Adult presentation of a rare mitochondrial tRNA Val gene mutation—an expanding clinical phenotype

Abstract

Background and purpose

Late‐onset mitochondrial disorders are diagnostically challenging with significant heterogeneity in disease presentation. A case is reported of a 67‐year‐old gentleman who presented with a 3‐month history of seizures, recurrent encephalopathy, ataxia and weight loss, preceded by recent initiation of haemodialysis for end‐stage chronic kidney disease.

Methods

Extensive work‐up including serological, cerebrospinal fluid, magnetic resonance imaging and electroencephalography was performed. Whole exome sequencing and muscle biopsy confirmed the diagnosis.

Results

Magnetic resonance imaging brain demonstrated a single non‐enhancing T2 fluid attenuated inversion recovery hyperintense cortical/subcortical signal change in the right temporal lobe and cerebellar atrophy. Given the subacute presentation of uncertain aetiology, he was empirically treated for autoimmune/paraneoplastic encephalitis. Despite radiological resolution of the cortical abnormality 2 weeks later, there was no clinical improvement. Further collateral history unveiled a mildly ataxic gait and longstanding hearing loss suggestive of a genetic cause. Whole exome sequencing revealed a likely pathogenic, heteroplasmic mitochondrial DNA variant in the MT‐TV gene, m.1659T>C, present at higher levels of heteroplasmy in muscle (91%) compared to other mitotic tissues. A high fat/protein diet and multivitamins including co‐enzyme Q10 were commenced. Treatment of the nutritional deficiency and avoidance of intermittent fasting due to unreliable oral intake secondary to encephalopathy probably contributed to the clinical improvement seen over the ensuing few months, with resolution of his encephalopathy and return to his baseline gait and weight.

Conclusion

An adult case is reported with an acute neurological presentation mimicking encephalitis, caused by a heteroplasmic m.1659T>C MT‐TV variant, previously reported once in a child who displayed a different clinical phenotype.

BACKGROUND

Mitochondrial cytopathies are multisystem complex disorders with significant heterogeneity in terms of disease onset and symptomatology [1]. Myopathy is a common presentation of adult‐onset mitochondrial disorders; however, the clinical spectrum can be heterogeneous given the multiorgan systems involved [1, 2]. A case is presented of a rare mitochondrial DNA variant in an adult male presenting with a mitochondrial encephalomyopathy and cystic kidney disease (CKD) requiring haemodialysis.

CASE

A 67‐year‐old right‐handed gentleman presented with a 3‐month history of recurrent encephalopathy, seizures, ataxia and weight loss. He was started on haemodialysis for end‐stage CKD 10 weeks prior. Treatment with levetiracetam 2000 mg/day stopped his seizures. His encephalopathy worsened with alternating agitation/drowsiness and he became bedbound. An extensive neurological work‐up was performed as below.

In light of the uncertain aetiology, he was treated empirically for autoimmune/paraneoplastic encephalitis with a 3‐month course of monthly intravenous immunoglobulin and a course of steroids, with no change in clinical status. Due to persistent encephalopathy, weight loss and nutritional depletion, a radiologically inserted percutaneous gastrostomy was inserted and enteral feeding was commenced.

Further collateral history revealed a sensorineural hearing loss and a mild unsteady gait for several decades, which prompted whole exome sequencing. No family members have been identified with this phenotype. The patient's brother and his deceased mother had Parkinson's disease, diagnosed at age 60 and 73 respectively.

Once the initial genetic pathogenic variant was identified, the patient was commenced on a ketogenic high fat diet with addition of co‐enzyme Q10, l‐arginine and vitamins A, E, C, B12. He was transferred back to his local hospital for rehabilitation. The patient's encephalopathy resolved over time and his gait and weight have returned to baseline.

INVESTIGATIONS

Magnetic resonance imaging (MRI) brain revealed a transient hyperintensity in the right temporal lobe (Figure 1a–c). Initial serum anti‐voltage‐gated potassium‐channel (anti‐VGKC) antibody was weakly positive. Repeat anti‐VGKC antibodies were negative in serum and cerebrospinal fluid. An infectious/inflammatory/paraneoplastic process was excluded (Table S1).

FIGURE 1.

