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Congenital myopathy

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Congenital myopathy

  2. 2. Outline: Congenital myopathy: Definition, classification, clinical features, differential diagnosis, investigations, management. Approach to a case of floppy infant Congenital muscular dystrophy: Definition, classification, clinical features, investigations, management. Recent advances Summary
  3. 3. Definition of congenital myopathy: The term “congenital myopathy” is applied to muscle disorders presenting in infancy with generalized muscle weakness and hypotonia followed by delayed developmental milestones. Neurol J Southeast Asia 2001; 6. Clinical and pathologic aspects of congenital myopathies Ikuya NONAKA MD
  4. 4. Background:  First report of a congenital myopathy was in 1956, when a patient with central core disease (CCD) was described.  In 1969, Dubowitz clarified the classification with his delineation of new myopathies later termed congenital myopathy.  The myopathy has been differentiated diagnostically on the basis of their morphologic characteristics.  With the advent of electron microscopy, enzyme histochemistry, immunocytochemistry, molecular genetic analysis , a number of morphologically distinct congenital myopathies have grown.  The mode of inheritance and gene loci are variable.
  5. 5. Epidemiology: Worldwide: Incidence:6 per 100,000 live births or 1/10th of all neuromuscular disorders. (wallgreen peterson 1990) 0.06% of all muscle diseases( ischizo nishino 2007) Regional studies in Northern Ireland and Western Sweden suggest prevalence between 3.5–5.0/100,000 in a pediatric population (Jungbluth H. Orphanet J Rare Dis 2007;2:31. )
  6. 6. India:  1.12% of the muscle disease( Deepali jain, Rohit Bhatia 2008)
  7. 7. Characteristic features:  Onset in early life with hypotonia, hyporeflexia, generalized weakness that is more often proximal than distal,  Poor muscle bulk  Dysmorphic features  Relatively non-progressive  Hereditary  Unique morphological features on histochemical or ultrastructural examination of the muscle biopsy sample that originate within the myofiber  Some cases have been reported as adult onset or as a progressive
  8. 8. Classification: North K. What's new in congenital myopathies?. Neuromuscul Disord. Jun 2008;18(6):433-42 1. Myopathies with protein accumulation a. Nemaline myopathy b. Myosin storage myopathy c. Cap disease d. Reducing body myopathy 2. Myopathies with cores a. Central core disease b. Core-rod myopathy c. Multiminicore disease 3. Myopathies with central nuclei a. Myotubular myopathy b. Centronuclear myopathy 4. Myopathies with fiber size variation Congenital fiber type disproportion
  9. 9. Congenital Myopathies with identified gene loci: Disorder inheritance Protein/gene chromosome 1. Nemaline myopathy a. NEM I b. NEM2 c. NEM3 AD AR AD/AR/Sporadic α-tropomyosin 3 Nebulin alpha-actin 1q22-q23 2q21-q22 1q42.1 2. Central core disease AD/Sporadic Ryanodine(RYR1) 19q13.1 3. Core rod myopathy AD Ryanodine(RYR1) 19q13.1 4. Congenital myopathies with cores AR Ryanodine(RYR1) 19q13.1 5. Myotubular myopathy X linked Myotubularin Xq28 6. Multi minicore AR Selenoprotein N 1p36 7. Hyaline body myopathy AD Cardiac myosin heavy chain 14q11.2
  10. 10. Incidence of congenital myopathy (1979-2000: National Center of Neurology and Psychiatry) Neurol J Southeast Asia December 2001 Types of congenital myopathy Number of patients (%) Nemaline myopathy 121 (27%) Severe infantile form 43 Benign congenital form 53 Adult onset form 25 Central core disease 27 (6%) Myotubular (centronuclear) myopathy 42 (9%) Severe infantile myotubular myopathy 30 (7%) Congenital fiber type disproportion 89 (20%) Congenital myopathy without specific features 31 (7%) Miscellaneous 109 (24%)
  11. 11. Congenital myopathies: A clinicopathological study of 25 cases Deepali Jain, Rohit Gulati IJPM 2008 Type % cases Central core disease 24 Multiminicore 20 Nemaline 20 CFTD 16 Centronuclear 12 Desminopathy 8
  12. 12. Congenital myopathies: Clinical and Pathological Study. Annals of Indian Academy of Neurology, 2007 by N. Gayathri, A. Nalini, F. Thaha Type of myopathy No of cases (total 39) Centronuclear 18 CFTD 15 Nemaline 2 Central core 2 Multiminicore 1 Tubular aggregates 1
