in lifeHeterogeneous group of muscle diseases the onset of which is early, often neonatal. They are either slowly progressive or non-progressive. Their prevalence is estimated to be 4.6 cases per 100,000 children. Histologically, there is an infiltration of the endomysium and perimysium by conjunctive fibers and an  alteration of muscle fibers: fibers of different sizes, signs of necrosis... There are isolated forms and forms with central nervous system involvement. One can also distinguish syndromic forms (60% of cases, autosomal recessive transmission, linked to a mutation of the fukutine proteins and in which merosin is normal) and non-syndromic forms that are either merosin-negative (deficiency in laminin α2) or merosin-positive (with CNS hypomyelination).

The most recent classification of these myopathies is as follows:

1. extracellular matrix anomalies

• anomaly of collagen VI : Ullrich or Bethlem congenital muscular dystrophy (UCMD 1, 2 and 3) [MIM 254 090 ]. Both myopathies (sometimes called collagen type 6-related myopathies) are due to amutation of the COL6A1 gene (21q22.3) coding for the α1-subunit of collegen type 6, or of the COL6A2 gene (21q22.3) coding for the α2-subunit of collegen type 6 or of the COL6A3 gene (2q37.3) coding for the α3-subunit of the collegen type 6

-        Bethlem myopathy type 1: [MIM 158810] classically, autosomal dominant transmission, but cases of autosomal recessive transmission have been reported. Onset in childhood or in the first decade of life, progressive atrophy of the chest and girdles muscles with contracture of the distal joints; wheelchair  bound after 50 years. Late respiratory impairment (diaphragm). No cardiac involvement. Normal or mildly increased  CPK levels

-        Ullric myopathy type 1: [MIM 254 090] autosomal recessive transmission but around 50% of cases are of autosomal dominant transmission. Neonatal hypotonia; contracture of muscles (stiff neck, kyphoscoliosis) and laxity of the distal joints; rapid loss of walking (around the end of the 1st decade), respiratory failure (restrictive syndrome with predominant diaphragm impairment) between 10 and 20 years of age; micrognathia: very severe ankylosis of the temporomandibular joint. Velvet-like skin at the level of the palms of the hands and the soles of the feet, and follicular hyperkeratosis. Possible immune deficiency with frequent respiratory infections. CPK level is normal or moderately increased. Intelligence and cardiac function are normal 

It seems that cyclosporin A treatment can slow the progression of early forms, the evolution of which is more severe. Few cases of anesthetic management have been reported with either total IV anesthesia or halogenated agents. No risk of MH and no case of rhabomyolysis has been reported even though collagen 6 is linked to the dystrophin-glycoprotein complex of the muscular membrane: it is better to avoid them. Avoid succinylcholine. Risk of difficult intubation because of contractures at the level of the neck or the temporo-maxillary joint. Contractures may render peripheral venous access and surgical positioning difficult. Abnormal scarring (keloid). A Bethlem myopathy type 2 [MIM 616 471] and an Ullrich myopathy type 2 [MIM 616 470] also exist: both are due to a mutation of the COL12A1 gene (6q13-q14) coding for the α1-subunit of collagen type 12. 

• congenital myosclerosis [MIM 255 600] 
  Autosomal recessive transmission of a mutation of the COL6A2 gene (21q22.3) coding for the α2-subunit of collegen type 6. Association of hypotonia and symmetric contracture of the joints. The temporomandibular joints can also be involved.

• Muscular dystrophy due to a deficiency in integrin α7 [MIM 613 204] . Very rare disorder. Autosomal recessive transmission of a mutation of the ITGA7 gene (12q13.2).  Important hypotonia since birth or the first months of life. Walking is delayed. Contractures develop around 3 to 10 years of age mostly at the level of the spine (scoliosis) but also the face, proximal joints and extensors of the fingers. Respiratory failure develops gradually and nocturnal ventilatory assistance is usually  necessary at the end of the first decade. Normal intelligence and heart function. Normal CPK level. The integrins are transmembranar proteins linking the muscle membrane to laminin α2, independent of the dystrophin-glycoprotein complex. Another form is caused by a mutation of the ITDA9 gene (3p21-3) coding for integrin 9.
  
