Clinical characteristics.

Collagen VI-related dystrophies (COL6-RDs) represent a continuum of overlapping clinical phenotypes with Bethlem muscular dystrophy at the milder end, Ullrich congenital muscular dystrophy (UCMD) at the more severe end, and a phenotype in between UCMD and Bethlem muscular dystrophy, referred to as intermediate COL6-RD.

• Bethlem muscular dystrophy is characterized by a combination of proximal muscle weakness and joint contractures. Hypotonia and delayed motor milestones occur in early childhood; mild hypotonia and weakness may be present congenitally. By adulthood, there is evidence of proximal weakness and contractures of the elbows, Achilles tendons, and long finger flexors. The progression of weakness is slow, and more than two thirds of affected individuals older than age 50 years remain independently ambulatory indoors, while relying on supportive means for mobility outdoors. Respiratory involvement is not a consistent feature.
• UCMD is characterized by congenital weakness, hypotonia, proximal joint contractures, and striking hyperlaxity of distal joints. Decreased fetal movements are frequently reported. Some affected children acquire the ability to walk independently; however, progression of the disease results in a loss of ambulation by age ten to eleven years. Early and severe respiratory insufficiency occurs in all individuals, resulting in the need for nocturnal noninvasive ventilation (NIV) in the form of bilevel positive airway pressure (BiPAP) by age 11 years.
• Intermediate COL6-RD is characterized by independent ambulation past age 11 years and respiratory insufficiency that is later in onset than in UCMD and results in the need for NIV in the form of BiPAP by the late teens to early 20s. In contrast to individuals with Bethlem muscular dystrophy, those with intermediate COL6-RD typically do not achieve the ability to run, jump, or climb stairs without use of a railing.

Diagnosis/testing.

The diagnosis of a COL6-RD can be suspected in a proband with characteristic clinical features, muscle imaging features, and muscle immunohistochemical features. The diagnosis can be confirmed by identification of a heterozygous or biallelic pathogenic variant(s) in COL6A1, COL6A2, or COL6A3.

Management.

Treatment of manifestations

• Bethlem muscular dystrophy. BiPAP as needed to support nocturnal ventilation and prevent right heart strain; scoliosis treatment per orthopedics; if surgical treatment for scoliosis is needed, coordinate with orthopedics, anesthesia, intensive care, and pulmonary specialists; physical therapy and occupational therapy to provide recommendations for joint stretching, swimming, and aquatherapy; treatment of Achilles tendon contractures per orthopedist.
• UCMD / intermediate COL6-RD. BiPAP to support ventilation and prevent right heart strain. Use of insufflator/exsufflator to promote airway clearance; treatment of scoliosis per orthopedist; if surgical treatment for scoliosis is needed, coordinate with orthopedics, anesthesia, intensive care, and pulmonary specialists; physical therapy and occupational therapy to provide recommendations for joint stretching, swimming, and aquatherapy; treatment of Achilles tendon contractures per orthopedist; feeding and nutrition support as needed for failure to thrive.

Surveillance

• Bethlem muscular dystrophy. Respiratory surveillance including annual pulmonary function tests (PFTs) in the upright and supine positions and polysomnogram for assessing for nocturnal hypoventilation with BiPAP initiation and follow-up polysomnograms as needed; annual clinical and radiographic assessment of scoliosis; annual cardiac evaluation with echocardiogram and EKG; annual physical therapy and occupational therapy assessment of muscle weakness, joint contractures, and need for mobility devices.
• UCMD / intermediate COL6-RD. Respiratory surveillance including PFTs in the upright and supine positions every six months and polysomnogram to assess for nocturnal hypoventilation for timely initiation of NIV in the form of BiPAP with follow-up polysomnograms every one to two years; annual clinical and radiographic assessment of scoliosis; annual cardiac evaluation with echocardiogram and EKG; physical therapy and occupational therapy assessments of muscle weakness, joint contractures, and need for mobility devices every six months; nutritional assessments every six months. Because respiratory insufficiency is a leading cause of failure to thrive, assessments of ventilation (with PFTs and polysomnogram) are essential as surveillance both for respiratory insufficiency and for failure to thrive.

Genetic counseling.

The COL6-RDs can be inherited in an autosomal dominant or an autosomal recessive manner. Bethlem muscular dystrophy is usually inherited in an autosomal dominant manner, although autosomal recessive inheritance has also been reported. UCMD and intermediate COL6-RD are typically caused by a de novo autosomal dominant COL6A1, COL6A2, or COL6A3 pathogenic variant. Less commonly, UCMD and intermediate COL6-RD are inherited in an autosomal recessive manner. Parental somatic mosaicism (and concomitant germline mosaicism) is not uncommon in the autosomal dominant COL6-RDs.

