Collagen Type Vi-Related Disorders

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2021-01-18

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Summary

Clinical characteristics.

Collagen type VI-related disorders represent a continuum of overlapping phenotypes with Bethlem myopathy at the mild end, Ullrich congenital muscular dystrophy (CMD) at the severe end, and two rare, less well-defined disorders – autosomal dominant limb-girdle muscular dystrophy and autosomal recessive myosclerosis myopathy – in between. Although Bethlem myopathy and Ullrich CMD were defined long before their molecular basis was known, they remain useful for clarification of prognosis and management.

Bethlem myopathy, characterized by the combination of proximal muscle weakness and variable contractures, affects most frequently the long finger flexors, elbows, and ankles. Onset may be prenatal (characterized by decreased fetal movements), neonatal (hypotonia or torticollis), in early childhood (delayed motor milestones, muscle weakness, and contractures), or in adulthood (proximal weakness and Achilles tendon or long finger flexor contractures). Because of slow progression, more than two thirds of affected individuals over age 50 years rely on supportive means for outdoor mobility. Respiratory involvement is rare and appears to be related to more severe muscle weakness in later life.

Ullrich CMD is characterized by congenital weakness and hypotonia, proximal joint contractures, and striking hyperlaxity of distal joints. Some affected children acquire the ability to walk independently; however, progression of the disease often results in later loss of ambulation. Early and severe respiratory involvement may require ventilatory support in the first or second decade of life.

Diagnosis/testing.

Diagnosis depends on typical clinical features; normal or only mildly elevated serum creatine kinase concentration; suggestive pattern on muscle magnetic resonance imaging (MRI); muscle biopsy with collagen VI immunolabeling (for suspected Ullrich CMD) or skin biopsy and dermal fibroblast culture with collagen VI immunolabeling (for suspected Bethlem myopathy); and molecular genetic testing of COL6A1, COL6A2, and COL6A3, the three genes encoding the three collagen VI peptide chains.

Management.

Treatment of manifestations: As needed based on clinical findings: physiotherapy regarding stretching exercises, splinting, and mobility aids; orthopedic assessment if surgery for Achilles tendon contractures is being considered; therapy for scoliosis. Respiratory: evaluation for nocturnal hypoventilation; prophylaxis of chest infections with vaccination and physiotherapy; aggressive treatment of pulmonary infections. Nutrition: assessment of nutritional status and growth; management of feeding difficulties.

Surveillance: Routine assessment of: muscle weakness, scoliosis, joint contractures, and mobility; respiratory function; and nutritional status.

Genetic counseling.

The Bethlem myopathy phenotype is usually inherited in an autosomal dominant manner and the UMD phenotype is usually inherited in an autosomal recessive manner; however, exceptions occur. In the few cases reported to date, it appears that autosomal dominant limb-girdle muscular dystrophy is inherited in an autosomal dominant manner and the myosclerosis myopathy phenotype is inherited in an autosomal recessive manner. Carrier testing for autosomal recessive collagen VI-related disorders and prenatal testing are possible if the pathogenic variants have been identified in an affected family member.

Diagnosis

The collagen type VI-related disorders, caused by mutation of COL6A1, COL6A2, or COL6A3, represent a clinical spectrum including Bethlem myopathy at the mild end, Ullrich congenital muscular dystrophy (CMD) at the severe end, and two less well-defined disorders – autosomal dominant limb-girdle muscular dystrophy and autosomal recessive myosclerosis myopathy – in between.

Note: Although these phenotypes are now recognized to comprise a continuum of overlapping phenotypes, the clinical designations are useful for clarification of prognosis and management.

Clinical findings

Bethlem myopathy is recognized clinically by the combination of the following [Jöbsis et al 1999]:

Proximal muscle weakness
Variable contractures, affecting most frequently the long finger flexors, elbows, and ankles

Ullrich congenital muscular dystrophy (CMD) is recognized clinically by the combination of the following [Voit 1998, Muntoni et al 2002]:

Congenital weakness and hypotonia
Proximal joint contractures
Striking hyperlaxity of distal joints

Note: As Bethlem myopathy may also present at birth, it may be difficult to categorize a neonate who has no family history of muscle disease into either Bethlem myopathy or Ullrich CMD initially; however, with time the stable acquisition of ambulation allows the diagnosis of Bethlem myopathy.