  
• rigid spine [MIM  602 711]
  Autosomal recessive transmission of a mutation of the SELENON or SEPN1 gene (1p36.11) that causes a  deficiency in selenoprotein, a protein of the endoplasmic reticulum the function of which is unknown. There is a contracture of the extensor muscles of the spine. CPK level is normal or low. 
  A special form is the rigid spine syndrome with a later onset in which the paraspinal musculature is particularly affected: this form is associated with difficulties for endotracheal intubation. Respiratory disease is rapidly debilitating and leads to right heart failure (cor pulmonale). Nighttime ventilatory assistance is needed early in childhood. A mutation of the ACTA1 gene (1q42.13) [MIM 604 801] may also be produce the same clinical presentation.

• congenital muscular dystrophy associated to dynamin 2
  autosomal dominant transmission of a mutation in the DNM2 gene (19p13.2) coding for dynamin, a ubiquitous GTPase involved in membrane flux. Other mutations in this gene produce a centronuclear myopathy or a subtype of Charcot-Marie-Tooth disease.
  
  
• congenital muscular dystrophies linked to an anomaly  of laminine A [MIM 613 205]
  Mutation in the LMNA gene (1q21.2) coding for laminin A/C. Hypotonia and generalized muscle weakness  during the first year. Major involvement of the axial muscles with inability to hold the head ("dropped head syndrome"). Walking becomes possible around  3 years of age. Muscle hypertrophy is usual with weakness of the limb girdles and facial muscles. Stiffness of the spine. Intelligence and brain MRI are normal. Cardiac involvement (atrial and/or ventricular rhythm disorders, sometimes cardiomyopathy) is common: it is sometimes necessary to insert an automatic defibrillator. Death from respiratory failure.

Specific references:

-        Vandenberghe W, Jacobs TF, Plasschaert FS, Willems J, Den Blauwen NM, Vereecke HE, Wouters P.
Anesthesia and perioperative management for a patient with Ullrich syndrome undergoing surgery for scoliosis.
Acta Anaesth Belg 2010; 61: 43-7.

-        Puangsuvan N, Mester RA, Ramachandran V, Tobias JD.
Perioperative care of a child with Ullrich congenital muscular dystrophy.
MEJ Anesth 2009; 20: 319-23.

-        Erbabacan R, Koksal GM, Seker TB, Ekici B, Ozcan R, Altindas F.
Anaesthesia management and use of sugammadex in a patient with Ullrich’s disease.
Turk J Anaesth Reanim 2015; 43: 356-9.

-        Martin DP, Tobias JD, Warhadpande S, Beebe A, Klamar J.
Perioperative care of a child with Ullrich congenital muscular dystrophy during posterior spinal fusion.
South Afr J Anaesth Analg 2013; 19: 73-6.

-        Grosu I, Truong D, Teodorescu S, Mousny M, Veyckemans F.
Anesthetic management of a child with Ullrich myopathy.
J Anesth 2012; 26: 636-7.

-        Duong KW, Redyy SC, Buchanan EP, Chen JH.
Mandibular and maxillary cysts in a pediatric patient with Pierre Robin sequence and Ullrich congenital muscular dystrophy.
Anesthesiology 2020; 133: 919-20.

-        Veyckemans F.
Anesthesia and Ullrich congenital muscular dystrophy (Letter).
Anesthesiology 2021; 134:813

-        Lovejoy H, Geib LN, Walters CB.
Perioperative pulmonary optimization with average volume-assured pressure support of a pediatric patient with Ullrich congenital muscular dystrophy : a case report.
A&A Practice 2021 ; 15 e01504

2. primary deficiency in α2 laminin (MDC1A or deficiency in merosin) [MIM 607 855]

