Brain MR imaging findings in children with congenital muscular dystrophies
Fabiana Vercellino1* ; Irene Meola1; Maria Chiara Strozzi2; Claudio Nettuno3; Cristina Lazzotti4; Patrizia Russo5
1Child Neuropsychiatry Unit, SS. Antonio e Biagio e Cesare Arrigo Hospital, Alessandria, Italy.
2Department of Maternal, Fetal and Neonatal Medicine. SS. Antonio e Biagio e Cesare Arrigo Hospital, Alessandria, Italy.
3Pediatric Intensive Care Unit, SS. Antonio e Biagio e Cesare Arrigo Hospital, Alessandria, Italy.
4Pediatric Orthopedic and Traumatology Unit, SS. Antonio e Biagio e Cesare Arrigo Hospital, Alessandria, Italy.
5Pediatric Radiology Unit, SS. Antonio e Biagio e Cesare Arrigo Hospital, Alessandria, Italy.
Received Date: 05/02/2022; Published Date: 03/03/2022.
*Corresponding author: Fabiana Vercellino, Child Neuropsychiatry Unit, SS. Antonio e Biagio e Cesare Arrigo Hospital, Alessandria, Italy.
Congenital muscular dystrophies (CMDs) are a heterogeneous group of disorders presenting early in life during infancy or soon after birth. Congenital hypotonia and muscular weakness, decreased or absent deep tendon reflexes, delayed motor milestones are common clinical features. Several conditions may manifest with infantile hypotonia, including anomalies of the nervous system with involvement of the spinal cord, anterior horn cell, peripheral nerves, neuromuscular junction, and muscles. The diagnostic evaluation is not easy, mainly in differentiating the various types of CMDs, and represents a challenge for the neonatologists and pediatricians.
Four children with CMDs were retrospectively analyzed: one with merosin-deficient CMD (MDC1A); two with Walker Warburg syndrome (WWS); and one with Ullrich myopathy (COL6-RD). In all the patients phosphokinase (CPK) concentration was elevated. Genetic tests were performed in two of the four patients. All the children were studied with MRI of the brain. In our series MRI findings concerning white matter were strikingly similar for three out of four patients. On T2-weighted images three cases had a diffuse and symmetrical increase in signal in the white matter of the cerebral hemispheres. Type II (cobblestone) lissencephaly, mid brain kinking, cerebellum hypoplasia, hydrocephalus and occipital meningocele were present in patient 2 and 3 as typically in WWS. The brain stem and the cerebellum were structurally normal in patient 1 and 4. Brain MRI findings play an important role in suspecting a specific CMD subtype in order to aid in the diagnosis of these rare disorders before performing genetic tests.
Keywords: Congenital muscular dystrophies; congenital hypotonia; brain MR imaging.
Congenital muscular dystrophies (CMDs) are a heterogeneous group of disorders presenting early in life during infancy or soon after birth with muscle weakness and hypotonia, sometime associated to severe brain involvement and histologically presenting with dystrophic lesions. They are classified on the basis of the clinical features, pathologic findings and pattern of inheritance. In fact most of these disorders are inherited and linked to specific genes. Several CDMs classifications have been proposed [1-3]. The main CMD subtypes, classified by pathogenic gene, are laminin alpha‐2 (merosin) deficiency (MDC1A), collagen VI‐related CMD (COL6-RD), the dystroglycanopathies -such as Walker‐Warburg syndrome (WWS), Fukuyama CMD (FCMD), and muscle‐eye‐brain disease (MEB)-, SELENON (SEPN1)‐related CMD, and LMNA‐related CMD (L‐CMD) . The incidence and prevalence of CMDs in various populations is not sufficiently known and may have been underestimated in early published CMD surveys owing to more limited diagnostic means available. Point prevalence in various studies ranges from 0.56 to 2.5 per 100,000 [5-10]. The relative frequency of CMD subtypes also varies in different populations. The most common CMD subtypes are laminin-α2 related CMD and dystroglycanopathies, followed by collagen VI-related CMD. The forms of congenital muscular dystrophy related to mutations in SEPN1 and LMNA are less frequent [9, 11]. CMDs are often autosomal recessive, but some cases have been found to follow autosomal dominant patterns, by direct inheritance, spontaneous mutations, or mosaicism. Clinical genetic testing is available for virtually all genes known to be associated with CMDs. However, many affected individuals remain without a genetic diagnosis, an indicator that novel disease genes have yet to be identified . Differential diagnosis of patients presenting with weakness in early infancy includes: Congenital myopathies like central core, nemaline road, and centronuclear myopathy and those secondary to metabolic disorders; Disorders of the myoneural junction including congenital myasthenia gravis and infant botulism and Neuropathies like spinal muscular atrophy (SMA) and hereditary motor sensory neuropathy (HMSN) . Nowadays the diagnosis is based on clinical presentation, laboratory tests and genetic investigations. Muscular biopsy can be an important diagnostic tool if genetic tests are not available. Brain MRI and muscular MRI are performed if available. We discuss brain MR imaging findings in our patients with CMDs trying to outline common features and differences in order to aid in the diagnosis of these rare disorders before performing genetic tests.
