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.

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.

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

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.

Because vision loss is often an early sign, Batten disease/NCL may be first suspected during an eye exam. An eye doctor can detect a loss of cells within the eye that occurs in the three childhood forms of Batten disease/NCL. However, because such cell loss occurs in other eye diseases, the disorder cannot be diagnosed by this sign alone. Often an eye specialist or other physician who suspects Batten disease/NCL may refer the child to a neurologist, a doctor who specializes in disease of the brain and nervous system. In order to diagnose Batten disease/NCL, the neurologist needs the patient's medical history and information from various laboratory tests.

Diagnostic tests used for Batten disease/NCLs include:

- Skin or tissue sampling. The doctor can examine a small piece of tissue under an electron microscope. The powerful magnification of the microscope helps the doctor spot typical NCL deposits. These deposits are found in many different tissues, including skin, muscle, conjunctiva, rectal and others. Blood can also be used. These deposits take on characteristic shapes, depending on the variant under which they are said to occur: granular osmophilic deposits (GRODs) are generally characteristic of INCL, while curvilinear profiles, fingerprint profiles, and mixed-type inclusions are typically found in LINCL, JNCL, and ANCL, respectively.

- Electroencephalogram or EEG. An EEG uses special patches placed on the scalp to record electrical currents inside the brain. This helps doctors see telltale patterns in the brain's electrical activity that suggest a patient has seizures.

- Electrical studies of the eyes. These tests, which include visual-evoked responses (VER) and electroretinograms (ERG), can detect various eye problems common in childhood Batten disease/NCLs.

- Brain scans. Imaging can help doctors look for changes in the brain's appearance. The most commonly used imaging technique is computed tomography (CT), which uses x-rays and a computer to create a sophisticated picture of the brain's tissues and structures. A CT scan may reveal brain areas that are decaying in NCL patients. A second imaging technique that is increasingly common is magnetic resonance imaging, or MRI. MRI uses a combination of magnetic fields and radio waves, instead of radiation, to create a picture of the brain.

- Enzyme assay. A recent development in diagnosis of Batten disease/NCL is the use of enzyme assays that look for specific missing lysosomal enzymes for infantile and late infantile only. This is a quick and easy diagnostic test.

Sandhoff disease can be detected through the following procedures (before it is apparent through physical examination): a biopsy removing a sample of tissue from the liver, genetic testing, molecular analysis of cells and tissues (to determine the presence of a genetic metabolic disorder), enzyme assay, and occasionally a urinalysis to determine if the above-noted compounds are abnormally stored within the body. For a child to suffer from this disease, both parents must be carriers, and both must transmit the mutation to the child. Thus, even in the case where both parents have the mutation, there is only a 25 percent chance their child will inherit the condition. Frequently, parents are given the opportunity to have a DNA screening if they are at high risk, to determine their carrier status before they have children. However, it is also highly recommended to undergo testing even for those parents who do not have a family history of Sandhoff disease. Over 95% of the families that have children with Sandhoff disease had no known prior family history of the condition, as the mutation in the HEXB gene is "silent," or recessive, and often passed undetected from one generation to the next Naturally, if an individual carries the mutation, he or she has a risk of transmitting it to the unborn child. Genetic counseling is recommended for those who have the mutation.

The most well known laboratory to perform the blood tests is through Lysosomal Diseases Testing Laboratory, Jefferson University with Dr. Wenger. Dr. Wenger’s laboratory does testing for all lysosomal diseases including Sandhoff and Tay-Sachs. They test for build-up of certain toxins in the body as well as a low count of enzymes.

It is possible for parents who are about to have a child or had a child with Sandhoff Disease can have a PGD or PEGD. PEGD is pre-embryonic genetic diagnosis for the parents that would not benefit from a pre-implantation genetic diagnosis because of their religion or negative attitude for the discarding of embryos. PEGD sequences the genome of the embryo to be produced by two parents if they were to conceive a child. If the family has a history of Sandhoff disease it is recommended they have their genome sequenced to ensure they are not carriers or to sequence the genome of their child.

The older classification of NCL divided the condition into four types (CLN1, CLN2, CLN3, and CLN4) based upon age of onset, while newer classifications divide it by the associated gene.

CLN4 (unlike CLN1, CLN2, and CLN3) has not been mapped to a specific gene.

There are three types of Sandhoff disease: classic infantile, juvenile, and adult late onset. Each form is classified by the severity of the symptoms as well as the age at which the patient shows these symptoms.

- Classic infantile form of the disease is classified by the development of symptoms anywhere from 2 months to 9 months of age. It is the most severe of all of the forms and will lead to death before the patient reaches the age of three. This is the most common and severe form of Sandhoff disease. Infants with this disorder typically appear normal until the age of 3 to 6 months, when development slows and muscles used for movement weaken. Affected infants lose motor skills such as turning over, sitting, and crawling. As the disease progresses, infants develop seizures, vision and hearing loss, dementia, and paralysis. An eye abnormality called a cherry-red spot, which can be identified with an eye examination, is characteristic of this disorder. Some infants with Sandhoff disease may have enlarged organs (organomegaly) or bone abnormalities. Children with the severe form of this disorder usually live only into early childhood.

