Primary mitochondrial myopathy: 12-month follow-up results of an Italian cohort.

OBJECTIVES: To assess natural history and 12-month change of a series of scales and functional outcome measures in a cohort of 117 patients with primary mitochondrial myopathy (PMM). METHODS: Twelve months follow-up data of 117 patients with PMM were collected. We analysed the 6-min walk test (6MWT), timed up-and-go test (× 3) (3TUG), five-times sit-to-stand test (5XSST), timed water swallow test (TWST), and test of masticating and swallowing solids (TOMASS) as functional outcome measures; the Fatigue Severity Scale and West Haven-Yale Multidimensional pain inventory as patient-reported outcome measures. PMM patients were divided into three phenotypic categories: mitochondrial myopathy (MiMy) without extraocular muscles involvement, pure chronic progressive external ophthalmoplegia (PEO) and PEO&MiMy. As 6MWT is recognized to have significant test-retest variability, we calculated MCID (minimal clinically important difference) as one third of baseline 6 min walking distance (6MWD) standard deviation. RESULTS: At 12-month follow-up, 3TUG, 5XSST and FSS were stable, while TWST and the perceived pain severity (WHYMPI) worsened. 6MWD significantly increased in the entire cohort, especially in the higher percentiles and in PEO patients, while was substantially stable in the lower percentile (< 408 m) and MiMy patients. This increase in 6MWD was considered not significant, as inferior to MCID (33.3 m). NMDAS total score showed a slight but significant decline at 12 months (0.9 point). The perceived pain severity significantly worsened. Patients with PEO performed better in functional measures than patients with PEO&MiMy or MiMy, and had lower values of NMDAS. CONCLUSIONS: PMM patients showed a slow global decline valued by NMDAS at 12 months; 6MWT was a more reliable measurement below 408 m, substantially stable at 12 months. PEO patients had better motor performance and lower NMDAS than PEO&MiMy and MiMy also at 12 months of follow-up.

Adult-onset mitochondrial movement disorders: a national picture from the Italian Network.

INTRODUCTION: Both prevalence and clinical features of the various movement disorders in adults with primary mitochondrial diseases are unknown. METHODS: Based on the database of the "Nation-wide Italian Collaborative Network of Mitochondrial Diseases", we reviewed the clinical, genetic, neuroimaging and neurophysiological data of adult patients with primary mitochondrial diseases (n = 764) where ataxia, myoclonus or other movement disorders were part of the clinical phenotype. RESULTS: Ataxia, myoclonus and movement disorders were present in 105/764 adults (13.7%), with the onset coinciding or preceding the diagnosis of the mitochondrial disease in 49/105 (46.7%). Ataxia and parkinsonism were the most represented, with an overall prevalence at last follow-up of 59.1% and 30.5%, respectively. Hyperkinetic movement disorders were reported in 15.3% at last follow-up, being the less common reported movement disorders. The pathogenic m.8344A > G and POLG variants were always associated with a movement disorder, while LHON variants and mtDNA single deletions were more commonly found in the subjects who did not present a movement disorder. The most common neuroimaging features were cortical and/or cerebellar atrophy, white matter hyperintensities, basal ganglia abnormalities and nigro-striatal degeneration. Almost 70% of patients with parkinsonism responded to dopaminergic therapy, mainly levodopa, and 50% with myoclonus were successfully treated with levetiracetam. CONCLUSION: Movement disorders, mainly ataxia and parkinsonism, are important findings in adult primary mitochondrial diseases. This study underlies the importance of looking for a mitochondrial etiology in the diagnostic flowchart of a movement disorder and may help direct genetic screening in daily practice.

Chronic inflammatory demyelinating polyradiculoneuropathy: can a diagnosis be made in patients not fulfilling electrodiagnostic criteria?

