The age of onset is almost always before 3 months of age. Many infants are born preterm (1/3 cases) and dysmature. The babies are frequently small for dates. The placenta may be abnormal with non-specific inflammation on histology. Umbilical cord anomalies have occasionally been reported. In severe cases, signs in the brain may be detected on prenatal ultrasound.

The presentation is pleiomorphic, making the diagnosis difficult, but the most common features of this disease involve the skin, joints, and central nervous system.

All have a maculopapular urticarial skin rash that is often present at birth (75% cases). It is probably more correctly described as an urticarial-like rash. The presence of the rash varies with time, and biopsy of these skin lesions shows a perivascular inflammatory infiltrate including granulocytes.

In about 35-65% of cases, arthritis occurs. Joint signs are variably expressed and can lead to transient swelling without sequelae between crises, or to unpredictable anomalies of growth cartilage and long bones epiphyses suggestive of a pseudo-tumour. Biopsies reveal hypertrophic cartilage without inflammatory cells. This most commonly affects the large joints (knees, ankles, elbows, and wrists) but may also involve the small joints of the hands and feet. It is usually bilateral and painful. A common and characteristic feature is giant kneecaps. Severe cases may result in contractures (joint deformities).

Most patients eventually have neurological problems. These manifest themselves in three principal ways: chronic meningitis, involvement of both the optic tract and eye, and sensorineural hearing loss. The chronic meningitis presents with the features of chronically raised intracranial pressure: headaches, vomiting, ventriculomegaly, hydrocephalus, macromegaly, cerebral atrophy, and optic atrophy. Some of these features may be evidenced on prenatal ultrasound. In 50% of cases, intellectual deficit occurs. Seizures occur in 25% of cases, but other manifestations are rare. Histological examination shows infiltration of the meninges with polymorphs.

Ocular manifestations occur in 80% of cases and include uveitis (70%), papillary involvement, conjunctivitis, and optical neuritis. If untreated, these may result in blindness (25%). The sensorineural hearing loss occurs in 75%, and tends to be progressive leading to deafness in 20% of cases.

Almost all children are remarkably short and have growth delay. Fever is extremely common but inconstant and is most often mild. Anemia is frequent. Other findings that have been reported include macrocephaly (95%), large fontanelle, prominent forehead, flattening of the nasal bridge (saddleback nose), short and thick extremities, and finger clubbing. The liver and/or spleen may be enlarged. Lymph node enlargement may also be present.

Later in life, secondary amyloidosis may occur. Delayed puberty and secondary amenorrhoea are not uncommon. Hoarseness due to inflammation of the laryngeal cartilage has also been reported.

All forms of MDDS are very rare. MDDS causes a wide range of symptoms, which can appear in newborns, infants, children, or adults, depending on the class of MDDS; within each class symptoms are also diverse.

In MDDS associated with mutations in "TK2", infants generally develop normally, but by around two years of age, symptoms of general muscle weakness (called "hypotonia"), tiredness, lack of stamina, and difficulty feeding begin to appear. Some toddlers start to lose control of the muscles in their face, mouth, and throat, and may have difficulty swallowing. Motor skills that had been learned may be lost, but generally the functioning of the brain and ability to think are not affected.

In MDDS associated with mutations in "SUCLA2" or "SUCLG1" that primarily affect the brain and muscle, hypotonia generally arises in infants before they are 6 months old, their muscles begin wasting away, and there is delay in psychomotor learning (learning basic skills like walking, talking, and intentional, coordinated movement). The spine often begins to curve (scoliosis or kyphosis), and the child often has abnormal movements (dystonia, athetosis or chorea), difficulty feeding, acid reflux, hearing loss, stunted growth, and difficulty breathing that can lead to frequent lung infections. Sometime epilepsy develops.

In MDDS associated with mutations in "RRM2B" that primarily affect the brain and muscle, there is again hypotonia in the first months, symptoms of lactic acidosis like nausea, vomiting, and rapid deep breathing, failure to thrive including the head remaining small, delay or regression in moving, and hearing loss. Many body systems are affected.

