Limb-girdle+MD

Limb-girdle muscular dystrophy is a rare, genetic disorder characterized by weakness and atrophy primarily affecting the proximal muscles of the shoulder and hip joints. Onset can occur across the lifespan, impairment can range from mild to severe, and progression may be steady or eventually plateau. There is no cure, but different treatment options can help people with LGMD to lead active and productive lives.
 * Limb-Girdle Muscular Dystrophy (LGMD) **
 * Introduction **

By way of review[*], voluntary muscle contraction begins with an initial motor command from upper motor neurons mainly in the primary motor cortex (PMC), located in the frontal lobe of the brain. Descending neurons travel through the internal capsule and convene & decussate at the level of the medullary pyramids to form the corticospinal tract (lateral tract for control of more distal musculature). The action potential from an initial motor command propagates down the myelinated axon of the corticospinal tract and synapses with an alpha-motor neuron in the ventral horn of the spinal cord at the level of the muscle to be activated. The alpha-MN axon exits the spinal cord via the ventral horn and terminates in the presynaptic cleft at the neuromuscular junction (Fig 1). Review the transmission of an action potential to the muscle fiber (Fig 2).
 * Functional Anatomy **





In the transmission of an action potential to the muscle, the wave of depolarization travels down the sarcolemma as voltage-gated ion channels open along the membrane and T-tubules, leading to the release of Ca2+ from the sarcoplasmic reticulum into the cytosol. At this point, there is more involved in muscle contraction than simply the excitation-coupling of actin and myosin, which we know about. Figures 3 and 4 offer insight into the complexity of muscle at the cellular level. Numerous proteins, many of which are not shown, play a role including but not limited to: maintaining structural integrity of the muscle fiber and contractile unit, offering "shock-absorbing" protection during contraction, and controlling substance-flow into and out of the nucleus[1,12]. Certain genes are responsible for coding one of many proteins that maintain the structural integrity of the muscle fiber and contractile unit (Fig 3 & 4). A gene can become miscoded or even lose a portion of the DNA sequence in the gene replication process, leading to an absent or abnormal protein and subsequent decrease in muscle contractile force [6]. Over 27 genes have been identified that are involved in LGMD[2]. There are two primary classifications, according to the mode of inheritance, and numerous subtypes associated with each. Note some of the most common discussed below.





Only one defective gene from an affected parent is needed to inherit LGMD[5]. Below find a list of common subtypes, subtype name, and the gene responsible, followed by a brief description.
 * LGMD1: Autosomal Dominant Inheritance **

 //LGMD1A: myotiliopathy: MYOT// Myotilin plays a role in anchoring the Z-line within the sarcomere (Fig 3), as well as an important signaling role[1]. Individuals show initial proximal girdle weakness that later progresses to distal weakness. Speech is also affected in this subtype of LGMD, with a distinctive nasal tone[12].

 //LGMD1B: laminopathy: LMNA// Lamins A and C provide structural support to the nuclear envelope, and also play a role in controlling what goes into and out of the nucleus[2]. This subtype of LGMD is associated with cardiac conduction anomalies[10].

 //LGMD1C: caveolinopathy: CAV3// Caveolin-3 is involved in organization of lipids and proteins[1]. Adolescent to early adulthood onset with slow progression and apart form typical LGMD characteristics, patients also experience muscle cramps[13].

Both genes have mutations within the chromosome due to reception from both asymptomatic carrier parents of a LGMD-mutated gene[5]. <span style="font-family: 'Times New Roman',serif; font-size: 13pt;">Below find a list of common subtypes, subtype names, and the gene responsible, followed by a brief description. //<span style="font-family: 'Times New Roman',serif; font-size: 13pt;">LGMD2A: calpainopathy: CAPN3 // <span style="font-family: 'Times New Roman',serif; font-size: 13pt;">Calpain is a membrane protein that serves an enzymatic role in sarcomere repair and maintenance [12]. Age of onset can vary from before the age of 12 to beyond 30 years. Some primary indicators include waddling gait on tip toes, scapular winging, and slight hyperl <span style="font-family: 'Times New Roman',serif; font-size: 13pt;">ordosis. Other complications include scoliosis and contractures [11].
 * <span style="font-family: 'Times New Roman',serif; font-size: 13pt;">LGMD2: Autosomal Recessive Inheritance **

<span style="font-family: 'Times New Roman',serif; font-size: 13pt;"> //LGMD2B: dysferlinopathy: DYSF// <span style="font-family: 'Times New Roman',serif; font-size: 13pt;">Dysferlin is involved in repairing lesions of the sarcolemma [1]. Slow progression of weakness and atrophy of the pelvic & shoulder girdles with adolescent or early adulthood onset[13].

