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מחלות עצב-שריר מולדות ופרוגרסיביות

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Presentation on theme: "מחלות עצב-שריר מולדות ופרוגרסיביות"— Presentation transcript:

1 מחלות עצב-שריר מולדות ופרוגרסיביות
המרפאה הנוירומוסקולרית לילדים במסגרת מרפאת מג"ן מרכז רפואי וולפסון

2 What are Neuromuscular Disorders?
Neuromuscular disorders affect some aspect of the lower motor neuron pathway This is distinct from disorders such as cerebral palsy, traumatic brain injury which affect the brain /spinal cord i.e. the upper motor neuron

3 Upper and Lower Motor neurons
Upper motor: * Brain and spinal cord Lower motor: * Anterior horn cell downwards

4 Lower Motor neuron Anterior Horn Cell Nerves Neuromuscular Junction
Muscle

5 Anterior Horn Cell Poliomyelitis Spinal Muscular Atrophy

6 Nerves Peripheral nerve lesions Neuropathies
e.g. Hereditary motor and sensory neuropathy

7 Neuromuscular Junction
Myasthenia Gravis Congenital Myasthenia

8 Muscle Myotonic disorders Metabolic myopathies Congenital myopathies
Muscular dystrophies Myotonic disorders Metabolic myopathies Congenital myopathies Inflammatory myopathies

9 Features of Lower Motor Neuron Lesions
Muscle wasting Fasciculation Decreased tone Weakness Decreased or absent reflexes

10 Anterior Horn Cell Spinal Muscular Atrophy * Severe (Type 1)
(Werdnig-Hoffman disease) * Intermediate (Type 2) * Mild (Type 3) (Kugelberg-Welander disease)

11 Spinal Muscular Atrophy
Usually autosomal recessive Progressive weakness and wasting Second most common neuromuscular disease in children

12 Muscular Dystrophies About 20 types of muscular dystrophy
All are caused by faulty genes Inheritance may be x-linked, autosomal dominant or autosomal recessive All result in progressive muscle weakness due to a breakdown in muscle

13 Examples of Muscular Dystrophies
X-Linked * Duchenne Muscular Dystrophy * Becker’s Muscular Dystrophy Recessive: * Autosomal Recessive Limb Girdle Muscular Dystrophy Dominant: * Fascio-Scapulo-Humeral Dystrophy

14

15

16 Myotonic Disorders Muscles are slow to relax after contracting
Slow relaxation often occurs after long periods of rest Examples: * Myotonic Dystrophy * Myotonia Congenita

17 Metabolic Myopathies Most present in childhood Caused by disorders of:
* Glycogen storage * Muscle lipids * Mitochondria

18 Congenital Myopathies
Present at birth with generalised weakness and hypotonia Examples include: * Central core disease * Multicore disease * Nemaline Myopathy

19 Inflammatory Myopathies
Prolonged inflammation of many muscles Caused by auto-immune response ? Initiated by viral infection Can be successfully treated with drugs e.g. steroids Examples: * Polymyositis * Dermatomyositis

20 Patterns of Weakness in Neuromuscular Disease
Muscle weakness presents in different ways in different neuromuscular diseases: Proximal / Distal Selective / Non-selective Symmetrical / Asymmetrical

21 Muscular Dystrophies קבוצת מחלות גנטיות המתאפיינת בחולשה ונוון שרירים המחמירים עם הזמן ושינויים מיקרוסקופיים אופייניים בשריר מהוות חלק מקבוצת מחלות גדולה יותר הנקראות מיופתיות במיופתיות הבעיה הראשונית קיימת בשריר עצמו ולא בעצב, כלי הדם או העצמות התומכות בהם.