In MDDS associated with mutations in "DGUOK" that primarily affect the brain and the liver, there are two forms. There is an early-onset form in which symptoms arise from problems in many organs in the first week of life, especially symptoms of lactic acidosis as well as low blood sugar. Within weeks of birth they can develop liver failure and the associated jaundice and abdominal swelling, and many neurological problems including developmental delays and regression, and uncontrolled eye movement. Rarely within class of already rare diseases, symptoms only relating to liver disease emerge later in infancy or in childhood.

In MDDS associated with mutations in "MPV17" that primarily affect the brain and the liver, the symptoms are similar to those caused by DGUOK and also emerge shortly after birth, generally with fewer and less severe neurological problems. There is a subset of people of Navajo descent who develop Navajo neurohepatopathy, who in addition to these symptoms also have easily broken bones that do not cause pain, deformed hands or feet, and problems with their corneas.

In MDDS associated with mutations in "POLG" that primarily affect the brain and the liver, the symptoms are very diverse and can emerge anytime from shortly after birth to old age. The first signs of the disease, which include intractable seizures and failure to meet meaningful developmental milestones, usually occur in infancy, after the first year of life, but sometimes as late as the fifth year. Primary symptoms of the disease are developmental delay, progressive intellectual disability, hypotonia (low muscle tone), spasticity (stiffness of the limbs) possibly leading to quadriplegia, and progressive dementia. Seizures may include epilepsia partialis continua, a type of seizure that consists of repeated myoclonic (muscle) jerks. Optic atrophy may also occur, often leading to blindness. Hearing loss may also occur. Additionally, although physical signs of chronic liver dysfunction may not be present, many people suffer liver impairment leading to liver failure.

In MDDS associated with mutations in "PEO1"/"C10orf2" that primarily affect the brain and the liver, symptoms emerge shortly after birth or in early infancy, with hypotonia, symptoms of lactic acidosis, enlarged liver, feeding problems, lack of growth, and delay of psychomotor skills. Neurologically, development is slowed or stopped, and epilepsy emerges, as do sensory problems like loss of eye control and deafness, and neuromuscular problems like a lack of reflexes, muscular atrophy, and twitching, and epilepsy.

In MDDS associated with mutations in the genes associated with mutations in "ECGF1"/"TYMP" that primarily affects the brain and the gastrointestinal tract, symptoms can emerge any time in the first fifty years of life; most often they emerge before the person turns 20. Weight loss is common as is a lack of the ability of the stomach and intestines to automatically expand and contract and thus move through it (called gastrointestinal motility) – this leads to feeling full after eating only small amounts of food, nausea, acid reflux, All affected individuals develop weight loss and progressive gastrointestinal dysmotility manifesting as early satiety, nausea, diarrhea, vomiting, and stomach pain and swelling. People also develop neuropathy, with weakness and tingling. There are often eye problems, and intellectual disability.

The syndromes within CAPS overlap clinically, and patients may have features of more than one disorder. In a retrospective cohort of 136 CAPS patients from 16 countries, the most prevalent clinical features were fever (84% of cases, often with concurrent constitutional symptoms such as fatigue, malaise, mood disorders or failure to thrive), skin rash (either urticarial or maculopapular rash; 97% of cases) especially after cold exposure, and musculoskeletal involvement (myalgia, arthralgia, and/or arthritis, or less commonly joint contracture, patellar overgrowth, bone deformity, bone erosion and/or osteolytic lesion; 86% of cases). Less common features included ophthalmological involvement (conjunctivitis and/or uveitis, or less commonly optic nerve atrophy, cataract, glaucoma or impaired vision; 71% of cases), neurosensory hearing loss (42% of cases), neurological involvement (morning headache, papilloedema, and/or meningitis, or less commonly seizure, hydrocephalus or mental retardation; 40% of cases), and AA amyloidosis (4% of cases). Age of onset is typically in infancy or early childhood. In 57% of cases, CAPS had a chronic phenotype with symptoms present almost daily, whereas the remaining 43% of patients experienced only acute episodes. Up to 56% of patients reported a family history of CAPS. Previous studies confirm these symptoms, although the exact reported rates vary.

Still's disease does not affect children under 6 months old.

