Mitochondrial Disorders Affecting the Nervous System

R.H. Haas, MB, BChir; Z. Zolkipli, MB, ChB


Semin Neurol. 2014;34(3):321-340. 

In This Article


Mitochondrial brain disease often affects both gray and white matter.[20] Patterns of brain involvement are helpful in defining phenotype, but heterogeneity even with the same molecular defect is common.[11,21,22] In Leigh disease, basal ganglia, brainstem nuclei, and white matter damage was first described by Dennis Leigh in 1951.[23] This early article contained an excellent description of the typical neuropathology. The neuropathological features of subacute necrotizing encephalomyelopathy (Leigh disease) are very similar to the lesions of Wernicke-Korsakoff syndrome due to alcoholic thiamin deficiency, spongiform white matter degeneration, capillary proliferation, gliosis, and relative preservation of neurons (Fig. 1). Thiamin is an essential cofactor for the E1 subunit of pyruvate dehydrogenase and deficiency of this enzyme accounts for an estimated 25% of Leigh disease cases.[24,25] MELAS has a vascular component not commonly seen in other mitochondrial encephalopathies. In MELAS, vascular endothelial energy failure with heavy succinic dehydrogenase staining indicates mitochondrial proliferation. MELAS patients may have reduced arginine levels. l-arginine or citrulline treatment as a substrate for nitric oxide synthetase (NOS) appears to be an effective acute and chronic treatment.[26,27] Patients with stroke-like episodes—often in a posterior nonvascular distribution—usually partially recover as do their symptoms, although after each episode there is some residual cortical injury.[28] There is focal hyperperfusion during the acute phase of MELAS stroke with decreased oxygen extraction both acutely and between stroke-like episodes.[29]

Figure 1.

Leigh syndrome: Subacute necrotizing encephalomyelopathy. (A) Brain slice showing necrotic lesions indicated (B) by arrows on T2-weighted magnetic resonance image (A, subfrontal white matter; B, putamen; C, thalamus).

White Matter Disease

White matter disease is increasingly recognized and acute or chronic leukoencephalopathy is one common presentation of mitochondrial brain disease.[30,31] Acute disseminated encephalomyelitis (ADEM) is a common misdiagnosis early in the course. White matter disease may be patchy or generalized. The vulnerability of oligodendroglia to oxidative injury is the likely substrate. Recently, diffusor tensor imaging abnormalities have been shown in pediatric mitochondrial disease patients even when conventional magnetic resonance imaging (MRI) is normal.[32] T2-weighted MRI signal changes are routinely seen in the classical syndromes (MELAS, MERRF, Kearns-Sayre syndrome, and Leigh syndrome).[33] Diffuse white matter involvement is a diagnostic feature of MNGIE due to thymidine phosphorylase deficiency,[34] and more recently many other defects in mtDNA maintenance have associated leukoencephalopathy.[30] Progressive cavitating leukoencephalopathy with periventricular and corpus callosal cysts has been described due to a variety of mitochondrial electron transport chain defects: complex I[35,36] and complex II[37] (Fig. 2).

Figure 2.

Cavitating leukodystrophy in a 1-year-old girl with encephalopathy following a febrile episode who went on to follow a neurodegenerative course. Complex I deficiency was confirmed in muscle. (A) Fluid-attenuated inversion-recovery axial image showing cystic white matter changes. (B) T1 sagittal image. Arrow points to a cyst in the corpus callosum. Courtesy of Dr. Sakkubai Naidu.

Spinal Cord Involvement

Spinal cord involvement is common in Leigh syndrome and was described in Dennis Leigh's first case.[23] An MRI identification of a pattern of extensive dorsal column and lateral corticospinal tract uniform involvement was reported in all eight patients with a syndrome of leukoencephalopathy with brainstem and spinal cord involvement and high lactate (LBSL) associated with a clinical course of progressive spasticity and ataxia.[38] This disorder was found on exome sequencing to be caused by autosomal recessive mutations in DARS2, which encodes mitochondrial aspartyl-tRNA synthetase. The phenotype has been expanded by an observational study of 78 patients, some with milder adult presentations, although the most common presentation was juvenile onset of slowly progressive ataxia, spasticity, and dorsal column dysfunction.[39] Axonal neuropathy was documented in five of eight patients with LBSL due to the DARS2 mutation.[40] An infantile rapidly progressive fatal phenotype of LBSL is also described.[41] Mitochondrial aminoacyl-tRNA synthetases represent a new category of mitochondrial brain disease with a spectrum of presentations from a severe Alpers phenotype[17] through LBSL to a milder leukoencephalopathy with ovarian failure.[42]

