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
GFAP
CD34
Midbrain
H&E
H&E
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
Leigh D. Subacute necrotizing encephalomyelopathy in an infant. J Neurol Neurosurg Psychiatry. 1951 Aug;14(3):216-21.
Vascular proliferation in
the anterior nucleus of
the thalamus. Perdrau's
silver stain x 90.
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.
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.
Total COX deficit Reference positive COX reaction
Lipid increase in muscle fibres Variability of muscle fibre diameter
Moslemi AR, Darin N. Molecular genetic and clinical aspects of mitochondrial disorders in childhood.
Mitochondrion. 2007 Jul;7(4):241-52.
Figure 2 from Werner JH Koopman et al. The EMBO Journal online publication 13 November 2012 doi:10.1038/emboj.2012.300
Genetic Origin & Functional Interaction
of the OXPHOS Complexes
© 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. Late-
adult onset Leigh syndrome. J Clin Neurosci. 2012 Feb;19(2):195-202.
References, cont.
• 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.
• 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