Materials and Methods
Four children with CMDs were retrospectively analyzed: n.1 with merosin-deficient CMD (MDC1A); n.2 and n. 3 with Walker Warburg syndrome (WWS); n. 4 with Ullrich myopathy (COL6-RD). Two were boys and two were girls. Case n.2 and n.3 were siblings. Parental consanguinity was found in all the families. One family was Turkish, the other two were Moroccan. All the patients showed general hypotonia and muscle weakness at birth. In patients with merosin-deficient CMD and Walker Warburg myopathy phosphokinase (CPK) concentration was markedly elevated (>1000 U/l, normal range<175 U/l), while was only mildly elevated in patient with COL6-RD. Genetic tests were performed in two of the four patients, one patient (n.2) was dead at the time of the study, her parents refused genetic tests for their daughter still alive. Children were studied with MRI of the brain. MRI were obtained on a 1.5-T imager. T1-weighted sagittal and axial images, T2-weighted sagittal and coronal images were obtained in all four patients. The MRI studies were analyzed for structural abnormalities of the cerebrum and cerebellum, cortical migration anomalies and white matter disorders. We also determined the presence of enlarged subarachnoid spaces, ventriculomegaly, abnormalities of the brain stem.
Patient 1 was the third child of a Moroccan couple. There was a history of consanguinity in parents (first cousins). Pregnancy and delivery were uneventful. At birth he had severe hypotonia and muscle weakness but he did not require ventilatory assistance. His head circumference was normal, no dysmorphic features were present. At the age of nine months (last follow up) he was still unable to hold his head up. He did not have respiratory problem. He was able to eat by mouth but his weight gain was poor. On examination he had myopathic facies and pectus carinatum. He was hypotonic with absent deep tendon reflexes and joint contractures of distal lower extremities. Speech development was normal (babbling). At birth his serum CPK was 46540 U/l. His echocardiogram was normal. EEG was unremarkable. We analyzed the LAMA2 gene sequencing and revealed a homozygous mutation c.3976C>T. The same mutation was found in both the parents in heterozygosis. Due to the result of genetic test, muscle biopsy was not performed. Magnetic resonance imaging (MRI) of the brain, performed when he was 5 months, showed diffuse high signal in the periventricular and subcortical white matter especially in the parieto-occipital lobes (Figure 1).
Figure 1: Axial T2-weighted MR images of Patient 1. Diffuse prolonged signal is present in the white matter especially in the parieto-occipital lobes.
The patient 2 and 3 were sisters. Their parents were consanguineous (first cousins), the family came from Morocco. The patient 2 was born at term. During pregnancy a severe cerebral malformation was revealed by prenatal ultrasound. From birth she exhibited marked hypotonia with generalized muscle weakness and respiratory difficulties. CPK was elevated (1100 U/l). She underwent a brain MRI which revealed cortical dysplasia (type II lissencephaly, Cobblestone type), multiple heterotopic subependymal nodules, mid brain kinking, cerebellum hypoplasia, high signal in the periventricular and subcortical white matter, hydrocephalus, occipital meningocele (Figure 2). Echocardiography was normal. She was unable to breath without support. She was unable to suck so a nasogastric tube for feeding was necessary. On examination the patient was hypotonic, deep tendon reflexes were diminished. She had joint contractures of upper and lower extremities, myopathic facies, microphthalmia. Her head circumference was normal at birth but increased due to hydrocephalus. Parents did not give consent for ventriculoperitoneal shunt. In the following years her motor milestones were markedly delayed. She was unable to hold her head up and to sit alone. Language was absent. She died when she was five years old. Clinical and radiological aspects were suitable for Walker Warburg syndrome.