  13. 13. Floppy infant Clinical signs in a floppy infant  Observation of a ‘frog-leg’ posture.  Reduced spontaneous movement, with the legs fully abducted and arms lying beside the body either extended or flexed  Significant head lag on traction or pull-to-sit manoeuvre and excessively rounded back when sitting (>33 weeks)  Rag-doll posture on ventral suspension  Vertical suspension test – feeling of ‘slipping through the hands’ when the infant is held under the arms  Various associated examination findings such as flat occiput or congenital dislocation of the hips, arthrogryposis
  14. 14. Hypotonia pith frog position
  15. 15. Hypotonia
  16. 16. Differential diagnosis
  17. 17. Indicators of hypotonia of central origin • Social and cognitive impairment • Dysmorphic features • Fisting of hands • Normal or brisk tendon reflexes • Features of pseudobulbar palsy • brisk jaw jerk • crossed adductor response or scissoring on vertical suspension • Features that may suggest an underlying spinal dysraphism • History suggestive of HIE, birth trauma or symptomatic hypoglycaemia • Seizures Indicators of peripheral hypotonia • Delay in motor milestones with relative normality of social and cognitive development • Family history of neuromuscular disorders/maternal myotonia • Reduced or absent deep tendon jerks and increased range of joint mobility • Frog-leg posture or ‘jug-handle’ • Myopathic facies (open mouth with tented upper lip, poor lip seal when sucking, lack of facial expression, ptosis and restricted ocular movements) • Muscle fasciculation
  18. 18. Investigations Laboratory Studies  Creatine kinase level  Normal or mildly elevated.  Moderately in central core disease (CCD) and also in asymptomatic carriers of the ryanodine receptor mutation in CCD. Other Tests  Electromyography and nerve conduction studies  Nerve conduction study is normal.  EMG is normal or shows myopathic pattern.  Rule out other diseases such as spinal muscular atrophy, congenital myasthenia, and hereditary neuropathy.  Electrocardiography (ECG)
  19. 19.  Imaging: Ultasound, MRI of the muscle may be helpful.  Procedures  Muscle biopsy: Gold standard  Light microscopy(H/E stain), Gomori trichrome stain, enzyme histochemistry, immunocytochemistry.  Ultrastructural examination of muscle is often necessary, since several of the pathologic features are based on the EM appearance of muscle.  Genetic analysis:  Not required for diagnosis  Very sensitive and specific in CCD  Only a research level tool
  20. 20. Nemaline myopathy:  Shy et al and Conen et al first described the disease in 1963  Classified into 3 major forms including the 1) severe infantile (congenital) 2) benign congenital (mild, nonprogressive or slowly progressive) 3)adult onset forms  Incidence: 0.2 per 1000 live births  More common in finland and 1 in 500 in Amish community  o.53% of all muscle disease and 22.6% of all congenital myopathies. (MC Sharma, S Gulati Neurology India 2007)  6 Genetic types
  21. 21. Genetics Disorder inheritance Protein/gene 1. NEM I AD α-tropomyosin 3 2. NEM 2 AR Nebulin 3.NEM 3 AD/AR/Sporadic alpha-actin 4. NEM 4 AD β-tropomyosin 5. NEM 5 AR Troponin T1 6. NEM 7 AR Cofilin 2
  22. 22. Severe infantile (congenital) form Benign congenital form Adult onset form •Muscle weakness and hypotonia at birth. •Facial muscle involvement •elongated, emotionless expression •high arched palate •usually die before 1 year of age • respiratory failure or infection ccommon. •Cardiomyopathy rare •Seizures rare •Floppy infants with delayed developmental milestones •Neck flexor weakness is prominent •95% patients generalized or predominantly proximal muscle weakness •5% weakness predominantly distal non-progressive or only slowly Progressive •Respiratory muscles •Non progressive minimal facial muscle involvement •Minimal proximal muscle weakness •Benign course
  23. 23. Head lag
  24. 24. Investigations  Sr CK normal o minimally elevated  Increased echogenecity in affected muscles on muscle USG  Myopathic pattern on EMG  Muscle MRI reveals patchy fatty degeneration of muscle groups  Histopathology diagnostic  Genetic analysis
  25. 25. Nemaline bodies Gomori trichrome stain H/E Stain
  26. 26. Electron microscopy
  27. 27. Central core disease:  Term coined by Greenfield in 1958  Mutation in the ryanodine receptor(CH 19q12.q13.2) Typical presentation  Autosomal dominant inheritance.  Onset is at birth or in early childhood  Nonprogressive limb weakness, mild facial weakness, and hypotonia.  Skeletal abnormalities include congenital hip dislocation, kyphoscoliosis, and foot deformities.
