الفهرس 
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Abstract
The muscular dystrophies are heterogeneous group of inherited disorders characterized by progressive muscle wasting and weakness. The limb–girdle muscular dystrophies (LGMD) are a heterogeneous group of disorders characterized by weakness and wasting of the pelvic and/or shoulder girdle muscles. The clinical course of LGMD ranges from severe forms with disease onset and rapid progression within the first decade of life, to milder forms with later onset and slower progression. There are currently 19 identified forms of autosomal dominant and autosomal recessive LGMD, and it is often difficult to distinguish between the various LGMD subtypes.
The limb girdle muscular dystrophy (LGMD) has been the subject of intense study over the last 10 years, revealing unexpected heterogeneity and insights into the possible pathogenesis of types of muscular dystrophy. Progress in defining these different types of LGMD represents a massive increase in our understanding of the molecular basis for these diseases. from practical view, however, achieving a diagnosis in an individual patient may remain complex, requiring the integration of clinical assessment of protein analysis and genetic studies. Therefore, diagnosis of LGMD increasingly relies on a combination of immunohistochemical and immunoblot analyses, followed by DNA sequencing to identify the primary mutation, which is essential for the provision of accurate genetic and prognostic counseling. Despite these comprehensive studies, the genetic etiology of many cases of LGMD is not yet known.
The aim of this work is the recognition of different types of limb girdle muscular dystrophy (LGMD) in Egyptian patients using the immuno-staining method.
The present study was conducted in muscle and nerve research laboratory, neurology unit of Neuropsychiatry Department, Ain Shams University Hospitals during the period between February (2004) and January (2008). It included one-handered (100) patients with proximal weakness of both lower limbs and/ or upper limbs whose age ranged from 10 to 52 years. They were 73 males and 27 females.
A full history and clinical examination, family pedigree, laboratory, neurophysiological and pathological study were done. The neurophysiological study included the classical electromyography, nerve conduction study and quantitative electromyography using the analysis of 20 motor unit potentials and turns/ amplitude analysis. The pathological study included histological, histochemical and immunostaining of muscle biopsy through protien analysis of ten antibiodies (Dystrophin R, Dystrophin N, Dystrophin C, α-SG, β-SG, γ-SG, δ-SG, Calpain-3, Dysferlin and Merosin ).
The primary diagnosis of limb girdle muscular dystrophy was based on the clinical data and neurological examination then on CK values, EMG and NCV studies. The final diagnosis based on the immunohistochemistry study of muscle biopsies.
The results of the present study are summarized as following:
According to the pathological classification, 64 patients were found to be dystrophic, 22 patients were found to be myopathic, 12 patients were found to be neuropathic and only 2 patients were found to be inflammatory. In LGMDs, 33 patients were found to be dystrophic and only 7 patients were myopathic.
According to immunostaining of muscle biopsy, we found 40 patients had LGMD (12 of them were dysferlinopathy, 6 patients were calpainopathy, 6 patients were sarcoglycanopathy and 16 patients were diagnosed as other (undetermined) type of LGMD, 27 patients were dystrophinopathy (14 patients were DMD, 11 patients were BMD and only 2 patients were carrier), 10 patients were congenital muscular dystrophy (merosin positive) and 23 patients had other diagnoses including spinal muscular atrophy, polymyositis, myasthenia gravis ,myotonia, metabolic myopathy, polyradiculoneuropathy and motor neuron disease.
Dysferlinopathies usually manifest in late adolescence or early adulthood with a slow progression of the disease regardless of age at onset . The patients remaining ambulatory until at least thirty years. Most patients were offsprings of consanguineous marriage of parents of 2nd degree cousins . The commonest presenting initial symptoms were tip-toes walking and difficulty in walking. Half patients have a scapular winging while none of them have calf hypertrophy. Contractures were more apparent in dysferlinopathy. The most prevalent type of contractures is Achilles tendon contracture. Rhomboids, Deltoids and biceps are more severely affected muscles while Serratus anterior is the least affected muscle. The affection of small muscles of the hands is not uncommon. In lower limbs, Hamstrings, Gastrocnemius, Glutei and hip adductors are more affected than their corresponding antagonist group. CK levels were elevated up to 50 times normal. Pathologically, Ragged red fibers are prominent feature in dyefrerlinopathy as well as focal lymphocytic infiltrates. Immunocytochemical analysis of dysferlin, showed a reduction (being traces) in the dysferlin immunostaining in 4 patients, while complete absence of immunostaining was observed in 8 patients What was striking is the observation of a secondary reduction of calpain-3 in all cases of dysferlinopathy.
Calpainopathies usually manifest as early as the end of the first decade to the early of the second. Our patients were ambulant. Most patients were offsprings of consanguineous marriage of 2nd degree of inheritance. Difficulty in running, in climbing up stairs and tip-toe walking were the first clinical presenting features. Scapular winging is prominent feature while calf hypertrophy is less common. Early primary contractures are prominent features in calpainopathy. Achilles tendon and elbow contractures are the most prevalent type. Deltoid is the almost always affected muscle in our patients. Supraspinatus, Infraspinatus and Serratus anterior are the earliest and commonest affected muscles while Triceps and Biceps are less common. Rhomboids and Pectoralis are affected to less extent.While in lower limbs,the hip adductors and gluteus maximus muscle were the earliest and commonest affected muscles with very striking sparing of the Hip abductors. Ilieopsoas and Gastrocnemius are affected to lesser extent. CK levels were elevated only up to 10 times the upper limit value. Pathologically, there is moderate variation in muscle fiber size. Necrosis with macrophages infeltration is found more frequent. Neither lobulated fibers, nor ragged red fibers can be observed. Immunohistochemically, there was a deficiency (even absent) calpain-3 immunostaining . What was striking is the observation of a secondary reduction of dysferlin (slightly weak or faint) immunostains in some cases of calpainopathy.
