Leigh syndrome
Updates to Article Attributes
Leigh diseasesyndrome, also known as subacute necrotisingnecrotizing encephalomyelopathy (SNEM), is a mitochondrial disorder with progressive neurodegenerative disorder andneurodegeneration that invariably leads to death, usually in childhood.
Epidemiology
Leigh syndrome is encountered in approximately 1 in 40,000 births, although some populations have much higher incidence (e.g. in Quebec, Canada) 9. There is no known gender or racial predilection 9.
Clinical presentation
Typically, symptoms become evident before the age of 2, with the presentation in later childhood (juvenile form) or adulthood (adult form) being uncommon. Symptoms include 6,9:
- psychomotor delay/regression
- superimposed signs of basal ganglia and brainstem dysfunction
- ataxia
- ophthalmoplegia
- dystonia
- respiratory rhythm disturbance
- cranial nerve palsies
Pathology
Leigh disease is one of many mitochondrial disorders, due to a broad range of genetic mutations in both nuclear DNA (nDNA) and mitochondrial DNA (mtDNA)8,9. As such it is
Nuclear DNA mutations are more common (~75%) and are inherited in a Mendelian fashion with both autosomal recessive and X-linked inheritance encountered 9.
Cases due to mitochondrial DNA are less common (25%) are therefore only inherited from the mother, as is the case with other mitochondrial disordersmothe 9. Some
Some mutations (e.g. SURF 1) are particularly devastating 1.
Chronic energy deprivation leads to histological features such as 3:
- spongiform degeneration
- capillary proliferation
- demyelination
- neuronal loss
- gliosis
These findings are similar to those seen in infarction 4.
Genetics
The inheritance pattern may be either autosomal recessive or X-linked.
Markers
CSF lactate may be elevated.
Radiographic features
CT
CT demonstrates regions of low-density matching areas of the abnormal T2 signal on MRI (see below) 5. Occasionally some of these areas can show contrast enhancement 5.
MRI
TheMRI abnormalities are heterogeneous and differ depending on the underlying genetic abnormality 8. Generally, the distribution tends to be symmetrical.
-
T2: characterised by high signal typically in 3:
- brainstem
- periaqueductal
graygrey matter - medulla
- midbrain
- putamen: characteristic but not always present 6
- other sites of T2 signal change include:
- the remainder of the corpus striatum [globus pallidus and caudate nucleus (heads)]
- subthalamic nuclei
- substantia nigra
- thalami
- involvement of cerebral or cerebellar white matter is unusual 3
- T1: usually demonstrates reduced signal in T2 abnormal areas, although some areas of hyperintensity can be seen, as can some enhancement
- DWI: in the acute setting some restricted diffusion may be evident
-
MR spectroscopy
- elevated choline
- occasionally elevated lactate
- reduced NAA
Treatment and prognosis
Prognosis is poor, with death usually occurring in childhood. The later the onset, the slower the deterioration. Death is most frequently due to respiratory failure 6.
History and etymology
It is named after Archibald Denis Leigh,British neuropathologist, who first described the condition in 1951 2,9.
Differential diagnosis
-
Wernicke encephalopathy (WE)
- similar appearance but different demographics
- mammillary bodies not involved in Leigh disease
- enhancement more common in WE
- haemorrhagic change more common in WE 4
- other mitochondrial disorders
- brainstem and basal ganglia involvement less pronounced
-
acute necrotising encephalitis of childhood
- lactate levels are usually normal
-<p><strong>Leigh disease</strong>, also known as <strong>subacute necrotising encephalomyelopathy </strong>(<strong>SNEM)</strong>, is a progressive neurodegenerative disorder and invariably leads to death in childhood.</p><h4>Clinical presentation</h4><p>Typically, symptoms become evident before the age of 2, with the presentation in later childhood (juvenile form) or adulthood (adult form) being uncommon. Symptoms include <sup>6</sup>:</p><ul>- +<p><strong>Leigh syndrome</strong>, also known as <strong>subacute necrotizing encephalomyelopathy </strong>(<strong>SNEM)</strong>, is a <a title="Mitochondrial disorder" href="/articles/mitochondrial-disorders">mitochondrial disorder</a> with progressive neurodegeneration that invariably leads to death, usually in childhood.</p><h4>Epidemiology</h4><p>Leigh syndrome is encountered in approximately 1 in 40,000 births, although some populations have much higher incidence (e.g. in Quebec, Canada) <sup>9</sup>. There is no known gender or racial predilection <sup>9</sup>. </p><h4>Clinical presentation</h4><p>Typically, symptoms become evident before the age of 2, with the presentation in later childhood (juvenile form) or adulthood (adult form) being uncommon. Symptoms include <sup>6,9</sup>:</p><ul>
