Mitochondrial glutamyl-aminoacyl tRNA synthetase deficiency, stemming from biallelic mutations in the EARS2 gene, was first described in 2012. With <50 cases reported globally, this condition exhibits a distinct phenotype of neonatal or childhood-onset, often referred to as leukoencephalopathy with thalamus and brainstem involvement and high lactate (LTBL). It has also been one of the few reversible mitochondrial disorders described. The natural history of these patients is poorly documented, ranging from clinical and radiological improvement to early death. Herein, we detail three cases from our centre, including follow-up on the Portuguese patient reported by Steenweg et al., These cases illustrate the phenotypic spectrum: i) rapidly progressive neonatal presentation with lactic acidemia and corpus callosum agenesis, leading to early death; ii) early onset with a severe, slowly progressive course; iii) early onset with a milder phenotype, showing some improvement and mild neurological symptoms. Additionally, we conducted a systematic literature review on cases of EARS2-deficient patients, focusing on clinical manifestations, laboratory findings, radiological aspects, and disease progression over time, along with respective data analysis. \"Patients with EARS2 deficiency typically present within the first year of life with a well-defined neurometabolic disorder picture, often including hypotonia and/or spasticity, along with neurodevelopmental delay or regression. There are no pathognomonic features specific to EARS2 deficiency, and no genotype-phenotype correlation has been identified.\" Comparing to initial characterization by Steenweg et al., this analysis reveals an expanded disease spectrum. We propose a novel strategy for clustering phenotypes into severe, moderate, or mild disease based on initial presentation, seemingly correlating with disease progression. The paucity of data on the disease\'s natural history highlights the need for a multicentric approach to enhance understanding and management. TAKE-HOME MESSAGE: Analysis of all cases published with EARS2 deficiency allows for establish disease spectrum and a novel strategy for clustering phenotypes which correlate to disease progression.

UNASSIGNED: Hypertrophic cardiomyopathy in the neonate has a diverse genetic background, and non-sarcomeric variants may not be identified on commercial genetic testing panels. NDUFB11 is an X-linked mitochondrial Complex I protein and is known to cause histiocytoid cardiomyopathy but has not been described in female infants with hypertrophic cardiomyopathy. We present this first reported case of obstructive hypertrophic cardiomyopathy in a female neonate secondary to a pathogenic variant in NDUFB11.
UNASSIGNED: A term female neonate presented following a prenatal diagnosis of biventricular hypertrophy and growth restriction. She developed lactic acidosis after birth and whole-genome sequencing identified a de novo variant in the mitochondrial Complex I gene, NDUFB11 (c.391G>A, p.Glu131Lys). There was progression of left ventricular hypertrophy and obstruction, with rapid development of heart failure symptoms. She was unresponsive to beta-blocker medical therapy and was not suitable for advanced mechanical support. There was subsequent clinical deterioration resulting in death by 3 months of age.
UNASSIGNED: Hemizygous variants in NDUFB11 have been associated with hypertrophic cardiomyopathy in male infants previously, and skewed X-linked inactivation likely resulted in the presentation described here in a female infant. This variant was not identifiable by commercial cardiomyopathy panels. We highlight the importance of rapid whole-genome sequencing in cases of infantile hypertrophic cardiomyopathy and the importance of genetic diagnosis in guiding prognosis and care for these individuals.

Progressive external ophthalmoplegia is a slowly progressive hereditary mitochondrial myopathy. Most mitochondrial disorders overlap clinically, enzymatically, and genetically. The most common enzyme defect is the combined deficit of complexes I and IV. Progressive external ophthalmoplegia particularly affects the extraocular muscles and is characterised by ophthalmoplegia, and bilateral ptosis. The ptosis and ophthalmoplegia is unresponsive to anticholinergics, with no effective treatment, but corrective surgery for ptosis as a palliative one. In this article, we report a rare case of a 16-year-old female with characterstic histological features consistent with progressive external ophthalmoplegia.

Progressive mitochondrial encephalopathy manifesting as developmental delay, regression, epilepsy, myoclonus, dystonia, and spasticity due to a novel compound heterozygous variant in NARS2 has not been reported. The patient is a 3.5-year-old female with normal psychomotor development until she experienced her first generalized status epilepticus at 4.5 months of age. After seizure control, generalized myoclonus and psychomotor regression became evident. She suffered from two other epileptic states and seizure control remained inadequate despite the use of multiple anti-seizure drugs. Neurologic examination revealed generalized hypotonia, discoordination, unstable eye contact, drooling, open mouth, myoclonus, periodic torticollis, and ankle contractions. Cerebral MRI revealed hydrocephalus ex vacuo due to diffuse cortical and subcortical atrophy bilaterally and incomplete myelination. Genetic testing at 12 months of age revealed the compound heterozygous variants chr11: 78204182C>T and chr11: 78282446A>AG in NARS2. Despite anti-seizure drugs, mitochondrial cocktail, and cannabidiol, the disease progressed to intractable seizures and severe tetraspasticity. In summary, this case demonstrates that compound heterozygous variants in NARS2 can phenotypically manifest exclusively in the brain with intractable epilepsy, myoclonus, developmental delay, regression, hypotonia, cerebral atrophy, and hypomyelination, followed by tetraspasticity and dystonia.

