Niemann–Pick type C has a wide clinical spectrum. Affected individuals may have enlargement of the spleen (splenomegaly) and liver (hepatomegaly), or enlarged spleen or liver combined (hepatosplenomegaly), but this finding may be absent in later onset cases. Prolonged jaundice or elevated bilirubin can present at birth. In some cases, however, enlargement of the spleen or liver does not occur for months or years – or not at all. Enlargement of the spleen or liver frequently becomes less apparent with time, in contrast to the progression of other lysosomal storage diseases such as Niemann–Pick disease, Types A and B or Gaucher disease. Organ enlargement does not usually cause major complications.

Progressive neurological disease is the hallmark of Niemann–Pick type C disease, and is responsible for disability and premature death in all cases beyond early childhood. Classically, children with NPC may initially present with delays in reaching normal developmental milestones skills before manifesting cognitive decline (dementia).

Neurological signs and symptoms include cerebellar ataxia (unsteady walking with uncoordinated limb movements), dysarthria (slurred speech), dysphagia (difficulty in swallowing), tremor, epilepsy (both partial and generalized), vertical supranuclear palsy (upgaze palsy, downgaze palsy, saccadic palsy or paralysis), sleep inversion, gelastic cataplexy (sudden loss of muscle tone or drop attacks), dystonia (abnormal movements or postures caused by contraction of agonist and antagonist muscles across joints), most commonly begins with in turning of one foot when walking (action dystonia) and may spread to become generalized, spasticity (velocity dependent increase in muscle tone), hypotonia, ptosis (drooping of the upper eyelid), microcephaly (abnormally small head), psychosis, progressive dementia, progressive hearing loss, bipolar disorder, major and psychotic depression that can include hallucinations, delusions, mutism, or stupor.

In the terminal stages of Niemann–Pick type C disease, the patient is bedridden, with complete ophthalmoplegia, loss of volitional movement and severe dementia.

Symptoms are related to the organs in which sphingomyelin accumulates. Enlargement of the liver and spleen (hepatosplenomegaly) may cause reduced appetite, abdominal distension, and pain. Enlargement of the spleen (splenomegaly) may also cause low levels of platelets in the blood (thrombocytopenia).

Accumulation of sphingomyelin in the central nervous system (including the cerebellum) results in unsteady gait (ataxia), slurring of speech (dysarthria), and difficulty in swallowing (dysphagia). Basal ganglia dysfunction causes abnormal posturing of the limbs, trunk, and face (dystonia). Upper brainstem disease results in impaired voluntary rapid eye movements (supranuclear gaze palsy). More widespread disease involving the cerebral cortex and subcortical structures causes gradual loss of intellectual abilities, causing dementia and seizures.

Bones also may be affected: symptoms may include enlarged bone marrow cavities, thinned cortical bone, or a distortion of the hip bone called coxa vara. Sleep-related disorders, such as sleep inversion, sleepiness during the day and wakefulness at night, may occur. Gelastic cataplexy, the sudden loss of muscle tone when the affected patient laughs, is also seen.

Niemann–Pick type C is a lysosomal storage disease associated with mutations in NPC1 and NPC2 genes. Niemann–Pick type C affects an estimated 1:150,000 people. Approximately 50% of cases present before 10 years of age, but manifestations may first be recognized as late as the sixth decade.

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.

Tay–Sachs disease is typically first noticed in infants around 6 months old displaying an abnormally strong response to sudden noises or other stimulus, known as the "startle response," because they are startled. There may also be listlessness or muscle stiffness (hypertonia). The disease is classified into several forms, which are differentiated based on the onset age of neurological symptoms.

- Infantile Tay–Sachs disease. Infants with Tay–Sachs disease appear to develop normally for the first six months after birth. Then, as neurons become distended with gangliosides, a relentless deterioration of mental and physical abilities begins. The child may become blind, deaf, unable to swallow, atrophied, and paralytic. Death usually occurs before the age of four.

- Juvenile Tay–Sachs disease. Juvenile Tay–Sachs disease is rarer than other forms of Tay–Sachs, and usually is initially seen in children between two and ten years old. People with Tay–Sachs disease develop cognitive and motor skill deterioration, dysarthria, dysphagia, ataxia, and spasticity. Death usually occurs between the age of five to fifteen years.

- Adult/Late-Onset Tay–Sachs disease. A rare form of this disease, known as Adult-Onset or Late-Onset Tay–Sachs disease, usually has its first symptoms during the 30s or 40s. In contrast to the other forms, late-onset Tay–Sachs disease is usually not fatal as the effects can stop progressing. It is frequently misdiagnosed. It is characterized by unsteadiness of gait and progressive neurological deterioration. Symptoms of late-onset Tay–Sachs – which typically begin to be seen in adolescence or early adulthood – include speech and swallowing difficulties, unsteadiness of gait, spasticity, cognitive decline, and psychiatric illness, particularly a schizophrenia-like psychosis. People with late-onset Tay–Sachs may become full-time wheelchair users in adulthood.

