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Congenital Myotonic Dystrophy

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Last Updated: 02 July 2021

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General | Latest Info

Myotonic Dystrophy is part of a group of inherited disorders called Muscular dystrophies. It is the most common form of Muscular Dystrophy that begins in adulthood. Myotonic Dystrophy is characterized by progressive muscle wasting and weakness. People with this disorder often have prolonged muscle contractions and are not able to relax certain muscles after use. For example, person may have difficulty releasing their grip on doorknob or handle. Also, affected people may have slur speech or temporary locking of their jaw. Other signs and symptoms of Myotonic Dystrophy include clouding of the lens of eye and abnormalities of electrical signals that control heartbeat. Some affected individuals develop a condition called diabetes mellitus, in which blood sugar levels can become dangerously high. Features of Myotonic Dystrophy often develop during a person's twenties or thirties, although they can occur at any age. Severity of condition varies widely among affected people, even among members of the same family. There are two major types of Myotonic Dystrophy: type 1 and type 2. Their signs and symptoms overlap, although type 2 tends to be milder than type 1. Muscle weakness associated with type 1 particularly affects muscles farthest from the center of the body, such as those of lower legs, hands, neck, and face. Muscle weakness in type 2 primarily involves muscles close to the center of the body, such as those of the neck, shoulders, elbows, and hips. Two types of Myotonic Dystrophy are caused by mutations in different genes. There are two variations of Myotonic Dystrophy type 1: mild and congenital types. Mild Myotonic Dystrophy is apparent in mid to late adulthood. Affected individuals typically have mild myotonia and cataracts. Congenital Myotonic Dystrophy is often apparent at birth. Characteristic features include weak muscle tone, inward-and upward-turning foot, breathing problems, delayed development, and intellectual disability. Some of these health problems can be life-threatening. Both types of Myotonic Dystrophy are inherited in autosomal dominant pattern, which means one copy of altered gene in each cell is sufficient to cause disorder. In most cases, affected person has one parent with condition. As Myotonic Dystrophy passes from one generation to the next, disorder generally begins earlier in life and signs and symptoms become more severe. This phenomenon is called anticipation. Evidence for anticipation appears only in Myotonic Dystrophy type 1. In this form of disorder, anticipation is caused by an increase in length of unstable region in DMPK gene. Longer unstable regions in CNBP gene do not appear to influence age of onset of Myotonic Dystrophy type 2.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

Congenital DM1

DM1 is the most prevalent form of condition and is generally the most severe. This form affects at least 1 in 2 300 people worldwide or 140 000 people in the United States alone, although prevalence may be significantly under-report. DM1 can occur from birth to old age, and is divided into further subtypes based on the age of the affected individual when symptoms first appear. Symptoms vary greatly between patients, from minor muscle pain to serious respiratory and cardiac issues. The congenital form of DM1 is the most severe version and has distinct symptoms that can be life-threatening. Below are explanations of three DM1 subtypes that vary based on age at onset: Congenital: Presents potentially life-threatening issues at birth. Congenital DM1 is the most severe and earliest occurring form of Myotonic Dystrophy. It occurs when a mother, who often is not aware she has DM1, passes mutation that causes DM1 onto her child. During pregnancy, she may have noticed less than normal levels of fetal activity, had condition called hydramnios where excess amniotic fluid accumulates, or had long, difficult labor. Childhood Onset: Typically first presented with intellectual disability, and learning disabilities. After relatively normal birth and infancy, individuals with childhood-Onset DM1 develop symptoms sometime between early childhood and early adolescence. The time of onset is often dependent on the astuteness of the observer, and is typically first Presents with intellectual disability, and learning disabilities. Adult Onset: characterized by distal muscle weakness, atrophy, myotonia and many other multisystemic issues. With adult-Onset DM1, symptoms can appear from late adolescence through old age, and usually worsen over time. Depending on the severity of symptoms, patients with adult DM1 may be categorized as having either a mild or classical form of disease. Individuals with mild form of adult-Onset DM1 are often not aware they have a disorder. Muscle symptoms may be attributed to general stiffness or arthritis. Non-muscle symptoms tend to be moderate and are often diagnosed and treated as independent issues. These individuals are unlikely to be diagnosed as having Myotonic Dystrophy unless a family member is identified with a more severe form of disease and testing is initiate.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

How early is diagnosis made?

Table I.