• Autosomal dominant. If a parent of the proband has the pathogenic variant identified in the proband and/or is affected, the risk to the sibs of inheriting the variant is 50%. The severity of COL6-RD manifestations may vary among family members who are heterozygous for the same pathogenic variant.
• Autosomal recessive. If both parents are known to be heterozygous for a pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives requires prior identification of the COL6A1, COL6A2, or COL6A3 pathogenic variants in the family.

Once the COL6A1, COL6A2, or COL6A3 pathogenic variant(s) have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Suggestive Findings

A COL6-RD should be suspected in individuals with the following clinical, imaging, and tissue findings.

Imaging Findings

Muscle MRI is an excellent diagnostic tool to identify suggestive findings of a COL6-RD and guide which individuals should undergo molecular analysis of COL6A1, COL6A2, and COL6A3. Some muscle MRI findings are more common and/or more striking in Bethlem muscular dystrophy, although some overlap exists among COL6-RD subtypes [Mercuri et al 2005, Mercuri et al 2010]. COL6-RD muscle imaging findings may be more difficult to recognize in older individuals with UCMD or intermediate COL6-RD as the muscles become more affected with age. Of note, similar muscle imaging patterns may be seen in other conditions, including calpainopathy [Barp et al 2020].

Upper leg

• In Bethlem muscular dystrophy the vastus lateralis muscle is typically strikingly affected, with a rim of abnormal signal along the periphery of the vastus lateralis and relative sparing of the central part, often referred to as an "outside-in" pattern. The rectus femoris muscle typically has evidence of abnormal signal within a central area of the muscle, surrounded by normal-appearing muscle, often referred to as a "central cloud" pattern [Bönnemann 2011] (see Figure 1). Of note, these same patterns can be appreciated in muscle ultrasound performed in individuals with Bethlem muscular dystrophy [Bönnemann et al 2003].
• In UCMD more diffuse involvement is typically observed with relative sparing of the sartorius, gracilis, and adductor longus. The "outside-in" pattern in the vastus lateralis and the "central cloud" pattern in the rectus femoris muscle may also been seen; however, as the disease progresses, these findings may be less obvious (see Figure 2).
• In intermediate COL6-RD the same muscle MRI findings described in Bethlem muscular dystrophy and UCMD can be seen.

Figure 1.

Muscle MRI findings in Bethlem muscular dystrophy Axial T₁-weighted images of the upper leg muscles of four individuals with Bethlem muscular dystrophy (a-d). Note the relative sparing of the central part of the vastus lateralis (white arrows) with a (more...)

Figure 2.

Muscle MRI findings in Ullrich congenital muscular dystrophy (UCMD) Axial T₁-weighted images of the upper leg muscles of four individuals with UCMD. There is diffuse involvement of the thigh with relative sparing of sartorius, gracilis, and rectus femoris (more...)

Lower leg. In Bethlem muscular dystrophy, intermediate COL6-RD, and UCMD a rim of abnormal signal at the periphery of soleus and gastrocnemii muscles can be seen.

Tissue Studies

Bethlem muscular dystrophy / intermediate COL6-RD

• Muscle biopsy early in the disease may show nonspecific myopathic changes but subsequently will show more typical dystrophic changes (degeneration, regeneration, and replacement of muscle with fat and fibrous connective tissue).
• Collagen VI immunolabeling of muscle tissue may show decreased collagen VI expression or mislocalized collagen VI (not colocalizing when double stained with other basement membrane markers such as perlecan, laminin or collagen IV) (Figure 3.)
• Immunocytochemical analysis of collagen VI in dermal fibroblast cultures can demonstrate decreased and/or abnormal-appearing collagen VI extracellular matrix deposition with increased intracellular retention seen with cell permeabilization for dominant-acting pathogenic variants [Hicks et al 2008] (Figure 4).

Figure 3.

Collagen VI immunohistochemical labeling in muscle in COL6-RD a. Collagen VI (red) and laminin γ-1 (green) colocalize in the basement membrane (resulting in a yellow color) in muscle from an individual without neuromuscular disease.

Figure 4.

Collagen VI immunocytochemical studies in dermal fibroblasts in COL6-RD A. The normal control with collagen VI labeling with antibody demonstrates an abundance of well-organized collagen VI microfibrils in a linear, unidirectional trend.

UCMD / intermediate COL6-RD

• Muscle biopsy commonly shows dystrophic features (degeneration, regeneration, and replacement of muscle with fat and fibrous connective tissue). Note: Muscle biopsies in children younger than age 30 months can have minimal findings (e.g., fiber atrophy, fiber type disproportion) with no evidence of dystrophic features [Schessl et al 2008].
• Collagen VI immunolabeling of muscle ranges from absent collagen VI to mislocalized collagen VI (not colocalizing when double stained with other basement membrane markers such as perlecan, laminin, or collagen IV) [Pan et al 2003, Ishikawa et al 2004].
• Immunocytochemical analysis of collagen VI in dermal fibroblast cultures may demonstrate loss of collagen VI matrix deposition or deposition of a dysmorphic matrix with strong intracellular immunoreactivity seen with permeabilization in those with dominant-acting pathogenic variants. It thus can be a useful adjunct to the diagnosis [Jimenez-Mallebrera et al 2006].

