G. Comi

Functional changes in Duchenne muscular dystrophy A 12-month longitudinal cohort study

Objective: The aim of the study was to assess different outcome measures in a cohort of ambulant boys with Duchenne muscular dystrophy (DMD) over 12 months in order to establish the spectrum of possible changes in relation to age and steroid treatment. Methods: The study is a longitudinal multicentric cohort study. A total of 106 ambulant patients with DMD were assessed using the 6-minute walk test (6MWT) and North Star Ambulatory Assessment (NSAA) at baseline and 12 months. Clinical data including age and steroid treatment were collected. Results: During the 12 months of the study, we observed a mean decline of 25.8 meters in the 6MWT with a SD of 74.3 meters. On NSAA, the mean decline was 2.2 points with a SD of 3.7. Not all the boys with DMD in our cohort showed a decline over the 12 months, with young boys showing some improvement in their 6MWT and NSAA scores up to the age of 7. NSAA and the 6MWT had the highest correlation (r = 0.52, p < 0.001). Conclusions: This study provides longitudinal data of NSAA and 6MWT over a 12-month period. These data can be useful when designing a clinical trial.

Clinical and biochemical correlations in mitochondrial myopathies treated with coenzyme Q10

We tested the efficacy of coenzyme Q10 (ubidecarenone, CoQ10) therapy in patients with Kearns-Sayre syndrome and other mitochondrial myopathies with chronic progressive external ophthalmoplegia (CPEO). We treated seven patients for 1 year with daily oral administration of 120 mg of CoQ10. Throughout the treatment most of our patients showed a progressive reduction of serum lactate and pyruvate levels following standard muscle exercise and generally improved neurologic functions. The ECG and echocardiogram showed no significant changes in our patients. None of our patients showed any improvement in ptosis and CPEO.

Mutated mitofusin 2 presents with intrafamilial variability and brain mitochondrial dysfunction

Background: The axonal forms of Charcot-Marie-Tooth (CMT2) disease are a clinically and genetically heterogeneous group of disorders. Mitofusin 2 gene (MFN2) mutations are the most common cause of CMT2. Complex phenotypes have been described in association with MFN2 gene mutations, including CMT2 with pyramidal features (hereditary motor and sensory neuropathy [HSMN V]) and CMT2 with optic atrophy (HMSN VI). Objective: To report on the clinical, neurophysiologic, and neuropathologic features of an Italian family with a novel MFN2 gene mutation and investigate brain functional parameters using magnetic resonance spectroscopy (MRS). Methods: Three family members, a father and his two sons, were affected by peripheral neuropathy, cognitive impairment, and poor nocturnal vision (also optic neuropathy in one case). A member of this family also showed spastic paraparesis. The MFN2 gene sequence was analyzed. A sural nerve biopsy as well as brain 1H-MRS and 31P-MRS were evaluated in two patients. Results: Affected family members carried a novel MFN2 missense mutation, namely R104W, located within the critical GTPase domain of the protein which affects a highly conserved amino acid position. Sural nerve biopsies showed a normal mitochondrial network, particularly at the nodes of Ranvier, upon electron microscopy examination. A significant defect of high energy phosphates (HEPs) in the visual cortex was observed at rest by 31P-MRS in the adult proband, while his son showed a defective recovery of HEPs after stimulation of the visual cortex. Conclusion: Cognitive impairment may be another feature of the MFN2-related phenotype. The widespread peripheral and CNS involvement, as well as the neurosensorial defects, underline the similarities among MFN2-related and primary mitochondrial disorders.

Remarkable infidelity of polymerase γA associated with mutations in POLG1 exonuclease domain

Objective: To better understand the still unknown pathologic mechanism involved in the accumulation of multiple mtDNA deletions in stable tissues. Methods: A large-scale screening of mtDNA molecules from skeletal muscle was performed in 14 patients with progressive external ophthalmoplegia (PEO) and 2 patients with mitochondrial neurogastrointestinal encephalomyopathy carrying mutations on ANT1, C10ORF2 or POLG1, and TP genes. Results: Patients with at least one mutation in the exonuclease domain of POLG1 showed the highest frequency of individually rare point mutations only in the mtDNA control region; in addition, high levels, in terms of frequency and heteroplasmy, of recurrent mutations (A189G, T408A, and T414G) and alterations affecting the (HT)D310 region were detectable in many of the patients. Two homozygous POLG1 mutations, within the exonuclease domain, were able to induce an increased mutational burden also in fibroblasts from patients with PEO. Conclusions: Specific POLG1 mutations directly affect the integrity of the mtDNA by reducing its proof-reading exonuclease activity, resulting in the accumulation of heteroplasmic levels of both randomly rare and recurrent point mutations in the skeletal muscle tissue and fibroblasts.

S.P.4 Functional changes in Duchenne muscular dystrophy: A 24 month longitudinal cohort study

Abstract Six minute walk test (6MWT), timed items and North Star Ambulatory Assessment (NSAA) are increasingly used as possible outcome measures in clinical trials in Duchenne Muscular Dystrophy (DMD). Longitudinal data have previously been reported following changes in their scores over a 12xa0month period. The aim of the study was to assess 6MWT and NSAA in a cohort of 119 ambulant DMD boys over 24xa0months in order to establish the spectrum of possible changes over a longer period of time. The study is a longitudinal multicentric cohort study. 119 ambulant DMD patients were assessed using 6MWT, NSAA at baseline 12 and 24xa0months. Clinical data including age and steroid treatment were collected. During the 24xa0months of the study, we observed a progressive decline in both measures that was more obvious in the second year. Not all the DMD boys in our cohort showed a decline as young boys showed some improvement in their 6MWT and NSAA scores up to the age of 7. Fifteen patients (12.6%) lost the ability to walk independently: 2/15 by the end of the first year and the other 13 in the second year. Another 22 patients (21.1%) were still able to walk independently but were unable to get up from supine (8/22 at baseline, 4 at 12xa0months, 10 at 24xa0months). Four children also lost the ability to perform the 6MWT (2 at 12xa0months and the other 2 at 24xa0months). This study provides longitudinal data of NSAA and 6MWT over a 24xa0month period. These data can be useful when designing a clinical trial.