Leigh syndrome: MRI findings in two children
1 Department of Diagnostic Imaging, Kuala Lumpur Hospital, Kuala Lumpur, Malaysia
2 Department of Genetics, Kuala Lumpur Hospital, Kuala Lumpur, Malaysia
Leigh syndrome is a progressive neurodegenerative disorder
of childhood. The symmetrical necrotic lesions in the basal ganglia and/or
brainstem which appear as hyperintense lesions on T2-weighted MRI is
characteristic and one of the essential diagnostic criteria. Recognising this
MR imaging pattern in a child with neurological problems should prompt the
clinician to investigate for Leigh syndrome. We present here two cases of Leigh
syndrome due to different biochemical/genetic defects, and discuss the subtle
differences in their MR neuroimaging features. � 2010 Biomedical Imaging
and Intervention Journal. All rights reserved.
Keywords: Leigh syndrome, MRI, SURF1, mitochondrial
Leigh syndrome (also termed subacute, necrotising
encephalopathy) is a progressive neurodegenerative disorder of childhood with
an estimated incidence of 1:40,000 births . Clinically, Leigh syndrome is
characterised by psychomotor delay or regression, muscular hypotonia, brainstem
signs (especially strabismus, nystagmus and swallowing difficulties), ataxia,
pyramidal signs, respiratory insufficiency, lactate acidemia and acute
deterioration after common infections. In most cases, dysfunction of the
respiratory chain enzymes is responsible for the disease, which could be due to
defects in either mitochondrial or nuclear DNA. Despite its considerable
clinical, genetic and biochemistry heterogeneity, the basic neuropathological
features in children affected by Leigh syndrome are almost identical; which are
focal, bilateral, and symmetric necrotic lesions associated with demyelination,
vascular proliferation and gliosis in the brainstem, diencephalon, basal
ganglia, and cerebellum . MR imaging can demonstrate these brain pathologies
and therefore plays an essential role in the diagnosis of Leigh syndrome [3-5].
This boy, the first child of nonconsanguineous parents,
had an uneventful perinatal history and normal development until 21 months when
he presented with regression. He slowly lost the ability to walk and eventually
could no longer walk at 3 years old. At 3 � years old, he presented with intractable
vomiting and breathing difficulties which required mechanical ventilation. He
had persistent metabolic acidosis with markedly raised blood lactate. His
clinical findings included truncal ataxia, nystagmus, muscular hypotonia,
increased deep tendon reflexes and bilateral Babinski sign. MRI of the brain
showed foci of discrete, bilaterally symmetric lesions in the basal ganglia,
brain stem and dentate nuclei (Figure 1). Respiratory chain enzymes study in
cultured fibroblasts showed severe reduction in Complex IV activity (Table 1).
Genetic study found two mutations in SURF1 gene (a heterozygous splice site
mutation c.751+1A>G and a heterozygous deletion c.756_757delCA). He was
treated with coenzyme Q10 and vitamins without much success. He
continued to deteriorate and died of respiratory failure at 4 � years old
during an episode of chest infection. No autopsy was performed.
This boy, the 3rd child of nonconsanguineous
parents, presented with developmental delay. At 18 months he had yet to be able
to walk independently and had no meaningful verbal expressions. Following a
febrile illness at 19 months old, he showed regression. There was nystagmus,
left eye divergent squint, mild muscular hypotonia and increased deep tendon
reflexes on clinical examination. MRI of the brain showed bilaterally symmetric
lesions in the basal ganglia and brain stem (Figure 2). The blood lactate was
persistently elevated. Respiratory chain enzymes study in cultured fibroblasts
showed severe reduction in Complex I activity (Table 1). Mitochondrial DNA
analysis did not find any pathogenic mutation. The underlying genetic defect
remained to be elucidated. When he was last reviewed at 2� years, his condition
was stable and he was able to walk with broad-based gait.
