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.

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.

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.

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 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.

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.

Pyruvate dehydrogenase deficiency can be diagnosed via the following methods:

- Blood test (Lactate and pyruvate levels)

- Urine analysis

- Magnetic resonance spectroscopy

- MRI

The differential diagnosis of pyruvate dehydrogenase deficiency can consist of either D-Lactic acidosis or abnormalities associated with gluconeogenesis.

Diagnosis of Bruck syndrome must distinguish the association of contractures and skeletal fragility. Ultrasound is used for prenatal diagnosis. The diagnosis of a neonate bears resemblance to arthrogryposis multiplex congenital, and later in childhood to osteogenesis imperfecta.

Microscopic analysis of the hair shows twisted hairs of unequal size and different shapes (pili torti, aniso- and poikilotrichosis), longitudinal breaks and breaks located at nodes (trichorrhexis nodosa). Scanning electron microscopy might reveal hair budding (trichorrhexis blastysis). Biochemical analysis may reveal sulfur-deficient brittle hair (trichothiodystrophy; note that disulfide bonds determine hair waviness).

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.

There are no methods for preventing the manifestation of the pathology of MSUD in infants with two defective copies of the BCKD gene. However, genetic counselors may consult with couples to screen for the disease via DNA testing. DNA testing is also available to identify the disease in an unborn child in the womb.

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.

In addition to genetic tests involving the sequencing of "PEX" genes, biochemical tests have proven highly effective for the diagnosis of Zellweger syndrome and other peroxisomal disorders. Typically, Zellweger syndrome 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.

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.)

On 9 May 2014, the UK National Screening Committee (UK NSC) announced its recommendation to screen every newborn baby in the UK for four further genetic disorders as part of its NHS Newborn Blood Spot Screening programme, including maple syrup urine disease.

Newborn screening for maple syrup urine disease involves analyzing the blood of 1–2 day-old newborns through tandem mass spectrometry. The blood concentration of leucine and isoleucine is measured relative to other amino acids to determine if the newborn has a high level of branched-chain amino acids. Once the newborn is 2–3 days old the blood concentration of branched-chain amino acids like leucine is greater than 1000 µmol/L and alternative screening methods are used. Instead, the newborn’s urine is analyzed for levels of branched-chain alpha-hydroxyacids and alpha-ketoacids.

Platelets may be enlarged. The membrane surface connected canalicular system is disrupted with prominent tubules and small membranous vesicles. Alpha granules may be missing from the platelets. Despite these abnormalities there is no increased tendency to bleed in this syndrome.

A 2014 study classified cases into three types—epidermolysis bullosa simplex (EBS), junctional epidermolysis bullosa (JEB), and dystrophic epidermolysis bullosa (DEB) -- and reviewed their times of death. The first two types tended to die in infancy and the last in early adulthood.

Treatment remains largely supportive. The behavioral disturbances of MPS-III respond poorly to medication. If an early diagnosis is made, bone marrow replacement may be beneficial. Although the missing enzyme can be manufactured and given intravenously, it cannot penetrate the blood–brain barrier and therefore cannot treat the neurological manifestations of the disease.

Along with many other lysosomal storage diseases, MPS-III exists as a model of a monogenetic disease involving the central nervous system.

Several promising therapies are in development. Gene therapy in particular is under Phase I/II clinical trial in France since October 2011 under the leadership of Paris-based biotechnology company Lysogene. Other potential therapies include chemical modification of deficient enzymes to allow them to penetrate the blood–brain barrier, stabilisation of abnormal but active enzyme to prevent its degradation, and implantation of stem cells strongly expressing the missing enzyme. For any future treatment to be successful, it must be administered as early as possible. Currently MPS-III is mainly diagnosed clinically, by which stage it is probably too late for any treatment to be very effective. Neonatal screening programs would provide the earliest possible diagnosis.

The flavonoid genistein decreases the pathological accumulation of glycosaminoglycans in Sanfilippo syndrome. "In vitro", animal studies and clinical experiments suggest that the symptoms of the disease may be alleviated by an adequate dose of genistein. Despite its reported beneficial properties, genistein also has toxic side effects.