22 Duchenne Muscular Dystrophy

23 Duchenne Muscular Dystrophy (DMD)
Onset: Early childhood - about 2 to 6 years. Symptoms: Generalized weakness and muscle wasting affecting limb and trunk muscles first. Calves often enlarged. Progression: Disease progresses slowly but will affect all voluntary muscles. Survival rare beyond late twenties. Inheritance: X-linked recessive

24 ממצאים קליניים

25 החמרה בסימנים עם הגיל

26 סימנים קליניים נוספים Cardiomyopathy: Dilated; especially > 15 years Mental retardation: mean IQ ~ 88 Night blindness Progression: Death years due to respiratory or cardiac failure

27 Laboratory Serum CPK: Very high
Troponin I: elevated above normal but not to levels like in cardiac ischemia Liver enzymes: high AST & ALT

28 ביופסית שריר Endomysial fibrosis
Variable fiber size: small fibers rounded hypercontracted muscle fibers Myopathic grouping Muscle fiber degeneration & regeneration

29 צביעות לדיסטרופין

30 דיסטרופין חתך רוחב בשריר המורכב מצרור סיבים. הדיסטרופין ממוקם מתחת לממברנה המקיפה כל סיב

31 תאחיזה ל כרומוסום X

32 אופן ההורשה הגן המקודד לדיסטרופין נמצא על כרומוסום X
הנשים הן נשאיות אשר בדרך כלל לא מבטאות את המחלה. X-linked recessive inheritance בכ 30% מדובר במוטציה חדשה

33 Genetic testing בכ 65% מהחולים יש חסרים או דופליקציות הניתנות לאתור Southern blot analysis Most of the PCR-based tests detect 95-98% of the deletions/duplications that are found by Southern blot analysis. Complex rearrangements are not always detected by PCR.

34 Western blot of dystrophin from dystrophinopathies
שורות 1,2 BMD שורה 3 NORMAL שורה 4 DMD

35 גן הדיסטרופין 79 אקסונים עם אינטרונים גדולים מקודד ל 3685 חומצות אמינו
7 טרנסקריפטים

36 תפקיד הדיסטרופין לאורך הממברנה ישנו צבר של חלבונים. הדיסטרופין קשור לצבר. סוגים שונים של מחלות מסוג muscular dystrophy מתרחשים כאשר כל אחד מהחלבונים פגום הדיסטרופין ממלא תפקיד במניעת נזקים לממברנה בזמן התכווצות השריר

37 DMD Duchenne muscular dystrophy Genotype: Dystrophin deficiency
96% with frameshift mutation 30% with new mutation 10% to 20% of new mutations are gonadal mosaic

38 Becker Muscular Dystrophy
 Onset: Adolescence or adulthood. Symptoms: Almost identical to Duchenne but often much less severe. Can be significant heart involvement. Progression: Slower and more variable than Duchenne with survival well into mid to late adulthood. Inheritance: X-linked recessive

39 BMD Genotype: Dystrophin mutations Deletion Point mutations
70% of patients: Usually In-frame Point mutations > 70 identified

40 Clinical features of myopathy Onset > 7 yrs Weakness
Proximal > Distal; symmetric; legs & arms Slowly progressive Severity & onset age correlate with muscle dystrophin levels

41 May be especially prominent in quadriceps or hamstrings
Calf pain on exercise Muscle hypertrophy: especially calves Failure to walk years

42 חלבוני השריר

43 Systemic Joint contractures: ankles & other joints
Cardiomyopathy: may occur before severe weakness Mental retardation

44 Myotonic Dystrophy

45 Myotonic Dystrophy Myotonic muscular dystrophy (MMD) is a form of muscular dystrophy that affects muscles and many other organs in the body. Unlike some forms of muscular dystrophy, MMD often does not become a problem until adulthood and usually allows people to walk and be independent throughout their lives.

46 Myotonic Dystrophy Weakness and wasting of voluntary muscles in the face, neck, and lower arms and legs are common in myotonic muscular dystrophy. Muscles between the ribs and those of the diaphragm, which moves up and down to allow inhalation and exhalation of air, can also be weakened.

47 מיוטוניה חסר יכולת לשחרר את השריר בדרך כלל המיוטוניה קלה
אופייני במיוחד קשיים בתפיסה או לחיצת יד מיוטוניה אינה אופיינית לשום מחלה אחרת מסוג Muscular Dystrophy

48 Myotonic Dystrophy Myotonic muscular dystrophy is often known simply as myotonic dystrophy and is occasionally called Steinert's disease, after a doctor who originally described the disorder in 1909. It's also called dystrophia myotonica, a Latin name, and therefore often abbreviated "DM."