BACKGROUND AND PURPOSE: The aim was to identify the clinical and diagnostic investigations that may help to support a diagnosis of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) in patients not fulfilling the European Federation of Neurological Societies and Peripheral Nerve Society (EFNS/PNS) electrodiagnostic criteria. METHODS: The data from patients with a clinical diagnosis of CIDP included in a national database were retrospectively reviewed. RESULTS: In all, 535 patients with a diagnosis of CIDP were included. This diagnosis fulfilled the EFNS/PNS criteria in 468 patients (87.2%) (definite in 430, probable in 33, possible in three, while two had chronic immune sensory polyradiculopathy). Sixty-seven patients had a medical history and clinical signs compatible with CIDP but electrodiagnostic studies did not fulfill the EFNS/PNS criteria for CIDP. These patients had similar clinical features and frequency of abnormal supportive criteria for the diagnosis of CIDP compared to patients fulfilling EFNS/PNS criteria. Two or more abnormal supportive criteria were present in 40 (61.2%) patients rising to 54 (80.6%) if a history of a relapsing course as a possible supportive criterion was also included. Increased cerebrospinal fluid proteins and response to immune therapy most frequently helped in supporting the diagnosis of CIDP. Response to therapy was similarly frequent in patients fulfilling or not EFNS/PNS criteria (87.3% vs. 85.9%). CONCLUSIONS: Patients with a clinical diagnosis of CIDP had similar clinical findings, frequency of abnormal supportive criteria and response to therapy compared to patients fulfilling EFNS/PNS criteria. The presence of abnormal supportive criteria may help in supporting the diagnosis of CIDP in patients with a medical history and clinical signs compatible with this diagnosis but non-diagnostic nerve conduction studies.

Risk factors for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP): antecedent events, lifestyle and dietary habits. Data from the Italian CIDP Database.

BACKGROUND AND PURPOSE: The role of lifestyle and dietary habits and antecedent events has not been clearly identified in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). METHODS: Information was collected about modifiable environmental factors and antecedent infections and vaccinations in patients with CIDP included in an Italian CIDP Database. Only patients who reported not having changed their diet or the lifestyle habits investigated in the study after the appearance of CIDP were included. The partners of patients with CIDP were chosen as controls. Gender-matched analysis was performed with randomly selected controls with a 1:1 ratio of patients and controls. RESULTS: Dietary and lifestyle data of 323 patients and 266 controls were available. A total of 195 cases and 195 sex-matched controls were used in the analysis. Patients eating rice at least three times per week or eating fish at least once per week appeared to be at decreased risk of acquiring CIDP. Data on antecedent events were collected in 411 patients. Antecedent events within 1-42 days before CIDP onset were reported by 15.5% of the patients, including infections in 12% and vaccinations in 1.5%. Patients with CIDP and antecedent infections more often had an acute onset of CIDP and cranial nerve involvement than those without these antecedent events. CONCLUSIONS: The results of this preliminary study seem to indicate that some dietary habits may influence the risk of CIDP and that antecedent infections may have an impact on the onset and clinical presentation of the disease.

Effects of short-to-long term enzyme replacement therapy (ERT) on skeletal muscle tissue in late onset Pompe disease (LOPD).

AIMS: Pompe disease is an autosomal recessive lysosomal storage disorder resulting from deficiency of acid α-glucosidase (GAA) enzyme. Histopathological hallmarks in skeletal muscle tissue are fibre vacuolization and autophagy. Since 2006, enzyme replacement therapy (ERT) is the only approved treatment with human recombinant GAA alglucosidase alfa. We designed a study to examine ERT-related skeletal muscle changes in 18 modestly to moderately affected late onset Pompe disease (LOPD) patients along with the relationship between morphological/biochemical changes and clinical outcomes. Treatment duration was short-to-long term. METHODS: We examined muscle biopsies from 18 LOPD patients at both histopathological and biochemical level. All patients underwent two muscle biopsies, before and after ERT administration respectively. The study is partially retrospective because the first biopsies were taken before the study was designed, whereas the second biopsy was always performed after at least 6 months of ERT administration. RESULTS: After ERT, 15 out of 18 patients showed improved 6-min walking test (6MWT; P = 0.0007) and most of them achieved respiratory stabilization. Pretreatment muscle biopsies disclosed marked histopathological variability, ranging from an almost normal pattern to a severe vacuolar myopathy. After treatment, we detected morphological improvement in 15 patients and worsening in three patients. Post-ERT GAA enzymatic activity was mildly increased compared with pretreatment levels in all patients. Protein levels of the mature enzyme increased in 14 of the 18 patients (mean increase = +35%; P < 0.05). Additional studies demonstrated an improved autophagic flux after ERT in some patients. CONCLUSIONS: ERT positively modified skeletal muscle pathology as well as motor and respiratory outcomes in the majority of LOPD patients.

