Fabry disease is suspected based on the individual's clinical presentation, and can be diagnosed by an enzyme assay (usually done on leukocytes) to measure the level of alpha-galactosidase activity. An enzyme assay is not reliable for the diagnosis of disease in females due to the random nature of X-inactivation. Molecular genetic analysis of the "GLA" gene is the most accurate method of diagnosis in females, particularly if the mutations have already been identified in male family members. Many disease-causing mutations have been noted. Kidney biopsy may also be suggestive of Fabry disease if excessive lipid buildup is noted. Pediatricians, as well as internists, commonly misdiagnose Fabry disease.

Bright's disease was historically 'treated' with warm baths, blood-letting, squill, digitalis, mercuric compounds, opium, diuretics, laxatives, and dietary therapy, including abstinence from alcoholic drinks, cheese and red meat. Arnold Ehret was diagnosed with Bright's disease and pronounced incurable by 24 of Europe's most respected doctors; he designed "The Mucusless Diet Healing System", which apparently cured his illness. William Howard Hay, MD had the illness and, it is claimed, cured himself using the Hay diet.

There is no specific pathological testing or technique available for the diagnosis of the disease, although the International Study Group criteria for the disease are highly sensitive and specific, involving clinical criteria and a pathergy test. Behçet's disease has a high degree of resemblance to diseases that cause mucocutaneous lesions such as "Herpes simplex" labialis, and therefore clinical suspicion should be maintained until all the common causes of oral lesions are ruled out from the differential diagnosis.

Visual acuity, or color vision loss with concurrent mucocutaneous lesions or systemic Behçet's disease symptoms should raise suspicion of optic nerve involvement in Behçet's disease and prompt a work-up for Behçet's disease if not previously diagnosed in addition to an ocular work-up. Diagnosis of Behçet's disease is based on clinical findings including oral and genital ulcers, skin lesions such as erythema nodosum, acne, or folliculitis, ocular inflammatory findings and a pathergy reaction. Inflammatory markers such ESR, and CRP may be elevated. A complete ophthalmic examination may include a slit lamp examination, optical coherence tomography to detect nerve loss, visual field examinations, fundoscopic examination to assess optic disc atrophy and retinal disease, fundoscopic angiography, and visual evoked potentials, which may demonstrate increased latency. Optic nerve enhancement may be identified on Magnetic Resonance Imaging (MRI) in some patients with acute optic neuropathy. However, a normal study does not rule out optic neuropathy. Cerebrospinal fluid (CSF) analysis may demonstrate elevated protein level with or without pleocytosis. Imaging including angiography may be indicated to identify dural venous sinus thrombosis as a cause of intracranial hypertension and optic atrophy.

The twins require the use of wheelchairs for mobility and are unable to speak without the assistance of electronic speaking aids. They experience persistent and painful muscle spasms which are worsened by emotional distress. They are currently living with their parents, with the assistance of hospice workers. Doctors continue to administer tests to the twins in search of a treatment.

Diagnosis of Dercum's disease is done through a physical examination. In order to properly diagnose the patient, the doctor must first exclude all other possible differential diagnosis. The basic criteria for Dercum's disease are patients with chronic pain in the adipose tissue (body fat) and patients who are also obese. Although rare, the diagnosis may not include obesity. Dercum's disease can also be inherited and a family medical history may aid in the diagnosis of this disease. There are no specific laboratory test for this disease. Ultrasound and magnetic resonance imaging can play a role in diagnosis.

A complete blood count may reveal anemia, which commonly is caused by blood loss leading to iron deficiency (a microcytic anemia) or by vitamin B deficiency (a macrocytic anemia), usually caused by ileal disease impairing vitamin B absorption. Rarely autoimmune hemolysis may occur. Ferritin levels help assess if iron deficiency is contributing to the anemia. Erythrocyte sedimentation rate (ESR) and C-reactive protein help assess the degree of inflammation, which is important as ferritin can also be raised in inflammation. Serum iron, total iron binding capacity and transferrin saturation may be more easily interpreted in inflammation. Anemia of chronic disease results in a normocytic anemia. Other causes of anemia include medication used in treatment of inflammatory bowel disease, like azathioprine, which can lead to cytopenia, and sulfasalazine, which can also result in folate deficiency. Testing for "Saccharomyces cerevisiae" antibodies (ASCA) and antineutrophil cytoplasmic antibodies (ANCA) has been evaluated to identify inflammatory diseases of the intestine and to differentiate Crohn's disease from ulcerative colitis. Furthermore, increasing amounts and levels of serological antibodies such as ASCA, antilaminaribioside [Glc(β1,3)Glb(β); ALCA], antichitobioside [GlcNAc(β1,4)GlcNAc(β); ACCA], antimannobioside [Man(α1,3)Man(α)AMCA], antiLaminarin [(Glc(β1,3))3n(Glc(β1,6))n; anti-L] and antichitin [GlcNAc(β1,4)n; anti-C] associate with disease behavior and surgery, and may aid in the prognosis of Crohn's disease.