  28. 28. Other presentations Autosomal recessive (and autosomal dominant) inheritance have been described with several different presentations. Presentation in infancy includes generalized weakness and atrophy, external ophthalmoplegia, and bulbar and respiratory weakness. Asymptomatic individuals may also present with a high creatine kinase (CK) level or malignant hyperthermia. About 25% of patients with CCD are susceptible to malignant hyperthermia
  29. 29. Investigations  Sr CK- Normal to mildly elevated  Muscle ultrasound- increase in echogenecity  Muscle MRI-selective involvement of following thigh muscles- sartorius, adductor magnus, gastrosoleus, peroneal group.  Muscle pathology:  Oxidative stains: cores are hypostained  Electron microscopy: excessive disorganisation of sarcomeres in the cores, severe fragmentation and decrease of Z bands.  Genetic analysis: PCR for CCD-RYR1 gene mutation(>60% positive)
  30. 30. Oxidase staining: Central cores
  31. 31. Central core disease - ultrastructural disorganization (Z-band streaming).
  32. 32. Centronuclear myopathy  Defined pathologically by the presence of central nuclei in increased number of fibres.  First reported as myotubular myopathy by spiro et al in 1966.  AD, AR and X linked forms
  33. 33. X linked form The most common is the severe X-linked form due to a mutation in myotubularin. At birth, severe weakness and hypotonia, feeding difficulty, and respiratory distress are present. Bilateral ptosis, facial weakness, and ophthalmoplegia are common. Skeletal features include pectus carinatum, knee and hip contractures, elongated birth length, narrow face, and macrocephaly. Systemic features may include cryptorchidism, pyloric stenosis, gallstones, hepatic dysfunction, spherocytosis, renal calcinosis.
  34. 34. The prognosis is poor  At least one third of those affected dying in the first year of life.  Seventy-five percent of survivors older than 1 year need ventilatory support Most carriers are asymptomatic.
  35. 35. AR variant Mutations in amphiphysin 2. Features include hypotonia, proximal weakness, facial weakness, ptosis, and ophthalmoplegia. Other features can include contractures and dilated cardiomyopathy. The course is slowly progressive, with more than 50% of patients surviving childhood.
  36. 36. AD variant: Mutations in dynamin 2 (DNM2) Most patients have a mild phenotype Onset in adolescence or adulthood Axial as well as distal more than proximal limb weakness and slow progression. Facial weakness, high-arched palate, ptosis, ophthalmoplegia, joint hyperlaxity, and contractures are common. Benign couse
  38. 38. Minicore (multicore) myopathy  So named because of the presence of core structures in the muscle fibres.  Autosomal recessive  Around half of cases caused by a genetic error in one of two genes- Selenoprotein N1 (SEPN1) and Ryanodine receptor 1 (RYR1).  4 Variants:  Classic form  Progressive form with hand involvement.  Antenatal form with arthrogryposis multiplex congenita (AMC).  Ophthalmoplegic form
  39. 39. Prognosis: variable course Diagnosis : Histopathology: • More type 1 fibres than type 2. • Within these fibres, there are structures which are called ‘cores’; which can be seen under the microscope. These structures are not specific to minicore myopathy, and so the clinical signs must be considered together with the muscle sample to give a diagnosis of minicore myopathy
  40. 40. Congenital fibre type disproportion:  Rare disease first described by Brooke  Autosomal recessive  Genetics: mutation in TPM3(75%), Selenoprotein N(1O%) and ACAT1(10%)  Child presents as presents as hypotonia, delayed motor milestones and dysmorphic facies.  Other clinical features can include facial, bulbar, and respiratory weakness; short stature; low body weight  Multiple joint contractures; scoliosis; long, thin face; and high- arched palate.