Revisiting mitochondrial ocular myopathies: a study from the Italian Network.

Ocular myopathy, typically manifesting as progressive external ophthalmoplegia (PEO), is among the most common mitochondrial phenotypes. The purpose of this study is to better define the clinical phenotypes associated with ocular myopathy. This is a retrospective study on a large cohort from the database of the "Nation-wide Italian Collaborative Network of Mitochondrial Diseases". We distinguished patients with ocular myopathy as part of a multisystem mitochondrial encephalomyopathy (PEO-encephalomyopathy), and then PEO with isolated ocular myopathy from PEO-plus when PEO was associated with additional features of multisystemic involvement. Ocular myopathy was the most common feature in our cohort of mitochondrial patients. Among the 722 patients with a definite genetic diagnosis, ocular myopathy was observed in 399 subjects (55.3%) and was positively associated with mtDNA single deletions and POLG mutations. Ocular myopathy as manifestation of a multisystem mitochondrial encephalomyopathy (PEO-encephalomyopathy, n = 131) was linked to the m.3243A>G mutation, whereas the other "PEO" patients (n = 268) were associated with mtDNA single deletion and Twinkle mutations. Increased lactate was associated with central neurological involvement. We then defined, among the PEO group, as "pure PEO" the patients with isolated ocular myopathy and "PEO-plus" those with ocular myopathy and other features of neuromuscular and multisystem involvement, excluding central nervous system. The male proportion was significantly lower in pure PEO than PEO-plus. This study reinforces the need for research on the role of gender in mitochondrial diseases. The phenotype definitions here revisited may contribute to a more homogeneous patient categorization, useful in future studies and clinical trials.

LOPED study: looking for an early diagnosis in a late-onset Pompe disease high-risk population.

OBJECTIVE: A multicentre observational study was aimed to assess the prevalence of late-onset Pompe disease (LOPD) in a large high-risk population, using the dried blood spot (DBS) as a main screening tool. DESIGN/METHODS: 17 Italian neuromuscular centres were involved in the late-onset Pompe early diagnosis (LOPED) study. Inclusion criteria were: (1) age ≥5 years, (2) persistent hyperCKaemia and (3) muscle weakness at upper and/or lower limbs (limb-girdle muscle weakness, LGMW). Acid α-glucosidase (GAA) activity was measured separately on DBS by fluorometric as well as tandem mass spectrometry methods. A DBS retest was performed in patients resulted positive at first assay. For the final diagnosis, GAA deficiency was confirmed by a biochemical assay in skeletal muscle, whereas genotype was assessed by GAA molecular analysis. RESULTS: In a 14-month period, we studied 1051 cases: 30 positive samples (2.9%) were detected by first DBS screening, whereas, after retesting, 21 samples were still positive. Biochemical and molecular genetic studies finally confirmed LOPD diagnosis in 17 cases (1.6%). The median time from the onset of symptoms/signs to diagnosis was 5 years. Among those patients, 35% showed presymptomatic hyperCKaemia and 59% showed hyperCKaemia+LGMW, whereas 6% manifested with LGMW. CONCLUSIONS: LOPED study suggests that GAA activity should be accurately screened by DBS in all patients referring for isolated hyperCKaemia and/or LGMW. A timely diagnosis was performed in five patients with presymptomatic hyperCKaemia, but two had already manifested with relevant changes on muscle morphology and MRI. Consequently, enzyme replacement therapy was started in 14/17 patients, including the 2 patients still clinically presymptomatic but with a laboratory evidence of disease progression.

Late-Onset Glycogen Storage Disease Type 2.