Establishing the Diagnosis

The diagnosis of a COL6-RD is established in a proband with the characteristic clinical, muscle imaging, and muscle immunohistochemical features described in Suggestive Findings and a heterozygous or biallelic pathogenic (or likely pathogenic) variant(s) in COL6A1, COL6A2, or COL6A3 identified by molecular genetic testing (see Table 1).

(1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) The identification of variant(s) of uncertain significance cannot be used to confirm or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (concurrent gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas comprehensive genomic testing does not. Because the phenotypes of COL6-RDs are broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype less distinguishable from many other inherited disorders with myopathy / muscular dystrophy are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

The phenotypes associated with collagen VI-related dystrophies (COL6-RDs), once thought to be distinct entities, were clinically defined long before their molecular basis was discovered. The COL6-RDs are now recognized to comprise a continuum of overlapping phenotypes with Bethlem muscular dystrophy at the mild end, Ullrich congenital muscular dystrophy (UCMD) at the severe end, and phenotypes in between that are now collectively categorized within a subgroup called intermediate COL6-RD. These clinical phenotypic designations play an important role in providing a prognosis for future motor and pulmonary function and thus help in improving anticipatory clinical care.

Genotype-Phenotype Correlations

COL6-RDs can be caused by either autosomal dominant or autosomal recessive pathogenic variants in COL6A1, COL6A2, and COL6A3 (see Molecular Genetics).

Pathogenic variants associated with autosomal dominant inheritance in COL6A1, COL6A2, and COL6A3 typically occur near the N terminal of the triple helical (TH) domain, which contains a critical region of 10 to 15 Gly-X-Y triplets; in-frame exon-skipping variants and glycine substitutions in this region tend to result in more severe phenotypes [Pace et al 2008, Butterfield et al 2013].

Pathogenic variants associated with autosomal recessive inheritance are typically nonsense or frameshift variants [Camacho Vanegas et al 2001]. However, biallelic missense variants may be pathogenic when located near the C-terminal end of the TH domain, where they will be excluded from assembly [Baker et al 2005, Petrini et al 2005, Zhang et al 2010].

COL6A1

• In-frame skipping of exon 14, encoding the dimer-stabilizing cysteine residue of the α1(VI) chain, tends to result in a milder phenotype (Bethlem muscular dystrophy to intermediate COL6-RD) [Foley et al 2013, Fan et al 2018].
• A deep intronic pathogenic variant in intron 11 (c.930+189C>T), resulting in a splice-gain event causing insertion of a pseudoexon and disruption of the N-terminal region of the TH domain, is associated with a consistent phenotype including delayed onset (with a paucity of neonatal symptoms and normal motor development during the first 1-2 years of life) followed by a rapid acceleration to severe UCMD with loss of ambulation and full-time dependence on wheelchair-assisted mobility by an average age of nine years, and initiation of nocturnal NIV by an average age of 13 years [Cummings et al 2017, Bolduc et al 2019].

COL6A2

• Nonsense variant p.Arg468Ter is located within the TH domain. When homozygous, this variant results in a complete loss of function of collagen VI and manifests as a UCMD phenotype [Valencia et al 2013].
• Nonsense variant Gln819Ter, which is 3' downstream of the C1 domain, results in a truncated α2(VI) chain lacking the C2 domain but not a complete loss of function of collagen VI. When homozygous, this variant results in a milder phenotype of Bethlem muscular dystrophy in which the severity of the joint contractures outweighs the muscle weakness. This phenotype has been referred to as "myosclerosis," and the muscles are reported to have a "woody" feel [Bradley et al 1973, Merlini et al 2008].

COL6A3. In-frame skipping of exon 16 results in the deletion of amino acids at the N-terminal region of the TH domain of the α3(VI) chain but conserves the cysteine residues needed for higher-order assembly and thus has a strong dominant negative effect, resulting in a more severe phenotype (UCMD) [Briñas et al 2010, Foley et al 2013, Bolduc et al 2014, Fan et al 2018].

Penetrance

Parents of individuals with recessively inherited COL6-RDs are usually heterozygous for a COL6A1, COL6A2, or COL6A3 pathogenic variant, but they do not manifest clinical symptoms of COL6-RD, even when predicted to be haploinsufficient for the respective gene.

