Leigh Syndrome due to MT-ATP6 Variants: A Case Presentation and the Review of the Literature Free

Leigh syndrome is a subacute necrotizing mitochondrial encephalomyelopathy characterized by demyelination, gliosis, necrosis, and capillary proliferation in the brain, brain stem, and spinal cord as a result of defects in mitochondrial respiratory enzyme chain or deficiency in pyruvate dehydrogenase (PDH) complex [1]. Although the most common form is the infantile type, symptoms may also manifest during childhood or adulthood [2].

Genetic transmission shows heterogeneity according to underlying biochemical defects. Mitochondrial diseases are caused by either mutations in mitochondrial DNA (mtDNA) or nuclear DNA. While maternal inheritance governs mtDNA mutations, the high mutation rate and heteroplasmy dynamics contribute to phenotypic heterogeneity [3]. Mutations affecting oxidative phosphorylation result in a decrease in the amount of ATP, leading to multisystemic signs and symptoms. Common clinical findings are increased lactate-related lethargy and metabolic acidosis, failure to thrive, hypotonia, intermittent ataxia, abnormal eye movements, and seizures in the early infantile period. Clinical findings may vary depending on the underlying genetic variation [4, 5]. Although lactic acidosis and high lactate levels in the cerebrospinal fluid (CSF) are important clues in reaching the diagnosis, these findings may not be present in all cases. In this article, a 7-month-old girl that was initially diagnosed with septic shock and later found to have Leigh encephalomyelopathy due to underlying MT-ATP6 deficiency is presented.

A 7-month-old girl was admitted to our clinic with fever, drowsiness, and wheezing due to an upper respiratory tract infection. She was admitted to the pediatric intensive care unit with the preliminary diagnosis of septic shock. Her medical history revealed parental consanguinity (parents being first-degree cousins) and hypotonicity that was diagnosed at postnatal 6 months. Transfontanelle sonography revealed increased thalamic echogenicity.

On physical examination, she was unconscious and her Glasgow Coma Scale score was found to be 3. Her pupils were miotic. She had high fever (39.9°C). The anterior fontanelle was open and normal in shape. The oropharynx and tonsils were found to be hyperemic. She had respiratory distress and tachypnea and was therefore intubated. The capillary refill time was also prolonged (5 s).

The initial laboratory assessments unveiled marked metabolic acidosis, evident in a plasma lactate level of 5 mmol/L (normal range [NR]: 0.5–1.6), which progressively escalated during follow-up to 22 mmol/L. Modest elevations in aspartate transaminase (AST) and alanine aminotransferase (ALT) were noted (AST: 53 U/L, NR <82, and ALT: 21 U/L, NR <56). Additionally, there were heightened levels of creatine kinase (120 U/L, NR: 34–204) and ammonia (117 μmol/L, NR: 11–51). The patient’s heightened C-reactive protein level (22 mg/dL, NR <0.8) and leukocytosis (24,980/mm³, NR: 4,000–11,000) prompted follow-up with a preliminary diagnosis of sepsis. Subsequently, a 10 mL/kg saline infusion bolus was administered. To address the metabolic acidosis, sodium bicarbonate infusion was initiated, and empirical antibiotic therapy commenced based on the initial diagnosis of sepsis. Adrenaline infusion was initiated due to hypotension. Thrombocytopenia-associated multiple-organ failure was considered in light of elevated D-dimer levels, thrombocytopenia, and elevated creatinine. Subsequent monitoring revealed substantially elevated lactate and liver transaminases (AST: 2,518 U/L, ALT: 5,600 U/L). Milrinone was introduced to ensure adequate tissue perfusion, and intravenous administration of hydrocortisone at a dosage of 100 mg/m²/day was initiated in response to hypotensive values.

The patient was also evaluated for an underlying inborn error of metabolism due to multisystemic involvement. Elevated C3 propionyl carnitine levels were detected by tandem mass spectrometry. Plasma amino acid analysis revealed elevated alanine (870 mmol/L, NR: 139–474) and extremely low citrulline (1.6 mmol/L, NR: 10–50) levels. Slightly elevated 3-methyl adipic acid and alpha-ketoglutaric acid excretion in urine organic acid analysis was detected.

With further clarification of the clinical picture, mitochondrial cytopathies were considered in the foreground. Therefore, evaluation in terms of systemic involvement was planned. Neuroimaging studies showed both cerebral and cerebellar atrophy. There were also diffuse hyperintensities and diffusion restrictions in the post-parietal region, which became especially evident in the diffusion-weighted series and in tractus corticospinalis. The patient also had delayed myelination. Increased diffuse intensity is observed in axial T2 series at the level of bilateral basal ganglia, in the anterior leg of the capsule internala, and in the anterior part of the corpus callosum (Fig. 1a–d). Based on the clinical and laboratory findings, mitochondrial disorders were considered to be the most relevant diagnosis, and carnitine (100 mg/kg/day-peroral), thiamine (50 mg/kg/day-peroral), coenzyme Q₁₀ (5 mg/kg/day-peroral) supplementations were initiated.

