Delineating MT-ATP6-associated disease: From isolated neuropathy to early onset neurodegeneration

Claudia Stendel, Christiane Neuhofer, Elisa Floride, Shi Yuqing, Rebecca D Ganetzky, Joohyun Park, Peter Freisinger, Cornelia Kornblum, Stephanie Kleinle, Ludger Schöls, Felix Distelmaier, Georg M Stettner, Boriana Büchner, Marni J Falk, Johannes A Mayr, Matthis Synofzik, Angela Abicht, Tobias B Haack, Holger Prokisch, Saskia B Wortmann, Kei Murayama, Fang Fang, Thomas Klopstock, ATP6 Study Group, Claudia Stendel, Christiane Neuhofer, Elisa Floride, Shi Yuqing, Rebecca D Ganetzky, Joohyun Park, Peter Freisinger, Cornelia Kornblum, Stephanie Kleinle, Ludger Schöls, Felix Distelmaier, Georg M Stettner, Boriana Büchner, Marni J Falk, Johannes A Mayr, Matthis Synofzik, Angela Abicht, Tobias B Haack, Holger Prokisch, Saskia B Wortmann, Kei Murayama, Fang Fang, Thomas Klopstock, ATP6 Study Group

Abstract

Objective: To delineate the phenotypic and genotypic spectrum in carriers of mitochondrial MT-ATP6 mutations in a large international cohort.

Methods: We analyzed in detail the clinical, genetical, and neuroimaging data from 132 mutation carriers from national registries and local databases from Europe, USA, Japan, and China.

Results: We identified 113 clinically affected and 19 asymptomatic individuals with a known pathogenic MT-ATP6 mutation. The most frequent mutations were m.8993 T > G (53/132, 40%), m.8993 T > C (30/132, 23%), m.9176 T > C (30/132, 23%), and m.9185 T > C (12/132, 9%). The degree of heteroplasmy was high both in affected (mean 95%, range 20%-100%) and unaffected individuals (mean 73%, range 20%-100%). Age at onset ranged from prenatal to the age of 75 years, but almost half of the patients (49/103, 48%) became symptomatic before their first birthday. In 28 deceased patients, the median age of death was 14 months. The most frequent symptoms were ataxia (81%), cognitive dysfunction (49%), neuropathy (48%), seizures (37%), and retinopathy (14%). A diagnosis of Leigh syndrome was made in 55% of patients, whereas the classic syndrome of neuropathy, ataxia, and retinitis pigmentosa (NARP) was rare (8%).

Conclusions: In this currently largest series of patients with mitochondrial MT-ATP6 mutations, the phenotypic spectrum ranged from asymptomatic to early onset multisystemic neurodegeneration. The degree of mutation heteroplasmy did not reliably predict disease severity. Leigh syndrome was found in more than half of the patients, whereas classic NARP syndrome was rare. Oligosymptomatic presentations were rather frequent in adult-onset patients, indicating the need to include MT-ATP6 mutations in the differential diagnosis of both ataxias and neuropathies.

Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

Figures

Figure 1. Distribution of the degrees of…
Figure 1. Distribution of the degrees of heteroplasmy
(A) Distribution of the degrees of heteroplasmy in different MT-ATP6-associated phenotypes and asymptomatic carriers. 1 = Leigh/Leigh-like syndrome; 2 = NARP syndrome; 3 = other phenotypes; 4 = asymptomatic carrier. (B) Heteroplasmy grades in every single patients. Each circle represents an individual with a MT-ATP6 mutation. The different tissues used for heteroplasmy assessment are represented by different colors. In probands, where more than one tissue was evaluated for heteroplasmy (n = 21), the highest value was selected. All values in all available tissues are shown in table e-1, links.lww.com/NXG/A213. 1 = Leigh/Leigh-like syndrome; 2 = NARP syndrome; 3 = other phenotypes; 4 = asymptomatic carrier. NARP = neuropathy, ataxia and retinitis pigmentosa.
Figure 2. Distribution of age at onset…
Figure 2. Distribution of age at onset and time diagnosis
(A) Age at symptom onset (years). (B) Distribution of age at symptom onset grouped by mutation. (C) Lag time between age at symptom onset and age at molecular diagnosis in 3 different age groups in years (0–1 1–6, >6).
Figure 3. Distribution and frequency of phenotypes…
Figure 3. Distribution and frequency of phenotypes and symptoms in our cohort
Bars indicate the percentage of patients with a given phenotype (green bars) or symptom (blue bars) of the total assessed for this phenotype or symptom.
Figure 4. Examples of brain MRI changes…
Figure 4. Examples of brain MRI changes detected in patients with MT-ATP6-associated disease
Number of the patient is given in the middle of the images. (A) FLAIR sequence of axial view showing symmetrical bilateral hyperintensities and partly cystic degeneration in the caudate nuclei and putamen (arrows on the left image), as well as bilateral hyperintensities in the medulla oblongata and hyperintensities on the left cerebellar hemisphere (arrows on the right image). (B) Sagittal view of T1 sequence shows a pronounced fronto-parietal and cerebellar atrophy. (C) Axial view of T2 sequence shows subtle unilateral hyperintensities in the left putamen (arrow on left and right image). (D) T2 sequence of sagittal view reveals a microcephaly and hypoplasia of the brainstem and cerebellum. (E) axial view of FLAIR sequence shows bilateral putaminal and caudate head signal alterations, atrophy and cystic changes (arrows on left image). Axial view of T2 sequence reveals a slight cerebellar atrophy and bilateral T2 hyperintensities within the cerebellar peduncles (right image). (F) T1 sequence of sagittal view shows cerebellar and cerebral atrophy and thinning of the corpus callosum (arrows on the left image), whereas basal ganglia structure appeared normal (arrows on right side). FLAIR = fluid-attenuated inversion recovery.

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