Limb girdle muscular dystrophy type 2G with myopathic-neurogenic motor unit potentials and a novel muscle image pattern

Abstract\ud \ud Background\ud Limb girdle muscular dystrophy type 2G (LGMD2G) is a subtype of autosomal recessive muscular dystrophy caused by mutations in the telethonin gene. There are few LGMD2G patients worldwide reported, and this is the first description associated with early tibialis anterior sparing on muscle image and myopathic-neurogenic motor unit potentials.\ud \ud \ud Case presentation\ud Here we report a 31 years old caucasian male patient with progressive gait disturbance, and severe lower limb proximal weakness since the age of 20 years, associated with subtle facial muscle weakness. Computed tomography demonstrated soleus, medial gastrocnemius, and diffuse thigh muscles involvement with tibialis anterior sparing. Electromyography disclosed both neurogenic and myopathic motor unit potentials. Muscle biopsy demonstrated large groups of atrophic and hypertrophic fibers, frequent fibers with intracytoplasmic rimmed vacuoles full of autophagic membrane and sarcoplasmic debris, and a total deficiency of telethonin. Molecular investigation identified the common homozygous c.157C > T in the TCAP gene.\ud \ud \ud Conclusion\ud This report expands the phenotypic variability of telethoninopathy/ LGMD2G, including: 1) mixed neurogenic and myopathic motor unit potentials, 2) facial weakness, and 3) tibialis anterior sparing. Appropriate diagnosis in these cases is important for genetic counseling and prognosis.We wish to thank the patient for participation in this study. We acknowledge\ud Cleides Campos de Oliveira, Leticia Nogueira and Simone Ferreira do\ud Nascimento for technical assistance. MV, LUY and CFA are supported by\ud FAPESP-CEPID, and INCT-CNPq, Capes- COFECUB

Missense mutations in the copper transporter gene ATP7A cause X-Linked distal hereditary motor neuropathy

Distal hereditary motor neuropathies comprise a clinically and genetically heterogeneous group of disorders. We recently mapped an X-linked form of this condition to chromosome Xq13.1-q21 in two large unrelated families. The region of genetic linkage included ATP7A, which encodes a copper-transporting P-type ATPase mutated in patients with Menkes disease, a severe infantile-onset neurodegenerative condition. We identified two unique ATP7A missense mutations (p.P1386S and p.T994I) in males with distal motor neuropathy in two families. These molecular alterations impact highly conserved amino acids in the carboxyl half of ATP7A and do not directly involve the copper transporter's known critical functional domains. Studies of p.P1386S revealed normal ATP7A mRNA and protein levels, a defect in ATP7A trafficking, and partial rescue of a S. cerevisiae copper transport knockout. Although ATP7A mutations are typically associated with severe Menkes disease or its milder allelic variant, occipital horn syndrome, we demonstrate here that certain missense mutations at this locus can cause a syndrome restricted to progressive distal motor neuropathy without overt signs of systemic copper deficiency. This previously unrecognized genotype-phenotype correlation suggests an important role of the ATP7A copper transporter in motor-neuron maintenance and function

Muscle Phenotypic Variability in Limb Girdle Muscular Dystrophy 2 G

Abstract Limb girdle muscular dystrophy type 2 G (LGMD2G) is caused by mutations in the telethonin gene. Only few families were described presenting this disease, and they are mainly Brazilians. Here, we identified one additional case carrying the same common c.157C > T mutation in the telethonin gene but with an atypical histopathological muscle pattern. In a female patient with a long duration of symptoms (46 years), muscle biopsy showed, in addition to telethonin deficiency, the presence of nemaline rods, type 1 fiber predominance, nuclear internalization, lobulated fibers, and mitochondrial paracrystalline inclusions. Her first clinical signs were identified at 8 years old, which include tiptoe walking, left lower limb deformity, and frequent falls. Ambulation loss occurred at 41 years old, and now, at 54 years old, she presented pelvic girdle atrophy, winging scapula, foot deformity with incapacity to perform ankle dorsiflexion, and absent tendon reflexes. The presence of nemaline bodies could be a secondary phenomenon, possibly associated with focal Z-line abnormalities of a long-standing disease. However, these new histopathological findings, characteristic of congenital myopathies, expand muscle phenotypic variability of telethoninopathy

Tempo de latencia do rocuronio e da succinilcolina e condicoes de intubacao traqueal

Background and Objectives - Pulmonary aspiration of gastric content during induction of anesthesia for emergency surgical procedures is a serious complication; fast endotracheal intubation under these circumstances is of vital importance to secure the airways. Despite its numerous side effects, succinylcholine is used for this purpose. Rocuronium is the most recently introduced aminoesteroid neuromuscular blocking drug with short onset. The objective of this study was to compare the onset time and intubating conditions of rocuronium and succinylcholine. Methods - After informed consent, forty-five patients were randomly allocated into three groups of 15: Group I (GI) = succinylcholine 1 mg.kg-1; Group II (GII) = rocuronium 0.6 mg.kg-1; Group III (GIII) = rocuronium 0.9 mg.kg-1. Every patient was premedicated with midazolam 15 mg per os and induction of anesthesia was made with fentanyl 10 μg.kg-1 and etomidate 0.3 mg.kg-1. The neuromuscular block was monitored with the TOP-Guard neuromuscular transmission monitor. The TOP-Guard neuromuscular monitor uses an accelerometer to measure the response to nerve stimulation. The stimulating electrodes were placed close to the course of the ulnar nerve at the wrist. The onset time was considered as the time between the end of neuromuscular drug injection and the twitch height (T1) decrease to 10%. Heart rate and arterial blood pressure were registered at 6 moments before and after induction of anesthesia. Results - The onset time results were: Group I, 71 s; Group II, 120 s and Group III, 70 s or GI = GIII < GII (F = 8.862; p < 0.01). There were 43 patients exhibiting excellent intubating conditions and 2 with good intubating conditions. Heart rate and arterial blood pressure showed alterations due to induction of anesthesia and intubation. Conclusions - Rocuronium 0.9 mg.kg-1 can be used in rapid sequence induction because it has a short onset time which is similar to that of succnylcholine. It is likely that rocuronium would be a good indication in patients with high intracranial pressure, burns and neuromuscular diseases