In both Bethlem myopathy and Ullrich CMD:

Intelligence is normal (in contrast to some other CMD subtypes).
Unusual skin features may be present, including follicular hyperkeratosis, and keloid or "cigarette-paper" scarring [Pepe et al 2002].
Serum creatine kinase concentration is normal or mildly elevated.

Muscle MRI. Bethlem myopathy and Ullrich CMD have distinct patterns of muscle involvement, although some overlap exists [Mercuri et al 2005].

In thigh muscles:
- In Bethlem myopathy the vasti muscles appear to be the most frequently and strikingly affected, with a rim of abnormal signal at the periphery of each muscle and relative sparing of the central part. A peculiar involvement of the rectus femoris with a central area of abnormal signal within the muscle is also a frequent finding. See Figure 1.
- In Ullrich CMD more diffuse involvement is observed with relative sparing of the sartorius, gracilis, and adductor longus. See Figure 2.
In calf muscles: Bethlem myopathy and Ullrich CMD often show a rim of abnormal signal at the periphery of soleus and gastrocnemii.

Figure 1.

Transverse T₁-weighted images through thigh muscles in four individuals with Bethlem myopathy (a-d). Note the relative sparing of the central part of the vastus lateralis with a rim of increased signal at the periphery of the muscle and the prominent (more...)

Figure 2.

Transverse T₁-weighted images through thigh muscles in four individuals with Ullrich CMD. Note the diffuse involvement of the thigh with relative sparing of sartorius, gracilis, and rectus femoris (arrows) in three young affected individuals (a-c). A (more...)

Tissue studies

Bethlem myopathy

Muscle biopsy reveals myopathic or dystrophic changes. Collagen VI immunolabeling is often normal or shows only subtle alterations.
Immunofluorescent analysis of collagen VI in dermal fibroblast cultures is predictive of Bethlem myopathy [Hicks et al 2008]. See Figure 3.

Figure 3.

Dermal fibroblasts in Bethlem myopathy A. Normal control with collagen VI labeling with antibody

Ullrich CMD

Muscle biopsy more commonly shows dystrophic features with degeneration and regeneration and replacement of muscle with fat and fibrous connective tissue. Collagen VI immunolabeling from the endomysium and basal lamina ranges from absent to moderately or markedly reduced, but may be normal around capillaries [Higuchi et al 2003].
Loss of collagen VI in dermal fibroblast cultures may be a useful adjunct to the diagnosis [Jimenez-Mallebrera et al 2006]. See Figure 3.

Molecular Genetic Testing

Genes. COL6A1, COL6A2, and COL6A3 are the three genes in which pathogenic variants are known to cause collagen type VI-related disorders.

Table 1.

Molecular Genetic Testing Used in Collagen VI-Related Disorders

Gene ¹	Proportion of Collagen VI-Related Disorders Attributed to Pathogenic Variants in This Gene ²	Method	Variants Detected ³
COL6A1	38%	Sequence analysis ⁴	Sequence variants
COL6A1	38%	Duplication/deletion analysis ⁵	Exon or whole-gene deletions ^6, 7, 8
COL6A2	44%	Sequence analysis ⁴	Sequence variants
COL6A2	44%	Duplication/deletion analysis ⁵	Exon or whole-gene deletions ^7, 8, 9
COL6A3	18%	Sequence analysis ⁴	Sequence variants
COL6A3	18%	Duplication/deletion analysis ⁵	Unknown; none reported ¹⁰

1.: See Table A. Genes and Databases for chromosome locus and protein.
2.: Author, personal observation
3.: See Molecular Genetics for information on allelic variants.
4.: Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
5.: Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intron regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.
6.: Highly similar heterozygous genomic deletions were identified in a deletion-prone region of COL6A1 in two individuals, one with a BM and one with an Ullrich CMD phenotype [Pepe et al 2006].
7.: A novel type of pathogenic variant underlying recessively inherited UCMD was reported in two families with Ullrich CMD with large genomic deletions of COL6A1 and COL6A2 on chromosome 21 [Foley et al 2011].
8.: Large or whole-gene deletions appear to be rare in collagen VI-related disorders.
9.: In addition to the finding described in footnote 5, a deep intron deletion in COL6A2 (identified by array CGH) was one of two biallelic pathogenic variants in an individual with a BM phenotype [Bovolenta et al 2010].
10.: No deletions or duplications involving COL6A3 have been reported to cause collagen type VI-related disorders.