Individuals with dominantly inherited COL6-RDs are heterozygous for a COL6A1, COL6A2, or COL6A3 pathogenic variant and are typically symptomatic.

Nomenclature

Bethlem muscular dystrophy. "Bethlem myopathy" was first used in 1976 to describe a "benign myopathy with autosomal dominant inheritance" [Bethlem & Wijngaarden 1976]. Since that time, "Bethlem myopathy" has been used to refer to the milder form of COL6-RD; however, over time it has been recognized that this is indeed a muscular dystrophy (and not a myopathy), as the histology of the muscle progresses to reveal more typical dystrophic changes (degeneration and regeneration and replacement of muscle with fat and fibrous connective tissue) and thus is consistent with that of a muscular dystrophy. Other terms in use:

• Mild form of COL6-related myopathy
• Mild form of COL6-related dystrophy
• Mild collagen VI myopathy

Ullrich congenital muscular dystrophy was first described in 1930 as a "congenital atonic sclerotic muscular dystrophy" [Ullrich 1930a, Ullrich 1930b]. Other terms in use:

• Severe form of COL6-related myopathy
• Severe form of COL6-related dystrophy
• Early-severe collagen VI myopathy
• Moderate-progressive collagen VI myopathy

Intermediate COL6-RD was first described in 2011 as "intermediate" phenotypes of COL6-RDs [Bönnemann 2011]. Historically, individuals with "intermediate" phenotypes of COL6-RD were classified as having "mild UCMD" or "severe Bethlem myopathy." A classification system for distinguishing an "intermediate" COL6-RD phenotype has been proposed based on both motor function and pulmonary function criteria [Foley et al 2013]. Other terms in use:

• Mild UCMD
• Severe Bethlem myopathy
• Moderate-progressive collagen VI myopathy
• Mild early-onset collagen VI myopathy

Prevalence

The exact prevalence of the COL6-RDs remains unknown. In northern England the prevalence of Bethlem muscular dystrophy is estimated at 0.77:100,000, and the prevalence of UCMD is estimated at 0.13:100,000 [Norwood et al 2009]. The COL6-RDs are the second most common form of congenital muscular dystrophy (CMD) in Japan (after Fukuyama CMD) [Okada et al 2007]. In an Australian study based on muscle immunohistochemistry, the COL6-RDs were the second most common form of CMD (after α-dystroglycanopathies) [Peat et al 2008].

Bethlem Muscular Dystrophy

When joint contractures are subtle or missed, the major differential diagnoses are the limb-girdle muscular dystrophies (LGMDs) (see Limb-Girdle Muscular Dystrophy Overview).

When joint contractures are a prominent feature, the major differential diagnoses are those summarized in Table 2a.

Ullrich Congenital Muscular Dystrophy and Intermediate COL6-RD

Note: Unlike Ullrich congenital muscular dystrophy (UCMD) and intermediate COL6-RD, the disorders in Table 2b are typically not associated with:

• The presence at birth of torticollis, kyphoscoliosis, and abnormal positioning of the hands & feet;
• The combination of proximal joint contractures with distal joint hyperlaxity;
• Muscle imaging findings in the rectus femoris muscle (of a "central cloud" pattern) and vastus lateralis muscle (of an "outside-in" pattern).

Evaluations Following Initial Diagnosis

Bethlem muscular dystrophy. To establish the extent of disease and needs in an individual diagnosed with Bethlem muscular dystrophy, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Ullrich congenital muscular dystrophy (UCMD) / intermediate collagen VI-related dystrophy (COL6-RD). To establish the extent of disease and needs in an individual diagnosed with UCMD, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Bethlem muscular dystrophy

• Disproportionate weakness of the diaphragm can cause nocturnal hypoventilation, even in individuals who remain independently ambulant. For forced vital capacity (FVC) measurements of 60% predicted or lower, noninvasive ventilation (NIV) in the form of bilevel positive airway pressure (BiPAP) should be initiated during a polysomnogram – with pressures adjusted to ensure adequate ventilation – and then consistently used while sleeping. If nocturnal BiPAP is started, BiPAP pressures should be carefully monitored and adjusted during repeat polysomnogram monitoring in order to provide adequate pressures as the body grows / pressure requirements increase related to progressive respiratory insufficiency.
• If BiPAP is not initiated when needed or inadequate BiPAP pressures are used, right-sided heart strain can be seen on echocardiogram monitoring. Optimization of BiPAP pressures can help to prevent the development of cor pulmonale.
• Surgical repair of scoliosis is rarely needed in individuals with Bethlem muscular dystrophy. If scoliosis surgery is considered, carefully planning for supporting respiratory needs preoperatively, intraoperatively, and postoperatively should be coordinated with orthopedic surgery, anesthesia, intensive care, and pulmonary teams.
• Physical therapy and occupational therapy assessments can provide recommendations for joint stretching and swimming/aquatherapy exercises, which promote stretching of the joints and conditioning of the muscles. Strategies to avoid excessive joint strain should be discussed with a physical therapist and occupational therapist, given that joint pain has been reported by some individuals with Bethlem muscular dystrophy.
• If Achilles tendon contractures are severe or asymmetric, thus adversely affecting gait, Achilles tendon release surgery can provide increased range of motion, especially if the Achilles tendon release is followed by casting. A noninvasive approach that can help promote improved range of motion of the Achilles tendons is serial casting.
• Surgical intervention on any joint contractures (beyond Achilles tendon release surgery) is not recommended, given the high postoperative risk of fixed contractures with complete loss of range of motion in individuals with Bethlem muscular dystrophy who have undergone joint surgery. New surgical approaches with the potential of avoiding the postoperative risk of fixed contractures should be carefully considered in consultation with neuromuscular specialists, physical therapists, and occupational therapists.

