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

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

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

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.

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

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.

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).

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)