<span style="font-family: 'Times New Roman',serif; font-size: 13pt;"> //LGMD2C, 2D, 2E, 2F: sarcoglycanopathy: SGCG, SGCA, SGCB, SCGD// <span style="font-family: 'Times New Roman',serif; font-size: 13pt;">These include defects of the α-, β-, γ-, and δ-sarcoglycans, all members of the sarcoglycan complex, a subcomplex of the dystrophin glycoprotein complex (Fig 4). The DGC protects muscle fibers by diverting stress from the sarcolemma to the extracellular matrix during contraction. Sarcoglycanopathy is such that when a mutation occurs in one of the proteins, there is consequent decrease in the others. This type of LGMD is unique in that onset can occur in childhood and progress with severity, or a later onset with milder symptoms. Indicators include cardiomyopathy, calf hypertrophy, and scapular winging[11,12].

//<span style="font-family: 'Times New Roman',serif; font-size: 13pt;">Muscle weakness // <span style="font-family: 'Times New Roman',serif; font-size: 13pt;">By definition, muscle weakness is the inability to create a normal, expected amount of force. Muscle weakness can occur due to injury anywhere along the path from the primary cortex down to the muscle. In LGMD patients, it is due to a dysfunction within the contractile unit itself. The mechanism by which this dysfunction occurs is only somewhat understood, but known to be a protein defect within the musculature due to genetic miscoding or deletion as discussed above[4].
 * <span style="font-family: 'Times New Roman',serif; font-size: 13pt;">Characteristics **

//<span style="font-family: 'Times New Roman',serif; font-size: 13pt;">Loss of range of motion // <span style="font-family: 'Times New Roman',serif; font-size: 13pt;">In assessing a patient for muscle weakness, the patient’s active and passive range of motion (AROM, PROM) is evaluated[4]. AROM is voluntary movement about the joint without assistance; PROM requires assistance from the examiner. Patients with LGMD will exhibit ability to move through the PROM but //inability// to move through the AROM; this is a key indicator of muscle weakness[*]. <span style="font-family: 'Times New Roman',serif; font-size: 13pt;">Further, activation of synergistic muscle groups to help perform a movement is not uncommon. For example, the patient will initiate trunk flexion and rotation to perform a reaching task. The patient’s strength at the shoulder joint to lift the arm to even partial flexion is compromised. Certain movements that most people take for granted become extremely difficult and complex.[*]

media type="youtube" key="7YkNtLhLl78" width="525" height="305" align="left"media type="youtube" key="7krchB1cbng" width="489" height="308" align="right"

<span style="font-family: 'Times New Roman',Times,serif;">Standing up from seated position & getting up out of bed with LGMD.

//<span style="font-family: 'Times New Roman',serif; font-size: 13pt;">Waddling gait // <span style="font-family: 'Times New Roman',serif; font-size: 13pt;">The LGMD "waddling" gait is attributed to weakness in the hip and pelvic girdle muscles, the hip abductors in particular. It is characterized by excessive body weight shifting to the support leg during the stance phase of walking gait, as well as faster contact time with increased force. [7] In the video below, John Graybill describes his inability to truly lift or stop his leg once the swing phase is initiated. Further note posterior tilt of the pelvis, lordosis of the spine, and trunk sway also characteristic of LGMD[*]. media type="youtube" key="wwos4VaCQ7E" width="560" height="315" <span style="font-family: 'Times New Roman',Times,serif;"> Limb-girdle muscular dystrophy walking gait.

