Case Reports / Journal of Clinical Neuroscience 21 (2014) 2009–2011
2009
Adult onset Leigh syndrome with mitochondrial DNA 8344 A>G mutation Jee-Young Han a, Jung-Joon Sung a,⇑, Hong-Kyun Park a, Byung-Nam Yoon b, Kwang-Woo Lee a a b
Department of Neurology, Seoul National University Hospital, Seoul National University College of Medicine, 28 Yongon-Dong, Chongno-gu, Seoul 110-744, Republic of Korea Department of Neurology, Inha University Medical College, Incheon, Republic of Korea
a r t i c l e
i n f o
Article history: Received 24 November 2013 Accepted 8 March 2014
Keywords: Adult-onset Leigh syndrome Mitochondrial disorders Mitochondrial encephalopathy Myoclonic epilepsy and ragged red fibers
a b s t r a c t We report a pedigree of adult-onset Leigh syndrome (LS) with mitochondrial mutation 8344 A>G. A 38-year-old woman presented with optic neuropathy, weakness and cognitive impairment. Family history of optic neuropathy and systemic involvement was suggestive of mitochondrial encephalopathy. Genetic and radiologic studies showed m.8344 A>G mutation with characteristics of LS. To our knowledge this is the first case of adult-onset LS demonstrating the m.8344 A>G mutation. Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction Leigh syndrome (LS) is a neurodegenerative disorder characterized by bilateral lesions in the basal ganglia, thalamus, and brainstem. The majority of cases present in children but adult-onset cases have been reported. We describe a family harboring an m.8344 A>G mutation with adult-onset LS.
2. Case presentation 2.1. Patient 1 A 38-year-old woman presented with progressive weakness and cognitive impairment. At age 28 she was diagnosed with bilateral optic neuropathy. She had a family history of visual loss (three siblings, mother and uncle). Screening for Leber’s hereditary optic neuropathy was negative for mitochondrial DNA 3460 G>A, 4171 C>A, 14484 T>C, and 11778 G>A mutations. She developed limb weakness and weight loss, at which time she was diagnosed with myopathy and underwent a muscle biopsy. Full immunohistologic evaluation was carried out, and the pathology (myofiber size variation, angulated atrophic myofibers, hyperstained myofibers in succinate dehydrogenase) was compatible with myopathy. There were neither ragged-red fibers in modified Gömöri stain nor mitochondrial abnormalities on electron microscopic examination. The initial sample amount was inadequate and its preparation was delayed, but the patient refused resampling. Blood tests for mutations for mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) (3243A>G, 3271T>C, 3252A>G, 3291T>C, 3256C>T, 3260A>G, 3303C>T, and 3302A>G) were all negative. Brain MRI showed bilateral putaminal necrosis (Fig. 1A–C). She had hypertension, dyslipidemia, and had commenced menopause in her mid-thirties. The patient had had multiple lipomas surgically removed. Memory loss was seen upon admission. Her Mini Mental State Examination score was 24/30, and her attention, calculation and time orientation were decreased. Motor function was grade IV in ⇑ Corresponding author. Tel.: +82 2 2072 2820; fax: +82 2 3672 7553. E-mail address: [email protected] (J.-J. Sung).
