Leigh-Like Syndrome With a Novel, Complex Phenotype Due to m.10191T>C in Mt-ND3

Leigh-like syndrome (LLS) due to the variant m.10191T>C in ND3 with a number of new phenotypic traits has not been published. In this case report, a 32-year-old woman diagnosed with Leigh-like syndrome presented with a complex novel, progressive, multisystem phenotype, manifesting in the brain (mild cognitive impairment, seizures, choreoathetosis, pseudotumor cerebri, hypersomnia, symmetric pallidal hypointensities, panda sign, calcifications, dysphagia), endocrine organs (empty sella syndrome, hypocorticism, hypoaldosteronism, hypogonadism), hematopoietic system (anemia, lymphocytosis), immune system (lymphocytosis, hypogammaglobulinemia), gut (reflux, diarrhea), kidneys (renal insufficiency, renal tubular acidosis, nephrolithiasis), muscles (myopathy, exercise intolerance, easy fatigability), peripheral nerves (small fiber neuropathy, dysautonomia), connective tissue (hyperlaxity of joints, bruising), and bones (scoliosis, Chiari malformation). A genetic workup revealed the known pathogenic variant m.10191T>C in ND3, which was also carried by the patient’s mother. This case demonstrates that the m.10191T>C variant in ND3 can phenotypically manifest with multisystem disease and that this disease is responsive to symptomatic treatment and application of additional compounds.


Introduction
Leigh syndrome is the most common mitochondrial disorder (MID) in pediatric patients, with an estimated incidence of 1 in 40,000 live births [1]. Leigh syndrome is characterized by progressive loss of mental and movement abilities (psychomotor regression) resulting in feeding problems, respiratory failure, and bilateral basal ganglia lesions on imaging. In addition to classical Leigh syndrome, there are a number of respiratory chain defects that also manifest with basal ganglia defects but with additional widespread multisystem involvement including the peripheral nerves, muscles, endocrine system, heart, liver, kidneys, and hematopoietic system (Leigh-like syndrome [LLS]) [2]. The onset of the disorder can be in early infancy or adulthood. Some patients with early-onset Leigh syndrome survive into adulthood. Currently, no successful treatment for Leigh syndrome exists, but there are many promising candidates. The prognosis is generally poor for classical Leigh syndrome and LLS, but fair for their adult-onset forms and patients who survive into adulthood. Leigh syndrome and LLS, similar to many other MIDs, have a heterogeneous genetic background and manifest with heterogeneous phenotypic expression and lifespan [2]. This case report seeks to introduce Leigh syndrome and LLS into the physician's clinical index of suspicion, even if the patient is older than the typical age of presentation or has an atypical phenotype [3][4][5][6][7][8][9][10][11][12][13].

Case Presentation
The patient was a 32-year-old woman diagnosed with LLS with a height and weight of 170 cm and 120 kg, respectively, born to non-consanguineous parents, with the following history ( Table 1): severe new-born jaundice, delayed speech development (stumbling until age 2), joint hypermobility from age 3 and recurrent sprains, dislocations, and easy bruising; exercise intolerance, reduced endurance, and exercise-induced muscle burning from age 5 which improves with rest, cool rags, and sugar, depression from age 5 being treated with antidepressants from age 12, micropsia from age 6, recurrent severe diarrhea from age 6 which did not stop earlier than after administration of ubiquinol at age 26, a first syncope of unknown etiology at age 7 which progressed to several syncopes per day around age 14 attributed to suspected orthostatic hypotension, migraine without aura manifesting with unilateral throbbing pain in the right middle cerebral artery starting at age 7 which responds to sumatriptan and indomethacin, and focal or generalized seizures starting with staring spells, but also tonic-clonic seizures with a frequency of several seizures per year from age 7.

FIGURE 1: Pedigree of the index patient
A clinical neurological exam revealed left ptosis, vertical diplopia, horizontal nystagmus, occasional choreoathetosis, and ataxia on tandem gait. Nerve conduction studies and needle electromyography were uninformative. Cerebral CT revealed abnormal calcifications ( Figure 2). Cerebral MRI demonstrated mild periventricular white matter hyperintensities, bilateral T2 and FLAIR hypointense lesions within the globus pallidus and midbrain, and a "face of the giant panda" sign ( Figure 1). No lactate peak was seen in magnetic resonance spectroscopy. Creatine kinase level was normal. There was mild renal insufficiency and mild hypertriglyceridemia. Lactate was slightly elevated but pyruvate was normal at rest. The lactate pyruvate ratio was 28 but decreased with aerobic training and medication. Serum levels of cortisol, adrenocorticotropic hormone, epinephrine, and aldosterone were lower than normal. The urine amino acid profile demonstrated very low organic acids (glycolic, 3-hydroxypropionic, 2-hydroxy-isovaleric, succinic, methylsuccinic, glutaric, malic, 3-hydroxy-adipic, adipic, 5-oxoproline, citric, isocitric), which is why renal tubular acidosis was diagnosed. A 6-minute walking test (6MWT) of arterial blood gases revealed hypoxia (38 mmHg) with uncompensated lactic acidosis immediately after exercise and uncompensated respiratory alkalosis 5 minutes after exercise. A second 6MWT 20 minutes later revealed post-exercise lactic acidosis with hyperoxia (excess of oxygen). VO 2 max testing demonstrated 14 mL O 2 /kg/min, which increased to 16 mL O 2 /kg/min with aerobic training. Neuropsychological testing demonstrated severe executive dysfunction, language-finding difficulties, and reduced processing speed which worsened on repeat testing.

