The Neurologic Manifestations of Mitochondrial Disease

Home , Leigh syndrome, Mitochondrial disease, Optic nerve hypoplasia

DEVELOPMENTAL DISABILITIES RESEARCH REVIEWS 16: 120 – 128 (2010)

THE NEUROLOGIC MANIFESTATIONS OF MITOCHONDRIAL DISEASE

Sumit Parikh* Neurogenetics and Metabolism, Cleveland Clinic, Cleveland, Ohio

The nervous system contains some of the body’s most metabol- such as surgery, exposure to mitochondrial toxins, or catabolic ically demanding cells that are highly dependent on ATP produced via stress such as prolonged fasting or malnutrition. mitochondrial oxidative phosphorylation. Thus, the neurological system is consistently involved in patients with mitochondrial disease. Symptoms However, for a disease with diverse genetic mechanisms differ depending on the part of the nervous system affected. Although and protean manifestations, unexplained neurological symptoms almost any neurological symptom can be due to mitochondrial disease, in a patient with other systemic issues can serve as the linchpin there are select symptoms that are more suggestive of a mitochondrial around which to establish an accurate diagnosis. Almost any problem. Certain symptoms that have become sine qua non with under- neurological symptom can be due to mitochondrial disease. lying mitochondrial cytopathies can serve as diagnostic ‘‘red-flags.’’ Here, the typical and atypical presentations of mitochondrial disease in the There are, however, select symptoms that are more suggestive nervous system are reviewed, focusing on ‘‘red flag’’ neurological symp- of a mitochondrial problem. From strokes in a nonvascular dis- toms as well as associated symptoms that can occur in, but are not spe- tribution with lactic acidosis in MELAS syndrome (mitochon- cific to, mitochondrial disease. The multitudes of mitochondrial syn- drial myopathy, encephalopathy, lactic acidosis, and stroke) to dromes are not reviewed in-depth, though a select few are discussed in epilepsia partialis continua (EPC) in POLG1 mediated mito- some detail. ' 2010 Wiley-Liss, Inc. Dev Disabil Res Rev 2010;16:120–128. chondrial disease, certain symptoms have become sine qua non with underlying mitochondrial cytopathies and can serve as diagnostic ‘‘red-flags’’ (Table 1). However, the neurological sys- Key Words: mitochondria; mitochondrial disease; neurological; neuropa- tem is infrequently involved in isolation. It is critical to evaluate thy; white matter; stroke; hearing loss; pigmentary retinopathy; Leigh POLG other organ systems whenever mitochondrial disease is sus- syndrome; ataxia; Alper syndrome; ; epilepsia partialis continua- pected, not only to allow for appropriate treatment but to help epilepsy; seizures; cerebellar degeneration; optic atrophy; myopathy; hypotonia; dysmotility better ensure an accurate genetic diagnosis. Here, the typical and atypical presentations of mitochondrial disease in the nervous system are reviewed, focusing on ‘‘red flag’’ neurological symptoms as well as associated symptoms that can occur in but are not specific to mitochondrial disease. The itochondrial diseases manifest with a wide array of multitudes of mitochondrial syndromes are not reviewed in-depth, symptoms, many times encompassing more than one though a select few are discussed in some detail. organ system. The nervous system contains some of M Of note, initial descriptions of mitochondrial disorders and the body’s most metabolically demanding cells that are highly phenotypes revolved around maternally inherited mitochondrial dependent on ATP produced via mitochondrial oxidative DNA (mtDNA) mutations. As our understanding of mitochondrial phosphorylation. In addition, ATP has direct neuro- and function has evolved, we understand that the majority of primary cotransmitter effects via purinoreceptors in both the central mitochondrial disorders and their associated neurological symptoms and peripheral nervous systems [Benarroch, 2010]. Thus the are caused by mutations in the nuclear DNA (nDNA). Thus, many neurological system is one of the few systems that is consis- of the common neurological symptoms discussed occur due to tently involved in patients whom a cellular ATP deficit exists. either mtDNA or nDNA mediated mitochondrial disease. As holds true for most patients with mitochondrial disease, no one specific symptom or finding occurs in all mitochondrial patients. Neurological problems, as with other RED-FLAG SYMPTOMS symptoms in mitochondrial disease, present in a relapsing- Where mitochondrial disorders should be first-and-foremost on remitting pattern, with incremental worsening and partial the differential. recovery. Symptoms differ depending on the part of the nervous system affected. Due to mitochondrial DNA (mtDNA) heteroplasmy and varying degrees of tissue distribution of de- *Correspondence to: Sumit Parikh, MD, Neurogenetics and Metabolism, Cleveland fective mitochondria, symptom severity fluctuates, even within Clinic, 9500 Euclid Avenue, S60, Cleveland, OH 44195. families who share a common genetic etiology to their disease. E-mail: [email protected] There is often a ‘‘threshold’’ of tissue involvement that must Received 8 March 2010; Accepted 6 July 2010 View this article online at wileyonlinelibrary.com. occur prior to symptom onset. Worsening or initiation of DOI: 10.1002/ddrr.110 symptoms is easily brought on by infections, medical stress ' 2010 Wiley -Liss, Inc. nine has been studied for patients with palsy (CP). Indeed, if the disease onset Table 1. Red-Flag MELAS which has a variable degree of occurred in the perinatal period, it can Neurologic Symptoms success in reducing the severity and dura- initially be difficult to discriminate tion of symptoms [Kubota et al., 2004]. L- between a patient with CP versus Leigh Cerebral stroke-like lesions (at times in a arginine is being studied as an agent to syndrome [Willis et al., 2000]. Symptoms nonvascular pattern) Bilateral deep gray matter lesions (Leigh help prevent metabolic strokes from other and MRI findings can fluctuate in severi- syndrome) etiologies as well, although the mecha- ty—often appearing at times of metabolic Encephalopathy-hepatopathy (Alpers nism by which it helps is uncertain. It is or catabolic stress. Partial recovery syndrome), especially after receiving also being used in an oral form to decrease can occur and might be associated valproate Cognitive degeneration the incidence of chronic strokes, but no with improvement on neuroimaging. Epilepsia partialis continua (EPC), evidence-base yet supports this indication. However, the condition is generally myoclonus, and status epilepticus progressive. Ataxia with or without cerebellar Bilateral deep gray matter lesions In addition to Leigh syndrome, degeneration (Leigh syndrome) isolated basal ganglia lesions can occur in Retinal degeneration, optic nerve atrophy, or ophthalmoplegia Leigh syndrome is defined by primary mitochondrial disease. Isolated Early-onset hearing loss bilateral, symmetric lesions involving bilateral striatal necrosis, in contrast, while the deep gray nuclei, often in a patchy at times due to primary mitochondrial fashion. Subcortical, midbrain, and pon- disease, more often occurs due to causes tine structures but especially the peria- such as glutaric aciduria, mutations of the Cerebral stroke-like lesions (at queductal grey and floor of the fourth SLC25A19 