the proximal muscles and grade V in distal muscles. There was no ataxia, deafness, or myoclonus. Follow-up brain MRI at 4 months after admission showed extended lesions (Fig. 1D, E). The baseline level of serum lactate was 4.8 mmol/L (normal range 0.7–2.5 mmol/L), and increased to 11.1 mmol/L in the aerobic exercise test. Fasting blood glucose and HbA1C were normal, but plasma insulin increased to 235.1 uIU/mL (normal range 1.8–15.38 uIU/mL). She developed diabetes mellitus soon after. Additional genetic tests for m.8344 A>G and 8993 T>G were done for the patient and her family. m.8344 A>G was found in our patient, an elder sister (Patient 2), an unaffected sister (age 30) and an uncle (age 65) (Fig. 2). Genetic tests were done using blood polymerase chain reaction sequencing. The patient showed developed decreased responsiveness, which progressed to generalized tonic-clonic seizure, then to status epilepticus. She was admitted to the Intensive Care Unit, and progressed to motor grade I power with bilateral ophthalmoplegia, dysphagia and respiratory depression. Symptoms improved with the antioxidants ubidecarenone 20 mg/day and L-carnitine 2700 mg/day and antiepileptic drugs (topiramate 600 mg/day and levetiracetam 3000 mg/day), however she became wheelchair-bound, although she did not require respiratory aids or suffer dysphagia. 2.2. Patient 2 The elder sister of Patient 1, aged 42, was diagnosed with bilateral optic neuropathy at age 27. Extremity weakness and dysarthria developed at age 40. She had a hysterectomy at age 36 due to severe menorrhagia. She complained of forgetfulness since her mid-thirties. Brain MRI showed typical LS lesions (Fig. 1F). 3. Discussion LS is a severe progressive metabolic neurodegenerative disorder with clinical and genetic heterogeneity. Most cases are reported in infants under the age of 2. Adult onset forms are rare, and to our knowledge only three patients have been reported with associated mutations (m.8993 T>G [1], m.1644 G>T [2], and m.9176 T>C [3]). The mitochondrial mutation of 8344 A>G is well known as a cause
2010
Case Reports / Journal of Clinical Neuroscience 21 (2014) 2009–2011
Fig. 1. Initial axial (A, B) diffusion weighted imaging (DWI) and (C) T2-weighted fluid attenuated inversion recovery (T2-FLAIR) MRI of Patient 1 showing high signal intensity lesions in bilateral basal ganglia and high frontal cortices. (D, E) Follow-up axial DWI images of Patient 1, showing involvement of the (D) corona radiata and (E) corpus callosum. (F) Axial T2-FLAIR MRI showing lesions characteristic of Leigh syndrome in Patient 2.
of myoclonic epilepsy with ragged-red fibers (MERRF) syndrome, accounting for 90% of patients. MERRF is characterized by myoclonic epilepsy, ataxia, myopathy, optic atrophy, peripheral neuropathy, and hearing loss, with dementia also being a common symptom [4,5]. Atypical phenotypes are known to be associated
with the m.8344 A>G mutation, and include LS [6], multiple symmetrical lipomatosis [7], spinocerebellar degeneration [8], and progressive external ophthalmoplegia [5]. Our patient presented with myopathy, cognitive impairment, optic neuropathy, ophthalmoplegia, and generalized tonic-clonic
Case Reports / Journal of Clinical Neuroscience 21 (2014) 2009–2011
2011
Fig. 2. Family pedigree indicating maternal inheritance with variable phenotypes. The brother of Patient 1 and 2, who had optic neuropathy, did not undergo genetic testing.
seizures at an advanced age. She also had impaired glucose tolerance, multiple lipomas, and premature ovarian failure. Laboratory findings indicated elevated levels of serum lactate and its accumulation with aerobic exercise. Neuroimaging was characteristic of LS. Her elder sister had optic neuropathy, dysarthria, cognitive impairment, weakness, and typical LS brain lesions. These findings are consistent with LS of adult onset. Association of m.8344 A>G and infantile LS has been implied in several reports [5,9–11], but this is the first case seen in an adult pedigree to our knowledge. The patients and their asymptomatic family members had the m.8344 A>G mutation. The distinctive feature of this pedigree was adult onset