Leigh syndrome is the most common clinical phenotype of
mitochondrial disorders in childhood. The diagnostic criteria are (1)
progressive neurological disease with motor and intellectual developmental
delay; (2) signs and symptoms of brainstem and/or basal ganglia disease; (3)
raised lactate levels in blood and/or cerebrospinal fluid (CSF); and (4)
characteristic symmetric necrotic lesions in the basal ganglia and/or brainstem
The most characteristic neuroradiological findings in
Leigh syndrome are bilateral, symmetric focal hyperintensities in the basal
ganglia, thalamus, substantia nigra, and brainstem nuclei at various levels on
T2-weighted MRI. These high T2 signals on MRI reflect the spongiform changes
and vacuolation in the affected brain structures [3-5]. Often, the basal
ganglia are affected before the brainstem. The upper brainstem followed by
lower brainstem would be affected with the progression of the disease.
Involvement of lower brainstem indicates advanced stage of the disease and the
occurrence of respiratory failure and sudden death. In most patients the
cerebral white matter is generally only involved in late stages of the disease.
Occasionally, patients may have atypical neuroimaging features such as diffuse
supratentorial leukodystrophy, unifocal or multifocal infarctions, diffuse or
focal cortical atrophy, or predominant cerebellar atrophy [2,6].
Considering that Leigh syndrome is the consequence of a
number of different biochemical and genetic defects that affect many aspects of
mitochondrial function, we could expect to find some variability of the MR
imaging findings among these patients. In Case 1, the underlying biochemical
abnormality was due to a severely decreased Complex IV enzyme activity with the
residual enzyme activity only 14% of the lower normal limit. This was due to
loss-of-function mutations of SURF1, which is a nuclear gene that
encodes a protein with putative that is probably involved in Complex IV
assembly or stabilisation . In Case 2, the Leigh syndrome was caused by an
isolated Complex I deficiency due to a yet to be elucidated genetic defect,
most probably a nuclear gene defect. In both cases, there were symmetrical
brain lesions involving the brainstem. Case 1 had additional lesions in the
basal ganglia, subthalamic nuclei and cerebellum. Our observation on Case 1 is
in harmony with a few recent studies that have suggested that symmetric T2
prolongation involving the subthalamic nuclei corresponds with Complex IV
deficiency caused by SURF1 mutation [3-5]. It was interesting to note that Case
2 had brainstem involvement prior to basal ganglia.
Our experience suggested that bilateral symmetric T2
prolongation involving multiple brainstem nuclei/structures associated with
basal ganglia abnormalities in a child with neurological problems should prompt
the clinician to consider Leigh syndrome and conduct further investigations
such as measurement of blood and/or CSF lactate, and respiratory chain enzymes
activities. Neuroradiological discriminative observation is very useful in
guiding the clinicians for the most appropriate enzymatic and genetic study in
Figure 1 (A): Axial T2-weighted image through the basal ganglia shows symmetrical hyperintense lesions involved thalamic posteromedial ventral nuclei (thin arrow), globus pallidi (thick arrow) and putamina (arrowhead). (B-D): Axial T2-weighted images through the brainstem show symmetrical involvement of reticular formation of midbrain (thin arrow in B), subthalamic nuclei (thick arrow in B), substantia nigra (thick arrow in C), dorsal midbrain (thin arrow in C) central tegmental tracts (thin arrow in D) and cerebellar nuclei region (thick arrow in D). (E-F): Coronal FLAIR images show symmetrical involvement of head of caudate nuclei (thick arrow in E), putamina (thin arrow in E) and dentate nuclei (thin arrow in F).
Figure 2 (A-C): Axial T2-weighted images through the brainstem show symmetrical hyperintense lesions involving central tegmental tracts (thin arrow in A), substantia nigra (thin arrow in B and C). (D): Axial T2-weighted image through basal ganglia shows putamen, globus pallidus and thalamus were not involved.
Table 1 Clinical, biochemical and MR imaging findings
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|Received 15 May 2009; received in revised form 22 July 2009,
accepted 27 September 2009
Correspondence: Clinical/Metabolic Geneticist, Kuala Lumpur Hospital, Jalan Pahang, 50586 Kuala Lumpur, Malaysia. Tel.: +603-26155555 (ext. 6926); Fax: +603-26948187; E-mail: email@example.com (Lock-Hock Ngu).
Please cite as: Kartikasalwah AL, Ngu LH,
Leigh syndrome: MRI findings in two children, Biomed Imaging Interv J 2010; 6(1):e6