Case 321: Leigh Syndrome.

HISTORY: A 9-month-old preterm male infant born at 33 weeks gestation presented with a 2-month history of developmental decline. The parents reported that over the past several months, they noted regression of milestones, where the infant stopped smiling, crying, expressing himself, or making eye contact. The parents also reported that the infant had multiple seizures during which he would wake up stiff and stare into space for 10-20 seconds while his lips would become blue. The parents were referred to a neurologist, where physical examination was notable for hypotonia. Electroencephalography (EEG) revealed frequent bilateral parietal epileptiform discharges. The patient was subsequently started on lacosamide. The patient's medical history was notable for abnormally low citrulline levels at birth, with negative results of urea cycle disorder testing at the time, along with left inguinal hernia repair performed 3 months ago. More recent laboratory analysis had shown persistently elevated serum lactate and alanine levels. There was no history of travel, recent infection, or vaccine administration. MRI of the brain with spectroscopy was performed for further evaluation.

Genotype-phenotype analysis of MT-ATP6-associated Leigh syndrome.

OBJECTIVES: Mitochondrial DNA (mtDNA)-associated Leigh syndrome (LS) is characterized by maternal inheritance, and the heteroplasmic mutant load of mtDNA pathogenic variants is known to affect clinical phenotypes. Among mtDNA pathogenic variants, variants of the MT-ATP6 gene account for most of reported cases. In this report, we aimed to describe the clinical and genetic findings of MT-ATP6-associated LS patients diagnosed at a single tertiary institution in Korea. METHODS: Thirteen patients with genetically confirmed MT-ATP6-associated LS were selected. We reviewed each patient's clinical findings, including general characteristics, biochemical parameters, brain MR images, muscle biopsy results, and heteroplasmic mutant load over a long-term follow-up period. RESULTS: MT-ATP6-associated LS was of predominantly early onset (age <2 years), although we identified 2 late-onset (>60 months) LS patients. The heteroplasmic mutant load estimated by next-generation sequencing was 96%-100% in all nucleotide change groups. Compared with other forms of MT-ATP6-associated LS, the m.8993T>G point mutation elicited a significantly higher rate of symptom onset before 2 years of age. Brain MRI showed bilateral basal ganglia involvement in all patients, followed by cerebral atrophy, brainstem and thalamus involvement, and cerebellar atrophy. After follow-up (median 7.2 years, range 1.4 to 11.5 years), LS with m.8993T>G point mutations had a slightly more severe clinical progression compared with other forms of MT-ATP6-associated LS. CONCLUSIONS: MT-ATP6-associated LS patients presented with a broad spectrum of clinical diagnoses and had a very high heteroplasmic mutant load. This study provides valuable data on MT-ATP6-associated LS that will inform subsequent studies on LS.

Spinal Nerve Roots Abnormalities on MRI in a Child with SURF1 Mitochondrial Disease.

Variants in SURF1, encoding an assembly factor of mitochondrial respiratory chain complex IV, cause Leigh syndrome (LS) and Charcot-Marie-Tooth type 4K in children and young adolescents. Magnetic resonance imaging (MRI) appearance of enlarged nerve roots with postcontrastographic enhancement is a distinctive feature of hypertrophic neuropathy caused by onion-bulb formation and it has rarely been described in mitochondrial diseases (MDs). Spinal nerve roots abnormalities on MRI are novel findings in LS associated with variants in SURF1. Here we report detailed neuroradiological and neurophysiologic findings in a child with LS and demyelinating neuropathy SURF1-related. Our case underlines the potential contributive role of spinal neuroimaging together with neurophysiological examination to identify the full spectrum of patterns in MDs. It remains to elucidate if these observations remain peculiar of SURF1 variants or potentially detectable in other MDs with peripheral nervous system involvement.

Biallelic Variants in PYROXD2 Cause a Severe Infantile Metabolic Disorder Affecting Mitochondrial Function.

Pyridine Nucleotide-Disulfide Oxidoreductase Domain 2 (PYROXD2; previously called YueF) is a mitochondrial inner membrane/matrix-residing protein and is reported to regulate mitochondrial function. The clinical importance of PYROXD2 has been unclear, and little is known of the protein's precise biological function. In the present paper, we report biallelic variants in PYROXD2 identified by genome sequencing in a patient with suspected mitochondrial disease. The child presented with acute neurological deterioration, unresponsive episodes, and extreme metabolic acidosis, and received rapid genomic testing. He died shortly after. Magnetic resonance imaging (MRI) brain imaging showed changes resembling Leigh syndrome, one of the more common childhood mitochondrial neurological diseases. Functional studies in patient fibroblasts showed a heightened sensitivity to mitochondrial metabolic stress and increased mitochondrial superoxide levels. Quantitative proteomic analysis demonstrated decreased levels of subunits of the mitochondrial respiratory chain complex I, and both the small and large subunits of the mitochondrial ribosome, suggesting a mitoribosomal defect. Our findings support the critical role of PYROXD2 in human cells, and suggest that the biallelic PYROXD2 variants are associated with mitochondrial dysfunction, and can plausibly explain the child's clinical presentation.