49 MD משתנה בחומרה אפילו באותה משפחה
לא לכל הפרטים ישנם כל התסמינים ולא לכולם באותה דרגת חומרה יש הבדל גדול בין הצורה הקונגניטלית לצורה המתבטאת בגיל מאוחר

50 סימנים קליניים A long, thin face with hollow temples, drooping eyelids and in men, balding in the front, is typical in myotonic dystrophy

51 MD לב: הפרעות הולכה- שינויים בא.ק.ג לעיתים קוצב שרירי הנשימה והבליעה
הפרעות במערכת העיכול הפרעות במערכת הגניקולוגית (בעיות ברלקסציה של שרירים לא רצוניים) עיניים –קטרקט מתפתח ברב החולים סכרת בד"כ קלה בעיות בהרדמה

52 CMD היפוטוניה קשה Floppy baby
בעיות בנשימה ובבליעה זקוקים להנשמה ולהאכלה חולשה קשה של שרירי הפנים אין מיוטוניה בשנים הראשונות שכיחות גבוהה של פגור שכלי בעיות בדבור ושמיעה דבור מאנפף כולם יפתחו את הצורה הבוגרת

53 A child born with congenital myotonic dystrophy is likely to have facial weakness and an upper lip that looks "tented." The eye muscles may also be affected.

54 הורשה תורשה אוטוזומלית דומיננטית

55 ביופסית שריר שינויים לא ספציפיים, גרעינים מרכזיים

56 הגן

57 CTG repeats expansion

58 DM1: Myotonin protein kinase (DMPK) protein
The expanded area of DNA is in a gene that carries instructions for a protein known as myotonin protein kinase. The expanded DNA is not in the "working" part of the gene Instead, in MD, the genetic flaw is in a part of a gene called the untranslated DNA

59 Anticipation Increased severity with progressive generations
מסביר את התופעה של החמרה בסימפטומים אצל הצאצאים מסביר את הופעת הצורה הקונגניטאלית It may be that the expanded DNA section affects the functioning of more than one gene, or it may cause clumps of genetic material to build up in the nuclei (control centers) of cells, affecting many cellular functions.

60 Myotubular Myopathy Centronuclear myopathy:
X-linked (MTM 1)   l Myotubularin Chromosome Xq27.3-q28; Recessive   

61 סימנים קליניים מופיעים לאחר הלידה ברב המקרים ב 50% פוליהידרמניוס
ב 50% פוליהידרמניוס סימנים אופיניים של פנים מיופתיים: פנים מוארכים היפוטוניה קשה ביותר פטוזיס חולשה קשה אי ספיקה של שרירי הנשימה

62 פרוגנוזה מוות בגיל 5 ח בממוצע
ישנם מקרים של שפור יחסי אחרי התקופה הנאונטאלית? חולשה מתקדמת 80% מאלה ששורדים מחוברים למכשיר הנשמה

63

64 נשאיות לעיתים, חולשה של שרירי הפנים סימנים בשלד: קיפוסקוליוזיס
Pes equinovarus חולשת שרירים פרוקסימלית Severe: 2° to skewed X-inactivation

65 ביופסית שריר גרעינים מרכזיים סיבים בגדלים שונים

66 Prenatal Diagnosis ניתן לבצע בדיקה מוליקולרית כיום לאתור המוטציה בחולה ובאמו ניתן לבדוק את המוטציה בהריון בבדיקת סיסי השלייה או במי שפיר

67 Congenital Muscular Dystrophies
היפוטוניה מאד אופיינית "floppy" infants אחור בהתפתחות אבני הדרך בחלק קטן יש גם בעיות למידה ופיגור שכלי

68 Congenital Muscular Dystrophies
מתחיל לאחר הלידה חולשת שרירים כללית מתקדמת לאט ברב המקרים הופעת קונטרקטורות ברב המקרים תורשה רצסיבית

69 פתולוגיה פגם גנטי בחלבוני השריר
It is important to note that just because the muscle weakness in CMD starts earlier, CMD is not automatically more severe than other forms of muscular dystrophy. The degree and rate of progression of muscle weakness varies with different forms of CMD and from one child to the next.

