Juvenile parkinsonism, hypogonadism and Leigh-like MRI changes in a patient with m.4296G>A mutation in mitochondrial DNA

doi:10.1016/j.mito.2013.01.012

Mitochondrion

Volume 13, Issue 2, March 2013, Pages 83-86

https://doi.org/10.1016/j.mito.2013.01.012 Get rights and content

Abstract

Leigh syndrome is a mitochondrial disease with considerable clinical and genetic variation. We present a 16-year-old boy with Leigh-like syndrome and broad developmental retardation, parkinsonism and hypogonadism. Sequencing of the entire mitochondrial DNA from blood revealed the m.4296G>A mutation in the MT-TI gene. The mutation was heteroplasmic with a 95% proportion of the mutant genome, while the proportion was 58% in the blood of the patient's clinically healthy mother. Our results suggest that m.4296G>A is pathogenic in humans, and that the phenotype related to this change includes Leigh-like syndrome in adolescence with parkinsonism and hypogonadism, in addition to the previously reported early infantile Leigh syndrome.

Highlights

► Leigh syndrome is a mitochondrial disease with large clinical and genetic variation. ► A 16-year-old boy presented with Leigh-like syndrome, parkinsonism and hypogonadism. ► Sequencing of the entire mtDNA revealed the m.4296G>A mutation in the MT-TI gene. ► We suggest that the m.4296G>A mutation is pathogenic and causes Leigh-like syndrome.

Introduction

Mitochondria are essential intracellular organelles that undertake many vital metabolic functions. The primary function of mitochondria is the production of ATP from ADP by the process of oxidative phosphorylation (OXPHOS). This process is dependent upon five multisubunit enzyme complexes that are under dual genetic control. Mitochondrial DNA (mtDNA) encodes 13 of the more than 80 subunits in these respiratory chain (RC) complexes and, in addition, the two rRNAs, and 22 tRNAs required in mitochondrial protein synthesis.

Mitochondrial disease refers primarily to pathological conditions that result from abnormal function of RC resulting in defective OXPHOS. Leigh syndrome (LS) is an extremely variable and multi-etiological entity in mitochondrial disease (Finsterer, 2008). Typically, LS is a devastating encephalopathy of infants and children, and results from a severe OXPHOS defect. Characteristic clinical features of LS include progressive psychomotor regression, hypotonia, ataxia, seizures, respiratory difficulties, dystonia, and problems with swallowing (Dahl, 1998). Brain imaging shows bilateral necrotizing lesions within the basal ganglia, thalami and in the brainstem (Lee et al., 2009). Lactate concentration is commonly elevated in blood and CSF. Genetic etiology of LS is highly variable. These include mtDNA deletions as well as mtDNA point mutations; the most common of these being m.8993T>G and m.8993T>C in the MTATP6 gene encoding the F_O subunit 6 of complex V (Makino et al., 2000, Uziel et al., 2011) in the mitochondrial RC. Mutations in several autosomal genes also result in LS, such as mutations in SURF1, encoding an assembly factor of RC complex IV (cytochrome c oxidase), and mutations in several complex I subunit-encoding genes (Lee et al., 2012, Uziel et al., 2011).

‘Leigh-like’ syndrome refers to cases that are clinically or neuroradiologically suggestive of LS but do not fulfill the stringent criteria (Rahman et al., 1996). These patients may present with milder phenotypes of mitochondrial disease that resemble LS, sometimes with onset of symptoms in adolescence or adulthood. Here we present a case of a Leigh-like syndrome in an adolescent boy with the clinical features of parkinsonism, cognitive decline and hypogonadism. Sequencing of the entire mtDNA revealed heteroplasmic m.4296G>A mutation in the MT-TI gene encoding mitochondrial tRNA^Ile.

