LASOP Resident/Fellow
Symposium 2013
Saloni Walia, MD
LAC+USC Medical Center
History
• 9 mo old with shock and shallow fast
breathing
• Born at 35 weeks due to oligohydramnios
• G6P6A0
• Normal growth and development till 5-6
months
• Decreased activity and crying
Milestones
• Unable to sit
• Unable to roll from side to side
• No eye contact or tracking
• No vocalizations
Physical Examination
• Hypotonia and hyper-reflexia
• Disconjugate gaze with poor response
to visual stimuli
• Kussmaul respirations
• Tachycardia and delayed capillary refill
Labs
• pH: 7.48 (7.35-7.45)
• paCO2: 15 mmHg (35-45)
• HCO3-: 10 mEq/L (22-26)
• Lactate: 6.5 mmol/L (0.5-2.2)
CT Head
Increased CSF spaces
Autopsy Findings
• Organomegaly:
– Heart: 50 grams (37 grams)
– Lungs: right: 88 grams; left: 75
grams (right – 53 grams; left – 47
grams)
– Liver: 297 grams (260 grams)
Midbrain
H&E
CD34
H&E
GFAP
Midbrain
Midbrain
Putamen – 10x
http://www.stonybrookmedicalcenter.org/sbumcfiles/images/220-001.jpg
Thalamus, Mammillary body
Muscle Biopsy
• No identifiable histochemical
abnormality.
• Most muscle fibers are 10 – 15 um
diameter, infrequently up to 20 um
Summary
• Three affected in one generation
• Lactic acidosis – anaerobic respiration
• Brain affected
Cultured Fibroblast Assay
Pt
Pt
Diagnosis?
LEIGH SYNDROME
Subacute necrotizing encephalomyelopathy
Criteria for Leigh Syndrome
• Progressive neurological disease with motor and
intellectual delay
• Signs and symptoms of brainstem and/or basal
ganglia disease
• Raised lactate levels in blood and/or CSF
• And one or more of the following
– Characteristic features of Leigh syndrome on
neuroimaging
– Typical neuropathological changes at
postmortem, or
– Typical neuropathology in a similarly affected
sibling
Rahman S, Blok RB, Dahl HH, Danks DM, Kirby DM, et al. Leigh syndrome: clinical features and biochemical and DNA
abnormalities. Ann Neurol. 1996 Mar;39(3):343-51.
Dennis Leigh, 1951
Vascular proliferation in
the anterior nucleus of
the thalamus. Perdrau's
silver stain x 90.
Leigh D. Subacute necrotizing encephalomyelopathy in an infant. J Neurol Neurosurg Psychiatry. 1951 Aug;14(3):216-21.
Leigh Syndrome
• Most common disorder of the
respiratory chain in infancy and
childhood
• Frequency of 1:40,000 live births
• Variants
– Late adult – onset
– French – Canadian variant
– Faroe Islands variant
•Munaro M, Tiranti V, Sandonà D, Lamantea E, Uziel G, Bisson R, Zeviani M. A single cell complementation class is
common to several cases of cytochrome c oxidase-defective Leigh's syndrome. Hum Mol Genet. 1997 Feb;6(2):221-8.
•Finsterer J. Leigh and Leigh-like syndrome in children and adults. Pediatr Neurol. 2008 Oct;39(4):223-35.
Leigh Syndrome
• Neurological manifestations
• Non neurological manifestations
• Laboratory findings
• Radiological features
McKelvie P, Infeld B, Marotta R, Chin J, Thorburn D, Collins S. Late-adult onset Leigh syndrome. J Clin
Neurosci. 2012 Feb;19(2):195-202.
McKelvie P, Infeld B, Marotta R, Chin J, Thorburn D, Collins S. Late-adult onset Leigh syndrome. J Clin
Neurosci. 2012 Feb;19(2):195-202.
