Niemann–Pick type C is diagnosed by assaying cultured fibroblasts for cholesterol esterfication and staining for unesterified cholesterol with filipin. The fibroblasts are grown from a small skin biopsy taken from a patient with suspected NPC. The diagnosis can be confirmed by identifying mutations in the NPC1 or NPC2 genes in 80–90% of cases. This specialized testing is available at Thomas Jefferson University Lysosomal Disease Testing Lab and the Mayo Clinic.

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 majority of patients is initially screened by enzyme assay, which is the most efficient method to arrive at a definitive diagnosis. In some families where the disease-causing mutations are known and in certain genetic isolates, mutation analysis may be performed. In addition, after a diagnosis is made by biochemical means, mutation analysis may be performed for certain disorders.

Type A Niemann–Pick disease (about 85% of cases) has an extremely poor prognosis, with most cases being fatal by the age of 18 months. Type B (adult onset) and type C (mutation affecting a different molecule) Niemann–Pick diseases have a better prognosis.

Diagnosis of the lipid storage disorders can be achieved through the use of several tests. These tests include clinical examination, biopsy, genetic testing, molecular analysis of cells or tissues, and enzyme assays. Certain forms of this disease can also be diagnosed through urine testing which will detect the stored material. Prenatal testing is also available to determine if the fetus will have the disease or is a carrier.

As of 2010, even with the best care, children with infantile Tay–Sachs disease usually die by the age of 4.

There are four types of Niemann–Pick disease in two categories. Patients with ASM deficiency are classified into type A and B. Type A patients exhibit hepatosplenomegaly in infancy and profound central nervous system involvement and unable to survive beyond two years of age. Type B patients also show hepatosplenomegaly and pathologic alterations of their lungs but usually without the involvement of their central nervous system. Some can develop significant life-threatening complications including liver failure, hemorrhage, oxygen dependency, pulmonary infections, and splenic rupture. Some develop coronary artery or valvular heart disease. In a longitudinal natural history study, nearly 20% of the patients died. For those classified into type C, they may have mild hepatosplenomegaly, but their central nervous system is profoundly affected.

- Niemann–Pick disease, SMPD1-associated, which includes types A and B

- Niemann–Pick disease, type C: subacute/juvenile, includes types C1 (95% of type C) and C2. Type C is the most common form of the disease Type C2 is a rare form of the disease.

The lifespan of patients with NPC is usually related to the age of onset. Children with antenatal or infantile onset usually succumb in the first few months or years of life, whereas adolescent and adult onset forms of Niemann–Pick type C have a more insidious onset and slower progression, and affected individuals may survive to the seventh decade. Adult cases of NPC are being recognized with increasing frequency. It is suspected that many patients affected by NPC are undiagnosed, owing to lack of awareness of the disease and the absence of readily available screening or diagnostic tests. For the same reasons the diagnosis is often delayed by many years.

The symptoms of LSD vary, depending on the particular disorder and other variables such as the age of onset, and can be mild to severe. They can include developmental delay, movement disorders, seizures, dementia, deafness, and/or blindness. Some people with LSDhave enlarged livers (hepatomegaly) and enlarged spleens (splenomegaly), pulmonary and cardiac problems, and bones that grow abnormally.

Niemann–Pick Type A, the most common type, occurs in infants and is characterized by jaundice, an enlarged liver, failure to thrive, progressive deterioration of the nervous system and profound brain damage. Children affected by Niemann Pick Type A rarely live beyond 18 months. Niemann–Pick Type A occurs more frequently among individuals of Ashkenazi (eastern and central European) Jewish descent than in other ethnicities. The incidence within the Ashkenazi population is approximately 1 in 40,000 people. The incidence for other populations is 1 in 250,000 people.

Niemann–Pick Type B involves an enlarged liver and spleen hepatosplenomegaly, growth retardation, and problems with lung function including frequent lung infections. Other signs include blood abnormalities such as abnormal cholesterol and lipid levels, and low numbers of blood cells involved in clotting (platelets). The brain is not affected in Type B and the disease often presents in the pre-teen years.

There are no specific treatments for lipid storage disorders; however, there are some highly effective enzyme replacement therapies for people with type 1 Gaucher disease and some patients with type 3 Gaucher disease. There are other treatments such as the prescription of certain drugs like phenytoin and carbamazepine to treat pain for patients with Fabry disease. Furthermore, gene thereapies and bone marrow transplantation may prove to be effective for certain lipid storage disorders. Diet restrictions do not help prevent the buildup of lipids in the tissues.