Hyperimmunoglobulin D syndrome in 50% of cases is associated with mevalonate kinase deficiency which can be measured in the leukocytes.

Reye syndrome progresses through five stages:

- Stage I

- Rash on palms of hands and feet

- Persistent, heavy vomiting that is not relieved by not eating

- Generalized lethargy

- Confusion

- Nightmares

- No fever usually present

- Headaches

- Stage II

- Stupor

- Hyperventilation

- Fatty liver (found by biopsy)

- Hyperactive reflexes

- Stage III

- Continuation of Stage I and II symptoms

- Possible coma

- Possible cerebral edema

- Rarely, respiratory arrest

- Stage IV

- Deepening coma

- Dilated pupils with minimal response to light

- Minimal but still present liver dysfunction

- Stage V

- Very rapid onset following stage IV

- Deep coma

- Seizures

- Multiple organ failure

- Flaccidity

- Hyperammonemia (above 300 mg/dL of blood)

- Death

The acute syndrome presents with rapidly progressive severe upper abdominal pain, yellow discoloration of the skin and whites of the eyes, liver enlargement, enlargement of the spleen, fluid accumulation within the peritoneal cavity, elevated liver enzymes, and eventually encephalopathy. The fulminant syndrome presents early with encephalopathy and ascites. Liver cell death and severe lactic acidosis may be present as well. Caudate lobe enlargement is often present. The majority of patients have a slower-onset form of Budd–Chiari syndrome. This can be painless. A system of venous collaterals may form around the occlusion which may be seen on imaging as a "spider's web". Patients may progress to cirrhosis and show the signs of liver failure.

On the other hand, incidental finding of a silent, asymptomatic form may not be a cause for concern.

MDDS are a group of genetic disorders that share a common pathology — a lack of functioning DNA in mitochondria. There are generally four classes of MDDS:

- a form that primarily affects muscle associated with mutations in the "TK2" gene;

- a form that primarily affects the brain and muscle associated with mutations in the genes "SUCLA2", "SUCLG1", or "RRM2B";

- a form that primarily affects the brain and the liver associated with mutations in "DGUOK", "MPV17", "POLG", or "PEO1" (also called "C10orf2"); and

- a form that primarily affects the brain and the gastrointestinal tract associated with mutations in "ECGF1" (also called "TYMP").

Symptoms of early infantile GM1 (the most severe subtype, with onset shortly after birth) may include neurodegeneration, seizures, liver enlargement (hepatomegaly), spleen enlargement (splenomegaly), coarsening of facial features, skeletal irregularities, joint stiffness, distended abdomen, muscle weakness, exaggerated startle response to sound, and problems with gait.

About half of affected patients develop cherry-red spots in the eye.

Children may be deaf and blind by age 1 and often die by age 3 from cardiac complications or pneumonia.

- Autosomal recessive disorder; beta-galactosidase deficiency; neuronal storage of GM1 ganglioside and visceral storage of galactosyl oligosaccharides and keratan sulfate.

- Early psychomotor deterioration: decreased activity and lethargy in the first weeks; never sit; feeding problems - failure to thrive; visual failure (nystagmus noted) by 6 months; initial hypotonia; later spasticity with pyramidal signs; secondary microcephaly develops; decerebrate rigidity by 1 year and death by age 1–2 years (due to pneumonia and respiratory failure); some have hyperacusis.

- Macular cherry-red spots in 50% by 6–10 months; corneal opacities in some

- Facial dysmorphology: frontal bossing, wide nasal bridge, facial edema (puffy eyelids); peripheral edema, epicanthus, long upper lip, microretrognathia, gingival hypertrophy (thick alveolar ridges), macroglossia

- Hepatomegaly by 6 months and splenomegaly later; some have cardiac failure

- Skeletal deformities: flexion contractures noted by 3 months; early subperiosteal bone formation (may be present at birth); diaphyseal widening later; demineralization; thoracolumbar vertebral hypoplasia and beaking at age 3–6 months; kyphoscoliosis. *Dysostosis multiplex (as in the mucopolysaccharidoses)

- 10–80% of peripheral lymphocytes are vacuolated; foamy histiocytes in bone marrow; visceral mucopolysaccharide storage similar to that in Hurler disease; GM1 storage in cerebral gray matter is 10-fold elevated (20–50-fold increased in viscera)

- Galactose-containing oligosacchariduria and moderate keratan sulfaturia

- Morquio disease Type B: Mutations with higher residual beta-galactosidase activity for the GM1 substrate than for keratan sulfate and other galactose-containing oligosaccharides have minimal neurologic involvement but severe dysostosis resembling Morquio disease type A (Mucopolysaccharidosis type 4).

