Ophthalmoplegia progressiva externa

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Classification according to ICD-10
H49.4 Ophthalmoplegia progressiva externa
ICD-10 online (WHO version 2019)

The ophthalmoplegia progressiva externa , also known as chronic progressive external ophthalmoplegia (CPEO) known is a neuro-ophthalmologic disease. The cause is usually a mitochondrially inherited disorder ( mitochondriopathy ), which leads to a slowly increasing paralysis of all external eye muscles and the eyelid lifter ( levator palpebrae superioris muscle ) over the years , as in MNGIE syndrome . If the ophthalmoplegia progressiva externa is accompanied by further symptoms, one speaks of the "Ophthalmoplegia plus" ("CPEO plus").

Clinical picture

Daguerreotype of an unknown man with ptosis from 1852

The occurrence of this disease is possible at any age. The earlier the disease breaks out, the more severe its course is usually. Central clinical signs are drooping of one or both eyelids ( ptosis ), as well as a sometimes massive restriction of movement of the eyes . Double vision often does not occur because the paralysis in both eyes is almost symmetrical and therefore there is no squint . Pain does not belong to this clinical picture either. Approximately 1% of all patients with ptosis have CPEO.

In contrast to central eye paralysis , all oculomotor brainstem functions such as saccades, optokinetics and the vestibulo-ocular reflex are intact, but slowed down because of the severe paralysis.

Ophthalmoplegia plus

In "Ophthalmoplegia plus" (CPEOplus), there are also muscular weaknesses (especially in the parts of the extremities close to the body, in the face and on the swallowing muscles), conduction disorders of the heart and endocrinopathies that manifest as diabetes mellitus , short stature or delayed puberty. It can also axonal polyneuropathy , dementia , pigmentary retinopathy and ataxia show. The transition to Kearns-Sayre syndrome is fluid. KSS refers to a combination of CPEO and pigmented retinopathy if the onset of the disease is before the age of around 20

etiology

In “Ophthalmoplegia plus”, sporadic, genetic diseases with singular, approx. 2–8 kb mtDNA deletions or, very rarely, duplications are found in about 50% of cases . In rare cases, maternally inherited point mutations of the mtDNA are found (most often the A3243G mutation). In addition, autosomal inheritance (autosomal dominant CPEO / adPEO), and rarely also autosomal recessive cases, occur in the context of nuclear gene changes that lead to multiple mtDNA deletions. These deletions are caused by a large number of different mutations that impair the repair, replication and maintenance of mitochondrial DNA or the entire mitochondria, including genes for polymerase 1 and 2, (POLG1 and POLG2), helicase (PEO), mitochondrial building blocks (deoxyguanine kinase, DGUOK), mitochondrial protein control (Paraplegin, SPG7), mitochondrial building blocks (RRM2B), mitochondrial exchange of ATP (SLC25A4) or mitochondrial t-RNA (MT-TL1) or also at mitochondrial fusion and splitting (OPA1).

In rare cases, maternally inherited point mutations of the mitochondrial DNA mtDNA are found (most frequently the A3243G mutation). This mutation is also associated with MELAS . There, however, the clinical picture is different. In addition, autosomal inheritance (autosomal dominant CPEO / adPEO), and rarely also autosomal recessive cases in the context of nuclear gene changes, which lead to multiple mtDNA deletions, also occur in CPEO.

Diagnosis

In addition to the diagnostics generally recommended for mitochondrial diseases such as creatine kinase , lactate dehydrogenase , resting lactate and pyruvate in the blood serum, a neurological examination status, the exclusion of a pathological increase in lactate using ergometry and electromyography , as well as muscle biopsy and molecular genetic diagnostics, are used in ophthalmoplegia progressiva externa additionally a thyroid hormone and antibody status and electroneurography are recommended. Nevertheless, the clinical signs of CPEO described above are so characteristic that a relatively reliable diagnosis is possible even without technical aids. The mutation can be identified here by sequencing the mitochondrial DNA.

Differential diagnoses

Possible differential diagnoses of CPEO are myasthenia , eye paralysis , oculomotor paresis (N.III paresis), brainstem lesions (not all types of eye movements are affected equally), senile ptosis or fibrosis syndrome .

therapy

A cure for this disease is not possible. A study is currently being carried out with 15 patients in Cambridge / England (ClinicalTrials.gov Identifier: NCT03432871). Their goal is to improve the mitochondrial dynamics that are affected in this disease.

At present, however, the symptomatic ptosis can be treated with plastic surgery (e.g. a frontal suspension with silicone ). Surgical treatment of ptosis is advantageous because the eyelid closes poorly and the cornea could dry out (exposure keratopathy). If there are double images, prism glasses or a squint operation are possible solutions. A pacemaker may be an option for arrhythmias.

