Discussion
Leigh syndrome is a rare progressive neurological disorder typically in
childhood that can be inherited as X-linked recessive, autosomal
recessive and mitochondrial trait. The incidence of this syndrome is
estimated approximately 2 in 100,000 births. Leigh syndrome may present
early in life with multiple characteristics such as weakness,
drowsiness, dystonia, psychomotor regression, cerebral hypotonia,
ataxia, developmental milestones delay, and signs of brainstem
involvement, seizures, visual loss and tachypnea. Some studies reported
the occurrence of sleep apnea syndrome and abdominal symptoms in these
patients (7). However, the exact mechanism
is unknown. Progressive respiratory failure is one of the main leading
causes of mortality among LS cases (8).
Elevated blood and CSF lactate, as well as pyruvate levels can be found
upon laboratory tests analysis. However, neuroimaging is a valuable tool
for the diagnosis of Leigh syndrome (9).
The present case was referred to Rasool Akram Hospital with the chief
complaint of progressive gaze palsy and also ataxia, intention tremor
and drowsiness. Her ocular examination revealed retinal atrophy and pale
disk. In a recent study, Jabeen et al .,
(10) reported a 37-year-old female with
Leigh syndrome who admitted with similar ocular symptoms including
bilateral horizontal gaze palsy and ataxic gait. The ocular involvement
is frequently reported in patients with Leigh syndrome. Many patients
with Leigh syndrome may suffer from ophthalmoplegia, a condition which
is associated with weakness or paralysis of the muscles responsible for
eyes movement (11). Some studies have
reported nystagmus, optic atrophy, ptosis, strabismus, and pigmentary
retinopathy in patients with Leigh syndrome
(11, 12).
Our case had also a past medical history of delayed development and
seizure. Abnormal cerebellar test results were detected including
abnormal tandem gait, intention tremor and ataxic gait. Most of the
reported LS patients like the present case excluded infections,
autoimmune diseases and toxins as the causes of presented symptoms (12).
The second brain MRI reported dorsal midbrain, cerebellar dentate
nucleus and bilateral putamen nuclei involvement. These symptoms pointed
towards a neurodegenerative disorder. A basic metabolic panel test
result showed normal serum ammonia, pyruvate, and amino acids contents
and normal blood and CSF lactate. Magnetic resonance spectroscopy
revealed an elevated lactate peak in involved areas which suggested a
possible mitochondrial disease. Eventually, the molecular genetic test
analysis using Whole exome sequencing
technique revealed a novel
variant, c.474-478dup p. (Tyr160Cysfs*31), in NDUFS4 gene. This
mutation leads to a shift in the reading frame starting at codon 160 and
could be responsible for the symptoms of Leigh syndrome. The new frame
reading ends in a stop codon 30 downstream. Therefore, genetic test
result confirmed the diagnosis of Leigh syndrome. Due to financial
problems, the patient’s parents did not allow to performing sanger
sequencing technique of themselves. She initially responded
significantly to mitochondrial treatment cocktail and significant
improvement was observed in clinical symptoms. The complete improvement
was observed in eye movements and gaze palsy; however, a mild intention
tremor and ataxia were detected during the examination time.
Unfortunately, ataxia and dysarthria gradually progressed despite use of
mitochondrial cocktail and she lost the ability to walk after one year.
Several studies showed similar initially responses to mitochondrial
treatment cocktail (including Vitamin B2, Vitamin B6, folic acid,
L-carnitine and coenzyme Q) in different cases
(10). Goldenberg et al .,
(7) reported a 22-year-old woman with
Leigh syndrome who had partial deficiency in cytochrome C oxidase. They
observed excellent response to mitochondrial treatment cocktail.
Molecular genetic studies illustrated that Leigh syndrome can be
resulted from defects or mutations in mitochondrial enzymes such as
pyruvate dehydrogenase (PDHA1 gene mutations)
(13), pyruvate carboxylase (SURF1gene mutations in nuclear genome), ATP synthase subunit-6, cytochrome C
oxidase, and subunits of complex-I (14).
Recent evidences identified 24 known mutations in mitochondrial genes
and 21 in nuclear genes in Leigh syndrome
(15). Here, we found NDUFS4 gene
mutation which was associated with Leigh syndrome. This gene is a
nuclear-encoded accessory subunit of mitochondrial complex I (NADH:
ubiquinone oxidoreductase). This complex removes electrons from NADH and
transfers them to the electron acceptor ubiquinone. Therefore, mutations
in NDUFS4 gene can cause mitochondrial respiratory chain
deficiencies. In another study, Leshinsky-Silver et al . (16)
reported a case with Leigh syndrome due to NDUFS4 mutation. The
patient developed predominant brainstem involvement. More recently,
Ortigoza-Escobar et al ., (17)
reported a patient with NDUFS4 gene mutation related to Leigh
syndrome.
These data has suggested that various symptoms and clinical features
could be found in Leigh syndrome. Variations in the disease severity and
the number of clinical features are probably due to different mutations
in mitochondrial genes. Therefore, further studies are necessary to
evaluate the relationship between genotype and phenotype. Our patient
was born from parents with consanguineous marriage; however, no evidence
of similar conditions was reported in his family. Since consanguineous
marriage is common in Iran, there may be a relationship between the
incidence of Leigh syndrome and consanguineous marriage. Therefore,
further considerations are required to evaluate the correlation.
Therefore, premarital genetic counseling and education may be helpful.
Leigh syndrome is a rare mitochondrial disease which is associated with
progressive neurological disorders. Our case presented with progressive
bilateral gaze palsy, ataxia, retinal atrophy, pale disk, unsteady gait,
intention tremor, and drowsiness. The brain MRI showed dorsal midbrain
and cerebellar dentate nucleus involvement. These symptoms pointed
towards a neurodegenerative disorder. MRS illustrated an elevated
lactate peak in involved area despite normal blood and CSF lactate which
indicated a mitochondrial disease. The genetic test analysis revealedNDUFS4 gene mutation which confirmed the diagnosis of Leigh
syndrome.