|Ahead of print
The expanding spectrum of dystrophinopathies: HyperCKemia to manifest female carriers
Renu Suthar1, Shivan Kesavan1, Indar K Sharawat2, Manisha Malviya1, Titiksha Sirari1, Bhupendra K Sihag3, Arushi G Saini1, Vishalavath Jyothi4, Naveen Sankhyan1
1 Pediatric Neurology Unit, Department of Pediatrics, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education & Research, Chandigarh, India
2 Pediatric Neurology Division, Department of Pediatrics, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India
3 Department of Cardiology, Postgraduate Institute of Medical Education & Research, Chandigarh, India
4 CSIR-Centre for Cellular and Molecular Biology (CCMB), Hyderabad, Telangana, India
|Date of Submission||21-Apr-2020|
|Date of Acceptance||07-Jul-2020|
|Date of Web Publication||02-Jul-2021|
Pediatric Neurology Unit, Department of Pediatrics, Postgraduate Institute of Medical Education and Research, Chandigarh.
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Background: X-linked dystrophinopathies have a wide spectrum of manifestation. The most common forms are severe Duchenne muscular dystrophy (DMD) and Becker’s muscular dystrophy (BMD). However, less common manifestations are isolated cardiomyopathy, myalgia, cramps, rhabdomyolysis, hyperCKemia, and manifest female carriers. Materials and Methods: This case series is a part of an ongoing long-term prospective cohort of children with DMD and BMD from the year 2013. The clinical details are maintained in the clinic files and standard management protocols are followed. For this case series, clinical details were collected from the clinic files and recorded on a case record proforma. Details of cardiology, radiology, and genetic investigations were collected. Results: We report cases of classical DMD, BMD, manifest female carrier with proximal pelvic girdle weakness, a female carrier with isolated dilated cardiomyopathy, and infantile-onset asymptomatic hyperCKemia. We also report less common but notable clinical presentations of DMD, autism, intellectual disability, epilepsy, and asymptomatic transaminitis. Conclusions: It is important for clinicians to be aware of these less common clinical presentations for prompt diagnosis, and to avoid unnecessary investigations. Here, we report the clinical spectrum of dystrophinopathies seen in pediatric neuromuscular clinic and emphasize the variability and expanding knowledge about different manifestations of dystrophinopathies.
Keywords: Becker’s muscular dystrophy, Duchenne muscular dystrophy, dystrophinopathy, pediatric
|How to cite this URL:|
Suthar R, Kesavan S, Sharawat IK, Malviya M, Sirari T, Sihag BK, Saini AG, Jyothi V, Sankhyan N. The expanding spectrum of dystrophinopathies: HyperCKemia to manifest female carriers. J Pediatr Neurosci [Epub ahead of print] [cited 2021 Dec 9]. Available from: https://www.pediatricneurosciences.com/preprintarticle.asp?id=320398
| Introduction|| |
Duchenne muscular dystrophy (DMD) is the most common clinical presentation of X-linked dystrophinopathies, with an incidence of 1 in 3500 boys. It is the most common and devastating form of dystrophinopathies leading to premature loss of ambulation and limiting the life span. Less common manifestations are Becker’s muscular dystrophy (BMD) and isolated Duchenne-associated cardiomyopathy (DCMP). Other rarer phenotypes are myalgia, cramps, rhabdomyolysis, asymptomatic hyperCKemia, and manifest female carriers., As dystrophinopathies are the most common form of muscular dystrophies, knowledge about various typical and atypical manifestations is important to avoid unnecessary invasive and costly investigations. The most common genetic abnormality in DMD is the presence of deletions in 65%, duplications in 10%–15%, and point mutations in another 10%–20% in the dystrophin gene. We describe the spectrum of dystrophinopathies seen in a pediatric neurology clinic and emphasize the clinical heterogenicity and diverse presentations.
