Ординатура / Офтальмология / Английские материалы / Essentials in Ophthalmology Pediatric Ophthalmology Neuro-Ophthalmology Genetics_Lorenz, Borruat_2008

266Cerebral Control of Eye Movements

16.Pierrot-Deseilligny C, Gray F, Brunet P (1986) Infarcts of both inferior parietal lobules with impairment of visually guided eye movements, peripheral visual inattention and optic ataxia. Brain 109:81–97

17.Pierrot-Deseilligny C, Gautier JC, Loron P (1988) Acquired ocular motor apraxia due to bilateral frontoparietal infarcts. Ann Neurol 23:199–202

18.Pierrot-Deseilligny C, Rivaud S, Gaymard B et al (1991) Cortical control of memory-guided saccades in man. Exp Brain Res 83:607–617

19.Pierrot-Deseilligny C, Rosa A, Masmoudi K et al (1991) Saccade deficits after a unilateral lesion affecting the superior colliculus. J Neurol Neurosurg Psychiatry 54:1106–1109

20.Pierrot-Deseilligny C, Ploner CJ, Müri RM et al (2002) Effects of cortical lesions on saccadic eye movements in humans. Ann NY Acad Sci 956:216–229

21.Ranalli PJ, Sharpe JA (1988) Vertical vestibuloocular reflex, smooth pursuit and eye-head tracking dysfunction in internuclear ophthalmoplegia. Brain 111:1299–1317

22.Rivaud S, Müri RM, Gaymard B et al (1994) Eye movement disorders after frontal eye field lesions in humans. Exp Brain Res 102:110–120

23.Thiers P, Bachor A, Faiss J et al (1991) Selective impairment of smooth-pursuit eye movements due to an ischemic lesion of the basal pons. Ann Neurol 29:443–448

24.Thurston SE, Leigh RJ, Crawford T et al (1988) Two distinct deficits of visual tracking caused by unilateral lesions of cerebral cortex in humans. Ann Neurol 23:266–273

25.Tijssen CC (1990) Conjugate deviation of the eyes in cerebral lesions. In: Daroff RB, Neetens A (eds) Neurological organization of ocular movement. Kügler-Ghedini, Amsterdam, pp 245–258

26.Westheimer G, Blair SM (1974) Functional organization of primate oculomotor system revealed by cerebellectomy. Exp Brain Res 21:463–472

27.Zee DS, Yamazaki A, Butler PH et al (1981) Effects of ablation of flocculus and paraflocculus on eye movements in primate. J Neurophysiol 46:878–899

Core Messages

■Extraocular muscles are predominantly affected in mitochondrial myopathies resulting in chronic progressive external ophthalmoplegia (CPEO).

■CPEO is one of the most common mani­ festations of mitochondrial disorders and can present as an isolated disorder or as part of syndromes with multisys­ temic involvement. Frequently patients suffer from exercise intolerance or proxi­ mal limb weakness.

■The underlying pathomechanisms are al­ terations of the respiratory chain due to mutations in mitochondrial or nuclear DNA.

■There are different modes of inheritance but sporadic occurrence is frequent.

■Diagnosis usually necessitates a limb muscle biopsy.

■There is limited causal therapy but there are several symptomatic treatments. Frontalis suspension is the method of first choice for ptosis surgery.

■Important differential diagnoses are ocu­ lopharyngeal muscular dystrophy and myasthenia.

15.1 Introduction

Extraocular muscles are predominantly affected in mitochondrial myopathies resulting in chronic progressive external ophthalmoplegia (CPEO). The reason for this is not fully understood but several differences between extraocular muscles and skeletal muscles do exist. Extraocular mus­ cles have smaller motor unit sizes, higher motor neuron discharge rates, higher blood flow, and higher mitochondrial content as compared to skeletal muscle (Yu Wai Man et al. 2005a). These differences may provide the extraocular muscles with a raised metabolic rate enabling them to achieve greater fatigue resistance than skeletal muscle. However, it is not understood why some but not other mitochondrial gene defects result in CPEO. The frequency of cytochrome c oxi­ dase (COX) negative fibres normally increases with age, but COX-negative fibres are encoun­ tered six times more frequently in extraocular muscles than in skeletal muscles, indicating that mitochondrial function in extraocular muscles is more vulnerable (Yu Wai Man et al. 2005a). This is important since the presence of COX-negative fibres is also a typical finding in mitochondrial disorders.

CPEO is caused by alterations of the respira­ tory chain localized at the inner mitochondrial membrane. The biochemical defects can be caused by primary defects of the mitochondrial DNA (mtDNA) or by defects within nuclear

268Chronic Progressive External Ophthalmoplegia

genes that encode for mitochondrial proteins that are imported into mitochondria.