optic neuropathy. Mutational loads were not measured due to laboratory limitations. We cannot confirm whether this could be seen as MERRF–LS overlapping syndrome, with its phenotype associated to its mutational loads in each tissue. This should be considered in further investigations. In conclusion, we report a family carrying the m.8344 A>G mutation with bilateral basal ganglia involvement and progressive neurologic symptoms, which can thus be diagnosed as LS. Conflicts of Interest/Disclosures The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication. Acknowledgement This work was supported by Grant No. 04-2011-0090 from the Seoul National University Hospital Research Fund. http://dx.doi.org/10.1016/j.jocn.2014.03.020
References [1] Nagashima T, Mori M, Katayama K, et al. Adult Leigh syndrome with mitochondrial DNA mutation at 8993. Acta Neuropathol 1999;97:416–22. [2] Chalmers RM, Lamont PJ, Nelson I, et al. A mitochondrial DNA tRNAVal point mutation associated with adult-onset Leigh syndrome. Neurology 1997;49: 589–92. [3] Ronchi D, Bordoni A, Cosi A, et al. Unusual adult-onset Leigh syndrome presentation due to the mitochondrial m.9176T>C mutation. Biochem Biophys Res Commun 2011;412:245–8. [4] Chinnery PF, Howell N, Lightowlers RN, et al. Molecular pathology of MELAS and MERRF. The relationship between mutation load and clinical phenotypes. Brain 1997;120:1713–21. [5] Silvestri G, Ciafaloni E, Santorelli F, et al. Clinical features associated with the A ? G transition at nucleotide 8344 of mtDNA (‘‘MERRF mutation’’). Neurology 1993;43:1200–6. [6] Berkovic SF, Shoubridge EA, Andermann F, et al. Clinical spectrum of mitochondrial DNA mutation at base pair 8344. Lancet 1991;338:457. [7] Berkovic SF, Andermann F, Shoubridge EA, et al. Mitochondrial dysfunction in multiple symmetrical lipomatosis. Ann Neurol 1991;29:566–9. [8] Howell N, Kubacka I, Smith R, et al. Association of the mitochondrial 8344 MERRF mutation with maternally inherited spinocerebellar degeneration and Leigh disease. Neurology 1996;46:219–22. [9] Orcesi S, Gorni K, Termine C, et al. Bilateral putaminal necrosis associated with the mitochondrial DNA A8344G myoclonus epilepsy with ragged red fibers (MERRF) mutation: an infantile case. J Child Neurol 2006;21:79–82. [10] Hammans SR, Sweeney MG, Brockington M, et al. The mitochondrial DNA transfer RNALysA ? G[8344] mutation and the syndrome of myoclonic epilepsy with ragged red fibres [MERRF]: Relationship of clinical phenotype to proportion of mutant mitochondrial DNA. Brain 1993;116: 617–32. [11] Rahman S, Blok RB, Dahl HH, et al. Leigh syndrome: clinical features and biochemical and DNA abnormalities. Ann Neurol 1996;39:343–51.
2009
Adult onset Leigh syndrome with mitochondrial DNA 8344 A>G mutation Jee-Young Han a, Jung-Joon Sung a,⇑, Hong-Kyun Park a, Byung-Nam Yoon b, Kwang-Woo Lee a a b
Department of Neurology, Seoul National University Hospital, Seoul National University College of Medicine, 28 Yongon-Dong, Chongno-gu, Seoul 110-744, Republic of Korea Department of Neurology, Inha University Medical College, Incheon, Republic of Korea
a r t i c l e
i n f o
Article history: Received 24 November 2013 Accepted 8 March 2014
Keywords: Adult-onset Leigh syndrome Mitochondrial disorders Mitochondrial encephalopathy Myoclonic epilepsy and ragged red fibers
a b s t r a c t We report a pedigree of adult-onset Leigh syndrome (LS) with mitochondrial mutation 8344 A>G. A 38-year-old woman presented with optic neuropathy, weakness and cognitive impairment. Family history of optic neuropathy and systemic involvement was suggestive of mitochondrial encephalopathy. Genetic and radiologic studies showed m.8344 A>G mutation with characteristics of LS. To our knowledge this is the first case of adult-onset LS demonstrating the m.8344 A>G mutation. Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction Leigh syndrome (LS) is a neurodegenerative disorder characterized by bilateral lesions in the basal ganglia, thalamus, and brainstem. The majority of cases present in children but adult-onset cases have been reported. We describe a family harboring an m.8344 A>G mutation with adult-onset LS.
