Kss Syndrome Case Study

Abstract

Objective: To report multisystemic abnormalities found in a patient with Kearns-Sayre syndrome.

Patient Methods: The case report of the 26 years old female with Kearns-Sayre syndrome started about 16 years ago has some uncommon cardiological aspect apart from endocrine dysfunction, pancerebellar manifestation, progressive external ophthalmoplegia, neurosensorial hearing loss, and peripheral neuropathy among others abnormalities. Ophthalmologic examination showed dystrophic features in the cornea and retina. CT Scan of the brain showed generalized cerebral and cerebellar atrophy and dilatation of the ventricular system, etc. In the skeletal muscle biopsy the typical signs of atrophy and ragged-red fibers were seen. Laboratory tests, CT scan of the chest, ECG and Ultrasound studies showed signs of myocardiopathy, heart block, interventricular septal defect, renal lesions, liver disease and others. Different clinical trial was using looking for improvement of the patient's manifestations.

Results: No improvement of the clinical manifestations was observed. The classical vitamin therapy did not improve this patient's condition. Endocrine dysfunctions such as non-insulin dependent diabetes and hypothyroidism, liver dysfunction and renal disease were well controlled with the common way of managements.Cell Culture, DNA/ RNA Analyses, Determination of mtDNA Copy number and Analyses of Mitochondria Translation Products are not available in our region but the clinical manifestation and laboratory test result were useful for confirmation of Kearns-Sayre syndrome. To our knowledge, this combination of clinical manifestation has never been described in Kearns-Sayre syndrome.

 

Introduction

Kearns-Sayre Syndrome (KSS) is a very uncommon fatal multisystem disorder which usually affects female and males before the age of 20, and it is characterized by progressive external ophthalmoplegia, mild skeletal muscle weakness, retinal pigmentation, left bundle branch block or intracardiac conduction defect1, hearing deficiencies, increased protein level in cerebrospinal fluid, cerebellar signs, impaired cognitive dysfunction, diabetes mellitus2 , and other endocrine disorders. It is a mitochodrial encephalomyopathy in which many different defects of the central and peripheral nervous system: optic atrophy, vestibular defect, myopathy, pyramidal signs, poor intellectual development or mental deterioration are present apart from hypogonadism, hypothyroidism, hypoparathyrodism, and renal dysfunction. For the other hand the considerable short stature of the patients and the lax posture, poor musculature, frequent secondary kyphoscoliosis, hyperlordosis, frequent wasting and typical fascies all contribute to their characteristic general appearance.

Several authors reported partial deletions of human mitochondrial DNA (mtDNA) in 1988 for a first time345 and partial duplication67 or coexistence of deletion and duplication by others 8

In this presentation, we have chosen to report on the case of a patient diagnosed as KSS with an associated hypothyroidism, hypoparathyroidism, diabetes mellitus and adrenocortical failure.

Report Of A Case

A 26 years-old female patient was born as the third child to healthy non-consanguineous parents. The family history was unremarkable, except for diabetes mellitus in the maternal grandfather and a history of “progressive and generalized weakness of unknown cause” of her oldest sister who remind in bed for the past four years. Pregnancy and birth were normal. Symptoms were first notice in this patient when she was near the age of 12 years. Up to then, she had presented normal neuropsychomotor development, without reference to neo- or perinatal intercurrents. Deficient growth in stature was evident at the age of 13 years when she began to complain of progressive “dropping eyes” plus sight disturbances without diplopia, and also progressive hearing loss, three years later she began to suffer of unsteady gait which progress slow and gradually up to date.

She also suffered from progressive muscle weakness and generalized muscle wasting resulting in a loss of more than 15 kg of body weight. During this time she repeated the standard level 3 four times at the school due to learning problems while she was complaining of asthenia, anorexia, dysphagia, easy fatigability, and paresthesia of the four limbs. Seven months prior admission she was treated for hyperpigmentation of the skin plus arterial hypotension since then all symptoms became worst and she attended to Neurology OPD clinic because of two attacks of left partial complex motor seizures a week before and to be admitted is decided. On examination in neurology ward she was assessed by two of us (FSH-AA). Her face was an unexpressed-rounded and greasy one with an incomplete palpebral ptosis bilaterally (Figure 1), the nails and teeth were normal She was very thin owing to generalized muscular wasting. Her weight was 41 kg, her height 153 cm (on the 2.5 percentile), and her head circumference 52 cm.