It is the most common congenital muscular dystrophy (40 % of cases) characterized by a  deficiency in merosin (α2 chain of the isoform 211 of laminin). It is caused by a mutation of the LAMA2 gene (6q22-23) that encodes for laminin α2. The laminins are glycoproteins of the extracellular matrix and the basement membrane of every cell. The laminins α2 and α4 are specific for the skeletal muscle. The complete absence of laminin α2 results in a severe phenotype: neonatal hypotonia is constant with feeding difficulties and breathing problems; a symptomatology of arthogryposis is possible. The evolution is variable but usually severe with contractures in flexion, scoliosis, and progressive respiratory insufficiency. There is a leukodystrophy at the MRI at the age of 6 months; other abnormalities of polymicrogyria type or brainstem hypoplasia or cerebellar hypoplasia (5 %), moderate mental retardation or epilepsy (30 %) can be observed. CPK levels are elevated especially during the first two years of life. The presentattion is less severe in case of partial deficiency in laminin α2: the phenotype is then similar to Emery-Dreifuss dystrophy and  LGMDR23 type limb girdles dystrophy. There is sometimes a cardiac involvement, often asymptomatic: right bundle branch block, cardiomyopathy. The deficiency in laminin α2 causes a secondary deficiency in α-dystroglycan and  α7 integrin, which in turn causes a failure of myogenesis, synaptogenesis and mechanical stability. A case of metabolic reaction similar to MH has been reported in a child anesthetized without triggering agents  but halogenated agents have been used in a series of 10 children without any problem. The α-dystroglycans O-glycosylation abnormalities described below can cause a secondary deficiency in laminin α2

Specific references:

-         Shukry M, Guruli ZV, Ramadhyani U. Suspected malignant hyperthermia in a child with laminin 2 (merosin) deficiency of the absence of triggering agents. Pediatr Anesth 2006; 16: 462-5.

-         Scrivener TA, Ross SM, Street NE, Webster RI, De Lima JC. A case series of general anesthesia in children with laminin alpha2 (merosin)-deficient congenital muscular dystrophy. 
Pediatr Anesth 2014; 24: 464-5.

-        Prégardien C, Pirotte T, Veyckemans F.
Pressure-support ventilation in a child with merosin-deficient congenital muscular dystrophy.
Acta Anaesth Belg 2016; 67: 139-41. 

3. α-dystroglycans anomalies

Disorders of O-mannosyl glycosylation (deficiency in dolichol-phosphate-mannose-synthase 1, 2 or 3), or of the glycosylation of α-dystroglycans have been identified: these pathologies are grouped under the name of α-dystroglycanopathies. The α-dystroglycans seem to establish a connection between the basement membrane and the cytoplasm and are coded for by the DAG1 gene: glycosylation is necessary to their binding to the proteins of the extracellular matrix such as laminin, neurexin etc. The resulting clinical phenotypes are not specific: a same mutation can produce different phenotypes. The severity of the disease seems to be related to the proportion of residual function of the α-dystroglycans.

Mild form: normal muscle function but eye and brain abnormalities.

Intermediate form: myopia,  pontocerebellar hypoplasia, pachygyria.

Severe form: degeneration of muscle fibers, agyria, blindness, severe  pontocerebellar hypoplasia.

CPK levels are very elevated in all forms.

Different mutations can produce hypoglycolysation of the dystroglycans:

• mutation of the LARGE1 gene (22q12.3) [MIM 613,154, 608 840]
• mutation of the DPM1 gene (20q13.13) [MIM 608,799]
• mutation of the DPM2 gene (9q34.11) [MIM 615,042]
• mutation of the DAG1 gene (3p21.31) [MIM 616,538]
• mutation of the RXLTI gene (12q14.2) [MIM 615 041]
• mutation of the B3GALNT2 gene (1q42.3) [MIM 615 181]
• mutation of the POMK gene (8p11.21) [MIM 615,249]
• mutation of the GMPPB gene (3p21.31) [MIM 615,351], with mental retardation
• mutation of the TRAPPC11 gene (4q35.1), with fatty liver disease and congenital cataracts
• mutation of the GOSR2 gene (17q21.32), with epilepsy

• Fukuyama congenital muscular dystrophy [ MIM253 800] 
  Fukuyama disease is common in Japan (12/100,000). Autosomal recessive transmission of a mutation of the FKTN gene coding for fukutin (9q31.2). Similar phenotypes are caused by a mutation of the FKRP (19q13) [MIM 606 612] or LARGE (22q12) [MIM 608 840] genes. Muscle involvement is generalized from birth: hypotonia, muscle contractures, progressive respiratory insufficiency. Calf and quadriceps muscle hypertrophy, macroglossia. Mental retardation is severe (microcephaly, micropolygyria, cerebral and cerebellar lissencephaly type II, epilepsy in 50%) and optical anomalies (nystagmus, strabismus, myopia, cataract) are associated. Cardiac involvement appears around the age of 10 years: dilated cardiomyopathy and heart failure. The death usually occurs around the age of 15 years.