gene, and viral or bacterial times in a nonvascular pattern) ventricle are affected to varying degrees. infections. [Solano et al., 2003] Metabolic strokes typically occur This condition is more commonly seen Some mitochondrial patients have due to an acute, relatively intense, regional in children and infrequently presents in been known to present with early-onset defect in cellular energy production. adults. Few other nonmitochondrial or Parkinsonism without visible basal gan- While they can occur at any age, they of- metabolic disorders lead to such sym- glia lesions. POLG1 and PINK1 muta- ten occur in patients that are not typically metric deep gray matter lesions, one of tions are known etiologies of this presen- at risk of stroke, particularly in individuals them being an acute necrotizing ence- tation [Davidzon et al., 2006]. Central younger than age 45. Since the injury to phalopathy due to RANBP2 gene dopamine deficiency has also been iden- cerebral tissue is not primarily due to mutations, affecting a nuclear pore pro- tified in select mitochondrial patients and reduced blood supply, the lesions do not tein [Neilson et al., 2009]. can lead to symptoms of basal ganglia dis- always follow a vascular distribution. Leigh syndrome was initially ease with normal neuroimaging [Garcia- However, an initial relatively small isolated described in 1951 when Dr. Denis Leigh Cazorla et al., 2007]. In these situations lesion may seem to exist in a single vascu- described a 7-month-old infant with treatment with L-dopa or a dopamine- lar territory. Rarely are strokes in mito- somnolence and spasticity that had a agonist may ameliorate some symptoms. chondrial patients caused by isolated vas- ‘‘subacute necrotizing encephalomyelop- cular pathology. Infrequently, strokes due athy’’ with neuropathological findings Encephalopathy-Hepatopathy to a vasculitis leading to Moya Moya have similar to those seen in Wernicke’s ence- (Alpers Syndrome), especially after been noted in select patients [Kotagal phalopathy [Leigh, 1951]. While initially receiving valproate et al., 1988]. linked to X-linked pyruvate dehydro- Alpers (or Alpers-Huttenlocher) Initial small strokes often mimic an genase complex deficiency, more Leigh syndrome is a mitochondrial disorder inflammatory, embolic, or neoplastic syndrome cases have now been linked to now known to mostly be due to muta- lesion. Symptoms vary depending on the patients with primary mitochondrial dis- tions in the nDNA encoded POLG1 portions of the brain involved. At times, ease. Multiple mtDNA and nDNA gene [Naviaux and Nguyen, 2004]. these lesions can partially or completely mutations and respiratory chain bio- POLG1 related mitochondrial diseases reverse, with or without treatment. chemical abnormalities have been associ- have a broad and still evolving range of Brain MRI with diffusion-weighted ated with this phenotype, especially phenotypes, of which Alpers syndrome imaging is abnormal in metabolic strokes involving impairment of Complex I or is common. Alpers syndrome can also and crucial in establishing a diagnosis. Complex IV function on respiratory be caused by defects in other genes MELAS is the prototypical mito- chain analysis of muscle tissue. When involved in mtDNA replication. chondrial disease presenting with strokes associated with nephropathy, a primary Early development is normal in prior to the age of 45 years. The ischemic disorder of CoQ10 biosynthesis may Alpers patients. They often have an ex- lesions in MELAS have a predilection for exist due to mutations in the PDSS2 plosive onset of seizures (EPC or status the occipital and parietal lobes. The gene [Lopez et al., 2006]. Regardless of epilepticus), at times triggered by a cata- lesions are extremely epileptogenic and genetic etiology, the injury may lead to bolic stressor such as prolonged fasting these patients may present with focal status findings of calcifications on CT scan or viral illness. Seizures are very difficult epilepticus, and EPC. MELAS strokes [Finsterer and Kopsa, 2005]. to control and may lead to the patient may present as migraines with visual auras. Most patients with Leigh syndrome receiving valproic acid (VPA), at which Strokes leading to visual hallucinations present with varying degrees of encephal- point liver failure and encephalopathy have been described. Metabolic strokes, opathy, and basal ganglia and brainstem occur [McFarland et al., 2008]. The some with features similar to MELAS syn- dysfunction. Patients often have somno- patient’s EEG may show a predominance drome, have been noted in multiple other lence, nystagmus, respiratory abnormal- of occipital discharges [Engelsen et al., mitochondrial disorders, including both ities, and ataxia. With basal ganglia injury, 2008a]. Of note, MELAS syndrome can mtDNA and nDNA mediated disease. varying degrees of dyskinesia and dystonia also present in this fashion. Alpers Acute treatment for metabolic can develop. The patient’s clinical find- patients having no lactic acidosis and strokes in the form of intravenous L-argi- ings may mimic those seen in cerebral normal mitochondrial respiratory chain

Dev Disabil Res Rev NEUROLOGIC MANIFESTATIONS OF MITOCHONDRIAL DISEASE PARIKH 121 testing in muscle have been described cerebral or cerebellar involvement. An leptiform discharges, POLG1-related [de Vries et al., 2008]. Thus, a high abrupt worsening of cognitive function mitochondrial disease is highly likely and index of suspicion is needed to make the in mitochondrial patients should never valproate should not be given until this correct diagnosis. automatically be attributed to worsening diagnosis is excluded. There is even dis- Hepatopathy and encephalopathy disease without an appraisal of other cussion as to whether select patients can also occur in other mitochondrial potentially treatable etiologies. A specific should receive POLG1 testing prior to disease patients as well, especially those treatment for mitochondrial disease initiating valproate therapy [Saneto et al., with mitochondrial DNA depletion due related cognitive decline does not exist. 2010]. to other nDNA gene mutations involved More common (and potentially in mitochondrial replication. These treatable) causes of EPC such as Rasmus- patients often present in infancy and Epilepsia partialis continua (EPC), sen encephalitis should be excluded. Mi- early childhood with a mixture of he- myoclonus, and status epilepticus tochondrial disease related EPC does not patic dysfunction and varying degrees of Although epilepsy is a common typically lead to hemicerebral atrophy— muscle and brain involvement [Mandel symptom in many mitochondrial disease though a case of ipsilateral cerebral and et al., 2001]. patients, two epilepsy subtypes raise the cerebellar atrophy in a patient with EPC likelihood of primary mitochondrial dis- and a POLG1 mutation has been Cognitive degeneration ease. These include myoclonic epilepsy reported [Lachhwani et al., 2008]. Treat- Although mitochondrial dysfunc- and epilepsia partialis continua. Other ment in mitochondrial disease-related tion has been linked to dementia that types of seizure conditions in mitochon- EPC is not different than in EPC due to may begin later in life such as Alzheimer drial patients are discussed later. other etiologies. disease, primary mitochondrial disease Myoclonic epilepsy, with or