MiTOCHONDRiAL DiSORDERS

The periodic paralyses are autosomal dominant conditions characterized by episodic weakness. Hyperkalaemic periodic paralysis causes shortlived attacks precipitated by rest after exercise, stress or potassium ingestion. It is caused by mutations in the muscle sodium channel SCN4A. Hypokalaemic periodic paralysis causes longer attacks of weakness precipitated by carbohydrate ingestion or rest following exercise. It is caused mainly by mutations in the L-type calcium channel gene CACNA1S, or rarely mutations in the SCN4A gene.


Mitochondrial function is essential to the energetic balance of all cells. The respiratory chain/oxida-tive phosphorylation mechanism is encoded by two separate genomes: the mitochondrial genome and the nuclear genome. Mutations in mitochondrial DNA or in nuclear DNA encoding mitochondrial proteins can therefore result in mitochondrial disorders. Mitochondrial DNA mutations are either sporadic or maternally transmitted while nuclear DNA mutations are sporadic or autosomal dominant or recessive. There is a wide spectrum of phenotypes associated with mitochondrial disorders.

Mitochondrial disorders are multisystem diseases and the presence of CNS abnormalities together with myopathy, neuropathy, optic/retinal abnormalities, deafness, cataracts, short stature and diabetes mellitus is suggestive of these conditions.


Mitochondrial DNA rearrangements are usually sporadic events in the germline, although maternal transmission of duplications and deletions has been reported in a small number of cases. Single mtDNA deletions result in three disorders: Kearns-Sayre syndrome (KSS), sporadic progressive external ophthalmoplegia (PEO) and Pearson’s syndrome.


The clinical phenotype associated with a mutation is dependent on a number of factors: the inherent pathogenicity of the mutation, the tissue distribution of the mutated gene, and the vulnerability of different tissues to energy demands.

Disorders due to mtDNA mutations

KSS is characterized by PEO, pigmentary retinopathy and has an onset at <20 years. It may be associated with a cerebellar syndrome, myopathy and endocrine dysfunction. Sporadic PEO is characterized by bilateral ptosis and external ophthalmoplegia and muscle weakness. Pearson's syndrome is characterized by the infantile onset of pancytopenia, pancreatic insufficiency and, subsequently, features of KSS.

Mitochondrial DNA point mutations are usually maternally inherited mutations. Some mutations in mtDNA may affect protein synthesis genes, i. e. tRNA and rRNA genes. In such cases, translation of all mitochondria-encoded proteins is perturbed and this leads to multiple defects in the respiratory chain. MELAS (mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes) is caused most commonly (in 80 per cent of cases) by the A3243G mutation in the tRNA gene for leucine. This condition presents with stroke-like episodes that may start with headache and vomiting and progress to encephalopathy, seizures and a focal neurological deficit. The stroke may be parietooccipital and may not conform to classic vascular territories. Other features of MELAS include deafness, ataxia, dementia and myopathy. The 3243 mutation described here can also cause other phenotypes: KSS, maternally inherited PEO and Leigh syndrome.

MERRF (myoclonus epilepsy with ragged red fibres) is caused by the A8344G mutation in the lysine tRNA gene. MERRF has been described earlier. Of note, the 8344 mutation may also cause Leigh syndrome. NARP (neurogenic weakness, ataxia and retinitis pigmentosa) has been described elsewhere, and is caused by a T8993G mutation in the ATPase 6 gene. LHON (Leber’s hereditary optic neuropathy) is characterized by subacute loss of vision bilaterally. Several mtDNA mutations can cause LHON, although the three most common are 11778 (ND4), 3460 (ND1) and 14484 (ND6). The age of onset is in the second to third decade and the penetrance is 40 per cent in males and only 10 per cent in females.

Disorders due to nuclear DNA mutations_

Several proteins that are critical to mitochondrial function are encoded by nuclear genes rather than mitochondrial genes. Therefore, nuclear DNA mutations may cause an array of mitochondrial phenotypes. Broadly, mutations occur in genes that are involved in subunits of the respiratory chain, genes that encode proteins essential for the assembly and turnover of the respiratory chain, genes that control the maintenance and integrity of mitochondrial DNA, genes involved in mitochondrial biogenesis, genes involved in mitochondrial transport and trafficking, and coenzyme Q pathway genes. A few illustrative examples of nuclear DNA giving rise to mitochondrial disorders are given below.

Mutations in the SURF-1 gene result in Leigh syndrome. SURF1 is a COX assembly factor. Leigh syndrome is a subacute encephalomyopathy, which presents as an early onset neurodegenerative disorder with cerebellar and pyramidal signs, seizures, dystonia and myopathy. MRI shows symmetric lesions in the basal ganglia. It has several genetic causes, all of which result in a defect in oxidative metabolism. The mutation may be in a nuclear gene, such as SURF-1, or in the mitochondrial DNA (e. g. 8993).

Nuclear factors are essential in mitochondrial DNA replication. Such factors include POLG1, which encodes the catalytic subunit of the mtDNA specific polymerase gamma, and TWINKLE, which encodes a mtDNA helicase. Mutations in POLG1 or TWINKLE result in mtDNA breakage syndromes such as autosomal dominant PEO. Mutations in POLG1 also underlie SANDO (sensory ataxia, neuropathy, dysarthria and ophthalmoplegia).

Mitochondria are organelles that undergo fission and fusion. Mitochondrial fusion requires the action of a GTPase called OPA1. Mutations in OPA1 cause an autosomal dominant optic atrophy, which is the most common inherited optic neuropathy.

NF1

NF1 has an incidence of 1:3-4000 and manifests with cafe-au-lait patches (>5 lesions >1.5 cm in adult), Lisch nodules in the iris, axillary/ groin pigmentation and the presence of cutaneous and/or plexiform neurofibromas. Associated features include scoliosis, renal artery stenosis, phaeochromocytomas, optic nerve tumours, rhabdomyosarcoma and peripheral nerve sheath tumours.


An approach to genetic diagnosis in mitochondrial disorders must begin with ascertaining the full clinical neurological and non-neurological phenotype, as well as family history. For a phenotype suggestive of mtDNA point mutations, the common mutations (3243, 8344 and 8993) may be screened for in blood samples. If this is negative, a muscle biopsy may be taken to look for the presence of ragged red fibres, perform respiratory chain enzymology, and analyse for mtDNA deletions. In the presence of multiple deletions, sequencing of nuclear genes involved in mtDNA maintenance (such as POLG1) may be considered. In appropriate cases, total sequence analysis of the mitochondrial genome may be undertaken in specialist centres.


Surveillance for visual acuity, blood pressure, and 24 hour catecholamine tesing should be performed regularly. Mutations in the NF1 gene include both deletions, rearrangements as well as point mutations. As the NF1 gene is so large, genetic testing without knowledge of the mutation in other family members is difficult.

NF2_

NF2 is less common than NF1, with an incidence of 1:30 000. It is characterized by bilateral vestibular schwannomas. Patients with NF2 may also develop meningiomas, including spinal meningiomas, ependymomas and astrocytomas. The NF2 gene encodes a protein called schwannomin, and mutations may be detected in 60-80 per cent of cases. Tumours in NF2 manifest two mutated copies of the gene, one of which is inherited, and the second is an acquired somatic mutation.

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