Pediatric Leigh Syndrome: Neuroimaging Features and Genetic Correlations.

The neurodiagnostic criteria of Leigh syndrome have not yet been clearly redefined based on the expanding of molecular etiologies. We aimed to analyze 20 years of clinical, genetic, and magnetic resonance studies from our Leigh syndrome cohort to provide a detailed description of central nervous system lesions in Leigh syndrome and their biological evolution in view of their genetic and clinical findings. Our study adds new neurodiagnostic insights to the current knowledge of Leigh syndrome, including association with overlapping syndromes, and the correlation of pathogenic genetic variants with neuroimaging phenotypes. ANN NEUROL 2020;88:218-232.

Cerebral blood flow and acute episodes of Leigh syndrome in neurometabolic disorders.

AIM: To investigate cerebral blood flow (CBF) in acute episodes of Leigh syndrome compared with basal state in patients carrying pathogenic mitochondrial disease gene variants responsible for neurometabolic disorders. METHOD: Arterial spin labelling (ASL) magnetic resonance imaging (MRI) sequences were used to measure CBF in 27 patients with mitochondrial respiratory chain enzyme deficiencies, ascribed to pathogenic variants of reported disease genes who were undergoing either urgent neuroimaging for acute episodes of Leigh syndrome (Group I: 15 MRI, seven females, eight males; mean age 7y; range 7mo-14y) or routine brain MRI (Group II: 15 MRI, eight females, seven males; mean age 5y 2mo; range 2mo-12y). RESULTS: Patients displayed markedly increased CBF in the striatum (2.8-fold greater, p<0.001 [1.05-2.53]) during acute episodes of Leigh syndrome compared to basal conditions. Detection of elevated CBF preceded identification of structural MRI lesions in four out of 15 cases. INTERPRETATION: Our results suggest that increased CBF is an overt hallmark of Leigh syndrome episodes and ASL MRI sequences should facilitate early diagnosis of acute episodes of Leigh syndrome, especially during the first attack in young children, when structural MRI is insufficiently informative.

Phenotypic variability and mutation hotspot in COX15-related Leigh syndrome.

COX15 mutations were shown to underlie Leigh syndrome (LS), a progressive subacute necrotizing encephalopathy caused by defects in the mitochondrial respiratory chain. Here, two siblings of consanguineous kindred presented in infancy with a syndrome of hypotonia, nystagmus, psychomotor retardation, and pyramidal signs. Toward the end of their second year, both patients developed progressive quadriparesis, convulsions, and pseudobulbar palsy. Similar to two previously reported cases, one of the two affected siblings had severe hypertrophic obstructive cardiomyopathy, hearing loss, and no visual response. Through linkage analysis and whole-exome sequencing, we identified a homozygous p.R217W mutation in Cytochrome C oxidase assembly protein COX15 homolog. Consistent with the known heterogeneity of mitochondrial diseases in general and that of LS in particular, several phenotypic features were markedly distinguished between the affected siblings and in relation to previous reports of COX15 mutations. Interestingly, of the previously reported five cases of COX15-mutated patients, all of different ethnic origins, three had a p.R217W mutation. We highlight p.R217W as a hotspot mutation in COX15 and delineate the phenotypic variability, both between the patients we describe and in all cases reported to date.

NDUFS6 related Leigh syndrome: a case report and review of the literature.

The genetic causes of Leigh syndrome are heterogeneous, with a poor genotype-phenotype correlation. To date, more than 50 nuclear genes cause nuclear gene-encoded Leigh syndrome. NDUFS6 encodes a 13 kiloDaltons subunit, which is part of the peripheral arm of complex I and is localized in the iron-sulfur fraction. Only a few patients were reported with proven NDUFS6 pathogenic variants and all presented with severe neonatal lactic acidemia and complex I deficiency, leading to death in the first days of life. Here, we present a patient harboring two NDUFS6 variants with a phenotype compatible with Leigh syndrome. Although most of previous reports suggested that NDUFS6 pathogenic variants invariably lead to early neonatal death, this report shows that the clinical spectrum could be larger. We found a severe decrease of NDUFS6 protein level in patient's fibroblasts associated with a complex I assembly defect in patient's muscle and fibroblasts. These data confirm the importance of NDUFS6 and the Zn-finger domain for a correct assembly of complex I.