Due to the wide range of genetic disorders that are presently known, diagnosis of a genetic disorder is widely varied and dependent of the disorder. Most genetic disorders are diagnosed at birth or during early childhood, however some, such as Huntington's disease, can escape detection until the patient is well into adulthood.

The basic aspects of a genetic disorder rests on the inheritance of genetic material. With an in depth family history, it is possible to anticipate possible disorders in children which direct medical professionals to specific tests depending on the disorder and allow parents the chance to prepare for potential lifestyle changes, anticipate the possibility of stillbirth, or contemplate termination. Prenatal diagnosis can detect the presence of characteristic abnormalities in fetal development through ultrasound, or detect the presence of characteristic substances via invasive procedures which involve inserting probes or needles into the uterus such as in amniocentesis.

Not all genetic disorders directly result in death, however there are no known cures for genetic disorders. Many genetic disorders affect stages of development such as Down syndrome. While others result in purely physical symptoms such as muscular dystrophy. Other disorders, such as Huntington's disease show no signs until adulthood. During the active time of a genetic disorder, patients mostly rely on maintaining or slowing the degradation of quality of life and maintain patient autonomy. This includes physical therapy, pain management, and may include a selection of alternative medicine programs.

Franklin's disease (gamma heavy chain disease)

It is a very rare B-cell lymphoplasma cell proliferative disorder which may be associated with autoimmune diseases and infection is a common characteristic of the disease. It is characterized by lymphadenopathy, fever, anemia, malaise, hepatosplenomegaly, and weakness. The most distinctive symptom is palatal edema, caused by nodal involvement of Waldeyer's ring.

Diagnosis is made by the demonstration of an anomalous serum M component that reacts with anti-IgG but not anti-light chain reagents. Bone marrow examination is usually nondiagnostic.

Patients usually have a rapid downhill course and die of infection if left untreated or misdiagnosed.

Patients with Franklin disease usually have a history of progressive weakness, fatigue, intermittent fever, night sweats and weight loss and may present with lymphadenopathy (62%), splenomegaly (52%) or hepatomegaly (37%). The fever is considered secondary to impaired cellular and humoral immunity, and thus recurrent infections are the common clinical presentation in Franklin disease. Weng et al. described the first case of Penicillium sp. infection in a patient with Franklin disease and emphasized the importance of proper preparation for biopsy, complete hematologic investigation, culture preparation and early antifungal coverage to improve the outcome.

The γHCD can be divided into three categories based on the various clinical and pathological features. These categories are disseminated lymphoproliferative disease, localized proliferative disease and no apparent proliferative disease.

- Disseminated lymphoproliferative disease is found in 57-66% of patients diagnosed with γHCD. Lymphadenopathy and constitutional symptoms are the usual features.

- Localized proliferative disease is found in approximately 25% of γHCD patients. This is characterized by a localization of the mutated heavy chains in extramedullary tissue, or solely in the bone marrow.

- No apparent proliferative disease is seen in 9-17% of patients with γHCD, and there is almost always an underlying autoimmune disorder.

The IgM type of heavy chain disease, μHCD, is often misdiagnosed as chronic lymphoid leukemia (CLL) because the two diseases are often associated with each other and show similar symptoms.

Sphingolipidoses (singular "sphingolipidosis") are a class of lipid storage disorders relating to sphingolipid metabolism. The main members of this group are Niemann–Pick disease, Fabry disease, Krabbe disease, Gaucher disease, Tay–Sachs disease and metachromatic leukodystrophy. They are generally inherited in an autosomal recessive fashion, but notably Fabry disease is X-linked recessive. Taken together, sphingolipidoses have an incidence of approximately 1 in 10,000, but substantially more in certain populations such as Ashkenazi Jews. Enzyme replacement therapy is available to treat mainly Fabry disease and Gaucher disease, and people with these types of sphingolipidoses may live well into adulthood. The other types are generally fatal by age 1 to 5 years for infantile forms, but progression may be mild for juvenile- or adult-onset forms.