  42. 42. Summary: Type Facial muscle ptosis Ext ophthalmo plegia Respirator y Skeletal deformity cardiac Nemaline +++ +++ - +++ ++ + CCD ++ + - + +++ + Core rod + + - - ++ - myotubular +++ +++ +++ +++ ++ - Centronuclear ++ ++ ++ +++ +++ - Multiminicore +++ + + +++ +++ ++ CFTD ++ - - + +++ - Sarcotubular ++ - - - - - Reducing body ++ ++ - +++ ++ -
  43. 43. Special clinical features: Clinical feature Congenital myopathy Cramps CCD Myopathy with tubular aggregates Calf hypertrophy Centronuclear myopathy Myasthenic fatures Myopathy with tubular aggregates Malignant hyperthermia CCD, Core rod Multimini core Neonatal lethal form X linked myotubular Nemaline
  44. 44. Cardiomyopathies associated with congenital myopathies Cardiomyopathy Myopathy Hypertrophic Nemaline myopathy Multicore myopathy Cytoplasmic body myopathy Desminopathy Myofibrillar myopathy Danon’s disease Dilated Nemaline myopathy CentronucIear myopathy CFTD Desminopathy Restrictive Desmin myopathy Myofibrillar myopathy Multicore myopathy
  45. 45. Floppy infant with pred proximal weakness, hyporeflexia, dysmorphic facies Nemaline Ptosis, ophthalmoplegia, respiratory involvement Cramps, ptosis, cardiomyopathy Congenital myopathy Facial muscle & neck flexor weakness, respiratory Contractures , Bulbar, respiratory weakness CFTD Myotubular and centronuclear Central core disease
  46. 46. Clinical suspicion of Cong myopathy NCS normal/EMG Myopathic Confirmation of diagnosis Muscle Biopsy: LM, IHC, EHC,EM , Genetic analysis Sr.CK, NCS/EMG Sr CK elevated in Central core disease
  47. 47. Treatment: • No definitive treatment. • Physiotherapy, occupational therapy • Use of splints, braces and orthosis • Contracture release, corrective surgeries. • Chest physiotherapy, prevention and management of aspiration pneumonitis, non invasive ventilation. • Nutrition and gastrostomy feeding. • Management of heart failure.
  48. 48. Congenital muscular dystrophy • 1903, Batten described 3 children who had proximal muscle weakness from birth whose biopsy showed chronic myopathic changes • In 1908, Howard coined the term congenital muscular dystrophy (CMD) when he described another infant with similar features. • Ullrich first described the combination of joint hyperlaxity and proximal contractures in 1930 in the German literature; which is known as Ullrich congenital muscular dystrophy. • In 1960, Fukuyama et al described a common congenital muscular dystrophy in Japan that always had features of muscular dystrophy and brain pathology.
  49. 49. Congenital muscular dystrophies are characterised by  Autosomal recessive disease  severe proximal weakness at birth  slowly progressive or nonprogressive.  Contractures are common  CNS abnormalities can occur.  Muscle biopsy shows signs of dystrophy
  50. 50. Muntoni and Voit 2004 Group Disorder Gene locus Gene Protein I Laminin α2 deficiency 6q2 LAMA2 Laminin a2 II.1 Fukuyama MDC 9q3 FUKUTIN Fukutin II.2 MEB disease 1p3 POMGnT1 Omannosyl GlcNac transferase II.3 Walker Warburg 9q34 POMT1 Omannosyl transferase II.4 CMDIc/LGMD2I 19q13 FKRP Fukutin related protein II.5 CMD1B 1q42 ? ? II.6 CMD1D 22q LARGE Glycosyl transferase III.1 Rigid spine muscular dystrophy 1p35 SEPN1 Selenoprotein N III.2 Ullrich CMD 21q22 COL6A1,A2 Collagen 6a1,a1 IV Integrin a7 deficiency ? INTEGRIN a7 Integrin a7 V Rare forms ? ? ?
