The identification of mutations in mtDNA and nuclear genes related to OXPHOS has furnished the bases for the actual classification mitochondrial disorders.

The first group of illnesses is characterized by the presence of mutations in mtDNA, that can be either sporadic, or maternally transmitted. A second group of disorders is caused by mutations in nuclear genes that make up or control oxidative phosphorylation (OXPHOS). Because many OXPHOS-related nuclear genes are still unkown in humans, several of these illnesses are classified only on the basis of biochemical alterations, revealed by the analysis of affected tissue (especially skeletal muscle).

1. MtDNA Mutations
This group includes syndromes caused by either large-scale rearrangements of mtDNA or mtDNA point mutations.

Mitochondrial disorders due to mutations in mtDNA genes*

Large-scale rearrangements (mtDNA deletions)**
Kearns-Sayre Syndrome(KSS)
Progressive External Ophthalmoplegia (PEO)
Pearson's Syndrome (congenital pancytopenia with sideroblastic anemia, and intestinal malabsorption due to insufficiency of the exocrine pabncreas)
Point Mutations*
Leber's Hereditary Optic Neuropathy (LHON)
Neurogenic muscle weakness, Ataxia, Retinitis Pigmentosa (NARP) syndrome
Maternally-Inherited Leigh Syndrrome (MILS)
Mitochondrial Encephalomyopathy, Lactic Acidosis and Stroke-like episodes (MELAS)
Myoclonic Epilepsy with Ragged-Red Fibers (MERRF)
Maternally Inherited Myopathy and Cardiomyopathy (MIMyCa)

* usually maternally inherited
** usually sporadic

Large-scale rearrangements of mtDNA
These can be either partial deletions of mtDNA or less frequently, partial duplications. Both types are heteroplasmic since they co-exist with normal mtDNA. These coarse alterations of mtDNA are almost invariably associated with Kearns-Sayre Syndrome, Progressive External Ophthalmoplegia and Pearson's Syndrome.

Kearns-Sayre Syndrome is a serious illness that occurs sporadically, and includes the triad of (1) Progressive External Ophthalmoplegia (PEO) with bilateral drooping eyelids (ptosis), (2) Pigmentary Retinopathy,and (3). onset before twenty years of age. Other frequent signs are poor growth, motor incoordination (ataxia) due to cerebellar failure, mental deterioration, deafness, and alterations of cardiac rhythm (Atrio-ventricular blocks) often requiring the application of a pace-maker.

Progressive External Ophthalmoplegia also occurs sporadically and is characterized by the appearance of bi-lateral ptosis and paralysis of eye-movement, often associated with weakness in girdle muscles of the shoulders and pelvis. It appears in adulthood.

Pearson's Syndrome is a rare sporadic disease affecting newborn or very young babies. It is characterized by sideroblastic anemia, pancytopenia ed failure of exocrine pancreas with intestinal malabsorption. A progressive improvement in the hematologic and gastro-intestinal situation takes place in children who survive the first years, but they usually develop a typical Kearns-Sayre Syndrome afterwards.

Alterazioni quantitative del mtDNA
A reduction of the amount of mtDNA is called "depletion". Usually this forms are infantile with a progressive course. The most involved organs are: skeletal muscle and heart, liver and brain. Depletions of the mtDNA are caused by mutations in the nuclear genes (see above "Mitochondriopathy due to mutations in nuclear genes").

Point mutations
These are clinical entities associated with the substitution of single bases or micro-insertions/micro-deletions in the mtDNA molecule. These mutations may concern genes encoding transfer RNAs (tRNA), ribosomal RNAs, (rRNA), or messenger RNAs (mRNA) that are then translated into proteins. Unlike mtDNA rearrangements, mtDNA point mutations are transmitted maternally. They are often, but not always, heteroplasmic. Even if more than one hundred point mutations have been described, in association with an extremely heterogeneous spectrum of clinical presentations, only a few of them are frequent and associated with well-defined clinical syndromes.

LLeber's Hereditary Optic Neuropathy (LHON, 0MIM535000) is a juvenile-onset condition affecting mostly males. It is characterized by acute or sub-acute loss of central vision due to rapidly progressive optic atrophy. This partial or complete, usually permanent loss of vision, is the only consistent manifestation of the disease which, more rarely, may also include alterations in cardiac rhythm (ventricular pre-excitation syndrome). The muscle biopsy does not show evidence of ragged-red fibers and is not necessary for the diagnosis of the disease. This disease is associated with mutations in the nucleotide positions 3460, 11778, or 14484 of mtDNA, in the gene encoding subunits ND1, ND4, and ND6 of complex I, respectively. Other mutations, all present in complex I mtDNA genes, have recently been identified. Many features of LHON remain to be clarified, including the extreme tissue specificity of the anatomical and clinical lesion, the prevalence among males, and the biochemical consequences of each mutation.

NARP Neurogenic muscle weakness, ataxia, retinitis pigmentosa (NARP, 0MIM551500) can also include, besides the above-mentioned symptoms, epilepsy, and sometimes mental deterioration. Symptoms usually appear in adulthood. Ragged-red fibers are absent in the muscle biopsy. The disease is associated with mutation T8993G in the gene encoding subunit 6 of mitochondrial ATPase (complex V of the respiratory chain). In patients presenting a less serious NARP phenotype, a transition T->C in the same position has also been described. The same T8993G mutation when present in >90% of total mitochondrial genomes, leads to the more severe, earlier onset Leigh syndrome (MILS, maternally inherited Leigh syndrome).

Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes, (MELAS, OMIM540000) is defined by the following symptoms: 1) stroke-like episodes caused by focal cerebral lesions, often localized in the parieto-occipital regions of the brain; 2) lactic acidosis or abnormal lactic levels in the blood (and cerebro-spinal fluid, CSF); 3) "ragged-red" fibers in the muscle biopsy. Other signs involving the central nervous system include mental deterioration, recurrent migraine with "cerebral" vomiting, focal or generalized epilepsy and neurosensorial deafness. The disease is transmitted maternally and the onset varies from early childhood to young adulthood.

MELAS syndrome is typically associated with mutation A3243G in the gene encoding tRNALeu(UUR). Other point mutations associated with MELAS have been reported, although they are much rarer than the A3243G.

Myoclonus Epilepsy with Ragged-Red Fibers, (MERRF, OMIM545000) is characterized by the association of myoclonus, epilepsy, muscle weakness and wasting, motor incoordination (ataxia) and sometimes, mental deterioration. Clinical manifestations can vary greatly even within the same family. This variation is attributed to the quantity of mutated mtDNA in relation to normal mtDNA (heteroplasmy) and to variation in the tissue distribution of the mutation. The major part of affected families carry an A8344G transition in the gene encoding tRNALys.

Numerous other point mutations of mtDNA have been associated with different clinical phenotypes in single patients or in a few families.

2. Mitochondriopathy due to mutations in nuclear genes
Over 90% of mitochondrial proteins are expressions of nuclear genes. It is therefore surprising to find that in respect to the amount of clinical and genetic observations regarding alterations caused by mtDNA mutations, the number of illnesses and syndromes associated with OXPHOS-related nuclear genes are quite rare. On the other hand, a growing number of degenerative hereditary diseases, especially in the neurological field, have been linked to mutations in genes encoding proteins that enter the mitochondrion and are more or less directly correlated to OXPHOS.

The proteins encoded by these genes are grouped in three categories:

Defects in structural components of the respiratory chain*
Complex I defects (Leigh's syndrome,Leukodystrophy, myoclonus)
Complex II defects (Leigh's Syndrome, Hereditary Paragangliomas)
Defects in the synthesis of coenzyme Q (Ataxia, myoglobinuria, seizures)
Defects in factors controlling OXPHOS or mtDNA metabolism*
Defects of SURF1 (Leigh's Syndrome)
Defects in SCO1 (infantile encephalomyopathy)
Defects in SCO2 (infantile cardiomyopathy)
Defects in COX10 (infantile encephalomyopathy)
Defects in COX15 (cardiomyopathy)
Defects in DGUOK (mitochondrial DNA-depletion sindrome, hepatocerebral form)
Defects in TK2 (mitochondrial DNA-depletion sindrome, myopathy)
Defects in POLG1 (progressive external ophtalmoplegia, Alpes sindrome)
Defects in BCSI disorder (infantile encephalomyopathy, tubulopathy, hepatopathy)
Defects in ANTI
Defects in Twinkle
Defects of Thymidine Phosphorylase (Mitochondrial Neuro-Gastro-Intestinal Encephalomyopathy, MNGIE)
Disorders of nuclear genes indirectly correlated to OXPHOS
Defects in OPA1 (dominant optic atrophy)
Defects in frataxin (Freidreich's Ataxia)
Defects in paraplegin (hereditary spastic paraplegia)
Defects of Tim 8/9 transporters (X-linked deafness-dystonia syndrome)

* mendelian heredity

The following is a brief outline of only one disease, Leigh's Syndrome, the most common and well-known of the group of diseases that result from abnormalities in nuclear genes related to mitochondrial OXPHOS. After an initial period of normal development in the first months of infancy, affected children present a progressive delay in psychomotor development, accompanied by incoordination of eye movements, recurrent vomiting, epilepsy, abnormalities in breathing rate, and lactic acidosis. These symptoms can be referred to symmetric lesions of neurological structures that originate, cross through, or are localized in the basal ganglia, brainstem and cerebellum.

The frequent increase in lactic acid levels in blood and CSF suggests an alteration in mitochondria energy metabolism.

In more than half the cases it is possible to document a genetic alteration. In about 20% of cases there are mutations in the ATPase 6 gene, most frequently the T8993G mutation associated with NARP/MILS mutation but occasionally also point mutations in other portions of the same gene. Rarely, Leigh syndrome is caused by mtDNA mutations affecting genes encoding Complex IV subunits, or mutations in tRNA genes. In about 30% of the cases the biochemical defect is a profound decrease in the activity of Complex IV activity (cytochrome c oxidase, COX) and the genetic alteration is due, in most cases, to mutations in an assembly gene of complex IV, called Surf-1. In other cases, the biochemical defect is found in Complex I or Complex II of the respiratory chain. Mutations in the subunits of these complexes have been identified in some patients. Finally, in 10% of the cases a deficiency in Pyruvate Dehydrogenase is detected, usually associated with mutations in the X-linked gene encoding subunit E-1-alpha of the enzyme.

Mutation map of mtDNA.