The clinical diagnosis is backed up by investigative findings. Citrulline level in blood is decreased. Mitochondrial studies or NARP mtDNA evaluation plays a role in genetic diagnosis which can also be done prenatally.

MDDS is diagnosed based on systemic symptoms presenting in infants, followed by a clinical examination and laboratory tests (for example, high lactate levels are common) medical imaging, and usually is finally confirmed and formally identified by genetic testing.

Blood lactate and pyruvate levels usually are elevated as a result of increased anaerobic metabolism and a decreased ratio of ATP:ADP. CSF analysis shows an elevated protein level, usually >100 mg/dl, as well as an elevated lactate level.

While the disease manifests early in life in most cases, diagnosis of the disease is often quite delayed. The symptoms that affected patients present vary, but the most common presenting symptoms are gastrointestinal issues such as nausea, vomiting, abdominal pain, and diarrhea, and neurologic or ocular symptoms such as hearing loss, weakness, and peripheral neuropathy. These gastrointestinal symptoms cause patients with MNGIE to be very thin and experience persistent weight loss and this often leads to MNGIE being misdiagnosed as an eating disorder. These symptoms without presentation of disordered eating and warped body image warrant further investigation into the possibility of MNGIE as a diagnosis. Presentation of these symptoms and lack of disordered eating are not enough for a diagnosis. Radiologic studies showing hypoperistalsis, large atonic stomach, dilated duodenum, diverticula, and white matter changes are required to confirm the diagnosis. Elevated blood and urine nucleoside levels are also indicative of MNGIE syndrome. Abnormal nerve conduction as well as analysis of mitochondria from liver, intestines, muscle, and nerve tissue can also be used to support the diagnosis.

A successful treatment for MNGIE has yet to be found, however, symptomatic relief can be achieved using pharmacotherapy and celiac plexus neurolysis. Celiac plexus neurolysis involves interrupting neural transmission from various parts of the gastrointestinal tract. By blocking neural transmission, pain is relieved and gastrointestinal motility increases. Stem cell therapies are currently being investigated as a potential cure for certain patients with the disease, however, their success depends on physicians catching the disease early before too much organ damage has occurred.

A detailed family history should be obtained from at least three generations. In particularly a history to determine if there has been any neonatal and childhood deaths: Also a way to determine if any one of the family members exhibit any of the features of the multi-system disease. Specifically if there has been a maternal inheritance, when the disease is transmitted to females only, or if there is a family member who experienced a multi system involvement such as: Brain condition that a family member has been record to have such asseizures, dystonia, ataxia, or stroke like episodes.The eyes with optic atrophy, the skeletal muscle where there has been a history of myalgia, weakness or ptosis. Also in the family history look for neuropathy and dysautonomia, or observe heart conditions such ascardiomyopathy. The patients history might also exhibit a problem in their kidney, such as proximal nephron dysfunction. An endocrine condition, for example diabetes and hypoparathyroidism. The patient might have also had gastrointestinal condition which could have been due to liver disease, episodes of nausea or vomiting. Multiple lipomas in the skin, sideroblastic anemia and pancytopenia in the metabolic system or short stature might all be examples of patients with possible symptoms of MERRF disease.

A neuro-ophthalmologist is usually involved in the diagnosis and management of KSS. An individual should be suspected of having KSS based upon clinical exam findings. Suspicion for myopathies should be increased in patients whose ophthalmoplegia does not match a particular set of cranial nerve palsies (oculomotor nerve palsy, fourth nerve palsy, sixth nerve palsy). Initially, imaging studies are often performed to rule out more common pathologies. Diagnosis may be confirmed with muscle biopsy, and may be supplemented with PCR determination of mtDNA mutations.

The severity and prognosis vary with the type of mutation involved.

DGUOK, POLG, and MPV17 related forms result in defects to the liver. Liver dysfunction is progressive in the majority of individuals with both forms of DGUOK-related MDS and is the most common cause of death. For children with the multi-organ form, liver transplantation provides no survival benefit.

Liver disease typically progresses to liver failure in affected children with MPV17-related MDS and liver transplantation remains the only treatment option for liver failure. Approximately half of affected children reported did not undergo liver transplantation and died because of progressive liver failure – the majority during infancy or early childhood. A few children were reported to survive without liver transplantation.

Other diseases can have a similar clinical presentation to Leigh syndrome; excluding other causes of similar clinical symptoms is often a first step to diagnosing Leigh disease. Conditions that can appear similar to Leigh disease include perinatal asphyxia, kernicterus, carbon monoxide poisoning, methanol toxicity, thiamine deficiency, Wilson's disease, biotin-responsive basal ganglia disease, and some forms of encephalitis. Perinatal asphyxia can cause bilateral ganglial lesions and damage to the thalamus, which are similar to the signs seen with Leigh syndrome. When hyperbilirubinemia is not treated with phototherapy, the bilirubin can accumulate in the basal ganglia and cause lesions similar to those seen in Leigh syndrome. This is not common since the advent of phototherapy.

Diagnosis of mitochondrial trifunctional protein deficiency is often confirmed using tandem mass spectrometry. It should be noted that genetic counseling is available for this condition. Additionally the following exams are available:

- CBC

- Urine test

Different genetic causes and types of Leigh syndrome have different prognoses, though all are poor. The most severe forms of the disease, caused by a full deficiency in one of the affected proteins, cause death at a few years of age. If the deficiency is not complete, the prognosis is somewhat better and an affected child is expected to survive 6–7 years, and in rare cases, to their teenage years.

Different types of ataxia:

- congenital ataxias (developmental disorders)

- ataxias with metabolic disorders

- ataxias with a DNA repair defect

- degenerative ataxias

- ataxia associated with other features.

