Expanded phenotypic spectrum of the m.8344A>G “MERRF” mutation: data from the German mitoNET registry

Abstract

The m.8344A>G mutation in the MTTK gene, which encodes the mitochondrial transfer RNA for lysine, is traditionally associated with myoclonic epilepsy and ragged-red fibres (MERRF), a multisystemic mitochondrial disease that is characterised by myoclonus, seizures, cerebellar ataxia, and mitochondrial myopathy with ragged-red fibres. We studied the clinical and paraclinical phenotype of 34 patients with the m.8344A>G mutation, mainly derived from the nationwide mitoREGISTER, the multicentric registry of the German network for mitochondrial disorders (mitoNET). Mean age at symptom onset was 24.5 years ±10.9 (6-48 years) with adult onset in 75 % of the patients. In our cohort, the canonical features seizures, myoclonus, cerebellar ataxia and ragged-red fibres that are traditionally associated with MERRF, occurred in only 61, 59, 70, and 63 % of the patients, respectively. In contrast, other features such as hearing impairment were even more frequently present (72 %). Other common features in our cohort were migraine (52 %), psychiatric disorders (54 %), respiratory dysfunction (45 %), gastrointestinal symptoms (38 %), dysarthria (36 %), and dysphagia (35 %). Brain MRI revealed cerebral and/or cerebellar atrophy in 43 % of our patients. There was no correlation between the heteroplasmy level in blood and age at onset or clinical phenotype. Our findings further broaden the clinical spectrum of the m.8344A>G mutation, document the large clinical variability between carriers of the same mutation, even within families and indicate an overlap of the phenotype with other mitochondrial DNA-associated syndromes.

Prevalence of Headache in Patients With Mitochondrial Disease: A Cross‐Sectional Study

“…However, the genotype‐phenotype correlation shows on the other hand that mutations of the mtDNA can lead to various syndromes and a clinical syndrome on the other hand might be caused by different mutations of mtDNA or nDNA . Headache is known as a common symptom in those patients and in some patients, the diagnostic criteria for migraine are fulfilled . However, it is unclear whether it is a common migraine in a patient with mitochondrial disease (coincident primary headache disorder) or a secondary migraine‐like headache caused by the mitochondrial disease (secondary headache disorder).…”

“…2 Headache is known as a common symptom in those patients and in some patients, the diagnostic criteria for migraine are fulfilled. [3][4][5][6] However, it is unclear whether it is a common migraine in a patient with mitochondrial disease (coincident primary headache disorder) or a secondary migraine-like headache caused by the mitochondrial disease (secondary headache disorder). The recent International Classification of Headache Disorders (ICHD-3 beta) considers only headache in MELAS as a subtype of "Headache attributed to genetic vasculopathy" (Table 1).…”

Patient care standards for primary mitochondrial disease: a consensus statement from the Mitochondrial Medicine Society

“…[58][59][60] Severe headaches in MELAS patients have been associated with stroke-like episodes and seizures. 58 There are no studies looking at the treatment of headache in patients with mitochondrial disease.…”

Mitochondrial DNA mutation load in a family with the m.8344A>G point mutation and lipomas: a case study

“…The m.8344A>G point mutation is generally associated with the clinical phenotype myoclonus epilepsy and ragged-red fibers (MERRF) [3]. However, clinical presentation in this patient group varies [4] and symptoms such as hearing impairment, migraine, and psychiatric disorders may be just as common [5], and clinical case reports have even associated the m.8344A>G genotype with a phenotype of multiple lipomas [6][7][8][9][10][11][12][13][14][15]. We report the clinical, physiological, morphological, and biochemical findings along with mtDNA mutation load in both mitotic and postmitotic tissues in five family members with the m.8344A>G point mutation lipomas in two.…”