# Unusual Phenotype and Disease Trajectory in Kearns–Sayre Syndrome

Authors: Josef Finsterer; Michael Winklehner; Claudia Stöllberger; Thomas Hummel
Journal: Case Reports in Neurological Medicine
 (2020)

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## Abstract

Objective. To describe unusual course and unusual phenotypic features in an adult patient with Kearns–Sayre syndrome (KSS). Case Report. The patient is a 49-year-old male with KSS, diagnosed clinically upon the core features, namely, onset before the age 20 of years, pigmentary retinopathy, and ophthalmoparesis, and the complementary features, namely, elevated CSF protein, cardiac conduction defects, and cerebellar ataxia. The patient presented also with other previously described features, such as diabetes, short stature, white matter lesions, hypoacusis, migraine, hepatopathy, steatosis hepatis, hypocorticism (hyponatremia), and cataract. Unusual features the patient presented with were congenital anisocoria, severe caries, liver cysts, pituitary enlargement, desquamation of hands and feet, bone chondroma, aortic ectasia, dermoidal cyst, and sinusoidal polyposis. The course was untypical since most of the core phenotypic features developed not earlier than in adulthood. Conclusions. KSS is a multisystem disease, but the number of tissues affected is higher than so far anticipated. KSS should be considered even if core features develop not earlier than in adulthood and if unusual features accompany the presentation.


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## Body

## 1. Introduction

Kearns–Sayre syndrome (KSS) is a mitochondrial disorder (MID) most frequently due to a single mtDNA deletion and rarely due to mtDNA point mutations [1, 2]. The diagnosis is established clinically if the three core features onset, <20 years of age, chronic progressive external ophthalmoplegia (CPEO), and pigmentary retinopathy, and at least one of the following features are present: cerebrospinal fluid (CSF) protein >100 mg/dl, cardiac conduction defects, or cerebellar dysfunction [1]. Here, we present an adult male with KSS with unusual phenotypic features and disease trajectory.