UCMD / intermediate COL6-RD

• NIV in the form of BiPAP is needed in all individuals with UCMD by approximately age 11 years and all individuals with intermediate COL6-RD by the teenage years.
• Use of an insufflator/exsufflator such as with a cough assist machine is essential for promoting coughing and expectoration of phlegm and airway clearance during respiratory infections and should be used as frequently as possible in order to help prevent the progression of upper respiratory infections to lower respiratory tract infections (pneumonias).
• Right-sided heart strain can be evident on echocardiogram in individuals with respiratory insufficiency who are not using NIV in the form of BiPAP when needed or who are using BiPAP at pressures that are inadequate for supporting ventilation. If left unadjusted, cor pulmonale can develop. Right-sided heart function typically normalizes once BiPAP pressures are adequate for supporting nocturnal ventilation.
• Bracing for scoliosis should be carefully approached, given how important movement of the chest wall is for respiration/ventilation in individuals with COL6-RDs. If spinal bracing is considered, a brace that does not cover the lower thorax and is less restrictive of chest wall movement should be considered (e.g., Garchois plexidur brace). Surgical repair of scoliosis using various forms of fixed instrumentation and dynamic instrumentation (in young and still growing children) is commonly indicated for individuals with UCMD and intermediate COL6-RD, the timing of which is based on the degree of spine curvature and the rate of progression. In preparation for scoliosis surgery, careful coordination between orthopedic, anesthesia, intensive care, and pulmonary teams is essential for planning the preoperative, intraoperative, and postoperative respiratory needs. In particular, NIV in the form of BiPAP should be initiated prior to scoliosis surgery. Most individuals with UCMD or intermediate COL6-RD will need to be extubated directly to BiPAP following scoliosis surgery, and thus BiPAP initiation prior to surgery is essential both for optimizing lung function preoperatively and for assuring familiarity and comfort with BiPAP postoperatively.
• Physical therapists and occupational therapists can provide recommendations for stretching of the joints as well as for swimming and aquatherapy exercises, which promote stretching of the joints and conditioning of the muscles.
• If Achilles tendon contractures are severe or are asymmetric, thus adversely affecting gait, Achilles tendon release surgery by an orthopedic surgeon can provide increased range of motion, especially if Achilles tendon release is followed by casting. Surgical intervention on any joint contractures (beyond Achilles tendon release surgery) is not recommended, given the high postoperative risk of fixed contractures with complete loss of range of motion / no movement at the joint in individuals with UCMD or intermediate COL6-RD who have undergone surgeries that disrupt the joint capsule. New surgical approaches with the potential of avoiding the postoperative risk of fixed contractures should be carefully considered in consultation with neuromuscular specialists, physical therapists, and occupational therapists.
• Feeding via a gastrostomy tube may be indicated for maintaining adequate nutrition and weight. The recurrence of failure to thrive at age ten to 12 years should prompt an evaluation for nocturnal hypoventilation via polysomnogram with continuous CO₂ monitoring.

Surveillance

Bethlem muscular dystrophy

• Respiratory function surveillance is of utmost importance, since unrecognized respiratory insufficiency is a leading cause of morbidity and mortality. Pulmonary function tests (PFTs) should be performed in both the upright (seated) and supine (lying down) positions at least annually to monitor the FVC. For FVC measurements of 60% predicted or lower, NIV in the form of BiPAP should be planned for and initiated during a polysomnogram – with pressures adjusted while CO₂ is monitored – in order to ensure that BiPAP pressures provide adequate ventilation.
• Annual clinical and radiographic assessment of scoliosis
• Annual cardiac evaluation with echocardiogram and EKG to evaluate for evidence of right-sided heart strain
• Annual neuromuscular assessment by physical therapy and occupational therapy including an evaluation of the distribution of muscle weakness and joint contractures to inform recommendations for stretching regimens and mobility devices. Potential asymmetries of joint contractures are important to assess, given their effect on gait, sitting posture, and overall function.