Until the 1970s and 1980s, when the disease's molecular genetics became known, the juvenile and adult forms of the disease were not always recognized as variants of Tay–Sachs disease. Post-infantile Tay–Sachs was often misdiagnosed as another neurological disorder, such as Friedreich's ataxia.

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 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.

Tay–Sachs disease is a genetic disorder that results in the destruction of nerve cells in the brain and spinal cord. The most common type, known as infantile Tay–Sachs disease, becomes apparent around three to six months of age with the baby losing the ability to turn over, sit, or crawl. This is then followed by seizures, hearing loss, and inability to move. Death usually occurs in early childhood. Less commonly the disease may occur in later childhood or adulthood. These forms are generally milder in nature.

Tay–Sachs disease is caused by a genetic mutation in the "HEXA" genes on chromosome 15. It is inherited from a person's parents in an autosomal recessive manner. The mutation results in problems with an enzyme called beta-hexosaminidase A which results in the buildup of the molecule GM2 ganglioside within cells, leading to toxicity. Diagnosis is by measuring the blood hexosaminidase A level or genetic testing. It is a type of sphingolipidoses.

The treatment of Tay–Sachs disease is supportive in nature. This may involve multiple specialities as well as psychosocial support for the family. The disease is rare in the general population. In Ashkenazi Jews, French Canadians of southeastern Quebec, and Cajuns of southern Louisiana, the condition is more common. Approximately 1 in 3,600 Ashkenazi Jews at birth are affected.

The disease is named after Waren Tay, who in 1881 first described a symptomatic red spot on the retina of the eye; and Bernard Sachs, who described in 1887 the cellular changes and noted an increased rate of disease in Ashkenazi Jews. Carriers of a single Tay–Sachs allele are typically normal. It has been hypothesized that being a carrier may confer protection from another condition such as tuberculosis, explaining the persistence of the allele in certain populations. Researchers are looking at gene therapy or enzyme replacement therapy as possible treatments.

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.

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.

Niemann–Pick disease, SMPD1-associated refers to two different types of Niemann–Pick disease which are associated with the SMPD1 gene.

There are approximately 1,200 cases of NPA and NPB worldwide with the majority of cases being Type B or an intermediate form.

Descriptions of type E and type F have been published, but they are not well characterized, and are currently classified under type B.

A lipid storage disorder (or lipidosis) can be any one of a group of inherited metabolic disorders in which harmful amounts of fats or lipids accumulate in some of the body’s cells and tissues. People with these disorders either do not produce enough of one of the enzymes needed to metabolize and break down lipids or they produce enzymes that do not work properly. Over time, this excessive storage of fats can cause permanent cellular and tissue damage, particularly in the brain, peripheral nervous system, liver, spleen and bone marrow.

Inside cells under normal conditions, lysosomes convert, or metabolize, lipids and proteins into smaller components to provide energy for the body.

Other lipid storage disorders that are generally not classified as sphingolipidoses include fucosidosis, Schindler disease and Wolman disease.

PASLI disease is a rare genetic disorder of the immune system. PASLI stands for “p110 delta activating mutation causing senescent T cells, lymphadenopathy, and immunodeficiency.” The immunodeficiency manifests as recurrent infections usually starting in childhood. These include bacterial infections of the respiratory system and chronic viremia due to Epstein-Barr virus (EBV) and/or cytomegalovirus (CMV). Individuals with PASLI disease also have an increased risk of EBV-associated lymphoma. Investigators Carrie Lucas, Michael Lenardo, and Gulbu Uzel at the National Institute of Allergy and Infectious Diseases at the U.S. National Institutes of Health and Sergey Nejentsev at the University of Cambridge, UK simultaneously described a mutation causing this condition which they called Activated PI3K Delta Syndrome (APDS).

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.

A genetic disorder is a genetic problem caused by one or more abnormalities in the genome, especially a condition that is present from birth (congenital). Most genetic disorders are quite rare and affect one person in every several thousands or millions.

Genetic disorders may be hereditary, passed down from the parents' genes. In other genetic disorders, defects may be caused by new mutations or changes to the DNA. In such cases, the defect will only be passed down if it occurs in the germ line. The same disease, such as some forms of cancer, may be caused by an inherited genetic condition in some people, by new mutations in other people, and mainly by environmental causes in other people. Whether, when and to what extent a person with the genetic defect or abnormality will actually suffer from the disease is almost always affected by the environmental factors and events in the person's development.

