Many rare diseases currently have little to no effective measures of diagnoses and treatments, primarily due to lack of representative patients and funding towards researching rare disease pathogenesis. For instance, a large group of rare diseases that have ineffective diagnoses and treatments are the neurological disorders. These disorders target the nervous system, which include the brain, spinal cord, and all the nerves that run throughout the human body. These disorders can be classified into two categories: those that affect the central nervous system (CNS - brain and spinal cord) and those that affect the peripheral nervous system (all bodily nerves that exist outside of the brain and spinal cord). Note that many commonly-known neurological disorders are not considered to be rare, including Alzheimer’s disease, Down syndrome, and Parkinson’s disease.

Figure 1: LS patients demonstrate symmetric abnormalities in midbrain lesions.

On the other hand, an example of a rare neurological disorder is Leigh syndrome (LS), which is a rare neurological disorder that affects the central nervous system, usually develops in infancy, and is inherited in an autosomal recessive manner.¹ There are a variety of symptoms categorized in three stages that provide a general basis for diagnosing individuals with LS. The symptoms that characterize stage I include stunted growth, vomiting, and diarrhoea. Some examples of symptoms exhibited in stage II are uncoordinated movement, dystonia, hypotonia, optic atrophy, and peripheral neuropathy. In stage III, symptoms such as dysarthria, dysphagia, and acute muscle atrophy are common, with death being the outcome. It is imperative to study the physiological defects of brain and muscle structures in LS for proper diagnosis. Lesions of the basal ganglia and the midbrain alongside additional abnormalities can be seen in the brainstem and spinal cord (Figure 1).² There is also a buildup of lipids in muscle tissue and a variability in muscle fibre diameter and organization (Figure 2).⁴ The gene that causes the majority of LS cases is SURF1, which codes for the SURF1 protein. Note that gene names are italicized while protein names are unitalicized. The SURF1 protein is a maintenance factor for the assembly of the cytochrome c oxidase (COX) complex that is important in oxidative phosphorylation (OXPHOS), a metabolic process occurring in the mitochondria of cells that creates adenosine triphosphate (ATP), the main energy provider of cells.⁶

Figure 2: Light microscopy cross-sections of muscle tissue in LS patients with a c. 841delCT mutation in the SURF1 gene.

In LS, most mutations in the SURF1 gene result in an abnormally truncated SURF1 protein, which decreases the stability of the resulting protein transcript and leads to a corresponding reduction in COX assembly. Since the COX transmembrane protein is integral in the synthesis of ATP, smaller quantities of COX embedded in the inner mitochondrial membrane decreases the enzymatic activity of COX in the electron transport chain. This reduction of COX activity, in turn, diminishes ATP production and lowers cellular energy levels. When aerobic respiration ceases to function due to a lack of oxygen, anaerobic respiration occurs. LS patients have increased concentrations of pyruvate and lactic acid in the blood, cerebrospinal fluid, and urine.² A lack of ATP in these cells can culminate in cell death in many tissues, which lead to the brain lesions and other symptoms that characterize LS.

““It is imperative to study the physiological defects of brain and muscle structures in LS for proper diagnosis.””

There are no effective treatments that successfully cure individuals afflicted with COX-associated LS.⁷ However, current treatments such as palliative care, lactic acidosis treatments, diet modifications, and drug interventions focus on alleviating the symptoms and side effects of LS. Chemical compounds currently tested to combat lactic acidosis, which is the acidification of the bloodstream due to an increase in lactic acid concentration and decrease in oxygen levels, include dichloroacetate and sodium bicarbonate, a buffer. However, peripheral neuropathy may occur with the use of these compounds. In terms of diet, the standard treatment is to implement an optimal energy intake diet appropriate to the patient’s age and activity levels. These diets take advantage of the limited ability of the mitochondria to produce energy despite COX deficiency or malfunction of other OXPHOS components. With respect to pharmacological treatments, a number of natural and synthetic compounds are being tested in isolation or combination. The most successful substances tested to date in treating the symptoms of specific OXPHOS defects include biotin and vitamin B1 (thiamine), and coenzyme Q₁₀ and its synthetic derivative EPI-743. However, the caveat that remains for many of the biochemical treatments is that there are minimal clinical improvements and adverse side effects.⁷ The hope for the future is to improve the diagnosis and treatment of LS and other rare neurological disorders.

Works Cited:

1. Tiranti V, Hoertnagel K, Carrozzo R, et al. Mutations of SURF-1 in Leigh Disease Associated with Cytochrome c Oxidase Deficiency. The American Journal of Human Genetics. 1998;63(6):1609-1621.

2. Van Coster R, Lombes A, De Vivo DC, et al. Cytochrome c oxidase-associated Leigh syndrome: Phenotypic features and pathogenetic speculations. J Neurol Sci. 1991;104(1):97-111.

3. Fig. 1. On MRI, the lesions seen in Leigh syndrome (LS) are characteristically high intensity on T2-weighted images and low intensity on T1-weighted images. In: Van Coster R, Lombes A, De Vivo DC, et al. Cytochrome c oxidase-associated Leigh syndrome: Phenotypic features and pathogenetic speculations [online]. Elsevier Science Publishers B.V.; 1991.

4. Pronicki M, Matyja E, Piekutowska-Abramczuk D, et al. Light and electron microscopy characteristics of the muscle of patients with SURF1 gene mutations associated with Leigh disease. J Clin Pathol. 2008;61(4):460-466. doi: 10.1136/jcp.2007.051060.

5. Fig. 2. Histochemical and histological findings in the muscle of patients with Leigh syndrome associated with c. 841delCT SURF1 gene mutation. In: Pronicki M, Matyja E, Piekutowska-Abramczuk D, et al. Light and electron microscopy characteristics of the muscle of patients with SURF1 gene mutations associated with Leigh disease [online]. group.bmj.com;2007.

6. Zhu Z, Yao J, Johns T, et al. SURF1, encoding a factor involved in the biogenesis of cytochrome c oxidase, is mutated in Leigh syndrome. Nat Genet. 1998;20(4):337-343.

7. Baertling F, Rodenburg RJ, Schaper J, et al. A guide to diagnosis and treatment of Leigh syndrome. J Neurol Neurosurg Psychiatry. 2014;85(3):257-265. doi: 10.1136/jnnp-2012-304426.

Cite This Article:

Chan G., Zheng K., Ho J. Rare Neurological Disorders. Illustrated by M. Yi. Rare Disease Review. August 2017. DOI:10.13140/RG.2.2.24510.59208.