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Exercise intolerance may be suggestive of metabolic myopathy or mitochondrial disorders. We report a family where 7 female subjects presented with various degree of exercise intolerance since childhood. A common and original feature shared by affected members was the increased volume of the masseter muscle systematically occurring after feeding, making them looking like a hamster. Limb muscle size was not affected by effort. Patients also complained of keloid scars and for some of them of congenital cataract. The index case underwent full examination including clinical assessment, electromyography, electro-retinography, muscle biopsy, pulmonary function testing, exercise test, genetic testing. Clinical and EDX examinations were normal. Exercise test was brief due to muscle fatigue but induced an important increase of lactates and lactate/pyruvate ratio. Morphological analysis and standard immunochemistry of the muscle biopsy were normal but analysis of the respiratory chain complexes from the muscle biopsy displayed a combined defect in the complexes I, III, and IV encoded by mitochondrial DNA, associated with an increase of complex II and citrate synthase. An increased number of muscle mtDNA copies was observed reflecting a probable mitochondrial proliferation. Whole mtDNA sequencing revealed the homoplasmic m.15992A > T variant in the mitochondrial tRNA (Pro) gene (MT-TP). This mutation does not affect the codon reading but modifies the efficiency of aminoacylation or of post-transcriptional modification, leading to less efficient translation. It was also found in 3 affected members apart from index case and is very likely to be pathological. The relationships between the gene mutation and the unusual clinical phenotype are not clear but are worthy of interest.

Mutations in the Fukutin-Related Protein gene ( FKRP ) account for a broad spectrum of phenotypes ranging from severe congenital muscular dystrophies to much milder limb-girdle muscular dystrophy (LGMD2I). In both, weakness and wasting of shoulder-girdle muscles, primary restrictive respiratory and cardiac involvement are classical features. To our knowledge, facial dysmorphic features have not been reported yet. The first woman developed, at age 12, a progressive pelvic weakness. Two biopsies were performed showing a dystrophic pattern with normal classical immunohistochemistry. At age 38, she was confined in a wheelchair and suffered from respiratory insufficiency. She also had a mild cardiomyopathy. As she presented macroglossia, analysis of the FKRP gene was performed and two compound mutations p.Leu276Ile and p.Glu343X were found. The second woman was born of a consanguineous union. From childhood, she had difficulties running and rising from the floor. At 12, she developed a limb-girdle weakness that confined her in a wheelchair at age 26. Vital capacity was normal, as well as US heart exam. Muscular biopsy showed classical dystrophic features with normal immunohistochemistry and Western blot. She had no macroglossia but her face looked alike our first FKRP patient. Indeed, both women presented hypertelorism, large palpebral fissures, depressed nasal bridge, prognathism and thick lips being responsible for a dramatic physical resemblance although they were unrelated. FKRP gene analysis was therefore performed and a homozygous mutation p.Leu276Ile was found. Limb-Girdle weakness associated with macroglossia and calf hypertrophy are classical clues for FKRP gene sequencing. Some mutations have more frequent macroglossia or calf hypertrophy than others. But facial dysmorphia has not been reported in this disease so far. This dysmorphia represent a real diagnosis help in our second patient and should be searched each time a LGMD patient is considered.

Hereditary Fibrosing Poikiloderma (HFP) with tendon contracture and pulmonary fibrosis has been described in a South-African family with autosomal dominant inheritance by Khumalo et al. in 2006. Recently, we confirmed the existence of this new syndrome by reporting four additional cases and identified the causative gene called FAM111B (NM_198947.3) by whole exome sequencing. Here we report the clinical and molecular data of seven independent patients: four males and three females (ages 3–38). Key features consist of: (i) congenital poikiloderma, hypotrichosis, hypohidrosis; (ii) muscle contractures in particular triceps surae and/or biceps brachii muscle contractures; (iii) progressive muscular weakness with a proximal and distal pattern and (iv) progressive pulmonary fibrosis. Muscle MRI showed extensive fatty infiltration confirmed by muscle biopsy. Histological examination of skeletal muscle revealed a partial loss of muscle tissue associated with extensive fibrofatty tissue infiltration regardless of age. There was no indication of denervation, necrosis, or inflammation. Microscopy of the skin showed a sclerodermiform aspect with fibrosis and alterations of the elastic network. FAM111B gene analysis identified five different missense variants (two mutations were shared respectively by three and two patients). All the mutations were predicted to localize in the trypsin-like cysteine/serine peptidase domain of the protein. We suggest gain of function or dominant negative mutations resulting in FAM111B enzymatic activity changes. Functional studies are ongoing to better understand the pathophysiology of this entity. In conclusion, HFP with tendon contracture, myopathy and pulmonary fibrosis, a phenotypically recognisable syndrome, is caused by autosomal dominant mutations in FAM111B gene. These findings provide genetic evidence for a new pathogenetic pathway for muscle impairment.