UCMD / intermediate COL6-RD

• Respiratory function surveillance is of utmost importance in UCMD and intermediate COL6-RD, since unrecognized or underrecognized respiratory insufficiency is the leading cause of morbidity and mortality. PFTs should be performed in both the upright (seated) and supine (lying down) positions every six months to monitor the FVC. For FVC measurements of 60% predicted or lower, NIV in the form of BiPAP should be planned for and initiated during a polysomnogram – with pressures adjusted while CO₂ is monitored – in order to ensure BiPAP pressures provide adequate ventilation.
• Annual clinical and radiographic spine assessment for scoliosis and kyphoscoliosis
• Annual cardiac evaluation with echocardiogram and EKG to screen for evidence of right-sided heart strain
• Annual neuromuscular evaluation by physical therapy and occupational therapy including an evaluation of the distribution of muscle weakness and joint contractures to inform recommendations for stretching regimens and mobility devices. Potential asymmetries of joint contractures are important to assess, given their effect on gait, sitting posture, and overall function.
• Annual nutrition assessment

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

For a pregnant woman with COL6-RD, careful pulmonary surveillance during pregnancy for potential increased needs for ventilatory support is recommended, particularly given the disproportionate weakness of the diaphragm in the COL6-RDs. A prenatal physiotherapy assessment for hip dislocation and/or hip contractures may be recommended, given that the presence and degree of decreased range of motion at the hips could affect considerations for delivery. An assessment of the overall level of muscle weakness is also recommended, which may help in predicting the degree of weakness of abdominal muscles and thus the potential for a difficult birthing process, which could also affect considerations for delivery.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

The collagen VI-related dystrophies (a continuum of overlapping phenotypes encompassing Bethlem muscular dystrophy, Ullrich congenital muscular dystrophy [UCMD], and intermediate collagen VI-related dystrophy [COL6-RD]) are associated with both autosomal dominant and autosomal recessive inheritance.

Bethlem muscular dystrophy is usually inherited in an autosomal dominant manner, although autosomal recessive inheritance has also been reported [Foley et al 2009, Gualandi et al 2009].

UCMD and intermediate COL6-RD are typically caused by a de novo autosomal dominant pathogenic variant of COL6A1, COL6A2, or COL6A3 [Allamand et al 2011, Bönnemann 2011, Butterfield et al 2013, Bolduc et al 2019, Aguti et al 2020]. Less commonly, UCMD and intermediate COL6-RD are inherited in an autosomal recessive manner.

Autosomal Dominant Inheritance – Risk to Family Members

Parents of a proband

• Some individuals diagnosed with autosomal dominant COL6-RD have an affected parent.
• Approximately 50%-75% of individuals diagnosed with COL6-RD have the disorder as the result of a de novo COL6A1, COL6A2, or COL6A3 pathogenic variant [Allamand et al 2010, Allamand et al 2011].
• Molecular genetic testing is recommended for the apparently asymptomatic parents of a proband with a presumed de novo pathogenic variant and for the parents of a proband with a positive family history (if the genetic status of the parents of a proband has not already been established).
• If the pathogenic variant found in the proband is not identified in either parent, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant. Note: A pathogenic variant is reported as "de novo" if: (1) the pathogenic variant found in the proband is not detected in parental DNA; and (2) parental identity testing has confirmed biological maternity and paternity. If parental identity testing is not performed, the variant is reported as "assumed de novo" [Richards et al 2015].
  • The proband inherited a pathogenic variant from a parent with germline – or somatic and germline – mosaicism [Armaroli et al 2015]. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in germ cells only.
• It should be noted that parental somatic mosaicism (and concomitant germline mosaicism) is not uncommon in the COL6-RDs [Armaroli et al 2015, Donkervoort et al 2015, D'Amico et al 2017, Fan et al 2018], and it is important to consider this possibility given the implications for recurrence risk assessment. Clinical findings in a mosaic parent may range from obvious manifestations to very subtle/mild findings apparent only on detailed neuromuscular clinical examination and/or muscle imaging.
• The family history of some individuals diagnosed with autosomal dominant COL6-RD may appear to be negative due to failure to recognize the disorder in a mildly symptomatic family member, early death of the parent before the onset of symptoms, or late onset in an affected parent. Therefore, an apparently negative family history cannot be confirmed unless detailed neuromuscular clinical examination of the parents has been performed and molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband.