Glycogenosis II (GSDII) is an autosomal recessive lysosomal storage disorder resulting from acid alpha-glucosidase (GAA) deficiency, subsequent lysosomal accumulation of glycogen in muscles, impairment of autophagic processes and progressive cardiac, motor and respiratory failure. The infantile form usually appears in the first month of life, progresses rapidly and presents with severe cardiac involvement and complete deficiency of alpha-glucosidase activity (< 1% of normal controls). The late-onset form is characterized by great variability of the phenotypical spectrum. Main findings are muscle weakness and severe respiratory insufficiency while cardiac involvement may be completely absent. Residual GAA enzyme activity may correlate with severity of phenotype but many adult patients sharing the same mutations present with a wide variability in residual enzyme activity, age of onset and rate of disease progression, thus supporting a role for other factors, i.e., post-translational modifications and modifier genes, in modulating disease presentation. Enzyme replacement therapy (ERT) with alglucosidase alfa stabilizes the disease or improves muscle and/or respiratory function. However, efficacy of ERT may be influenced by several factors including age when ERT begins, extent of muscle damage, degree of defective autophagy, diversity in muscle fiber composition, difficulties in delivery of the therapeutic agent and antibody production. Further studies should be warranted to investigate factors determining the differences in clinical expression and therapeutic response in order to achieve better clinical and therapeutic management of these patients.

Myopathic involvement and mitochondrial pathology in Kennedy disease and in other motor neuron diseases.

Kennedy disease (spinal and bulbar muscular atrophy, or SBMA) is a motor neuron disease caused by a CAG expansion in the androgen-receptor (AR) gene. Increasing evidence shows that SBMA may have a primary myopathic component and that mitochondrial dysfunction may have some role in the pathogenesis of this disease. In this article, we review the role of mitochondrial dysfunction and of the mitochondrial genome (mtDNA) in SBMA, and we present the illustrative case of a patient who presented with increased CK levels and exercise intolerance. Molecular analysis led to definitive diagnosis of SBMA, whereas muscle biopsy showed a mixed myopathic and neurogenic process with "mitochondrial features" and multiple mtDNA deletions, supporting some role of mitochondria in the pathogenesis of the myopathic component of Kennedy disease. Furthermore, we briefly review the role of mitochondrial dysfunction in two other motor neuron diseases (namely spinal muscular atrophy and amyotrophic lateral sclerosis). Most likely, in most cases mtDNA does not play a primary role and it is involved subsequently. MtDNA deletions may contribute to the neurodegenerative process, but the exact mechanisms are still unclear. It will be important to develop a better understanding of the role of mitochondrial dysfunction in motoneuron diseases, since it may lead to the development of more effective strategies for the treatment of this devastating disorder.

The brain in late-onset glycogenosis II: a structural and functional MRI study.

BACKGROUND: Late-onset glycogenosis type II (GSD II) is a rare, multisystem disorder mainly affecting limb and respiratory muscles due to acid alpha glucosidase deficiency. Despite evidence at autopsy of glycogen accumulation in the brain, no study exploring brain functions is yet available. OBJECTIVE: Our objective in this study was to assess brain changes in late-onset GSD II. METHODS: Each patient underwent a standardized neuropsychological assessment, regional grey-matter (GM) atrophy, and resting-state functional magnetic resonance imaging (RS-fMRI). Functional connectivity maps of the salience (SN) and default-mode (DMN) networks were considered. A group of age- and gender-matched healthy controls was enrolled for MRI comparisons. P values family-wise error (FWE) cluster level corrected inferior to 0.05 were considered. RESULTS: Nine GSD II patients (age 46.6 ± 8.0; 55% male) were recruited. No significant GM atrophy was found in patients compared with controls (n = 18; age 48.0 ± 9.8,;40% male). Functional connectivity within the SN was selectively reduced in patients, and cingulate gyrus and medial frontal cortex were mainly involved. Accordingly, patients had significant impairment of executive functions (as measured by Wisconsin Card Sorting test), whereas other cognitive domains were within mean normal ranges. CONCLUSIONS: Our findings extend the clinical spectrum of GSD II by indicating that brain changes occur in this muscular disorder. Above all, these results should lead to better examinations of therapeutic approaches and perspectives for the affected patients. Further studies evaluating in depth these issues are warranted.

Observational clinical study in juvenile-adult glycogenosis type 2 patients undergoing enzyme replacement therapy for up to 4 years.