with- often presents with cognitive impair- out progressive symptoms, is often a pre- ment and loss of previously achieved senting manifestation of mitochondrial Ataxia with or without cerebellar cognitive abilities [Finsterer, 2009b]. disease at any age. Nonepileptic photic, degeneration One study found that up to 60% of mi- action or postural myoclonus may also Progressive ataxia with or without tochondrial patients have some degree of occur. With myoclonus, syndromic mi- cerebellar degeneration can be seen in a cognitive decline, whether mild, moder- tochondrial diseases due to mtDNA gene variety of mitochondrial diseases. Ataxia ate or severe [Kartsounis et al., 1992]. mutations, especially myoclonic epilepsy in mitochondrial patients occurs due to The decline can be slow and steady or with ragged red fibers (MERRF) and primary cerebellar degeneration, a sen- abrupt and severe. This decline is not MELAS are often invoked. However, sory polyneuropathy, an axonal motor specific to one subtype of mitochondrial symptoms can be due to nonsyndromic, neuropathy, worsening encephalopathy, disease and can occur in patients with nDNA mediated disease as well, includ- or primary muscle weakness. Consider- disease caused by either mitochondrial ing POLG1 disease. There is often cog- ing that Friedreich’s Ataxia is a mito- or nuclear DNA mutations. nitive decline and worsening of balance, chondrial disorder (since the Frataxin When modest in nature, or seem- coordination and motor function, which protein is located in mitochondria and ingly subjective in report, the decline is invokes a progressive myoclonic epilepsy involved in iron transport and respiratory quantifiable on neuropsychological test- (PME) phenotype. The myoclonus is function), ataxia is an extremely com- ing. Such testing is therefore helpful in partially responsive to treatment but typi- mon presentation of mitochondrial sorting out simple inattention or behav- cally difficult to control. Multiple thera- disease. Curiously, primary cerebellar ioral causes of poor cognitive perform- peutic agents are frequently attempted hypoplasia is an infrequent finding in ance and in objectively tracking over with variable success. primary mitochondrial disease though a time what may initially seem to be a EPC, manifesting as regular/irreg- mtDNA mutation in a tRNA synthetase nominal decline ular clonic seizures in succession limited gene has been reported to cause such a Impairment, with or without to one part of the body, can be a presen- finding [Edvardson et al., 2007]. regression, can be limited to one domain tation of and recurring problem in mito- Historically, mitochondrial DNA of cortical development such as speech chondrial disease—especially in patients deletion syndromes (chronic progressive or can affect multiple modalities. Prob- with POLG1 and TWINKLE nuclear external ophthalmoplegia [CPEO], and lems with executive function, attention, gene mutations or MELAS [Lonnqvist Kearns-Sayre syndrome [KSS]) have memory, and personality can develop. et al., 2009a]. However, such a presenta- been associated with ataxia. Patients These symptoms do not always correlate tion has also been noted in Leigh syn- with KSS have been found to have cer- with visible changes on neuroimaging, drome, nonspecific electron transport ebellar and olivary degeneration [Wray although cortical volume loss might be chain defects and other mtDNA muta- et al., 1995]. They may also have a neu- noted over time. As with all mitochon- tions [Elia et al., 1996]. These patients ropathy leading to ataxia as well. drial symptoms, these issues can fluctuate may develop concomitant encephalop- MERRF, a mitochondrial DNA point in severity. However, in many cases, slow athy, cognitive decline or hepatopathy, mutation disorder, also presents with progression of cognitive dysfunction even if these features are not present at ataxia, although not in isolation and occurs. Serial neuropsychological testing disease-onset. typically in association with myoclonus is useful in quantifying the extent of Of all known mitochondrial disor- and epilepsy. decline and may help in long-term care ders, both MELAS and POLG1-related The discovery of POLG1 disease planning. mitochondrial disease most commonly and primary CoQ deficiency in some Cognitive issues typically do not present with EPC at disease onset. In a patients with cerebellar ataxia with cere- arise in isolation. Invariably, other neu- child with previously normal develop- bellar atrophy suggests that nDNA-based rological symptoms are typically present, ment, an explosive onset of focal epi- mitochondrial disease may in fact be whether due to Leigh syndrome, a con- lepsy, EPC or status epilepticus, and at commonly involved in isolated cerebellar comitant leukoencephalopathy, or other times a predominance of occipital epi- diseases. Over a dozen nuclear genes

122 Dev Disabil Res Rev NEUROLOGIC MANIFESTATIONS OF MITOCHONDRIAL DISEASE PARIKH leading to mitochondrial disease have Retinal degeneration, specifically a neurological symptom or finding. In now been linked to cerebellar degenera- pigmentary retinopathy, is often seen in contrast to optic nerve atrophy, congen- tion and ataxia [Finsterer, 2009a]. Even syndromic and nonsyndromic mitochon- ital optic nerve hypoplasia may also be an early infantile onset spinocerebellar drial diseases. Depending on whether seen in infant and childhood-onset mi- ataxia phenotype has been described there is cone or rod involvement, tochondrial disease. One series identi- with TWINKLE mutations. [Nikali patients may present with night-vision fied up to 12% of patients with nonsyn- et al., 2005] difficulties, central or peripheral vision dromic mitochondrial disease as having Primary CoQ10 deficiency is due loss with decreased visual acuity, and this finding [Taban et al., 2006]. to mutations in one of at least five known color-vision deficits. However, the oph- Lastly, abnormalities in coordinat- nDNA genes and presents with ataxia in thalmic findings are often present prior ing eye muscle movements and weakness childhood as well as associated cognitive to symptom onset and a dilated eye exam in muscles of eyelid closure are common delays and epilepsy. Global cerebellar at- is crucial in patients undergoing a mito- in some patients with mitochondrial dis- rophy is typically present [Mollet et al., chondrial evaluation. With retinal disease. These are symptoms often associated 2007]. Plasma CoQ10 levels may not be ease, the dilated eye exam shows findings with myasthenia gravis. Patients may sufficiently sensitive for diagnosis and similar to what is seen with retinitis pig- complain of droopy eyelids or double- leukocyte or muscle CoQ10 levels are mentosa and/or visible macular changes, vision. The triad of ptosis, ophthalmopa- thus needed for diagnosis. Lactic acidosis with a salt-and-pepper retinopathy and resis, and weakness in eye closure has clas- is often absent. High-dose CoQ10 ther- altered macular pigmentation [Rose sically been associated with the mtDNA apy is typically very beneficial and one of et al., 2008]. This finding is not unique deletion syndromes (KSS and CPEO). the few mitochondrial conditions for to mitochondrial disease and noted in Ptosis and eye muscle alignment problems which it has a proven efficacy. many other metabolic disorders, such as can occur