  51. 51. Genetic defects
  52. 52. • The incidence of CMD has been estimated at 4.7 x 10-5 and its prevalence at 6.8 x 10-5 (Mostacciuolo et al. 1996 Genetic epidemiology of congenital muscular dystrophy in a sample from north-east Italy). • The estimated prevalence is approximately 7-12 cases per 100,000 children. • In Japan, Fukuyama congenital muscular dystrophy is fairly common. It is approximately 50% as common as Duchenne muscular dystrophy. • Few cases from India. ( Merosin negative congenital muscular dystrophy: a short report. Ralte AM, Sharma MC, Gulati S, Das M, Sarkar C)
  53. 53. DIFFERENTIAL DIAGNOSIS:  Congenital Myopathies  Dystrophinopathies  Emery-Dreifuss Muscular Dystrophy  Limb-Girdle Muscular Dystrophy  Metabolic Myopathies  Spinal Muscular Atrophy
  54. 54. Congenital muscular dystrophy with laminin-α2 deficiency (MDC1A, classic CMD, merosin-deficient CMD)  Accounts for 40-50% of all MDC.  Mutation on chr 6 in the LAMA2 gene that codes for laminin- α2.  More than 90 different missense, nonsense, splice-site, and deletion mutations have been described.  Expression of laminin-α2 is related to disease severity.  Laminin-α2 is expressed in the basement membrane of striated muscle, cerebral blood vessels, Schwann cells, and skin
  55. 55. • At birth or in the first few months of life, patients may have severe hypotonia, weakness, feeding difficulty, and respiratory insufficiency. • Contractures are common. • External ophthalmoplegia may occur late. • Most infants eventually sit unsupported, but standing is rare. • Weakness is static or minimally progressive • Complications are related to respiratory compromise, feeding difficulty, scoliosis, and (in approximately one third) cardiopulmonary disease. • A sensory motor demyelinating neuropathy is present in many patients, but it may not be clinically relevant.
  56. 56. CLINICAL FEATURES • CNS manifestations may be present. – Mild mental retardation or perceptual-motor difficulties – Seizures occur in up to 30% of patients. – White-matter changes, most often in periventricular – Structural brain changes include enlargement of the lateral ventricles, focal cortical dysplasia, occipital polymicrogyria and/or agyria, and hypoplasia of the pons and/or cerebellum.
  57. 57. Investigations  Sr CK- moderately high  Brain MRI- T2 Hyperintense white matter changes.  Histopathology: Variable fibe size Increased endomysial connective tissue. Increased internal nuclei, hypercontracted fibres.  Muscle laminin staining: Specific.
  58. 58. Images:
  59. 59. Merosin + Merosin - Somewhat Merosin -
  60. 60. Fukuyama CMD • Autosomal recessive disease • Mutation in the fukutin gene on 9q • Most common in Japan and rare elsewhere in the world. • Fukutin is a putative glycosyltransferase. . • Patients with Fukuyama congenital muscular dystrophies have complete loss (or nearly complete loss) of glycosylated α- dystroglycan in the brain and muscle.
  61. 61. • Present in utero with poor fetal movements. • Characteristics: generalised weakness, abnormal eye function, mental retardation and seizures. • Progressive weakness and respiratory failure ensue, with death usually occurring in the mid teens. • Cardiac disease develops after age 10 years, resulting in dilated cardiomyopathy and congestive heart failure. • Severe cases may cause retinal detachment, microphthalmos, cataracts, hyperopia, or severe myopia.
  62. 62. • Cerebral changes are always present. Type II lissencephaly is the characteristic finding in this disease, as in all other glycosyltransferases. Abnormalities range from cobblestone polymicrogyria and/or pachygyria to complete agyria due to neuronal migration abnormalities. Dysplasia of the pyramidal tracts is common. Ventricular dilation, if present, is mild. Delayed myelination is noted on MRI. Cerebellar cysts are common.
  63. 63. Brain imaging in FCMDAjay Garg, Sheffali Gulati Neurology India December 2004 Vol 52 Issue 4
  64. 64. Fukuyama CMD  severely retarded, had many seizures  marked contractures of the limbs.  too weak to support her own weight.  disease was nonprogressive.  Her two brothers also had the same illness
  65. 65. Investigations: • Moderate to marked elevation in Sr.CK • Myopathic EMG • MRI Brain • HISTOPATHOLOGY AND IMMUNOHISTOCHEMISTRY: • Histology of muscle: Essentially a picture of dystrophic myopathy. • Immunohistochemistry: Decreased staining for dystrophin- associated proteins and for merosin.