Biallelic variants in COX4I1 associated with a novel phenotype resembling Leigh syndrome with developmental regression, intellectual disability, and seizures.

Autosomal recessive COX4I1 deficiency has been previously reported in a single individual with a homozygous pathogenic variant in COX4I1, who presented with short stature, poor weight gain, dysmorphic features, and features of Fanconi anemia. COX4I1 encodes subunit 4, isoform 1 of cytochrome c oxidase. Cytochrome c oxidase is a respiratory chain enzyme that plays an important role in mitochondrial electron transport and reduces molecular oxygen to water leading to the formation of ATP. Defective production of cytochrome c oxidase leads to a variable phenotypic spectrum ranging from isolated myopathy to Leigh syndrome. Here, we describe two siblings, born to consanguineous parents, who presented with encephalopathy, developmental regression, hypotonia, pathognomonic brain imaging findings resembling Leigh-syndrome, and a novel homozygous variant on COX4I1, expanding the known clinical phenotype associated with pathogenic variants in COX4I1.

Relapsing necrotising encephalomyelopathy due to RANBP2 mutation.

A young woman with a history of previously undiagnosed episodic neurological deterioration since early childhood associated with viral illnesses developed fulminant encephalitis. Standard investigations gave no diagnosis. Next-generation sequencing identified a heterozygous mutation c.1754C>T (p.Thr585Met) in the RANBP2 gene, giving the diagnosis of recurrent acute necrotising encephalopathy type 1. This condition is probably underdiagnosed, especially in adults, and should be considered in patients with recurrent encephalopathy.

Perioperative risk assessment for successful kidney transplant in leigh syndrome: a case report.

BACKGROUND: Leigh syndrome (LS) is a rare neurodegenerative mitochondrial disorder which typically presents in childhood but has a varied clinical course. Renal involvement such as proximal tubulopathy in patients with mitochondrial disorders has been described. However, end stage renal disease (ESRD) is uncommon and literature regarding patients undergoing kidney transplantation is limited. Successful deceased donor renal transplant has not been previously described in a patient with Leigh Syndrome. CASE PRESENTATION: We report a 21-year-old Han Chinese man who presented with limb weakness and unsteady gait, which progressed rapidly over a period of months until he was wheelchair-bound. He subsequently developed ESRD and was commenced on hemodialysis. Investigations revealed a m.13513G > A mutation with clinical and radiological features consistent with LS. His mitochondrial disease stabilised and he underwent a multidisciplinary assessment for deceased donor kidney transplantation to identify and minimise the LS-associated perioperative risks and potential negative effects of immunosuppressants on his LS. Successful kidney transplantation followed with excellent graft function three and a half years post-transplant and improvement in the patient's physical function. CONCLUSION: This case highlights the importance of careful pre-transplant perioperative risk assessment and post-transplant care in a rare and heterogeneous neurological disease to achieve an ultimately excellent clinical outcome. To our knowledge, this is the first report of successful deceased donor kidney transplant in a patient with known LS.

A patient with mitochondrial disorder due to a novel mutation in MRPS22.

MRPS22 gene defect is a very rare newly discovered mitochondrial disorder. We report a 4-month-old severely affected male infant with MRPS22 mutation. Whole exome sequencing revealed a novel homozygous splicing mutation c.339 + 5 G > A in MRPS22 gene. He has mild dysmorphism, hypotonia, developmental delay but not hypertrophic cardiomyopathy and tubulopathy which differ from other majority of reported patients. Therefore, hypertrophic cardiomyopathy and tubulopathy may not be considered as constant features of MRPS22. With this case report, we also present first symmetrical bilateral brainstem and medial thalamic lesions, and cerebellar and cerebral atrophy on a brain MR imaging follow-up of ten months.

Mitochondrial respiratory chain disorders in the Old Order Amish population.