| Materials and Methods|| |
This case series is a part of an ongoing long-term prospective cohort of children with DMD and BMD from the year 2013. The clinical details are maintained in the clinic files, and standard management protocols are followed. For this case series, clinical details were collected from the clinic files and recorded on a case record pro forma. Details of cardiology, radiology, and genetic investigations were collected.
| Cases 1, 2, and 3|| |
A 9-year-old boy (case 1) presented with delayed attainment of motor milestones and difficulty in running and climbing stairs from 4 years of age. He also had a history of recurrent falls, difficulty in getting up from sitting position and climbing upstairs. He was born to non-consanguineous parents with an unremarkable prenatal and perinatal period. On examination, anthropometry was age appropriate. He had marked pseudohypertrophy of bilateral calf muscles, vastus, deltoid, brachioradialis, biceps, triceps, and tongue. He had neck flexor muscle weakness, with a strength of 3/5 on the MRC (Medical Research Council) scale. Clinical examination showed positive valley sign and Gower’s sign. Reflexes were elicitable, and there were no tremors or fasciculations. His serum creatinine phosphokinase (CPK) levels were markedly elevated to 12,400 U/L. The functional assessment showed upper limb Brooke scale was 1/5 and lower limb Vignos scale was 3/5, Gower’s time was 8s, and 6-min walk distance was 356 m. Electrocardiogram (ECG) showed biventricular hypertrophy and two-dimensional (2D)-echocardiography (2D-ECHO) showed an ejection fraction of 55%. Multiplex ligation probe assay (MLPA) for the dystrophin gene (79 exons) showed a deletion in exon 44. He was initiated on oral prednisolone at 0.75mg/kg/day, supportive devices night splints, ankle-foot orthosis, and muscle stretching were advised. He remained ambulatory till 10 years of age, and currently, at 14 years of age, he is a wheelchair user.
The younger sister (case 2), a 9-year-old girl presented with a similar history of difficulty in getting up from sitting position from 7 years of age. She was noted to have difficulty in rising from the floor, climbing stairs, and riding a bicycle. There was no history suggestive of calf pain, dark-colored urine, muscle cramps, or stiffness. She was born at term with normal prenatal and perinatal period, and her development was age appropriate. Examination showed age-appropriate weight, height, and head circumference. Her cognition and higher mental functions were normal. She had pseudohypertrophy of bilateral deltoid and gastrocnemius muscles. She had proximal pelvic girdle muscle weakness, power at the hip flexors was -3/5 bilaterally, neck flexors were 3/5, and truncal muscles were 4/5 on the MRC scale, and Gower’s sign was positive. Her serum CPK levels were elevated to 7000 unit/L, and echocardiography showed normal ejection fraction. Her karyotype was 46 XX, and DMD gene MLPA showed heterozygous deletion of exon 44 confirming a diagnosis of manifest female carrier.
Mother of proband and case 2, a 32-year-old female was diagnosed to have clinically asymptomatic dilated cardiomyopathy during preanesthetic evaluation for cholecystectomy. The 2D-ECHO revealed an ejection fraction of 25%–30%, global hypokinesia with severe left ventricular systolic dysfunction, mild mitral, and tricuspid regurgitation. She was initiated on metoprolol and carvedilol. Thyroid profile and antineutrophilic antibodies were negative. She was evaluated along with the children (Case 1 and 2) in a pediatric neuromuscular clinic, and her examination revealed the presence of bilateral calf hypertrophy and hyperCKemia. MLPA in the mother showed the presence of a heterozygous deletion in the exon 44, suggestive of manifest female carrier status. She was managed with metoprolol, carvedilol, and diuretics.