- Juvenile form of the disease shows symptoms starting at age 3 ranging to age 10 and, although the child usually dies by the time they are 15, it is possible for them to live longer if they are under constant care. Symptoms include autism, ataxia, motor skills regression, spacticity, and learning disorders.

- Adult onset form of the disease is classified by its occurrence in older individuals and has an effect on the motor function of these individuals. It is not yet known if Sandhoff disease will cause these individuals to have a decrease in their life span.

Juvenile and adult onset forms of Sandhoff disease are very rare. Signs and symptoms can begin in childhood, adolescence, or adulthood and are usually milder than those seen with the infantile form of Sandhoff disease. As in the infantile form, mental abilities and coordination are affected. Characteristic features include muscle weakness, loss of muscle coordination (ataxia) and other problems with movement, speech problems, and mental illness. These signs and symptoms vary widely among people with late-onset forms of Sandhoff disease.

The diagnosis of ML is based on clinical symptoms, a complete medical history, and certain laboratory tests.

Sandhoff disease is a rare, autosomal recessive metabolic disorder that causes progressive destruction of nerve cells in the brain and spinal cord. The disease results from mutations on chromosome 5 in the HEXB gene, critical for the lysosomal enzymes beta-N-acetylhexosaminidase A and B. Sandhoff Disease is clinically indistinguishable from Tay-Sachs Disease. The most common form, infantile Sandhoff disease, is usually fatal by early childhood.

Tay–Sachs disease is a rare autosomal recessive genetic disorder that causes a progressive deterioration of nerve cells and of mental and physical abilities that begins around six months of age and usually results in death by the age of four. It is the most common of the GM2 gangliosidoses. The disease occurs when harmful quantities of cell membrane gangliosides accumulate in the brain's nerve cells, eventually leading to the premature death of the cells.

Mutations in the GM2A gene cause GM2-gangliosidosis, AB variant. This condition is inherited in an autosomal recessive pattern.

The GM2A gene provides instructions for making a protein called the GM2 activator. This protein is required for the normal function of beta-hexosaminidase A, a critical enzyme in the nervous system that breaks down a lipid called GM2 ganglioside. If mutations in both alleles at this locus disrupt the activity of the GM2 activator, beta-hexosaminidase A cannot perform its normal function. As a result, gangliosides accumulate in the central nervous system until they interfere with normal biological processes. Progressive damage caused by buildup of gangliosides leads to the destruction of nerve cells.

GM2-gangliosidosis, AB variant is extremely rare. In contrast with both Tay-Sachs disease and Sandhoff disease, in which many mutant polymorphic alleles have been discovered, including pseudodeficiency alleles, very few GM2A mutations have been reported. When AB variant is reported, in often occurs with consanguineous parents or in genetically isolated populations.

GM2A is expressed in many tissues, and the GM2 activator protein has been reported to have other cellular functions. Because AB variant is so rarely diagnosed, it is likely that most mutations of GM2A are fatal at the embryionic or fetal stage of development in homozygotes and genetic compounds, and thus are never observed clinically.

Gangliosidosis contains different types of lipid storage disorders caused by the accumulation of lipids known as gangliosides. There are two distinct genetic causes of the disease. Both are autosomal recessive and affect males and females equally.

GM2-gangliosidosis, AB variant is a rare, autosomal recessive metabolic disorder that causes progressive destruction of nerve cells in the brain and spinal cord. It has a similar pathology to Sandhoff disease and Tay-Sachs disease. The three diseases are classified together as the GM2 gangliosidoses, because each disease represents a distinct molecular point of failure in the activation of the same enzyme, beta-hexosaminidase. AB variant is caused by a failure in the gene that makes an enzyme cofactor for beta-hexosaminidase, called the GM2 activator.

The other two types are closely related.

Mucolipidosis types II and III (ML II and ML III) result from a deficiency of the enzyme N-acetylglucosamine-1-phosphotransferase, which phosphorylates target carbohydrate residues on N-linked glycoproteins. Without this phosphorylation, the glycoproteins are not destined for lysosomes, and they escape outside the cell.

Due to the condition's rarity, it is frequently misdiagnosed, often as cerebral palsy. This results in patients often living their entire childhood with the condition untreated.

The diagnosis of SS can be made from a typical history, a trial of dopamine medications, and genetic testing. Not all patients show mutations in the GCH1 gene (GTP cyclohydrolase I), which makes genetic testing imperfect.