70 CMD 3 major groups: merosin-negative
merosin-positive with out CNS involvement merosin-positive with neuronal migration disorders

71 Merosin חלבון הנמצא ברקמת החבור העוטפת את סיב השריר
נקרא גם laminin alpha 2 Chromosome 6q22 Recessive במחלה קלה: מוטציות, קיים חלבון

72 Merosin (laminin a2-chain)
Location Basement membrane Muscle, Skin, CNS & Peripheral nerve (Schwann cells) Binds to a-Dystroglycan in basal lamina

73 חלבוני השריר

74 Merosin deficient MD חולשת השרירים תלויה בכמות המרוזין
מחולשה קשה וחסר הליכה עד חולשה קלה והופעת הליכה לקראת גיל 3 קונטרקטורות הפרעות נשימה פרכוסים אינטיליגנציה תקינה לרב לעיתים הפרעות למידה

75 בדיקות עזר Laboratory CK: Moderately high
MRI of CNS: White matter changes (Increased signal on T2); Cortex usually normal

76 ביופסית שריר וריאביליות בסיבים ריבוי רקמת חבור

77 צביעה למרוזין Merosin (Laminin a2) staining
Usually absent: 95% with absent merosin have gene mutation Partial merosin loss: milder disability or later onset

78 Prenatal Diagnosis ניתן לבדוק נוכחות מרוזין ע"י צביעה של ביופסיה מסיסי השליה

79 Spinal Muscular Atrophy
In 1850, the first form of the disorder was identified in adults by two French physicians, François-Amilcar Aran and Guillaume Duchenne. Toward the end of the 19th century, two German doctors, Guido Werdnig and Johann Hoffmann, described the disease in children. In the early 1950s, Eric Klas Henrik Kugelberg and Lisa Welander, identified still another form of the disease.

80 SMA פוגעת בעיקר בנוירונים המוטוריים השולטים בשרירי הגוף הרצוניים.
שרירי הפנים כמעט ולא נפגעים

81 SMA Progressive degeneration and loss of the anterior horn cells (i.e., lower motor neurons) in the spinal cord and sometimes in the brainstem nuclei, Causes lower motor neurons in the base of the brain and the spinal cord to disintegrate, preventing them from delivering electrical and chemical signals that muscles depend on for normal function.

82 SMA השרירים הלא רצוניים לא נפגעים אין פגיעה בשמיעה או ראייה
אינטליגנציה תקינה אפילו מעל הממוצע

83 SMA SMA type 1 Werding Hoffman SMA type 2
SMA type 3 Kugelberg Welander Autosomal recessive Types 1, 2 and 3 appear to be variants of the same condition, because they all appear to arise from a defect in the same gene on chromosome 5. It is possible that different defects in the same gene may give rise to the different types of SMA.

84 SMA type 1 Werding Hoffman Infantile Muscular Atrophy
הופעה לפני הלידה ועד גיל 3 ח חולשת שרירים כללית קשיים בבליעה ובנשימה החמרה הדרגתית ומוות מוקדם

85 אבחנה בילודים לעיתים ירידה בתנועות העובר היפוטוניה קשה וחסר תנועות
קונטרקטורות פסיקולציות בלשון וחסר החזרים אי ספיקה נשימתית מעורבות של שרירי הפנים בשלב מאוחר יותר

86 Type II (Chronic) אבחנה לפני גיל שנתיים יכולים לשבת אבל לא להתיישב
חולשת שרירים פרוקסימלית הרגליים יותר פגועות מהידיים תחושה תקינה אין החזרים

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88

89 Type III Mild Kugelberg-Welander or Juvenile Spinal Muscular Atrophy
אבחנה לאחר 18 חדשים ועד נערות יכולים ללכת ולעמוד עם קשיים מופיע רעד עדין אין פסיקולציות

90 The diagnosis of SMA after the neonatal period
Poor muscle tone and symmetric muscle weakness that spares the ocular muscles and only involves the facial muscles and diaphragm late in the course Delayed acquisition of motor skills Anterior horn involvement evident as tongue fasciculations (seen in only 65% of patients) and absence of deep tendon reflexes Normal reaction to sensory stimuli Normal intellect

91 ביופסית שריר Grouped atrophy Small muscle fibers are often rounded
Pyknotic nuclear clumps are not present. Large muscle fibers are hypertrophied