in other mitochondrial disor- Although POLG1 mutations can disorders of glycosylation, peroxisomal ders as well, with or without other find- lead to primary cerebellar degeneration, disorders, the neuronal ceroid lipofusci- ings of myopathy. These findings have [Winterthun et al., 2005] a sensory nosis, and other syndromic genetic con- frequently been described in patients with ataxic neuropathy can also occur. In ditions including Cohen syndrome. nDNA mutations, including POLG1 and combination with dysarthria and oph- TWINKLE [Milone et al., 2008]. thalmoplegia, the constellation of symptoms is known by the mnemonic Early-onset hearing loss SANDO syndrome [Milone et al., 2008] ‘‘Over a dozen nuclear Some patients with mitochondrial though ophthalmoplegia is not a consist- genes leading to disease may have impaired hearing or ent finding in many patients. Ataxia and have hearing loss as their initial present- imbalance due to a mixed sensory and mitochondrial disease ing symptom. motor neuropathy (Charcot-Marie- have now been linked to Syndromic mitochondrial hearing Toothe-like picture) has also been seen loss has been attributed to multiple in patients with POLG1 & TWINKLE cerebellar degeneration known causes of mitochondrial disease. mutations or mitochondrial fusion/fis- and ataxia.’’ Hearing loss can present at any age, but sion gene defects [Chen and Chan, typically begins in childhood. It infre- 2009]. Of note, mutations in fusion/fis- quently exists in isolation and other neu- sion genes can also lead to a hereditary rological or systemic manifestations of spastic paraplegia presentation. Isolated optic nerve atrophy has mitochondrial disease are also eventually Other causes of ataxia from a sen- classically been associated with Leber’s he- present. Sensorineural hearing loss is sory neuropathy in mitochondrial reditary optic neuropathy (LHON), a more often peripheral due to auditory patients include the disorder of mito- mtDNA disease due to one of several nerve or cochlear dysfunction but can be chondrial neurogastrointestinal encephal- point mutations and with mutations in central due to coexisting cortical disease. opathy syndrome (MNGIE) due to the OPA1 gene. In LHON, first described The peripheral hearing loss initially thymidine phosphorylase deficiency and in 1871, one of three common mtDNA affects high frequencies and leads to a disturbed mitochondrial nucleoside point mutations leads to a sudden-onset of characteristic ‘‘flat’’ audiogram [Chin- pools. These patients also have severe unilateral or bilateral painless vision loss, nery et al., 2000]. Cochlear dysfunction dysmotility, cachexia, and leukoence- typically in the late-teen or young adult leads to absent otoacoustic emissions. A phalopathy. Bone marrow transplantation years. The condition affects males more of- maternal inheritance pattern of deafness might be curative in this condition. ten than females and a genotype-pheno- and coexisting diabetes with or without type relationship exists. The second eye, if retinal changes invokes the possibility of not affected at onset, is typically sympto- Maternally Inherited Diabetes and Retinal degeneration, optic nerve atrophy, matic several weeks to months later. Alco- Deafness Syndrome and a mtDNA or ophthalmoplegia hol, tobacco-use, and other mitochondrial 3243A?G mutation [Laloi-Michelin Ophthalmologic pathology is very poisons are possible symptomatic triggers. et al., 2009]. Mohr-Tranebjaerg syn- common in mitochondrial disease Improvement in visual acuity after disease drome, a condition that often presents patients, typically affecting either the onset is rare. LHON patients may have with deafness, but progresses to include retina, optic nerve, or eye and eyelid other mild neurological symptoms that can cortical blindness with optic atrophy, muscles. Since the retinal pigment epi- be quite subtle. A multiple sclerosis (MS)- dystonia, and developmental delay, thelium and eye muscles are among the like illness in women with LHON has occurs due to mutations in the X-linked most metabolically active and energy- been described [Yu-Wai-Man et al., 2009]. DDP gene, encoding a mitochondrial demanding cells in the human body, Optic nerve atrophy can also be protein translocase. [Jin et al., 1996] these areas frequently become affected seen in patients with other mitochon- Nonsyndromic sudden hearing in mitochondrial disease. drial diseases but rarely as an isolated loss in mitochondrial patients typically

Dev Disabil Res Rev NEUROLOGIC MANIFESTATIONS OF MITOCHONDRIAL DISEASE PARIKH 123 occurs days to weeks after receiving ami- (Table 2). The level of developmental noglycoside antibiotics. This type of disability varies from mild to severe. Table 2. Associated hearing loss is exposure- and not dose- Neuroimaging in these cases is not Neurologic Symptoms related. It is noted in individuals with always helpful. Delayed myelination is of- select mtDNA mutations, especially the ten the most common finding [Saneto Developmental delay ? ? Epilepsy 3243A G, 961delT, 7443/4/5A G et al., 2008]. Malformations of cortical Myopathy or hypotonia and 1555A?G mtDNA mutations [Pre- development can occur, but are not fre- Sensitivity to general anesthesia zant et al., 1993]. However, even with- quent findings. Disorganization of the White matter disease out aminoglycoside exposure, individuals cortical mantle is typically subtle and often Dysmotility Migraines with these mtDNA mutations are at a microscopic with MRI visible lesions typ- Neuropathy higher risk of early-onset ‘‘idiopathic’’ ically not present in most patients. On Fatigue and exercise intolerance hearing loss. The American College of occasion, mitochondrial disorders have Medical Genetics recommends mito- been linked with a variety of malforma- chondrial DNA studies for these point tions including cortical heterotopias, and mutations in such cases, especially when polymicrogyri [Keng et al., 2003]. Visible MELAS and POLG1 disease may mimic there is a maternal inheritance pattern changes are often restricted to the corpus an occipital lobe epilepsy syndrome [ACMG, 2002]. callosum [Brown, 2005]. With serial [Engelsen et al., 2008b] or cause status epi- Other mtDNA point mutations imaging, patients are more likely to have lepticus [Wolf et al., 2009]. leading to these symptoms have been changes associated with neuronal loss and In mitochondrial disease, epilepsy identified as well. The hearing loss in cerebral atrophy. These findings are dis- onset can occur at any age and be of a these cases is typically bilateral, nonprog- tinct from the spongiosis or cavitation variety of subtypes. Historically, general- ressive, and nonsyndromic in that there seen with Leigh syndrome, select white ized epilepsies have been associated with are no other associated symptoms sug- matter abnormalities, or metabolic genetic disorders. However, most gestive of mitochondrial or neurological strokes. patients with mitochondrial disease and disease. Interestingly, pigmentary abnor- There is also a possible link epilepsy have focal- or multiregional dis- malities including early-onset graying of between mitochondrial disease and some charges. In one series, over 60% of mito- hair and hypopigmented patches of the types of autism. Some patients with mitochondrial patients had these type of EEG skin have been noted more commonly