Testing Strategy

To confirm/establish the diagnosis in a proband

Clinical evaluation
Measurement of serum creatine kinase concentration
Muscle MRI for Bethlem myopathy
Note: Muscle MRI is not always done in Ullrich CMD because of the difficulty associated with sedating babies and small children.
Tissue evaluation
- For suspected Ullrich CMD: muscle biopsy with collagen VI immunolabeling
- For suspected Bethlem myopathy: skin biopsy and dermal fibroblast culture with collagen VI immunolabeling
Molecular genetic testing of COL6A1, COL6A2, COL6A3
Using genomic DNA derived from peripheral blood samples, sequence analysis of the three genes encoding collagen VI detected putative pathogenic variants in [Lampe et al 2005] (see Note):
- 66% of individuals clinically classified as having Bethlem myopathy
- 56% of individuals with Bethlem myopathy with an unusually severe phenotype
- 79% of individuals with Ullrich CMD

Note: (1) The low variant detection rate is largely attributable to the high degree of genetic heterogeneity in Bethlem myopathy and Ullrich CMD, rather than failure to detect COL6A pathogenic variants; however, deep intronic and cryptic variants are not detectable by sequence analysis. Deletion/duplication analysis does not increase the variant detection frequency greatly, if at all. (2) The recent finding of compound heterozygous pathogenic variants for autosomal recessive forms of collagen type VI-related disorders emphasizes the importance of sequencing the entire coding region of the three genes (COL6A1, COL6A2, COL6A3) to ensure detection of two mutant alleles, when present [Gualandi et al 2009].

Carrier testing for relatives at risk for autosomal recessive forms of collagen VI-related disorders requires prior identification of the pathogenic variants in the family.

Note: Carriers (heterozygotes) for autosomal recessive forms of collagen type VI-related disorders are not at risk of developing the disorder.

Predictive testing for at-risk asymptomatic adult family members requires prior identification of the pathogenic variants in the family.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the pathogenic variants in the family.

Clinical Characteristics

Clinical Description

The phenotypes associated with collagen type VI-related disorders, once thought to be distinct entities, were clinically defined long before their molecular basis was discovered. The collagen type VI-related disorders are now recognized to comprise a continuum of overlapping phenotypes with Bethlem myopathy at the mild end, Ullrich congenital muscular dystrophy (CMD) at the severe end, and two less well-defined disorders – autosomal dominant limb-girdle muscular dystrophy and autosomal recessive myosclerosis myopathy – in between. Although these phenotypes are now recognized to overlap and fall on a continuum, these clinical designations are useful for clarification of prognosis and management.

Bethlem Myopathy

The onset of Bethlem myopathy ranges from prenatal to mid-adulthood. Prenatal onset is characterized by decreased fetal movements; neonatal onset with hypotonia or torticollis; early-childhood onset with delayed motor milestones, muscle weakness, and contractures; and adult onset (4th-6th decade) with proximal weakness and Achilles tendon or long finger flexor contractures. As some adults are unaware of weakness, age of onset cannot always be established.

The contractures may come and go during childhood, but nearly all affected individuals eventually exhibit flexion contractures of the fingers, wrists, elbows, and ankles. These contractures can become disabling when combined with muscle weakness.

Individuals can have moderate weakness and atrophy of the muscles of the trunk and limbs with proximal muscles being more involved than distal muscles and extensors more than flexors.

As a result of slow but ongoing progression of the condition, more than two thirds of affected individuals over age 50 years need supportive means (i.e., canes, crutches, or wheelchair) for outdoor mobility [Jöbsis et al 1999, Pepe et al 1999b].

Respiratory muscle and especially diaphragmatic involvement necessitating artificial nocturnal respiratory support is part of the clinical spectrum but is rare and appears to be related to severe weakness occurring in later life [Haq et al 1999]. Respiratory failure may supervene prior to loss of ambulation and may be associated with diaphragmatic weakness [Haq et al 1999].