Sibs of a proband. The risk to the sibs of a proband depends on the genetic status of the proband's parents:

• If a parent of the proband has the pathogenic variant identified in the proband and/or is affected, the risk to the sibs of inheriting the variant is 50%.
• The severity of COL6-RD manifestations may vary among family members who are heterozygous for the same pathogenic variant. The most significant intrafamilial clinical variability is observed in families segregating COL6A1, COL6A2, or COL6A3 pathogenic variants associated with intermediate COL6-RD.
• If the proband has a known pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is presumed to be greater than that of the general population because of the significant possibility of parental mosaicism. Parental somatic mosaicism (and concomitant germline mosaicism) with full penetrance of the pathogenic variant in heterozygous offspring is not uncommon in the COL6-RDs [Donkervoort et al 2015].
• If the parents have not been tested for the pathogenic variant but are clinically unaffected, the recurrence risk to the sibs of a proband is presumed to be greater than that of the general population because of possibility of reduced penetrance in a heterozygous parent or parental somatic and germline mosaicism.

Offspring of a proband. Each child of an individual with an autosomal dominant COL6-RD has a 50% chance of inheriting the COL6A1, COL6A2, or COL6A3 pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the pathogenic variant identified in the proband and/or is affected, the parent's family members may be at risk.

Autosomal Recessive Inheritance – Risk to Family Members

Parents of a proband

• The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one COL6A1, COL6A2, or COL6A3 pathogenic variant based on family history).
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a COL6A1, COL6A2, or COL6A3 pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent, the following possibilities should be considered:
  • One of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017].
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Individuals who are heterozygotes (carriers) for a pathogenic variant associated with autosomal recessive COL6-RD do not appear to develop manifestations of the disorder.

Sibs of a proband

• If both parents are known to be heterozygous for a COL6A1, COL6A2, or COL6A3 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Individuals who are heterozygotes (carriers) for a pathogenic variant associated with autosomal recessive COL6-RD do not appear to develop manifestations of the disorder.

Offspring of a proband. Unless an affected individual's reproductive partner also has an autosomal recessive COL6-RD or is a carrier, offspring will be obligate heterozygotes for a pathogenic variant in COL6A1, COL6A2, or COL6A3.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a COL6A1, COL6A2, or COL6A3 pathogenic variant.

Carrier detection. Carrier testing for at-risk relatives requires prior identification of the COL6A1, COL6A2, or COL6A3 pathogenic variants in the family.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022]. Note: DNA can also be extracted from a dermal fibroblast culture, which may be available when a skin biopsy has been performed for COL6-RD diagnostic purposes (immunocytochemistry to assess collagen VI expression).

Prenatal Testing and Preimplantation Genetic Testing

Once the COL6A1, COL6A2, or COL6A3 pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

Collagen VI is expressed in the extracellular matrices of several tissues and tissue components including muscle, blood vessels, nerves, skin, tendons, cartilage, intervertebral discs, lenses, and internal organs [Hessle & Engvall 1984, Keene et al 1988, Kuo et al 1997]. The extracellular matrix of skeletal muscle has been termed the "myomatrix" [Bönnemann 2011], with the collagen VI-related dystrophies (COL6-RDs) thus being considered primary disorders of the myomatrix.

The assembly of collagen VI is a complex multistep process. Association of the three genetically distinct subunits α1(VI), α2(VI), and α3(VI) to form a triple helical monomer is followed by staggered assembly into disulfide-bonded antiparallel dimers [Furthmayr et al 1983, Chu et al 1988, Colombatti et al 1995], which then align to form tetramers, also stabilized by disulfide bonds [Furthmayr et al 1983, Chu et al 1988, Bonaldo et al 1990, Chu et al 1990]. The tetramers are then secreted extracellularly and align in an end-to-end fashion, forming beaded microfilaments as the final product of collagen VI assembly [Furthmayr et al 1983, Engvall et al 1986, Lamandé et al 1998, Baldock et al 2003].

