The disorders associated with mutation of the 13 genes most commonly associated with CMD are summarized in Table 1 [Muntoni & Voit 2004, Quijano-Roy et al 2008]. Description of several less known CMD subtypes, reported in a limited number of individuals, follows Table 1. To date, data for all CMD subtypes are insufficient to make any firm genotype/phenotype correlations or to provide definitive prognosis or anticipatory guidance based on CMD subtype.
Of note, in large cohorts of individuals with CMD causative pathogenic variants can be identified in 25%-50% of cases, underscoring the need for ongoing investigation into the genetic causes of CMD [Peat et al 2008] and the need to consider disorders included in the Differential Diagnosis in the evaluation of an individual with possible CMD.
Clinical Findings in the Disorders Described in Table 1
Laminin alpha-2 deficiency (LAMA2-related CMD [MDC1A]) is characterized by congenital hypotonia, delayed or arrested motor milestones, and feeding difficulties. Muscle weakness is absent or slowly progressive. Respiratory insufficiency and orthopedic complications may become severe, with diffuse joint contractures and spinal rigidity. Progressive restrictive respiratory insufficiency occurs in all non-ambulatory persons. Nocturnal mechanical ventilation or continuous ventilation via tracheostomy may be required either early on or beyond age ten to 15 years [Bönnemann et al 2011]. Most children with laminin alpha-2 deficiency who have complete deficiency of the protein merosin do not acquire independent walking, but ambulation in those with partial merosin deficiency with later onset has been reported.
With time affected children develop typical myopathic facies and some develop external ophthalmoplegia and may appear to have an enlarged head with parents relaying difficulty in pulling T-shirts over the head. Of note, retrospective data on 15 children with laminin alpha-2 deficiency from one CMD center revealed that 53% had a head circumference above the 90th centile [Author, personal observation].
Cognitive abilities are normal in the majority of affected individuals. Seizures are observed in 20%-30% [Bönnemann 2009].
Brain MRI demonstrates diffuse white matter signal abnormalities sparing the cerebellum, corpus callosum, and internal capsule. Children may initially be misdiagnosed as having a leukodystrophy. The MRI findings can be found consistently beyond age six months. White matter changes do not regress with time. A small number of individuals have structural changes with focal cortical dysplasia that tends to involve the occipital and temporal lobes.
Nerve conduction studies show reduced velocities during disease demonstrating a peripheral neuropathy.
Inheritance is autosomal recessive.
The collagen VI-deficient CMDs were previously known as Ullrich congenital muscular dystrophy (UCMD) and Bethlem myopathy (see Collagen VI-Related Disorders). Although originally described as separate entities, UCMD and Bethlem myopathy represent a clinical continuum; intermediate phenotypes are common. In a recent study of 49 individuals with collagen VI myopathy, Briñas et al [2010] referred to three phenotypes:
Early/severe. Ambulation never achieved
Moderate progressive. Ambulation attained and lost
Mild. Ambulation into adulthood
Homozygous premature termination codon-causing pathogenic variants in the triple helix domains were associated with the early/severe phenotype and dominant de novo in-frame exon-skipping variants; glycine missense variants were associated with the moderate progressive phenotype [Briñas et al 2010].
Terminology:
UCMD (first described as "scleroatonic myopathy") is characterized by
congenital weakness and hypotonia along with congenital joint or spinal rigidity or deformities. The combination of proximal joint contractures and a striking hyperlaxity of the distal joints is characteristic. Some affected children have acquired the ability to walk independently; however, disease progression often results in loss of ambulation. Early and severe respiratory involvement may require ventilatory support in the first or second decade of life.
Bethlem myopathy is characterized by the combination of proximal muscle weakness and variable contractures, affecting most frequently the long finger flexors, elbows, and ankles.
Although the first reports of UCMD showed autosomal recessive transmission, most affected individuals identified in recent years have a de novo autosomal dominant pathogenic variant. Bethlem myopathy is typically caused by autosomal dominant pathogenic variants, but a few instances of autosomal recessive transmission have been reported [Allamand et al 2010].
Dystroglycanopathies are characterized by a broad CMD phenotypic spectrum with and without intellectual disability, eye involvement, and brain findings (Table 2).
Several CMD phenotypes known to be dystroglycanopathies were initially described as syndromes (in descending order of severity):
Eye manifestations can include either unilateral or bilateral microcornea and/or microphthalmia, hypoplastic or absent optic nerves, and colobomas that may involve the retina. Anterior chamber malformations include cataracts, iris hypoplasia or malformation, and abnormal or shallow anterior chamber angle which can result in glaucoma. Retinal dysplasia or detachment may occur. In individuals with milder manifestations of a dystroglycanopathy, high myopia or optic disc pallor may be the only ocular manifestation.
Brain MRI may demonstrate structural abnormalities (e.g., hydrocephalus, brain stem hypoplasia, cerebellar cysts) or abnormalities in neuronal migration (cobblestone lissencephaly or polymicrogyria), which are common [Kirschner & Bönnemann 2004]. White matter changes may regress with time [Louhichi et al 2004].
Hindbrain malformations can include atrophy of the cerebellar vermis and hemispheres and flattening of the pons and brain stem [Muntoni & Voit 2004]. Other findings can include partial absence of the corpus callosum, hypoplasia of the pyramidal tracts, and obstructive hydrocephalus requiring a shunt.
WWS, MEB disease, and FCMD were considered separate entities long before their molecular basis was known. When clinically defined, these three disorders did not include milder phenotypes in which the brain MRI was normal or showed less severe cortical or cerebellar malformations. The spectrum of the dystroglycanopathies is now known to include the milder phenotype of limb-girdle muscle muscular dystrophy, with and without cognitive impairment.