BACKGROUND: Leber hereditary optic neuropathy is a genetic disease of mitochondrial inheritance characterized by bilateral irreversible vision loss, predominantly affecting males. We report the first genetically authenticated Sri Lankan case of Leber hereditary optic neuropathy, illustrating its characteristic features of male predominance and variable penetrance.
METHODS: A 15-year-old previously healthy Sri Lankan boy presented with painless progressive vision loss in his right eye, followed by vision loss in his left eye within 3 months. There was no history of drug or toxin exposure, or a family history of vision loss. His parents were nonconsanguineous. On examination, he could only perceive light. Funduscopy revealed bilateral optic atrophy. Routine hematological and biochemical blood tests, including inflammatory markers, were normal. Cranial magnetic resonance imaging was unremarkable. Optical coherence tomography, and the clinical presentation, suggested a diagnosis of Leber hereditary optic neuropathy, which was confirmed by detection of m.14484T > C pathogenic variant in the MT-ND6 gene through targeted genetic analysis for the three common pathogenic variants in mitochondrial deoxyribonucleic acid. He was homoplasmic for the variant, and his asymptomatic mother and two female siblings were also found to be harboring the variant with homoplasmy.
CONCLUSIONS: This case report is intended to increase awareness of Leber hereditary optic neuropathy, and highlights the need to consider this rare diagnosis in the appropriate clinical context. It also illustrates the phenomena of incomplete penetrance and male predominance, and suggests the possibility of an X-linked gene governing Leber hereditary optic neuropathy disease expression, which warrants further investigation.

A myoclonic epilepsy with ragged-red fibers (MERRF) patient who carried the m.8344A>G variant in the homoplasmic form manifested a milder phenotype than his sister who carried the same variant in the heteroplasmic form, which has not yet been reported. The 27-year-old male, with an uneventful history, presented at age 19 with fatigue and persistent tremor in both hands. When he talked for a long time, his speech would slow down, and he would stutter. Although electroencephalography showed spike-wave complexes in both occipital projections with generalization, no anti-seizure drugs were given. At age 20, the patient suffered a fall due to muscle weakness. From age 21, generalized myocloni occurred. Because the sister had been diagnosed with MERRF-plus syndrome, the patient underwent genetic testing, which revealed the m.8344A>G variant in homoplasmy. L-carnitine was started. At age 27, the patient experienced a first \"syncope\" after a long walk, which subsequently recurred up to 2-3 times per day. EEG showed low-amplitude spikes, slow-spike waves at the posterior vertex, and generalized slow-spike waves. Clonazepam was recommended but declined by the patient. In conclusion, the m.8344A>G variant may manifest milder and with a later onset in the homoplasmic as compared to the heteroplasmic form. Further, the homoplasmy of the m.8344A>G variant appears to be more beneficial than harmful.

(1) Background: In this paper, we report on three cases of hypoacusis as part of a complex phenotype and some rare gene variants. An extensive review of literature completes the newly reported clinical and genetic information. (2) Methods: The cases range from 2- to 11-year-old boys, all with a complex clinical picture and hearing impairment. In all cases, whole exome sequencing (WES) was performed, in the first case in association with mitochondrial DNA study. (3) Results: The detected variants were: two heterozygous variants in the TWNK gene, one likely pathogenic and another of uncertain clinical significance (autosomal recessive mitochondrial DNA depletion syndrome type 7-hepatocerebral type); heterozygous variants of uncertain significance PACS2 and SYT2 genes (autosomal dominant early infantile epileptic encephalopathy) and a homozygous variant of uncertain significance in SUCLG1 gene (mitochondrial DNA depletion syndrome 9). Some of these genes have never been previously reported as associated with hearing problems. (4) Conclusions: Our cases bring new insights into some rare genetic syndromes. Although the role of TWNK gene in hearing impairment is clear and accordingly reflected in published literature as well as in the present article, for the presented gene variants, a correlation to hearing problems could not yet be established and requires more scientific data. We consider that further studies are necessary for a better understanding of the role of these variants.

Kearns Sayre Syndrome (KSS) is a rare mitochondrial disease characterized by a primary dysfunction of the mitochondrial respiratory chain. Cardiac involvement is a poor prognostic factor of KSS. Pregnancy and delivery in a KSS patient with cardiac involvement is uncommon, and strategies for the supervision and management of this group remain unclear. Herein, we report and discuss pregnancy and delivery complicated with acute cardiopulmonary failure in a woman with KSS.

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MPV17-related mitochondrial DNA maintenance defect (MPV17 deficiency) is a rare, autosomal recessive mitochondrial DNA depletion syndrome with a high mortality rate in infancy and early childhood due to progression to liver failure. Liver transplantation for children with MPV17 deficiency has been considered controversial due to uncertainty about the potential progression of extrahepatic manifestations following liver transplantation.
We describe our institution\'s experience for two infants diagnosed with infantile MPV17 deficiency who presented in acute on chronic liver failure, but with normal development and normal neurological status who successfully underwent liver transplantation.
Both patients underwent successful liver transplantation with normal development and neurological status at 3 years and 16 months post-transplant, respectively.
In this rare disease population, we describe two infants with MPV17 deficiency who underwent liver transplantation for acute on chronic liver failure who continue to have normal development, without progression of neurological disease. MPV17 deficiency should not be considered a contraindication to liver transplantation.