Low serum levels of vitamin D are associated with Crohn's disease. Further studies are required to determine the significance of this association.

A small bowel follow-through may suggest the diagnosis of Crohn's disease and is useful when the disease involves only the small intestine. Because colonoscopy and gastroscopy allow direct visualization of only the terminal ileum and beginning of the duodenum, they cannot be used to evaluate the remainder of the small intestine. As a result, a barium follow-through X-ray, wherein barium sulfate suspension is ingested and fluoroscopic images of the bowel are taken over time, is useful for looking for inflammation and narrowing of the small bowel. Barium enemas, in which barium is inserted into the rectum and fluoroscopy is used to image the bowel, are rarely used in the work-up of Crohn's disease due to the advent of colonoscopy. They remain useful for identifying anatomical abnormalities when strictures of the colon are too small for a colonoscope to pass through, or in the detection of colonic fistulae (in this case contrast should be performed with iodate substances).

CT and MRI scans are useful for evaluating the small bowel with enteroclysis protocols. They are also useful for looking for intra-abdominal complications of Crohn's disease, such as abscesses, small bowel obstructions, or fistulae. Magnetic resonance imaging (MRI) is another option for imaging the small bowel as well as looking for complications, though it is more expensive and less readily available. MRI techniques such as diffusion-weighted imaging and high-resolution imaging are more sensitive in detecting ulceration and inflammation compared to CT.

Common clinical signs and symptoms of Whipple's disease include diarrhea, steatorrhea, abdominal pain, weight loss, migratory arthropathy, fever, and neurological symptoms. Weight loss and diarrhea are the most common symptoms that lead to identification of the process, but may be preceded by chronic, unexplained, relapsing episodes of non-destructive seronegative arthritis, often of large joints.

Diagnosis is made by biopsy, usually by duodenal endoscopy, which reveals PAS-positive macrophages in the lamina propria containing non-acid-fast gram-positive bacilli. Immunohistochemical staining for antibodies against "T. whipplei" has been used to detect the organism in a variety of tissues, and a PCR-based assay is also available. PCR can be confirmatory if performed on blood, vitreous fluid, synovial fluid, heart valves, or cerebrospinal fluid. PCR of saliva, gastric or intestinal fluid, and stool specimens is highly sensitive, but not specific enough, indicating that healthy individuals can also harbor the causative bacterium without the manifestation of Whipple's disease, but that a negative PCR is most likely indicative of a healthy individual.

Endoscopy of the duodenum and jejunum can reveal pale yellow shaggy mucosa with erythematous eroded patches in patients with classic intestinal Whipple's disease, and small bowel X-rays may show some thickened folds. Other pathological findings may include enlarged mesenteric lymph nodes, hypercellularity of lamina propria with "foamy macrophages", and a concurrent decreased number of lymphocytes and plasma cells, per high power field view of the biopsy.

A D-Xylose test can be performed, which is where the patient will consume 4.5g of D-xylose, a sugar, by mouth. The urine excretion of D-Xylose is then measured after 5 hours. The majority of D-Xylose is absorbed normally, and should be found in the urine. If the D-Xylose is found to be low in the urine, this suggests an intestinal malabsorption problem such as bacterial overgrowth of the proximal small intestine, Whipple's Disease, or an autoimmune with diseases such as Celiac's Disease (allergy to gluten) or Crohn's Disease (autoimmune disease affecting the small intestine). With empiric antibiotic treatment after an initial positive D-Xylose test, and if a follow-up D-Xylose test is positive (decreased urine excretion) after antibiotic therapy, then this would signify it is not bacterial overgrowth of the proximal small intestine. Since Whipple's disease is so rare, a follow-up positive D-Xylose test more likely indicates a non-infectious etiology and more likely an autoimmune etiology. Clinical correlation is recommended to rule out Whipple's disease.

The diagnosis is clinical, not based upon serology. At least seven sets of diagnostic criteria have been devised, however the Yamaguchi criteria have the highest sensitivity. Diagnosis requires at least five features, with at least two of these being major diagnostic criteria.

