MDDS is diagnosed based on systemic symptoms presenting in infants, followed by a clinical examination and laboratory tests (for example, high lactate levels are common) medical imaging, and usually is finally confirmed and formally identified by genetic testing.

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.

The diagnosis is based on observing the patient and finding the constellation of symptoms and signs described above. A few blood tests help, by showing signs of long standing inflammation. There is no specific test for the disease, though now that the gene that causes the disease is known, that may change.

Routine laboratory investigations are non specific: anaemia, increased numbers of polymorphs, an elevated erythrocyte sedimentation rate and elevated concentrations of C-reactive protein are typically all the abnormalities found. Lumbar puncture shows elevated levels of polymorphs (20-70% of cases) and occasionally raised eosinophil counts (0-30% of cases). CSF neopterin may be elevated.

The X ray changes are unique and charactistic of this syndrome. These changes include bony overgrowth due to premature ossification of the patella and the long bone epiphyses in very young children and bowing of long bones with widening and shortening periosteal reaction in older ones.

Audiometry shows a progressive sensineural deafness. Visual examination shows optic atrophy and an increase in the blind spot. CT is usually normal but may show enlargement of the ventricles. MRI with contrast may show enhancement of leptomeninges and cochlea consistent with chronic meningitis. EEG shows is non specific with slow waves and spike discharges.

Polymorphs tend to show increased expression of CD10.

DGUOK, POLG, and MPV17 related forms result in defects to the liver. Liver dysfunction is progressive in the majority of individuals with both forms of DGUOK-related MDS and is the most common cause of death. For children with the multi-organ form, liver transplantation provides no survival benefit.

Liver disease typically progresses to liver failure in affected children with MPV17-related MDS and liver transplantation remains the only treatment option for liver failure. Approximately half of affected children reported did not undergo liver transplantation and died because of progressive liver failure – the majority during infancy or early childhood. A few children were reported to survive without liver transplantation.

A diagnosis can be made by measuring cultured tissue samples for increased levels of free sialic acid. Prenatal testing is also available for known carriers of this disorder.

In addition to genetic tests involving "PEX" genes, biochemical tests have proven highly effective for the diagnosis of infantile Refsum disease and other peroxisomal disorders. Typically, IRD patients show elevated very long chain fatty acids in their blood plasma. Cultured primarily skin fibroblasts obtained from patients show elevated very long chain fatty acids, impaired very long chain fatty acid beta-oxidation, phytanic acid alpha-oxidation, pristanic acid alpha-oxidation, and plasmalogen biosynthesis.

The diagnosis of nephronophthisis can be obtained via a renal ultrasound, family history and clinical history of the affected individual according to Stockman, et al.

Because CAPS is extremely rare and has a broad clinical presentation, it is difficult to diagnose, and a significant delay exists between symptom onset and definitive diagnosis. There are currently no clinical or diagnostic criteria for CAPS based solely on clinical presentation. Instead, diagnosis is made by genetic testing for "NLRP3" mutations. Acute phase reactants and white blood cell count are usually persistently elevated, but this is aspecific for CAPS.

Mutation analysis of the "ATP7B" gene, as well as other genes linked to copper accumulation in the liver, may be performed. Once a mutation is confirmed, it is possible to screen family members for the disease as part of clinical genetics family counseling. Regional distributions of genes associated with Wilson's disease are important to follow, as this can help clinicians design appropriate screening strategies. Since mutations of the WD gene vary between populations, research and genetic testing done in countries like the USA or United Kingdom can pose problems as they tend to have more mixed populations.

The usual initial investigations include chest X ray, electrocardiogram and echocardiography. Typical findings are those of an enlarged heart with non specific conduction defects. Biochemical investigations include serum creatine kinase (typically increased 10 fold) with lesser elevations of the serum aldolase, aspartate transaminase, alanine transaminase and lactic dehydrogenase. Diagnosis is made by estimating the acid alpha glucosidase activity in either skin biopsy (fibroblasts), muscle biopsy (muscle cells) or in white blood cells. The choice of sample depends on the facilities available at the diagnostic laboratory.

In the late onset form, the findings on investigation are similar to those of the infantile form with the caveat that the creatinine kinases may be normal in some cases. The diagnosis is by estimation of the enzyme activity in a suitable sample.

On May 17, 2013 the Secretary's Discretionary Advisory Committee on Heritable Diseases in Newborns and Children (DACHDNC) approved a recommendation to the Secretary of Health and Human Services to add Pompe to the Recommended Uniform Screening Panel (RUSP). The HHS secretary must first approve the recommendation before the disease is formally added to the panel.