• Muscle-Eye-Brain (MEB) disease [MIM 253 280]  
  The Muscle - Eye - Brain disease has been initially reported in Finland. Autosomal recessive transmission of a mutation of:

-         the POMGNT1 gene (1p32-34) [MIM 253 280], responsible for the synthesis of a protein in the Golgi apparatus. 

-        the FKRP gene (19q13.32) [MIM 613 153]

-        the POMT2 gene (14q24.3) [MIM 613 150, 613 156]

-        the GMPPB gene (3p21.31) [MIM 615 350]

It combines glaucoma, cataracts, corneal anomalies, mental retardation, dysmyelination and brain abnormalities similar to those of Fukuyama disease. Epilepsy is frequent. Hydrocephalus requiring drainage may be present. A case of acute rhabdomyolysis after the use of halothane and succinylcholine has been reported.

• Walker-Warburg syndrome (or HARD or lissencephaly type II) 

It is usually caused by a mutation of:

-        the FCMD gene (9q31.2) [MIM 613 512]

-        the  POMT1 gene (9q34.13) [MIM 263 670, 607 423]

-        the POMT2 gene (14q24.3) [MIM 613 510, 613 152]

-        the FKRP gene (19q13.32) [MIM 613 513]

-        the POMGNT1 (1p34.1) [MIM 253 280, 613 511]

-        the ISPD (7p21.1) [MIM 614 643]

-        the POMGNT2 (3p22.1) [MIM 614 830]

-        the B4GAT1 (11q13.2) [MIM 615 287]

The typical form is rapidly lethal following pneumonia, seizures or cardiac failure. Microphthalmia, glaucoma, corneal opacities, coloboma. Brainstem hypoplasia, arachnoid cysts and defects of the posterior fossa with hydrocephalus. CPK level is elevated. This syndrome is sometimes referred to as HARD, the acronym for "Hydrocephalus Agyria Retinal Dysplasia-Dandy-Walker" and ± E for "Occipital Encephalocele". There is no cardiac involvement. 

• Congenital dystroglycanopathy with or without mental retardation(formerly MDC1C)  and secondary deficiency in laminin. [MIM 606 612]
  It is caused by a mutation of the FKRP gene (fukutin-related protein) on 19q13.32. A wide range of anomalies is described from a severe form of MEB to a form similar to Duchenne disease or a moderate  LGMDR23 type limb girdle dystrophy. The typical form is similar to a deficiency in α2-laminin (MDC1A). There is hypertrophy of the calves and tongue, and a weakness of the facial muscles. Dilated cardiomyopathy may occur in 50 % of cases. Intelligence and brain MRI are normal.

• CMD with mental retardation and pachygyria (MDC1D) Autosomal recessive transmission of a transfer of the LARGE gene on chromosome 22 (q). Profound mental retardation and hypotonia.

Specific references:

-        Nakazato A, Shime H, Morooka K, Nonaka I.
Anesthesia-induced rhabdomyolysis in a patient with Fukuyama type congenital muscular dystrophy.
Brain & Development 1983, 5: 243.

-        Karhunen U.
Serum creatine kinase levels after succinylcholine in children with muscle-eye-brain disease.
Can J Anaesth 1988; 35: 90-2.

-        Gropp A, Kern C, Frei FJ.
Anaesthetic management of a child with muscle-eye-brain disease.
Pediatr Anesth 1994; 4: 197-200.

-        Hackmann T, Skidmore DL, MacManus B.
Case report of cardiac arrest after succinylcholine in a child with Muscle-Eye-Brain disease.
A&A Case Reports 2017: 9: 244-7.

-        Hackmann T, Skidmore DL, MacManus B.
Case report of cardiac arrest after succinylcholine in a child with Muscle-Eye-Brain disease.
A&A Case Reports 2017 (in press).

-        Sahajananda H, Meneges J.
Anaesthesia for a child with Walker-Warburg syndrome.
Pediatr Anesth 2003;13: 624-8.

-        Kose EA, Bakar B, Ates G, Aliefendioglu D, Pan A.
Anesthesia for a child with Walker-warburg syndrome.
Rev Bras Anestesiol 2014; 64: 128-30.