92 SMN-survival motor neuron
נגרמת ע"י מוטציות ב SMN gene (chromosomal locus 5q11-q13) The SMN region is unusually complex, with repetitive sequences, pseudogenes, retrotransposable elements, deletions, and inverted duplications

93 לבריאים יש שני עותקים של SMN על כל אחד מהכרומוסומים SMN1 tel ו SMN2 cent
מקשה על הבדיקות המוליקולריות

94 Molecular genetic tests of SMNT
Direct DNA analysis to detect a homozygous deletion of exon 7 of SMNT (designated D7 SMNT), which is used for confirmation of the clinical diagnosis of SMA in about 95% of patients with SMA and for prenatal testing.

95 Dosage test that determines the number of exon 7 SMNT -containing gene copies present in an individual, which is used for carrier detection. Such testing is clinically available in a limited number of laboratories

96 Genotype-Phenotype Correlations
Several studies have shown that the neuronal apoptosis inhibitory protein gene (NAIP) gene, which is in close proximity to the SMN gene, is more frequently deleted in severe SMA. Approximately 45% of patients with SMA1 were shown to have NAIP deletions, whereas only 12-18% of patients with type II and III SMA were deleted for NAIP

97 SMN1 (SMNT; telomeric SMN gene) mutations
Present in 95% of SMA patients Carrier frequency in population: 1.8% Incidence of disease: 1 in 6,000 to 8,000 births

98 SMN1 & SMN2 genes: Correlation with disease severity
Milder disease (SMA II or III) with Increased SMN2 gene copy number Absence of both SMN1 & SMN2 genes: Lethal No SMN1 gene & 1 copy of SMN2: Death < 1 month of age

99 5q CHROMOSOMES Typical SMN mutations in SMA
SMN1 Normal gene SMN1 Mutation types Deletion: More severe SMA Conversion to SMN2 gene: Milder SMA SMN2 gene: Variations More copies: Correlate with milder SMA SMN2 mutations alone: Do not produce SMA

100 Correlation with disease severity
SMA type I: Mostly deletions; Few missense point mutations SMA type II Mutations convert SMN1 gene to SMN2 SMN2 gene copy number: > 3 Missense point mutations more common SMA type III Total full length SMN protein: ? Best correlation with SMA severity

101 LIMB-GIRDLE MUSCULAR DYSTROPHIES
Pediatric Neuromuscular Clinic Metabolic-Neurogenetic Service Wolfson Medical Center

102 Introduction The limb-girdle muscular dystrophies (LGMD) are a group of genetically heterogeneous MD presenting with weakness of hip and shoulder girdle. Coined by Stevenson 1953, Walton and Natrass 1954 to account for occurrence of cases not clearly X-linked or FSH MD. Continuing problem in classification.

103 Introduction Clinical overlap with genetically distinct disorders –e.g SMA and mitochondrial and metabolic myopathies may present with limb-girdle weakness. Molecular pathogenesis known in 14 (3AD, 11AR) types (<50%). Each type may be clinically heterogeneous. Some are allelic with other forms of muscular dystrophy. Some have unique pathogenic mechanisms.

104 Clinical Criteria Onset
Pelvic or shoulder girdle muscles or both simultaneously involved. Onset of weakness in distal, facial or extra-articular muscles should suggest alternative diagnoses, though these muscles may be involved later in the course of the disease. Most individuals with LGMD begin to exhibit symptoms between adolescence and adulthood.

105

106 Clinical In more severe cases, symptoms manifest during childhood.
Progression Progression of the weakness is inevitable but variable. Involvement of other systems is rare. Proximal areas are more severely affected than those muscle groups distal to the body. The heart and “bulbar” muscles are generally spared.

107 Clinical Proximal weakness. Scapular winging. Gower’s sign.
Quadriceps myopathy -atrophy of the lower portion of the quadriceps is most conspicuous.

108 Labs CK is always elevated in recessive cases and may be used as a presymptomatic test in families where elevation of CK has been documented. In dominant families CK is normally no greater than 6 times normal, while in recessive families in may be as high as 200 times normal. Muscle CT scanning may also provide evidence of hypodensity of the involved muscles

109 Labs Electromyography and muscle biopsy usually provide evidence of non-specific myopathic or dystrophic changes. Recruitment of an excessively large number of motor unit action potential (MUAP) Alteration in the morphology of MUAP; small shorter and polyphasic. Increase in insertional activity, fibrillation potentials and positive sharp waves.