Total COX deficit
Lipid increase in muscle fibres
Reference positive COX reaction
Variability of muscle fibre diameter
Pronicki M, Matyja E, Piekutowska-Abramczuk D, Szymanska-Debinska T, Karkucinska-Wieckowska A, et al. Light and
electron microscopy characteristics of the muscle of patients with SURF1 gene mutations associated with Leigh disease. J
Clin Pathol. 2008 Apr;61(4):460-6.
Moslemi AR, Darin N. Molecular genetic and clinical aspects of mitochondrial disorders in childhood.
Mitochondrion. 2007 Jul;7(4):241-52.
Genetic Origin & Functional Interaction
of the OXPHOS Complexes
Figure 2 from Werner JH Koopman et al. The EMBO Journal online publication 13 November 2012
doi:10.1038/emboj.2012.300
© 2012 European Molecular Biology Organization.
Other Mutations
• Mutations in proteins involved in
mitochondrial translation
• Mutations in proteins involved in
mtDNA maintenance : SURF1
• Coenzyme-Q Deficiency
• Pyruvate Dehydrogenase Complex
Deficiency
Moslemi AR, Darin N. Molecular genetic and clinical aspects of mitochondrial disorders in childhood. Mitochondrion. 2007 Jul;7(4):241-52.
Management
• High doses of thiamine, coenzyme-Q,
or L-carnitine
Piao YS, Tang GC, Yang H, Lu DH. Clinico-neuropathological study of a Chinese case of familial
adult Leigh syndrome. Neuropathology 2006;26:218-21.
Differential Diagnosis
• Wernicke’s encephalopathy
• Methyl alcohol poisoning
• Other mitochondrial disorders
• Infarct
References
•
•
•
•
•
Leigh D. Subacute necrotizing encephalomyelopathy in an infant. J
Neurol Neurosurg Psychiatry. 1951 Aug;14(3):216-21.
Munaro M, Tiranti V, Sandonà D, Lamantea E, Uziel G, Bisson R,
Zeviani M. A single cell complementation class is common to several
cases of cytochrome c oxidase-defective Leigh's syndrome. Hum Mol
Genet. 1997 Feb;6(2):221-8.
Finsterer J. Leigh and Leigh-like syndrome in children and adults.
Pediatr Neurol. 2008 Oct;39(4):223-35.
Rahman S, Blok RB, Dahl HH, Danks DM, Kirby DM, et al. Leigh
syndrome: clinical features and biochemical and DNA abnormalities.
Ann Neurol. 1996 Mar;39(3):343-51.
McKelvie P, Infeld B, Marotta R, Chin J, Thorburn D, Collins S. Lateadult onset Leigh syndrome. J Clin Neurosci. 2012 Feb;19(2):195-202.
References, cont.
•
•
•
•
•
Pronicki M, Matyja E, Piekutowska-Abramczuk D, SzymanskaDebinska T, Karkucinska-Wieckowska A, et al. Light and electron
microscopy characteristics of the muscle of patients with SURF1 gene
mutations associated with Leigh disease. J Clin Pathol. 2008
Apr;61(4):460-6.
Moslemi AR, Darin N. Molecular genetic and clinical aspects of
mitochondrial disorders in childhood. Mitochondrion. 2007
Jul;7(4):241-52.
Koopman WJ, Distelmaier F, Smeitink JA, Willems PH. OXPHOS
mutations and neurodegeneration. EMBO J. 2013 Jan 9;32(1):9-29.
Moslemi AR, Darin N. Molecular genetic and clinical aspects of
mitochondrial disorders in childhood. Mitochondrion. 2007
Jul;7(4):241-52.
Piao YS, Tang GC, Yang H, Lu DH. Clinico-neuropathological study of a
Chinese case of familial adult Leigh syndrome. Neuropathology
2006;26:218-21.
Acknowledgements
• Anna D. Mathew, MD
• Shoji Yano, MD, PhD
• Carol Ann Miller, MD