| Case 4|| |
A 5-month-old boy was admitted with a history of acute febrile illness and rapid breathing. On examination, he had tachycardia and tachypnea, fine crepitations over both lung fields, and mild hepatomegaly. Chest X-ray showed cardiomegaly with a cardiothoracic (CT) ratio of 55%. Diagnosis of viral myocarditis was considered, and echocardiography showed global hypokinesia, and ejection fraction was 20%. His serum CPK-MB levels were raised to 280 U/L, and CPK total was 5500 unit/L. He received intravenous immunoglobulin at 2g/kg for viral myocarditis. He was evaluated for asymptomatic hyperCKemia. There was no significant family history, and birth and perinatal history were uneventful. He showed gradual recovery from the viral myocarditis and could be tapered off from inotropes. HyperCKemia was persistent during follow-up. MLPA for the dystrophin gene showed the deletion of exon 51 in the heterozygous state. Repeat 2D-ECHO during follow-up showed normal contractile function with an ejection fraction of 55%. Currently, at 1.5 years of age, the child has a mild motor delay, and he is on a regular six-monthly follow-up.
| Case 5|| |
A 4-year-old boy presented with a history of stereotypic behavior and language delay. He was born at term with lower segment cesarean section, with normal APGAR scores and adequate birth weight. His developmental milestones were markedly delayed in the social and language sector; although he started walking by 15 months of age. He had a poor eye to eye contact, abnormal vocalization, and absence of joint attention and pointing. He had stereotypic, intrusive hand flapping movement and head-banging episodes. The mother also noted that he had difficulty in getting up from sitting and supine position, and he required support for getting up. On examination, anthropometry was age appropriate; he had bilateral calf muscles and brachioradialis hypertrophy with normal elicitable reflexes. His serum CPK levels were elevated to 17,360 U/L. Family history was significant for similarly affected elder brother, with language delay, poor eye to eye contact, and progressive proximal muscle weakness. Currently, at 12 years of age, he is nonambulatory and wheelchair dependent. Investigations in the elder sibling showed normal karyotyping; MLPA for dystrophin gene was negative, and muscle biopsy was suggestive of muscular dystrophy and complete absence of dystrophin staining on immunohistochemistry. DMD gene sequencing in the index case showed the presence of single base pair duplication in the exon 53 at c.782dupG. Mother was clinically asymptomatic, and family history was negative. He was managed with physiotherapy, night splints, and oral corticosteroids. For his severe autistic behavior, he was initiated on oral aripiprazole and clonidine.
| Case 6|| |
An 11-year-old, developmentally normal boy presented with a history of difficulty in running, climbing stairs, and difficulty in getting up from sitting position from 9 years of age. Unusual prominence of bilateral calf muscles was also noted from the past 6 months. There was no history suggestive of upper limb weakness, chewing, swallowing difficulty, and diurnal fluctuations in symptoms. He was born at term, with an uncomplicated perinatal period; developmental milestones were achieved age appropriately. Family history was unremarkable, and he had two younger sisters, clinically asymptomatic. On examination, weight was at −1.8 z score, height was at −1.5 z score, and OFC (occipitofrontal circumference) was 50cm. His higher mental functions were normal; motor system examination revealed hypertrophy of bilateral calf muscles and deltoid muscles. He had proximal weakness in the lower limb, with the power of 4/5 in the hip flexors and −4/5 in hip extensors on the MRC scale. Reflexes were elicitable, Gower’s sign and valley sign were positive. His CPK levels were elevated to 10,509 U/L. The cardiac evaluation showed the presence of dilated cardiomyopathy, mild left ventricle systolic dysfunction, and ejection fraction was 45%. MLPA for dystrophin gene showed deletions of exon 45 to 48; in-frame mutation was suggestive of BMD with DCMP. His Gower’s time was 4s, and he was managed with deflazacort and enalapril for dilated cardiomyopathy.