Cardiac function is usually normal [Mohire et al 1988, de Visser et al 1992].

Ullrich Congenital Muscular Dystrophy (CMD)

In addition to characteristic muscle weakness of early onset, proximal joint contractures, and hyperelasticity of the wrists and ankles, other features observed are congenital hip dislocation, prominent calcanei, and a transient kyphotic deformity at birth.

With time, the distal hyperlaxity can evolve into marked finger flexion contractures and tight Achilles tendons [Furukawa & Toyokura 1977, Muntoni et al 2002].

Some affected children acquire the ability to walk independently; however, progression of the disease often results in later loss of ambulation.

Rigidity of the spine is often associated with scoliosis.

Early and severe respiratory involvement may require artificial ventilatory support in the first or second decade of life.

Failure to thrive is common.

Follicular hyperkeratosis over the extensor surfaces of upper and lower limbs and keloid and cigarette paper scar formation are common.

Cardiac involvement has not been documented to date.

Other Phenotypes

The two additional conditions included in the spectrum of collagen VI myopathies are:

Autosomal dominant limb-girdle muscular dystrophy caused by pathogenic variants in COL6A1/COL6A2 in three families and COL6A3 in one family [Scacheri et al 2002]. Although some affected individuals had mild weakness with only limited functional impairment, others had a more severe, dystrophic-like weakness with findings including Gower’s maneuver, toe walking, and loss of ambulation. Joint contractures were either absent or much milder than those of typical Bethlem myopathy. Whereas findings of Bethlem myopathy are typically present in infancy, the age at onset in these three families ranged from infancy, to early childhood, to adulthood.
Autosomal recessive myosclerosis myopathy caused by mutation of COL6A2 in two individuals from one family [Merlini et al 2008]. Myosclerosis myopathy is characterized by difficulty in walking in early childhood, toe walking, and progressive contractures of calf muscles. In the early 30s the muscles are slender with a firm "woody" consistency and associated with contractures that restrict range of motion of many joints.

Genotype-Phenotype Correlations

In 42 individuals with collagen VI-related myopathy with onset before age two years, biallelic pathogenic variants that caused premature termination codons (associated with autosomal recessive inheritance) were associated with the most severe phenotypes (ambulation never achieved), whereas heterozygous de novo in-frame exon skipping and glycine missense variants (associated with autosomal dominant inheritance) were associated with the moderate-progressive phenotypes (loss of ambulation) [Briñas et al 2010].

In autosomal recessive Ullrich congenital muscular dystrophy (CMD), a large number of pathogenic variants appear to result in premature termination codons with consequent nonsense-mediated mRNA decay. Premature termination codons occur by nonsense variants [Demir et al 2002, Giusti et al 2005, Lampe et al 2005] or frameshift-inducing deletions [Higuchi et al 2001, Giusti et al 2005, Lampe et al 2005], insertions [Camacho Vanegas et al 2001], duplications [Lampe et al 2005], and splice changes [Camacho Vanegas et al 2001, Ishikawa et al 2002]. Splice variants leading to in-frame exon deletions as well as in-frame deletions are other common pathogenic variant types in Ullrich CMD [Demir et al 2002, Ishikawa et al 2004, Baker et al 2005, Lampe et al 2005].

Bethlem myopathy and Ullrich CMD represent a clinical continuum in which individuals presenting with intermediate phenotypes could be considered to have either "mild Ullrich CMD" or "severe Bethlem myopathy." In this context, heterozygous single amino acid substitutions disrupting the Gly-Xaa-Yaa motif of the highly conserved triple helical domain have been described in a milder form of Ullrich CMD [Giusti et al 2005, Lampe et al 2005]. As for Bethlem myopathy, given the high number of variants resulting in benign amino acid changes described for the genes encoding collagen VI subunits, it is difficult to be certain about the pathogenicity of missense variants other than glycine substitutions within the triple helical domain.

In autosomal dominant Ullrich CMD, heterozygous splice site variants leading to in-frame exon deletions and heterozygous in-frame deletions in the coding region share a common motif: they preserve a unique cysteine important for dimer formation, allowing secretion of abnormal tetramers with a consequent dominant-negative effect on microfibrillar assembly [Pan et al 2003, Baker et al 2005].