The Old Order Amish populations in the US are one of the Plain People groups and are descendants of the Swiss Anabaptist immigrants who came to North America in the early eighteenth century. They live in numerous small endogamous demes that have resulted in reduced genetic diversity along with a high prevalence of specific genetic disorders, many of them autosomal recessive. Mitochondrial respiratory chain deficiencies arising from mitochondrial or nuclear DNA mutations have not previously been reported in the Plain populations. Here we present four different Amish families with mitochondrial respiratory chain disorders. Mutations in two mitochondrial encoded genes leading to mitochondrial respiratory chain disorder were identified in two patients. In the first case, MELAS syndrome caused by a mitochondrial DNA (mtDNA) mutation (m.3243A>G) was identified in an extended Amish pedigree following a presentation of metabolic strokes in the proband. Characterization of the extended family of the proband by a high resolution melting assay identified the same mutation in many previously undiagnosed family members with a wide range of clinical symptoms. A MELAS/Leigh syndrome phenotype caused by a mtDNA mutation [m.13513G>A; p.Asp393Asn] in the ND5 gene encoding the ND5 subunit of respiratory chain complex I was identified in a patient in a second family. Mutations in two nuclear encoded genes leading to mitochondrial respiratory chain disorder were also identified in two patients. One patient presented with Leigh syndrome and had a homozygous deletion in the NDUFAF2 gene, while the second patient had a homozygous mutation in the POLG gene, [c.1399G>A; p.Ala467Thr]. Our findings identify mitochondrial respiratory chain deficiency as a cause of disease in the Old Order Amish that must be considered in the context of otherwise unexplained systemic disease, especially if neuromuscular symptoms are present.

Spasticity secondary to Leigh syndrome managed with selective dorsal rhizotomy: a case report.

PURPOSE: Selective dorsal rhizotomy (SDR) is a surgical technique used to treat spasticity in children secondary to cerebral palsy (CP). METHOD: We report, to the best of our knowledge for the first time, the case of a child who underwent SDR for the management of spasticity secondary to Leigh syndrome. RESULT: SDR resulted in excellent functional outcome with significant improvement in spasticity. This result contributes to the mounting evidence that SDR could be used to alleviate spasticity secondary not only to CP but also to other pathologies as well.

Lesional perfusion abnormalities in Leigh disease demonstrated by arterial spin labeling correlate with disease activity.

BACKGROUND: Leigh disease is a metabolic disorder of the mitochondrial respiratory chain culminating in symmetrical necrotizing lesions in the deep gray nuclei or brainstem. Apart from classic gliotic/necrotic lesions, small-vessel proliferation is also characteristic on histopathology. We have observed lesional hyperperfusion on arterial spin-labeling (ASL) sequence in children with Leigh disease. OBJECTIVE: In this cross-sectional analysis, we evaluated lesional ASL perfusion characteristics in children with Leigh syndrome. MATERIALS AND METHODS: We searched the imaging database from an academic children's hospital for "arterial spin labeling, perfusion, necrosis, lactate, and Leigh" to build a cohort of children for retrospective analysis. We reviewed each child's medical record to confirm a diagnosis of Leigh disease, excluding exams with artifact, technical limitations, and without ASL images. We evaluated the degree and extent of cerebral blood flow and relationship to brain lesions. Images were compared to normal exams from an aged-matche cohort. RESULTS: The database search yielded 45 exams; 30 were excluded. We evaluated 15 exams from 8 children with Leigh disease and 15 age-matched normal exams. In general, Leigh brain perfusion ranged from hyperintense (n=10) to hypointense (n=5). Necrotic lesions appeared hypointense/hypoperfused. Active lesions with associated restricted diffusion demonstrated hyperperfusion. ASL perfusion patterns differed significantly from those on age-matched normal studies (P=<.0001). Disease activity positively correlated with cerebral deep gray nuclei hyperperfusion (P=0.0037) and lesion grade (P=0.0256). CONCLUSION: Children with Leigh disease have abnormal perfusion of brain lesions. Hyperperfusion can be found in active brain lesions, possibly associated with small-vessel proliferation characteristic of the disease.

The neuroimaging of Leigh syndrome: case series and review of the literature.

Leigh syndrome by definition is (1) a neurodegenerative disease with variable symptoms, (2) caused by mitochondrial dysfunction from a hereditary genetic defect and (3) accompanied by bilateral central nervous system lesions. A genetic etiology is confirmed in approximately 50% of patients, with more than 60 identified mutations in the nuclear and mitochondrial genomes. Here we review the clinical features and imaging studies of Leigh syndrome and describe the neuroimaging findings in a cohort of 17 children with genetically confirmed Leigh syndrome. MR findings include lesions in the brainstem in 9 children (53%), basal ganglia in 13 (76%), thalami in 4 (24%) and dentate nuclei in 2 (12%), and global atrophy in 2 (12%). The brainstem lesions were most frequent in the midbrain and medulla oblongata. With follow-up an increased number of lesions from baseline was observed in 7 of 13 children, evolution of the initial lesion was seen in 6, and complete regression of the lesions was seen in 3. No cerebral white matter lesions were found in any of the 17 children. In concordance with the literature, we found that Leigh syndrome follows a similar pattern of bilateral, symmetrical basal ganglia or brainstem changes. Lesions in Leigh syndrome evolve over time and a lack of visible lesions does not exclude the diagnosis. Reversibility of lesions is seen in some patients, making the continued search for treatment and prevention a priority for clinicians and researchers.