Among congenital myopathies, X-linked recessive myotubular myopathy is one of the most severe forms. The majority of patients present with severe hypotonia at birth and respiratory insufficiency and most of them die in the first year of life. However, there is phenotypic variability. Here, we report two patients carrying a missense mutation in MTM1 gene and presenting with a mild phenotype. The first boy was born on time with respiratory insufficiency and generalised hypotonia. He required ventilator support for 3 weeks, and then he went home without specific care. He walked at 11 month. He is now 24 and can run, practices canoe and works as a salesperson. At the exam, he presents mild proximal weakness and restrictive syndrome with no ventilator support (VC = 57%). His brother was born on time with respiratory insufficiency and hypotonia. He stayed in intensive care unit for 6 weeks, then went home without support. He walked at 18 months. Respiratory involvement was more severe than his brother with a severe restrictive syndrome (VC = 33%) but the young man refused non-invasive night-time ventilation proposed at the age of 16. Being now 20, he can walk without any difficulty but cannot run. Clinical exam reveals a mild proximal weakness. Both patients underwent muscle biopsy showing the typical centronuclear myopathy pattern. Molecular analysis of MTM1gene found a hemizygous mutation c.575A>G in exon 8 leading to a missense p.Tyr192Cys. A decreased level of the MTM1 protein was observed by western blot analysis on lymphoblasts. To date, about 300 different mutations in around 540 families have been identified in MTM1 gene, including point mutations, insertions and small and large deletions and duplication. Around 70% of patients presenting with a mild or moderate phenotype carries a missense mutation, which is also the most frequent type of mutation. Another patient has been described with the same mutation (c.575A>G) and presented also with a mild phenotype.

X-linked myopathy with excessive autophagy (XMEA) is an X-recessive linked myopathy due to mutations in the VMA 21 gene. This gene encodes a chaperone molecule necessary for the binding of V-ATPase to the lysosomic membrane. The disease is therefore characterized by the absence of normal acid pH within the lysosomes. Lysosomal pH raising reduces lysosomal degradative ability. It is responsible for neuropathological abnormalities which include autophagic vacuoles resulting from the fusion between lysosomes and autophagosomes. Similar or close neuropathological patterns can be observed in quite distinct disorders such as lysosome-associated membrane protein 2 (LAMP-2) myopathy (Danon’s disease) or colchicine induced myopathy. We studied muscle biopsies from three adult patients presenting with XMEA confirmed by genetic testing and compared them to muscles biopsies from one patient with Danon’s disease and one patient with a myopathy related to colchicine treatment. In XMEA, pathological features associate a “mild” myopathic aspect with an increased number of abnormal giant autophagic vacuoles. These vacuoles displace the normal structures of the myocytes with neither significant cytosolic abnormalities nor glycogene increase. They seems to be expulsed in the immediate surrounding of the cell within abnormal folding of the basal lamina. Presumably, this abnormal content is the primary event inducing a membrane attack complex deposit. This aspect is quite different from the one observed in the patient with LAMP2 negative Danon’s disease where the autophagic vacuoles are associated with glycogene storage and are not expulsed outside. On the other hand, the colchicine myopathy offers a very close ultrastructural aspect and is thought to be the consequence of impaired migration and fusion of autophagosomes and lysosomes. In conclusion, separate pathophysiological mechanisms can lead to similar vacuolation patterns.

Introduction L’HNPP est classiquement liee a une deletion ou a des mutations du gene de la PMP22. Les mutations du gene MPZ sont habituellement responsables de phenotype de Charcot Marie Tooth de type demyelinisant. Objectifs Decrire une nouvelle mutation dans le gene de la MPZ associee a un phenotype HNPP. Methodes Nous decrivons quatre patients de deux familles non apparentees, presentant un phenotype clinique et electrophysiologique d’HNPP sans anomalie sur le gene de la PMP22. Un examen clinique et electromyographique a ete realise chez tous ces patients. Une etude du gene de la MPZ en biologie moleculaire a ete realisee. Resultats Dans ces deux familles, une mutation non-sens (Tyr145Stop) dans l’exon 3 du gene MPZ a ete mise en evidence. Ce phenotype est caracterise par l’evolution frequente vers une neuropathie longueur — dependante et un tableau demyelinisant et axonal precoce a l’electroneuromyographie. Discussion Cette nouvelle description elargit le champ phenotypique des mutations du gene MPZ. Elle fait poser des questions sur les correlations genotype-phenotype des mutations de MPZ : pourquoi certaines mutations sont responsables de phenotypes severes et d’autres non ? Dans nos familles, la mutation est responsable de la fabrication d’une proteine tronquee. L’hypothese la plus probable pour expliquer le phenotype modere est celle d’une haplo-insuffisance. Conclusion Les mutations du gene MPZ pourraient expliquer certains cas d’HNPP ne presentant pas d’anomalie sur le gene de la PMP22.

Four dissimilar cases of vasculatis related to HIV-1 infection led us to consider the mechanism of vascular lesions (direct involvement of HIV or opportunistic agents (CMV) or auto-immune disease. Therapy is difficult in such cases because of possible worsening of immunodepression.

A three-year old child was anaesthetized by halothane. Cardiac arrest occurred soon after the injection of suxamethonium. Signs of rhabdomyolysis associated with hyperkalemia were present. The diagnosis of Duchenne muscular dystrophy was obtained afterwards.