In terms of the diagnosis for glycogen storage disease type III, the following tests/exams are carried out to determine if the individual has the condition:

- Biopsy (muscle or liver)

- CBC

- Ultrasound

- DNA mutation analysis (helps ascertain GSD III subtype)

Serum copper is low, which may seem paradoxical given that Wilson's disease is a disease of copper excess. However, 95% of plasma copper is carried by ceruloplasmin which is often low in Wilson's disease. Urine copper is elevated in Wilson's disease and is collected for 24 hours in a bottle with a copper-free liner. Levels above 100 μg/24h (1.6 μmol/24h) confirm Wilson's disease, and levels above 40 μg/24h (0.6 μmol/24h) are strongly indicative. High urine copper levels are not unique to Wilson's disease; they are sometimes observed in autoimmune hepatitis and in cholestasis (any disease obstructing the flow of bile from the liver to the small bowel).

In children, the penicillamine test may be used. A 500 mg oral dose of penicillamine is administered, and urine collected for 24 hours. If this contains more than 1600 μg (25 μmol), it is a reliable indicator of Wilson's disease. This test has not been validated in adults.

The first cases of NSF were identified in 1997, but NSF was first described as an independent disease entity in 2000. While skin involvement is on the foreground, the process may involve any organ and resembles diffuse scleroderma or systemic sclerosis. In 2006, the link between NSF and gadolinium-containing contrast agents was made. As a result, gadolinium-containing contrast is now considered contraindicated in patients with an estimated glomerular filtration rate (a measure of renal function) under 60 and especially under 30 ml/mn. One retrospective study of the Veterans Affairs Electronic Medical Record found no cases of NSF among 141 patients receiving hemodialysis for chronic kidney disease who received gadoteridol.

Onset of adult GM1 is between ages 3 and 30.

Symptoms include muscle atrophy, neurological complications that are less severe and progress at a slower rate than in other forms of the disorder, corneal clouding in some patients, and dystonia (sustained muscle contractions that cause twisting and repetitive movements or abnormal postures). Angiokeratomas may develop on the lower part of the trunk of the body. Most patients have a normal size liver and spleen.

Prenatal diagnosis is possible by measurement of Acid Beta Galactosidase in cultured amniotic cells.

Chronic liver disease takes several years to develop and the condition may not be recognised unless there is clinical awareness of subtle signs and investigation of abnormal liver function tests.

Testing for chronic liver disease involves blood tests, imaging including ultrasound and a biopsy of the liver. The liver biopsy is a simple procedure done with a fine thin needle under local anaesthesia. The tissue sample is sent to a laboratory where it is examined underneath a microscope.

The differential diagnosis of glycogen storage disease type III includes GSD I, GSD IX and GSD VI. This however does not mean other glycogen storage diseases should not be distinguished as well.

This remains a challenge in clinical practice due to a lack of reliable markers. Many other conditions lead to similar clinical as well as pathological pictures. To diagnose hepatotoxicity, a causal relationship between the use of the toxin or drug and subsequent liver damage has to be established, but might be difficult, especially when idiosyncratic reaction is suspected. Simultaneous use of multiple drugs may add to the complexity. As in acetaminophen toxicity, well established, dose-dependent, pharmacological hepatotoxicity is easier to spot. Several clinical scales such as CIOMS/RUCAM scale and Maria and Victorino criteria have been proposed to establish causal relationship between offending drug and liver damage. CIOMS/RUCAM scale involves a scoring system that categorizes the suspicion into "definite or highly probable" (score > 8), “probable” (score 6-8), “possible” (score 3-5), “unlikely” (score 1-2) and “excluded” (score ≤ 0). In clinical practice, physicians put more emphasis on the presence or absence of similarity between the biochemical profile of the patient and known biochemical profile of the suspected toxicity (e.g., cholestatic damage in amoxycillin-clauvonic acid ).

Radiologic osteosclerosis and histology are the main diagnostic features. Diagnosis can often be difficult because of the rareness of ECD as well as the need to differentiate it from LCH. A diagnosis from neurological imaging may not be definitive. The presence of symmetrical cerebellar and pontine signal changes on T2-weighted images seem to be typical of ECD, however, multiple sclerosis and metabolic diseases must also be considered in the differential diagnosis. ECD is not a common cause of exophthalmos but can be diagnosed by biopsy. However, like all biopsies, this may be inconclusive. Video-assisted thoracoscopic surgery may be used for diagnostic confirmation and also for therapeutic relief of recurrent pericardial fluid drainage.