chondrial disease have an associated atypi- findings [Canafoglia et al., 2001]. Such in one cohort with the 1555A?G cal autism phenotype. These patients usu- discharges lead to partial or secondary mutation [Nye et al., 2000] and palmo- ally have more than isolated autism. They generalized clinical events with behavior plantar keratoderma has been associated present with at least one or more symp- arrest, and a tonic or clonic motor com- with the 7445A?G mutation in two tom not typical of autistic spectrum disor- ponent to their ictal activity. Myoclonic families [Sevior et al., 1998]. ders including but not limited to pre- or seizures and segmental myoclonus are of- In syndromic mitochondrial disease, peri-natal complications, significant tone ten seen. Most patients have more than hearing impairment may remain unde- abnormalities, gastrointestinal dysfunc- one type of seizure type. Atypical ab- tected due to the focus on other, often tion, exercise intolerance, and/or other sence, primary generalized and atonic more severe symptoms. However, most organ system involvement outside of the events can also occur, although isolated patients with syndromic and nonsyn- central nervous system (CNS) [Weissman generalized epilepsy is rare in mitochon- dromic cochlear or peripheral hearing loss et al, 2008]. drial disease. Infantile spasms (West syn- often respond well to treatment with bin- drome) do not occur frequently and are aural amplification. Thus, periodic audiol- Epilepsy seen more commonly in pyruvate dehy- ogy screening of mitochondrial patients is Many mitochondrial disease patients drogenase deficiency [Sadleir et al., recommended. In those patients with con- present with epilepsy or develop epilepsy 2004]. It is possible that mitochondrial comitant central disease, treatment via over the course of their disease. In fact, up diseases remain underdiagnosed in chil- hearing aids is less effective. Cochlear im- to 60% of patients with biochemically dren with West syndrome [Blanco-Barca plantation should be considered in those confirmed mitochondrial disease have epi- et al., 2004]. Central dopamine and with isolated and mtDNA-related syn- lepsy, most of whom will have seizures re- folate deficiency may occur in mitochon- dromic peripheral hearing loss. Such a sur- fractory to treatment [Khurana et al., drial patients and may provoke epilepsy gery should be approached with caution 2008]. In one study of children with re- in some individuals [Garcia-Cazorla especiallyinthepresenceofcoexisting fractory seizures and no diagnosis, almost a et al., 2008; Ramaekers et al., 2007]. cognitive issues [Sinnathuray et al., 2003]. third of patients had biochemical evidence Although treatment efficacy varies, of mitochondrial dysfunction [Parikh epilepsy in mitochondrial disease is typi- Other Neurological Symptoms et al., 2008]. Even in nonmitochondrial cally difficult to treat. All anticonvulsants disease patients, mitochondrial dysfunction and nonmedical treatments have been Developmental issues may contribute to epileptogenesis in tem- attempted including the ketogenic diet Development and cognition are poral lobe epilepsy [Waldbaum and Patel, and vagal nerve stimulator. The ketogenic invariably involved in mitochondrial 2009]. New onset mitochondrial disease diet and vagal nerve stimulator have had disease, whether due to a patient having symptoms may also present with seizures modest and mixed success though are safe global impairment from early childhood or status epilepticus, potentially due to a in many mitochondrial patients [Hudson (static encephalopathy), or an acquired metabolic stroke [Canafoglia et al., 2001]. and Chinnery, 2006; Arthur et al., 2007]. loss of cortical function of varying se- Such a presentation is commonly seen in Preliminary data suggest that the mecha- verity. Many patients with early child- patients with MELAS. Both POLG1 and nism of action of the ketogenic diet may hood onset mitochondrial disease have TWINKLE-related mitochondrial diseases involve decreasing mitochondrial dys- global developmental delays affecting may present with recurrent status epilepti- function in epileptogenic cells [Bough, cognitive as well as motor function cus [Lonnqvist et al., 2009b]. Both 2008]. IV infusions of arginine may bene-

124 Dev Disabil Res Rev NEUROLOGIC MANIFESTATIONS OF MITOCHONDRIAL DISEASE PARIKH fit some patients with status epilepticus in or night-time cramps are an occasional ease. Any mitochondrial disease leading MELAS and other mitochondrial cytopa- complaint. to cognitive decline and dementia may thies, although this therapy has been bet- Previously silent muscle disease in bring out personality changes and infre- ter studied for the indication of acute mitochondrial patients can be brought quently psychosis. metabolic strokes [Toribe et al., 2007]. out by certain medications, such as sta- Treatment for all psychiatric Whether or not utilization of valproic acid tins or exposures to other mitochon- symptoms is similar to those in patients is safe in mitochondrial patients remains drial toxins. Select exposures, such as without mitochondrial disease. Caution unsettled, although it is contraindicated in antiretroviral therapies, may directly lead is warranted for agents that may have most patients with POLG1 mutations and to mitochondrial depletion and symp- autonomic and cardiac side-effects. may aggravate symptoms in other mito- toms of muscle weakness even though chondrial cytopathies including TWIN- the patient does not have a primary mi- Sensitivity to general anesthesia KLE gene mediated disease and MELAS tochondrial disorder [Scruggs and Dirks Anesthesia, whether local, re- [Lonnqvist et al., 2009a]. Naylor, 2008]. gional, or general typically exerts tran- Surgical management of mito- Subjective or objective dysphagia sient mitochondrial inhibition [Murav- chondrial epilepsy is typically contraindi- and dysarthria from weakness can occur chick and Levy, 2006]. Thus it is plausi- cated since these patients often have mul- in some. Select patients who may present ble that in patients with mitochondrial tiple regions of epileptiform discharges with a motor neuropathy may also have dysfunction, anesthetics may lead to along with the potential for other regions associated weakness. When a motor worsening or onset of symptoms, or of the brain to become epileptogenic as neuropathy is the primary or most atypical reactions. the disease progresses. The exception to predominant symptom, a mitochondrial Some mitochondrial disease this rule may be in patients with coexist- depletion syndrome or fusion/fission patients are noted to be more sensitive to ing focal malformations of cortical devel- defect is often present. general anesthesia, and can have delayed opment. arousal despite receiving an age- or Fatigue and exercise intolerance weight-appropriate dose [Morgan et al., Fatigue and asthenia are common 2002]. Postanesthesia decompensation or Myopathy or hypotonia complaints in most mitochondrial patients. malignant hyperthermia is known to Many mitochondrial disorders pre- Even when mitochondrial disease patients occur. The use of a bispectral index mon- senting in childhood have associated hypo- only have modestly quantifiable muscle itor to gauge anesthetic dosing has been tonia or myopathy ranging from mild to weakness, symptoms of fatigue and