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.

Glycine encephalopathy (also known as non-ketotic hyperglycinemia or NKH) is a rare autosomal recessive disorder of glycine metabolism. After phenylketonuria, glycine encephalopathy is the second most common disorder of amino acid metabolism. The disease is caused by defects in the glycine cleavage system, an enzyme responsible for glycine catabolism. There are several forms of the disease, with varying severity of symptoms and time of onset. The symptoms are exclusively neurological in nature, and clinically this disorder is characterized by abnormally high levels of the amino acid glycine in bodily fluids and tissues, especially the cerebral spinal fluid.

Glycine encephalopathy is sometimes referred to as "nonketotic hyperglycinemia" (NKH), as a reference to the biochemical findings seen in patients with the disorder, and to distinguish it from the disorders that cause "ketotic hyperglycinemia" (seen in propionic acidemia and several other inherited metabolic disorders). To avoid confusion, the term "glycine encephalopathy" is often used, as this term more accurately describes the clinical symptoms of the disorder.

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.

Depending on the affected gene(s), this disorder may present symptoms that range from mild to life-threatening.

- Stroke

- Progressive encephalopathy

- Seizure

- Kidney failure

- Vomiting

- Dehydration

- Failure to thrive and developmental delays

- Lethargy

- Repeated Yeast infections

- Acidosis

- Hepatomegaly

- Hypotonia

- Pancreatitis

- Respiratory distress

The hallmark of encephalopathy is an altered mental state. Characteristic of the altered mental state is impairment of the cognition, attention, orientation, sleep–wake cycle and consciousness. An altered state of consciousness may range from failure of selective attention to drowsiness. Hypervigilance may be present; with or without: congnitive deficits, headache, epileptic seizures, myoclonus (involuntary twitching of a muscle or group of muscles) or asterixis ("flapping tremor" of the hand when wrist is extended).

Depending on the type and severity of encephalopathy, common neurological symptoms are loss of cognitive function, subtle personality changes, inability to concentrate. Other neurological signs may include dysarthria, hypomimia, problems with movements (they can be clumsy or slow), ataxia, tremor. Another neurological signs may include involuntary grasping and sucking motions, nystagmus (rapid, involuntary eye movement), jactitation (restless picking at things characteristic of severe infection), and respiratory abnormalities such as Cheyne-Stokes respiration (cyclic waxing and waning of tidal volume), apneustic respirations and post-hypercapnic apnea. Focal neurological deficits are less common.

Encephalopathies exhibits both neurologic and psychopathologic symptoms.

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.

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

Methylmalonic acidemia (MMA), also called methylmalonic aciduria, is an autosomal recessive metabolic disorder. It is a classical type of organic acidemia. The result of this condition is the inability to properly digest specific fats and proteins, which in turn leads to a buildup of a toxic level of methylmalonic acid in the blood.

Methylmalonic acidemia stems from several genotypes, all forms of the disorder usually diagnosed in the early neonatal period, presenting progressive encephalopathy, and secondary hyperammonemia. The disorder can result in death if undiagnosed or left untreated. It is estimated that this disorder has a frequency of 1 in 48,000 births, though the high mortality rate in diagnosed cases make exact determination difficult. Methylmalonic acidemias are found with an equal frequency across ethnic boundaries.

Wernicke encephalopathy (alcoholic encephalopathy) also develop Korsakoff's syndrome, characterized by amnestic-confabulatory syndrome: retrograde amnesia, anterograde amnesia, confabulations (invented memories), poor recall and disorientation.

Anti-NMDA receptor encephalitis is the most common autoimmune encephalitis. It can cause paranoid and grandiose delusions, agitation, hallucinations (visual and auditory), bizarre behavior, fear, short-term memory loss, confusion.

HIV encephalopathy develop dementia ( †).

The classic triad of symptoms found in Wernicke's encephalopathy is:

- ophthalmoplegia (later expanded to other eye movement abnormalities, most commonly affecting the lateral rectus or any eye sign. Lateral nystagmus is most commonly seen although lateral rectus palsy, usually bilateral, may be seen).

- ataxia (later expanded to imbalance or any cerebellar signs)

- confusion (later expanded to other mental changes. Has 82% incidence in diagnosis cases)

However, in actuality, only a small percentage of patients experience all three symptoms, and the full triad occurs more frequently among those who have overused alcohol.