Sarcoglycanopathies had their onset in the first decade of life. None of our patients were wheel-chair bound. Most patients were off springs of consanguineous marriage of either 2nd or 3rd degree of inheritance. Difficulty in standing and in climbing up stairs are the first presenting features. Calf hypertrophy and scapular winging are the major signs in our patients. Contractures are uncommon. Deltoids, Supraspinatus, Infraspinatus and Rhomboids are commonly affected muscles while Biceps is affected to less extent with sparing of Triceps muscles. In lower limbs, a striking feature is early involvement of Hip adductors with sparing of the abductors. The prominent weakness of Hamstring muscles with comparatively less affected Quadriceps is observed. Tibialis anterior was the most frequently involved distal muscles but to a lesser degree compared to its proximal counterparts. Markedly elevated serum CK values above 50 times the upper limit value were observed in sarcoglycanopathy. Pathologically, all muscle biopsies showed variation of fiber size of severe degree . There is marked necrosis with marked macrophages infiltration and adipose tissue infiltration. Immunohistochemistry in LGMD 2C, alpha- sarcoglycan staining is preserved with severely reduced beta and delta sarcoglycan subunit staining and absent gamma sarcoglycan staining. In LGMD 2E, alpha- sarcoglycan staining is preserved with faint beta and gamma sarcoglycan subunit staining and absent delta sarcoglycan staining. In all cases of sarcoglycanopathy, the dystrophin staining was preserved.
Regarding the histopathological diagnosis, the dystrophic process is the most common pattern in dysferlinopathy, calpainopathy, sarcoglycanopathy and the undetermined type while the myopathic pattern is only found in the other (undetermined) type.
According to the initial manifestations, dysferlinopathy is subdivided into three subtypes: proximal type, anterior compartment type and Miyoshi myopathy. The proximal and anterior compartment types have an earliar age of onset and relatively prolonged duration of illness than Miyoshi myopathy. Difficulty in climbing, tip-toes walking and heal walking are the initial presenting symptoms in patients with proximal type, anterior compartment type and Miyoshi myopathy respectively. Scapular winging and Achilles tendon contracture are the prominent feature in both anterior compartment type and Miyoshi myopathy. Elbow contracture is uncommon in proximal type. The affection of deltoid muscle is the prominent feature in all clinical phenotypes of dysferlinopathy .Wasting of biceps is predominant feature in Miyoshi myopathy while in lower limbs, quadriceps, gastrocenamious and tibialis posterior are more commonly affected muscles. Pectoralis muscle is most common affected muscle in proximal type while Hamstring muscle affection is the cardinal sign in proximal type. In those with anterior compartment type wasting was observed in deltoid and biceps while in lower limbs it affected mainly gastrocnemius and tibialis anterior. Glutei affection is the prominent feature in all clinical phenotypes of dysferlinopathy.
Pathologically, the muscle biopsy of the three clinical phenotypes of dysferlinopathy implied the same features seen in dysferlinopathy except no connective tissue proliferation, fatty replacement or fiber splitting observed in most cases with MM type. Regenerating fibers and necrotic fibers with marked macrophage infilteration are the cardinal signs in MM. Focal lymphocytic infiltrates, and moth-eaten fibers were more common in proximal type. In anterior compartment type, most cases had both fiber splitting and regenerating fibers. Ragged red fibers were observed in most cases of proximal type .
According to the immunohistochemistry results, sarcoglycanopathy is subdivided into three subtypes: β-SG, γ-SG and δ- SG. δ- SG has an earliar age of onset and relatively prolonged duration of illness than β-SG and γ-SG. Difficulty in climbing stairs is the initial presenting symptom in patients with β-SG and γ-SG while difficulty in standing is the cardinal symptom in δ- SG. Scapular winging and calf hypertrophy are the prominent feature in δ- SG. Contracture is uncommon in β-SG and γ-SG. However, Achilis tendon contracture is rare in δ- SG. The affection of deltoid muscle and rhomboids are the prominent features in all clinical phenotypes of sarcoglyconapathy. Wasting of biceps is uncommon but can observed in δ- SG. Serratus anterior, supraspinatus and infraspinatus muscles are affected in β-SG and δ- SG. The glutei are the prominent feature in all types of sarcoglycanopathy. Hamstring and quadriceps affection are the cardinal sign in β-SG and γ – SG. Gastrocenamious and hip adductors are common affected muscles in γ – SG.
Pathologically, ragged red fibers are more common features in γ – SG while the opaque and moth-eaten fibers are uncommon but can be found in some cases with δ- SG.
Regarding to the last group of patients, other types (undetermined) of LGMD, had their onset in the late of 2nd decade of life. Half patients were off springs of consanguineous marriage of 2nd degree of inheritance. Cardiac manifestations were observed in 3 patients in the form of diminished heart sounds and mild mitral valve insufficiency. Initial symptoms were the difficulty in climbing up stairs and walking. Scapular winging was present from the early stage with prominent calves. The elevation in CK was a relatively low. They showed positive immunohistochemistry to all used antibodies.