exer- recommended by some. Prolonged pro- severe. The earlier the onset of symptoms, cise intolerance are frequent. These pofol use (greater than 30–60 minutes) the more often myopathy and hypotonia patients may state they have a sense of gen- may lead to lactic acidosis. In addition, occur together. In those patients with later eralized weakness, although little actual mitochondrial patients with underlying onset symptoms, myopathy may present muscle weakness is identified on functional hypotonia and myopathy may be more without hypotonia, in association with testing. When further pressed, the term sensitive to the effects of neuromuscular other neurological symptoms. ‘‘weakness’’ is being used to describe exer- blockade. In general, it is recommended However, myopathy or hypotonia cise intolerance and easy fatigability after to use caution with dosing anesthetic can present in isolation in primary mito- modest amounts of activity [Tarnopolsky agents as well as to limit their frequency chondrial disease. A severe congenital and Raha, 2005]. Objective exercise test- and length-of-use. myopathy due to Complex IV disease has ing and quantifying the resting metabolic been described, but can also be seen rate is often useful in measuring the extent White matter disease when other aspects of mitochondrial of disability in these patients. Ironically, a Rarely do mitochondrial disorders function are impaired [Salviati et al., graded exercise regimen with aerobic present with an isolated progressive leu- 2002]. The myopathy is at times severe reconditioning and modified endurance kodystrophy though some degree of enough to mimic spinomuscular atrophy. training is one of the few proven methods white matter pathology is common. As Severe muscle involvement from infancy to improve mitochondrial health. [Taivas- mentioned previously, mitochondrial has also been noted in mtDNA depletion salo and Haller, 2005] disorders commonly lead to delays in de- disorders due to mutations in nuclear velopmental myelination. Metabolic genes involved in mitochondrial replica- Psychiatric disease strokes may lead to multiple or confluent tion [Durham et al., 2005]. Moderate to Psychiatric symptoms are com- lesions in the white matter. Both severe myopathy can occur in isolation in mon in mitochondrial disease. Depres- mtDNA-mediated syndromic mitochon- these conditions [Spinazzola et al., 2009]. sion and anxiety are more commonly drial disorders and nDNA mediated mi- Congenital muscular dystrophy with mi- seen in mitochondrial disease patients tochondrial diseases can lead to scattered tochondrial abnormalities on muscle harboring mtDNA mutations than can or confluent white matter lesions. These testing has been reported in patients hav- be attributed only to living with a findings may lead one to initially consider ing associated cardiomyopathy [Nishino chronic disease. In one cohort, 54% of a diagnosis of MS. Women with LHON et al., 1998]. patients with biochemically proven mi- may also have white matter lesions and Regardless of the cause and severity tochondrial disease had depression, 17% symptoms both mimicking MS [Yu-Wai- of myopathy, creatine kinase (CK) activity had bipolar disease and 11% had anxiety Man et al., 2009]. is typically only modestly elevated. There and panic-attacks [Fattal et al., 2007]. Although nonspecific central white are exceptions including myopathy due In addition to relatively common matter lesions are often seen in some to mutations in TK2 [Oskoui et al., psychiatric conditions, patients with patients with mitochondrial disease, cystic 2006]. In patients with muscle weakness, cognitive decline or metabolic strokes or vacuolar lesions can also occur. Most secondary fatty acid oxidation defects, may also have visual hallucinations. Au- lesions often involve both white and grey intermittent rhabdomyolysis and hyper- ditory hallucinations have not been fre- matter, as in Leigh disease. Lesions can CK-emia may also occur. Exertional quently described in mitochondrial dis- occur in both cortical and cerebellar

Dev Disabil Res Rev NEUROLOGIC MANIFESTATIONS OF MITOCHONDRIAL DISEASE PARIKH 125 regions. In certain mitochondrial disor- with MELAS and select mtDNA muta- increase morbidity can improve quality of ders, such as MNGIE, white matter tions, migraines in most mitochondrial life. abnormalities are often present years patients do not represent a metabolic or Neurological symptoms infre- before the onset of neurological symp- ischemic stroke. Rarely do migraines quently occur in isolation, although at dis- toms [Lerman-Sagie et al., 2005]. A syn- present as the only symptom of mito- ease onset, they may be the sole or most drome of ‘‘leukoencephalopathy with chondrial disease. Typically the nature of prominent finding. Once mitochondrial brainstem and spinal cord involvement the migraine itself is not unique in mito- disorders are raised in the differential, a and lactate elevation’’ (LBSL) has been chondrial disease and treatment is the careful step-wise approach to assess the attributed to a nDNA mutation impairing same as in other migraneurs. health of other organ systems and affected mitochondrial tRNA function. Patients In a patient with migraine head- aspects of the neurological system is with this condition develop slowly pro- aches, a diagnosis of mitochondrial disease needed. Identifying organ involvement gressive ataxia, spasticity, and dorsal col- might be pursued if there are other more prior to the onset of symptoms may allow umn dysfunction. They may have mild specific neurological symptoms, or the for preventative care and precautions. cognitive decline. MRI shows nonho- patient is having complicated migraines The treatment of most neurologi- mogenous cerebral white matter abnor- with focal neurological symptoms such as cal symptoms in mitochondrial disease malities and selective involvement of weakness during their headache. is similar to treatment instituted for brainstem and spinal tracts [Scheper et al., Early evidence suggests that a select other neurological diseases. However, 2007]. few patients with atypical cyclic vomiting certain precautions must be taken. syndrome may harbor mitochondrial Deterioration with valproate, anesthesia, Dysmotility mutations, although this research is still or when a patient faces catabolic stres- Even though dysmotility primarily evolving. sors such as medical procedures can of- leads to gastrointestinal symptoms, its eti- ten be avoided with implementation of ology lies in dysfunction of the enteric Other Symptoms metabolic precautions. Preventing pro- nervous system [Zimmer et al., 2009]. While mitochondrial disorders can longed fasting with dextrose-containing Patients often have secondary gastro- cause almost any neurological symptom, IV fluids prior to and during a catabolic esophageal reflux, slow gastric emptying, some conditions are not frequent or dis- stress (including initiation of the keto- and constipation. They often present tinct enough to raise suspicion for a mi- genic diet) and avoiding or limiting the with bouts of abdominal pain due to tochondrial disease diagnosis. use of potential mitochondrial poisons pseudo-obstruction. As briefly mentioned above, a he- are simple maneuvers that can stave off In some patients, especially those reditary spastic paraparesis presentation symptomatic worsening and