2. Case presentation 2.1. Patient 1 A 38-year-old woman presented with progressive weakness and cognitive impairment. At age 28 she was diagnosed with bilateral optic neuropathy. She had a family history of visual loss (three siblings, mother and uncle). Screening for Leber’s hereditary optic neuropathy was negative for mitochondrial DNA 3460 G>A, 4171 C>A, 14484 T>C, and 11778 G>A mutations. She developed limb weakness and weight loss, at which time she was diagnosed with myopathy and underwent a muscle biopsy. Full immunohistologic evaluation was carried out, and the pathology (myofiber size variation, angulated atrophic myofibers, hyperstained myofibers in succinate dehydrogenase) was compatible with myopathy. There were neither ragged-red fibers in modified Gömöri stain nor mitochondrial abnormalities on electron microscopic examination. The initial sample amount was inadequate and its preparation was delayed, but the patient refused resampling. Blood tests for mutations for mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) (3243A>G, 3271T>C, 3252A>G, 3291T>C, 3256C>T, 3260A>G, 3303C>T, and 3302A>G) were all negative. Brain MRI showed bilateral putaminal necrosis (Fig. 1A–C). She had hypertension, dyslipidemia, and had commenced menopause in her mid-thirties. The patient had had multiple lipomas surgically removed. Memory loss was seen upon admission. Her Mini Mental State Examination score was 24/30, and her attention, calculation and time orientation were decreased. Motor function was grade IV in ⇑ Corresponding author. Tel.: +82 2 2072 2820; fax: +82 2 3672 7553. E-mail address: [email protected] (J.-J. Sung).
the proximal muscles and grade V in distal muscles. There was no ataxia, deafness, or myoclonus. Follow-up brain MRI at 4 months after admission showed extended lesions (Fig. 1D, E). The baseline level of serum lactate was 4.8 mmol/L (normal range 0.7–2.5 mmol/L), and increased to 11.1 mmol/L in the aerobic exercise test. Fasting blood glucose and HbA1C were normal, but plasma insulin increased to 235.1 uIU/mL (normal range 1.8–15.38 uIU/mL). She developed diabetes mellitus soon after. Additional genetic tests for m.8344 A>G and 8993 T>G were done for the patient and her family. m.8344 A>G was found in our patient, an elder sister (Patient 2), an unaffected sister (age 30) and an uncle (age 65) (Fig. 2). Genetic tests were done using blood polymerase chain reaction sequencing. The patient showed developed decreased responsiveness, which progressed to generalized tonic-clonic seizure, then to status epilepticus. She was admitted to the Intensive Care Unit, and progressed to motor grade I power with bilateral ophthalmoplegia, dysphagia and respiratory depression. Symptoms improved with the antioxidants ubidecarenone 20 mg/day and L-carnitine 2700 mg/day and antiepileptic drugs (topiramate 600 mg/day and levetiracetam 3000 mg/day), however she became wheelchair-bound, although she did not require respiratory aids or suffer dysphagia. 2.2. Patient 2 The elder sister of Patient 1, aged 42, was diagnosed with bilateral optic neuropathy at age 27. Extremity weakness and dysarthria developed at age 40. She had a hysterectomy at age 36 due to severe menorrhagia. She complained of forgetfulness since her mid-thirties. Brain MRI showed typical LS lesions (Fig. 1F). 3. Discussion LS is a severe progressive metabolic neurodegenerative disorder with clinical and genetic heterogeneity. Most cases are reported in infants under the age of 2. Adult onset forms are rare, and to our knowledge only three patients have been reported with associated mutations (m.8993 T>G [1], m.1644 G>T [2], and m.9176 T>C [3]). The mitochondrial mutation of 8344 A>G is well known as a cause
2010
Case Reports / Journal of Clinical Neuroscience 21 (2014) 2009–2011
Fig. 1. Initial axial (A, B) diffusion weighted imaging (DWI) and (C) T2-weighted fluid attenuated inversion recovery (T2-FLAIR) MRI of Patient 1 showing high signal intensity lesions in bilateral basal ganglia and high frontal cortices. (D, E) Follow-up axial DWI images of Patient 1, showing involvement of the (D) corona radiata and (E) corpus callosum. (F) Axial T2-FLAIR MRI showing lesions characteristic of Leigh syndrome in Patient 2.