//<span style="font-family: 'Times New Roman',serif; font-size: 13pt;">Pulmonary Complications // <span style="font-family: 'Times New Roman',serif; font-size: 13pt;">Primarily seen in LGMD2I (not among those previously discussed), the risk of respiratory failure is due to weakness in muscles of respiration. Patients at risk are asymptomatic (e.g. absence of dyspnea) and clinicians should order pulmonary function tests to assess risk. Spinal deformities such as scoliosis can also interfere with pulmonary function [10].

//<span style="font-family: 'Times New Roman',serif; font-size: 13pt;">Cardiomyopathy // <span style="font-family: 'Times New Roman',serif; font-size: 13pt;">Some subtypes alongside typical manifestations of LGMD are also accompanied by heart complications, including LGMD1A, LGMD1B, LGMD1D, LGMD1E, LGMD2C–K, LGMD2M–P[10,12]. Complications include dilated myocardium, rhythm disturbances, increased contractility, decreased ejection fraction, ischemia, and hypokinesia [1,8,12].

<span style="font-family: 'Times New Roman',serif; font-size: 13pt;">Medical consultation is usually sought after an individual begins to notice unusual characteristics including the waddling gait, difficulty walking or running, and/or needing to push themselves up when rising from a seated position because of hip & thigh weakness[5]. Some of the primary diagnostic tools following initial suspicion of LGMD are described below. <span style="font-family: 'Times New Roman',serif; font-size: 13pt;">Blood creatine kinase (CK) concentration <span style="font-family: 'Times New Roman',serif; font-size: 13pt;">Absent or abnormal proteins associated with the sarcolemma cause the membrane to break down and allow leakage of creatine kinase, among other substances, into the bloodstream (remember from exercise physiology that creatine kinase is an important enzyme in the energy required for muscle contraction!) These elevated blood-CK levels can be found in a blood test; a useful diagnostic for muscular dystrophy in general.[2,3]
 * <span style="font-family: 'Times New Roman',serif; font-size: 13pt;">Diagnosis **

<span style="font-family: 'Times New Roman',serif; font-size: 13pt;">Electromyography <span style="font-family: 'Times New Roman',serif; font-size: 13pt;">Detectable on an EMG, LGMD often demonstrates a pattern of activity that determines disorder at the level of the muscle itself and rules out pathology at the neuronal, descending pathway, or higher brain center levels[2,10].

<span style="font-family: 'Times New Roman',serif; font-size: 13pt;">Muscle biopsy & genetic testing <span style="font-family: 'Times New Roman',serif; font-size: 13pt;">Muscle biopsy can establish diagnosis of specific LGMD subtypes including our sarcoglycan, calpain, and dysferlin protein defects. This is done using biochemical testing (immunostaining/immunoblotting) of the sample [11]. Further genetic testing is used to identify mutant genes on specific chromosomes. Identification of the specific gene responsible for the LGMD case is important for patient prognosis (e.g. risk of cardiomyopathy or respiratory complications) and disease management (e.g. genetic counseling) [3,11].

<span style="font-family: 'Times New Roman',serif; font-size: 13pt;">Physical therapy to promote mobility, flexibilty, and prevent contractures. Physical therapy, moderate activity, and stretching also have been observed to potentially slow disease progression and prevent further muscle atrophy[5,6]. <span style="font-family: 'Times New Roman',serif; font-size: 13pt;">Strength training & aerobic exercise can benefit LGMD patients. However, risk of exercise-induced muscle damage is present and therefore consultation of a professional is advised before beginning any exercise regimen[*,3,6,10]. <span style="font-family: 'Times New Roman',serif; font-size: 13pt;">Occupational therapy to help overcome challenges and promote quality of life. <span style="font-family: 'Times New Roman',serif; font-size: 13pt;">Corticosteroids have shown potential to slow down the disease progress and even improve muscle strength[3,10]. <span style="font-family: 'Times New Roman',serif; font-size: 13pt;">Assistive devices for balance in walking such as canes, walkers, or in severe cases wheelchair assistance. <span style="font-family: 'Times New Roman',serif; font-size: 13pt;">Gene transfer is essentially an attempt to replace a defective gene with a normal gene[3]. A 2011 study published by the National Institute of Arthritis and Musculoskeletal and Skin Diseases successfully performed a transfer of the alpha-sarcoglycan gene to three LGMD2D patients. Results included the production of the alpha-sarcoglycan protein for three months in all three subjects, and two out of three showed increase in muscle fiber diameter, indicating reversal of the disease affects[9].
 * <span style="font-family: 'Times New Roman',serif; font-size: 13pt;">Treatment **