-        Valk MJA, Loer ST, Schober P, Dettwiler S.
Perioperative considerations in Walker-Warburg syndrome.
Clin Case Reports 2015; 3: 744-8.

4. congenital muscular dystrophies linked to a recessive  mutation of RYR1 gene
   Some mutations (autosomal recessive transmission) of the RYR1 gene (19q13.1-13.2) may present with a clinical picture similar to a congenital muscular dystrophy or congenital myopathy without pictures of 'cores' on muscle biopsy. Neonatal hypotonia (including facial) and rapidly progressive scoliosis. CPK levels are moderately elevated. 
   Reminder: some autosomal dominant transmitted mutations of the RYR1 gene  can produce congenital myopathies (central core and other forms) and susceptibility to malignant hyperthermia (see this term).

5. Congenital muscular dystrophy with hyperlaxity
   Mutations of CHKB gene (22q13.33) coding for the β-choline-kinase which is involved in the synthesis of phosphatidylcholine, produce a clinical picture of congenital muscular dystrophy with giant mitochondria. Some cognitive impairment is observed but the brain MRI is normal. There is also an intense pruritus and acanthosis nigricans.
   
   
6. Congenital muscular dystrophy with hyperlaxity
   It is observed in Canadians of French origin.Mutation of a gene on 3p23-21. Muscle weakness associated with contractures of the proximal muscles and distal hyperlaxity. It evolves more slowly than the Ullrich and Bethlem myopathies.
   
   
7. congenital muscular dystrophies type Davignon-Chauveau [MIM 617 066]
   It has been described in a French family. Autosomal recessive transmission of a mutation of the TRIP4 (15q22.31). hypotonia, respiratory failure, progressive contracture of the muscles of the neck, scoliosis

8. congenital muscular dystrophy with cataract and mental retardation [MIM 617 404]
   Autosomal recessive transmission of a mutation of the INPP5K gene (17p13.3). Epilepsy is sometimes associated.
   
   
9. Congenital muscular dystrophy associated to GOLGA2
   Autosomal recessive transmission of a mutation of the GOLGA2 gene (9q34.11) with cerebral involvement.
   
   
10. Congenital muscular dystrophy associated to MSTO1
    Autosomal recessive transmission of a mutation of the MSTO1 gene (1q22) causing an mitochondrial myopathy (anomalies of the fusion and the distribution of the mitochondrias) and ataxia.

Anesthetic implications: 

risk of difficult intubation. Preoperative ECG and echocardiography. Risk of intracranial hypertension and obstructive apneas in case of brain involvement. Gut motility is reduced. Avoid succinylcholine, because there is a risk of hyperkalemia. Risk of rhabdomyolysis induced by the halogenated agents even if they have been used without problems in several cases.

References : 

-   Moore WE, Watson RL, Summary JJ. 
Massive myoglobinuria precipitated by halothane and succinylcholine in a member of a family with elevation of serum creatine phosphokinase. 
Anesth Analg 1976, 55: 680-2

-        Hermans MCE, Pinto YM, Merkies ISJ, de Die-Smulders CEM, Crijns JHGM, Faber CG. 
Hereditary muscular dystrophies and the heart. 
Neuromuscul Disord 2010; 20: 479-92.

-        Finsterer J, Ramaciotti C, Wang CH, Wahbi K, Rosenthal D, Duboc D; Melacini P. 
Cardiac findings in congenital muscular dystrophies. 
Pediatrics 2010 ; 126 : 538-45.

-        Mercuri E, Muntoni F. 
Muscular dystrophies. 
Lancet 2013 ; 381 :845-60.

-        Bönneman CG, Wang CH, Quijano-Roy S, Deconinck N et al. 
Diagnostic approach to the congenital muscular dystrophies. 
Neuromusc Disord 2014; 24: 289-311

-        Tuncali B, Boya H, Arac S.
Caudal block combined with propofol infusion using laryngeal mask airway in a spontaneously ventilating child with merosin-positive occidental type congenital muscular dystrophy.
J Clin Anesth 2016: 32: 196-7

-        Benarroch L, Bonne G, Rivier F, Hamroun D.
The 2020 version of the gene table of neuromuscular disorders.
Neuromusc Dis 2019 ; 29 : 980-1018 ou  http://www.musclegenetable.fr.

Updated: July 2021