Budd–Chiari syndrome is a very rare condition, affecting 1 in a million adults. The condition is caused by occlusion of the hepatic veins that drain the liver. It presents with the classical triad of abdominal pain, ascites, and liver enlargement. The formation of a blood clot within the hepatic veins can lead to Budd–Chiari syndrome. The syndrome can be fulminant, acute, chronic, or asymptomatic.

Cryopyrin-associated periodic syndrome (CAPS) is a group of rare, heterogeneous autoinflammatory disease characterized by interleukin 1β-mediated systemic inflammation and clinical symptoms involving skin, joints, central nervous system, and eyes. It encompasses a spectrum of three clinically overlapping autoinflammatory syndromes including familial cold autoinflammatory syndrome (FCAS, formerly termed familial cold-induced urticaria), the Muckle–Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease (NOMID, also called chronic infantile neurologic cutaneous and articular syndrome or CINCA) that were originally thought to be distinct entities, but in fact share a single genetic mutation and pathogenic pathway.

About half the people with Wilson's disease have neurological or psychiatric symptoms. Most initially have mild cognitive deterioration and clumsiness, as well as changes in behavior. Specific neurological symptoms usually then follow, often in the form of parkinsonism (cogwheel rigidity, bradykinesia or slowed movements and a lack of balance are the most common parkinsonian features) with or without a typical hand tremor, masked facial expressions, slurred speech, ataxia (lack of coordination) or dystonia (twisting and repetitive movements of part of the body). Seizures and migraine appear to be more common in Wilson's disease. A characteristic tremor described as "wing-beating tremor" is encountered in many people with Wilson's; this is absent at rest but can be provoked by extending the arms.

Cognition can also be affected in Wilson's disease. This comes in two, not mutually exclusive, categories: frontal lobe disorder (may present as impulsivity, impaired judgement, promiscuity, apathy and executive dysfunction with poor planning and decision making) and subcortical dementia (may present as slow thinking, memory loss and executive dysfunction, without signs of aphasia, apraxia or agnosia). It is suggested that these cognitive involvements are related and closely linked to psychiatric manifestations of the disease.

Psychiatric problems due to Wilson's disease may include behavioral changes, depression, anxiety disorders, and psychosis. Psychiatric symptoms are commonly seen in conjunction with neurological symptoms and are rarely manifested on their own. These symptoms are often poorly defined and can sometimes be attributed to other causes. Because of this, diagnosis of Wilson's disease is rarely made when only psychiatric symptoms are present.

Onset of late infantile GM1 is typically between ages 1 and 3 years.

Neurological symptoms include ataxia, seizures, dementia, and difficulties with speech.

Causes for similar symptoms include

- Various inborn metabolic disorders

- Viral encephalitis

- Drug overdose or poisoning

- Head trauma

- Liver failure due to other causes

- Meningitis

- Kidney failure

- Shaken baby syndrome

Liver disease may present itself as tiredness, increased bleeding tendency or confusion (due to hepatic encephalopathy) and portal hypertension. The latter, a condition in which the pressure in the portal vein is markedly increased, leads to esophageal varices, blood vessels in the esophagus that may bleed in a life-threatening fashion, as well as enlargement of the spleen (splenomegaly) and accumulation of fluid in the abdominal cavity (ascites). On examination, signs of chronic liver disease such as spider angiomata (small distended blood vessels, usually on the chest) may be observed. Chronic active hepatitis has caused cirrhosis of the liver in most by the time they develop symptoms. While most people with cirrhosis have an increased risk of hepatocellular carcinoma (liver cancer), this risk is relatively very low in Wilson's disease.