Also a much more diverse range of symptoms has been found in patients with this condition, including:

- pupillary changes, retinal hemorrhage, papilledema, impaired vision and hearing, vision loss

- hearing loss,

- fatigability, apathy, irritability, drowsiness, psycho and/or motor slowing

- dysphagia, blush, sleep apnea, epilepsy and stupor

- lactic acidosis

- memory impairment, amnesia, depression, psychosis

- hypothermia, polyneuropathy, hyperhidrosis.

Although hypothermia is usually diagnosed with a body temperature of 35 °C / 95° Fahrenheit, or less, incipient cooling caused by deregulation in the CNS needs to be monitored because it can promote the development of an infection. The patient may report feeling cold, followed by mild chills, cold skin, moderate pallor, tachycardia, hypertension, tremor or piloerection. External warming techniques are advised to prevent hypothermia.

Among the frequently altered functions are the cardio circulatory. There may be tachycardia, dyspnea, chest pain, orthostatic hypotension, changes in heart rate and blood pressure. The lack of thiamine sometimes affects other major energy consumers, the myocardium, and also patients may have developed cardiomegaly. Heart failure with lactic acidosis syndrome has been observed. Cardiac abnormalities are an aspect of the WE, which was not included in the traditional approach, and are not classified as a separate disease.

Infections have been pointed out as one of the most frequent triggers of death in WE. Furthermore, infections are usually present in pediatric cases.

In the last stage others symptoms may occur: hyperthermia, increased muscle tone, spastic paralysis, choreic dyskinesias and coma.

Because of the frequent involvement of heart, eyes and peripheral nervous system, several authors prefer to call it Wernicke disease rather than simply encephalopathy.

Early symptoms are nonspecific, and it has been stated that WE may present nonspecific findings. In Wernicke Korsakoff’s syndrome some single symptoms are present in about one-third.

The mildest form of hepatic encephalopathy is difficult to detect clinically, but may be demonstrated on neuropsychological testing. It is experienced as forgetfulness, mild confusion, and irritability. The first stage of hepatic encephalopathy is characterised by an inverted sleep-wake pattern (sleeping by day, being awake at night). The second stage is marked by lethargy and personality changes. The third stage is marked by worsened confusion. The fourth stage is marked by a progression to coma.

More severe forms of hepatic encephalopathy lead to a worsening level of consciousness, from lethargy to somnolence and eventually coma. In the intermediate stages, a characteristic jerking movement of the limbs is observed (asterixis, "liver flap" due to its flapping character); this disappears as the somnolence worsens. There is disorientation and amnesia, and uninhibited behaviour may occur. In the third stage, neurological examination may reveal clonus and positive Babinski sign. Coma and seizures represent the most advanced stage; cerebral oedema (swelling of the brain tissue) leads to death.

Encephalopathy often occurs together with other symptoms and signs of liver failure. These may include jaundice (yellow discolouration of the skin and the whites of the eyes), ascites (fluid accumulation in the abdominal cavity), and peripheral edema (swelling of the legs due to fluid build-up in the skin). The tendon reflexes may be exaggerated, and the plantar reflex may be abnormal, namely extending rather than flexing (Babinski's sign) in severe encephalopathy. A particular smell ("foetor hepaticus") may be detected.

Depending on the location of the brain lesion different symptoms are more frequent:

- Brainstem tegmentum. - Ocular: pupillary changes. Extraocular muscle palsy; gaze palsy: nystagmus.

- Hypothalamus. Medulla: dorsal nuc. of vagus. - Autonomic dysfunct.: temperature; cardiocirculatory; respiratory.

- Medulla: vestibular region. Cerebellum. - Ataxia.

- Dorsomedial nuc. of thalamus. Mammillary bodies. - Amnestic syndrome for recent memory.

Mamillary lesion are characteristic-small petechial hemorrhages are found.

- Diffuse cerebral dysfunction.- Altered cognition: global confusional state.

- Brainstem: periaqueductal gray.- Reduction of consciousness

- Hypothalamic lesions may also affect the immune system, which is known in alcohol abusers, causing dysplasias and infections.

A characteristic feature of isovaleric acidemia is a distinctive odor of sweaty feet. This odor is caused by the buildup of a compound called isovaleric acid in affected individuals.

In about half of cases, the signs and symptoms of this disorder become apparent within a few days after birth and include poor feeding, vomiting, seizures, and lack of energy that can progress to coma. These medical problems are typically severe and can be life-threatening. In the other half of cases, the signs and symptoms of the disorder appear during childhood and may come and go over time. They are often triggered by an infection or by eating an increased amount of protein-rich foods.

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

Hyperammonemia (or hyperammonaemia) is a metabolic disturbance characterised by an excess of ammonia in the blood. It is a dangerous condition that may lead to brain injury and death. It may be primary or secondary.