Disease subtypeClinical findingsRepeat sizeAge of onset
Normal (premutation)Noneup to 49N/A
MildMild myotonia, cataracts50-15020-70 years
ClassicWeakness, cataracts, myotonia, cardiac rhythm disturbances100-100010-30 years
Congenitalprenatal onset severe hypotonia, respiratory failure, neurocognitive impairment in survivors>2000birth

Type 2 myotonic dystrophy: many features similar to DM1, but with no risk of transmission of congenital form. Due to tetranucleotide repeat-CCTG-within CNBP gene. Symptoms are typically later in onset, and not associated with diminished lifespan. Charcot-Marie-Tooth disease: hereditary motor and sensory peripheral neuropathy affecting primarily distal muscle groups. Several subtypes exist. Associate with sensory loss and slow nerve conduction. Slowly progressive and frequently results in pes cavus. While most are inherited as autosomal dominant traits, there are X-link recessive and autosomal recessive types. Myotonia congenita: rare condition defined by muscle stiffness that first appears in early childhood or infancy. All skeletal muscles are involve. Stiffness tends to improve with warmup period of exercise. Due to a mutation in the CLCN1 gene. Periodic paralysis: 2 main types exist that are associated either with hyper-or hypokalemia, latter being more common. Hypokalemia occurs in conjunction with attacks of paralytic weakness. Attacks last from 1 to several hours. Inherit as autosomal dominant with reduced penetrance. Manifestations of Classic DM1 change over the course of the patient's lifetime. Multiple organ systems that are affected sometimes overshadow underlying neuromuscular deficits. However, weakness, muscle pain and myotonia are the most consistent features. Diagnosis is established by DNA Testing. Individuals with DM1 have an abnormal number of trinucleotide repeat CTG, which is normally found in 5-34 copies in the unaffected population. There is a rough correlation between the severity of disease and the number of Repeats find. Repeat number over 50 is always associated with disease, although age at diagnosis varies widely. Severe disease is not typically present until repeat size exceeds 100.


Myotonic Dystrophy Testing & Diagnosis

Your path to correct myotonic dystrophy diagnosis can be long and complex, as medical professionals see these cases so infrequently that they often arent familiar with DM. Also, because symptoms of DM can mimic more common diseases, you may undergo months-or even years-of medical testing to rule out other potential causes. Once a disorder is suspect, it is not difficult to get a DM diagnosis, but if it takes a long time for your diagnosis, youre not alone. On average, it takes more than six years to reach diagnosis of DM1 and more than 10 years to confirm DM2.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions.

Table II.

Organ systemManifestations
Gastrointestinaldysphagia, gastroparesis, constipation
Ocularcataracts, ptosis
Endocrinehypogonadism (males), hyperinsulinism
CNSexcessive sleepiness, sleep apnea
Skinpremature balding (males)
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Pediatric Myotonic Dystrophy

Myotonic dystrophy refers to two rare genetic disorders of muscle that actually affect multiple systems of the body. The disorder is abbreviated DM, which is For dystrophia myotonia. This is the Latin name for disorder. There are two main types of DM. DM type 1 can be further classified as mild DM1, classic DM1 and congenital DM1. Mild DM1 is characterized by clouding of lenses of eyes and sustain muscle contractions, in which muscles do not relax after use. Classic DM1 is characterized by muscle weakness and wasting, myotonia, early-onset Cataracts, and abnormalities in heart conduction of electrical impulses. Congenital DM1 is characterized by muscle weakness, difficulty breathing, intellectual disability and early death. DM type 2 causes similar symptoms to DM1, but is generally a less severe disorder and does not cause congenital disease. DM1 is caused by alteration in DMPK gene. DM2 is caused by alteration in CNBP gene. These alterations are inherited in autosomal dominant manner. DM is a type of muscular dystrophy. Muscular dystrophies are characterized by weakness and degeneration of various voluntary muscles of the body. Each disorder is characterized by specific abnormalities in muscle biopsy from patients. DM1 is also know as Steinert disease, named after Dr. Steinert who, along with colleagues, first described the classic form in medical literature in 1909. DM2 is also know as Ricker syndrome or proximal myotonic dystrophy or PROMM.


What is myotonic muscular dystrophy?

Your childs doctor will most likely schedule a clinic visit to: ask you about your childs symptoms, development, medical history and family history. Examine your child and look for patterns of muscle weakness and wasting, myotonia and other signs of muscular dystrophy Blood test to check the level of enzyme that is higher when muscles are damage Genetic test to look for changes in 1 of genes that cause MMD Electromyogram test to measure electrical signals in muscles Muscle biopsy to see whether your childs Muscle cells appear normal Seattle Childrens also offer Genetic counseling and testing for parents and other family members of children with muscular dystrophy. To understand how MMD is affecting your child, your Seattle Childrens team may suggest other tests and exams, such as: Tests of motor skills and strength Electrocardiogram Tests of lung function Blood Tests to check for thyroid problems or insulin resistance Sleep studies Vision exam Swallowing evaluation Cognitive Tests