Sometimes a lumbar puncture is performed to measure concentrations of biopterin and neopterin, which can help determine the exact form of dopamine-responsive movement disorder: early onset parkinsonism (reduced biopterin and normal neopterin), GTP cyclohydrolase I deficiency (both decreased) and tyrosine hydroxylase deficiency (both normal).

In approximately half of cases, a phenylalanine loading test can be used to show decreased conversion from the amino acid phenylalanine to tyrosine. This process uses BH4 as a cofactor.

During a sleep study (polysomnography), decreased twitching may be noticed during REM sleep.

An MRI scan of the brain can be used to look for conditions that can mimic SS (for example, metal deposition in the basal ganglia can indicate Wilson's disease or pantothenate kinase-associated neurodegeneration). Nuclear imaging of the brain using positron emission tomography (PET scan) shows a normal radiolabelled dopamine uptake in SS, contrary to the decreased uptake in Parkinson's disease.

Other differential diagnoses include metabolic disorders (such as GM2 gangliosidosis, phenylketonuria, hypothyroidism, Leigh disease) primarily dystonic juvenile parkinsonism, autosomal recessive early onset parkinsonism with diurnal fluctuation, early onset idiopathic parkinsonism, focal dystonias, dystonia musculorum deformans and dyspeptic dystonia with hiatal hernia.

- Diagnosis - main

- typically referral by GP to specialist Neurological Hospital e.g. National Hospital in London.

- very hard to diagnose as condition is dynamic w.r.t. time-of-day AND dynamic w.r.t. age of patient.

- correct diagnosis only made by a consultant neurologist with a complete 24-hour day-cycle observation(with video/film) at a Hospital i.e. morning(day1)->noon->afternoon->evening->late-night->sleep->morning(day2).

- patient with suspected SS required to walk in around hospital in front of Neuro'-consultant at selected daytime intervals to observe worsening walking pattern coincident with increased muscle tension in limbs.

- throughout the day, reducing leg-gait, thus shoe heels catching one another.

- diurnal affect of condition: morning(fresh/energetic), lunch(stiff limbs), afternoon(very stiff limbs), evening(limbs worsening), bedtime(limbs near frozen).

- muscle tension in thighs/arms: morning(normal), lunch(abnormal), afternoon(very abnormal), evening(bad), bedtime(frozen solid).

- Diagnosis - additional

- lack of self-esteem at school/college/University -> eating disorders in youth thus weight gains.

- lack of energy during late-daytime (teens/adult) -> compensate by over-eating.

In those with SS, symptoms typically dramatically improve with low-dose administration of levodopa (L-dopa). L-DOPA exists as a biochemically significant metabolite of the amino acid phenylalanine, as well as a biological precursor of the catecholamine dopamine, a neurotransmitter. (Neurotransmitters are naturally produced molecules that may be sequestered following the propagation of an action potential down a nerve towards the axon terminal, which in turn may cross the synaptic junction between neurons, enabling neurons to communicate in a variety of ways.) Low-dose L-dopa usually results in near-complete or total reversal of all associated symptoms for these patients. In addition, the effectiveness of such therapy is typically long term, without the complications that often occur for those with Parkinson's disease who undergo L-dopa treatment. Thus, most experts indicate that this disorder is most appropriately known as dopa-responsive dystonia (SS).

No data are available on mortality associated with SS, but patients surviving beyond the fifth decade with treatment have been reported. However, in severe, early autosomal recessive forms of the disease, patients have been known to pass away during childhood. Girls seem to be somewhat more commonly affected. The disease less commonly begins during puberty or after age 20, and very rarely, cases in older adults have been reported.

Due to commonly being misdiagnosed, it is common for the disease to remain untreated. When left untreated, patients often need achilles tendon surgery by the age of 21. They will also struggle with walking, an ability that will degrade throughout the day. Power napping can provide temporary relief in untreated patients. It also impairs development into adulthood, reduces balance, and reduces calf muscle development. Socially, it can result in depression, lack of social skills, and inability to find employment.

Diagnosis is made primarily through physical assessment of the skin, family history of Mongolian spots, and subjective data given by the care giver. No tests are currently available for diagnosing Mongolian spots.

Mongolian spots usually resolve by early childhood and hence no treatment is generally needed if they are located in the sacral area. However, sometimes it may be required for extra sacral lesions to have surgical correction. Q-switched alexandrite lasers have been used for treatment. Good results are obtained if treatment is initiated before the age of 20 years. In a study done by the University of Tokyo, the effectiveness of the Q-switched alexandrite laser in treating Mongolian spots was evaluated. A retrospective study was done from April 2003 to September 2011. 16 patients, aged 14-55, were treated with Q-switched alexandrite laser. A good therapeutic outcome was achieved on the whole group, however two patients with sacral Mongolian spots suffered from inflammatory hyperpigmentation, and two patients got post inflammatory hypopigmentation after seven sessions of laser treatment.