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.

MYH7-related myopathies: clinical, histopathological and imaging findings in a cohort of Italian patients.

BACKGROUND: Myosin heavy chain 7 (MYH7)-related myopathies are emerging as an important group of muscle diseases of childhood and adulthood, with variable clinical and histopathological expression depending on the type and location of the mutation. Mutations in the head and neck domains are a well-established cause of hypertrophic cardiomyopathy whereas mutation in the distal regions have been associated with a range of skeletal myopathies with or without cardiac involvement, including Laing distal myopathy and Myosin storage myopathy. Recently the spectrum of clinical phenotypes associated with mutations in MYH7 has increased, blurring this scheme and adding further phenotypes to the list. A broader disease spectrum could lead to misdiagnosis of different congenital myopathies, neurogenic atrophy and other neuromuscular conditions. RESULTS: As a result of a multicenter Italian study we collected clinical, histopathological and imaging data from a population of 21 cases from 15 families, carrying reported or novel mutations in MYH7. Patients displayed a variable phenotype including atypical pictures, as dropped head and bent spine, which cannot be classified in previously described groups. Half of the patients showed congenital or early infantile weakness with predominant distal weakness. Conversely, patients with later onset present prevalent proximal weakness. Seven patients were also affected by cardiomyopathy mostly in the form of non-compacted left ventricle. Muscle biopsy was consistent with minicores myopathy in numerous cases. Muscle MRI was meaningful in delineating a shared pattern of selective involvement of tibialis anterior muscles, with relative sparing of quadriceps. CONCLUSION: This work adds to the genotype-phenotype correlation of MYH7-relatedmyopathies confirming the complexity of the disorder.

Italian validation of INQoL, a quality of life questionnaire for adults with muscle diseases.

BACKGROUND AND PURPOSE: A quality of life (QoL) questionnaire for neuromuscular diseases was recently constructed and validated in the United Kingdom in a sample of adult patients with a variety of muscle disorders. Preliminary results suggested it could be a more relevant and practical measure of QoL in muscle diseases than generic health measures of QoL. The purpose of our work was: (i) To validate INQoL in Italy on a larger sample of adult patients with muscle diseases (ii) to compare INQoL to SF-36. METHODS: We have translated into Italian and applied language adaptations to the original UK INQoL version. We studied 1092 patients with different muscle disorders and performed (i) test-retest reliability (n = 80); (ii) psychometric (n = 345), known-group (n = 1092), external criterion (n = 70), and concurrent validity with SF-36 (n = 183). RESULTS: We have translated and formally validated the Italian version of INQoL confirming and extending results obtained in the United Kingdom. In addition to good results in terms of reliability, known-group and criterion validity, a comparison with the SF-36 scales showed a stronger association between INQoL total index and SF-36 physical (r = -0.72) than mental (r = -0.38) summary health indexes. When considering comparable domains of INQoL and SF-36 with respect to an objective measure of muscle strength assessment (MMRC), regression analysis showed a stronger correlation using INQoL rather than SF-36 scores. CONCLUSIONS: INQoL is recommended to assess QoL in muscle diseases because of its ability to capture physical limitations that are specifically relevant to the muscle condition.

Facioscapulohumeral muscular dystrophy: hearing loss and other atypical features of patients with large 4q35 deletions.

BACKGROUND AND PURPOSE: Patients affected by facioscapulohumeral muscular dystrophy (FSHD) with unusual large 4q35 deletions tend to present atypical features in early childhood. We explored the clinical presentation of patients with a very short 4q35 fragment (10-13 kb) focusing on hearing loss, a still debated FSHD extra-muscular manifestation. PATIENTS AND METHODS: We evaluated six cases with EcoRI 4q35 fragment size ranging from 10 to 13 kb. Assessment of hearing function was carried out by otoscopy, audiometry and auditory-evoked brainstem responses (ABR). Patient data were compared with those of 28 similar subjects reported in the literature. RESULTS: Sensorineural hearing loss was found in four patients, who presented infantile-onset dystrophic phenotype. Hearing loss was associated with mental retardation in three of them and with epilepsy in two. Auditory ability of the other two cases was mildly impaired. If findings related to 28 similar cases reported to date are also considered, auditory impairment appears evident in 68% of these subjects. CONCLUSIONS: Hearing loss represents a characteristic feature of FSHD patients with a large 4q35 deletion. Moreover, when considering only cases with 10-11 kb, it appears to be associated with early-onset dystrophic phenotype, with mental retardation (92%) and possibly with epilepsy (58%).