About 5% of all people are diagnosed only when they develop fulminant acute liver failure, often in the context of a hemolytic anemia (anemia due to the destruction of red blood cells). This leads to abnormalities in protein production (identified by deranged coagulation) and metabolism by the liver. The deranged protein metabolism leads to the accumulation of waste products such as ammonia in the bloodstream. When these irritate the brain, the person develops hepatic encephalopathy (confusion, coma, seizures and finally life-threatening swelling of the brain).

Typically, the signs and symptoms of juvenile nephronophthisis are limited to the kidneys. They include polyuria, polydipsia, weakness, and fatigue.

Anemia, growth retardation, no hypertension.

Proteinuria and hematuria are usually absent. Polyuria is resistant to vasopressin.

When other organ systems are affected, symptoms can include situs inversus, heart abnormalities, and liver fibrosis. Juvenile nephronophthisis can also be associated with other rare disorders, including Senior–Løken syndrome and Joubert syndrome.

Symptoms present by eight months of age and are marked by developmental delay followed by neurological complications such as seizures, involuntary eye movements, and ataxia, involuntary muscle movements and failure to gain weight and grow at the expected rate (failure to thrive). Babies with this condition also have and enlarged liver and spleen (hepatosplenomegaly) and enlarged heart (cardiomegaly).

Acute liver failure is defined as "the rapid development of hepatocellular dysfunction, specifically coagulopathy and mental status changes (encephalopathy) in a patient without known prior liver disease".

The disease process is associated with the development of a coagulopathy of liver aetiology, and clinically apparent altered level of consciousness due to hepatic encephalopathy. Several important measures are immediately necessary when the patient presents for medical attention. The diagnosis of acute liver failure is based on physical exam, laboratory findings, patient history, and past medical history to establish mental status changes, coagulopathy, rapidity of onset, and absence of known prior liver disease respectively.

The exact definition of "rapid" is somewhat questionable, and different sub-divisions exist which are based on the time from onset of first hepatic symptoms to onset of encephalopathy. One scheme defines "acute hepatic failure" as the development of encephalopathy within 26 weeks of the onset of any hepatic symptoms. This is sub-divided into "fulminant hepatic failure", which requires onset of encephalopathy within 8 weeks, and "subfulminant", which describes onset of encephalopathy after 8 weeks but before 26 weeks. Another scheme defines "hyperacute" as onset within 7 days, "acute" as onset between 7 and 28 days, and "subacute" as onset between 28 days and 24 weeks.

The main features of acute liver failure are rapid-onset jaundice, weakness, and eventually, changes in mental status that can begin as mild confusion but progress to coma.

Chronic liver failure usually occurs in the context of cirrhosis, itself potentially the result of many possible causes, such as excessive alcohol intake, hepatitis B or C, autoimmune, hereditary and metabolic causes (such as iron or copper overload, steatohepatitis or non-alcoholic fatty liver disease).

Juvenile nephronophthisis causes fibrosis and scarring of the kidneys, which accounts for the symptoms observed. The kidneys also often have corticomedullary cysts.

- Inability to conserve sodium because of defect of tubules leading to polyuria and polydipsia.

- Anemia is attributed to a deficiency of erythropoietin production by failing kidneys.

- Growth retardation, malaise and pallor are secondary to anemia.

- No hypertension as nephronophthisis is a salt-losing enteropathy.

Symptomatic presentation usually occurs between 6 and 24 months of age, but the majority of cases have been documented in children less than 1 year of age. The infantile form involves multiple organ systems and is primarily characterized by hypoketotic hypoglycemia (recurring attacks of abnormally low levels of fat breakdown products and blood sugar) that often results in loss of consciousness and seizure activity. Acute liver failure, liver enlargement, and cardiomyopathy are also associated with the infantile presentation of this disorder. Episodes are triggered by febrile illness, infection, or fasting. Some cases of sudden infant death syndrome are attributed to infantile CPT II deficiency at autopsy.

Chronic liver disease in the clinical context is a disease process of the liver that involves a process of progressive destruction and regeneration of the liver parenchyma leading to fibrosis and cirrhosis. "Chronic liver disease" refers to disease of the liver which lasts over a period of six months. It consists of a wide range of liver pathologies which include inflammation (chronic hepatitis), liver cirrhosis, and hepatocellular carcinoma. The entire spectrum need not be experienced.

