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.

There are exceptions, but levels of alpha-glucosidase determines the type of GSD II an individual may have. More alpha glucosidase present in the individuals muscles means symptoms occur later in life and progress more slowly. GSD II is broadly divided into two onset forms based on the age symptoms occur.

Infantile-onset form is usually diagnosed at 4–8 months; muscles appear normal but are limp and weak preventing them from lifting their head or rolling over. As the disease progresses heart muscles thicken and progressively fail. Without treatment death usually occurs due to heart failure and respiratory weakness.

Late or later onset form occurs later than one to two years and progresses more slowly than Infantile-onset form. One of the first symptoms is a progressive decrease in muscle strength starting with the legs and moving to smaller muscles in the trunk and arms, such as the diaphragm and other muscles required for breathing. Respiratory failure is the most common cause of death. Enlargement of the heart muscles and rhythm disturbances are not significant features but do occur in some cases.

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.

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.

Diagnosis: A special urine test is available to check for any partially broken-down-sugars. If they are present, a skin or blood sample will be taken to test for below-normal amounts of alpha-fucosidase.

- Fucosidosis is an autosomal recessive disorder, which means that both parents have to have the mutation and pass it on to the child. When both parents have the mutation, there is a 25% chance of each child having fucosidosis.

A diagnosis is made by measuring the enzymatic activity of alpha--mannosidase in white blood cells. If there is a decreased level of the enzyme in comparison to standard levels, a diagnosis can be made. It is thought that this disorder might be under-diagnosed for a few different reasons—the diagnosis is often made late in the disease's progression, symptoms are often mild, or the biochemical diagnosis does not yield conclusive results.

The life expectancy in alpha-mannosidosis is highly variable. Individuals with early onset severe disease often do not survive beyond childhood, whereas those with milder disorders may survive well into adult life.

Type 2 appears when a child is around 18 months of age and in considered milder than Type 1 but still severe. Symptoms include:

- Symptoms similar to Type 1 but milder and progress more slowly.

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.

Diagnosis often can be made through clinical examination and urine tests (excess mucopolysaccharides are excreted in the urine). Enzyme assays (testing a variety of cells or body fluids in culture for enzyme deficiency) are also used to provide definitive diagnosis of one of the mucopolysaccharidoses. Prenatal diagnosis using amniocentesis and chorionic villus sampling can verify if a fetus either carries a copy of the defective gene or is affected with the disorder. Genetic counseling can help parents who have a family history of the mucopolysaccharidoses determine if they are carrying the mutated gene that causes the disorders.

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.

Seven distinct clinical types and numerous subtypes of the mucopolysaccharidoses have been identified. Although each mucopolysaccharidosis (MPS) differs clinically, most patients generally experience a period of normal development followed by a decline in physical and/or mental function. (Note: MPS-V and MPS-VIII are no longer in use as designations for any disease.)

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.

Hemoglobin H disease is a type of alpha thalassemia caused by impaired production of three of the four alpha globins, coded by genes HBA1 and HBA2.

Diagnosis of megalencephaly has changed over the years, however, with the development of more advanced equipment, physicians have been able to confirm the disorder with better accuracy. Usually, a physical exam is first performed when characteristics of megalencephaly have appeared. This typically occurs at birth or during early child development. A physician will then take head measurements in order to determine the circumference. This is known as the head circumference. Then a family background will be recorded in order to determine if there has been a history of megalencephaly in the family.

A neurological exam will then be performed using the technology of an MRI machine in order to confirm the diagnosis of megalencephaly. These imaging tests give detailed information regarding brain size, volume asymmetry and other irregular developments linked with MCAP, MPPH and hemimegalencephaly.

There is also a strong correlation of epilepsy and megalencephaly and this can aid doctors in their diagnosis.

If a diagnosis of megalencephaly is confirmed, the child is referred to a specialist who focuses on managing the symptoms and improving lifestyle. Since megalencephaly is usually presented with autism, the goal of treatment is to improve deficiencies associated with autistic causes. Additionally, since each patient has unique symptoms, there is no one specific treatment method and therefore is heavily reliant on symptoms associated with an individual.

The type II and XI collagenopathies are a group of disorders that affect connective tissue, the tissue that supports the body's joints and organs. These disorders are caused by defects in type II or type XI collagen. Collagens are complex molecules that provide structure, strength, and elasticity to connective tissue. Type II and type XI collagen disorders are grouped together because both types of collagen are components of the cartilage found in joints and the spinal column, the inner ear, and the jelly-like substance that fills the eyeball (the vitreous). The type II and XI collagenopathies result in similar clinical features.

Genetic changes are related to the following types of collagenopathy, types II and XI.

The system for classifying collagenopathies is changing as researchers learn more about the genetic causes of these disorders.The clinical features of the type II and XI collagenopathies vary among the disorders, but there is considerable overlap. Common signs and symptoms include problems with bone development that can result in short stature, enlarged joints, spinal curvature, and arthritis at a young age. For some people, bone changes can be seen only on X-ray images. Problems with vision and hearing, as well as a cleft palate with a small lower jaw, are common. Some individuals with these disorders have distinctive facial features such as protruding eyes and a flat nasal bridge.