Ammonia is a substance that contains nitrogen. It is a product of the catabolism of protein. It is converted to the less toxic substance urea prior to excretion in urine by the kidneys. The metabolic pathways that synthesize urea involve reactions that start in the mitochondria and then move into the cytosol. The process is known as the urea cycle, which comprises several enzymes acting in sequence.

Infants with LPI are usually symptom-free when breastfed because of the low protein concentration in human milk, but develop vomiting and diarrhea after weaning. The patients show failure to thrive, poor appetite, growth retardation, enlarged liver and spleen, prominent osteoporosis and osteopenia, delayed bone age and spontaneous protein aversion. Forced feeding of protein may lead to convulsions and coma. Mental development is normal if prolonged episode of hyperammonemia can be avoided. Some patients develop severe pulmonary and renal complications. High levels of plasma glutamine and glycine are observed.

The low incidence of this syndrome is often related to aldolase A's essential glycolytic role along with its exclusive expression in blood and skeletal muscle. Early developmental reliance and constitutive function prevents severe mutation in successful embryos. Infrequent documentation thus prevents clear generalisation of symptoms and causes. However five cases have been well described. ALDOA deficiency is diagnosed through reduced aldoA enzymatic activity, however, both physiological response and fundamental causes vary.

SBCADD is included as a secondary target condition in most newborn screening programs, as the key analyte is the same as is used to identify isovaleric acidemia. Most cases have been Hmong individuals, who are asymptomatic. There are isolated case reports where individuals have been identified with SBCADD in addition to developmental delay and epilepsy. It is currently unclear what the complete clinical presentation of SBCADD looks like. There is some concern that these cases with additional symptoms may reflect an ascertainment bias rather than being a true representation of the clinical spectrum of the disease. Currently, there is no accepted treatment, as most affected individuals do not require any. Some recommend avoidance of valproic acid, as it can be a substrate for 2-methylbutyryl-CoA dehydrogenase.

Northern Epilepsy Syndrome causes recurrent seizures between the ages of five to ten. These seizures, that may last up to 15 minutes, can be classified mostly as tonic-clonic, but partial seizures could also occur. The seizures commonly involve muscle rigidity, convulsions, and loss of consciousness. Generally, the recurrence is one to two times per month.

In the years following the onset of seizures, a noticeable decrease in intellectual capacity is observed.

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.

Hepatic encephalopathy (HE) is an altered level of consciousness as a result of liver failure. Onset may be gradual or sudden. Other symptoms may include movement problems, changes in mood, or changes in personality. In the advanced stages it can result in a coma.

Hepatic encephalopathy can occur in those with acute or chronic liver disease. Episodes can be triggered by infections, GI bleeding, constipation, electrolyte problems, or certain medications. The underlying mechanism is believed to involve the build up of ammonia in the blood, a substance that is normally removed by the liver. The diagnosis is typically made after ruling out other potential causes. It may be supported by blood ammonia levels, an electroencephalogram, or a CT scan of the brain.

Hepatic encephalopathy is possibly reversible with treatment. This typically involves supportive care and addressing the triggers of the event. Lactulose is frequently used to decrease ammonia levels. Certain antibiotics and probiotics are other potential options. A liver transplant may improve outcomes in those with severe disease.

More than 40% of people with cirrhosis develop hepatic encephalopathy. More than half of those with cirrhosis and significant HE live less than a year. In those who are able to get a liver transplant, the risk of death is less than 30% over the subsequent five years. The condition has been described since at least 1860.

During puberty, seizure frequency increases to one to two times per week. Mental function has a rapid decline, as observed by a lack of coordination, failure to complete education, and fine motor activities. In rare cases, some suffered from loss of vision.

Isovaleric acidemia is a rare autosomal recessive metabolic disorder which disrupts or prevents normal metabolism of the branched-chain amino acid leucine. It is a classical type of organic acidemia.

Symptoms of enolase deficiency include exercise-induced myalgia and generalized muscle weakness and fatigability, both with onset in adulthood. Symptoms also include muscle pain without cramps, and decreased ability to sustain long term exercise.

2-Methylbutyryl-CoA dehydrogenase deficiency, also called 2-Methylbutyryl glycinuria or short/branched-chain acyl-CoA dehydrogenase deficiency (SBCADD), is an autosomal recessive metabolic disorder. It causes the body to be unable to process the amino acid isoleucine properly. Initial case reports identified individuals with developmental delay and epilepsy, however most cases identified through newborn screening have been asymptomatic.