<span style="font-family: 'Times New Roman',serif; font-size: 13pt;">The purpose of this guide was to give insight into the neurological mechanisms behind the scenes of limb-girdle muscular dystrophy. We reviewed processes leading up to the contraction of muscle down to the cellular level, discussed some key proteins involved in structural makeup of the muscle cell, and how disturbances in these proteins due to genetic mutation lead to the muscle disease. We now can identify primary characteristics, some of the more common subtypes, various diagnostic techniques, and know of different treatment options for LGMD patients. Limb-girdle muscular dystrophy may change a life as it was former known, but Breslin put it best when he said that he can do anything you can do, if only a little differently.
 * <span style="font-family: 'Times New Roman',serif; font-size: 13pt;">Summary **

<span style="font-family: 'Times New Roman',serif; font-size: 13pt;">Atrophy: loss of muscle mass <span style="font-family: 'Times New Roman',serif; font-size: 13pt;">Autosomal dominant: o <span style="font-family: 'Times New Roman',serif; font-size: 17.3333px;">nly one defective gene from an affected parent is needed to inherit LGMD <span style="font-family: 'Times New Roman',serif; font-size: 13pt;">Autosomal recessive: b <span style="font-family: 'Times New Roman',serif; font-size: 17.3333px;">oth genes have mutations within the chromosome due to reception from both asymptomatic carrier parents of a LGMD-mutated gene <span style="font-family: 'Times New Roman',serif; font-size: 13pt;">Contracture: restriction of movement at the joints due to tissue damage and shortening <span style="font-family: 'Times New Roman',serif; font-size: 13pt;">Limb-girdle muscular dystrophy: genetic, progressive weakness & atrophy primarily of the shoulder and hip girdles <span style="font-family: 'Times New Roman',serif; font-size: 13pt;">Lordosis: anterior curvature of the lumbar spine <span style="font-family: 'Times New Roman',serif; font-size: 13pt;">Muscle weakness: inability to produce expected amount of muscular force <span style="font-family: 'Times New Roman',serif; font-size: 13pt;">Myopathy: muscle disease
 * <span style="font-family: 'Times New Roman',serif; font-size: 13pt;">Glossary of Terms **

<span style="font-family: 'Times New Roman',serif; font-size: 13pt;">Jamie Breslin describes living with LGMD, from the slow onset of the disease to daily challenges and playing the drums, in this 10 minute-long Youtube video.
 * <span style="font-family: 'Times New Roman',serif; font-size: 13pt;">Further Inquiry **

<span style="font-family: 'Times New Roman',serif; font-size: 13pt;">Limb-Girdle Muscular Dystrophy (LGMD) with Neurologist Dr. Matthew Harms of Columbia University – start at 6:23 for LGMD patient story.

<span style="font-family: 'Times New Roman',serif; font-size: 13pt;">Compromised respiratory function due to LGMD poses increased risk of anesthesia-related complications; another seemingly simple thing that LGMD patients must be aware and cautious of. This case report describes the methodical approach taken to minimize risk for an LGMD patient undergoing surgery.

<span style="font-family: 'Times New Roman',serif; font-size: 13pt;">1. Describe the expected age of onset, three primary complications, mode of inheritance, and gene involved in a patient with LGMD2A (calpainopathy).
 * <span style="font-family: 'Times New Roman',serif; font-size: 13pt;">Quiz **

<span style="font-family: 'Times New Roman',serif; font-size: 13pt;">2. A person experiencing muscle atrophy due to LGMD-associated weakness should simply push harder at the gym to prevent or even reverse loss of mass and strength. True / False

<span style="font-family: 'Times New Roman',serif; font-size: 13pt;">3. Which of the following is //not// characteristic of the LGMD gait? Circle all that apply. <span style="font-family: 'Times New Roman',serif; font-size: 13pt;">a. Trunk sway <span style="font-family: 'Times New Roman',serif; font-size: 13pt;">b. Slower contact time <span style="font-family: 'Times New Roman',serif; font-size: 13pt;">c. Increased force upon contact <span style="font-family: 'Times New Roman',serif; font-size: 13pt;">d. Anterior pelvic tilt <span style="font-family: 'Times New Roman',serif; font-size: 13pt;">e. Lordosis

