Case presentation
An 8-year-old girl was admitted to Rasool Akram hospital with bilateral
horizontal gaze palsy, ataxia and drowsiness. The gaze palsy was
initiated in the right eye during the last year and then gradually
affected the left eye during the previous month. She developed unsteady
gait, drowsiness, progressive ataxia, intention tremor and seizure
during the admission time. The past medical history of the patient
revealed that she was the first child of the family, from a
consanguineous marriage. She had also developmental milestone delay. She
had the history of seizure around 4 years ago, without current
medication therapy. The genetic background of the patient’s family tree
is shown in figure 1. According to the pedigree, the case of 4-1 is the
first child of the family to be the result of kinship marriage. Her
grandmother (case 2-1) died of a brain tumor. In the case of 4-4, the
hand is paralyzed, which is found to be non-congenital and due to lack
of oxygen.
The vital signs were stable during her admission time. She was confused;
however, she responded to verbal stimulations. Horizontal gaze palsy was
detected in both eyes under ocular examinations, without any vertical
gaze palsy. Nystagmus was not observed during the examination .The
normal light reflection was detected in her pupils. Ocular examination
revealed retinal atrophy and pale disk in both sides. Cranial nerve
examination was normal. Deep tendon reflexes (DTR) were Brisk.
Cerebellar examination revealed positive tandem gait, intention tremor,
ataxic and wide based gait. The results of finger-to-nose and heel to
shin tests were detected normal. The biochemical test results, complete
blood count (CBC) and electrolytes were reported within the normal
ranges. Dorsal midbrain involvements were reported in brain Magnetic
resonance imaging (MRI) (Figure 2), which was provided one month ago out
of our center. Total abdominal and pelvic ultrasounds were performed in
order to rule out the possibility of organomegaly and malignancy.
Electroencephalography (EEG) was performed showing slowing background
activity prominent in posterior area without epileptiform discharges.
On the 5th day of admission, the patient presented a
generalized tonic-clonic (GTC) seizure lasted for one minute.
Cerebrospinal fluid (CSF) was analyzed for cells, biochemical tests,
lactated dehydrogenase (LDH), and lactate contents that the results were
reported acceptable. Anti- Neuromyelitis optica antibody (NMO), IgG
index and oligoclonal bands (OCB) tests were performed for the
possibility of autoimmune diseases. A basic metabolic panel test was
performed for the assessment of serum ammoniac, lactate, pyruvate, and
amino acids content with high performance liquid chromatography (HPLC)
method. The possibility of specific metabolic syndromes was ruled out
with all normal metabolic results. The patient received biotin, Vitamin
B1, B12 and Vitamin E to evaluate the possibility of
Wernicke-Korsakoff syndrome. However, no change in signs and symptoms
was observed following these treatments. Serum immunoglobulins were
evaluated in order to rule out the possibility of ataxia telangiectasia
and other immune deficiencies. The laboratory test results including
ANA; Anti-ds-DNA; serum complements (C3, C4, C5), SSA-Ro, SSA-LA; RPR;
AFP; Anti-GM Ab (IgM and IgA); β2 glycoproteins; Anti-phospholipids;
Anti- cardiolipin (IgM and IgG); HLA (B5 and B51); and serum ACE were
within normal values. Therefore, the possibility of neuro-Behcet
disease, lupus erythematous, neuro-brucellosis, and neuro-sarcoidosis
was declined by detecting laboratory results. The infectious diseases
biomarkers were performed to rule out the possibility of infectious
diseases including HIV Ab, VDRL, Anti-toxoplasma Ab (IgM and IgG),
wright and 2ME. Wilson’s disease was evaluated by 24-hour urine copper
test. Serum levels of vitamin B12 and folic acid were
normal. Listeria infection was a recommended diagnosis due to midbrain
involvement. So, Ampicillin and Gentamycin was then started empirically.
On the 10th day of admission, the second brain MRI was
performed with and without contrast for the second time (Figure 3).
Abnormal high signal flair and T2 lesions were detected in medulla,
Midbrain,
bilateral
putamen nuclei and cerebellar dentate nucleus. Corticosteroid pulse
therapy was started to resolve involved areas, increased signal in
midbrain, progressive ophthalmoplegia and consequently the possibility
of inflammatory lesions.
On the 15th day of admission, Magnetic Resonance
Spectroscopy (MRS) demonstrated an elevated lactate peak in involved
areas which could indicate the possibility of mitochondrial disease
(Figure 4). Mitochondrial treatment cocktail (including Vitamin B2,
Vitamin B6, folic acid, L-carnitine and coenzyme Q) was prescribed for
the patient. Gaze palsy of the eyes, ataxia, tremor and ophthalmoplegia
were improved relatively. The patient was discharged with mitochondrial
treatment cocktail and oral prednisolone (1mg/kg/day). The patient was
examined again two weeks after discharge.
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 (including Vitamin B2, Vitamin B6, folic acid,
L-carnitine and coenzyme Q), and she lost the ability to walk after one
year. Whole exome sequencing was done to evaluate any genetic disorder.
In this work 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. Finally, the molecular genetic test
result showed mutation in NDUFS4 gene, confirming the diagnosis
of Leigh syndrome. Due to financial problems, the patient’s parents did
not allow to performing sanger sequencing technique
of themselves.