The objective of this study was to describe a large Italian cohort of patients with late-onset glycogen storage disease type 2 (GSDII) at various stages of disease progression and to evaluate the clinical effectiveness of alglucosidase alpha enzyme replacement therapy (ERT). Previous studies showed in late-onset patients ERT efficacy against placebo and variable response in uncontrolled studies. Seventy-four juvenile or adult GSDII patients were treated with ERT in a multicenter open label, non-randomized study, from 12 months up to 54 months. Recombinant human alpha glucosidase (rh-GAA) was injected by intravenous route at 20 mg/kg every second week. Patients were divided into three groups according to ERT duration: Group A received treatment for 12-23 months (n = 16), Group B for 24-35 months (n = 14), and Group C for more than 36 months (n = 44). Clinical assessment included a 6-min walk test (6MWT), forced vital capacity (FVC), the Walton and Gardner-Medwin score, the number of hours of ventilation, body mass index, echocardiography and blood creatine kinase (CK). Included in our cohort were 33 males and 41 females (M:F = 0.8:1), with a mean age at first symptoms of 28.3 years (range 2-55 years) and a mean age of 43 years at study entry (range 7-72 years). Seven wheelchair bound patients, as well as 27 patients requiring ventilation support, were included. After treatment we could observe an increase in distance walked on the 6MWT in the large majority of patients (48/58; 83%), with an overall mean increase of 63 m (from 320 ± 161 to 383 ± 178 m). After treatment in the majority of patients FVC was improved or unchanged (45/69; 65%). In ventilated patients we observed an improvement in average number of hours off the ventilator (from 15.6 to 12.1 h). Six patients stopped mechanical ventilation and two others started it. The effect of therapy was not related to ERT duration. Nine of 64 patients (13%) that underwent to echocardiography showed a variable degree of cardiac hypertrophy (left ventriculum or septum), and a positive effect was observed after 36 months of ERT in one adult case. Discontinuation of treatment occurred in four patients: one drop-off case, one patient died for a sepsis after 34 months of treatment and two patients stopped ERT for worsening of general clinical condition. Mild adverse effects were observed in four cases (5%). This study represents the largest cohort of late-onset GSDII patients treated with ERT, and confirm a positive effect of treatment. These results, obtained in a large case series on therapy, indicate a favourable effect of ERT therapy, even in more advanced stage of the disease.

Clinical, morphological and genetic studies in a cohort of 21 patients with myofibrillar myopathy.

The term myofibrillar myopathies (MFM) refers to uncommon neuromuscular disorders that pathologically are characterized by myofibrillar degeneration and ectopic expression of several proteins. MFM are partly caused by mutations in genes that encode mainly Z-disk-related proteins (desmin, alphaB-crystallin, myotilin, ZASP, filamin C and BAG3). We reviewed clinical, light and electron microscopy, immunohistochemistry, immunoblotting and genetic findings of 21 patients with MFM (15 unrelated patients and three pairs of brothers) investigated at our neuromuscular center. MFM patients begin to show symptoms at any age, from juvenile to late adult life and present a different distribution of muscle weakness. Cardiac involvement and peripheral neuropathy are common. Typical histological features include focal areas with reduction/loss of ATPase and oxidative enzyme activity, and amorphous material (eosinophilic on hematoxylin and eosin and dark blue on Engel-Gomori trichrome) in these abnormal fiber areas. Electron microscopy shows disintegration of myofibrils starting from the Z-disk and accumulation of granular and filamentous material among the myofilaments. Immunohistochemical studies demonstrate focal accumulation of desmin, alphaB-crystallin and myotilin in abnormal muscle fibers while immunoblot analysis does not highlight differences in the expression of these proteins also including ZASP protein. Therefore, unlike immunoblot, immunohistochemistry together with light and electron microscopy is a useful diagnostic tool in MFM. Finally three of our 21 patients have missense mutations in the desmin gene, two brothers carry missense mutations in the gene encoding myotilin, one has a missense mutation in alphaB-crystallin, and none harbour pathogenic variations in the genes encoding ZASP and BAG3.

Mitochondrial diseases: a nosological update.

Mitochondrial diseases are disorders caused by impairment of the mitochondrial respiratory chain, characterized by clinical-genetic heterogeneity and frequent multisystemic involvement. It is difficult to establish a precise genotype/phenotype correlation and obtain a definitive nosology. Today's genetic classification distinguishes disorders caused by defects in the mitochondrial genome (sporadic or maternally-inherited) from disorders caused by defects in the nuclear genome (autosomally-inherited). We report an updated classification, briefly review the main clinical syndromes and describe the most recent genetic knowledge.

Eyelid ptosis from sympathetic nerve dysfunction mistaken as myopathy: a simple test to identify this condition.