<span style="font-family: 'Times New Roman',serif; font-size: 13pt;">4. One of the distinguishing characteristics of limb-girdle muscular dystrophy is a progressive loss of cognitive function. True / False

<span style="font-family: 'Times New Roman',serif; font-size: 13pt;">5. Muscle weakness as a characteristic of LGMD is due to lesion at which location along the descending motor pathway? <span style="font-family: 'Times New Roman',serif; font-size: 13pt;">a. Primary motor cortex <span style="font-family: 'Times New Roman',serif; font-size: 13pt;">b. Upper motor neuron axon <span style="font-family: 'Times New Roman',serif; font-size: 13pt;">c. Internal capsule <span style="font-family: 'Times New Roman',serif; font-size: 13pt;">d. Spinal cord <span style="font-family: 'Times New Roman',serif; font-size: 13pt;">e. Could be any of the above <span style="font-family: 'Times New Roman',serif; font-size: 13pt;">f. None of the above

<span style="font-family: 'Times New Roman',serif; font-size: 13pt;">6. Describe how you would go about diagnosing a patient with LGMD. Why is determining the genetic subtype important?

//<span style="font-family: 'Times New Roman',serif; font-size: 13pt;">Answers // <span style="font-family: 'Times New Roman',serif; font-size: 13pt;">1. varies between 30 years <span style="font-family: 'Times New Roman',serif; font-size: 17.3333px;">– any: <span style="font-family: 'Times New Roman',serif; font-size: 13pt;">waddling, tip toes, contractures, <span style="font-family: 'Times New Roman',serif; font-size: 17.3333px;">scapular winging, hyperlordosis, scoliosis – <span style="font-family: 'Times New Roman',serif; font-size: 13pt;">autosomal recessive – CAPN3 <span style="font-family: 'Times New Roman',serif; font-size: 13pt;">2. False! While physical activity can benefit LGMD patients and is encouraged, certain stressful exercises can actually //hasten// muscle damage in LGMD. Physical activity should be limited to moderate intensity and non-weight bearing if possible <span style="font-family: 'Times New Roman',serif; font-size: 13pt;">3. B, D <span style="font-family: 'Times New Roman',serif; font-size: 13pt;">4. False <span style="font-family: 'Times New Roman',serif; font-size: 13pt;">5. F <span style="font-family: 'Times New Roman',serif; font-size: 13pt;">6. Initial suspicion of unusual symptoms > blood CK test > EMG > muscle biopsy & genetic test. Prognosis (i.e. disease expectations), further monitoring & evaluation of various risks, and management of symptoms (i.e. treatment)