Kufs disease is one of many diseases categorized under a disorder known as neuronal ceroid lipofuscinosis (NCLs). NCLs are broadly described to create problems with vision, movement and cognitive function. Among all NCLs diseases, Kufs is the only one that does not affect vision, and although this is a distinguishing factor of Kufs, NCLs are typically differentiated by the age at which they appear in a patient

Kufs is a neuronal disease, meaning it affects the nervous system, specifically voluntary movement and intellectual function. Symptoms of Kufs can manifest anytime between adolescence and adulthood, however it usually appears around age 30.

There are two types of Kufs: Type A and Type B. Type A causes seizures, myoclonic epilepsy (muscle jerks), dementia, ataxia (compromised muscle coordination), tremors and tics, dysarthria (speech difficulties), confusion, and psychotic behaviour. Although similar to Type A, patients with Type B do not suffer from myoclonic epilepsy or dysarthria, and they do display changes in personality. It is occasional that patients present with skin disorders causing dryness, roughness, and scaliness. The skin symptoms specifically, are a result of Keratin buildup in the skin cells (see ‘Genetic Causes’ for more information). Regardless of the type, most Kufs patients do not survive more than 15 years after their symptoms have manifested.

The confirmatory diagnosis is made via brain biopsy, however, other tests can be used to help such as MRI, EEG, CT, as well as the physical exam and history

Marchiafava-Bignami disease is routinely diagnosed with the use of an MRI due to the fact that the majority of clinical symptoms are non-specific. Before the use of such imaging equipment, it was unable to be diagnosed until autopsy. The patient usually has a history of alcoholism or malnutrition and neurological symptoms are sometimes present and can help lead to a diagnosis. MBD can be told apart from other neural diseases due to the symmetry of the lesions in the corpus callosum as well as the fact that these lesions don’t affect the upper and lower edges.

There are two clinical subtypes of MBD

Type A- Stupor and coma predominate. Radiological imaging shows involvement of the entire corpus callosum. This type is also associated with symptoms of the upper motor neurons.

Type B- This type has normal or only mildly impair mental status and radiological imaging shows partial lesions in the corpus callosum.

Diagnosis

Originally NEMO deficiency syndrome was thought to be a combination of Ectodermal Dysplasia (ED) and a lack of immune function, but is now understood to be more complex disease. NEMO Deficiency Syndrome may manifest itself in the form of several different diseases dependent upon mutations of the IKBKG gene such as Incontinentia pigmenti or Ectodermal dysplasia.

The clinical presentation of NEMO deficiency is determined by three main symptoms:

1. Susceptibility to pyogenic infections in the form of severe local inflammation

2. Susceptibility to mycobacterial infection

3. Symptoms of Ectodermal Dysplasia

To determine whether or not patient has NEMO deficiency, an immunologic screen to test immune system response to antigen may be used although a genetic test is the only way to be certain as many individuals respond differently to the immunological tests.

Commonly Associated Diseases

NEMO deficiency syndrome may present itself as Incontinentia pigmenti or Ectodermal dysplasia depending on the type of genetic mutation present, such as if the mutation results in the complete loss of gene function or a point mutation.

Amorphic genetic mutations in the IKBKG gene, which result in the loss of gene function, typically present themselves as Incontinetia Pigmenti (IP). Because loss of NEMO function is lethal, only heterozygous females or males with XXY karyotype or mosaicism for this gene survive and exhibit symptoms of Incontinetia Pigmenti, such as skin lesions and abnormalities in hair, teeth, and nails. There are a variety of mutations that may cause the symptoms of IP, however, they all involve the deletion of exons on the IKBKG gene.

Hypomorphic genetic mutations in the IKBKG gene, resulting in a partial loss of gene function, cause the onset of Anhidrotic ectodermal dysplasia with Immunodeficiency (EDA-IP). The lack of NEMO results in a decreased levels of NF-κB transcription factor translocation and gene transcription, which in turn leads to a low level of immunoglobulin production. Because NF-κB translocation is unable to occur without proper NEMO function, the cell signaling response to immune mediators such as IL-1β, IL-18, and LPS are ineffective thus leading to a compromised immune response to various forms of bacterial infections.

Treatment

The aim of treatment is to prevent infections so children will usually be started on immunoglobulin treatment. Immunoglobulin is also known as IgG or antibody. It is a blood product and is given as replacement for people who are unable to make their own antibodies. It is the mainstay of treatment for patients affected by primary antibody deficiency. In addition to immunoglobulin treatment, children may need to take antibiotics or antifungal medicines to prevent infections or treat them promptly when they occur. Regular monitoring and check-ups will help to catch infections early. If an autoimmune response occurs, this can be treated with steroid and/or biologic medicines to damp down the immune system so relieving the symptoms.