Pathogenic variants in a number of genes (ISPD, POMT1, POMT2, POMGNT1, FKTN, FKRP, and LARGE1) lead to alpha dystroglycan-related muscular dystrophy. The proteins encoded by these genes (which are involved in critical steps in both O-mannosylation and the elaboration of glycan chains on alpha dystroglycan) include:
Isoprenoid synthase (encoded by ISPD) involved early in O-mannosylation;
Known glycosyltransferases (encoded by POMT1, POMT2, and POMGNT1); and
Proteins involved in a specific glycan epitope that confers laminin binding (encoded by FKTN, FKRP, and LARGE1).
Although "one gene, one syndrome" was initially postulated, it is now known that pathogenic variants in any one of the seven genes results in a broad phenotypic spectrum. The most phenotypic variability is observed with pathogenic variants in FKTN and FKRP, which result in phenotypes ranging from WWS to CMD, LGMD, elevated creatine kinase (CK), and exercise intolerance without intellectual disability and normal brain MRI. Homozygous and compound heterozygous ISPD pathogenic variants are associated with a severe dystroglycanopathy subtype of CMD with brain and eye involvement (Walker-Warburg phenotype) [Willer et al 2012].
Certain clinical findings can help direct one to the specific gene involved:
Microcephaly.
POMT1 and POMT2
Macrocephaly and epilepsy.
POMGNT1
Cardiac involvement.
FKRP, FKTN, POMT1
It is unclear at this time if certain central nervous system abnormalities are associated with mutation of specific genes.
Inheritance is autosomal recessive.
Table 2.
Findings in the α-Dystroglycanopathies
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| Phenotype | Findings |
|---|
| Motor Function | Eye | Central Nervous System | Intellectual Disability / Epilepsy |
|---|
| Cortex | Cerebellum | Brain Stem | Hydrocephalus |
|---|
| Walker-Warburg syndrome (WWS) | Absent psychomotor acquisitions | Severe 1 | Cobblestone lissencephaly | Very hypoplastic | Severely hypoplastic | Constant | Severe |
| Muscle-eye-brain (MEB) disease | Ambulation may be acquired | Common 2 | Frontoparietal pachygyria; polymicrogyria | Vermis hypoplasia, cyst, dysplastic | Usually hypoplastic | Common | Severe intellectual disability; refractory epilepsy; behavioral problems |
| Fukuyama CMD (FCMD) | Ambulation may be acquired | Variable / mild | Variable (from normal or only simplification of gyri to severe) | Hypoplasia, cysts, polymicrogyria | Usually normal | Rare | Moderate |
| Intermediate phenotypes (MDC1D, CRB-CMD) | Ambulation may be acquired | Rare / mild | Variable | Variable | Variable | Variable | Mild to moderate |
| CMD with intellectual disability | Ambulation may be acquired | Rare / mild | None | None | None | None | Mild to moderate |
| CMD no intellectual disability (MDC1C) | Ambulation may be acquired | None / mild | None | None | None | None | None |
- 1.
Severe congenital myopia, congenital glaucoma, pallor of the optic discs, and retinal hypoplasia
- 2.
Microphthalmia, retinal detachment, retinal hypoplasia, anterior chamber malformation, cataracts
SELENON (SEPN1)-related CMD.
SELENON pathogenic variants were initially described in CMD characterized by selective spinal rigidity and normal expression of the protein merosin (rigid spine muscular dystrophy type 1 [RSMD1]). It is now known that "rigid spine syndrome" is not specific to this subtype of CMD and that some spinal rigidity resulting from paraspinal contractures may develop in other CMD subtypes.
Clinical features tend to be homogeneous: cervicoaxial weakness early in life that may be associated with delay in motor milestones and development of spinal stiffness often associated with thoracic spinal lordosis and a characteristic "S"-shaped thoracic scoliosis. Progressive respiratory insufficiency is aggravated by diaphragmatic weakness. Early nocturnal hypoventilation prior to adulthood in a person who is still ambulatory is the distinct feature of this CMD subtype.
MRI shows selective involvement of the sartorius and major adductor muscles in the thigh giving a characteristic medial thigh wasting, notable on physical examination.
SELENON pathogenic variants are also reported in the classic form of multiminicore myopathy, in congenital fiber-type disproportion myopathy, and in a desminopathy with Mallory body-like inclusions.
LMNA-related CMD (L-CMD) is part of the spectrum of laminopathies (also known as nuclear envelopathies). L-CMD may present with a severe picture in the first six months of life (absence of head or trunk support) or with progressive loss of head support after acquisition of sitting or walking ability (dropped head syndrome). Often hypotonia and weakness of the axial-cervical muscles is rapidly progressive, followed by more slowly progressive weakness the proximal upper limbs and distal lower limbs. Facial muscles are spared. With time, the characteristic findings are head lag, thoracic and lumbar spinal hyperextension (rigidity), lower limb contractures, and talipes equinovarus but no significant upper limb contractures. Restrictive lung disease resulting in respiratory insufficiency occurs as muscle weakness progresses. Mechanical ventilation may be required before age two years in those more severely affected.
L-CMD can be considered as an early-onset variant of Emery Dreifuss muscular dystrophy (EDMD), without some of the typical early findings of EDMD (elbow contractures and major cardiac complications). Nonetheless, these findings may develop in time.
Genetic testing has identified a number of de novo dominant pathogenic variants which have not been found in persons with milder phenotypes of EDMD. Moreover, among the small number of affected individuals identified to date, several share the same pathogenic variant suggesting a possible phenotype-genotype correlation.