Penetrance

Parents of individuals with recessively inherited collagen VI-related disorders are usually heterozygous for a COL6A1, COL6A2, or COL6A3 pathogenic variant, but do not appear to manifest any related symptoms.

Individuals with dominantly inherited collagen VI-related disorders are heterozygous for a COL6A1, COL6A2, or COL6A3 pathogenic variant and are symptomatic. However, careful clinical examination may be necessary to identify findings diagnostic of a collagen type VI-related disorder in their minimally symptomatic parents [Peat et al 2007].

Anticipation

Anticipation is not observed.

Nomenclature

Bethlem myopathy was first described as "benign myopathy with autosomal dominant inheritance" [Bethlem & Wijngaarden 1976]. Other terms in use:

Benign congenital myopathy
Benign congenital muscular dystrophy
Benign congenital myopathy with contractures

Ullrich CMD was first described as "congenital atonic sclerotic muscular dystrophy" [Ullrich 1930]. Other terms used in the past:

Congenital hypotonic sclerotic muscular dystrophy
Congenital muscular dystrophy with distal laxity

Prevalence

Prevalence is estimated at 0.77:100,000 in Bethlem myopathy and 0.13:100,000 in Ullrich CMD [Norwood et al 2009]; the disorders are probably currently underdiagnosed.

Both conditions have been described in individuals from a variety of ethnic backgrounds.

Differential Diagnosis

The differential diagnosis of the two major phenotypes observed in the collagen VI-related disorders is discussed below. Of note, a normal to mildly elevated CK, suggestive findings on muscle MRI, and the lack of a cardiac phenotype generally distinguish the collagen type VI-related disorders from these other disorders.

Bethlem myopathy. When contractures are subtle or missed, the major differential diagnoses are the limb-girdle muscular dystrophies (LGMDs) [Scacheri et al 2002].

When contractures are a prominent feature, the major differential diagnoses are X-linked or autosomal dominant Emery-Dreifuss muscular dystrophy, both of which are associated with serious cardiac complications [Pepe et al 2002].

Immunohistochemical testing (i.e., western blotting and immunohistochemistry) performed on muscle biopsy and/or molecular genetic testing can help to establish the diagnosis of some LGMD subtypes such as sarcoglycanopathy, calpainopathy, and dysferlinopathy as well as X-linked or autosomal dominant Emery-Dreifuss muscular dystrophy.

Ullrich congenital muscular dystrophy (CMD). In the neonatal period, the differential diagnosis includes the following:

Other forms of CMD. These do not generally present with the distal hyperlaxity characteristic of Ullrich CMD and are usually associated with serum creatine kinase concentrations higher than those observed in Ullrich CMD. Biochemical testing (i.e., western blotting and immunohistochemistry) performed on the muscle biopsy and molecular genetic testing can help to establish the diagnosis of some CMD subtypes such as LAMA2-related muscular dystrophies (MDC1A) or MDC1C (caused by pathogenic variants in FKRP). In addition, brain MRI may show white matter changes in some CMD subtypes (e.g., LAMA2-related muscular dystrophies) and structural abnormalities in others (e.g., Walker-Warburg syndrome, muscle-eye-brain disease, and Fukuyama congenital muscular dystrophy [FCMD]).
Spinal muscular atrophy (SMA). SMA shows features of denervation rather than myopathic or dystrophic changes on muscle biopsy. It can usually be diagnosed by demonstrating pathogenic variants in SMN1 or SMN2.
Forms of Ehlers-Danlos syndrome, classic type or Marfan syndrome. Neither of these disorders is typically associated with significant muscle weakness or an abnormal muscle biopsy, but they may be confused with Ullrich CMD because of joint laxity.
Rigid spine syndromes. A proportion of rigid spine syndromes are caused by pathogenic variants in SELENON (SEPN1) (OMIM 606210), which may overlap with Ullrich CMD later as the phenotype develops.