CPEO is one of the most common manifesta­ tions of mitochondrial disorders. The frequency of the most common mtDNA defect, single large-scale deletions, was estimated to be at least 1–2/100,000 in Finland and the UK (Chinnery et al. 2000; Remes et al. 2005). These deletions of mtDNA were found in approximately 50% of patients with CPEO.

CPEO can present as an isolated disorder or as the leading manifestation of a syndrome charac­ terized by multisystemic involvement. Although CPEO is a prominent feature of mitochondrial myopathies it is important to know that mito­ chondrial myopathies without CPEO and multi­ systemic involvement are now increasingly rec­ ognized (Müller et al. 2005; Swalwell et al. 2006).

et al. 2005). This is surprising since suppression usually only occurs in early childhood.

15.2.2CPEO Plus: Multisystemic Involvement

15.2.2.1 Muscle Impairment

Muscle weakness is often not restricted to the extraocular or facial muscles. Many pa­ tients suffer from exercise intolerance. In most but not all, neurological examination shows limb weakness, most prominent in the proximal muscles of the lower extremities. These patients typically have difficulties rising from a squatting position. However, many different multisystemic symptoms apart from muscle weakness are pos­ sible.

15.2 Clinical Features

15.2.1 Ophthalmoplegia and Ptosis

Ptosis is frequently the first symptom, and old photographs are helpful for establishing the age of onset, which is variable: typically in the teen­ age years or early adulthood (Zierz et al. 1990) although childhood or late adulthood is also

15 possible. Ophthalmoparesis develops over many years and may lead to complete ocular paralysis. Ptosis may occur unilaterally at first, but will sub­ sequently become bilateral (Fig. 15.1). Addition­ ally, many patients have some weakness of the or­ bicularis muscle. Patients with inadequate Bell’s phenomenon and lagophthalmos are at risk for corneal exposure especially after ptosis surgery. Severe weakness of the facial muscles can pres­ ent as facies myopathica. Some patients come to medical attention only when ptosis is covering the optic axis. Patients use their frontalis muscles to lift their eyelids and show compensatory chin elevation. Ophthalmoplegia is often symmetrical and causes no complaints since patients simply turn their heads. A minority of patients suffer from diplopia. Sometimes there is no dipolpia be­ cause the unilateral ptosis results in the occlusion of one eye. Richardson et al. (2005) investigated 25 adult patients with CPEO: 13 patients showed a manifest deviation but only 7 had diplopia. The other 6 patients showed suppression (Richardson

15.2.2.2 Visual Impairment

Retinal degeneration in CPEO differs from typi­ cal retinitis pigmentosa and frequently assumes a salt-and-pepper like appearance (Fig. 15.2a), but there are also patients with areas of hypopig­ mentation and hyperpigmentation (Fig. 15.2b). Only a few patients have an optic atrophy or a juvenile cataract. Visual function is impaired in most patients with CPEO, but severe impairment of visual acuity is rare (Isashiki et al. 1998; Mul­ lie et al. 1985).Yu Wai Man et al. (2005b) stud­ ied 40 patients using the Visual Function Index (VF-14), a questionnaire containing 14 questions to measure how sight problems affect health sta­ tus. This study demonstrated visual impairment in 95% of the patients. Patients reported having most difficulties with reading small print and driving at night. However, there was no correla­ tion between VF-14 scores and ocular motility parameters, ptosis, or retinopathy (Yu Wai Man et al. 2005b).

15.2.2.3Specific CPEO Plus Syndromes

Kearns-Sayre syndrome was defined as a very severe multisystemic phenotype characterized by CPEOwithretinopathy,onsetofthediseasebefore

270

15

(Fig. 15.4). There is one common deletion with a length of 5 kb. The deletion break points are typi­ cally characterized by direct repeats. In approxi­ mately 50% of patients with CPEO single deletions of mtDNA can be detected (Moraes et al. 1989). Most cases of CPEO with single deletions are sporadic. It is therefore postulated that deletions occur in the oocyte and mitotic segregation dur­ ing embryogenesis results in high levels of deleted mtDNA in certain tissues such as muscle but low levels in other tissues including the germline cells. This can explain why mother-to-offspring trans­ mission of single deletions is rarely observed, with a low risk of 4% for affected mothers of having an affected child (Chinnery et al. 2004).