Figure 1
Figure 1: Patient's face (with permission of patient and author)

Skin examination showed hyperpigmentation of the elbow region, in both creases of the hands and mucosal areas. Examination of the neck shows a diffuse enlargement of the thyroid gland. BP 95/65 mmHg She was very cooperative and answered question adequately. She was also well orientated and no language or speech problems were detected, however all memory functions were diminished and the sensory attention was also affected. Cranial nerves VII, IX and X were affected bilaterally. Trousseau's and Chvosteck's signs were negative Ophthalmological examination revealed retinal dystrophy with visual acuity of 3/10 (right) and 5/10 (left).

Complementary exams showed: elevated CSF protein concentration (106 mg/dl) and normal glucose level. Decreased serum level of sodium, chloride, bicarbonate, calcium, low T4 and TSH were seen while serum level of potassium was persistent mild elevated, glucose: 12 mmol/l; mild increase in creatine phosphate and lactate were present, serum phosphate, alkaline phosphatase, creatinine, aspartate aminotransferase, albumin, total protein, and magnesium were normal. Hyperphosphaturia, hyperaminoaciduria and glucosuria were not found in urianalyis. No skeletal abnormalities were observed, and audiological evaluation demonstrated significant bilateral sensorineural hearing loss.

Twelve-lead electrocardiography (ECG) showed a 2:1 atrioventricular (AV) block with slow ventricular rate. Intermittent complete AV block, and complete left bundle branch block (Figure 2). The patient submitted to muscular biopsy of the thigh muscle which showed the presence of ragged-red fibers (RRF) to Masson trichromic stain (Figure 3-4). CT-scan carried out at 16 years of evolution revealed signs of generalized cerebral and cerebellar atrophy and areas of hypointensity in basal ganglia (figure 5) and on CT-scan of the chest signs of dilated cardiomyopathy were observed (Figure 6) and also confirmed by cardiac ultrasonography tests which also showed a small right kidney (5.6 cm) and left kidney (8.2 cm)

Figure 2
Figure 3
Figure 3: Masson trichromic stain
Figure 4
Figure 4: Masson trichromic stain
Figure 5
Figure 6

Discussion

Mitochondrial diseases have numerous phenotypic expression, and form an heterogeneous group of genetic diseases in which the production of energy fails, most patients with mitochondrial disorders are diagnosed by finding a respiratory chain enzyme defect or a mutation in the mitochondrial DNA, due to our lack of technological resources the diagnosis for this patient clinically is made. These mitochondrial disease are well known in childhood but can onset in adulthood and its may remains unrecognized9, although onset before age of 20 years is a general rule, this process has been reported in patients older than 20 years 1011

Most of the combined clinical manifestation present in our patient had been reported previously such as: due to pituitary growth hormone deficiency2 5, secondary to disconnection of Purkinje cells at the dentate nucleus12 , ,1 due to cricopharingeal achalasia13, of cochlear and retrocochlear origin which does not have a pronostic value for the progression of the disorder14, because of degeneration of the retina although KSS that involved no retinal pathology had been also reported15 , heart block is a known associated signs of KSS since the first description in 19581 involvement of the cardiac conduction system due to the mitochondrial disorder is the most important prognostic factor16 and the prophylactic implantation of definitive pacemarker is recommended16 17 with a subsequent prolongation of the live expectancy in spite of the probable complications from the dilated cardiomyopathy by itself18

Some laboratory investigations also revealed similar results to reported in the medical literature such as: abnormal creatine phosphate, lactate, serum phosphate, alkaline phosphate, aspartate aminotransferase, total protein and electrolytes, and increased CSF protein level due to oncocytic transformation of choroids plexus epithelial cells Delta-mtDNAs-related19 Anatomopathological examination of the muscle biopsy showed also similarities (ragged-red fibers). We agreed that same comments on radiographic tests, EKG and cardiac ultrasonography could be made. MRI is not performed because is was not available, but the characteristic finding in KSS are well known and consist in a combination of the high-signal foci in subcortical cerebral white matter and in the brain stem, globus pallidus or thalamus20

Hypoparathyroidism and an associated renal tubular dysfunction has been recently described21 Our patient presented normal serum dosage of phosphorus and the serum level for calcium was always decreased, so that the diagnosis of paratyroid disorder was, in spite of absents of episodes of carpopedal spasms and other signs, therefore considered. Have been reported other uncommon associations such as: focal and generalized dystonia with deletion of 5.9 kb from mtDNA 22, Toni-Debre-Fanconi syndrome with focal deficiency of cytochrome-c-oxidase23 .and acquired primary adrenocortical failure24 In our patient the classic clinical picture of KSS is associated with some endocrinopathies: diabetes mellitus, hypothyroidism, probable hypoparathyroidism and well documented adrenocortical failure. To the best of our knowledge, this is the first report on this type of association, suggesting “KSS plus”.