-<li>superimposed signs of <a href="/articles/basal-ganglia">basal ganglia</a> and <a title="Brainstem" href="/articles/brainstem">brainstem</a> dysfunction<ul>- +<li>superimposed signs of <a href="/articles/basal-ganglia">basal ganglia</a> and <a href="/articles/brainstem">brainstem</a> dysfunction<ul>
-</ul><h4>Pathology</h4><p>Leigh disease is one of many <a href="/articles/mitochondrial-disorders">mitochondrial disorders</a>, due to a broad range of genetic mutations in mitochondrial DNA (mtDNA). As such it is only inherited from the mother, as is the case with other mitochondrial disorders. Some mutations (e.g. SURF 1) are particularly devastating <sup>1</sup>. </p><p>Chronic energy deprivation leads to histological features such as <sup>3</sup>:</p><ul>- +</ul><h4>Pathology</h4><p>Leigh disease is one of many <a href="/articles/mitochondrial-disorders">mitochondrial disorders</a>, due to a broad range of genetic mutations in both nuclear DNA (nDNA) and mitochondrial DNA (mtDNA) <sup>8,9</sup>.</p><p>Nuclear DNA mutations are more common (~75%) and are inherited in a Mendelian fashion with both autosomal recessive and X-linked inheritance encountered <sup>9</sup>. </p><p>Cases due to mitochondrial DNA are less common (25%) are therefore only inherited from the mothe <sup>9</sup>. </p><p>Some mutations (e.g. SURF 1) are particularly devastating <sup>1</sup>. </p><p>Chronic energy deprivation leads to histological features such as <sup>3</sup>:</p><ul>
-</ul><p>These findings are similar to those seen in infarction <sup>4</sup>.</p><h5>Genetics</h5><p>The inheritance pattern may be either autosomal recessive or X-linked.</p><h5>Markers</h5><p>CSF lactate may be elevated.</p><h4>Radiographic features</h4><h5>CT</h5><p>CT demonstrates regions of low-density matching areas of the abnormal T2 signal on MRI (see below) <sup>5</sup>. Occasionally some of these areas can show contrast enhancement <sup>5</sup>.</p><h5>MRI</h5><p>The distribution tends to be symmetrical. </p><ul><li>- +</ul><p>These findings are similar to those seen in infarction <sup>4</sup>.</p><h5>Genetics</h5><p>The inheritance pattern may be either autosomal recessive or X-linked.</p><h5>Markers</h5><p>CSF lactate may be elevated.</p><h4>Radiographic features</h4><h5>CT</h5><p>CT demonstrates regions of low-density matching areas of the abnormal T2 signal on MRI (see below) <sup>5</sup>. Occasionally some of these areas can show contrast enhancement <sup>5</sup>.</p><h5>MRI</h5><p>MRI abnormalities are heterogeneous and differ depending on the underlying genetic abnormality <sup>8</sup>. Generally, the distribution tends to be symmetrical. </p><ul><li>
-<li>periaqueductal gray matter</li>- +<li>periaqueductal grey matter</li>
-</ul><h4>Treatment and prognosis</h4><p>Prognosis is poor, with death usually occurring in childhood. The later the onset, the slower the deterioration. Death is most frequently due to respiratory failure <sup>6</sup>.</p><h4>History and etymology</h4><p>It is named after <strong>Archibald Denis</strong> <strong>Leigh</strong>,<strong> </strong>British neuropathologist, who first described the condition in 1951 <sup>2</sup>.</p><h4>Differential diagnosis</h4><ul>- +</ul><h4>Treatment and prognosis</h4><p>Prognosis is poor, with death usually occurring in childhood. The later the onset, the slower the deterioration. Death is most frequently due to respiratory failure <sup>6</sup>.</p><h4>History and etymology</h4><p>It is named after <strong>Archibald Denis</strong> <strong>Leigh</strong>,<strong> </strong>British neuropathologist, who first described the condition in 1951 <sup>2,9</sup>.</p><h4>Differential diagnosis</h4><ul>
References changed:
- 8. Saneto RP, Friedman SD, Shaw DW. Neuroimaging of mitochondrial disease. Mitochondrion. 8 (5-6): 396-413. <a href="https://doi.org/10.1016/j.mito.2008.05.003">doi:10.1016/j.mito.2008.05.003</a> - <a href="https://www.ncbi.nlm.nih.gov/pubmed/18590986">Pubmed</a> <span class="ref_v4"></span>
- 9. Ruhoy IS, Saneto RP. The genetics of Leigh syndrome and its implications for clinical practice and risk management. The application of clinical genetics. 7: 221-34. <a href="https://doi.org/10.2147/TACG.S46176">doi:10.2147/TACG.S46176</a> - <a href="https://www.ncbi.nlm.nih.gov/pubmed/25419155">Pubmed</a> <span class="ref_v4"></span>