Hypertrophic cardiomyopathy was detected in the patient’s follow-up echocardiograms. The alpha-glucosidase level was found to be normal at 49.70 pmol/punch/hour (NR >7.50), which ruled out Pompe disease. Dopamine and dobutamine infusion was started due to the worsening of the patient’s clinical condition. The patient died on the 22nd day of his hospitalization because of hypertrophic cardiomyopathy and multiorgan failure. Posthumous mtDNA sequencing showed a homoplasmic m.8993T>G(c.467T>G p.Leu156Arg) variant in the MT-ATP6 gene that was previously reported to be pathogenic and concretized our diagnosis.

In 1951, Denis Leigh described subacute necrotizing encephalomyelopathy as a result of an autopsy of a 7-month-old baby that showed symmetrical lesions in the thalamus, midbrain, pons, medulla, and posterior part of the spinal cord. Leigh syndrome has been postulated to be related to compromised cerebral mitochondrial energy production. The main biochemical defect is in the mitochondrial respiratory enzyme chain, especially cytochrome oxidase (cox) complexes IV and I, or deficiency in PDH enzyme complex and pyruvate carboxylase enzyme. Enzymatic deficiencies can be detected by histochemical studies using fresh muscle tissue and skin fibroblast cultures [3, 6, 7].

Although Leigh syndrome may present with different symptoms depending on residual enzyme activity, it is, however, not a singular entity; rather, it comprises distinct clinical subtypes that can exhibit variations in terms of onset, severity, and progression. These subtypes, mainly categorized as “early onset” and “late onset,” offer intriguing insights into the heterogeneity of the disease and call for a comprehensive exploration to better understand the underlying mechanisms, diagnosis, and management strategies [8, 9]. Early-onset Leigh syndrome typically manifests in infants or young children, and it shows a rapidly progressive course. This subtype is associated with severe neurological symptoms, including muscle weakness, poor motor coordination, and developmental regression. Affected individuals often experience difficulties in feeding and may encounter respiratory issues. The distinct clinical features of early-onset Leigh syndrome raise critical questions about its genetic underpinnings and pose a challenge to healthcare providers and caregivers in their quest for effective therapeutic interventions [10‒12].

On the other hand, late-onset Leigh syndrome is a less prevalent yet equally intriguing variant of the condition. Symptoms begin in childhood or even adulthood and tend to be milder compared to the early-onset form. Patients with late-onset Leigh syndrome may present with muscle weakness, ataxia (lack of muscle coordination), and cognitive decline. The decelerated disease progression observed in these instances introduces intricacy to the clinical spectrum of Leigh syndrome, necessitating a meticulous examination of the underlying genetic and biochemical determinants [13‒16].

To comprehensively elucidate the diverse spectrum of Leigh disease manifestations across distinct developmental stages, it is imperative to present the characteristics associated with prenatal, infantile, childhood, and adult-onset presentations. In the prenatal form of Leigh disease, marked by severe enzyme deficiencies, there is a predilection for congenital brain malformations. These abnormalities may include lactic acidosis, corpus callosum agenesis, cystic lesions in white matter, and involvement of the basal ganglia [17]. Moving into the infantile stage, neurological examinations often unveil a constellation of clinical features. Among these are hypotonicity, ataxia, choreoathetosis, progressive encephalopathy, and diminished deep tendon reflexes. Bilateral positive Babinski sign, tremor, spastic diplegia/quadriplegia, and microcephaly are also frequently observed. Additionally, tonic-clonic seizures, external ophthalmoplegia, ptosis, optic eye movements, and dysconjugation may manifest, contributing to the clinical complexity of this stage [18]. In the adult-onset presentation, the manifestations may evolve, potentially presenting with a more subtle clinical phenotype. It is crucial to recognize that the progression and clinical heterogeneity of Leigh disease demand vigilant consideration and a nuanced approach for accurate diagnosis. Importantly, the presented case, initially misinterpreted as septic shock during an encephalopathic stage, underscores the necessity for heightened awareness across various stages of disease presentation to expedite timely and precise diagnostic assessments [19].

Diagnosing mitochondrial diseases is a big challenge for clinicians. Unlike aminoacidopathies or organic acidemias, biochemical markers are not definitive for the diagnosis. The most important laboratory findings are high lactate and pyruvate levels in blood and CSF, hyperalaninemia in serum, urine, and CSF, and high alpha-ketoglutarate in urine and serum. Our patient had high alanine and low citrulline levels. In recent studies, low citrulline levels are seen as a predictive value for MT-ATP6 defects [20, 21]. We also think that low plasma citrulline levels may help clinicians with the diagnosis of MT-ATP6 defects. As reported in the literature, citrulline was found to be quite low in our patients. We had to rule out proximal urea cycle defects. Citrulline was low but not accompanied by hyperammonemia. Furthermore, the findings of urine organic acid analysis and urine and plasma amino acid analyses were not in favor of urea cycle defects.