Figure 2: Axial T2-weighted MR images of Patient 2. Cerebral cortical dysplasia (type II lissencephaly, Cobblestone type), high signal in the periventricular and subcortical white matter, hydrocephalus.
The patient 3 was the sister of patient 2. Her problems were the same. She was born at term, by caesarian section performed for cerebral malformation revealed by prenatal ultrasound. She had global hypotonia, generalized muscle weakness and respiratory difficulties. Her head circumference was normal at birth but increased due to hydrocephalus. She showed two small occipital and parietal meningoceles. Her serum CPK level was 4370 U/l. EEG showed hypostructured activity with bilateral slow waves. Cerebral MRI revealed cortical dysplasia (type II lissencephaly, Cobblestone type) over temporo-occipital areas, cerebellar hypoplasia especially of the vermis, mid brain kinking, small posterior fossa, high signal in the periventricular and subcortical white matter. Triventricular hydrocephalus with partial pellucid sept agenesis and hypoplasic optic bulbs with abnormalities of the crystalline and vitreous, retinal detachment were also present (Figure 3). Clinical and radiological aspects were suitable for Walker Warburg syndrome. The head circumference increased since the first days of life and a ventriculoperitoneal shunt was necessary. At the last visit the child was 12 months. Her motor milestones were markedly delayed. She was unable to hold her head up and to sit alone. Language was absent. She was able to breath without support but she was fed by nasogastric tube. Clinical and radiological aspects were suitable for Walker Warburg syndrome.The parents refused to do genetic tests for both.
Figure 3: Sagittal T1-weighted MR images of Patient 3. Cerebral cortical dysplasia (type II lissencephaly, Cobblestone type), triventricular hydrocephalus, cerebellar hypoplasia, mid brain kinking, small posterior fossa.
Patient 4 was the fifth child of healthy consanguineous (first cousins) Moroccan parents. His head circumference was normal. Global hypotonia, proximal elbow and knee contractures and hyperlaxity of the distal joints were noted at birth. He had congenital hip dislocation. He acquired ambulation, showing a mild delay (18 months). At last follow up clinical examination showed bilateral proximal muscle weakness, affecting the upper more than the lower limbs, distal laxity in the wrist and in the extensor of the fingers, proximal contractures, spinal involvement with kyphosis and severe scoliosis, talipes equinovarus. Muscle weakness was stable up to 5 years; then progressively worsened with increasing age, resulting in frequent falls, difficulty in standing up and raising arms above the shoulders. He presented severe tendon Achilles tightness, corrected by surgical lengthening at 6 years old; after surgery, he didn’t restart walking. Cognitive, language and social development were appropriate. Examinations of the respiratory systems (spirometry) was normal; echocardiography and serial EKG were normal. Serum creatine kinase (CK) levels was only mildly elevated (max 493 U/l). Other hematological test results were normal. Electromyography (EMG) presented mild myopathic abnormalities and motor and sensory nerve conduction study was normal. The muscle biopsy (H&E stain, modified Gömöri Trichrome, oxidative stains, ATPase stains) showed the typical histological pattern of muscle anomalies of dystrophic lesions. Immunohistochemical examination showed a complete absence of collagen VI immunoreactivity. Genetic tests found an homozygous deletion c.6284delG (p. Gly2095Alafs*12) in exon 18 of the COL6A3 coding sequence (encoding the α3 chains of collagen VI) carrying a pathogenetic significance. Brain MRI findings were normal.
Figure 4: Axial T1-weighted and T2- weighted MR images of Patient 4.
Case summaries for all four children are presented in (Table 1 and 2).
Table 1: Case summaries.
CPK: creatine phosphokinase. No: not performed
Table 2: Brain MRI findings.
MRI: magnetic resonance imaging; WM: white matter.