The symptoms and signs of Bright's disease were first described in 1827 by the English physician Richard Bright, after whom the disease was named. In his "Reports of Medical Cases", he described 25 cases of dropsy (edema) which he attributed to kidney disease. Symptoms and signs included: inflammation of serous membranes, hemorrhages, apoplexy, convulsions, blindness and coma. Many of these cases were found to have albumin in their urine (detected by the spoon and candle-heat coagulation), and showed striking morbid changes of the kidneys at autopsy. The triad of dropsy, albumin in the urine and kidney disease came to be regarded as characteristic of Bright's disease. Subsequent work by Bright and others indicated an association with cardiac hypertrophy, which was attributed by Bright to stimulation of the heart. Subsequent work by Mahomed showed that a rise in blood pressure could precede the appearance of albumin in the urine, and the rise in blood pressure and increased resistance to flow was believed to explain the cardiac hypertrophy.

It is now known that Bright's disease is due to a wide range of diverse kidney diseases; thus, the term "Bright's disease" is retained strictly for historical application. The disease was diagnosed frequently in patients with diabetes; at least some of these cases would probably correspond to a modern diagnosis of diabetic nephropathy.

Life expectancy with Fabry disease for males was 58.2 years, compared with 74.7 years in the general population, and for females 75.4 years compared with 80.0 years in the general population, according to registry data from 2001 to 2008. The most common cause of death was cardiovascular disease, and most of those had received kidney replacements.

Amniocentesis or chorionic villus sampling can be used to screen for the disease before birth. After birth, urine tests, along with blood tests and skin biopsies can be used to diagnose Schindler disease. Genetic testing is also always an option, since different forms of Schindler disease have been mapped to the same gene on chromosome 22; though different changes (mutations) of this gene are responsible for the infantile- and adult-onset forms of the disease.

The disease may be diagnosed by its characteristic grouping of certain cells (multinucleated globoid cells), nerve demyelination and degeneration, and destruction of brain cells. Special stains for myelin (e.g.; luxol fast blue) may be used to aid diagnosis.

Surgical treatment of arterial manifestations of BD bears many pitfalls, since the obliterative endarteritis of vasa vasorum causes thickening of the medial layer and splitting of elastin fibers. Therefore, anastomotic pseudoaneurysms are likely to form, as well as pseudoaneurysms at the site of puncture in case of angiography or endovascular treatment; furthermore, early graft occlusion may occur.

For these reasons, invasive treatment should not be performed in the acute and active phases of the disease when inflammation is at its peak. The evaluation of disease’s activity is usually based on relapsing symptoms, ESR (erythrocyte sedimentation rate), and serum levels of CRP (C‐reactive protein).

Endovascular treatment can be an effective and safe alternative to open surgery, with less postoperative complications, faster recovery time, and reduced need for intensive care, while offering patency rates and procedural success rates comparable with those of surgery. This notwithstanding, long‐term results of endovascular treatment in BD are still to be determined.

People with AOSD generally experience one of two patterns in the disease:

- a debilitating pattern of fevers, pain, and other systemic symptoms, or

- a somewhat less aggressive pattern, in which the main symptom is arthritis and chronic joint pain.

One set of 21 adult-onset Still's disease patients were divided into four types, according to clinical course patterns. These included monocyclic systemic disease, polycyclic systemic disease, chronic articular monocyclic systemic disease, and chronic articular polycyclic systemic disease. People with chronic articular disease and polyarticular disease were at higher risk to develop disabling arthritis.

Infants with Schindler disease tend to die within 4 years of birth, therefore, treatment for this form of the disease is mostly palliative. However, Type II Schindler disease, with its late onset of symptoms, is not characterized by neurological degeneration. There is no known cure for Schindler disease, but bone marrow transplants have been trialed, as they have been successful in curing other glycoprotein disorders.

The disease appears to be progressive in nature. The Fields twins started having problems when they were four years old. By the time they had reached the age of nine, they were having difficulty walking and needed frames to assist them with walking. Their muscles have been gradually deteriorating over time. The disease affects the twins' nerves, causing them to make involuntary muscle movements such as trembling in the hands.

The extent of the disease is still unknown as the two women are only 21. However, the disease has had no apparent effect on their brains or personalities. Doctors do not know if the disease is fatal and, if so, what the life expectancy of one with this disease is. If the cause of the disease is genetic, there is a chance that the twins could pass it on to their future children.

Urbach–Wiethe disease is typically diagnosed by its clinical dermatological manifestations, particularly the beaded papules on the eyelids. Doctors can also test the hyaline material with a periodic acid-Schiff (PAS) staining, as the material colors strongly for this stain.

