Congenital Muscular Dystrophies

Definition of CMD

Classically, the term congenital muscular dystrophy includes a group of genetically, clinically, and biochemically distinct entities sharing clinical and pathological features such as early presentation of weakness and hypotonia and dystrophic features on muscle biopsy. The term congenital implies origin of the pathological process during fetal life, which distinguishes these variants from later onset, postnatal conditions such as Duchenne muscular dystrophy (DMD) and limb girdle muscular dystrophies (LGMDs). It is nevertheless appreciated that the onset of the clinical symptoms might be delayed as not all affected children have frank symptoms at birth, but they will start developing weakness, contractures, and delayed motor milestones in the first year of life.

This “expanded” definition can be confusing, however, when assessing children in whom allelic mutations result in a broad spectrum of clinical syndromes, ranging from severe CMDs with clear prenatal onset to mild LGMD variants with onset in childhood, adolescence, or adulthood. This is particularly confusing when the severity of their conditions overlaps between CMD and LGMD and in the presence of central nervous system involvement, when delayed motor milestones could be attributed to muscle weakness, or global developmental delay, or a combination of the two. This is best exemplified by mutations in genes responsible for secondary dystroglycanopathy, such as FKRP, FKTN, POMT1, POMT2 , or ISPD . Many authors have therefore followed a pragmatic approach that includes in the CMD definition children with onset of weakness prenatally or before ambulation is acquired, while LGMD, in contrast, refers to all other cases with later onset weakness, with overt clinical signs after ambulation has been acquired at an appropriate age.

The definition of CMD should also take into account that some disorders classically labeled as CMD do not always have the typical dystrophic pattern but only milder myopathic changes, at least in the muscle available for the routine diagnostic procedures. Indeed, in some conditions such as rigid spine syndrome or rigid spine muscular dystrophy 1 (RSMD1), a phase of “myopathic” changes can precede dystrophic abnormalities, or some muscles (such as the paraspinal muscles) may have more severe involvement than others.

A comprehensive definition of CMD could therefore be that of a heterogeneous group of genetically, clinically, and biochemically distinct entities sharing clinical and pathological features, with onset of clinical signs at birth or typically in the first 12 months. In some variants such as Ullrich CMD and SEPN1-related myopathies, the onset can be delayed even beyond the end of the first year. Muscle biopsy reveals a dystrophic or myopathic pattern without other diagnostic features suggestive of a structural congenital myopathy or a metabolic disorder.

Classification

The first attempt at a rational classification of CMD was proposed in 1994 by the International Consortium on CMD, which recommended recognizing forms of CMD with structural brain changes from a classical or “pure” CMD without structural brain abnormalities. The original cornerstone in the CMD classification came after the identification of the deficiency of the extracellular matrix protein merosin (more specifically the laminin α2 chain of the merosin trimer) in a subset of CMD cases, followed shortly thereafter by the isolation of the responsible gene ( LAMA2 , encoding for the laminin α2 chain of the merosin trimer) on chromosome 6. This allowed the subdivision of the “pure” form into two groups, merosin-deficient and merosin-positive CMD, according to the presence or deficiency of merosin. The term merosin-positive CMD then became commonly used to describe variants other than merosin-deficient CMD; however, this term is no longer used as the majority of patients in this category now have well described conditions, with specific patterns of abnormal protein expression and/or with specific primary genetic defects. The most common subtypes in this category are the Ullrich phenotype with distal laxity, RSMD1, and LMNA-CMD, well-recognized variants in which the genetic basis has been identified.

Another major breakthrough came in the last decade following the discovery that various forms of CMD are characterized by a profound depletion of the glycosylation of α-dystroglycan. The underlying genetic defects in these disorders, which are collectively described as dystroglycanopathies , are mutations in known or putative glycosyltransferase enzymes, which are involved in the process of constructing an unusual glycostructure on α-dystroglycan.

In the last few years, CMDs have been classified according to combined clinical, genetic and pathological approaches :

• 1.

  Forms of CMD due to mutations in genes encoding for structural proteins of the basal lamina or extracellular matrix or receptors for extracellular matrix proteins. This category includes mutations in the collagen 6 genes, laminin α2 (merosin), in integrin α7 and the more recent variant due to integrin α9 gene deficiency. Mutations in DAG1 (dystroglycan 1 gene) have very recently also been described and clearly belong to this subgroup.

• 2.

  Forms secondary to genes encoding for putative or confirmed glycosyltransferases that affect the glycosylation of α-dystroglycan. These include Fukuyama CMD, muscle-eye-brain (MEB) disease, Walker-Warburg syndrome (WWS), MDC1C and MDC1D, and other phenotypes associated with mutations in one of the 15 known genes.

• 3.

  Defects of nuclear envelope proteins (LMNA and nesprin).

• 4.

  Defects of proteins with thus far unknown function localized in the endoplasmic reticulum, which include the form of CMD with rigid spine syndrome secondary to mutations in the SEPN1 gene.

• 5.

  CMD with mitochondrial structural abnormalities (CMDmt).

Table 29.1 provides a list of the known genes responsible for CMD and of the phenotypes associated with mutations in each of them. The locations of a number of proteins described in this chapter are shown in Figure 29.1 . In this chapter, we will specifically concentrate on new findings related to diagnosis, clinical management, and differential diagnosis of the most common forms of CMD.