Clinical Guidance

COL6-RDs can be caused by either autosomal dominant or autosomal recessive pathogenic variants in COL6A1, COL6A2, and COL6A3 . 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 . Pathogenic variants associated with autosomal recessive inheritance are typically nonsense or frameshift variants . 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 .

COL6A1

Source: GeneReviews — "Collagen VI-Related Dystrophies"

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.

Source: GeneReviews — "Collagen VI-Related Dystrophies"

Diagnostic Criteria

Formal diagnostic criteria for collagen VI-related dystrophies (COL6-RDs) have not been established. The COL6-RDs are caused by a pathogenic variant(s) in COL6A1, COL6A2, or COL6A3 and represent a clinical spectrum including Bethlem muscular dystrophy at the milder end, Ullrich congenital muscular dystrophy (UCMD) at the more severe end, and intermediate COL6-RD, between Bethlem muscular dystrophy and UCMD. Note: Although these phenotypes are now recognized to comprise a continuum of overlapping phenotypes, the clinical designations are useful for providing a prognosis of future motor and pulmonary function and thus help to improve anticipatory clinical care.

Suggestive Findings

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

Clinical Findings

Source: GeneReviews — "Collagen VI-Related Dystrophies"

Differential Diagnosis

The differential diagnosis of the phenotypes observed in the collagen VI-related dystrophies (COL6-RDs) is discussed in this section. Of note, a normal-to-mildly elevated CK, suggestive findings on muscle MRI, lack of a cardiac phenotype, and normal-to-high intelligence are hallmarks of the COL6-RDs and help in distinguishing them from other disorders.

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.

Disorders with Joint Contractures to Consider in the Differential Diagnosis of Bethlem Muscular Dystrophy

Source: GeneReviews — "Collagen VI-Related Dystrophies"

Management Guidelines

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 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 3.

Recommended Evaluations Following Initial Diagnosis in Individuals with Bethlem Muscular Dystrophy

System/Concern | Evaluation | Comment

Musculoskeletal

| • Neuromuscular exam to evaluate degree distribution of muscle weakness its effects on mobility

• Exam of joint contractures, esp assessing for asymmetry of Achilles tendon contractures

• PT OT assessment

|

Pulmonary

| Baseline polysomnogram w/continuous CO2 monitoring | During childhood to assess ventilation during deep sleep

Pulmonary function tests in both upright (seated) supine (lying down) positions w/forced vital capacity monitored closely | Starting at age 5 yrs

Cardiology

| Eval w/cardiologist incl echocardiogram EKG | To evaluate for right-sided heart strain in those w/respiratory insufficiency who are not using NIV or have inadequate BiPAP pressures

Other

| Consultation w/clinical geneticist /or genetic counselor |

BiPAP = bilevel positive airway pressure; NIV = noninvasive ventilation; OT = occupational therapy; PT = physical therapy

Source: GeneReviews — "Collagen VI-Related Dystrophies"

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.

Source: GeneReviews — "Collagen VI-Related Dystrophies"

Surveillance Guidelines

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.

Source: GeneReviews — "Collagen VI-Related Dystrophies"