Section snippets

Case report

The patient is a boy, whose prenatal and early development had been unremarkable, though obstipation was noted already in the first year of life, and he had gained weight slowly. He learned to walk at age 13 months. He first presented to a pediatrician at age 9 years, because of overweight, excessive sweating, and suspected hypogonadism. At that time, he was 135.7 cm and 42.1 kg; (BMI 31.0), but otherwise clinical examination was unremarkable. No further investigations were performed. The boy's

Clinical investigations

At age 16 years, the patient was investigated thoroughly by a child neurologist. The work-up included brain magnetic resonance (MR) imaging, heart ultrasound, electrocardiography (ECG), electroencephalography (EEG), cerebrospinal fluid (CSF) examination, electrophysiological and histopathological examination of the skeletal muscle, nerve conduction velocities, comprehensive laboratory examinations of blood and urine, and genetic investigations on DNA extracted from blood.

Molecular methods

DNA purification from

The index patient

Brain MR imaging at age 16 years revealed subacute, bilateral abnormalities in the putamina and the caudate nuclei were oedemic (Fig. 1A). Thirteen months later, chronic, necrotic changes were seen in the same brain regions (Fig. 1B). The imaging findings suggested a Leigh-like mitochondrial disorder. Heart ultrasound and ECG were normal. EEG revealed slight general disturbance but no epileptiform abnormalities. CSF was normal including lactate (2.4 mmol/l; laboratory reference, 0.6–2.7 mmol/l).

Discussion

We found an adolescent boy with Leigh-like syndrome and clinical features of parkinsonism, cognitive decline and hypogonadism, who harbored the heteroplasmic m.4296G>A mutation in mtDNA. This mutation has previously been reported in oncocytic pituitary adenoma cells (Porcelli et al., 2010) and in a patient with infantile LS (Cox et al., 2012). The brain MRI findings of our patient were considered compatible with LS, but otherwise the phenotype was clearly different from that reported recently

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LS (also known as subacute necrotizing encephalomyelopathy) is a progressive neurodegenerative disorder of the central nervous system that primarily affects the spinal cord, basal ganglia, pons, cerebellum and thalamus, as well as causes demyelination of optic nerves (Westarp et al., 1992; Duff et al., 2015; Gerards et al., 2016). Other mtDNA mutations, such as m.4296G>A (tRNAIle) (Martikainen et al., 2013), m.5523T>G and m.5559A>G (tRNATrp) (Mkaouar-Rebai et al., 2009), m.13513G>A (ND5) (Shanske et al., 2008), m.13514A>G (ND5) (Bannwarth et al., 2013), m.9191T>C (ATP6) (Moslemi et al., 2005) and m.9478T>C (COIII) (Mkaouar-Rebai et al., 2011), are also reportedly associated with LS (Fig. 1). The ailment has an incidence rate of one in 40,000 live births (Lake et al., 2015).
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Juvenile parkinsonism, hypogonadism and Leigh-like MRI changes in a patient with m.4296G>A mutation in mitochondrial DNA

Abstract

Highlights

Introduction

Section snippets

Case report

Clinical investigations

Molecular methods

The index patient

Discussion

Neuromuscul. Disord.

Mitochondrion

Am. J. Hum. Genet.

Am. J. Hum. Genet.

Pediatr. Neurol.

Pediatr. Neurol.

Pediatr. Neurol.

Lancet

Parkinsonism Relat. Disord.

Mitochondrion

Lancet Neurol.

Biochem. Biophys. Res. Commun.

Semin. Fetal Neonatal. Med.

Mitochondrial tRNA(Thr) mutations and lethal infantile mitochondrial myopathy

Am. J. Hum. Genet.

Cytochrome c oxidase partial deficiency-associated Leigh disease presenting as an extrapyramidal syndrome

J. Child Neurol.

Parkinson's syndrome and Parkinson's disease in mitochondrial disorders

Mov. Disord.

Human mitochondrial database

Parkinson syndrome, neuropathy, and myopathy caused by the mutation A8344G (MERRF) in tRNALys

Neurology

Spectrum of myopathic findings in 50 patients with the 3243A>G mutation in mitochondrial DNA

Brain

Conformation sensitive gel electrophoresis for simple and accurate detection of mutations: comparison with denaturing gradient gel electrophoresis and nucleotide sequencing

Proc. Natl. Acad. Sci. U. S. A.

Parkinson syndrome, neuropathy, and myopathy caused by the mutation A8344G (MERRF) in tRNA^Lys