20 cases has since been documented in the twin towns of Colorado City, Arizona and Hildale, Utah among an inbred community of the Fundamentalist Church of Jesus Christ of Latter Day Saints.

While the disease manifests early in life in most cases, diagnosis of the disease is often quite delayed. The symptoms that affected patients present vary, but the most common presenting symptoms are gastrointestinal issues such as nausea, vomiting, abdominal pain, and diarrhea, and neurologic or ocular symptoms such as hearing loss, weakness, and peripheral neuropathy. These gastrointestinal symptoms cause patients with MNGIE to be very thin and experience persistent weight loss and this often leads to MNGIE being misdiagnosed as an eating disorder. These symptoms without presentation of disordered eating and warped body image warrant further investigation into the possibility of MNGIE as a diagnosis. Presentation of these symptoms and lack of disordered eating are not enough for a diagnosis. Radiologic studies showing hypoperistalsis, large atonic stomach, dilated duodenum, diverticula, and white matter changes are required to confirm the diagnosis. Elevated blood and urine nucleoside levels are also indicative of MNGIE syndrome. Abnormal nerve conduction as well as analysis of mitochondria from liver, intestines, muscle, and nerve tissue can also be used to support the diagnosis.

A successful treatment for MNGIE has yet to be found, however, symptomatic relief can be achieved using pharmacotherapy and celiac plexus neurolysis. Celiac plexus neurolysis involves interrupting neural transmission from various parts of the gastrointestinal tract. By blocking neural transmission, pain is relieved and gastrointestinal motility increases. Stem cell therapies are currently being investigated as a potential cure for certain patients with the disease, however, their success depends on physicians catching the disease early before too much organ damage has occurred.

The following list includes such examples:

- - hyperammonemia due to ornithine transcarbamylase deficiency

- - hyperinsulinism-hyperammonemia syndrome (glutamate dehydrogenase 1)

- - hyperornithinemia-hyperammonemia-homocitrullinuria

- - hyperammonemia due to N-acetylglutamate synthetase deficiency

- - hyperammonemia due to carbamoyl phosphate synthetase I deficiency (carbamoyl phosphate synthetase I)

- - hyperlysinuria with hyperammonemia (genetics unknown)

- Methylmalonic acidemia

- Isovaleric acidemia

- Propionic acidemia

- Carnitine palmitoyltransferase II deficiency

- Transient hyperammonemia of the newborn, specifically in the preterm

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.

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.

Prevention of EAH focuses on reducing fluid consumption to avoid fluid retention before, during, and after exercise.

Laboratory: normal metabolic and infective screening. An increase in the number of white cells (particularly lymphocytes) in the CSF, and high levels of interferon-alpha activity and neopterin in the CSF are important clues - however, these features are not always present. More recently, a persistent elevation of mRNA levels of interferon-stimulated gene transcripts have been recorded in the peripheral blood of almost all cases of AGS with mutations in "TREX1", "RNASEH2A", "RNASEH2C", "SAMHD1", "ADAR1" and "IFIH1", and in 75% of patients with mutations in "RNASEH2B". These results are irrespective of age. Thus, this interferon signature appears to be a very good marker of disease.

Genetics: pathogenic mutations in any of the seven genes known to be involved in AGS.

EAH is categorized by having a blood serum or plasma sodium level below normal, which is less than 135 mmol/l. Asymptomatic EAH is not normally detected unless the athlete has had a sodium blood serum or plasma test. Hyponatremic encephalopathy may be detect using brain imaging studies and pulmonary edema may be confirmed by x-ray.

Diagnosis of Wernicke's encephalopathy or disease is made clinically. Caine et al. in 1997 established criteria that Wernicke's encephalopathy can be diagnosed in any patient with just two or more of the main symptoms noted above. The sensitivity of the diagnosis by the classic triad was 23% but increased to 85% taking two or more of the four classic features. This criteria is challenged because all the cases he studied were alcoholics.

Some consider it sufficient to suspect the presence of the disease with only one of the principal symptoms. Some British hospital protocols suspect WE with any one of these symptoms: confusion, decreased consciousness level (or unconsciousness, stupor or coma), memory loss, ataxia or unsteadiness, ophthalmoplegia or nystagmus, and unexplained hypotension with hypothermia. The presence of only one sign should be sufficient for treatment.