Cerebral CT of the brain (sagittal plane) showing abnormal calcifications in the subarachnoid space
CCT: cerebral CT, FLAIR: fluid attenuated inversion recovery Muscle biopsy revealed >10% ragged-red fibers with corresponding ragged-blue fibers on succinate dehydrogenase staining, subsarcolemmal deposits on succinate-dehydrogenase staining, 2% cytochrome-C oxidase-negative fibers which was at a frequency much greater than would be expected in a patient of this age-and denervation with fiber-type grouping ( Figure 3). At the time of the study, the index patient was on polypharmacy with 46 compounds ( Table 2). Despite being a triathlete and competitive para-swimmer, and eating <1000 kcal/d, the patient had difficulty losing weight. The patient is currently able to sufficiently perform all activities of daily living. Despite mild progression, the prognosis has to be assessed as good.

Discussion
The index patient was interesting in several respects. First, the patient was diagnosed with progressive LLS which began in childhood and continued into adulthood. Second, the patient showed previously undescribed phenotypic characteristics of a multisystem MID due to the m.10191T>C variant. Accordingly, LLS manifested not only in the brain (mild cognitive impairment, seizures, choreoathetosis, pseudotumor cerebri, hypersomnia, symmetric pallidal hypointensities, panda sign, calcifications, empty sella, dysphagia) but also in the endocrine organs (hypocorticism, hypoaldosteronism, empty sella, hypogonadism), hematopoietic system (anemia), cellular immune system (lymphocytosis, hypogammaglobulinemia, high CD19 cells, B-cell lymphocytosis), gut (reflux and diarrhea), kidneys (renal insufficiency, renal tubular acidosis, nephrolithiasis), muscles (ptosis, myopathy, hyperoxia), peripheral nerves (small fibre neuropathy, dysautonomia), connective tissue (easy bruising, impaired wound healing, hyperlaxity of joints), and bones (scoliosis, Chiari malformation). Third, the patient was in extreme polypharmacy mainly due to experiences with self-medication.
Previously reported phenotypic manifestations of m.10191T>C carriers were comprehensively reviewed in a report by Li et al., in which 28 patients were discussed [4]. Phenotypic manifestations of the m.10191T>C variant reported in these 28 patients included cognitive impairment, migraine, seizures, anopia or hemianopia, myocloni, myoclonic epilepsy, stroke-like episodes, ataxia, optic atrophy, large fiber neuropathy, spasticity, nystagmus, tremor, myopathy including ptosis and ophthalmoparesis, hearing loss, cardiac involvement including bradycardia, hypothermia, vomiting, micrognathia, pes equinovarus, and short stature ( Table 1) [4]. Of these manifestations, only cognitive impairment, epilepsy, delayed speech development, and migraine were also found in the index patient. Another study investigated seven patients carrying the m.10191T>C variant; interestingly, none presented with central nervous system involvement, whereas four presented with myopathy, one with respiratory failure, six with cardiac involvement, one with gastrointestinal disease, three with endocrinopathy, four with renal disease, three with ophthalmologic impairment, six with hypoacusis, and five with bone abnormalities [3]. Another patient, a 24-year-old woman with the m.10191T>C variant, only started presenting clinical manifestations at the age of 18 when she developed myocloni and seizures [4]. During the course of the disease, she also developed mild quadriparesis and generalized muscle wasting due to myopathy [4]. Therefore, the patient's phenotype differed in some aspects from other reports of patients with the m.10191T>C variant ( Table 1).
The high number of unusual phenotypic manifestations in the index patient as compared to previous reports could be explained by variants in genes other than ND3. Whether the m.12770A>G variant in MT-ND5 contributed to the phenotypic heterogeneity remains speculative, this variant has been previously associated with mitochondrial encephalopathy, lactic acidosis, and stroke-like episode syndrome. An argument against mutations in nuclear mitochondrial genes contributing to the phenotypic heterogeneity is that none were present in whole exome sequencing. The multisystem nature of LLS is a strong argument for its diagnosis, as is the striking cerebral imaging. In this case report, cerebral imaging was not only striking for bilateral pallidal hypointensities but also for the face of the giant panda sign, or the "panda sign," which refers to the appearance of the midbrain when the red nucleus and substantia nigra are surrounded by a high T2 signal in the tegmentum. The panda sign is classically seen in Wilson's disease, although a similar appearance is seen whenever the white matter in the region is diffusely abnormal. In addition to Wilson's disease, the panda sign has been described in Japanese encephalitis, rabies, sarcoidosis, acute disseminated encephalitis, toxic leukoencephalopathy, Leigh syndrome, and LLS. With the exception of LLS, all other differential diagnoses with the panda sign were ruled out in the index patient based on clinical presentation, disease course, laboratory findings, and imaging.
Interestingly, the patient did not require anti-seizure drugs other than gabapentin. This may be because she was also taking fenofibrate, which is known to increase ketone bodies. Ketone bodies are known to have an anticonvulsant effect, particularly in patients with a MID (ketogenic diet).
The high CD19 count, mild hypogammaglobulinemia, and borderline-low immunoglobulin M may have been due to the heavy reliance of B cells on oxidative phosphorylation compared to T cells. C10orf2 variants have been reported to affect immune cells in MID patients. In addition, systemic inflammation has been documented in NDUFS4 knockout mice.
The present study was limited in that the heteroplasmy rate was not determined, and no biochemical studies were performed to assess respiratory chain functions. However, the m.10191T>C variant showed poor correlations with heteroplasmy, symptoms, and lifespan.