Leigh syndrome

Leigh syndrome, also known as subacute necrotising encephalomyelopathy (SNEM), is a mitochondrial disorder with progressive neurodegeneration 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.

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%) and only inherited from the mother ⁹. 

Some mutations (e.g. SURF1) 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

MRI 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 grey 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.

The factors associated with a worse outcome are ¹⁰:

• disease onset before 6 months of age
• admission to an intensive care
• brainstem lesions
• MRS lactate peak

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
• Biotin-thiamine-responsive basal ganglia disease