  66. 66. Muscle eye brain disease • Mutations in POMT1, POMT2, POMGnT1, fukutin, and FKRP can cause this syndrome. • In a series of 92 patients with congenital muscular dystrophy, 14 were found to have muscle-eye-brain disease/Fukuyama congenital muscular dystrophy phenotype.(Godfrey C, Clement Brain. Oct 2007;130(Pt 10). • Seizures are common. • CNS abnormalities are always present, including moderate-to-severe mental retardation. • Eye abnormalities are similar but more severe than those of Fukuyama CMD. • Cerebral changes are similar to those of Fukuyama CMD.
  67. 67. Walker-Warburg syndrome  Mutations in all 6 glycotransferases have resulted in this most severe form of congenital muscular dystrophy.  Most severe of all alpha dystroglycanopaties.  Eye abnormalities include microphthalmos, hypoplastic optic nerve, ocular colobomas, retinal detachment, cataracts, glaucoma, iris malformation, and corneal opacities, all of which lead to blindness.  Brain abnormalities include complete type II lissencephaly with agyria.
  69. 69. Rigid-spine syndrome with muscular dystrophy  Autosomal recessive  Mutation in the selenoprotein N gene (SEPN1).  Presentation is at birth or within the first year of life  Scapular winging and facial and bulbar weakness are common.  Contractures usually develop at age 3-10 years.  Respiratory insufficiency is common and progressive  Muscle weakness is slowly progressive.  The cardiac system is usually normal.  Intelligence and brain MRIs are normal.
  70. 70. Ullrich congenital muscular dystrophy  Autosomal recessive (or more rarely dominant) disorder  Mutation in 1 of the 3 collagen type VI genes (COL6A1, COL6A2, COL6A3).  Typical features include presentation in the neonatal period  with hypotonia, kyphosis of the spine, proximal joint contractures, torticollis, and hip dislocation.  Distal joint hyperlaxity with a protruding calcaneus  Weakness involves distal more than proximal muscles.  Progressive disability, usually due to contractures, leads to loss of ambulation after 2-10 years.
  71. 71.  Respiratory insufficiency invariably develops in the first or second decade.  Facial dysmorphism is common and includes micrognathia, a round face with drooping of the lower lids, and prominent ears.  Skin changes can include follicular hyperkeratosis, keratosis pilaris, and keloids.  Intelligence and brain MRIs are normal.  Cardiac function is normal.
  72. 72. UCMD: Report of nine cases from India A Nalini, N Gayatri Neurology India 2009
  73. 73. Muscle weakness,contractures,cogni tive decline, seizures CMD MEB Walker Warburg Fukuyama CMD Eye involvement, brain malformations, raised CK Distal > proximal weakness, distal joint hyperlaxity, proximal contractures, skin changes Ullrich’s CMD Proximal> distal weakness RSMD Merosin def CMD
  74. 74. Management  No specific treatment is available for any of the congenital muscular dystrophies.  Aggressive supportive care is essential to preserve muscle activity, to allow for maximal functional ability, and to prolong the patient's life expectancy.  Management of pulmonary and cardiac problems.
  75. 75. Non invasive ventilation:
  76. 76. G tube implantation: Physiological and most acceptable way of feeding for long term
  77. 77. Surgical Care • Orthopedic surgery is often necessary in patients who live several years with their disease to prevent contractures and scoliosis Post scoliosis Surgery:
  78. 78. Gene therapy  Agrin which binds to laminin and to α-drystroglycan might be able to functionally rescue the weakened muscle caused by LAMA2 mutations.  The Agrin transgene improved the general health, lifespan and locomotory activity of the mutant mice.  This study demonstrates the potential for gene therapy using non-homologous proteins that functionally compensate for gene mutation.
  79. 79. Summary  Congenital myopathies not so uncommon in india, and an important diagnosis to be considered in a floppy infant  Muscle histopathology is the gold standard for diagnosis.  Of the congenital muscular dystrophies, only merosin deficiency and Ullrich’s CMD are reported from india.  Contractures, Brain involvement and dystrophic changes in muscle are the hallmark of CMD  Gene therapy in the coming years can bring in a definite solution to the problems.
  80. 80. Thank you