110 Genetics Mode of inheritance
The majority of LGMD cases are inherited in an autosomal recessive manner; however several rare dominantly inherited subtypes have recently been classified at the molecular level. Current estimates suggest that approximately 10% of all patients with LGMD may have a dominant mutation.

111 LGMD 1A AD 5q31 Myotilin LGMD 1B AD 1q11-21 Lamin A/C LGMD 1C AD 3p25
Nasal speech Rare LGMD 1B AD 1q11-21 Lamin A/C Uncommon AD-EDMD; Dunnigan-type familial partial lipodsytrophy; dilated cardiomyopathy and cardiac conduction system defect LGMD 1C AD 3p25 Caveolin 3 Typical LGMD, or CK elevation without myopathy, myalgia, cramps, rippling muscle disease. Rare LGMD 2A AR 15q15-21 Calpain-3 Distal wasting, walk on outsides of feet, scapular winging, onset in thighs and adductors 33% of AR-LGMD with normal dystrophin LGMD 2B AR 2p13 Dysferlin Extremely high CK; may have distal weakness 40% of AR-LGMD with normal dystrophin Miyoshi myopathy; distal myopathy LGMD 2C AR 13q12 gamma-sarcoglycan Sarcoglycanopathies collectively account for ~10% of AR-LGMD with normal dystrophin LGMD 2D AR 17q12-21 alpha-sarcoglycan LGMD 2E AR 4q12 beta-sarcoglycan LGMD 2F AR 5q33-34 delta-sarcoglycan LGMD 2G AR 17q11-12 Telethonin Rimmed vacuoles in muscle;variable CK Rare LGMD 2H AR 9q31-34 TRIM32 Slowly progressive Rare; Manitoba Hutterites only LGMD 2I AR 19q13.4 Fukutin-related protein Muscle hypertrophy Unknown frequency Congenital muscular dystrophy 1C

112

113 Biopsy Non-specific changes including
Variation of myofiber size with increased endomysial connective tissue Increased central nuclei

114 Biopsy Degenerating and regenerating fibers are seen but they are rarely prominent and usually scattered throughout the muscle with no tendency to group as in DMD. Necrotic fibers contain Trichrome (+) material that may resemble IBM.

115 Biopsy Ring fibers are frequent and can be observed in 50% of cases.
In ring fibers, the normal longitudinal orientation of the myofibrils is lost.

116 Biopsy Many fibers show a “moth eaten” appearance with stains for oxidative enzymes. Focal decrease in the intermyofibrillar mitochondrial population, most evident in type 1 fibers

117 Immunohistochemistry may be very useful
Differentiating from dystrophinopathy 17% of suspected LGMD had a dystrophinopathy (Arikawa, 1991)

118 Autosomal Recessive LGMD

119 Sarcoglycanopathies

120 Sarcoglycanopathies Heterotetrameric transmembrane complex .
Interacts with dystroglycan complex but does not bind dystrophin directly. Plasma membrane stabilization. Most frequent is a SG (17q) b SG (4q) is second most common g SG (13q) severe childhood autosomal recessive muscular dystrophy d SG (5q) least common (Brazil)

121 Sarcoglycanopathies Generally manifest earlier in life (3-5 years of age) than other LGMD. Clinical presentation: Limb-girdle muscle weakness with atrophy, scapular winging. Severe cases resemble DMD. Pain and cramping typical. Calf hypertrophy early. Ankle contractures. Cardiac involvement not common. Extremely elevated CK ( x higher than other LGMD).

122 Sarcoglycanopathies Primary mutations in b- or d-sarcoglycan leads to secondary loss of all elements in the complex. Mutation in a-sarcoglycan (adhalin) leads to milder loss. Mutation in g-sarcoglycan is least disruptive. These generalizations not reliable, DNA confirmation recommended.

