THREE CASE SERIES INVOLVING PROGRESIVE MOTOR DEFICIT

The muscular dystrophyes are a group of inherited, non-infl amatory disorders, consisting of progresive muscle wasting, without perripheral or central nerve involvement. We present a series of three cases involving progresive motor defi cit and their different evolutions. The fi rst case is about a 57 year old female patient, without a signifi cant family medical history, presenting for progresive motor defi cit involving the shoulder and pelvic muscles, started at the age of 20 year old, when she was diagnosed with a sporadic form of limb-girdle muscular dystrophy. The second case is about a 27 year old male, diagnosed with muscular dystrophy at the age of 15. The third case is about a 43 year old male admitted for frequent falls and weakness of the limbs, mainly distal, started 10 years ago. He was diagnosed with myotonic dystrophy. Although there is still no treatment for muscular dystrophies, the pathology is under investigation in clinical trials.


INTRODUCTION
The muscular dystrophies are a group of inherited, non-infl amatory disorders consisting of progresive muscle wasting, without perripheral or central nerve involvement. A defi nite fi ber degeneration can be observed, without morphologic aberrations. The incidence of MD varies, Duchenne being the most common, with an inheritance pattern of 1 case per 3,500 live male births (1). Other types of MD are less common, LGMD occuring in only 1.3% of the MD patients.
The MD are a result of pathologic genetic coding of the proteins from the structure of the skeletal muscle fi ber. There are multiple proteins involved in the complex interactions of the muscle membrane and the extracellular environment (2). For sarcolemal stability, dystrophin and dystrophin-associated glycoproteins (DAGs) are some of the most important elements (3). The dystrophin gene is located on the short arm of chromosome X, near the p21 locus and codes for the large protein Dp427, wich contains 3,685 aminoacids (4). The size of the protein is responsable for its susceptibility to sporadic mutations. Dystrophin associates with actin at the N-terminus and DAG complex at the C-terminus, forming a complex that interacts with laminin in the extracellular matrix.
The lack of dystrophin (Duchenne MD) leads to cellular instability, with progressive leakage of in-tracellular components, resulting in high levels of creatine kinase. Less active forms of dystrophin may still function as a sarcolemmal anchor, but they allow some leakage of intracellular substance (classic Becker MD).
The other types of muscular dystrophies are caused by alterations in the coding of one of the DAG complex proteins. Gene defects in these proteins can lead to alterations in cellular permeability. Because of the different mechanism of action and location within the body, there can be associated effects.
The symptomatology onset can occur from birth to over 50 years old, the patients presenting, most often, progressive, symmetrical, proximal limb muscular atrophy (or in some cases pseudohypertrophy), spine curvature disorders. They can complain of frequent falls, respiratory diffi culties, contractures and pain in the involved muscles. The cardiopulmonary involvement can be present from the begining of the disease. The life expectancy in MD patients can vary from 20 years (Duchenne) to an almost normal life span (facioscapulohumeral MD).

CASE PRESENTATIONS
We present a series of three cases involving progresive motor defi cit and their different evolutions.
The fi rst case is about a 57 year old female patient, hypertensive, dislipidemic, with a personal medical history of untreated type II diabetes for about 4 years, without a signifi cant family medical history, admitted for progresive motor defi cit involving the shoulder and pelvic muscles. The symptomatology started at the age of 20, with weakness of the right shoulder muscles, followed 2 years later by weakness of the left shoulder muscles, manifested by diffi culties in the abduction of the upper limbs over the head level. Lately, at the age of 30 the motor defi cit also involved the pelvic muscles, the patient affi rming diffi culties in rising from a seated position, in climbing and descending stairs.
Objective examination at the admission date: thorax deformed by kiphoscoliosis, scapular protrusion (scapula alata) -the right side being more affected than the left, muscle wasting involving the biceps brachii, triceps brachii, supraspinatus and infraspinatus muscles, quadriceps femoris, without deep or superfi cial sensitivity impairment, without cranial nerves involvement, normal deep tendon refl exes (Fig. 1).