The follow-up patient was discharged on the March 5,2021 and followed up 3 months after discharge, reviewed for blood potassium 4.48 mmol/L, estradiol (E2)5.2pg/ml, 24 h urinary free cortisol (24h-UFC), 399ug / 24h, and levels were increased compared with those at diagnosis. Review cortisol and ACTH rhythm: Cor 8Am 1.26ug/dL; Cor4Pm<1.00ug/dL ; ACTH 8Am 29.10pg/ml(10-46); ACTH 4Pm26.90pg/ml, ACTH levels decreased, but the rhythm has not appeared. The abdominal CT showed: bilateral abnormal strengthening nodules and mass shadow of the adrenal glands, including solid, lipid and confounding density, and the right scan was about 16x12mm, and the left was about 113x83mm, which showed little change from the previous. After this follow-up, the adjusted prednisone tablet was 7.5 mg/d acetate, and the patient continued to follow-up thereafter 2 Discussion of 17-hydroxylase deficiency representing about 1% of CAH was first reported by Biglieri et al  in 1966.CYP17A1 is the pathogenic gene of the disease, located at 10q24-25, the gene spans 6569bp, composed of seven introns and 8 exons, expressed in both human adrenal and gonad .More than 100 mutations in the CYP17A1 gene are associated with 17-hydroxylase deficiency, including point mutations, insertion, deletion, and frameshift mutations, and the mutations are mostly located at the C terminus. Genetic mutation studies in 26 Chinese OHP patients showed .The c.985_987delinsAA and c.1460_1469del are the most common types of mutations, accounting for 60.8% and 21.7% of the mutant alleles, respectively.CYP17A1 encodes a cytochrome P450c17 protein with two enzymatically active : 17-hydroxylase acting on 17-hydroxylation of progesterone and pregnenolone; 17,20-lyase catalyzes the conversion of 17-hydroxyenolone and 17-hydroxyprogesterone to deHEA and androdione, respectively.17-hydroxylase deficiency contains two types, a deficiency of 17-hydroxylase / 17,20-lyase deficiency (17-hydroxylase / 17,20-lyasedeficiency, 17OHD) and only 17,20-lyase deficiency (isolated17,20-lyasedeficiency, ILD).This patient belongs to 17OHD, and the deficiency of both enzymes resulted in limited synthesis of cortisol, androgen, and estrogen, while corticosterone, 11-deoxycorticosterone (11-deoxycorticosterone, DOC) produced increased .Disorder of cortisol synthesis can weaken the negative feedback inhibition on the pituitary, leading to increased ACTH generation and adrenal hyperplasia; decreased estrogen can be menstruation, breast and female genital development; low androgens can hinder the growth of pubic and axillary hair and reduce estrogen generation as a precursor substance. Because corticosterone acts as glucocorticoid, patients generally have no manifestations of primary adrenal dysfunction; increased DOC can cause water and sodium retention and low renin hypertensive , accompanied by hypokalemia, alkalism and weak limbs. The vast majority of patients are similar to the patient, with low potassium and hypertension , different from other patients: one is the diagnosis age, at 24, but for the secondary signs at puberty, leading to late diagnosis, and most 17OHD patients mainly primary amenorrhea and puberty, diagnosis age is under 20, the patient bilateral adrenal hyperplasia, the left adrenal mass size is about 98x83mm.A similar case was reported by Lee  et al, mainly for abdominal pain and hypertension, with a massive adrenal cortical adenoma with a left mass size of about 100x63x86mm, which was rare in the reported cases. Imaging characteristics of nine patients with 17-hydroxylase deficiency by Wang  et al showed that the average maximum area of 640.1mm2 on the transverse axis of the adrenal gland was only about 3 times greater than the normal value (150mm2), while the size of the adrenal mass increased more than 10 times the normal value. In terms of treatment, exogenous supplementation of glucocorticoids can feed back to inhibit ACTH and adrenal hyperplasia, reduce the secretion of halocorticoids, help relieve hypertension and hypoblood potassium, and iatrogenic Cushing syndrome should be avoided as far as possible. For female patients with 17OHD, estrogen replacement therapy should be performed if diagnosed at the appropriate time of puberty or in adults.In recent years, when estradiol is recommended instead of oral or percutaneous estrogen, the treatment should start at a lower initial dose and gradually increase to an adult dose. Oral estradiol was started at a dose of 0.5 mg/d, then raised to 1 – 2 mg/d within 1 – 3 years or transdermal absorption at 25 g / d and then gradually increased to 75 – 100 g / d .In conclusion, the diagnosis of 17-hydroxylase deficiency should be identified and differentiated as soon as possible, improve the medical history and physical examination, focus on sexual development problems; improve the relevant laboratory and imaging examination, and finally make the final diagnosis through the genetic test results. Patients with 17OHD should be clearly diagnosed and treated as soon as possible, in order to obtain normal growth, development and reproductive capacity.