## 2. Case Report

The patient is a 49-year-old male, with height 161 cm, weight 85 kg, and a history of preterm birth at gestational week 34 from nonconsanguineous parents, congenital anisocoria, developmental delay, hypoacusis, and tetra-ataxia (Table1). During childhood general downslowing, chronic fatigue, and sicca syndrome of the eyes occurred. He repeatedly experienced respiratory infections and oral herpetic infections and once painless desquamation of the hands and foot soles (Table 1). He was successfully trained and worked as a hairdresser until the age of 38 years in his parent’s hair saloon and retired at the age of 40 years.Table 1
Disease trajectory of the presented patient over 49 years of age.
Onset (age)
Manifestation
Therapy
Intrauterine
Premature birth (7 weeks earlier)
None
Birth
Congenital anisocoria
None
Infancy
Developmental delay
None
Infancy
Hypoacusis
Hearing devices since age 39
Childhood
Downslowing, chronic fatigue
None
Childhood
Sicca syndrome + recurrent conjunctivitis
Eye drops
Childhood
Recurrent respiratory infections
Antibiotics
Childhood
Recurrent herpetic infections, stomatitis
Virostatics
5 y
Painless desquamation of hands and feet
None
6 y
Ophthalmoparesis (first recognised)
None
7 y
Tetra-ataxia
None
18 y
Severe caries
Full prosthesis
27 y
Right-sided inguinal hernia
Bassini surgery
29 y
Sacral dermoidal cyst
Surgery
30 y
Bifascicular block∗
None
30 y
Erythema nodosa of feet
Steroids
35 y
Hyper-CKemia
None
35 y
Hyperuricemia
Diet
35 y
Hyponatremia, hypokalemia
NaCl, KCl
36 y
Somnolence, infection, suspected BE, SLE
Antibiotics, virostatics, endobolin, steroids
36 y
Suspected SLE
None
36 y
Elevated CSF protein
None
36 y
Dysarthria
None
36 y
Polyposis of nasal sinuses
None
36 y
Gait disturbance, falls
None
36 y
Neuropsychological deficits
Training
37 y
Arterial hypertension
Antihypertensives
37 y
Hepatopathy
None
37 y
Liver cysts
None
37 y
Rhabdomyolysis (CK: 2673 U/L)
None
38 y
Chondroma/fibroma of the right femur
None
38 y
Steatosis hepatis
None
44 y
Suspected SLE, Na↓, K↓, migraine
Analgesics
45 y
Fall, rib fracture, pneumothorax
Drainage
45 y
Diabetes
Antidiabetics
47 y
Cataract bilaterally
Surgery
49 y
Aortic ectasia
None
∗Left anterior hemiblock plus right bundle branch block, SLE: stroke-like episode, nr: not relevant, CSF: cerebrospinal fluid, BE: Bickerstaff encephalitis.At age of 30 years, left anterior hemiblock and right bundle-branch-block were recorded. Since age 35, recurrent mild elevation of creatine-kinase (CK) was noted. Aldolase and myoglobin were also elevated. Since age 35, recurrent electrolyte disturbances (hypokalemia and hyponatremia) and hyperuricemia developed. At age 36, he experienced a first episode of disorientation, impaired cognition, bradyphrenia, and secessus urinae. Clinical exam revealed bilateral ophthalmoparesis and dysarthria. Magnetic resonance imaging (MRI) showed subcortical hyperintensities in a nonvascular distribution, which were hyperintens on diffusion-weighted imaging (DWI) and apparent diffusion coefficient (ADC) (Figure1). Neuropsychological testing revealed attention deficits, disability of encoding visual contents, adjustment disorder, and depression. The patient was diagnosed with suspected Bickerstaff encephalitis and questionable seizures. Following these episodes, his gait became disturbed with occasional falls due to increased ataxia. At age 37, he experienced an untriggered rhabdomyolysis. Muscle biopsy from the deltoid muscle suggested muscular dystrophy as only fat but no muscle tissue was detected (Table 2). At age 38, he underwent a second muscle biopsy from the left lateral vastus muscle which showed cytochrome-C-oxidase (COX)-negative fibers (Figure 2(a)), glycogen depositions (Figure 2(b)), fiber splitting, and ragged-red fibers (Figure 2(c)). Electron microscopy showed abnormally shaped and structured mitochondria, megaconia, abnormal glycogen and lipid depositions, and dark bodies (Figures 2(d) and 2(e)). At age 44, migraine developed. At age 47, he underwent cataract surgery bilaterally (Table 1). At age 49, diabetes was diagnosed. Transthoracic echocardiography was normal except for mild enlargement of the ascending aorta (Figure 3).Figure 1
Cerebral MRI at age 36 showing mild, band-like T2-hyperintensities in the white matter bilaterally (upper left) and the midbrain (lower panels) and mild cerebellar atrophy (upper right).Table 2
Crucial investigations carried out during the disease trajectory.
Date/age
Investigation
Result
2000, 30 years
Echocardiography
“Pulmonary insufficiency”
1.1.06
Lumbar puncture
Protein 167 mg/dl, otherwise normal
3.1.06
EEG
Normal
3.1.06
Lumbar puncture
Protein 107 mg/dl, otherwise normal
5.1.06, 35 years
Nerve conduction studies
Normal
4.1.06, 36 years
Cerebral MRI
T2-hyperintensities, subcortical, mesencephalon, DWI, ADC hyperintense enlarged pituitary gland, sinusoidal polyposis
12.1.06
Neuropsychological testing
Attention deficit, disability of encoding visual contents, adjustment disorder, and depression
13.1.06
Cerebral MRI
Unchanged to previously
17.1.06
Lumbar puncture
Protein 152 mg/dl, otherwise normal
1/2006
Ophthalmologic investigation
Strabism, fundus tabulates, AM atrophy, papillary excavation
24.2.06
Cerebral MRI
Band-like T2-, DWI-, ADC-hyperintensities in the ML and mesencephalon bilaterally
2.1.06
Abdominal ultrasound
Normal
1/06
Lumbar puncture
Protein 167 mg/dl
16.12.06
Ophthalmologic investigation
Pigmentary epithelium shifts, retinal dystrophy, rod/cone degeneration (RP suspected)
8/07
Muscle biopsy (deltoid)
Fat, no muscle
12.9.07
CK
2673 U/L (rhabdomyolysis)
10.8.07
Myoglobin
152 ng/ml (n, 19–92 ng/ml)
2.8.07
X-ray of the lungs
Normal width of aorta
6.8.07
Echocardiography
Normal
8.8.07
Liver enzymes
Elevated
9.8.07
Abdominal CT
Multiple liver cysts
13.8.07
Muscle biopsy
No muscle tissue, only fat
13.2.08
Muscle MRI
Chondroma right femur
19.2.08, 38 years
Muscle biopsy (left lateral vastus)
Indicates mitochondrial myopathy
15.12.08
Cerebral MRI
Cerebellar atrophy
19.12.08
Needle electromyography
Increased polyphasia exclusively
WMLs: white matter lesions, RP: retinitis pigmentosa.Figure 2
(a–c) Neuropathology of muscle biopsy (left vastus lateralis muscle) presents myopathic changes with single COX-negative fibers (a) COX/SDH double-labeling, mildly increased PAS-positivity in few fibers (b) arrow, muscle fiber splitting, and ragged-red fibers (c) Gomori-trichrome stain, asterisk. (d and e) Electron microscopy images illustrate increased numbers of fat vacuoles (d and e, arrow heads) between densly packed subsarcolemmal mitochondria (d) plus. Some mitochondria show single dark bodies in higher magnification (e) arrow.Figure 3
Echocardiographic parasternal long axis view showing the ectatic ascending aorta, measuring 37 mm in diameter.The family history was positive for hypotonia (mother), diabetes (father, brother of father, grandmother from the father’s side, grand-grandfather from the father’s side), carcinoma (father), and stroke (father). Neurological exam at age 49, revealed short stature, microcephaly, facial dysmorphism, myopathic face, ophthalmoparesis, pupils nonreactive to light, anisocoria (left: 5 mm, right: 3 mm, unrounded), divergence of bulbs, ophthalmoparesis (abduction right bulb 60° abduction left bulb: 15° vertical movements impossible), bilateral ptosis (right > left), reduced corneal reflexes, hypoacusis requiring bilateral hearing devices, dysarthria, dropped head, weakness for right elbow extension and flexion, reduced tendon reflexes on the upper limbs, ataxia and brady-dysdiadochokinesia on the upper limbs, marked wasting of the thighs, ataxia on the lower limbs, truncal ataxia, and ataxic stance, and gait. Gnome calves bilaterally, which were described at age 38 were no longer present. The last medication included indapamide, furosemide/spironolactone, simvastatin, NaCl, KCl, coenzyme-Q (60 mg/d), and vitamin-D.