Kidney failure is common, present in more than 50% of ALF patients, either due to original insult such as paracetamol resulting in acute tubular necrosis or from hyperdynamic circulation leading to hepatorenal syndrome or functional kidney failure. Because of impaired production of urea, blood urea does not represent the degree of kidney impairment.

Signs of chronic liver disease detectable on clinical examination can be divided into those that are associated with the diagnosis of chronic liver disease, associated with decompensation and associated with the cause.

Theoretically, a mutation in any of the may cause disease, but below are some notable ones, with short description of symptoms:

- Adrenoleukodystrophy; leads to progressive brain damage, failure of the adrenal glands and eventually death.

- Alport syndrome; glomerulonephritis, endstage kidney disease, and hearing loss.

- Androgen insensitivity syndrome; variable degrees of undervirilization and/or infertility in XY persons of either gender

- Barth syndrome; metabolism distortion, delayed motor skills, stamina deficiency, hypotonia, chronic fatigue, delayed growth, cardiomyopathy, and compromised immune system.

- Blue cone monochromacy; low vision acuity, color blindness, photophobia, infantile nystagmus.

- Centronuclear myopathy; where cell nuclei are abnormally located in skeletal muscle cells. In CNM the nuclei are located at a position in the center of the cell, instead of their normal location at the periphery.

- Charcot–Marie–Tooth disease (CMTX2-3); disorder of nerves (neuropathy) that is characterized by loss of muscle tissue and touch sensation, predominantly in the feet and legs but also in the hands and arms in the advanced stages of disease.

- Coffin–Lowry syndrome; severe mental retardation sometimes associated with abnormalities of growth, cardiac abnormalities, kyphoscoliosis as well as auditory and visual abnormalities.

- Fabry disease; A lysosomal storage disease causing anhidrosis, fatigue, angiokeratomas, burning extremity pain and ocular involvement.

- Hunter's Syndrome; potentially causing hearing loss, thickening of the heart valves leading to a decline in cardiac function, obstructive airway disease, sleep apnea, and enlargement of the liver and spleen.

- Hypohidrotic ectodermal dysplasia, presenting with hypohidrosis, hypotrichosis, hypodontia

- Kabuki syndrome; multiple congenital anomalies and mental retardation.

- Spinal and bulbar muscular atrophy; muscle cramps and progressive weakness

- Lesch-Nyhan syndrome; neurologic dysfunction, cognitive and behavioral disturbances including self-mutilation, and uric acid overproduction (hyperuricemia)

- Lowe Syndrome; hydrophthalmia, cataracts, intellectual disabilities, aminoaciduria, reduced renal ammonia production and vitamin D-resistant rickets

- Menkes disease; sparse and coarse hair, growth failure, and deterioration of the nervous system

- Nasodigitoacoustic syndrome; mishaped nose, brachydactyly of the distal phalanges, sensorineural deafness

- Nonsyndromic deafness; hearing loss

- Norrie disease; cataracts, leukocoria along with other developmental issues in the eye

- Occipital horn syndrome; deformations in the skeleton

- Ocular albinism; lack of pigmentation in the eye

- Ornithine transcarbamylase deficiency; developmental delay and mental retardation. Progressive liver damage, skin lesions, and brittle hair may also be seen

- Siderius X-linked mental retardation syndrome; cleft lip and palate with mental retardation and facial dysmorphism, caused by mutations in the histone demethylase PHF8

- Simpson-Golabi-Behmel syndrome; coarse faces with protruding jaw and tongue, widened nasal bridge, and upturned nasal tip

- Spinal muscular atrophy caused by UBE1 gene mutation; weakness due to loss of the motor neurons of the spinal cord and brainstem

- Wiskott-Aldrich syndrome; eczema, thrombocytopenia, immune deficiency, and bloody diarrhea

- X-linked Severe Combined Immunodeficiency (SCID); infections, usually causing death in the first years of life

- X-linked sideroblastic anemia; skin paleness, fatigue, dizziness and enlarged spleen and liver.