Immunohistochemical skin labeling for antibodies for the ECM1 protein as labeling has been shown to be reduced in the skin of those affected by Urbach–Wiethe disease. Staining with anti-type IV collagen antibodies or anti-type VII collagen antibodies reveals bright, thick bands at the dermoepidermal junction.

Non-contrast CT scans can image calcifications, but this is not typically used as a means of diagnosing the disease. This is partly due to the fact that not all Urbach-Wiethe patients exhibit calcifications, but also because similar lesions can be formed from other diseases such as herpes simplex and encephalitis. The discovery of mutations within the ECM1 gene has allowed the use of genetic testing to confirm initial clinical diagnoses of Urbach–Wiethe disease. It also allows doctors to better distinguish between Urbach–Wiethe disease and other similar diseases not caused by mutations in ECM1.

Three main approaches have been used to prevent or reduce the incidence of Tay–Sachs:

- Prenatal diagnosis. If both parents are identified as carriers, prenatal genetic testing can determine whether the fetus has inherited a defective gene copy from both parents. Chorionic villus sampling (CVS), the most common form of prenatal diagnosis, can be performed between 10 and 14 weeks of gestation. Amniocentesis is usually performed at 15–18 weeks. These procedures have risks of miscarriage of 1% or less.

- Preimplantation genetic diagnosis. By retrieving the mother's eggs for in vitro fertilization, it is possible to test the embryo for the disorder prior to implantation. Healthy embryos are then selected and transferred into the mother's womb, while unhealthy embryos are discarded. In addition to Tay–Sachs disease, preimplantation genetic diagnosis has been used to prevent cystic fibrosis and sickle cell anemia among other genetic disorders.

- Mate selection. In Orthodox Jewish circles, the organization Dor Yeshorim carries out an anonymous screening program so that carrier couples for Tay–Sachs and other genetic disorders can avoid marriage.

The detection of tumours specific to VHL disease is important in the disease's diagnosis. In individuals with a family history of VHL disease, one hemangioblastoma, pheochromocytoma or renal cell carcinoma may be sufficient to make a diagnosis. As all the tumours associated with VHL disease can be found sporadically, at least two tumours must be identified to diagnose VHL disease in a person without a family history.

Genetic diagnosis is also useful in VHL disease diagnosis. In hereditary VHL, disease techniques such as southern blotting and gene sequencing can be used to analyse DNA and identify mutations. These tests can be used to screen family members of those afflicted with VHL disease; "de novo" cases that produce genetic mosaicism are more difficult to detect because mutations are not found in the white blood cells that are used for genetic analysis.

Batten disease is rare, so may result in misdiagnosis, which in turn causes increased medical expenses, family stress, and the chance of using incorrect forms of treatment. Nevertheless, Batten disease can be diagnosed if properly detected. Vision impairment is the most common observable symptom to detect the disease. Children are more prevalent, and should be suspected more for juvenile Batten disease. Children or someone suspected to have Batten disease should initially be seen by an optometrist or ophthalmologist. A fundus eye examination that aids in the detection of common vision impairment abnormalities, such as granularity of the retinal pigment epithelium in the central macula will be performed. Though it is also seen in a variety of other diseases, a loss of ocular cells should be a warning sign of Batten disease. If Batten disease is the suspected diagnosis, a variety of tests is conducted to help accurately confirm the diagnosis, including:

- Blood or urine tests can help detect abnormalities that may indicate Batten disease. For example, elevated levels of dolichol in urine have been found in many individuals with NCL. The presence of vacuolated lymphocytes—white blood cells that contain holes or cavities (observed by microscopic analysis of blood smears)—when combined with other findings that indicate NCL, is suggestive for the juvenile form caused by "CLN3" mutations.

- Skin or tissue sampling is performed by extracting a small piece of tissue, which then is examined under an electron microscope. This can allow physicians to detect typical NCL deposits. These deposits are common in tissues such as skin, muscle, conjunctiva, and rectum. This diagnostic technique is useful, but other invasive tests are more reliable for diagnosing Batten disease.

- Electroencephalogram (EEG) is a technique that uses special probes attached on to the individual's scalp. It records electrical currents/signals, which allow medical experts to analylze electrical pattern activity in the brain. EEG assists in observing if the patient has seizures.

- Electrical studies of the eyes are used, because as mentioned, vision loss is the most common characteristic of Batten disease. Visual-evoked responses and electroretinograms are effective tests for detecting various eye conditions common in childhood NCLs.