Several conditions may manifest with infantile hypotonia, including anomalies of the central or peripheral nervous system with involvement of the spinal cord, anterior horn cell, peripheral nerves, neuromuscular junction, and muscles. Different muscular diseases share common clinical symptoms such as hypotonia and weakness, contractures, delayed motor milestones. The diagnostic evaluation is not easy mainly in differentiating the various types of CMDs, and represents a challenge for the neonatologists and pediatricians. Brain MRI findings play an important role in suspecting a specific CMD subtype in order to prioritize testing to arrive at a final genetic diagnosis. Brain MR imaging findings may help the clinicians in the diagnosis of rare disorders before performing genetic tests. Performing clinical and molecular diagnosis is extremely important for genetic counseling, prognosis, and anticipatory or prospective treatment. Once the pathogenic variant(s) have been identified in an affected family member, it is possible to perform prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for CMD.
- Bönnemann CG. The collagen VI‐related myopathies: Muscle meets its matrix. Nat Rev Neurol. 2011; 7:379‐90. [DOI: 10.1038/ nrneurol.2011.81].
- Bönnemann CG, Wang CH, Quijano-Roy S, Deconinck N, Bertini E, Ferreiro A, et al. Diagnostic approach to the congenital muscular dystrophies. Neuromuscul Disord. 2014; 24:289-311. [DOI:10.1016/j.nmd.2013.12.011].
- Caro P A, Scavina M, Hoffman E, Pegoraro E, Marks HG. MR imaging findings in children with merosin-deficient congenital muscular dystrophy. Am J Neuroradiol. 1999; 20:324-326.
- Darin N, Tulinius M. Neuromuscular disorders in childhood: a descriptive epidemiological study from western Sweden. Neuromuscul Disord. 2000; 1 0:1-9. [DOI: 10.1016/s0960-8966(99)00055-3].
- Di Blasi C, Bellafiore E, Salih MA, Manzini MC, Moore SA, Seidahmed MZ, et al. Variable disease severity in Saudi Arabian and Sudanese families with c.3924 + 2 T > C mutation of LAMA2. BMC Res Notes. 2011; 4:534. [DOI: 10.1186/1756-0500-4-534].
- Falsaperla R, Praticò AD, Ruggieri M, Parano E, Rizzo R, Corsello G, et al. Congenital muscular dystrophy: from muscle to brain. Ital J Pediatr. 2016; 42:78. [DOI: 10.1186/s13052-016-0289-9].
- Fu XN, Xiong H. Genetic and Clinical Advances of Congenital Muscular Dystrophy. Chin Med J. 2017; 130:2624‐31. [DOI: 10.4103/0366-6999.217091].
- Graziano A, Bianco F, D'Amico A, Moroni I, Messina S, Bruno C, et al. Prevalence of congenital muscular dystrophy in Italy: a population study. Neurology. 2015; 84:904-11. [DOI: 10.1212/WNL.0000000000001303].
- Hughes MI, Hicks EM, Nevin NC, Patterson VH. The prevalence of inherited neuromuscular disease in Northern Ireland. Neuromuscul Disord. 1996; 6:69-73. [DOI: 10.1016/0960-8966(94)00017-4].
- Incecik F, Herguner OM, Ceylaner S, Altunbasak S. Merosin-negative congenital muscular dystrophy: Report of five cases. J Pediatr Neurosci. 2015; 10:346-9. [DOI: 10.4103/1817-1745.174432].