Acknowledgements

We are extremely grateful to Lourdes Valdes Perez for her invaluable collaboration.

References

1. Kearns TP, and Sayre GP.Retinitis pigmentosa, external ophthalmoplegia, and complete heart block. Arch. Ophthalmol 1958:60;280-289.
2. Berenberg RA Lumping or splitting? "Ophthalmoplegia plus" or Kearns-Sayre syndrome? Ann Neurol 1977:1;37-43.
3. Holt IL, Harding AE, and Morgan-Hughes JA: Deletetions of mitochondrial DN in patients with mitochondrial myopathies. Nature 1988:331;717-719.
4. Lestienne P, and Ponsot G. Kearns-Sayre syndrome with muscle mitochondrial DNA deletion (letter) Lancet 1988:1;885.
5. Zeviani M, Moraes CT, DiMauro S, Nakase H, Bonilla E, Schon EA, and Rowland LP. Deletions of mitochondrial DNA in Kearns-Sayre syndrome. Neurology 1988:38; 1339-1346.
6. Poulton J Deadman ME, and Gardiner RM. Tandem direct duplications of mitochondrial DNA in mitochondrial myopathy: analysis of nueclotide sequence and tissue distribution. Nucleic Acids Res 1989:17;10223-10229.
7. Poulton J et al. Deficiency of the human mitochondrial transcription factor h-mtTFA in infantile mitochondrial myopathy is associated with mtDNA depletion Hum. Mol.Genet. 1994:3;1763-1769.
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9. Serratrice J, Desnuelle C, Granel B, de Roux-Serratrice C, Disdier P, Weiller PJ. Mitochondrial disease in adults. Rev Med Intern 2001; 22 Supl 3:356s-366s.
10. Franco E, Bautista J, Kuque R, Chinchon I, García-Lozano R, Aguilera I, Campos Y, Arenas J. Mitochondrial encephalomyopathy of late presentation with progressive with progressive ophthalmoplegia, tremor and diffuse leukoencephalopathy. Neurologia; 1999:463-466.
11. Seneca S, Verhelst, De Meirleir L, Meir F, Ceuterick-De Grote C, Lissens W, Van Coster R.A new mithocondrial point mutation in the transfer RNA (Leu) gene in a patient with a clinical phenotype resembling Kearns-Sayre syndrome. Arch Neurol 2001; 58:113-1118.
12. Tanji K, Dimauro S, Bonilla E. Disconnection of cerebellar Purkinje cell in Kearns-Sayre syndrome. Neurol Sci 1999;166(1):64-70.
13. Korblum C, Broicher R, Walther E, Seibel P, Reichmann H, Klockgether T, Herbverhold C, Schroder R. Cricopharyngeal achalasia is a common cause of dysphagia in patients with mtDNA deletions. Neurology 2001;56(10):1409-1412.
14. Zwirner P, Wilichowski E. Progressive sensorineural loss in children with mitochondrial encephalomyopathies. Laryngoscope 2001;111(3):515-521.
15. Rajakannan,Gayathri,Prasad W, Ramakrishanan R, Prajna NV. Kearns-Sayre syndrome: an atypical presentation. Indian J Ophthalmol 2000;48(1):54-55.
16. Lee KT, Lai WT, Hwang CH, Yen HW, Voon WC, Sheu SH. Atrioventricular block in Kearns-Sayre syndrome: a case report.
17. Barragan-Campos HM, Barrer-Ramirez CF, Iturralde Torres P, Ilarraza-Lomeli H, Avila-Casado MC, Estanol B, Dorantes J, Oseguerra J.Kearns-Sayre syndrome an absolute indication for prophylactic implantation of definite pacemaker? Arch Inst Cardiol Mex 1999;69(6):559-565.
18. Provenzale JM, VanLandingham K. Cerebral infarction associated with Kearns-Sayre syndrome-related cardiomyopathy. Neurology 1996;46(3):826-828.
19. Tanji K, Schon EA, DiMauro S, Bonilla E. Kearns-Sayre syndrome:oncocytic transformation of choroids plexus epithelium. J.Neurol Sci 2000;178(1):29-36.
20. Chu BC, Terae S, Takahashi C, Kikuchi Y, Miyasaka K, Abe S, Minowa K, Sawamura T. MRI of the brain in the Kearns-Sayre syndrome: report of four cases and a review. Neuroradiology 1999;41(10):759-764.
21. Katsanos KH, Elisaf M, Bairaktari E, Tsianos EV. Severe hypomagnesemia and hypoparathyroidism in Kearns-Sayre syndrome. Am J Nephrol 2001;21(2):150-153.
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24. Vaidya B, Pearce S, Kendall-Taylor P. Rcent advances in the molecular genetics of congenital and acquired primary adrenocortical failure. Clin Endocrinol(OXF) 2000;53(4):403-418.