neurologi- with thymidine phosphorylase deficiency has been noted with mitochondrial cal decline. n leading to MNGIE, dysmotility symp- fusion/fission defects, typically due to toms often present years prior to the mutations in nDNA genes [Chen and onset of their other neurological issues Chan, 2009]. Isolated sensory neuropathy REFERENCES and encephalopathy. However, these or myelopathy are not typically seen in Arthur TM, Saneto RP, de Menezes MS, et al. patients typically have an abnormal brain mitochondrial disease but may occur in 2007. Vagus nerve stimulation in children MRI showing extensive white matter the setting of other symptoms. with mitochondrial electron transport chain deficiencies. Mitochondrion 7:279–283. disease. A motility disorder without leu- Lastly, while autonomic dysfunction Benarroch EE. 2010. Adenosine triphosphate: a koencephalopathy has been described in has been discussed as a possible and plausi- multifaceted chemical signal in the nervous a few select MNGIE patients and those ble problem in mitochondrial patients, system. Neurology 74:601–607. with POLG1 mutations [Van Goethem very little empiric data currently exists to Blanco-Barca O, Pintos-Martinez E, Alonso-Mar- et al., 2003]. Pseudo-obstruction has also support this concern. tin A, et al. 2004. Mitochondrial encephalo- myopathies and West’s syndrome: a fre- been seen in many other mitochondrial quently underdiagnosed association Rev diseases as well [Chitkara et al., 2003]. CONCLUSION Neurol 39:618–623. There is nothing unique about Mitochondrial disorders, whether Bough K. 2008. Energy metabolism as part of the dysmotility from mitochondrial causes due to nDNA or maternally inherited anticonvulsant mechanism of the ketogenic compared to more common etiologies mtDNA causes, present with a wide diet Epilepsia 49(Suppl 8):91–93. Brown GK. 2005. Congenital brain malformations such as postviral infection or other causes breadth of neurological symptoms involv- in mitochondrial disease J Inherit Metab Dis of neuropathy such as diabetes or Parkin- ing almost all aspects of the nervous sys- 28:393–401. sonism. However, motility problems in tem. Recent advances have demonstrated Canafoglia L, Franceschetti S, Antozzi C, et al. these other conditions tend not to drasti- that nDNA mediated causes of mitochon- 2001. Epileptic phenotypes associated with cally worsen over time and remain drial disorders are more common than mitochondrial disorders Neurology 56: 1340–1346. relatively static. In addition, making a previously thought. POLG1 related dis- Chen H, Chan DC. 2009. Mitochondrial dynam- diagnosis of MNGIE is important since ease in particular is a frequent offender, ics–fusion, fission, movement, and mitoph- bone marrow transplantation may serve leading to neurological involvement. agy-in neurodegenerative diseases Hum Mol as a cure. From peripheral nerves and muscle, Genet 18:R169–R176. to cortex, deep brain nuclei, cerebellum Chinnery PF, Elliott C, Green GR, et al. 2000. The spectrum of hearing loss due to mito- Migraine headache and cyclic vomiting and spine, mitochondrial disorders invari- chondrial DNA defects Brain 123:82–92. Migraine headaches have been ably cause variable symptoms affecting Chitkara DK, Nurko S, Shoffner JM, et al. 2003. described more commonly in mitochon- any or all neurological organs. Recogni- Abnormalities in gastrointestinal motility are drial patients, especially those whose dis- tion of select, unexplained, red-flag symp- associated with diseases of oxidative phos- ease has a maternal inheritance pattern. toms that are pathognomonic for a mito- phorylation in children. Am J Gastroenterol 98:871–877. These headaches are considered to be dis- chondrial disorder may help effectively CMG. 2002. Genetics evaluation guidelines for tinct from strokes presenting as migraines focus the diagnostic and genetic evalua- the etiologic diagnosis of congenital hearing in MELAS patients. Outside of patients tion. Treating neurological symptoms that loss. Genetic evaluation of congenital hear-

126 Dev Disabil Res Rev NEUROLOGIC MANIFESTATIONS OF MITOCHONDRIAL DISEASE PARIKH ing loss expert panel. ACMG statement. Lachhwani DK, Parikh S, Gupta A, et al. 2008. tary disturbances, and spinal anomalies. Tera- Genet Med 4:162–171. Ipsilateral cerebral and cerebellar atrophy tology 61:165–171. Davidzon G, Greene P, Mancuso M, et al. 2006. with evidence of mitochondrial dysfunction: Oskoui M, Davidzon G, Pascual J, et al. 2006. Early-onset familial parkinsonism due to evolving phenotype in Rasmussen’s encepha- Clinical spectrum of mitochondrial DNA POLG mutations. Ann Neurol 59:859–862. litis. Epilepsia 49 (Suppl 7):223. depletion due to mutations in the thy- de Vries MC, Rodenburg RJ, Morava E, et al. Laloi-Michelin M, Meas T, Ambonville C, et al. midine kinase 2 gene. Arch Neurol 63: 2008. Normal biochemical analysis of the 2009. The clinical variability of maternally 1122–1126. oxidative phosphorylation (OXPHOS) sys- inherited diabetes and deafness is associated Parikh S, Cohen BH, Gupta A, et al. 2008. Meta- tem in a child with POLG mutations: a cau- with the degree of heteroplasmy in blood bolic testing in the pediatric epilepsy unit tionary note. J Inherit Metab Dis. Short leukocytes J Clin Endocrinol Metab 94: Pediatr Neurol 38:191–195. Report #108 online. 3025–3030. Prezant TR, Agapian JV, Bohlman MC, et al. Durham SE, Bonilla E, Samuels DC, et al. 2005. Leigh D. 1951. Subacute necrotizing encephalo- 1993. Mitochondrial ribosomal RNA muta- Mitochondrial DNA copy number threshold myelopathy in an infant. J Neurol Neurosurg tion associated with both antibiotic-induced in mtDNA depletion myopathy. Neurology Psychiatry 14:216–221. and non-syndromic deafness Nat Genet 65:453–455. Lerman-Sagie T, Leshinsky-Silver E, Watemberg 4:289–294. Edvardson S, Shaag A, Kolesnikova O, et al. 2007. N, et al. 2005. White matter involvement in Ramaekers VT, Weis J, Sequeira JM, et al. 2007. Deleterious mutation in the mitochondrial mitochondrial diseases Mol Genet Metab Mitochondrial complex I encephalomyop- arginyl-transfer RNA synthetase gene is 84:127–136. athy and cerebral 5-methyltetrahydrofolate associated with pontocerebellar hypoplasia. Lonnqvist T, Paetau A, Valanne L, et al. 2009a. deficiency. Neuropediatrics 38:184–187. Am J Hum Genet 81:857–862. Recessive twinkle mutations cause severe Rose LV, Rose NT, Elder JE, et al. 2008. Oph- Elia M, Musumeci SA, Ferri R, et al. 1996. Leigh epileptic encephalopathy Brain 132:1553– thalmologic presentation of oxidative phos- syndrome and partial deficit of cytochrome c 1562. phorylation diseases of childhood. Pediatr oxidase associated with epilepsia partialis Lonnqvist T, Paetau A, Valanne L, et al. 209b. Neurol 38:395–397. continua Brain Dev 18:207–211. Recessive twinkle mutations cause severe ep- Sadleir LG, Connolly MB, Applegarth D, et al. Engelsen BA, Tzoulis C, Karlsen B, et al. 2008a. ileptic encephalopathy Brain 132:1553–1562. 2004. Spasms in children with definite and POLG1 mutations cause a syndromic epi- Lopez LC, Schuelke M, Quinzii CM, et al. 2006. probable mitochondrial disease Eur J Neurol lepsy with occipital lobe predilection. Brain Leigh syndrome with nephropathy and 11:103–110. 