- Kang PB, Morrison L, Iannaccone ST, Graham RJ, Bönnemann CG, Rutkowski A. Evidence-based guideline summary: evaluation, diagnosis, and management of congenital muscular dystrophy: Report of the Guideline Development Subcommittee of the American Academy of Neurology and the Practice Issues Review Panel of the American Association of Neuromuscular & Electrodiagnostic Medicine. Neurology. 2015; 84:1369-78. [DOI: 10.1212/WNL.0000000000001416.s].
- Leite CC, Lucato LT, Martin MG, Ferreira LG, Resende MB, Carvalho MS, et al Merosin-deficient congenital muscular dystrophy (CMD): a study of 25 Brazilian patients using MRI. Pediatr Radiol. 2005; 35:572-9. [DOI: 10.1007/s00247-004-1398-y].
- Mah JK, Korngut L, Fiest KM, Dykeman J, Day LJ, Pringsheim T, et al Systematic Review and Meta-analysis on the Epidemiology of the Muscular Dystrophies. Can J Neurol Sci. 2016; 43:163-77. [DOI: 10.1017/cjn.2015.311].
- Martin PT. The dystroglycanopathies: the new disorders of O-linked glycosylation. Semin Pediatr Neurol. 2005; 12:152-8. [DOI: 10.1016/j.spen.2005.10.003].
- Mostacciuolo ML, Miorin M, Martinello F, Angelini C, Perini P, Trevisan CP. Genetic epidemiology of congenital muscular dystrophy in a sample from north–east Italy. Hum Genet. 1996; 97:277-279. [DOI: 10.1007/BF02185752].
- Muntoni F, Brockington M, Blake DJ, Torelli S, Brown SC. Defective glycosylation in muscular dystrophy. Lancet. 2002; 360:1419-21. [DOI: 10.1016/S0140-6736(02)11397-3].
- Muntoni F, Valero de Bernabe B, Bittner R, Blake D, van Bokhoven H, Brockington M, et al. 114th ENMC International Workshop on Congenital Muscular Dystrophy (CMD) 17-19 January 2003, Naarden, The Netherlands: (8th Workshop of the International Consortium on CMD; 3rd Workshop of the MYO-CLUSTER project GENRE). Neuromuscul Disord. 2003; 13:579–88. [DOI: 10.1016/S0140-6736(02)11397-3].
- Norwood FL, Harling C, Chinnery PF, Eagle M, Bushby K, Straub V. Prevalence of genetic muscle disease in Northern England: in-depth analysis of a muscle clinic population. Brain. 2009; 132:3175-3186. [DOI: 10.1093/brain/awp236].
- Oliveira J, Santos R, Soares-Silva I, Jorge P, Vieira E, Oliveira ME, et al. LAMA2 gene analysis in a cohort of 26 congenital muscular dystrophy patients. Clin Genet. 2008; 74:502-12. [DOI: 10.1111/j.1399-0004.2008.01068.x].
- Parano E, Fiumara A, Falsperla R, Vita G, Trifiletti RR. Congenital muscular dystrophy: correlation of muscle biopsy and clinical features. Pediatr Neurol. 1994; 10:233-6. [DOI: 10.1016/0887-8994(94)90029-9].
- Parano E, Pavone L, Fiumara A, Falsaperla R, Trifiletti RR, Dobyns WB. Congenital muscular dystrophies: clinical review and proposed classification. Pediatr Neurol. 1995; 13:97-103. [DOI: 10.1016/0887-8994(95)00148-9].
- Parija D, Tadi P. Congenital Muscular Dystrophy. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan 31.
- Philpot J, Sewry C, Pennock J, Dubowitz V. Clinical phenotype in congenital muscular dystrophy: correlation with expression of merosin in skeletal muscle. Neuromuscul Disord. 1995; 5:301-5. [DOI: 10.1016/0960-8966(94)00069-l].
- Reed UC. Congenital muscular dystrophy. Part I: a review of phenotypical and diagnostic aspects. Arq Neuropsiquiatr. 2009; 67:144-68. [DOI: 10.1590/s0004-282x2009000100038].
- Sframeli M, Sarkozy A, Bertoli M, Astrea G, Hudson J, Scoto M, et al. Congenital muscular dystrophies in the UK population: Clinical and molecular spectrum of a large cohort diagnosed over a 12-year period. Neuromuscul Disord. 2017; 27:793-803. [DOI: 10.1016/j.nmd.2017.06.008].