Direct sequence analysis of genomic DNA from blood can be used to perform a mutation analysis for the TALDO1 gene responsible for the Transaldolase enzyme.

Clinical diagnosis is conducted on individuals with age onset between late teens and late forties who show the initial characteristics for the recessive autosomal cerebellar ataxia.

The following tests are performed:

- MRI brain screening for cerebellum atrophy.

- Molecular genetic testing for SYNE-1 sequence analysis.

- Electrophysiologic studies for polyneurotherapy

- Neurological examination

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) can be performed to identify the mothers carrying the recessive genes for cerebellar ataxia.

Congenital lactic acidosis can be suspected based on blood or cerebrospinal fluid tests showing high levels of lactate; the underlying genetic mutation can only be diagnosed with genetic testing.

Autozygome analysis and biochemical evaluations of urinary sugars and polyols can be used to diagnose Transaldolase Deficiency. Two specific methods for measuring the urinary sugars and polyols are liquid chromatographytandem mass spectrometry and gas chromatography with flame ionization detection.

Succinic acid has been used successfully to treat MELAS syndrome, and also Leighs disease. Patients are managed according to what areas of the body are affected at a particular time. Enzymes, amino acids, antioxidants and vitamins have been used.

Also the following supplements may help:

- CoQ10 has been helpful for some MELAS patients. Nicotinamide has been used because complex l accepts electrons from NADH and ultimately transfers electrons to CoQ10.

- Riboflavin has been reported to improve the function of a patient with complex l deficiency and the 3250T-C mutation.

- The administration of L-arginine during the acute and interictal periods may represent a potential new therapy for this syndrome to reduce brain damage due to impairment of vasodilation in intracerebral arteries due to nitric oxide depletion.

- There is also a case report where succinate was successfully used to treat uncontrolled convulsions in MELAS patients, although this treatment modality is yet to be thoroughly investigated or widely recommended.

Mitochondrial diseases are usually detected by analysing muscle samples, where the presence of these organelles is higher. The most common tests for the detection of these diseases are:

1. Southern blot to detect big deletions or duplications

2. PCR and specific mutation analysis

3. Sequencing

The diagnosis varies from individual to individual, each is evaluated and diagnosed according to their age, clinical phenotype and pressed inheritance pattern. If the Individual has been experiencing myoclonus the doctor will run a series of genetic studies to determine if its a mitochondrial disorder.

The molecular genetic studies are run to identify the reason of for the mutations underlying the mitochondrial dysfunction. This approach will avoid the need for a muscle biopsy or an exhaustive metabolic evaluation. After the sequencing the mitochondrial genomes, four points mutations in the genome can be identified which are associated with MERRF: A8344G, T8356C, G8361A, and G8363A. The point mutation A8344G is mostly associated with MERRF, in a study published by Paul Jose Lorenzoni from the Department of neurology at University of Panama stated that 80% of the patients with MERRF disease exhibited this point mutation. The remaining mutations only account for 10% of cases, and the remaining 10% of the patients with MERRF did not have an identifiable mutation in the mitochondrial DNA.

If a patient does not exhibit mitochondrial DNA mutations, there are other ways that they can be diagnosed with MERRF. They can go through computed tomography (CT) or magnetic resonance imaging (MRI).The classification for the severity of MERRF syndrome is difficult to distinguish since most individuals will exhibit multi-symptoms. For children with complex neurologic or multi-system involvement, as the one described below, is often necessary.

Management for mitochondrial trifunctional protein deficiency entails the following:

- Avoiding factors that might precipitate condition

- Glucose

- Low fat/high carbohydrate nutrition

Bloom syndrome is diagnosed using any of three tests - the presence of quadriradial (Qr, a four-armed chromatid interchange) in cultured blood lymphocytes, and/or the elevated levels of Sister chromatid exchange in cells of any type, and/or the mutation in the BLM gene. The US Food and Drug Administration (FDA) announced on February 19, 2015 that they have authorized marketing of a direct-to-consumer genetic test from 23andMe. The test is designed to identify healthy individuals who carry a gene that could cause Bloom Syndrome in their offspring.

Infant mortality is high for patients diagnosed with early onset; mortality can occur within less than 2 months, while children diagnosed with late-onset syndrome seem to have higher rates of survival. Patients suffering from a complete lesion of mut0 have not only the poorest outcome of those suffering from methylaonyl-CoA mutase deficiency, but also of all individuals suffering from any form of methylmalonic acidemia.

A patient’s DNA is sequenced from a blood sample with the use of the ABI Big Dye Terminator v.3.0 kit. Since this is a genetic disease, the basis of diagnosis lies in identifying genetic mutations or chromosomal abnormalities. The DNA sequence can be run with CLN8 Sanger Sequencing or CLN8 Targeted Familial Mutations whether its single, double, or triple Exon Sequencing. Also, preliminary evidence of the disease can be detected by means of MRI and EEG. These tests identify lipid content of the brain and any anomaly from the norm may be linked to Northern epilepsy.

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.

Diagnosis of MSS is based on clinical symptoms, magnetic resonance imaging (MRI) of the brain (cerebellar atrophy particularly involving the cerebellar vermis), and muscle biopsy.

It can be associated with mutations of the SIL1 gene, and a mutation can be found in about 50% of cases.

Differential diagnosis includes Congenital Cataracts Facial Dysmorphism Neuropathy (CCFDN), Marinesco–Sjögren like syndrome with chylomicronemia, carbohydrate deficient glycoprotein syndromes, Lowe syndrome, and mitochondrial disease.