| Case 7|| |
A 3-year-old boy during evaluation for acute abdominal pain noted to 6 to 7 times elevation in aspartate amino transaminases (AST) and alanine transaminase (ALT). He did not have a history of jaundice, anorexia, vomiting, encephalopathy, rash, high-colored urine, drug or toxin ingestion, or transfusion of blood products. Subsequent follow-ups, after recovery from acute illness, his AST and ALT levels were elevated. He was suspected to have chronic liver disease. He was born at term, with an uncomplicated prenatal and perinatal period, to non-consanguineous parents. On examination, he had age-appropriate anthropometry, normal cognitive function, pseudohypertrophy of bilateral calf and deltoid muscles, proximal muscle weakness in the lower limbs, and positive Gower’s sign. However, parents never reported difficulty in walking, running, or climbing stairs. Gower’s time was 3s, and serum CPK levels were elevated to 8400 U/L. MLPA for the dystrophin gene showed a deletion of exons 45–51. He was managed with physiotherapy, orthotic devices, and muscle stretching exercises and was initiated on oral steroids at 6 years of age.
| Case 8|| |
A 7-year-old boy presented with developmental delay and difficulty in walking and running. He was second born to non-consanguineous parents, with an uncomplicated prenatal and perinatal period. His motor milestones were significantly delayed as he could achieve neck control at 1 year, standing at 3.5 years, and walking at 4.5 years. He always had difficulty in walking, running, and rising from the floor, and he could never climb up the stairs. He also had delayed attainment of language and cognitive milestones. From 5 years of age, parents noticed that he had increasing difficulty in rising from sitting or supine position. He had three episodes of unprovoked seizures and was on valproate for seizure control. His weight was 13.5kg (<3rd centile), height was 115cm (<3rd centile), and OFC was 48.5cm (<3rd centile). There was no neurocutaneous marker, and he had severe generalized wasting; however, bilateral calf muscles were hypertrophied. He had marked proximal weakness in both upper and lower limb, Brooke upper limb score was 2, and Vignos lower limb score was 5; he could not rise from the floor, and he could walk once made to stand for few meters. His cardiac evaluation was normal, and serum CPK was 10,400 U/L. DMD gene MLPA for 79 exons showed a deletion of exon 49–50. Magnetic resonance imaging (MRI) of the brain showed subependymal nodular heterotopias. He was managed with oral prednisolone, orthotic, supportive devices, and was continued on valproate. He was nonambulatory at 9 years of age.
| Discussion|| |
Dystrophinopathies are X-linked recessive disorder secondary to deficiency of dystrophin protein. The major dystrophinopathies are DMD and BMD, caused by a mutation in the dystrophin gene on Xp21. DMD is the most severe form of dystrophinopathies, causing proximal weakness and loss of ambulation by 10–13 years of age, BMD has a presentation like DMD, but has a relatively milder course. In addition to DMD and BMD, there is an intermediate group of patients with mild DMD or severe BMD phenotype, also known as intermediate or outliers. The other less common dystrophinopathies include isolated DMD-associated cardiomyopathy, muscle cramps and myoglobinuria, asymptomatic hyperCKemia, and manifest DMD/BMD carrier females. In this case series, we report the spectrum of dystrophinopathies diagnosed and managed in the pediatric neuromuscular clinic. We report cases of classical DMD, BMD, manifest female carrier with proximal pelvic girdle weakness, a female carrier with isolated DCMP, and infantile-onset asymptomatic hyperCKemia. We also report less common but notable clinical presentations of DMD, autism, intellectual disability, epilepsy, and asymptomatic transaminitis.
