with the classic Leigh disease presentation, whereas lower levels of heteroplasmy are associated with the NARP (neurologic weakness, ataxia, and retinitis pigmentosa) phenotype. Other mutations reported in association with the Leigh disease phenotype include the A324G MELAS mutation as well as the A8344G MERRF mutation256 and G1544T tRNAval, deletions and depletions of mtDNA levels.134

Mitochondrial Encephalomyelopathy

and Stroke-Like Episodes (MELAS)

MELAS is the mitochondrial disease that is most consistently associated with retrochiasmal visual loss.34 MELAS is characterized by recurrent abrupt attacks of headache, vomiting, focal and generalized seizures, and focal neurologic symptoms and signs lasting hours to days. There is a posterior cerebral predilection for damage, and visual disturbances have been reported in more than half of patients. It is not uncommon for patients with MELAS to have CPEO, pigmentary retinopathy, or optic atrophy.34

The hallmark of this syndrome is the occurrence of strokelike episodes that result in hemiparesis, hemianopia, or cortical blindness. Focal or generalized seizures, recurrent migrainelike headaches, vomiting, short stature, hearing loss, and muscle weakness are common. The syndrome usually develops during childhood and has a relapsing and remitting course, with strokelike episodes separated by periods of variable resolution that results in progressive neurologic dysfunction and dementia. Initial symptoms of MELAS begin in early childhood and include headache (which may be indistinguishable from complicated migraine), vomiting, seizures, and reversible neurological deficits, including visual disturbances.152 The recovery following the strokelike events may be surprisingly good, but recurrences of neurologic deficits occur, ultimately leaving patients with hemiparesis, hemianopia, or complete blindness.

Patients with otherwise characteristic MELAS syndrome may have ptosis and external ophthalmoplegia suggestive of CPEO.97 Angiographic studies have failed to demonstrate significant vascular occlusions, leading to the hypothesis that these are metabolic strokes caused by an area of brain exceeding its respiratory ability rather than by thromboembolism. MR imaging studies in this condition show edema in affected areas that are not restricted to specific vascular distributions.210 Patients with MELAS have been described as showing parietooccipital hypodensity on CT scanning and T2 prolongation on MR.19 On pathologic examination, spongiform changes are primarily in the gray matter.

Neuroimaging studies demonstrate radiolucent areas on CT scans and areas of hyperintense signal on T2-weighted MRI.50 These lesions predominantly involve the cortex and subcortical white matter, may cross the boundaries of the

major arterial territories, and are more common in parietooccipital regions than in other regions. These lesions may appear transitory because as the initial lesions resolve, new and often adjacent lesions appear.

A point mutation in mitochondrial transfer RNA at position 3,243 can be identified in most patients with this syndrome.131 The resulting biochemical abnormalities include decreased respiratory activity in complexes I, III, and IV. There are no clinical differences between patients who have the point mutation in mtDNA and those with MELAS syndrome who do not have the mutation.131 This finding illustrates the heterogeneity of mitochondrial energy metabolism abnormalities noted earlier. Prenatal diagnosis for MELAS syndrome is now possible.39

Myoclonic Epilepsy and Ragged Red Fibers (MERRF)

This relatively uncommon condition consists of myoclonic epilepsy, generalized epilepsy, ataxia, proximate weakness, fatigability, spasticity, sensory loss, dysarthria, optic atrophy, and dementia.134 Onset can occur at any age and is variable even within families. Muscle biopsy shows ragged red fibers seen in the other conditions. Myoclonus is usually the presenting symptom and is often precipitated by noise, photic stimulation, or action. Epilepsy and ataxia soon follow. Myopathy is generally subclinical or mild. Optic atrophy may develop; however, there is no ophthalmoplegia or retinal abnormality in this disease. Biochemical aberrations may include elevations of serum pyruvate or pyruvate and lactate and reduced activities of complexes I and IV.134 This condition has a point mutation in mitochondrial transfer RNA encoded by a mutation of mtDNA at the 8344 nucleotide pair. The most common mutation is the heteroplasmic mtDNA A8344G mutation, which is present in both muscle and blood.140 However, other mutations within the same tRNA gene, t8356C and G8363C, are also found in association with this phenotype.239

Mitochondrial Depletion Syndrome

Mitochondrial depletion syndrome (MDS) typically manifests as neonatal or infantile-onset fatal lactic acidosis with severe hypotonia and progressive liver failure.134 mtDNA levels are typically reduced to less than 5% of normal.219 MDS is a common cause of lactic acidosis presenting in infancy.339 In one study of children with hypotonia, weakness, and developmental delay, 10% were found to have MDS.203 Other features may include seizures, ophthalmoplegia, renal Fanconi syndrome, congestive heart failure, and cataracts. CNS signs and symptoms may be present in 20% of patients. The clinical course is fatal, with death by 1 year of age.134