Twin 1

The data presented below were reported by the mother in a speech-language pathology during the first care in June 2000, when the patient was 11 years old.

- There is no family history of hearing loss and syndromes.

- There were no intercurrences during gestation.

- Report of mumps and chickenpox, about 3 years old.

- Neuropsychomotor and language development according to age, however, without previous specialized assessments.

- Hearing complaints began at the age of ten. The T1 patient responded to her name when the voice was very loud and also reported bilateral tinnitus.

Objective tests, such as imitanciometry, transient and distortion product otoacoustic emissions (EOA and DP) and brainstem auditory evoked potential (BERA), and subjective exams such as pure tone audiometry (PTA) were analyzed, and speech perception tests (SPT) (Chart 1).

Chart 1 Results of the objective examinations of twin 1 (2000 and 2014) 

Exam performedRight ear (RE)Left ear (LE)
ImmittanciometryCurve type A Reflexes absent in 2000 and 2014Curve type A Reflexes absent in 2000 and 2014
EOAt e EOAPDNo record in medical records in 2000 Absent in 2014No record in medical records in 2000 Absent in 2014
BERA clickNo record in medical records in 2000 Absent in 2014No record in medical records in 2000 Absent in 2014

Subtitle: EOAt = Transient Evoked Otoacoustic Emissions; EOA = Distortion product evoked otoacoustic emissions; BERA = Auditory Evoked Brain Stem Potential

The results of the subjective exams were compatible with the electrophysiological ones, in both moments of evaluation, as shown in Figure 1.

Figure 1 Pure tone audiometry - twin 1 

In 2000, after the examinations, the professionals could diagnose hearing loss as bilateral sensorineural hearing loss and thus, adapt the individual sound amplification device and perform the respective validation and verification tests. However, in 2014, there was a significant progression of the degree of hearing loss, which became profound bilateral, requiring replacement of the hearing aid with another, higher and more recent technology, as well as redoing the verification tests (Figure 2).

Figure 2 Amplified threshold search with Individual Sound Amplification Apparatus - twin 1 

In the year 2000, the application of the speech perception test (SPT) with individual sound amplification device in all patients was not yet common. They were performed only in those whose cases would be presented at a meeting, to discuss cochlear implant surgery (CI). For this reason, in the T1 patient’s chart, a SPT evaluation was only found in 2014. The right ear (RE) score was: detection of Ling test sounds for /a/, /u/, /i/ and /m/= 100% and for /s/ and /∫/ = 0%; Name discrimination = 100%; Discrimination of the question affirmation = 0%; Vocabulary extension = 44%; Identification of sentence length = 60% and sentence identification = 0%

In the left ear (LE), the scores found were: detection of Ling test sounds for /a/, /i/, /u/ and /m/ = 100% and for /s/ and /∫/ = 0%; Name discrimination = 90%; Discrimination of the question /affirmation = 0%; Vocabulary extension = 28%; Identification of sentence length = 30% and sentence identification = 0%.

Despite the progression of hearing loss, twin 1 had good vocabulary and oral language, since the hearing loss was post-lingual. There were no specific examinations of language in the medical record. It is believed that the reason is that the patient is already in adolescence in 2000 and later in adulthood in 2014, and there are no specific language protocols in the hospital sector to evaluate these age groups.

After the examinations, the case was selected to be discussed by the multidisciplinary team regarding the need for surgery for the cochlear implant (CI). Several criteria were approached, based on the analysis of other professionals, such as social worker, psychologist, otorhinolaryngologist and speech therapist, and based on SUS and hospital criteria at the time.

Regarding the speech-language analysis, the main criterion for indication of surgery was the low result in the tests of speech perception in closed set and the difficulty in open set. In addition, practitioners were concerned that they would not have other hearing aids options in the future if hearing loss were to progress. Still, the team doctors emphasized that the patient was losing other functions, including vision. Therefore, it was necessary that she maintained a good oral communication, to preserve her quality of life, despite the other difficulties caused by the syndrome.