FIGURE 1. Case 1 of progressive motor defi cit.
Paraclinical: CK-233UI/L, LDH-358UI/L, cholesterol -332 mg/dL, glucose-108 mg/dL, glycated hemoglobin -6.45%. The electromyography objectifi ed the presence of a myopathy at the scapulohumeral and pelvic muscles. The quadriceps muscle biopsy revealed mild muscular dystrophy. Taking into consideration the clinical and paraclinical aspects of this case, we put the diagnosis of limb-girdle muscular dystrophy -sporadic form.
The second case is about a 27 year old male, diagnosed with muscular dystrophy at the age of 15. He is admitted for painful contractions and motor defi cit of the scapulohumeral and pelvic muscles. From the family medical history, we mention the mother (deceased at 55 year old due to a respiratory complication) and two brothers (from the total of seven) diagnosed with muscular dystrophy.
Objective clinical examination: underweight (BMI-16.6), scapulae alatae, muscle wasting of the biceps and triceps brachii (Fig. 2), supraspinatus and infraspinatus, trapezius, serratus anterior, rhomboideus major and quadriceps femoralis muscles, impossibility of lifting the upper limbs over the shoulder level, but with normal distal strength and impossibility of rising from seated position (Gower's sign), without swallowing impairment, deep or superfi cial sensitivity loss, walk possible without assistance for short distances (up to 100m).
The laboratory/ancillary examinations revealed: CK-859UI/L, normal EKG and chest radiography. Deltoid muscle biopsy revealed moderate muscular dystrophy. The patient was diagnosed with an inherited form of LGMD.
The third case is about a 43 year old male, with a personal medical history of hepatitis B virus infection (2002), very few data regarding the family medical history (he was adopted), an uncle (that he never met) deceased at approximately 45 year old from an unknown chronic disease. The patient was admitted for frequent falls and weakness of the limbs, mainly distal. The symptomatology started 10 years ago and aggravated during the last 4 years.
Objective clinical examination: symmetrical muscle atrophy of the limbs, mainly distal, facial muscle wasting with incomplete eyelid occlusion, absence of the forehead folds, impossibility of rising the eyebrow, shuffl ed gait, myotonic phenomenon (Fig. 3).
Laboratory/Ancillary examination results revealed: CK-259UI/L, TGO-28UI/L, TGP-56UI/L, normal EKG and spirometry. The EMG shows myotonic discharge with normal ENG. The muscle biopsy objectifi es a muscular dystrophy. Considering the clinical and paraclinical aspects of the case we diagnosed the patient with Steinert's disease.

DISCUSSION AND CONCLUSIONS
We have to take into consideration the diagnosis of muscular dystrophy even in patients without a family history of MD, in up to one third of the cases the gene involved being subject to a sudden abnormal change (spontaneous mutation) (5).
The evolution of a patient diagnosed with MD can be very variable even in the same group (the fi rst and the second cases presented being diagnosed with LGMD), due to a high heterogeneity. The limb-girdle muscular dystrophy group consists of two subgroups (8 forms of autosomal dominant LGMD1A to LGMD1H and 24 forms of autosomal recessive LGMD2A to LGMD2X) (6).
Although there is still no treatment for MD, the pathology is under intense investigation in clinical trials. In gene therapy, healthy immature myoblasts are introduced into the diseased muscles, which then fuse and stimulate dystrophin to reverse the degeneration that occurs in the affected muscles (7).
In 2011, there was performed a meta-analysis of all clinical trials using creatine monohydrate supplements in neuromuscular disorders. In patients with dystrophinopathies and type II myotonic myopathy, a modest but signifi cant increase in maximum voluntary contraction versus placebo can be observed (8).
One study demonstrated that the Ataluren treatment increases the expression of full-length dystrophin protein in human and mouse primary muscle cells containing the premature stop codon mutation for Duchenne muscular dystrophy and rescues the striated muscle function (9). Although in 2010 the preliminary results of a 2b phase of a clinical trial for Duchenne MD showed no signifi cant improvement in the six minute walk distance after 48 weeks of trial, the medication was approved by EMA in 2014. In November 2016, the selling company announced the agreement on pricing and reimbursement terms in Romania.