Some types of recessive gene disorders confer an advantage in certain environments when only one copy of the gene is present.

Clinically, PASLI disease is characterized by recurrent sinopulmonary infections that can lead to progressive airway damage. Patients also suffer from lymphoproliferation (large lymph nodes and spleen), chronic viremia due to EBV or CMV, distinctive lymphoid nodules at mucosal surfaces, autoimmune cytopenias, and EBV-driven B cell lymphoma. Importantly, the clinical presentations and disease courses are variable with some individuals severely affected, whereas others show little manifestation of disease. This “variable expressivity,” even within the same family, can be striking and may be explained by differences in lifestyle, exposure to pathogens, treatment efficacy, or other genetic modifiers.

Individuals that are homozygotes for Tangier's disease develop various cholesterol ester depositions. These are especially visible in the tonsils, as they may appear yellow/orange. The cholesterol esters may also be found in lymph nodes, bone marrow, the liver and spleen.

Due to the cholesterol ester depositions the tonsils may be enlarged. Hepatosplenomegaly (enlarged liver and spleen) is common.

Neuropathy and cardiovascular disease are the most devastating developments caused by Tangier's disease.

High-density lipoproteins are created when a protein in the bloodstream, Apolipoprotein A1 (apoA1), combines with cholesterol and phospholipids. The cholesterol and phospholipids used to form HDL originate from inside cells but are transported out of the cell into the blood via the ABCA1 transporter. People with Tangier disease have defective ABCA1 transporters resulting in a greatly reduced ability to transport cholesterol out of their cells, which leads to an accumulation of cholesterol and phospholipids in many body tissues, which can cause them to increase in size. Reduced blood levels of high-density lipoproteins is sometimes described as hypoalphalipoproteinemia.

People affected by this condition also have slightly elevated amounts of fat in the blood (mild hypertriglyceridemia) and disturbances in nerve function (neuropathy). The tonsils are visibly affected by this disorder; they frequently appear orange or yellow and are extremely enlarged. Affected people often develop premature atherosclerosis, which is characterized by fatty deposits and scar-like tissue lining the arteries. Other signs of this condition may include an enlarged spleen (splenomegaly), an enlarged liver (hepatomegaly), clouding of the cornea, and early-onset cardiovascular disease.

Tangier disease is a rare disorder with approximately 50 cases identified worldwide. This disorder was originally discovered on Tangier Island off the coast of Virginia, but has now been identified in people from many different countries.

Progressive myoclonus epilepsy (PME) is a rare epilepsy syndrome caused by a variety of genetic disorders. The syndrome includes myoclonic seizures and tonic-clonic seizures together with progressive neurological decline.

The following symptoms (signs) are consistent with complement deficiency in general:

The precise symptoms of a primary immunodeficiency depend on the type of defect. Generally, the symptoms and signs that lead to the diagnosis of an immunodeficiency include recurrent or persistent infections or developmental delay as a result of infection. Particular organ problems (e.g. diseases involving the skin, heart, facial development and skeletal system) may be present in certain conditions. Others predispose to autoimmune disease, where the immune system attacks the body's own tissues, or tumours (sometimes specific forms of cancer, such as lymphoma). The nature of the infections, as well as the additional features, may provide clues as to the exact nature of the immune defect.

Acquired hypocomplementemia may occur in the setting of bone infections (osteomyelitis), infection of the lining of the heart (endocarditis), and cryoglobulinemia. Systemic lupus erythematosus is associated with low C3 and C4 Membranoproliferative glomerulonephritis usually has low C3.

Primary immunodeficiencies are disorders in which part of the body's immune system is missing or does not function normally. To be considered a "primary" immunodeficiency, the cause of the immune deficiency must not be secondary in nature (i.e., caused by other disease, drug treatment, or environmental exposure to toxins). Most primary immunodeficiencies are genetic disorders; the majority are diagnosed in children under the age of one, although milder forms may not be recognized until adulthood. While there are over 100 recognized PIDs, most are very rare. About 1 in 500 people in the United States are born with a primary immunodeficiency. Immune deficiencies can result in persistent or recurring infections, autoinflammatory disorders, tumors, and disorders of various organs. There are currently no cures for these conditions; treatment is palliative and consists of managing infections and boosting the immune system.

Membranoproliferative glomerulonephritis ("MPGN"), also known as mesangiocapillary glomerulonephritis, is a type of glomerulonephritis caused by deposits in the kidney glomerular mesangium and basement membrane (GBM) thickening, activating complement and damaging the glomeruli.

MPGN accounts for approximately 4% of primary renal causes of nephrotic syndrome in children and 7% in adults.

It should not be confused with membranous glomerulonephritis, a condition in which the basement membrane is thickened, but the mesangium is not.