Mechanism of disease causation

• Pathogenic variants associated with autosomal dominant inheritance. Heterozygous variants causing in-frame exon skipping (e.g., splice site variants, in-frame deletions) in any of the three COL6 genes are a common cause of all severities of COL6-RD. Dominantly acting exon skips occur at exons located in the N-terminal region of the triple helical (TH) domains of the collagen VI α chains. A strong dominant-negative effect can result from an in-frame exon skip variant if it does not disrupt the essential cysteine residues for dimer and tetramer formation. As a result, mutated and normal monomers assemble into dimers and tetramers, so that only 1/4 of the dimers and 1/16 of the tetramers are composed entirely of normal chains. Since 15/16 tetramers contain mutated chains, and mutated tetramers cannot properly align with normal tetramers, the final assembly of collagen VI microfibrils cannot proceed. A milder dominant-negative effect can result from dominant variants that disrupt the essential cysteine residues, preventing the formation of monomers and dimers with abnormal collagen VI chains. As a result, all tetramers secreted are composed of normal collagen VI chains, albeit at less than half the quantity of controls [Pan et al 2003, Baker et al 2005, Lampe et al 2005, Pepe et al 2006, Lampe et al 2008].
  Other dominant-negative variants that commonly occur in the COL6-RDs are heterozygous single-amino-acid substitutions disrupting the Gly-Xaa-Yaa motifs of the highly conserved N-terminal triple helical domains of any of the three COL6 genes, so-called glycine variants [Lampe et al 2005, Lucioli et al 2005]. Similar to the exon skip pathogenic variants, such pathogenic glycine variants will act as dominant when located in the "assembly competent" N-terminal end of the triple helical domain.
  An additional recurrent dominant-negative pathogenic variant consists of a deep-intronic change in intron 11 of COL6A1 (c.930+189C>T), which creates a donor splice site that prompts the insertion of a 72-nucleotide in-frame pseudoexon into approximately half of the mRNA transcripts originating from the pathogenic variant allele [Cummings et al 2017, Bolduc et al 2019]. This mRNA translates into an α1(VI) chain in which the N-terminus of the triple helical domain is interrupted by a 24-amino acid sequence insertion, but in which the cysteine residue critical for dimerization is not affected, thus allowing incorporation of the variant chain into collagen VI assembly and secretion, resulting in a strong dominant-negative effect and impaired microfibrillar assembly [Bolduc et al 2019]. Due to its deep intronic location, this pathogenic variant may be missed on exon-only-based platforms.
• Autosomal recessively acting loss-of-function pathogenic variants. Most pathogenic variants associated with autosomal recessive disease in the COL6-RDs to date are nonsense or frameshift variants [Camacho Vanegas et al 2001]. Some pathogenic variants have been shown to result in the absence of collagen VI because of nonsense-mediated mRNA decay [Zhang et al 2002]. Biallelic nonsense variants in the COL6 genes usually result in a severe phenotype [Camacho Vanegas et al 2001, Higuchi et al 2001, Ishikawa et al 2002, Peat et al 2007, Briñas et al 2010].
  Intragenic deletions and splice site variants can also result in a transcript which is out of frame [Ishikawa et al 2002, Lucarini et al 2005] or a chain which is assembly incompetent (pathogenic variants at the C terminal region of the triple helical domain) [Lampe et al 2008]. The observation that heterozygous deletions of COL6A1 and/or COL6A2 do not result in COL6-RD indicates that haploinsufficiency of the COL6 genes is not a mechanism of disease causation [Foley et al 2011].
  Of note, missense variants in compound heterozygosity with other missense variants may be pathogenic – the pathogenicity of which depends on the location and effects of the particular variants. Homozygous missense variants are a less common cause of COL6-RD but can result in a phenotype of UCMD if affecting crucial functions or interactions of the collagen VI protein [Baker et al 2005, Petrini et al 2005, Zhang et al 2010].

Gene-specific laboratory considerations

• Given the highly polymorphic nature of COL6A1, COL6A2, and COL6A3, clarification of variants of uncertain significance requires careful study. This is particularly true for missense variants outside the highly conserved N-terminal triple helical domains. For variants of uncertain significance, segregation testing, muscle imaging (MRI and/or ultrasound), and studies of collagen VI immunoreactivity in muscle and dermal fibroblasts (immunohistochemical studies and immunocytochemistry studies) are essential [Bönnemann 2011]. To identify variants affecting splicing, studies performed on RNA (extracted from skin fibroblasts or muscle) can be helpful [Camacho Vanegas et al 2001, Ishikawa et al 2002, Lucarini et al 2005].
• A recurrent deep-intronic COL6A1 variant in intron 11 (c.930+189C>T) can be missed with exome sequencing or targeted sequencing (exon-only based platforms).

Author History

Véronique Bolduc, PhD (2021-present)
Carsten G Bönnemann, MD, habil (2021-present)
Katharine Mary Bushby, MD, MBCHB FRCP; University of Newcastle upon Tyne (2004-2021)
Sandra Donkervoort, MS, CGC (2021-present)
Kevin M Flanigan, MD; Nationwide Children's Hospital (2004-2021)
A Reghan Foley, MD, MD(Res) (2021-present)
Debbie Hicks, PhD; University of Newcastle upon Tyne (2012-2021)
Anne Katrin Lampe, MD; Western General Hospital (2004-2021)
Payam Mohassel, MD (2021-present)

Revision History

• 11 March 2021 (sw) Comprehensive update posted live
• 9 August 2012 (me) Comprehensive update posted live
• 6 April 2007 (me) Comprehensive update posted to live Web site
• 25 June 2004 (me) Review posted to live Web site
• 18 February 2004 (kf) Original submission

Note: Pursuant to 17 USC Section 105 of the United States Copyright Act, the GeneReview "Collagen VI-Related Dystrophies" is in the public domain in the United States of America.

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