Optic Atrophy

In relation to optic atrophy, two common causes of early-onset visual failure are mitochondrial diseases. The visual system has high energy requirements.[43] Autosomal dominant optic atrophy (OPA1) has widespread CNS manifestations in 20% of carriers with bilateral sensorineural deafness, ataxia, myopathy, progressive external ophthalmoplegia (PEO), and peripheral neuropathy.[44] Muscle biopsy even in patients with only optic atrophy show cytochrome C oxidase-deficient fibers and multiple mitochondrial DNA deletions.[45] OPA1 is an inner mitochondrial membrane protein mutation affecting mitochondrial fusion to the network configuration.[46] The earliest optic nerve change is early loss of retinal ganglion cells within the papillomacular bundle.[47] This loss of retinal ganglion cells is also the earliest retinal change in LHON . First identified as an mtDNA disease in 1988,[4] LHON is caused 90% of the time by one of three pathogenic mtDNA complex I mutations (m.3460G > A, m.11778G > A, and m.14484T > C). Typically young adult males are affected with unilateral vision loss, followed by involvement of the other eye 8 weeks later (Fig. 3).[48] Leber hereditary optic neuropathy may have spinal cord involvement,[49] leading to confusion with neuromyelitis optica due to the NMO aquaporin antibody and multiple sclerosis (MS).[50] Female carriers of LHON mutations more often have a multiple sclerosis phenotype.[51] Although genetic mitochondrial disease may present with an MS phenotype, there is increasing evidence of mitochondrial dysfunction in sporadic MS disease, with white matter astrocytes playing an important role.[52,53] Mitochondria are crucial for the innate immunity response and play an important role in apoptosis, in part mediated through purinergic signaling.[54] It is hypothesized that pathological permeability transition pore (PTP) opening plays a role in the white matter degeneration in MS.[55]

Figure 3.

Early unilateral R eye involvement in Leber hereditary optic neuropathy due to the mtDNA G11778A mutation. (From: Perez F, Anne O, Debruxelles S, et al. Leber's optic neuropathy associated with disseminated white matter disease: a case report and review. Clin Neurol Neurosurg 2009;111(1):83–86 with permission.)

Peripheral Neuropathy

Peripheral neuropathy is a common manifestation of mitochondrial disease.[56] Mechanisms include failure of mitochondrial fusion, mutations affecting 2-oxoglutarate and pyruvate dehydrogenase, and disorders affecting oxidative phosphorylation leading to reduced ATP production and the disorders that result in mtDNA depletion. Mitochondrial neuropathies can be classified into disorders with neuropathy as the only or predominant feature, neuropathy as a key feature, and disorders with neuropathy as a minor feature.56 The common mtDNA diseases—MELAS due to tRNAleu(UUR) mutations (commonly m.3243A > G) and neuropathy ataxia and retinitis pigmentosa (NARP) caused by ATPase 6 mutations (most often m.8993T > G)—frequently cause peripheral neuropathy. Nuclear mitochondrial gene defects such as pyruvate dehydrogenase deficiency and disorders of mtDNA maintenance; mitochondrial polymerase (PolG)[7] C10ORF2, encoding the Twinkle helicase[57] and the rare disorder Navajo neurohepatopathy due to MPV17 mutations[58,59] also have peripheral neuropathy as a variable feature. Sensorineural hearing loss is the most common neuropathy in mitochondrial disease. When diabetes mellitus accompanies sensorineural hearing loss, a search for MELAS mutations should be performed.[60] Neuropathies are generally axonal in mitochondrial disease, although demyelination can occur, particularly mtDNA maintenance disorders such as PolG, Twinkle, and thymidine phosphorylase deficiency. Neuropathy is the major feature in disorders due to mitochondrial fusion resulting from mitofusin2 (MTF2) mutations that are responsible for Charcot-Marie-Tooth disease CMT2A, CMT5, CMT6, and CMT2K phenotypes. Although mitofusin mutation phenotypes typically have neuropathy as the major feature, type 2A2 may have extensive CNS involvement including optic neuropathy and a MS phenotype with age of onset 1 year to 45 years in an American kindred of Northern European and Cherokee American Indian descent.[61]

POTS and Autonomic Neuropathy

Symptoms of autonomic neuropathy are often reported by patients with mitochondrial disease. These include postural orthostatic tachycardia syndrome (POTS), temperature instability, heat and cold intolerance, tachycardia, and the symptoms of gastrointestinal (GI) dysmotility discussed below.[62] Unfortunately, these types of symptoms are difficult to objectively confirm, overlap with psychosomatic disease, and are often downplayed by physicians. It is clear that other neuropathies are common in mitochondrial disease[56] and it is very likely that autonomic neuropathy is often overlooked.