(a), (b) MRI brain fluid attenuated inversion recovery (FLAIR) sequence demonstrating T2 FLAIR hyperintense cortical/subcortical signal change in the right temporal lobe which resolved on repeat scan. (b) Hypointensities in the basal ganglia represent prominent perivascular spaces. (c) MRI brain T2 FLAIR sequence demonstrating prominent cerebellar atrophy. (d) Vastus lateralis muscle biopsy. Haematoxylin and eosin staining: myopathic features with variation in fibre size and some fibres showing excess of internalized nuclei. (e) COX histochemical assessment showed significant COX‐deficient muscle fibres (pale brown). (f) Sequential COX and succinate dehydrogenase histochemistry better demonstrates the mosaic pattern of COX‐deficient muscle fibres (COX‐deficient fibres are blue, COX‐positive fibres are brown).

Whole exome sequencing identified a likely pathogenic m.1659T>C variant in the MT‐TV gene (heteroplasmy 59% in blood‐derived DNA), absent in the gnomAD and GenBank databases. Vastus lateralis muscle biopsy revealed evidence of a mitochondrial myopathy (Figure 1d–f), with high heteroplasmy level (91%) for the m.1659T>C variant and lower heteroplasmy in mitotic tissues (71% in urine, 45% in buccal mucosa). Single‐fibre studies demonstrated variant segregation with the cytochrome c oxidase (COX) histochemical defect in the muscle, supporting the pathogenicity of the m.1659T>C variant.

DISCUSSION

To date, more than 350 mitochondrial DNA variants have been identified [1]. Pathogenic variants in MT‐TV have been associated with mitochondrial disease such as mitochondrial encephalopathy, lactic acidosis and stroke‐like episodes (MELAS), Leigh syndrome, axonal Charcot–Marie–Tooth disease and ataxia, myoclonus and deafness [2]. The heterogeneity, variability of clinical syndromes and presentation at all stages of life can pose diagnostic challenges [1, 2].

A rare case of mitochondrial disorder secondary to MT‐TV variant m.1659T>C is reported, and has been reported once in the literature previously in a paediatric patient [2]. The clinical presentation in our case differs significantly from the paediatric case where a clinical picture of learning difficulty, hemiplegia, movement disorder and symmetrical putaminal high signal abnormality on MRI was evident [2].

This case highlights the importance of considering mitochondrial disorders as a potential diagnosis in patients presenting with a fluctuating encephalopathy, seizures, deafness and ataxia at all ages, as well as CKD which in our patient was felt to be a phenotypic expression of this MT‐TV variant. Our patient presented and progressed fairly rapidly to kidney failure and never underwent a kidney biopsy because of small kidneys. Other potential causes for renal disease, for example vasculitis, connective tissue disease, and other genetic causes of CKD were excluded. From a management perspective our patient's clinical presentation and management aligns most closely to that adopted in MELAS. According to the literature, management of mitochondrial diseases varies considerably between countries. In the United States, nutritional optimization, empirical vitamin and other cofactor administration (‘vitamin cocktails’) are advocated even though it remains unproven that such treatment can alter the disease progression [3]. On the other hand, the importance of active seizure management at the outset of stroke‐like episodes is highlighted by the European consensus statement [4]. Whilst the mitochondrial stroke‐like signal abnormalities “relapse and remit” on serial MRIs, accelerated neurodegeneration and brain atrophy are usually evident following these episodes [5]. Our patient had a steady improvement with nutritional repletion via percutaneous endoscopic gastrostomy feeding, with emphasis on a high fat diet and addition of oral vitamins including co‐enzyme Q10, vitamins A, E, C, B12 and l‐arginine. Breakthrough focal seizures are still an ongoing challenge in our patient but establishing a definite diagnosis allowed the introduction of a timely and optimal management moving forward.

AUTHOR CONTRIBUTIONS

Eimear Joyce: Conceptualization; writing – original draft; writing – review and editing; data curation. Mohib Ali: Investigation; data curation; writing – original draft. Georgia Richard: Investigation; writing – original draft; data curation. Siobhan Kelly: Investigation; writing – original draft; data curation. Fiachra Martin: Investigation; writing – review and editing; data curation. Peter J. Conlon: Investigation; writing – review and editing; data curation. Anna Whelehan: Data curation; writing – review and editing; investigation. Yi Shiau Ng: Investigation; writing – original draft; writing – review and editing; data curation; supervision. Stela Lefter: Investigation; writing – original draft; visualization; writing – review and editing; supervision; conceptualization.

CONFLICT OF INTEREST STATEMENT

The authors have no conflict of interest to declare.

Supporting information

Table S1.

Joyce E, Ali M, Richard G, et al. Adult presentation of a rare mitochondrial tRNA Val gene mutation—an expanding clinical phenotype. Eur J Neurol. 2024;31:e16405. doi: 10.1111/ene.16405

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available from the corresponding author upon reasonable request.