15.3.3Defects of Intergenomic Communication with Multiple Deletions

of mtDNA

In contrast to single deletions of mtDNA, mul­ tiple deletions of mtDNA were observed in pa­ tients with autosomal inheritance of CPEO (Ze­ viani et al. 1989), indicating that these mtDNA deletions are not the primary gene defect but secondary changes due to a nuclear gene muta­

tion. Consequently several nuclear gene defects have been identified in the last years. They are lo­ cated in genes that are important for replication of mtDNA. Thus those forms of CPEO are clas­ sified as defects of intergenomic communication (Fig. 15.5).

The most important nuclear genes are: poly­ merase gamma (POLG) 1, progressive external ophthalmoplegia (PEO) 1 (also called C10orf1 or Twinkle), and adenine nucleotide transloca­ tor (ANT) 1. POLG1 mutations are located in the catalytic subunit of the mitochondrial polymerase (Van Goethem et al. 2001). They are frequently associated with CPEO but also with other mi­ tochondrial disorders. The PEO1 gene encodes for the mitochondrial helicase (Spelbrink et al. 2001). Mutations in the ANT1 gene were found in only some families with CPEO (Deschauer et al. 2005; Kaukonen et al. 2000). In patients with MNGIE, mutations in the thymidine phosphory­ lase (TP) gene were identified. There are single patients with TP mutations who show no gas­ trointestinal symptoms (Gamez et al. 2002) and have only CPEO. ANT1 and TP mutations result in an altered nucleotide pool in the mitochondria that can explain defective replication. Mutations in the ANT1 gene and in the PEO1 gene were identified in autosomal-dominant CPEO. Muta­

tions in the POLG1 gene were identified in au­ tosomal-dominant as well as in recessive CPEO. Dominant POLG1 mutations are located in the catalytic domain and recessive mutations in the proof-reading domain. TP mutations are reces­ sive mutations.

In patients with sporadic CPEO and multiple mtDNA deletions, mutations in POLG1, PEO1 and ANT1 are rare, indicating that other prob­ ably autosomal recessive gene defects exist (Hud­ son et al. 2005). Recently a dominant mutation was identified in the POLG2 gene, the accessory

subunit of polymerase gamma, in a single patient among 100 patients with multiple mtDNA dele­ tions but without mutations in POLG1, PEO1, and ANT1 genes, indicating that POLG2 defects are very rare (Longley et al. 2005).

15.3.4 Point Mutations of mtDNA

Rarely, point mutations of mtDNA, which are in­ herited maternally, can be associated with CPEO. A common point mutation of mtDNA is the

Fig. 15.5.  Defects of intergenomic communication. Mutations of different nuclear genes result in defect proteins that in turn cause (multiple) deletions of mtDNA

3243A>G mutation that is located in one of the two mitochondrial tRNA genes for leucine. This mutation is typically associated with MELAS (mitochondrial encephalopathy, lactic acidosis, stroke-like episodes) syndrome, but CPEO was also observed in patients carrying this muta­ tion (Deschauer et al. 2001). Moreover several very rare point mutations can be associated with CPEO (www. mitomap.org).

15.3  Genetics 273

15.3.6Genotype–Phenotype Correlation

There are different defects of mtDNA and nuclear genes underlying CPEO. This also implies different modes of inheritance. Up to now no clear genotype–phenotype cor­ relation has been established in patients with CPEO. However, there are hints that retinopa­ thy can be observed in CPEO with single dele­ tions or the 3243A>G mutation, but it seems to be uncommon in patients with multiple dele­ tions of mtDNA (Kawai et al. 1995). A common symptom of patients with the 3243A>G mtDNA mutation is hearing loss (Deschauer et al. 2001). The SANDO syndrome is associated not only with POLG1 mutations but also with PEO1 mutations (Hudson et al. 2005). The MNGIE syndrome is typically associated with recessive mutations in the TP gene (Nishino et al. 1999), but sometimes also with POLG1 mutations. POLG1 mutations seem to be the most frequent nuclear gene defects within disorders of interge­ nomic communication. They can be associ­ ated with a broad spectrum of diseases including CPEO with parkinsonism but also classical mi­ tochondrial syndromes such as MELAS without CPEO (Deschauer et al. 2007). The various geno­ types, phenotypes, and modes of inheritance of these diseases are described in Table 15.2.

15.3.5 Coenzyme Q Deficiency

Another rare autosomally inherited mito­ chondrial myopathy is caused by coenzyme Q deficiency. This is important since coenzyme Q deficiency is treatable by oral supplementation. Recently the first genetic defects in genes that are necessary for the biosynthesis of coenzyme Q were discovered, i.e., para-hydroxybenzo­ ate-polyprenyl transferase, decaprenyl diphos­ phate synthase subunit 1 and 2 (DiMauro et al. 2007). However, mutations in these genes have not yet been identified in patients with CPEO, although coenzyme Q deficiency is documented in CPEO (Zierz et al. 1989). Probably there is a secondary coenzyme Q deficiency in CPEO. Fre­ quent signs in patients with genetically proven primary coenzyme Q deficiency are myopathy and cerebellar ataxia (DiMauro et al. 2007).