The clinical presentation of DMD, BMD, and the intermediate syndrome is stereotyped with progressive proximal weakness, first involving the pelvic girdle manifesting with difficulty in rising from the floor, climbing upstairs, difficulty in running, walking, and frequent falls. Subsequently, contractures develop at bilateral tendo Achillis, hip flexors, and knee. Later, there is a weakness of shoulder muscles, limitation of abduction, and raising arms above head, and dilated cardiomyopathy. The age of onset and progression of weakness varies in DMD and BMD. Boys with DMD tend to lose ambulation by 11–13 years of age, intermediates by 16–18 years, and BMD after the third decade. Examination shows selective hypertrophy of gastrocnemius, soleus, vastus, deltoid, and brachioradialis muscles, and atrophy of pectoral muscles. Selective atrophy and hypertrophy of muscles of shoulder girdle muscles give the classical valley sign. In the classical cases of DMD, the age of diagnosis is 4–5 years in developed countries. However, the mean age of diagnosis in our country is 6–7 years of age.,, The reading frame rule holds true for the classical presentations; in-frame mutations preserving the reading frame are associated with a less severe phenotype of intermediate or BMD.
The diagnosis of dystrophinopathies is often delayed or missed in the case of atypical clinical features, especially in the presence of profound intellectual disability, autism, and epilepsy. Wu et al. reported six children with autism among 158 subjects with DMD; the prevalence much higher than the control population. Duchenne natural history study (DNHS) reported neurodevelopmental problems in a cohort of 4–9 years old boys with DMD. The most common neurodevelopmental problems were speech delay (33%), mild developmental delay (24%), significant behavioral problems (16.5%), language impairment (14.5%), learning disability (14.5%), attention-deficit hyperactivity disorder (5%), and autism spectrum disorder (3%). Authors have reported more frequent neurodevelopmental issues in boys having mutations downstream to exon 51. The use of glucocorticoids was not associated with neurodevelopmental problems. Fujino et al. from Japan reported that 19.6% of boys with DMD had features of autism according to the Autism Spectrum Disorders Rating Scale.
Ricotti et al. reported neurodevelopmental emotional and behavioral issues in 134 boys with DMD. Among them, 26% had an intellectual disability, 21% had autistic spectrum disorder, 21% had hyperactivity, and 44% had inattention. In our series, case 5 of two siblings had severe autistic features, and case 8 had severe intellectual disability and epilepsy. Similar to cognitive and behavioral issues, epilepsy is also common in boys with DMD. Pane et al. reported 6.3% of boys with DMD had epilepsy, and 85% of boys with epilepsy had normal cognitive functioning. The precise pathogenesis of cognitive impairment in DMD remains unclear; it is proposed that the reduced expression of brain isoforms of dystrophin protein Dp71 and Dp140, primarily expressed in fetal brain, hippocampus, and cerebral cortex layers, is responsible for intellectual disability. Hendriksen et al. studied brain-related comorbidities and epilepsy in 228 children with DMD, 7.9% boys had epilepsy and other psychological comorbidities as attention-deficit hyperactivity disorder, obsessive-compulsive disorder, anxiety disorders, and sleep. Cardas et al. recently reported two infants with epileptic spasm with electroencephalogram (EEG) hypsarrhythmia. In these cases, history was not suggestive of muscular dystrophy in family members, and workup for epileptic encephalopathy was negative. During the laboratory investigation, elevated serum CPK levels were noted, and sequencing of the dystrophin gene showed the pathogenic deletion and point mutation in each case. So, in nutshell, epilepsy, including the epileptic encephalopathy, which can occur in DMD, before the onset of manifest weakness. The examples mentioned here points toward the often ignored consequences of dystrophin deficiency.
Case 8, in this series, had a unique presentation with severe weakness, marked intellectual disability, and epilepsy. MRI of brain showed the presence of cortical malformation and nodular heterotopias. Classically cortical malformations are seen with congenital muscular dystrophies (CMDs), especially with syndromic CMDs such as Walker–Warberg syndrome, Fukuyama type muscular dystrophy, muscle eye brain disease CMDs, or dystroglycanopathies. Cortical atrophy and ventriculomegaly have been reported in association with DMD and BMD.