Neuroimaging also supported our diagnosis. As an imaging method, MRI may show enlargement of the ventricles, cerebral atrophy, and partial or complete absence of the corpus callosum. In particular, the detection of symmetrical cystic lesions, symmetrical cortex, basal ganglia, cerebellum involvement, and generalized hypomyelination in the MRI of a patient with progressive neurological symptoms is highly significant for Leigh syndrome. In the brain MRI of our case, there were bilateral atrophy and diffuse hyperintensities. Examination of brain MRI data from 85 patients revealed abnormalities in an overwhelming 95% of cases, offering profound insights into the characteristic imaging features associated with this mitochondrial disorder [22]. Among the notable findings, basal ganglia and brain stem lesions, classic hallmarks of Leigh syndrome, were identified in 65% and 32% of patients, respectively, with a notable co-occurrence in 22% of cases. Additionally, cerebellar atrophy was evident in 16% of patients, while cortical/subcortical atrophy manifested in 13%, underlining the diverse and multifaceted nature of neuroimaging presentations in ATP6-related disease. These findings collectively emphasize the pivotal role of neuroimaging in unraveling the distinct radiological landscape of ATP6-associated Leigh syndrome. The observed variability in imaging presentations underscores the clinical heterogeneity within this genetically defined cohort, reinforcing the need for a comprehensive and nuanced approach to both diagnosis and understanding the pathological correlates of this complex mitochondrial disorder [23].

Variations in mtDNA (maternal inheritance or sporadic) and nuclear DNA (Mendelian inheritance or sporadic) may cause mitochondrial disorders [24]. A decrease in the amount of ATP as a result of mutations affecting oxidative phosphorylation causes multisystemic signs and symptoms. The nervous system, retina, heart and skeletal muscle, liver, and kidneys are the most affected organs. Of these, the brain and skeletal muscles are affected to varying degrees in all cases, without exception. Genetic transition modality shows heterogeneity. For example, a study carried out by Na et al. [23] identified known pathogenic mutations in 31 patients with Leigh syndrome. The most common causes were MT-ATP6 (n = 21) followed by MT-ND3 (n = 7) and MT-ND5 (n = 4) gene variations, respectively. In many other different studies, MT-ATP6 variations have also been highlighted as a common cause of mitochondrial pathologies with a wide range of clinical findings and age of onset [22, 25‒27]. Therefore, the genotype-phenotype correlation in Leigh Syndrome related to mtDNA could guide the development of specific treatment strategies [28]. Approximately 20% of cases is caused by mutations in the MT-ATP6 gene, which encodes for complex V [25].

There is no effective treatment for mitochondrial cytopathies. First of all, the treatment of metabolic acidosis as well as a ketogenic diet is essential, although it is not very effective in the long term. PDH enzyme cofactors such as thiamine, carnitine, and lipoic acid are widely used in clinics. Recently, in a study by Peretz et al. [21], additional citrulline and mitochondria cocktail treatments were given to 6 patients with Leigh syndrome with MT-ATP6 deficiency, who were found to have low citrulline and high C5-OH, and these patients did not experience metabolic crisis and developmental regression. Dichloroacetate, an E1 kinase inhibitor, has been used additionally.

In our patient, carnitine was started on the first day of hospitalization due to the suspicion of an underlying metabolic disease, and after the diagnosis of Leigh’s syndrome, thiamine and coenzyme Q₁₀ were added to the treatment. Our patient died on the 22nd day of hospitalization due to heart failure.

As a result, mitochondrial diseases may present as encephalopathy, shock, and hypotonia, as seen in our case. Low plasma citrulline levels can be attributed to various factors, including reduced absorption and synthesis of citrulline in the gut. Disruptions in the gut microbiome, such as imbalances in microbial populations, can influence citrulline metabolism and absorption, potentially contributing to lower plasma citrulline levels. Additionally, certain medical conditions and dietary factors can impact citrulline levels, highlighting the multifaceted nature of this biomarker [29, 30]. However, citrulline is discussed as a biomarker in the literature, especially in MT-ATP6 gene defects. Mitochondrial disease should be considered in the differential diagnosis, especially in patients with multisystem involvement.

We would like to thank everyone who contributed to the medical care of our patient and the parents of our patient who encouraged and allowed us to share our case with the literature in addition to showing the utmost love and care to their children.

The patient’s parents have given their written informed consent to publish this case (including publication of images). This case report was conducted ethically in accordance with the World Medical Association Declaration of Helsinki. The paper is exempt from Ethical Committee approval. Ethical approval was not required for this study in accordance with national guidelines.

The authors have no conflicts of interest to declare.

The study did not receive funding.

H.T.A., E.S., Ö.S.N., and A.O.: clinical evaluation, follow-up, data collection, and drafting the manuscript. M.B.Ö.: radiologic diagnosis and drafting the manuscript. H.T.A. and A.O.: interpretation of metabolic investigations and data, tailoring diagnosis and treatment, and revising the manuscript. All authors have read, reviewed, and approved the final manuscript.

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.