Acquired isolated unilateral or bilateral blepharoptosis has many aetiologies. When the pupils are normal, a myasthenic syndrome or myopathy has to be ruled out. If the tests for myasthenia gravis are negative, the next step is to perform a muscle biopsy to establish a diagnosis. Muscle examination may show a mitochondrial disorder, non-specific abnormalities or be quite normal. We identified three patients, who had previously undergone various investigations, including a muscle biopsy, whose lid ptosis disappeared using eye drops containing naphazoline nitrate, a sympathomimetic drug, thus suggesting partial Horner's syndrome. We emphasise the usefulness of this simple and cheap test before performing more traumatic and expensive investigations.

The role of muscle biopsy in investigating isolated muscle pain.

OBJECTIVE: To evaluate the muscle biopsy findings from 240 patients who had isolated muscle pain. METHODS: Histopathology, immunohistochemistry for dystrophin, dystrophin-related proteins, major histocompatibility complex type I, and biochemical analysis of glycolytic and mitochondrial respiratory chain enzymes were performed on muscle biopsies. An attempt was made to correlate pathologic data and clinical findings (sex, age, quality and distribution of symptoms, serum CK levels, and EMG recording). RESULTS: We have described five groups of patients based on muscle biopsy findings: 51.6% had heterogeneous myopathic abnormalities; only 19% of them had a specific myopathic picture, i.e., central nuclei myopathy, central core disease, myopathy with tubular aggregates or with trabecular fibers or abnormalities of fiber typing; 20% had signs of respiratory chain dysfunction but only one patient had a probable mitochondrial disease; 7% had a neurogenic pattern; 2.4% had a metabolic myopathy (phosphorylase or phosphofructokinase deficiency); and 19% had normal muscle biopsy. No clear-cut correlation between muscle biopsy and clinical data was observed except for those patients with a metabolic myopathy. CONCLUSIONS: The probability that a patient complaining only of muscle pain and with a normal neurologic examination has a definite muscle pathology is 2%. Only patients with sole exercise-related muscle pain and sCK seven times higher than the normal value are strongly suspected of having a metabolic myopathy. A rigorous selection of patients is needed before performing a muscle biopsy.

Expression of late myogenic differentiation markers in sarcoplasmic masses of patients with myotonic dystrophy.

Sarcoplasmic masses contain disorganized myofibrillar material and are a striking feature of myotonic dystrophy. However their significance is still unclear. Using immunocytochemistry we studied the expression of cytoskeletal proteins (desmin and vimentin), dystrophin, markers of myogenic differentiation (foetal myosin, neural cell adhesion molecule, bcl-2, insulin-like growth factor-I, fibroblast growth factor, retinoblastoma protein and myoD1), cell cycle regulators (Cdk2, p16, p27 and p57) and muscle proteases (ubiquitin, micro and m calpain and cathepsin D) in muscle biopsies from four patients with myotonic dystrophy. Sarcoplasmic masses were strongly positive for desmin, neural cell adhesion molecule, bcl-2, insulin-like growth factor I, retinoblastoma protein and p57, weakly positive for dystrophin and p16 and negative for vimentin, fibroblast growth factor, myoD1, Cdk2 and p27. Immunoreactivity for foetal myosin was detected only in a few fibres (< 1%). Our data suggest that the late myogenic differentiation programme is activated in sarcoplasmic masses although these areas do not reach complete maturation.

A non-syndromic hearing loss caused by very low levels of the mtDNA A3243G mutation.

We described a patient with progressive non-syndromic hearing loss (NSHL) harboring the A3243G mutation in the mitochondrial DNA (mtDNA). Muscle biopsy showed scattered ragged-red, cytochrome c oxidase negative fibers, whereas the biochemical analysis of the mitochondrial respiratory chain complexes was normal. Restriction fragment length polymorphism (RFLP) analysis showed A3243G mtDNA transition, present at very low in patient's muscle (3%) and in urinary sediments (1%), and not detectable in blood and buccal mucosa. The patient was submitted to a bilateral cochlear implantation with post-operative excellent hearing and communicative outcomes. Our findings indicate that A3243G mutation may be responsible both for SHL and NSHL, may be depending on the levels of mutated mtDNA. Patients with hearing loss due to mtDNA mutations should be considered as good candidates for cochlear implantation.