Persistent elevation of serum creatine kinase (CK) hyperCKemia is defined as the presence of serum CK values >1.5 times the upper limit of normal (ULN) in the least two measurements. Total serum CPK levels arise largely from skeletal muscles with a minor component from cardiac muscles. Serum CK reflects muscle integrity and fluctuates with the level of muscle activity; hence, hyperCKemia is a nonspecific marker of muscle damage. Serum CPK levels may be elevated in several conditions such as physical activity, cardiac disorders, neurogenic, and myogenic conditions. Marked CPK elevation is seen in DMD/BMD, limb-girdle muscular dystrophy, dermatomyositis, immune-mediated necrotizing myopathies, inherited and acquired rhabdomyolysis, and myoglobinuria. Case 4 in this case series also noted to have elevated CK levels during investigations. Viral myocarditis resolved with therapy; however, persistent hyperCKemia was secondary to dystrophinopathy in this case. DMD, BMD, Pompe disease, sarcoglycanopathies, ANO5, and RYR1 are important causes of hyperCKemia in the presence of mild to moderate proximal weakness.
Similarly, the asymptomatic elevation of AST/ALT in infants or boys in early childhood can be seen in DMD/BMD, when weakness is not very apparent. AST, ALT, and LDH are often considered as liver enzymes; however, these can be elevated in cardiac and skeletal muscle disorders. Munsat et al. reported 95% children <10 years of age with DMD had elevated AST and ALT levels. In DMD and BMD, elevated AST and ALT are of muscle origin, and levels correlate with CPK levels. Persistent elevation of AST/ALT in the absence of liver disorders often suggests the presence of DMD, and unnecessary investigation for rare liver can be avoided.
Although dystrophinopathies are X-linked recessive disorders and they predominantly manifest in males, recent studies have reported a significant proportion of manifest female carriers. About two-thirds of mothers of boys with DMD are believed to be carriers of the disease. The clinical presentation of manifest carriers varies widely; isolated DMCP or proximal weakness is most common. Asymptomatic female carriers have hyperCKemia, cramps, myalgia, camptocormia, or mild proximal weakness. About 2%–22% manifest female carriers are reported in several series.,,, Florian et al. reported a mother and daughter duo, heterozygous for dystrophin gene deletion with isolated DCMP, in the absence of other clinical features. They showed similar cardiac involvement in the cardiac MRI with regional inferolateral wall hypokinesia, the ejection fraction of 55%, and subepicardial nonischemic late-gadolinium enhancement. Cardiac muscle biopsy showed a mosaic pattern of dystrophin expression in the cardiomyocytes; however, skeletal muscle biopsy showed normal dystrophin expression.
In our series, we have two manifest female carriers, a 9-year-old girl with proximal weakness and pseudohypertrophy, and an adult female with isolated DCMP. The most commonly reported symptom in manifest carriers is mild proximal muscle weakness, which is often asymmetric and progressive. Brioschi et al. reported 18 female carriers of DMD, among this, 38% were symptomatic with proximal and neck muscle weakness, and hyperCKemia. Rest 11 female carriers had hyperCKemia, muscle biopsy in all showed dystrophic features, and mosaic pattern on dystrophin staining. X chromosome inactivation has been proposed as a possible mechanism for symptomatic female carriers, with mutated wild type X chromosome and mutated dystrophin gene being active in all muscles. However, the exact correlation between expression, transcript levels, or relative proportion of wild type transcripts is not clear.
| Conclusion|| |
Dystrophinopathies have a wide spectrum of presentation; the clinicians well recognize the classical presentation of DMD and BMD. However, expanding phenotypes in DMD include the presence of autism, intellectual disability, and epilepsy. Asymptomatic hyperCKemia and transaminitis are the less well-recognized presentation in asymptomatic young DMD or female carriers. Clinicians from various streams may encounter these less reported phenotypes. Besides, manifest female carriers are not a well-known entity for neurologists and cardiologists. Awareness of other manifestations of dystrophinopathies helps in recognizing and treating patients earlier and in avoiding unnecessary investigations.
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Conflicts of interest
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