Since interleukin 1β plays a central role in the pathogenesis of the disease, therapy typically targets this cytokine in the form of monoclonal antibodies (such as canakinumab), binding proteins/traps (such as rilonacept), or interleukin 1 receptor antagonists (such as anakinra). These therapies are generally effective in alleviating symptoms and substantially reducing levels of inflammatory indices. Case reports suggest that thalidomide and the anti-IL-6 receptor antibody tocilizumab may also be effective.

Currently, there is no cure for infantile Refsum disease syndrome, nor is there a standard course of treatment. Infections should be guarded against to prevent such complications as pneumonia and respiratory distress. Other treatment is symptomatic and supportive. Patients show variable lifespans with some individuals surviving until adulthood and into old age.

Histologically, ECD differs from Langerhans cell histiocytosis (LCH) in a number of ways. Unlike LCH, ECD does not stain positive for S-100 proteins or Group 1 CD1a glycoproteins, and electron microscopy of cell cytoplasm does not disclose Birbeck granules. Tissue samples show xanthomatous or xanthogranulomatous infiltration by lipid-laden or foamy histiocytes, and are usually surrounded by fibrosis. Bone biopsy is said to offer the greatest likelihood of reaching a diagnosis. In some, there is histiocyte proliferation, and on staining, the section is CD68+ and CD1a-.

Individuals presenting with Type III galactosemia must consume a lactose- and galactose-restricted diet devoid of dairy products and mucilaginous plants. Dietary restriction is the only current treatment available for GALE deficiency. As glycoprotein and glycolipid metabolism generate endogenous galactose, however, Type III galactosemia may not be resolved solely through dietary restriction.

Diagnosis of canine phosphofructokinase deficiency is similar to the blood tests used in diagnosis of humans. Blood tests measuring the total erythrocyte PFK activity are used for definitive diagnosis in most cases. DNA testing for presence of the condition is also available.

Treatment mostly takes the form of supportive care. Owners are advised to keep their dogs out of stressful or exciting situations, avoid high temperature environments and strenuous exercise. It is also important for the owner to be alert for any signs of a hemolytic episode. Dogs carrying the mutated form of the gene should be removed from the breeding population, in order to reduce incidence of the condition.

All patients with clinical or laboratory evidence of moderate to severe acute hepatitis should have an immediate measurement of prothrombin time and careful evaluation of mental status. If the prothrombin time is prolonged by ≈ 4–6 seconds or more (INR ≥ 1.5),

and there is any evidence of altered sensorium, the diagnosis of ALF should be strongly suspected, and hospital admission is mandatory. Initial laboratory examination must be extensive in order to evaluate both the etiology and severity.

- Initial laboratory analysis

- Prothrombin time/INR

- Complete blood count

- Chemistries

- Liver function test: AST, ALT, alkaline phosphatase, GGT, total bilirubin, albumin

- Creatinine, urea/blood urea nitrogen, sodium, potassium, chloride, bicarbonate, calcium, magnesium, phosphate

- Glucose

- Amylase and lipase

- Arterial blood gas, lactate

- Blood type and screen

- Paracetamol (acetaminophen) level, toxicology screen

- Viral hepatitis serologies: anti-HAV IgM, HBSAg, anti-HBc IgM, anti-HCV

- Autoimmune markers: ANA, ASMA, LKMA, immunoglobulin levels

- Ceruloplasmin level (when Wilson's disease suspected)

- Pregnancy test (females)

- Ammonia (arterial if possible)

- HIV status (has implication for transplantation)

History taking should include a careful review of possible exposures to viral infection and drugs or other toxins. From history and clinical examination, the possibility of underlying chronic disease should be ruled out as it may require different management.

A liver biopsy done via the transjugular route because of coagulopathy is not usually necessary, other than in occasional malignancies. As the evaluation continues, several important decisions have to be made; such as whether to admit the patient to an ICU, or whether to transfer the patient to a transplant facility. Consultation with the transplant center as early as possible is critical due to the possibility of rapid progression of ALF.

Standard of care for treatment of CPT II deficiency commonly involves limitations on prolonged strenuous activity and the following dietary stipulations:

- The medium-chain fatty acid triheptanoin appears to be an effective therapy for adult-onset CPT II deficiency.

- Restriction of lipid intake

- Avoidance of fasting situations

- Dietary modifications including replacement of long-chain with medium-chain triglycerides supplemented with L-carnitine