In particular in cases in which a primary coenzyme Q10 deficiency could be demonstrated, a therapeutic attempt with 50 - 300 mg coenzyme Q10 daily should be discussed. In this case, the aim of treatment is to bypass the defects in the respiratory chain and thus ensure maximum ATP production. Study results inconsistent: however, reduced lactate level has no clinical relevance. Many mitochondrial diseases have in common that they lead to an increase in reactive oxygen species (ROS) in the mitochondria, which further damage them and lead to progressive dysfunction.

Mitochondrially directed antioxidants are already used in the treatment of Leber's hereditary optic neuropathy (LHON) .

Idebenone , riboflavin , creatine monohydrate and L-carnitine are used on a trial basis in therapeutic trials .

See also

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Individual evidence

  1. ^ Pfeiffer MJ: Chronic Progressive External Ophthalmoplegia Ptosis: Problems with Diagnostics and Treatment . In: Klin Monatsbl Augenheilkd . tape 235 , no. 1 , January 2018, p. 31-33 , doi : 10.1055 / s-0043-124370 .
  2. ↑ Yamashita S et al .: Genotype and phenotype analyzes in 136 patients with single large-scale mitochondrial DNA deletions . In: J Hum Genet. tape 53 , no. 7 , January 2018, p. 598-606 , doi : 10.1007 / s10038-008-0289-8 , PMID 18414780 .
  3. ↑ Milone M et al .: Polymerase gamma 1 mutations: Clinical Correlations . In: Neurologist . tape 16 , no. 2 , March 2010, p. 84-91 , doi : 10.1097 / NRL.0b013e3181c78a89 , PMID 20220442 .
  4. ↑ Milone M et al .: POLG-related disorders: defects of the nuclear and mitochondrial genome interaction . In: Neurology . tape 77 , no. 20 , November 15, 2011, pp. 84-91 , doi : 10.1212 / WNL.0b013e318238863a , PMID 22084276 .
  5. ↑ Pitceathly RD et al .: Adults with RRM2B-related mitochondrial disease have distinct clinical and molecular characteristics . In: Brain . tape 135 , no. 11 , November 2012, p. 3392-403 , doi : 10.1093 / brain / aws231 , PMID 23107649 .
  6. ↑ Ronchi D et al .: Next-generation sequencing reveals DGUOK mutations in adult patients with mitochondrial DNA multiple deletions . In: Brain . tape 137 , no. 5 , May 2014, p. 1323-36 , doi : 10.1093 / brain / aws258 , PMID 23043144 .
  7. ↑ Pfeffer G et al .: Mutations in the SPG7 gene cause chronic progressive external ophthalmoplegia through disordered mitochondrial DNA maintenance . In: Brain . tape 137 , no. 5 , May 2014, p. 1323-36 , doi : 10.1093 / brain / awu060 , PMID 24727571 .
  8. ↑ Carelli V et al .: Syndromic parkinsonism and dementia associated with OPA1 missense mutations . In: Ann. Neurol. tape 78 , no. 1 , July 2015, p. 21-38 , doi : 10.1002 / ana.24410 , PMID 25820230 .
  9. ↑ Mariotti C et al .: Genotype to phenotype correlations in mitochondrial encephalomyopathies associated with the A3243G mutation of mitochondrial DNA . In: J Neurol. tape 242 , no. 5 , May 1995, pp. 304-12 , PMID 7643139 .
  10. ↑ Herbert Kaufmann (Ed.): Strabismus. With the collaboration of Wilfried de Decker et al. Enke, Stuttgart 1986, ISBN 3-432-95391-7 , p. 394.
  11. ↑ Nicotinamide Riboside and Mitochondrial Biogenesis , ClinicalTrials.gov, accessed October 23, 2018
  12. ↑ Pedro Enrique Jiménez Caballero, Monica Serviá Candela, Clara Isabel Cabeza Álvarez, Araceli Álvarez Tejerina:: Chronic progressive external ophthalmoplegia: a report of 6 cases and a review of the literature. In: The Neurologist. Vol. 13, No. 1, 2007, ISSN  1074-7931 , pp. 33-36, PMID 17215725 , doi: 10.1097 / 01.nrl.0000252953.49721.f5 .
  13. ^ Franco-Iborra S et al .: Mitochondrial Quality Control in Neurodegenerative Diseases: Focus on Parkinson's Disease and Huntington's Disease . In: Front. Neurosci. tape 12 , no. 342 , May 23, 2018, doi : 10.3389 / fnins.2018.00342 , PMID 29875626 .
  14. ↑ Finsterer J et al .: Mitochondrial disorders of the retinal ganglion cells and the optic nerve . In: Mitochondrion . tape 42 , September 2018, p. 1–10 , doi : 10.1016 / j.mito.2017.10.003 , PMID 29054473 .

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