131:818–828. CoQ10 deficiency due to decaprenyl Salviati L, Sacconi S, Rasalan MM, et al. 2002. Engelsen BA, Tzoulis C, Karlsen B, et al. 2008b. diphosphate synthase subunit 2 (PDSS2) Cytochrome c oxidase deficiency due to a POLG1 mutations cause a syndromic epi- mutations. Am J Hum Genet 79:1125–1129. novel SCO2 mutation mimics Werdnig- lepsy with occipital lobe predilection Brain Mandel H, Szargel R, Labay V, et al. 2001. The Hoffmann disease. Arch Neurol 59:862–865. 131:818–828. deoxyguanosine kinase gene is mutated in Saneto RP, Friedman SD, Shaw DW. 2008. Neu- Fattal O, Link J, Quinn K, et al. 2007. Psychiatric individuals with depleted hepatocerebral mi- roimaging of mitochondrial disease Mito- comorbidity in 36 adults with mitochondrial tochondrial DNA. Nat Genet 29:337–341. chondrion 8:396–413. cytopathies CNS Spectr 12:429–438. McFarland R, Hudson G, Taylor RW, et al. 2008. Saneto RP, Lee IC, Koenig MK, et al. 2010. Finsterer J. 2009a. Mitochondrial ataxias. Can J Reversible valproate hepatotoxicity due to POLG DNA testing as an emerging standard Neurol Sci 36:543–553. mutations in mitochondrial DNA polymer- of care before instituting valproic acid ther- Finsterer J. 2009b. Mitochondrial disorders, cogni- ase gamma (POLG1). Arch Dis Child apy for pediatric seizure disorders. Seizure tive impairment and dementia J Neurol Sci 93:151–153. 19:140–146. 283:143–148. Milone M, Brunetti-Pierri N, Tang LY, et al. Scheper GC, van der Klok T, van Andel RJ, et al. Finsterer J, Kopsa W. 2005. Basal Ganglia calcifi- 2008. Sensory ataxic neuropathy with oph- 2007. Mitochondrial aspartyl-tRNA synthe- cation in mitochondrial disorders Metab thalmoparesis caused by POLG mutations. tase deficiency causes leukoencephalopathy Brain Dis 20:219–226. Neuromuscul Disord 18:626–632. with brain stem and spinal cord involvement Garcia-Cazorla A, Quadros EV, Nascimento A, Mollet J, Giurgea I, Schlemmer D, et al. 2007. and lactate elevation. Nat Genet 39: et al. 2008. Mitochondrial diseases associated Prenyldiphosphate synthase, subunit 1 534–539. with cerebral folate deficiency Neurology (PDSS1) and OH-benzoate polyprenyltrans- Scruggs ER, Dirks Naylor AJ. 2008. Mechanisms 70:1360–1362. ferase (COQ2) mutations in ubiquinone of zidovudine-induced mitochondrial toxic- Garcia-Cazorla A, Serrano M, Perez-Duenas B, deficiency and oxidative phosphorylation ity and myopathy. Pharmacology 82:83–88. et al. 2007. Secondary abnormalities of neuro- disorders. J Clin Invest 117:765–772. Sevior KB, Hatamochi A, Stewart IA, et al. 1998. transmitters in infants with neurological disor- Morgan PG, Hoppel CL, Sedensky MM. 2002. Mitochondrial A7445G mutation in two ders. Dev Med Child Neurol 49: 740–744. Mitochondrial defects and anesthetic sensi- pedigrees with palmoplantar keratoderma Hudson G, Chinnery PF. 2006. Mitochondrial tivity. Anesthesiology 96:1268–1270. and deafness. Am J Med Genet 75:179–185. DNA polymerase-gamma and human disease Muravchick S, Levy RJ. 2006. Clinical implica- Sinnathuray AR, Raut V, Awa A, et al. 2003. A Hum Mol Genet 15:R244–R252. tions of mitochondrial dysfunction Anesthe- review of cochlear implantation in mito- Jin H, May M, Tranebjaerg L, et al. 1996. A novel siology 105:819–837. chondrial sensorineural hearing loss Otol X-linked gene. DDP, shows mutations in fami- Naviaux RK, Nguyen KV. 2004. POLG muta- Neurotol 24:418–426. lies with deafness (DFN-1), dystonia, mental tions associated with Alpers’ syndrome and Solano A, Roig M, Vives-Bauza C, et al. 2003. deficiency and blindness Nat Genet 14:177–180. mitochondrial DNA depletion Ann Neurol Bilateral striatal necrosis associated with a Kartsounis LD, Troung DD, Morgan-Hughes JA, 55:706–712. novel mutation in the mitochondrial ND6 et al. 1992. The neuropsychological features Neilson DE, Adams MD, Orr CM, et al. 2009. gene. Ann Neurol 54:527–530. of mitochondrial myopathies and encephalo- Infection-triggered familial or recurrent cases Spinazzola A, Invernizzi F, Carrara F, et al. 2009. myopathies Arch Neurol 49:158–160. of acute necrotizing encephalopathy caused Clinical and molecular features of mitochon- Keng WT, Pilz DT, Minns B, et al. 2003. by mutations in a component of the nuclear drial DNA depletion syndromes. J Inherit A3243G mitochondrial mutation associated pore. RANBP2 Am J Hum Genet Metab Dis 32:143–158. with polymicrogyria Dev Med Child Neurol 84:44–51. Taban M, Cohen BH, David Rothner A, et al. 45:704–708. Nikali K, Suomalainen A, Saharinen J, et al. 2006. Association of optic nerve hypoplasia Khurana DS, Salganicoff L, Melvin JJ, et al. 2008. 2005. Infantile onset spinocerebellar ataxia is with mitochondrial cytopathies. J Child Epilepsy and respiratory chain defects in caused by recessive mutations in mitochon- Neurol 21:956–960. children with mitochondrial encephalopa- drial proteins Twinkle and Twinky Hum Taivassalo T, Haller RG. 2005. Exercise and train- thies. Neuropediatrics 39:8–13. Mol Genet 14:2981–2990. ing in mitochondrial myopathies. Med Sci Kotagal S, Peterson PL, Martens ME, et al. 1988. Nishino I, Kobayashi O, Goto Y, et al. 1998. A Sports Exerc 37:2094–2101. Impaired NADH-CoQ reductase activity in new congenital muscular dystrophy with mi- Tarnopolsky MA, Raha S. 2005. Mitochondrial a child with moyamoya syndrome Pediatr tochondrial structural abnormalities. Muscle myopathies: diagnosis, exercise intolerance, Neurol 4:241–244. Nerve 21:40–47. and treatment options. Med Sci Sports Exerc Kubota M, Sakakihara Y, Mori M, et al. 2004. Nye JS, Hayes EA, Amendola M, et al. 2000. My- 37:2086–2093. Beneficial effect of L-arginine for stroke-like elocystocele-cloacal exstrophy in a pedigree Toribe Y, Tominaga K, Ogawa K, et al. 2007. episode in MELAS Brain Dev 26:481–483; with a mitochondrial 12S rRNA mutation, Usefulness of L-arginine infusion for status discussion 480. aminoglycoside-induced deafness, pigmen- epilepticus in mitochondrial myopathy, ence-

Dev Disabil Res Rev NEUROLOGIC MANIFESTATIONS OF MITOCHONDRIAL DISEASE PARIKH 127 phalopathy, lactic acidosis, and stroke-like trum disorder patients: a cohort analysis ease caused by POLG1 mutations: EEG and episodes. No To Hattatsu 39:38–43. PLoS One 3:e3815. MRI features Epilepsia 50:1596–1607. Van Goethem G, Schwartz M, Lofgren A, et al. Willis TA, Davidson J, Gray RG, et al. 2000. Wray SH, Provenzale JM, Johns DR, et al. 1995. 2003. Novel POLG mutations in progressive Cytochrome oxidase deficiency presenting as MR of the brain in mitochondrial myopathy. external ophthalmoplegia mimicking birth asphyxia. Dev Med Child Neurol AJNR Am J Neuroradiol 16:1167–1173. mitochondrial neurogastrointestinal ence- 42:414–417. Yu-Wai-Man P, Griffiths PG, Hudson G, et al. phalomyopathy. Eur J Hum Genet 11: Winterthun S, Ferrari G, He L, et al. 2005. Auto- 2009. Inherited mitochondrial optic neuro- 547–549. somal recessive mitochondrial ataxic syn- pathies J Med Genet 46:145–158. Waldbaum S, Patel M. 2009. Mitochondria, oxi- drome due to mitochondrial polymerase Zimmer V, Feiden W, Becker G, et al. 2009. dative stress, and temporal lobe epilepsy Epi- gamma mutations. Neurology 64: Absence of the interstitial cell of Cajal net- lepsy Res 88:23–45. 1204–1208. work in mitochondrial neurogastrointestinal Weissman JR, Kelley RI, Bauman ML, et al. Wolf NI, Rahman S, Schmitt B, et al. 2009. Sta- encephalomyopathy. Neurogastroenterol Motil 2008. Mitochondrial disease in autism spec- tus epilepticus in children with Alpers’ dis- 21:627–631.

128 Dev Disabil Res Rev NEUROLOGIC MANIFESTATIONS OF MITOCHONDRIAL DISEASE PARIKH