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

INTRODUCTION

Congenital Myotonic Dystrophy is an autosomal dominant Genetic disorder caused by trinucleotide repeat expansion of CTG in DMPK gene on chromosome 19q 13. 3 DM is more than just Muscular Dystrophy as affected individuals show involvement of other organ systems such as cataracts, cardiac conduction anomalies, insulin resistance, congenital form being associated with developmental disabilities, etc. Two major forms are described in literature. Myotonic Dystrophy Type 1, also know as Steinert Disease Myotonic Dystrophy Type 2, which is a milder version of DM1. Like any trinucleotide expansion repeat diseases, larger number of repeats are associated with severity of disease. Natural History: incidence of CMD is 1 in 47619 live births, and mortality in neonatal period is up to 40%. Severe CMD demonstrates a unique biphasic course; in which neonatal symptoms improve / stabilize in surviving neonates before adult-onset symptoms present in later life.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

CLINICAL CLASSIFICATION AND NATURAL HISTORY

Fatigue, daytime sleepiness, and concentration difficulties are frequently reported symptoms in DMs. In DM1, cognitive deficits were initially attributed to low IQ or mental retardation, but recent studies show that this assumption was wrong for large cohort of patients and mainly applies to cases of congenital myotonic dystrophy. In fact, for the classic phenotype of DM1, neuropsychological deficits are as variable as muscular symptoms, and even recent publications about the correlation of CTG-repeat size and neuropsychological deficits show contradictory study results. There seems to be a correlation between diffuse brain alterations in primarily white and secondary gray matter, linking DM1 to a group of brain disconnection disorders. Caso et al. Investigate 51 DM1 patients and found a correlation between changes in brain white matter and cognitive impairment. Cerebral white matter hyperintensities have been observed in both DM1 and DM2 patients, especially in those older than 40 years, but their clinical and functional significance still remain unclear. In a recent study about the educational profile of large cohort of young DM1 patients, no significant differences compared to healthy population were find, assuming that cognitive and concentration disturbances may occur later in the course of disease in the context of variable premature cognitive decline, as suggested by study of Modoni et al. Mild cognitive and behavioral symptoms are also present in DM2 patients. In particular, altered visuo-spatial and executive functions, reduce attention and flexibility of thinking, avoidant behavioral trait, and depression have been detected in these patients. In many cases, neuropsychological disturbances jeopardize the ability to work and reduce quality of life more than muscular symptoms. Excessive daytime sleepiness, fatigue, and concentration difficulties may also be caused by central sleep disturbances or sleep apnea. Sleep-disordered breathing is one of the earliest manifestations and occurs in a high percentage of patients with DM1, but overlapping symptoms of nocturnal hypoventilation and CNS symptoms may delay diagnosis and treatment. Chronic central sleep-disorder breathing has an impact on quality of life, morbidity, and mortality and should be assessed frequently in every patient with DM1. Until now, little is known about changes in CNS causing cognitive deficits and central sleep disrupt breathing. Almost every clinical study is conducted with usually more affected DM1 patients, therefore data for DM2 patients is limit. On a molecular basis, MBNL1 and probably CELF may both be involved in CNS alterations, but little is known about molecular defects causing highly variable CNS symptoms in DM1. Above mention aspects lead to discussion as to whether CNS dysfunction is caused by altered neurodevelopment, by neuro-dysfunction or by neurodegeneration within the definition of progeroid diseases. The Hypothesis of neurodegenerative disease is endorse by findings of tau pathology and neurofibrillary degenerations, even if no correlations with CTG-repeat length were find. Overall, CNS dysfunction seems to be multifactorial. The most frequent, early and typical extramuscular manifestation is the occurrence of early-onset cataract, observed in about 50-60% of patients.


Types of Myotonic Dystrophy

Myotonic dystrophy includes two major types, DM1 and DM2, both caused by genetic defects. They result in multisystem disorders characterized by skeletal muscle weakness and myotonia, cardiac abnormalities, cataracts, and other abnormalities. DM1, most common type, results from abnormal DNA expansion in DMPK gene on chromosome 19. DM2 arises from abnormal expansion of DNA in the ZNF9 gene on chromosome 3. Within DM1 are additional subtypes, depending on the person's age at the onset of symptoms. The age of onset is roughly correlated with the size of diseases associated with DNA expansion; larger expansions associated with earlier disease onset. Congenital-onset DM1 may arise before birth with decreased fetal movement and is characterized by severe muscle weakness, profound hypotonia, poor feeding, joint contractures, cognitive impairment, respiratory failure, and other developmental abnormalities. Childhood-or juvenile-onset DM1 begins during childhood and is characterized by cognitive and behavioral symptoms, muscle weakness, myotonia, anxiety, mood disorders, attentional deficits, and other symptoms. Some patients may have arrhythmias when playing sports, and in 10% of patients, cardiomyopathy and heart failure might be diagnosed Adult-onset DM1 begin in adolescence or early adulthood and is characterized by slowly progressive weakness, myotonia, cardiac abnormalities, respiratory weakness, cataracts, and, sometimes, mild to moderate cognitive difficulties Mild DM1-usually appear in 20-to 70-year-old patients, typically after age 40. This Mild form of DM1 is characterize by Mild weakness, myotonia, and cataracts DM2 sometimes call PROMM has not been see in congenital-onset form and rarely begin in Childhood. Therefore, it is not described into subtypes. DM2 tends to involve proximal muscles rather than distal muscles that are first to be affected in DM1. In general, DM2 is a less severe disease than classic DM1. However, it may affect walking ability earlier than DM1 because it causes early weakening of hip muscles. DM2 is rare compared to DM1, except in people of German descent. Below is a general comparison of the major features of DM1 and DM2.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