Therefore, we opted for the left side CI surgery, as decided by surgeons. Activation occurred in February 2015 (Figure 3).

Figure 3 Amplified threshold search with cochlear implant - twin 1 

Regarding the SPT with CI, performed one month after the activation in March 2015, the patient detected all the sounds of the Ling test, but could not perform other speech tests, complaining that she had not yet become accustomed to all Sounds, because the CI was very different from the individual sound amplification device, which it used for 15 years. The best results appeared eight months after the activation, when the patient performed the SPT in open set, with a result of 45% for the list of sentences. However, regular follow-ups are still being done for new mappings and guidelines.

Twin 2

The data presented below, as well as for the twin 1, were reported by the mother in a speech-language pathology during the first care in June 2000, when the patient was 11 years old.

- There is no family history of hearing loss and syndromes.

- There were no complications during pregnancy and delivery.

- Contracted mumps and chickenpox near 3 years of age.

- Neuropsychomotor and language development, according to age, however, without previous specialized assessments,

- Hearing complaints began at the age of ten. The T2 patient responded to her name only when the voice was very strong and also reported bilateral tinnitus

Objective tests, such as imitanciometry, transient and distortion product otoacoustic emissions (EOA and DP) and brainstem auditory evoked potential (BERA), and subjective exams such as pure tone audiometry (PTA) were analyzed, and speech perception tests (SPT) (Chart 2).

Chart 2 Results of the objective examinations of the twin 2 hearing (2000 and 2014) 

Exam performedRight ear (RE)Left ear (LE)
ImmittanciometryCurve type A Reflexes absent in 2000 and 2014Curve type A Reflexes absent in 2000 and 2014
EOAt e EOAPDNo record in medical records in 2000 Absent in 2014No record in medical records in 2000 Absent in 2014
BERA clickAbsent in 2000 Absent in 2014Absent in 2000 Absent in 2014

Subtitle: EOAt = Transient Evoked Otoacoustic Emissions; EOA = Distortion product evoked otoacoustic emissions; BERA = Auditory Evoked Brain Stem Potential

The results of the subjective exams were compatible with the electrophysiological ones, in both moments of evaluation, as shown in Figure 4.

Figure 4 Pure Tone Audiometry - twin 2 

After all evaluations, in 2000, when twin 2 was 11 years old, the professionals diagnosed the patient with mild sensorineural hearing loss in the left ear and moderate degree in the right ear. Therefore, individual sound amplification device adaptation, compatible with this type of hearing loss, was performed as well as validation and verification tests.

In 2014, when the patient was 25 years old, hearing loss progression was observed, as shown in Figure 4. Thus, the diagnosis changed to bilateral severe grade hearing loss, which made it necessary to Tests to verify their benefits (Figure 5).

Figure 5 Amplified threshold search with Individual Sound Amplification Apparatus - twin 2 

In relation to SPT with individual sound amplification device, performed in 2014, the patient was able to perform all the tests in closed set and obtained a result of 80% in RE and 97% in LE, for the open set tests (list of sentences).

As for patient T1, despite the progression of hearing loss, the T2 patient had good vocabulary and oral language, since hearing loss is post-lingual. There were no specific examinations of language in the medical record. It is believed that the reason is that the patient is already in adolescence in 2000 and later in adulthood in 2014, and there are no specific language protocols in the hospital sector to evaluate these age groups.

The case was also selected for a multidisciplinary meeting, to discuss the CI, including, to compare the results with those of the twin 1. All professionals, such as social worker, psychologist, otorhinolaryngologist and speech therapist, reported the results of their evaluations and, of this information and of the criteria established by SUS and the hospital in 2014, twin 2 were not indicated for CI surgery.

In relation to speech-language evaluation, the main factor for not indicating the CI was a good percentage of correct answers in the SPT with individual sound amplification device, demonstrating that the device still provided a benefit. Therefore, it was decided to keep the twin 2 in audiological follow-up, to verify if the hearing loss will progress. Even though this may happen, practitioners believe that there are still other individual sound amplification device replacement options to maintain good oral communication of the patient, which makes it unnecessary at the moment to undergo surgery, since the benefits of CI are very Similar to those that individual sound amplification device still provides. However, once that is no longer provides the same benefits, the case of twin 2 will again be discussed by a multidisciplinary team, regarding the need for CI, to avoid that the progressive loss aggravates the patient’s current good communication.

All data referring to the discussion of cases T1 and T2 by the multidisciplinary team were collected in the medical records, from an interview with the professionals responsible for the case.

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