Summary for the Clinician

■More than half of patients show sporadic CPEO and approximately one-third have an autosomal-dominant or -recessive in­ heritance pattern. Maternal inheritance, which is typical of other mitochondrial disorders, is rare in CPEO.

■Sporadic CPEO is associated with single deletions of mtDNA.

■Autosomal CPEO is caused by mutations in different nuclear genes that are impor­ tant for mtDNA replication, secondarily leading to multiple deletions of mtDNA.

■Maternal inheritance is seen with point mutations of mtDNA.

15.4 Diagnostics

Diagnosis of CPEO requires a close collaboration between the ophthalmologist, neurologist, and laboratory investigators. Analysis of the family history is extremely important. In this regard it is helpful to perform a clinical examination of the family members as some patients may be asymp­ tomatic but have a mild form of CPEO. Moreover

15 multisystemic involvement can be oligosymp­ tomatic in family members, e.g., solely diabetes or hearing loss.

In every patient with suspected CPEO, a full neurological examination should be performed in addition to the ophthalmological examina­ tion. Moreover additional laboratory or technical examinations can be helpful. Laboratory testing should include resting lactate, indicating im­ paired oxidative phosphorylation if elevated. A more sensitive test is to measure lactate after lowlevel cycling exercise (30 W for 15 min), showing a lactate increase (Fig. 15.6) with a sensitivity of 70%. Sometimes lactate elevation can be observed in patients with other myopathies, but specificity is 90% (Hanisch et al. 2006a). Elevated creatine kinase can indicate myopathy affecting the limbs. Measurement of glucose metabolism can disclose diabetes mellitus. An audiogram can detect sub­ clinical hearing impairment; electrophysiological examination of the peripheral nerves, subclinical

neuropathy. Cardiac examination should include electrocardiography and echocardiography. To detect cerebral involvement, brain magnetic resonance imaging (MRI) and analysis of cere­ brospinal fluid (elevated protein or lactate) are helpful but not mandatory if no clinical signs of cerebral involvement are found. Apart from the

Fig. 15.6.  Changes of serum lactate in 22 patients with CPEO after bicycle exercise shown in red compared to normal controls shown in blue. Error bars show one standard deviation, circles show mean values

diagnostic point of view, the search for diabetes and cardiac conduction defects are mandatory as these disorders are potentially treatable.

inclusions. However, for diagnostic purposes electron microscopy is not necessary in general.

15.4.1Myohistological Investigations

Diagnosis can be confirmed by histological ex­ amination of a muscle biopsy sample. A biopsy of the extraocular muscles is not appropriate since CPEO patients show typical myohisto­ logical changes in biopsy samples from the limbs even without limb weakness. Mitochondrial pro­ liferation is seen in modified Gomori Trichrome staining and in succinate dehydrogenase (SDH) staining showing ragged red fibres (Fig. 15.7a). Sequential histochemical staining for cyto­ chrome c oxidase (COX) and SDH reveals a mosaic pattern of COX-positive and COX-nega­ tive fibres (Fig. 15.7b). However, mitochondrial abnormalities in muscle biopsy samples are also seen in ageing and other muscle diseases. On the other hand some patients with CPEO show only minor changes in histology (less than 5% abnor­ mal fibres) (Deschauer et al. 2003). Thus, diag­ nosis of CPEO sometimes needs a multi-level approach and sometimes only molecular genetic testing can confirm the diagnosis. Electron mi­ croscopy typically shows enlarged and irregu­ larly shaped mitochondria with paracrystalline

15.4.2 Biochemical Investigations

Biochemistry of muscle biopsy samples also of­ ten shows mitochondrial proliferation, indicated by an increase of mitochondrial enzymes that are not encoded by mtDNA, such as citrate synthase or SDH. Additionally a decrease of respiratory chain complexes, characteristically a combined defect, can be observed (Gellerich et al. 2002). But generally, biochemistry is not as important as histology for the diagnosis of CPEO since measurement is complex and available only in specialized laboratories. However, if histology shows lipid accumulation in addition to mito­ chondrial proliferation, coenzyme Q levels in muscle should be measured, because coenzyme Q deficiency also impairs fatty acid metabolism. This is important in order to detect treatable co­ enzyme Q deficiency.

15.4.3Molecular Genetic Investigations

Genetic analysis is important not only for con­ firming the diagnosis but also for genetic counsel­ ling. The gold standard for detection of mtDNA