Though only definitively diagnosable by genetic sequence testing, including a G band analysis, ATR-16 syndrome may be diagnosed from its constellation of symptoms. It must be distinguished from ATR-X syndrome, a very similar disease caused by a mutation on the X chromosome, and cases of alpha-thalassemia that co-occur with intellectual disabilities with no underlying genetic relationship.

The differential diagnosis is quite extensive and includes

- Buschke–Fischer–Brauer disease

- Curth–Macklin ichthyosis

- Gamborg Nielsen syndrome

- Greither disease

- Haber syndrome

- Hereditary punctate palmoplantar keratoderma

- Jadassohn–Lewandowsky syndrome

- Keratosis follicularis spinulosa decalvans

- Keratosis linearis with ichthyosis congenital and sclerosing keratoderma syndrome

- Meleda disease

- Mucosa hyperkeratosis syndrome

- Naegeli–Franceschetti–Jadassohn syndrome

- Naxos disease

- Olmsted syndrome

- Palmoplantar keratoderma and leukokeratosis anogenitalis

- Pandysautonomia

- Papillomatosis of Gougerot and Carteaud

- Papillon–Lefèvre syndrome

- Punctate porokeratotic keratoderma

- Richner–Hanhart syndrome

- Schöpf–Schulz–Passarge syndrome

- Unna Thost disease

- Vohwinkel syndrome

- Wong's dermatomyositis

A1AT deficiency remains undiagnosed in many patients. Patients are usually labeled as having COPD without an underlying cause. It is estimated that about 1% of all COPD patients actually have an A1AT deficiency. Thus, testing should be performed for all patients with COPD, asthma with irreversible airflow obstruction, unexplained liver disease, or necrotizing panniculitis. The initial test performed is serum A1AT level. A low level of A1AT confirms the diagnosis and further assessment with A1AT protein phenotyping and A1AT genotyping should be carried out subsequently. The Alpha-1 Foundation offers free, confidential testing.

As protein electrophoresis does not completely distinguish between A1AT and other minor proteins at the alpha-1 position (agarose gel), antitrypsin can be more directly and specifically measured using a nephelometric or immunoturbidimetric method. Thus, protein electrophoresis is useful for screening and identifying individuals likely to have a deficiency. A1AT is further analyzed by isoelectric focusing (IEF) in the pH range 4.5-5.5, where the protein migrates in a gel according to its isoelectric point or charge in a pH gradient.

Normal A1AT is termed M, as it migrates toward the center of such an IEF gel. Other variants are less functional and are termed A-L and N-Z, dependent on whether they run proximal or distal to the M band. The presence of deviant bands on IEF can signify the presence of alpha-1 antitrypsin deficiency. Since the number of identified mutations has exceeded the number of letters in the alphabet, subscripts have been added to most recent discoveries in this area, as in the Pittsburgh mutation described above. As every person has two copies of the A1AT gene, a heterozygote with two different copies of the gene may have two different bands showing on electrofocusing, although a heterozygote with one null mutant that abolishes expression of the gene will only show one band. In blood test results, the IEF results are notated as, e.g., PiMM, where Pi stands for protease inhibitor and "MM" is the banding pattern of that person.

Other detection methods include use of enzyme-linked-immuno-sorbent-assays in vitro and radial immunodiffusion.

Alpha 1-antitrypsin levels in the blood depend on the genotype. Some mutant forms fail to fold properly and are, thus, targeted for destruction in the proteasome, whereas others have a tendency to polymerize, thereafter being retained in the endoplasmic reticulum. The serum levels of some of the common genotypes are:

- PiMM: 100% (normal)

- PiMS: 80% of normal serum level of A1AT

- PiSS: 60% of normal serum level of A1AT

- PiMZ: 60% of normal serum level of A1AT

- PiSZ: 40% of normal serum level of A1AT

- PiZZ: 10-15% (severe alpha-1 antitrypsin deficiency)

Treatments for ATR-16 syndrome depend on the symptoms experienced by any individual. Alpha thalassemia is usually self-limiting, but in some cases may require a blood transfusion or chelating treatment.

Familial renal amyloidosis (or familial visceral amyloidosis, or hereditary amyloid nephropathy) is a form of amyloidosis primarily presenting in the kidney.

It is associated most commonly with congenital mutations in the fibrinogen alpha chain and classified as a dysfibrinogenemia (see Hereditary Fibrinogen Aα-Chain Amyloidosis). and, less commonly, with congenital mutations in apolipoprotein A1 and lysozyme.

It is also known as "Ostertag" type, after B. Ostertag, who characterized it in 1932 and 1950.

Since there are very few treatment methods focused on managing megalencephaly, future research is targeted at inhibiting mutation of the pathway. However, this next step could be met with several complications as understanding the underlying mechanism of the mutation is a difficult task. The genetic coding that initiates a single mutation is sporadic and patterns are hard to detect in many cases.

Even thought very little research has been done to create inhibitors of the PI3K-AKT pathway, several pharmaceutical companies have begun to focus their interests in designing a prevention method for this purpose.

The diagnosis of this condition can be done via the following:

- Flow cytometry

- Bleeding time analysis