CURRENT TREATMENT AND MANAGEMENT

No specific treatment is available for any of congenital muscular dystrophies. Aggressive supportive care is essential to preserve muscle activity, to allow for maximal functional ability, and to prolong patient's life expectancy. Cardiac complications are especially common in patients with mutation in FKRP and occasionally in patients with laminin-2 deficiency. Treatment of dilate cardiomyopathy with ACE inhibitors and beta-blockers may be necessary. Children with congenital Muscular Dystrophy may have other neurologic treatment issues, including seizure management, need for supplementary gastric tube feedings, ophthalmologic care, and general medical concerns that occur in profoundly retarded children. As with other hereditary myopathies, team approach, including neurologist, pulmonologist, ophthalmologist, cardiologist, orthopedic surgeon, physical medicine specialist, orthotist, and counselors, is required to ensure the best possible care. In patients with CMD with familial junctional epidermolysis bullosa besides above standard measures, management must include supportive care to protect skin from blistering, appropriate dressings, and prevention of secondary infections. Activities should minimize skin trauma.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

GENETICS AND PATHOGENESIS OF DM1

The Location of CCTG expansion within intron 1 of ZNF9 is similar to DM1 CTG expansion, in that both repeats are transcribed into RNA but do not alter the protein coding portion of the gene. The normal function of ZNF9 as a nucleic acid-binding protein appears unrelated to any of Proteins encode in the DM1 region of chromosome 19. Similarly, genes in the DM2 region bear no obvious relationship to genes near the DM1 locus. Even if DM2 expansion alters regulation of ZNF9 and other genes in the DM2 region, it would be unlikely that alterations in regulation of different sets of Proteins at DM1 and DM2 loci would result in diseases with such strikingly similar multisystemic features. The first suggestion that CUG-containing transcripts were involved in DM1 pathogenesis come from FISH experiments demonstrating that CUG-containing nuclear RNA foci accumulate in DM1 cells. Evidence that DM1 and DM2 share a common pathogenic RNA mechanism comes from experiments showing that similar CCUG-containing RNA foci are found in DM2 muscle. These results demonstrate that CCTG expansion is expressed at the RNA level, but additional experiments are needed to determine if RNA foci contain entire unprocessed ZNF9 transcript or if transcript is normally processed but intron or repeat tract alone resist degradation forming RNA foci. Additional evidence that RNA foci containing DM1 and DM2 repeat motifs behave in similar manner is that several forms of RNA-binding protein muscleblind colocalize to repeat-containing foci in both diseases. Although additive model of DM1 suggest that CUG repeats in RNA cause myotonia and Muscular Dystrophy of DM1, causes of other DM featuresincluding cardiac conduction defects and cataractshad been ascribed to haploinsufficiency of genes in the DM1 region. Clinical and molecular parallels between DM1 and DM2 suggest a simpler model of DM pathogenesis, in which clinical features common to both diseasesincluding myotonia, Muscular Dystrophy, cataracts, cardiac arrythmias, insulin insensitivity and diabetes, hypogammaglobulinemia, and testicular failureare caused by pathogenic effects of RNA containing CUG and CCUG expansions although DM1 and DM2 phenotypes are strikingly similar, they are not identical. DM2 does not show congenital form or mental retardation that can occur in DM1. Downstream differences in CUG vs. CCUG expansions could be responsible for clinical distinctions between these diseases, as could differences in temporal or spatial levels of transcripts containing expand repeats. A possible mechanism for congenital DM1 has been suggested by Fillipova and colleagues, who show that methylation at DM1 locus in congenital cases can increase expression of DMPK, resulting in higher levels of CUG-containing transcripts and more severe congenital phenotype. Alternatively, differences between DM1 and DM2 could involve locus-specific genes such as DMPK, SIX5, or DMWD for DM1, and ZNF9 for DM2. The multisystemic nature of DM results in varied symptoms in affected individuals, although almost all affected individuals have clinically identifiable muscle involvement at time of diagnosis.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

Sources

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

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