123

124 Calpainopathy (LGMD2A)

125 Calpainopathy (LGMD2A)
The most common single genetic cause of LGMD CAPN3 gene (15q). Calpain (nonlysosomal Ca++ dependent protease) associated with sarcomere. Maintains sarcomere size and elasticity. Function in the myofiber is not known– probable role in membrane signaling and repair. Calpain is unstable, so immunostain is not reliable. Direct sequencing of the gene.

126 Calpainopathy (LGMD2A)
Usually presents in the second decade of life. Gluteus maximus and thigh adductors predominately involved. Spares quadriceps. Consistently develop heel cord contractures – toe walking, later hips knees and elbows. Abdominal laxity and hyperlordosis. CK elevated but lower than seen in sarcoglycan disease.

127 Dysferlinopathy

128 Dysferlinopathy LGMD2B caused by mutations in the DYSF gene (2p).
Dysferlin is normally present at the plasma membrane probable role in membrane signaling and repair. Mutations may lead to either LGMD2B or Miyoshi myopathy (can have both in same pedigree). These tend to resemble each other as disease advances. Diagnosis relies on Western Blot analysis and immunostaining

129 Dysferlinopathy Manifests in 2nd decade of life.
Involves most of leg muscles but tends to spare shoulder girdle musculature (upper extremity involvement of biceps). Usually do not see scapular winging or calf hypertrophy. Diagnosis relies on Western Blot analysis and immunostaining (Note: may frequently see inflammation and rimmed vacuoles on biopsy).

130

131 Telethoninopathy (LGMD 2G )

132 Telethoninopathy Newly recognized form of AR LGMD
Described in 4 Brazilian families LGMD 2G (17q) Telethonin is a sarcomeric protein preferentially expressed in striated muscle, and accumulates in the Z line with alpha-actinin Onset in childhood; small or large calves Affects upper and lower proximal muscles but also involves distal leg muscles early – ankle dorsiflexion weakness. Diagnosis is by immunohistochemistry (may also see rimmed vacuoles on biopsy)

133 Other Autosomal Recessive LGMD:
LGMD 2H seen only in Manitoba Hutterites. TRIM32 mapped to 9q (4.4 kb from fukutin). LGMD2J Titin deficient late onset distal tibial myopathy. Double mutants have severe limb-girdle pattern.

134 LGMD 2I (19q) Fukutin-related protein (FKRP)
Involved in glycosylation of a-dystroglycan. Mutations cause abnormal glycosylation and disrupt link between dystroglycan and laminin. Most are CMD’s or simulate dystrophinopathy. Milder LGMD with infant to adult onset. Severe CMD picture with cerebellar cysts. Reduced laminin alpha-2 immunostain.

135 Autosomal Dominant LGMD

136 Myotilinopathy (LGMD 1A)

137 Myotilinopathy Myotilin gene (5q).
Myotilin is a sarcomeric protein that binds to alpha-actinin and is localized to the Z-line. Anticipation suggesting unstable trinucleotide repeat. LE weakness precedes UE weakness, reduced DTR’s. Facial weakness in some patients. Frequent heel cord contractures.

138 Myotilinopathy 50% of patients have “a distinctive nasal, dysarthric speech”. CK elevated (2-9 fold). Histology: rimmed vacuoles. EM: rod like bodies.

139 Laminopathy (LGMD 1B)

140 Laminopathy Mutation on chromosome 1q resulting in altered lamin A/C protein product. Allelic with autosomal dominant Emery-Dreifuss muscular dystrophy Onset in childhood in one half. LE extremity weakness precedes UE weakness. Slowly progressive. Cardiac irregularities, AV conduction disturbances, bradycardia, syncope, sudden cardiac death.

141 Caveolinopathy (LGMD 1C)

142 Caveolinopathy CAV3 3p25. Caveolin is involved in membrane traffic and signal transduction in smooth and skeletal muscle. Manifests in early childhood with mild to moderate proximal muscle weakness, calf hypertrophy, elevated CK. May have muscle rippling or mounding with percussion. May be asymmetric.

143 LGMD 1D Chromosome 6q gene not known
Significant cardiac pathology: “familial dilated cardiomyopathy with conduction disease and myopathy”. No testing is available

144 LGMD 1E Two large pedigrees map to 7q
Adult onset, proximal weakness, dysphagia, Pelger-Huet anomaly (granulocytes with abnormal nuclei)


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