of myoclonic epilepsy with ragged-red fibers (MERRF) syndrome, accounting for 90% of patients. MERRF is characterized by myoclonic epilepsy, ataxia, myopathy, optic atrophy, peripheral neuropathy, and hearing loss, with dementia also being a common symptom [4,5]. Atypical phenotypes are known to be associated
with the m.8344 A>G mutation, and include LS [6], multiple symmetrical lipomatosis [7], spinocerebellar degeneration [8], and progressive external ophthalmoplegia [5]. Our patient presented with myopathy, cognitive impairment, optic neuropathy, ophthalmoplegia, and generalized tonic-clonic
Case Reports / Journal of Clinical Neuroscience 21 (2014) 2009–2011
2011
Fig. 2. Family pedigree indicating maternal inheritance with variable phenotypes. The brother of Patient 1 and 2, who had optic neuropathy, did not undergo genetic testing.
seizures at an advanced age. She also had impaired glucose tolerance, multiple lipomas, and premature ovarian failure. Laboratory findings indicated elevated levels of serum lactate and its accumulation with aerobic exercise. Neuroimaging was characteristic of LS. Her elder sister had optic neuropathy, dysarthria, cognitive impairment, weakness, and typical LS brain lesions. These findings are consistent with LS of adult onset. Association of m.8344 A>G and infantile LS has been implied in several reports [5,9–11], but this is the first case seen in an adult pedigree to our knowledge. The patients and their asymptomatic family members had the m.8344 A>G mutation. The distinctive feature of this pedigree was adult onset optic neuropathy. Mutational loads were not measured due to laboratory limitations. We cannot confirm whether this could be seen as MERRF–LS overlapping syndrome, with its phenotype associated to its mutational loads in each tissue. This should be considered in further investigations. In conclusion, we report a family carrying the m.8344 A>G mutation with bilateral basal ganglia involvement and progressive neurologic symptoms, which can thus be diagnosed as LS. Conflicts of Interest/Disclosures The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication. Acknowledgement This work was supported by Grant No. 04-2011-0090 from the Seoul National University Hospital Research Fund. http://dx.doi.org/10.1016/j.jocn.2014.03.020
References [1] Nagashima T, Mori M, Katayama K, et al. Adult Leigh syndrome with mitochondrial DNA mutation at 8993. Acta Neuropathol 1999;97:416–22. [2] Chalmers RM, Lamont PJ, Nelson I, et al. A mitochondrial DNA tRNAVal point mutation associated with adult-onset Leigh syndrome. Neurology 1997;49: 589–92. [3] Ronchi D, Bordoni A, Cosi A, et al. Unusual adult-onset Leigh syndrome presentation due to the mitochondrial m.9176T>C mutation. Biochem Biophys Res Commun 2011;412:245–8. [4] Chinnery PF, Howell N, Lightowlers RN, et al. Molecular pathology of MELAS and MERRF. The relationship between mutation load and clinical phenotypes. Brain 1997;120:1713–21. [5] Silvestri G, Ciafaloni E, Santorelli F, et al. Clinical features associated with the A ? G transition at nucleotide 8344 of mtDNA (‘‘MERRF mutation’’). Neurology 1993;43:1200–6. [6] Berkovic SF, Shoubridge EA, Andermann F, et al. Clinical spectrum of mitochondrial DNA mutation at base pair 8344. Lancet 1991;338:457. [7] Berkovic SF, Andermann F, Shoubridge EA, et al. Mitochondrial dysfunction in multiple symmetrical lipomatosis. Ann Neurol 1991;29:566–9. [8] Howell N, Kubacka I, Smith R, et al. Association of the mitochondrial 8344 MERRF mutation with maternally inherited spinocerebellar degeneration and Leigh disease. Neurology 1996;46:219–22. [9] Orcesi S, Gorni K, Termine C, et al. Bilateral putaminal necrosis associated with the mitochondrial DNA A8344G myoclonus epilepsy with ragged red fibers (MERRF) mutation: an infantile case. J Child Neurol 2006;21:79–82. [10] Hammans SR, Sweeney MG, Brockington M, et al. The mitochondrial DNA transfer RNALysA ? G[8344] mutation and the syndrome of myoclonic epilepsy with ragged red fibres [MERRF]: Relationship of clinical phenotype to proportion of mutant mitochondrial DNA. Brain 1993;116: 617–32. [11] Rahman S, Blok RB, Dahl HH, et al. Leigh syndrome: clinical features and biochemical and DNA abnormalities. Ann Neurol 1996;39:343–51.