Several support and research groups have been established to speed the development of new treatments for Sanfilippo syndrome.

Courses of treatment for children with is dependent upon the severity of their case. Children with OHS often receive physical and occupational therapy. They may require a feeding tube to supplement nourishment if they are not growing enough. In an attempt to improve the neurological condition (seizures) copper histidine or copper chloride injections can be given early in the child’s life.

However, copper histidine injections have been shown ineffective in studies of copper metabolic-connective tissue disorders such as OHS.

MPS-III A, B, C and D are considered to be clinically indistinguishable, although mutations in different genes are responsible for each disease. The following discussion is therefore applicable to all four conditions.

The disease manifests in young children. Affected infants are apparently normal, although some mild facial dysmorphism may be noticeable. The stiff joints, hirsuteness and coarse hair typical of other mucopolysaccharidoses are usually not present until late in the disease. After an initial symptom-free interval, patients usually present with a slowing of development and/or behavioral problems, followed by progressive intellectual decline resulting in severe dementia and progressive motor disease. Acquisition of speech is often slow and incomplete. The disease progresses to increasing behavioural disturbance including temper tantrums, hyperactivity, destructiveness, aggressive behaviour, pica and sleep disturbance. As affected children have normal muscle strength and mobility, the behavioural disturbances are very difficult to manage. The disordered sleep in particular presents a significant problem to care providers. In the final phase of the illness, children become increasingly immobile and unresponsive, often require wheelchairs, and develop swallowing difficulties and seizures. The life-span of an affected child does not usually extend beyond late teens to early twenties.

Although the clinical features of the disease are mainly neurological, patients may also develop diarrhea, carious teeth, and an enlarged liver and spleen. There is a broad range of clinical severity. The disease may very rarely present later in life as a psychotic episode.

Of all the MPS diseases, MPS III produces the mildest physical abnormalities. It is important, however, that simple and treatable conditions such as ear infections and toothaches not be overlooked because of behavior problems that make examination difficult. Children with MPS III often have an increased tolerance of pain. Bumps and bruises or ear infections that would be painful for other children often go unnoticed in children with MPS III. Parents may need to search for a doctor with the patience and interest in treating a child with a long-term illness. Some children with MPS III may have a blood-clotting problem during and after surgery.

The diagnosis may be confirmed by assay of enzyme levels in tissue samples and gene sequencing. Prenatal diagnosis is possible.

Collagen, type II, alpha 1 (primary osteoarthritis, spondyloepiphyseal dysplasia, congenital), also known as COL2A1, is a human gene that provides instructions for the production of the pro-alpha1(II) chain of type II collagen.

The tests to verify Sack–Barabas syndrome are biochemical samples such as collagen typing (performed on a skin biopsy sample) or collagen gene mutation testing. There is no cure for Ehlers-Danlos syndrome, so individual problems and symptoms must be evaluated and cared for accordingly.

Blood tests are neede to differentiate FVII deficiency from other bleeding disorders. Typical is a discordance between the prolonged prothrombin time (PT) and normal levels for the activated partial thromboplastin time (APTT). FVII levels are <10IU/dl in homozygous individuals, and between 20-60 in heterozygous carriers. The FCVII: C assay supports the diagnosis.

The FVII gene (F7) is found on chromosome 13q34. Heterogeneous mutations have been described in FVII deficient patients.

The malabsorption resulting from lack of bile acid has resulted in elemental formula being suggested, which are low in fat with < 3% of calories derived from long chain triglycerides (LCT). However, reduced very long chain fatty acids (VLCFA) has not been shown to reduce blood VLCFA levels , likely because humans can endogenously produce most VLCFA. Plasma VLCFA levels are decreased when dietary VLCFA is reduced in conjunction with supplementation of Lorenzo’s oil (a 4:1 mixture of glyceryl trioleate and glyceryl trierucate) in X-ALD patients . Since docosahexaenoic acid (DHA) synthesis is impaired [59], DHA supplementation was recommended, but a placebo-controlled study has since showed no clinical efficacy . Due to the defective bile acid synthesis, fat soluble supplements of vitamins, A, D, E, and K are recommended.