Neuromuscular Junction Disease

Neuromuscular junction disease does occur in mitochondrial disease. Patients may have positive titers of acetylcholine receptor antibodies and typically have ophthalmoplegia with ptosis along with fatigability. MUSK antibody positive myasthenia patients have mitochondrial abnormalities on muscle biopsy, including cytochrome oxidase (COX) negative fibers and mitochondrial aggregates.[63] Several case reports have reported mitochondrial myopathy patients diagnosed with myasthenia on the basis of fatigability with electrodecremental electromyography (EMG) and some response to anticholinesterase treatment or steroids.[64–66] Patients may present in acute crisis with sudden deterioration or weakness.[67] Ben Yaou et al reported 12 cases of thymectomy for myasthenic symptoms diagnosed as autoimmune myasthenia in patients later found to have mitochondrial myopathy.[68] The authors suggest that in the absence of relevant criteria arguing for myasthenia gravis (significant variability of muscle weakness, positive titer of anti-AChR or anti-MUSK antibodies, decremental EMG response), a muscle biopsy is required before thymectomy to exclude a mitochondrial disease.

Mitochondrial Myopathy

Skeletal and cardiac muscle are both frequently involved in mitochondrial disease. There are many excellent reviews of the mitochondrial myopathies.[69–71] Ocular myopathy including ptosis and PEO is a common feature of mtDNA deletion disease,[70,72] but also occurs in MELAS and mtDNA depletion diseases. The eye muscles are constantly moving, are particularly energy dependent, and have a very high mitochondrial content.[73] Along with this comes rapid accumulation of COX negative fibers and mtDNA deletions—even during normal aging—predisposing the ocular muscles to easily manifest mitochondrial disease.[74]

The classical pathological finding in skeletal muscle is the presence of ragged red fibers most clearly seen on the modified Gomori trichrome stain (Fig. 4A). COX negative fibers are frequent (Fig. 4B). These fibers are even more easily identified and quantified as ragged blue fibers, produced by counterstaining of succinic dehydrogenase (SDH) and COX. This pathological marker is predominantly a feature of adult disease and is rarely seen in children. A more common finding is subsarcolemmal mitochondrial proliferation (thought to be an attempt to overcome the mitochondrial defect) (Fig. 4C). In children with mitochondrial muscle symptoms, histochemistry and electron microscopy (EM) are frequently normal, but mitochondrial proliferation that does not reach the level of ragged red fibers may be seen.[11] Histochemical features of mitochondrial myopathy include prominent NADH reductase and SDH staining and COX negativity. There may be lipid and or glycogen accumulation. Structural abnormalities of mitochondria including proliferation and creatinine phosphokinase intramitochondrial paracrystalline inclusions may be seen on EM (Fig. 4C). Paracrystalline inclusions indicate mtDNA abnormality and this diagnostic finding is most often seen in adults with mtDNA point mutations or deletions, and in mtDNA depletion. The most common presentation of mitochondrial muscle disease is exercise intolerance with weakness in more severe cases of skeletal muscle involvement. In pediatric patients, myopathy manifestations include motor developmental delay, hypotonia, exercise intolerance, and less commonly weakness. A retrospective analysis of 113 children with definite mitochondrial disease based on modified Walker criteria found that 60% had predominantly neuromuscular manifestations, 44% had nonspecific encephalomyopathy, but cardiomyopathy was found in 40%—most commonly hypertrophic cardiomyopathy in 58% of patients in the cardiac group, whereas 29% had dilated cardiomyopathy.[75] The mortality was much higher in the group with cardiomyopathy, 18% surviving at 16 years of age compared with 95% survival in the group with neuromuscular disease, but no cardiomyopathy.[75]

Figure 4.

Mitochondrial myopathy. (A) Ragged red fibers modified Gomori stain. (B) COX negative fiber. (C) Subsarcolemmal mitochondrial accumulation with paracrystalline inclusions on electron microscopy, mtDNA deletion disease.

Gastrointestinal Dysmotility

This common feature of mitochondrial disease is likely a combination of nerve and smooth muscle energy failure. The most severe manifestation that is often fatal occurs in MNGIE, where marked atrophy and fibrosis of the external layer of the muscularis is seen and megamitochondria can be identified in the submucosal and myenteric ganglion cells as well as in smooth muscle cells of the muscularis mucosae and muscularis propria of the entire GI tract.[76] Giordano et al reported mtDNA depletion, mitochondrial proliferation, and smooth cell atrophy in the external layer of the muscularis propria, in the stomach, and in the small intestine of MNGIE patients.[34] Pseudo-obstruction is a life-threatening complication in mitochondrial encephalomyopathies likely caused by autonomic neuropathy along with smooth muscle myopathy. It may occur acutely in some cases resulting in laparotomy or chronically with intermittent symptoms. A retrospective review of 20 cases noted MELAS, MERRF, and deletion disease as causes.[77] The author has seen pseudo-obstruction in NARP disease and it is common in MNGIE.[78]