The congenital myopathies and congenital muscular dystrophies are defined based upon clinically apparent muscle weakness at birth or in early infancy. While some patients may not be recognized to be symptomatic until a later age, the onset of disease is the one that begins prenatally or in infancy. There can be varying degrees of severity from very severe prenatal onset to subtle motor difficulties.

The congenital myopathies are a group of disorders often with characteristic histopathological findings on muscle biopsy and typically marked by a disease course that is relatively stable over longer periods of follow-up. While historically these disorders have been defined by the characteristic histological findings, it is important to note that the absence of such findings does not always preclude some of these diagnoses. There can be a range of histopathological features seen in these disorders, and the variability in histological findings within particular disorders may partly be explained by the age of biopsy and the site of biopsy. Symptoms can often begin prenatally, with findings of polyhydramnios, decreased fetal movement, and breech position. At birth, findings of arthrogryposis of the upper and lower extremity may be seen, as well as hip dislocations and osteopenia related to poor fetal movement, sometimes leading to fractures under delivery. Within this group of disorders, there is great clinical variability, with many of the entities ranging from a severe and even lethal neonatal form with fetal akinesia to a later onset or milder form. At the most severe end of the spectrum (of those who survive in utero to delivery) are infants who have trace to no movements of the extremities, severe inability to feed, and respiratory failure. Patients may have ophthalmoplegia, in particular in the centronuclear myopathies (Pierson et al. 2005). Some patients can have pronounced facial weakness as well. CK levels are often normal or can be mildly elevated. See Table 3 for a list of genetic causes and “classic” histological features seen in the congenital myopathies (Pierson et al. 2005; Jungbluth et al. 2003; Goebel 2005). Overall, patients with congenital myopathy tend to be stable over long periods of time and even make motor gains. The predominant factors that correlate with mortality or morbidity in this group of disorders are the existence of severe respiratory failure and risk of aspiration (to food or secretions).

The congenital muscular dystrophies are a heterogeneous group of disorders where the muscle reveals dystrophic or myopathic features without clear structural changes consistent with congenital myopathies. The main congenital muscular dystrophies include the following disorders: disorders of alpha-dystroglycan glycosylation (which can have significant brain involvement), collagen VI disorders, and laminin α2 CMD. See Table 4 for a list and summary of these disorders, key clinical features, and genetic causes. Collagen VI-related congenital muscular dystrophy has more striking upper extremity involvement (involving contractures and joint laxity) that will be further discussed in section “Diagnostic Features in Inherited Muscle Disease and Concepts of Upper Extremity Involvement” of this chapter.

In general this group of disorders tends to be more progressive in nature. The onset is typically either prenatally, at birth, or within the first year of life. Clinical features include diffuse weakness, contractures (either in infancy or some that develop later in childhood), and potential central nervous system involvement in some (e.g., developmental delays, seizures, spasticity). The maximum motor skill achieved can vary. In the more severe of the congenital disorders of muscle, ambulation may not be achieved, while in a more moderate group ambulation may be achieved and later lost. In those representing the severe end of the spectrum, patients may also have significant upper extremity involvement – and yet the patients are significantly dependent on upper extremity function for tasks such as feeding, use of wheelchair, writing, typing, and other activities of daily living. Children may make motor gains early in life, but will eventually show some decline in function. The rate of decline and age of decline vary by disease and also from patient to patient within the same disease. The degree of deterioration and degree of impairment also vary greatly in this group of disorders. Pathophysiologically, subgroups of disorders in this category are caused by abnormalities of the extracellular matrix of the muscle cell membrane, intracellular molecules, and inner nuclear matrix proteins. See Table 4 which will review the genetic causes of congenital muscular dystrophy (Sparks et al. 2012; Godfrey et al. 2007). Several of the alpha-dystroglycanopathies represent the more severe end of the spectrum with neonatal onset of severe weakness, cognitive impairment, visual impairment, and CNS MRI changes. CMDs with more striking and unique upper extremity involvement include the collagen VI disorders where there is distal hyperlaxity combined with proximal upper extremity contractures that are progressive in nature. This will be discussed further in a later section of this chapter.

In addition to the abovementioned disorders, myotonic dystrophy is a disorder that can have congenital onset or later in life onset (as there is anticipation and increased severity from one generation to the next). Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are autosomal dominant multisystem disorders. DM1 is caused by expansion of a CTG trinucleotide repeat in the noncoding region of the DMPK gene, with increased repeats correlating to disease severity. DM1 can affect skeletal muscle, smooth muscle, cardiac muscle, as well as the eye, endocrine system, and central nervous system (Bird 2013). Clinical findings and severity in DM1 are variable from mild to severe, with three predominant phenotypes: mild, classic, and severe congenital. In classic DM1, weakness and muscle wasting of facial muscles (especially temporal wasting), atrophy of the forearm flexor muscles, weakness of long finger flexors, and weakness of ankle dorsiflexors can be seen. Patients can have prominent myotonia, but this is often not present on examination of neonates with suspected congenital myotonic dystrophy. In its most severe form, in those patients with congenital myotonic dystrophy, severe neonatal hypotonia and respiratory failure with feeding difficulties can be seen. In patients with congenital DM1, weakness is more diffuse, but most notably, there is very striking facial weakness as compared to the typical or later onset DM1. Respiratory failure and prolonged ventilator dependence in patients with congenital DM1 correlates with higher rates of mortality. Patients with myotonic dystrophy, especially those with the congenital form, often have intellectual disability, personality disorder, cataracts, and cardiac conduction deficits. DM2 tends to be milder and have a later onset in life. DM2 is characterized by myotonia and muscle dysfunction, with onset in childhood or adult years, and is less commonly associated with cardiac conduction defects, cataracts, or insulin insensitivity (as is seen in DM1). The onset of myotonia tends to be later in life, often not until the third decade. Muscle weakness and pain may be episodic or fluctuating, with predominant involvement of neck flexors, finger flexors, elbow extensors, and hip flexors and extensors (Dalton et al. 2013). Expansion of the CCTG repeat on the CNBP (ZNF9) gene causes DM2.

In contrast to those disorders with onset perinatally or in infancy, there are certain muscle diseases that more distinctly have onset during the childhood, adolescent, or adult years. This includes dystrophinopathies, myotonic dystrophy (although this can also have a severe congenital form as discussed above), Emery-Dreifuss muscular dystrophy, FSHD, Pompe disease, and limb-girdle muscular dystrophies (LGMDs). While there are some exceptions, these are a group of disorders predominantly affecting the shoulder and pelvic girdle muscles with age of onset in childhood, adolescence, or even adulthood. This group of disorders is marked by gradual progression of weakness over time. Although proximal muscles are affected first, over time, distal muscles can become involved. CK levels generally tend to be elevated. Muscle biopsy reveals dystrophic changes, and immunohistochemical stains can be helpful in narrowing down the diagnosis.