In some severely affected patients, NEMO deficiency syndrome is treated using a bone marrow or blood stem cell transplant. The aim is to replace the faulty immune system with an immune system from a healthy donor.

When suspected, the diagnosis can be confirmed by laboratory measurement of IgA level in the blood. SigAD is an IgA level < 7 mg/dL with normal IgG and IgM levels (reference range 70–400 mg/dl for adults; children somewhat less).

The only currently available method to diagnose Unverricht–Lundborg disease is a genetic test to check for the presence of the mutated cystatin B gene. If this gene is present in an individual suspected of having the disease, it can be confirmed. However, genetic tests of this type are prohibitively expensive to perform, especially due to the rarity of ULD. The early symptoms of ULD are general and in many cases similar to other more common epilepsies, such as juvenile myoclonic epilepsy. For these reasons, ULD is generally one of the last options doctors explore when looking to diagnose patients exhibiting its symptoms. In most cases, a misdiagnosis is not detrimental to the patient, because many of the same medications are used to treat both ULD and whatever type of epilepsy the patient has been misdiagnosed with. However, there are a few epilepsy medications that increase the incidence of seizures and myoclonic jerks in patients with ULD, which can lead to an increase in the speed of progression, including phenytoin, fosphenytoin, sodium channel blockers, GABAergic drugs, gabapentin and pregabalin.

Other methods to diagnose Unverricht–Lundborg disease are currently being explored. While electroencephalogram (EEG) is useful in identifying or diagnosing other forms of epilepsy, the location of seizures in ULD is currently known to be generalized across the entire brain. Without a specific region to pinpoint, it is difficult to accurately distinguish an EEG reading from an individual with ULD from an individual with another type of epilepsy characterized by generalized brain seizures. However, with recent research linking ULD brain damage to the hippocampus, the usefulness of EEG as a diagnostic tool may increase.

Magnetic Resonance Imaging (MRI) is also often used during diagnosis of patients with epilepsy. While MRIs taken during the onset of the disease are generally similar to those of individuals without ULD, MRIs taken once the disease has progressed show characteristic damage, which may help to correct a misdiagnosis.

While ULD is a rare disease, the lack of well defined cases to study and the difficulty in confirming diagnosis provide strong evidence that this disease is likely under diagnosed.

The basic tests performed when an immunodeficiency is suspected should include a full blood count (including accurate lymphocyte and granulocyte counts) and immunoglobulin levels (the three most important types of antibodies: IgG, IgA and IgM).

Other tests are performed depending on the suspected disorder:

- Quantification of the different types of mononuclear cells in the blood (i.e. lymphocytes and monocytes): different groups of T lymphocytes (dependent on their cell surface markers, e.g. CD4+, CD8+, CD3+, TCRαβ and TCRγδ), groups of B lymphocytes (CD19, CD20, CD21 and Immunoglobulin), natural killer cells and monocytes (CD15+), as well as activation markers (HLA-DR, CD25, CD80 (B cells).

- Tests for T cell function: skin tests for delayed-type hypersensitivity, cell responses to mitogens and allogeneic cells, cytokine production by cells

- Tests for B cell function: antibodies to routine immunisations and commonly acquired infections, quantification of IgG subclasses

- Tests for phagocyte function: reduction of nitro blue tetrazolium chloride, assays of chemotaxis, bactericidal activity.

Due to the rarity of many primary immunodeficiencies, many of the above tests are highly specialised and tend to be performed in research laboratories.

Criteria for diagnosis were agreed in 1999. For instance, an antibody deficiency can be diagnosed in the presence of low immunoglobulins, recurrent infections and failure of the development of antibodies on exposure to antigens. The 1999 criteria also distinguish between "definitive", "probable" and "possible" in the diagnosis of primary immunodeficiency. "Definitive" diagnosis is made when it is likely that in 20 years, the patient has a >98% chance of the same diagnosis being made; this level of diagnosis is achievable with the detection of a genetic mutation or very specific circumstantial abnormalities. "Probable" diagnosis is made when no genetic diagnosis can be made, but the patient has all other characteristics of a particular disease; the chance of the same diagnosis being made 20 years later is estimated to be 85-97%. Finally, a "possible" diagnosis is made when the patient has only some of the characteristics of a disease are present, but not all.