CONGENITAL MYOPATHY &

CONGENITAL MUSCULAR DYSTROPHY

BY- ABDUL QAVISR NEUROLOGY

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

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

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.

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. )

India:

1.12% of the muscle disease( Deepali jain, Rohit Bhatia 2008)

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

course.

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 coresa. 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

Congenital Myopathies with identified gene loci:Disorder inheritance Protein/gene chromosome

1. Nemaline myopathy

a. NEM I

b. NEM2c. NEM3

ADARAD/AR/Sporadic

α-tropomyosin 3Nebulinalpha-actin

1q22-q232q21-q221q42.1

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

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%)

Congenital myopathies: A clinicopathological study of 25 casesDeepali Jain, Rohit Gulati

IJPM 2008

Type % cases

Central core disease 24

Multiminicore 20

Nemaline 20

CFTD 16

Centronuclear 12

Desminopathy 8

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

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

Hypotonia pith frog position

Hypotonia

Differential diagnosis

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

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)

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

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

• NEM 2 most common of all.

GeneticsDisorder 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

Severe infantile (congenital) form

Benign congenital form Adult onset form

•Muscle weakness andhypotonia 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 infantswith delayed developmental milestones

•Neck flexor weakness is prominent

•95% patientsgeneralizedor predominantly proximal muscle weakness

•5% weakness predominantly distalnon-progressive or only slowly Progressive

•Respiratory muscles

•Non progressive minimal facial muscle involvement

•Minimal proximal muscle weakness

•Benign course

Head lag

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

Nemaline bodies

Gomori trichrome stain H/E Stain

Electron microscopy

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.

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

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)

Oxidase staining: Central cores

Central core disease - ultrastructural disorganization (Z-band streaming).

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

X linked formThe 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.

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.

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.

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

MUSCLE PATHOLOGY INCENTRONUCLEAR MYOTUBULAR

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

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

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.

HISTOPATHOLOGY:

Summary:

Type Facial muscle

ptosis Ext ophthalmoplegia

Respiratory Skeletal deformity

cardiac

Nemaline +++ +++ - +++ ++ +

CCD ++ + - + +++ +

Core rod + + - - ++ -

myotubular +++ +++ +++ +++ ++ -

Centronuclear ++ ++ ++ +++ +++ -

Multiminicore +++ + + +++ +++ ++

CFTD ++ - - + +++ -

Sarcotubular ++ - - - - -

Reducing body ++ ++ - +++ ++ -

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 rodMultimini core

Neonatal lethal form X linked myotubularNemaline

Cardiomyopathies associated with congenital myopathies

Cardiomyopathy Myopathy

HypertrophicNemaline myopathyMulticore myopathyCytoplasmic body myopathyDesminopathyMyofibrillar myopathyDanon’s disease

Dilated Nemaline myopathyCentronucIear myopathyCFTDDesminopathy

Restrictive Desmin myopathyMyofibrillar myopathyMulticore myopathy

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

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

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.

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.

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

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 ? ? ?

Genetic defects

• 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)

DIFFERENTIAL DIAGNOSIS:

Congenital Myopathies

Dystrophinopathies

Emery-Dreifuss Muscular Dystrophy

Limb-Girdle Muscular Dystrophy

Metabolic Myopathies

Spinal Muscular Atrophy

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

• 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.

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.

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.

Images:

Merosin + Merosin - Somewhat Merosin -

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.

• 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.

• 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.

Brain imaging in FCMDAjay Garg, Sheffali Gulati Neurology India December 2004 Vol 52 Issue 4

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

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.

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.

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.

HIERARCHY OF ORGAN INVOLVEMENT IN ALPHA DYSTROGLYCANOPATHY

CEREBRUM

EYES P

ONS

CEREBELLUM

STRIATED MUSCLE

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.

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.

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.

UCMD: Report of nine cases from IndiaA Nalini, N Gayatri

Neurology India 2009

Muscle weakness,contractures,cogni

tive decline, seizures

CMD

MEBWalker WarburgFukuyama CMD

Eye involvement, brain malformations, raised CK

Distal > proximal weakness, distal joint hyperlaxity, proximal contractures,

skin changes

Ullrich’s CMD

Proximal> distal weakness

RSMDMerosin def CMD

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.

Non invasive ventilation:

G tube implantation: Physiological and most acceptable way of feeding for long term

Surgical Care

• Orthopedic surgery is often necessary in patients who live several years with their disease to prevent contractures and scoliosis

Post scoliosis Surgery:

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.

The Scientist 2001, 2(1):20010920-01

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.

Thank

you