Congenital Disorders of Glycosylation

The carbohydrate-deficient glycoprotein syndromes are a group of lysosomal storage disorders in which there is a defective glycosylation of secretory, lysosomal, and mem- brane-bound proteins.166,185 Because the function of glycoproteins include transport and membrane receptor proteins, glycoprotein hormones, complement factors, immunoglobulins, and other enzymes, abnormalities in their synthesis manifests in a broad range of systemic effects.342 These syndromes usually become apparent in the early neonatal periods, with failure to thrive and multisystem organ failure, especially involving the liver and heart. In addition to the neonatal onset, clinical features of carbohydrate-deficient glycoprotein syndromes include the lower motor-neuron impairment of the legs more than the arms, subcutaneous fat pads, strabismus, and retinitis pigmentosa. Neuroimaging typically shows enlargement of the cisterna magna with brainstem and cerebellar hypoplasia.6

Ophthalmologic features are common and include strabismus, nystagmus, and a retinal degeneration with severely diminished scotopic ERG waveform.10 Less common findings include congenital cataract, retinochoroidal coloboma, glaucoma, and retinitis pigmentosa.220 The most common form, type 1a, produces prominent neurologic dysfunction in infancy. Patients with carbohydrate-deficient glycoprotein syndrome 1a can present with panting tachypnea, a nystagmus resembling ocular flutter,293 and a slowly progressive pigmentary retinopathy resembling what is seen in mitochondrial disease.109,293

Horizons

Ongoing identification of gene-causing mutations in combination with newer MR imaging techniques such as diffusion tensor imaging and proton spectroscopy, are being applied to genetic metabolic disorders to differentiate hypometabolic disorders from cystic degeneration and myelin vacuolization.329 Several new potential therapies are currently under investigation. Most of these therapies (enzyme replacement therapy, gene therapy, bone marrow transplantation, neural stem cell therapy, molecular or pharmacological chaperone therapy), are designed to restore enzyme activity.297 Others (substrate deprivation, metabolic bypass therapy) do not restore enzyme activity, but are designed to reduce levels of the compounds that accumulate in lysosomes. CNS diseases, which are proving to be the most refractory to treatment, will probably require a combination of therapeutic approaches to reverse or halt their devastating effects.

Bone marrow and stem cell transplantation require the need for an immunologically-matched healthy bone marrow

donor.297 Blood (mesenchymal cells) and brain (neural stem cells) provide the two major sources of stem cells. Although stem cells have been shown to spread through the brain in mice, it is unclear whether the number of cells necessary to make replace a deficient enzyme cells numbers can be delivered in humans. It is anticipated that stem cells could be genetically manipulated before transplantation to increase production of the missing enzyme.297

Enzyme replacement therapy involves replacement of the defective enzyme with a functional enzyme molecule that has been manufactured in the laboratory.297 Although it has shown efficacy in treating several disorders including Gaucher disease type 1, mucopolysaccharidosis, Fabry disease, Pompe disease, it does not work well for diseases primarily involving the CNS because the enzymes do not easily cross the blood–brain barrier.297

Gene therapy introduces a functional version of the gene that is mutated in affected individuals to replace or augment its function.119,297 The gene can be introduced as free DNA, in a lipid coat (liposome), or as part of a viral vector. At present, viral delivery is the most common approach. Viral delivery requires modification of a specific virus so that it cannot cause disease and then having it carry the gene for the missing enzyme to the brain or other target organ. This promising therapy is currently limited by a number of real and potential difficulties. These include: (1) the inherent difficulty of creating effective vectors, especially for gene delivery to non-dividing cells within the brain, (2) the need to introduce the gene into a large number of cells to have a clinical effect; (3) the potential for an oncogenic event as a result of the random insertion of the gene into the host cell chromosomes; and (4) the extensive review processes now needed for all gene therapy trials.119,297 Gene therapy is being currently researched as a treatment for numerous disorders, including Canavan disease.119,297

Molecular chaperone therapy provides a new and novel therapeutic approach for the treatment of neurodegenerative diseases.200,297 When a protein or enzyme is misfolded because of a genetic mutation and is unable to adopt the correct functional shape,200,297 it is destroyed within the cell, leading to decreased amounts of enzyme that gets transported from the endoplasmic reticulum to the lysosome, and therefore reduced enzyme activity.200,297 Pharmacological chaperones are small molecules that bind to and stabilize the functional form or three-dimensional shape of a misfolded protein in a cell, allowing it to be efficiently trafficked from the endoplasmic reticulum and distributed to the lysosome in the cell, which increases enzyme activity and cellular function and reduces the stress of the abnormal substrate on cells.200,297

Substrate deprivation (also called substrate synthesis inhibition, substrate reduction, and substrate balancing) utilizes molecular inhibitors to decrease the production of the molecule that typically accumulates to high levels in persons with lysosomal storage diseases.297 For example, children with Tay–