As a much more diverse range of symptoms has been found frequently in patients it is necessary to search for new diagnostic criteria, however Wernicke's encephalopathy remains a clinically-diagnosed condition. Neither the MR, nor serum measurements related to thiamine are sufficient diagnostic markers in all cases. Non-recovery upon supplementation with thiamine is inconclusive.

The sensitivity of MR was 53% and the specificity was 93%. The reversible cytotoxic edema was considered the most characteristic lesion of WE. The location of the lesions were more frequently atypical among non-alcoholics, while typical contrast enhancement in the thalamus and the mammillary bodies was observed frequently associated with alcohol abuse. These abnormalities may include:

- Medial thalami, periaqueductal gray matter, mamillary bodies, and brainstem nuclei edema (Zuccoli G.). Involvement is always bilateral symmetrical. Value of DWI in the diagnosis of WE is minimal. Axial FLAIR MRI images represent the best diagnostic MRI sequence. Contrast material may highlight involvement of the mamillary bodies.

There appears to be very little value for CT scans.

Thiamine can be measured using an erythrocyte transketolase activity assay, or by activation by measurement of in vitro thiamine diphosphate levels. Normal thiamine levels do not necessarily rule out the presence of WE, as this may be a patient with difficulties in intracellular transport.

At the moment there are no therapies specifically targeting the underlying cause of AGS. Current treatments address the symptoms, which can be varied both in scope and severity. Many patients benefit from tube-feeding. Drugs can be administered to help with seizures / epilepsy. The treatment of chilblains remains problematic, but particularly involves keeping the feet / hands warm. Physical therapy, including the use of splints can help to prevent contractures and surgery is sometimes required. Botox (botulinium toxin) has sometimes caused severe immune reactions in some AGS patients, and the high risk of possible further brain damage must be considered before giving Botox. Occupational therapy can help with development, and the use of technology (e.g. Assistive Communication Devices) can facilitate communication. Patients should be regularly screened for treatable conditions, most particularly glaucoma and endocrine problems (especially hypothyroidism). The risk versus benefit of giving immunizations also must be considered, as some AGS patients have high immune responses or flares that cause further brain damage from immunizations but other patients have no problems with immunizations; on the other hand, AGS patients have died from illnesses that can be immunized against, so the family must consider the risk vs. benefit of each immunization vs. risk of the actual virus if they choose not to immunize. As of 2017, there are current drug trials being conducted that may lead to drug treatments for AGS.

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".

There are hospital protocols for prevention, supplementing with thiamine in the presence of: history of alcohol misuse or related seizures, requirement for IV glucose, signs of malnutrition, poor diet, recent diarrhea or vomiting, peripheral neuropathy, intercurrent illness, delirium tremens or treatment for DTs, and others. Some experts advise parenteral thiamine should be given to all at-risk patients in the emergency room.

In the clinical diagnosis should be remembered that early symptoms are nonspecific, and it has been stated that WE may present nonspecific findings. There is consensus to provide water-soluble vitamins and minerals after gastric operations.

In some countries certain foods have been supplemented with thiamine, and have reduced WE cases. Improvement is difficult to quantify because they applied several different actions. Avoiding alcohol and having adequate nutrition reduces one of the main risk factors in developing Wernicke-Korsakoff syndrome.

Cord blood gas analysis can be used to determine if there is perinatal hypoxia/asphyxia, which are potential causes of hypoxic-ischemic encephalopathy or cerebral palsy, and give insight into causes of intrapartum fetal distress. Cord blood gas analysis is indicated for high-risk pregnancies, in cases where C-sections occurred due to fetal compromise, if there were abnormal fetal heart rate patterns, Apgar scores of 3 or lower, intrapartum fever, or multifetal gestation.

Evidence of brain injury related to the hypoxic-ischemic events that cause neonatal encephalopathy can be seen with brain MRIs, CTs, magnetic resonance spectroscopy imaging or ultrasounds.

Neonatal encephalopathy may be assessed using Sarnat staging.

