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.