## 3. Discussion

The presented patient is interesting in several aspects. Though clinical manifestations of KSS developed already in early infancy and childhood, the majority of the typical phenotypic features (CPEO, pigmentary retinopathy, elevated CSF protein, and cardiac conduction defects) and hepatopathy were recognised not earlier than in adulthood. Possibly, the typical features of KSS required for establishing the diagnosis [1, 2] were present already earlier; however, they were not recognied before age 30. KSS was suspected for the first time at age 39. An argument in favor of the diagnosis of KSS is that the mother was not affected suggesting that there was no transmission of a pathogenic mtDNA variant but rather spontaneous occurrence of a single mtDNA deletion, which is the cause in 96% of cases [3].Another interesting point is the phenotype. Though the patient fulfilled the diagnostic criteria for KSS, he additionally presented with a plethora of manifestations, of which some have been reported earlier in KSS. In addition to the features required for diagnosing KSS, the patient presented with the known features of diabetes [4], hypocorticism (hyponatremia) [5], short stature [6], white matter lesions [7], hypoacusis [1], migraine [8], hepatopathy [9], steatosis [10], and cataract [11]. Features so far unreported in KSS include congenital anisocoria, severe caries, liver cysts, pituitary enlargement, desquamation of hands and feet, bone chondroma, aortic ectasia, dermoidal cyst, and polyposis of nasal sinuses. Whether all these features are truly attributable to the underlying metabolic defect remains speculative and requires further investigations, but from other MIDs it is well known that such features can be part of the phenotype [12]. The reason for the high number of novel phenotypic features could be that previous cases were not thoroughly investigated or that the genetic cause of the present patient was different from that of the previous cases.Concerning the recurrent deteriorations of the phenotype during infections or spontaneously, it cannot be excluded that these conditions were in fact seizures or stroke-like episodes (SLEs), which remained unrecognized and recovered spontaneously. At least 4 of these episodes were documented. An argument for SLEs is that MRI at the first episode at age 36 showed subcortical T2-hyperintensities, which were also hyperintense on DWI and ADC and not confined to a vascular territory, suggesting a vasogenic edema. Whether arterial hypertension should be regarded as a manifestation of the MID is questionable but there are indications from Chinese studies that arterial hypertension can be in fact a phenotypic feature of an MID [4].Limitations of the study were that the diagnosis was not confirmed by genetic investigations, that the mother was not investigated for the presence of a MID, and that no biochemical investigations of the muscle homogenate were carried out.In conclusion, this case shows that KSS is indeed a multisystem disease affecting all types of tissues and that the phenotypic presentation may be broader than so far anticipated.



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*Source: 7368527-2020-02-28.xml*