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