Tempo de latencia e duracao do efeito do brometo de rocuronio no paciente submetido ao transplante renal

Background and Objectives - Successful cadaver kidney transplantation relies on a fast procedure. Patients with chronic renal failure may present with a delayed gastric emptying making it critical a fast tracheal intubation and airway maintenance. Rocuronium a recently introduced nondepolarizing neuromuscular blocker with a fast onset. The aim of this study was to evaluate onset time and duration of rocuronium effects in patients undergoing renal transplantation. Methods - Sixty patients were allocated into two groups of 30: Group R (GR) = patients undergoing renal transplantation and Group N (GN) = patients with normal renal function. All patients were premedicated with oral midazolam (15 mg) and anesthesia was induced with 30 μg.kg-1 alfentanil, 0.3 mg.kg-1 etomidate and 0.6 mg.kg-1 rocuronium injected through a central venous catheter. neuromuscular block was monitored by acceleromyography in the ulnar nerve pathway. The following parameters were evaluated: time between administration of rocuronium and first twitch reduction to 5% after supra-maximal stimulation (T1) (onset time = OT); time for first twitch to return to 25% (clinical duration = R25); time elapsed between 25% and 75% recovery of first twitch (relaxation recovery time = R25-75). Heart rate (HR) and mean blood pressure (MBP) were recorded in 6 moments. Results - Median OT was 31 sec. in GR and 47 sec. in GN. Median R25 was 51.5 min in GR and 33.5 min in GN. Median R25-75 was 28 min in GR and 20 min in GN. MBP and HR were higher in GR. Tracheal intubation conditions were excellent for most patients in both groups. Conclusions - These results open the possibility of 0.6 mg.kg-1 rocuronium being injected through a central venous catheter when a faster onset is needed. Due to wide differences in individual responses, monitoring of neuromuscular block is recommended

Limb girdle muscular dystrophy type 2G with myopathic-neurogenic motor unit potentials and a novel muscle image pattern

Abstract Background Limb girdle muscular dystrophy type 2G (LGMD2G) is a subtype of autosomal recessive muscular dystrophy caused by mutations in the telethonin gene. There are few LGMD2G patients worldwide reported, and this is the first description associated with early tibialis anterior sparing on muscle image and myopathic-neurogenic motor unit potentials. Case presentation Here we report a 31 years old caucasian male patient with progressive gait disturbance, and severe lower limb proximal weakness since the age of 20 years, associated with subtle facial muscle weakness. Computed tomography demonstrated soleus, medial gastrocnemius, and diffuse thigh muscles involvement with tibialis anterior sparing. Electromyography disclosed both neurogenic and myopathic motor unit potentials. Muscle biopsy demonstrated large groups of atrophic and hypertrophic fibers, frequent fibers with intracytoplasmic rimmed vacuoles full of autophagic membrane and sarcoplasmic debris, and a total deficiency of telethonin. Molecular investigation identified the common homozygous c.157C > T in the TCAP gene. Conclusion This report expands the phenotypic variability of telethoninopathy/ LGMD2G, including: 1) mixed neurogenic and myopathic motor unit potentials, 2) facial weakness, and 3) tibialis anterior sparing. Appropriate diagnosis in these cases is important for genetic counseling and prognosis

Characterizing the molecular phenotype of an Atp7a(T985I) conditional knock in mouse model for X-linked distal hereditary motor neuropathy (dHMNX)

ATP7A is a P-type ATPase essential for cellular copper (Cu) transport and homeostasis. Loss-of-function ATP7A mutations causing systemic Cu deficiency are associated with severe Menkes disease or its milder allelic variant, occipital horn syndrome. We previously identified two rare ATP7A missense mutations (P1386S and T994I) leading to a non-fatal form of motor neuron disorder, X-linked distal hereditary motor neuropathy (dHMNX), without overt signs of systemic Cu deficiency. Recent investigations using a tissue specific Atp7a knock out model have demonstrated that Cu plays an essential role in motor neuron maintenance and function, however the underlying pathogenic mechanisms of ATP7A mutations causing axonal degeneration remain unknown. We have generated an Atp7a conditional knock in mouse model of dHMNX expressing Atp7a(T985I), the orthologue of the human ATP7A(T994I) identified in dHMNX patients. Although a degenerative motor phenotype is not observed, the knock in Atp7a(T985I/Y) mice show altered Cu levels within the peripheral and central nervous systems, an increased diameter of the muscle fibres and altered myogenin and myostatin gene expression. Atp7a(T985I/Y) mice have reduced Atp7a protein levels and recapitulate the defective trafficking and altered post-translational regulatory mechanisms observed in the human ATP7A(T994I) patient fibroblasts. Our model provides a unique opportunity to characterise the molecular phenotype of dHMNX and the time course of cellular events leading to the process of axonal degeneration in this disease