Management

Evaluations Following Initial Diagnosis

Bethlem myopathy. To establish the extent of disease and needs of an individual diagnosed with Bethlem myopathy, the following evaluations are recommended:

Evaluation of degree of muscle weakness and mobility
Joint examination for contractures
Physiotherapy assessment and advice regarding stretches/splints for contractures and mobility aids
Possibly orthopedic evaluation if surgery is to be considered for tendon Achilles contractures
Assessment of respiratory status
- Seek history of clinical symptoms of nocturnal hypoventilation such as early morning nausea and headaches, daytime somnolence.
- Inquire about frequency and severity of chest infections; if any concerns, perform spirometry and nocturnal pulse oximetry.

Ullrich congenital muscular dystrophy (CMD). To establish the extent of disease and needs of an individual diagnosed with Ullrich CMD, the following evaluations are recommended:

Evaluation of degree of muscle weakness and mobility
Examination of back for scoliosis
Joint examination for contractures and hyperlaxity
Physiotherapy assessment and advice regarding stretches/splints for contractures and mobility aids such as swivel walkers and standing frames to achieve upright posture and protect against the development of scoliosis and other contractures
Possibly x-rays of thoracolumbar spine and orthopedic evaluation if scoliosis is clinically suspected
Possibly orthopedic evaluation if hip dislocation is suspected or surgery is to be considered for tendon Achilles contractures
Assessment of respiratory status
- Seek history of clinical symptoms of nocturnal hypoventilation such as early morning nausea and headaches, daytime somnolence.
- Inquire about frequency and severity of chest infections; if any concerns, perform spirometry and nocturnal pulse oximetry.
Assessment of growth and feeding. Feeding difficulties may manifest as failure to thrive or excessive time taken to finish eating a meal.

Treatment of Manifestations

Bethlem myopathy

Physiotherapy and possibly orthopedic management of contractures are useful to maintain mobility. Contractures may be dynamic and may require stretching and splinting.
Symptoms of nocturnal hypoventilation respond well to noninvasive respiratory support such as mask ventilation [Wallgren-Pettersson et al 2004].
Approximately two thirds of individuals over age 50 years need supportive aids for outdoor mobility [Jöbsis et al 1999].

Ullrich CMD

Children require active physiotherapy management as soon as the diagnosis is established to promote mobility and independence. Early mobilization in standing frames is important to achieve upright posture and protect against the development of scoliosis and other contractures.
Contractures tend to be aggressive and may require surgery.
Feeding difficulties may manifest as failure to thrive or excessive time taken to finish eating a meal. Consultation with a nutrition specialist may be required to boost calorie intake; for serious problems, feeding by gastrostomy may be the best solution to promote a normal weight gain.
Respiratory support with nocturnal ventilation usually becomes necessary in the first or second decade and can be effective in reducing symptoms, promoting quality of life, and allowing normal schooling [Wallgren-Pettersson et al 2004].
Scoliosis frequently develops in the first or second decade and requires active management including surgery.

Prevention of Secondary Complications

Prophylaxis of chest infections with vaccination and physiotherapy as well as early and aggressive use of antibiotics may prevent further respiratory problems in both disorders.

Surveillance

Bethlem myopathy

Clinical assessment of muscle weakness, joint contractures, and mobility to inform physiotherapeutic advice regarding stretches/splints and mobility aids
Assessments of respiratory function to detect asymptomatic decline. (Assess clinically by seeking history of clinical symptoms of nocturnal hypoventilation such as early-morning nausea and headaches, daytime somnolence; inquire about frequency and severity of chest infections; if any concerns, perform spirometry and nocturnal pulse oximetry.)

Assessments should be repeated regularly, possibly annually, depending on the clinical status of the individual.

Ullrich CMD

Clinical assessment of muscle weakness, scoliosis, joint contractures, and mobility to inform physiotherapeutic advice regarding stretches/splints and mobility aids
Once scoliosis is evident, regular orthopedic follow up
Assessments of respiratory function to detect asymptomatic decline. (Assess clinically by seeking history of clinical symptoms of nocturnal hypoventilation such as early-morning nausea and headaches, daytime somnolence; inquire about frequency and severity of chest infections; if any concerns, perform spirometry and nocturnal pulse oximetry.)
Clinical assessment of nutritional status

Assessments should be repeated regularly, possibly biannually, depending on the clinical status of the individual.

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 a collagen VI-related disorder, no specific pregnancy management issues exist; however, prenatal physiotherapy may be indicated.

Therapies Under Investigation

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