<span style="font-family: 'Times New Roman',serif;">[*] Comments marked with an asterisk are based off my own observations with a LGMD patient and/or personal notes from current or past classes taken. <span style="font-family: 'Times New Roman',serif;">[1] Angelini C, Tasca E, Nascimbeni AC, Fanin M. Muscle fatigue, nNOS and muscle fiber atrophy in limb girdle muscular dystrophy. //Acta Myologica// 33(3): 119-126, 2014. <span style="font-family: 'Times New Roman',serif;"> [] [10 Dec. 2017]. <span style="font-family: 'Times New Roman',serif;">[2] Cotta A, Carvalho E, Lopes da-Cunha-Junior A, Paim JF, Navarro MM, Valicek J, Menezes MM, Nunes SV, Neto RX, Takata RI, Vargas AP. Common recessive limb girdle muscular dystrophies differential diagnosis: why and how? //Arq Neuropsiquiatr// 72(9): 721-734, 2014. <span style="font-family: 'Times New Roman',serif;"> [] [10 Dec. 2017]. <span style="font-family: 'Times New Roman',serif;">[3] Emery AH. Muscular Dystrophy [Online]. 3rd ed. OUP Oxford. [] [10 Dec. 2017]. <span style="font-family: 'Times New Roman',serif;">[4] Levin MC. Weakness [Online]. Merck Manual. <span style="font-family: 'Times New Roman',serif;"> [] [10 Dec. 2017]. <span style="font-family: 'Times New Roman',serif;">[5] Limb-Girdle Muscular Dystrophy [Online]. //Genetics Home Reference,// NIH U.S. National Library of Medicine. <span style="font-family: 'Times New Roman',serif;"> [|https://ghr.nlm.nih.gov/condition/limb-girdle-muscular-dystrophy#] [10 Dec. 2017]. <span style="font-family: 'Times New Roman',serif;">[6] Limb-Girdle Muscular Dystrophy [Online]. Muscular Dystrophy Association. <span style="font-family: 'Times New Roman',serif;"> [] [10 Dec. 2017]. <span style="font-family: 'Times New Roman',serif;">[7] Maricelli JW, Lu QL, Lin DC, Rodgers BD. Trendelenburg-Like Gait, Instability and Altered Step Patterns in a Mouse Model for Limb Girdle Muscular Dystrophy 2i. //PLoS ONE// 11(9): 1-19, 2016. <span style="font-family: 'Times New Roman',serif;"> [] [10 Dec. 2017]. <span style="font-family: 'Times New Roman',serif;">[8] Mascarenhas DAN, Spodick DH, Chad DA, Gilchrist J, Townes PL, Degirolami U, Mudge GH, Maki DW, Bishop RL. Cardiomyopathy of limb-girdle muscular dystrophy. //Journal of the American College of Cardiology// 24(5): 1328-1333, 1994. <span style="font-family: 'Times New Roman',serif;"> [] [10 Dec. 2017]. <span style="font-family: 'Times New Roman',serif;">[9] Mendell JR, Rodino-Klapac LR, Rosales XQ, Coley BD, Galloway G, Lewis S, Malik V, Shilling C, Byrne BJ, Conlon T, Campbell KJ, Bremer WG, Taylor LE, Flanigan KM, Gastier-Foster JM, Astbury C, Kota J, Sahenk Z, Walker CM, Clark KR. Sustained alpha-sarcoglycan gene expression after gene transfer in limb-girdle muscular dystrophy, type 2D. NIH National Institute of Arthritis and Musculoskeletal and Skin Diseases 68(5): 629-638, 2011. <span style="font-family: 'Times New Roman',serif;"> [] [10 Dec. 2017]. <span style="font-family: 'Times New Roman',serif;">[10] Narayanaswami P, Weiss M, Selcen D, David W, Raynor E, Carter G, Wicklund M, Barohn RJ, Ensrud E, Griggs RC, Gronseth G, Amato AA. Evidence-based guideline summary: Diagnosis and treatment of limb-girdle and distal dystrophies. //Neurology// 83(16): 1453-1463, 2014. <span style="font-family: 'Times New Roman',serif;"> [] [10 Dec. 2017]. <span style="font-family: 'Times New Roman',serif;">[11] Pegoraro E, Hoffman EP. Limb-Girdle Muscular Dystrophy Overview [Online]. //GeneReviews//, University of Washington. <span style="font-family: 'Times New Roman',serif;"> [] [10 Dec. 2017]. <span style="font-family: 'Times New Roman',serif;">[12] Piccolo F, Moore SA, Mathews KD, Campbell KP. Limb-Girdle Muscular Dystrophies. //Neuromuscular Disorders// 17 273-291, 2001. <span style="font-family: 'Times New Roman',serif;"> [] [10 Dec. 2017]. <span style="font-family: 'Times New Roman',serif;">[13] Lopate G. <span style="color: #2a2a2a; font-family: 'Times New Roman',serif;">Limb-Girdle Muscular Dystrophy Clinical Presentation [Online]. Medscape. <span style="color: #2a2a2a; font-family: 'Times New Roman',serif;"> [] [10 Dec. 2017].
 * <span style="font-family: 'Times New Roman',serif; font-size: 13pt;">References **

<span style="font-family: 'Times New Roman',serif; font-size: 13pt;">For Pat, my inspiration – whose spunk and sass always make me laugh.
 * <span style="font-family: 'Times New Roman',serif; font-size: 13pt;">Acknowledgment **