Blood tests, cerebrospinal fluid examination by lumbar puncture (also known as spinal tap), brain imaging studies, electroencephalography (EEG), and similar diagnostic studies may be used to differentiate the various causes of encephalopathy.

Diagnosis is frequently clinical. That is, no set of tests give the diagnosis, but the entire presentation of the illness with nonspecific test results informs the experienced clinician of the diagnosis.

Rapid diagnosis is important to attempt to prevent further damage to the brain and further neurologic deficits. It is a diagnosis of exclusion, so a full work up for other possible etiologies (hepatic, uremic, infectious, oncologic) should be performed. Screening for heavy metals, as well as other toxins, should be done immediately as those are some of the most common causes and the patient can then remove themselves from the dangerous environment. In addition, a full examination of blood (CBC) and metabolites (CMP) should be done.

Stimmler syndrome is an autosomal recessive genetic disorder whose symptoms appear before birth or during infancy. In a study of two sisters born within a year of each other, both with Stimmler syndrome, it was found that high levels of alanine, pyruvate, and lactate were present in both the blood and urine. It was believed that the alanine was derived from the pyruvate.

Symptoms for the disease include microcephaly, a low birth weight, dwarfism, small teeth, and diabetes. The symptoms of Stimmler syndrome are closely related to a disease studied by Haworth et al. in 1967 as well as Leigh subacute necrotizing encephalopathy with lactic acidosis

A mutation in the ZNHIT3 gene - a nuclear zinc finger protein involved in transcriptional regulation and in small nucleolar ribonucleoprotein particle assembly has been shown to be the cause of the Finnish-type of PEHO syndrome. However, the syndrome appear to be genetically heterogeneous and it might reflect an underlying genetic tubulinopathy, with biallelic mutations in the gene PRUNE1 also identified in non-Finnish patients with PEHO syndrome.

The diagnosis of hepatic encephalopathy can only be made in the presence of confirmed liver disease (types A and C) or a portosystemic shunt (type B), as its symptoms are similar to those encountered in other encephalopathies. To make the distinction, abnormal liver function tests and/or ultrasound suggesting liver disease are required, and ideally liver biopsy. The symptoms of hepatic encephalopathy may also arise from other conditions, such as cerebral haemorrhage and seizures (both of which are more common in chronic liver disease). A CT scan of the brain may be required to exclude haemorrhage, and if seizure activity is suspected an electroencephalograph (EEG) study may be performed. Rarer mimics of encephalopathy are meningitis, encephalitis, Wernicke's encephalopathy and Wilson's disease; these may be suspected on clinical grounds and confirmed with investigations.

The diagnosis of hepatic encephalopathy is a clinical one, once other causes for confusion or coma have been excluded; no test fully diagnoses or excludes it. Serum ammonia levels are elevated in 90% of people, but not all hyperammonaemia (high ammonia levels) is associated with encephalopathy. A CT scan of the brain usually shows no abnormality except in stage IV encephalopathy, when cerebral oedema may be visible. Other neuroimaging modalities, such as magnetic resonance imaging (MRI), are not currently regarded as useful, although they may show abnormalities. Electroencephalography shows no clear abnormalities in stage 0, even if minimal HE is present; in stages I, II and III there are triphasic waves over the frontal lobes that oscillate at 5 Hz, and in stage IV there is slow delta wave activity. However, the changes in EEG are not typical enough to be useful in distinguishing hepatic encephalopathy from other conditions.

Once the diagnosis of encephalopathy has been made, efforts are made to exclude underlying causes (such as listed above in "causes"). This requires blood tests (urea and electrolytes, full blood count, liver function tests), usually a chest X-ray, and urinalysis. If there is ascites, diagnostic paracentesis (removal of a fluid sample with a needle) may be required to identify spontaneous bacterial peritonitis (SBP).

The treatment of PRES dependent on its cause. Anti-epileptic medication may also be appropriate.

The diagnosis is typically made clinically with magnetic resonance imaging of the brain often revealing hyperintensities on "T"-weighed imaging. Three patterns have been described: superior frontal sulcus, dominant parieto-occipital, and holohemispheric watershed.