- Computed tomography (CT) or magnetic resonance imaging (MRI) are diagnostic imaging tests which allow physicians to better visualize the appearance of the brain. MRI imaging test uses magnetic fields and radio waves to help create images of the brain. CT scan uses x-rays and computers to create a detailed image of the brain's tissues and structures. Both diagnostic imaging test can help reveal brain areas that are decaying, or atrophic, in persons with NCL.

- Measurement of enzyme activity specific to Batten disease may help confirm certain diagnoses caused by different mutations. Elevated levels of palmitoyl-protein thioesterase is involved in "CLN1". Acid protease is involved in "CLN2". Cathepsin D is involved in "CLN10".

- DNA analysis can be used to help confirm the diagnosis of Batten disease. When the mutation is known, DNA analysis can also be used to detect unaffected carriers of this condition for genetic counseling. If a family mutation has not previously been identified or if the common mutations are not present, recent molecular advances have made it possible to sequence all of the known NCL genes, increasing the chances of finding the responsible mutation(s).

In infantile Krabbe disease, death usually occurs in early childhood. A 2011 study found 1, 2, 3 year survival rates of 60%, 26%, and 14%, respectively. A few survived for longer and one was still alive at age 13. Patients with late-onset Krabbe disease tend to have a slower progression of the disease and live significantly longer.

Treatment is with penicillin, ampicillin, tetracycline, or co-trimoxazole for one to two years. Any treatment lasting less than a year has an approximate relapse rate of 40%. Recent expert opinion is that Whipple's disease should be treated with doxycycline with hydroxychloroquine for 12 to 18 months. Sulfonamides (sulfadiazine or sulfamethoxazole) may be added for treatment of neurological symptoms.

Protein function tests that demonstrate a reduce in chorein levels and also genetic analysis can confirm the diagnosis given to a patient. For a disease like this it is often necessary to sample the blood of the patient on multiple occasions with a specific request given to the haematologist to examine the film for acanthocytes. Another point is that the diagnosis of the disease can be confirmed by the absence of chorein in the western blot of the erythrocyte membranes.

Diagnosis of lymphoid tumors in poultry is complicated due to multiple etiological agents capable of causing very similar tumors. It is not uncommon that more than one avian tumor virus can be present in a chicken, thus one must consider both the diagnosis of the disease/tumors (pathological diagnosis) and of the virus (etiological diagnosis). A step-wise process has been proposed for diagnosis of Marek’s disease which includes (1) history, epidemiology, clinical observations and gross necropsy, (2) characteristics of the tumor cell, and (3) virological characteristics

The demonstration of peripheral nerve enlargement along with suggestive clinical signs in a bird that is around three to four months old (with or without visceral tumors) is highly suggestive of Marek's disease. Histological examination of nerves reveals infiltration of pleomorphic neoplastic and inflammatory lymphocytes. Peripheral neuropathy should also be considered as a principal rule-out in young chickens with paralysis and nerve enlargement without visceral tumors, especially in nerves with interneuritic edema and infiltration of plasma cells.

The presence of nodules on the internal organs may also suggest Marek's disease, but further testing is required for confirmation. This is done through histological demonstration of lymphomatous infiltration into the affected tissue. A range of leukocytes can be involved, including lymphocytic cell lines such as large lymphocyte, lymphoblast, primitive reticular cells, and occasional plasma cells, as well as macrophage and plasma cells. The T cells are involved in the malignancy, showing neoplastic changes with evidence of mitosis. The lymphomatous infiltrates need to be differentiated from other conditions that affect poultry including lymphoid leukosis and reticuloendotheliosis, as well as an inflammatory event associated with hyperplastic changes of the affected tissue.

Key clinical signs as well as gross and microscopic features that are most useful for differentiating Marek’s disease from lymphoid leukosis and reticuloendotheliosis include (1) Age: MD can affect birds at any age, including 5% in unvaccinated flocks; (4) Potential nerve enlargement; (5) Interfollicular tumors in the bursa of Fabricius; (6) CNS involvement; (7) Lymphoid proliferation in skin and feather follicles; (8) Pleomorphic lymphoid cells in nerves and tumors; and (9) T-cell lymphomas.

In addition to gross pathology and histology, other advanced procedures used for a definitive diagnosis of Marek’s disease include immunohistochemistry to identify cell type and virus-specific antigens, standard and quantitative PCR for identification of the virus, virus isolation to confirm infections, and serology to confirm/exclude infections.

The World Organisation for Animal Health (OIE) reference laboratories for Marek’s disease include the Pirbright Institute, UK and the USDA Avian Disease and Oncology Laboratory, USA.