Collagen VI CMD (Ullrich CMD and Bethlem Myopathy)
Ullrich CMD is characterized by muscle weakness, proximal joints contractures and distal joint hyperflexibility from birth. Other symptoms may include: rigid lower spine, kyphosis (curved upper spine), skin changes (hyperkeratosis pilaris, keloid formation, soft/velvety skin), respiratory complications, high-arched palate, posterior protrusion of the calcaneus, and slow disease progression.
It can be diagnosed by a muscle and/or skin biopsy which shows a deficiency or mutation in one of 3 collagen VI genes. For definitive genetic testing, consultation with your doctor and resources available at www.genetests.org.
Bethlem myopathy and Ullrich CMD are a continuum. This means that they are not 2 “distinct diseases” except at the extremes of the spectrum: a child who has a very early UCMD and a very late onset adult with Bethlem myoypathy. The collagen VI myopathies (UCMD and Bethlem) share progressive contracture development, skin findings, breathing issues and mutations in 1 of the 3 collagen VI genes.
Adults with Bethlem Myopathy can have tight tendons at the back of their ankles, as well as tightness of various other joints (elbows, knees, joints in the back) and especially some of the muscles in the hands. Other symptoms such as poor stamina/poor exercise tolerance and difficulties walking upstairs or doing tasks which require lifting the arms above the head are related to the subtle muscle weakness that tends to go with Bethlem myopathy.
As with all the CMDs, because it is a rare disorder people with Bethlem myopathy may often have had other diagnoses suggested in the past.
Merosin Deficient CMD
Children with merosin deficient CMD are born with muscle weakness, floppy tone and may have early breathing and feeding problems with progressive joint contractures. Few, achieve the ability to walk, though children with both partial merosin deficiency or specific mutations leading to complete merosin deficiency can achieve and maintain walking through early adulthood.
Diagnosis is made by muscle or skin biopsy and brain MRI findings of abnormal white matter. For definitive genetic testing, consultation with your doctor and resources available at www.genetests.org.
Dystroglycanopathy CMD (POMT1, POMT2, POMGnT1, LARGE, Fukutin, FKRP)
The Dystroglycanopathies are a group of diseases that represent a spectrum of neurologic and physical impairment. Those that present in infancy are classified as congenital muscular dystrophy and often have brain involvement, including seizures and developmental delay though may be cognitively normal. Those that present in childhood or adulthood are classified as limb girdle muscular dystrophy with predominantly muscle involvement though may have mild cognitive involvement. Speech may be involved.
Infants who present with more severe involvement are labeled as Walker Warburg Syndrome, Muscle Eye Brain disease and Fukuyama Muscular Dystrophy, many with abnormal MRI brain findings including structural abnormalities and lissencephaly (abnormal neuronal migration during brain development as an embryo).
For definitive genetic testing, consultation with your doctor and resources available at www.genetests.org.
Read more about the Dystroglycanopathies
Dystroglycanopathy Yahoo! group started in 2008, 20 members
Walker Warburg Yahoo! Group started in 1999, 174 members
Lissencephaly Yahoo! Group started in 1999, 723 members (There are other disorders besides CMD that lead to lissencephaly).
SEPN1 related myopathy (formerly known as Rigid Spine Muscular Dystrophy, RSMD)
Selenoprotein Deficient CMD (SEPN1) also know as Rigid Spine Muscular Dystrophy presents with axial muscle weakness (head lag, “weak neck”), development of rigid spine (scoliosis) and breathing problems (while stlll walking) often in early childhood. Many children show loss of medial thigh muscles and thin stature with a characteristic spine curvature. A person with a SEPN1 mutation may have a muscle biopsy that resembles muscle biopsy findings seen in congenital myopathy. A muscle biopsy in a person with a SEPN1 mutation may show congenital fiber type disporportion or multi-minicores. A person may be given a clinical diagnosis of Congenital Fiber Type Disporportion or Multi-Minicore myopathy which are descriptions of muscle biopsy findings, not genetic diagnoses. People with mutations in the RYR1 gene can have similar looking muscle biopsy findings. It is important to confirm a SEPN1 diagnosis genetically, as people with L-CMD (a mutation in the lamin A/C gene) can have a very similar clinical presentation. In SEPN1 related myopathies there is no primary heart involvement, while in L-CMD close surveillance for heart arrhythmias and enlargement of the heart needs to happen on an annual basis due to heart involvement.
L-CMD is a recently recognized CMD subtype. It is caused by a mutation in the lamin A/C gene not to be confused with laminin alpha 2 gene that is deficient in Merosin or Laminin Alpha 2 deficient CMD. Kids with L-CMD present with necks that are extremely weak, leading to difficulty in controlling their head. This is referred to as “dropped head syndrome”. They tend to have foot drop, meaning that the foot is not able to lift itself with strength in arms and legs preserved. They may have progression of their weakness early on in the toddler years. Kids with L-CMD require early and frequent monitoring of their breathing and heart status.
Mutations in the ryanodine receptor gene RYR1 have until recently been associated with two forms of congenital myopathy – central core disease and multi-minicore disease. It has now become apparent that mutations in this gene can also underly a form of congenital muscular dystrophy (CMD). Congenital myopathy and congenital muscular dystrophy are terms originally derived from the description of muscle biopsy findings, with characteristic abnormalities of muscle architecture detected on staining and electron microscopy termed congenital myopathy and findings of muscle fiber degeneration, regeneration and fibrosis termed dystrophy. It seems however, that the distinction between the two can be fluent. An overlap between congenital myopathy and muscular dystrophy for instance applies to the SEPN1 related myopathies and there will likely be additional genes discovered that straddle both. As such, a more appropriate and more neutral term maybe congenital muscle disease which encompasses both the congenital myopathies, congenital muscular dystrophies and the overlapping subtypes, even extending into late onset or limb girdle presentations.
People with a CMD presentation of a RYR1 mutation typically have inherited the disease in an autosomal recessive fashion, meaning one copy from mom and one from dad. The clinical presentation is variable as in all CMDs. Findings at birth include hypotonia or floppiness, facial weakness, and weakness of the eye muscles in some. Some children achieve the ability to walk, but others may not. Difficulties in feeding, breathing and swallowing may lead to the need for g-tube placement and breathing support with BiPAP or a ventilator, sometimes at a very young age. Affected children frequently have a nasal quality to their voice. In some, frequent chest infections may occur early on together with a progressive scoliosis if the disease is severe. Cognitively the children are at grade level and above.
Undiagnosed CMD, Including Merosin Positive
Some children and adults with CMD do not have genetic confirmation of disease. This means that either genetic testing was done and no mutation identified or genetic testing has not been completed or revisited. Clinical picture and muscle or skin biopsy may point towards a known CMD type.
There are still new genes to be discovered that will lead to a CMD genetic diagnosis. In other words, in 30-50% of Walker Warburg cases a genetic mutation is not found in any of the existing 6 dystroglycanopathy genes. Children and adults who look like they have collagen VI CMD may not carry a mutation in the collagen VI genes. This means there are additional genes to be discovered.
Merosin positive CMD is not a genetic diagnosis. It means that a person has merosin present on muscle or skin biopsy and a clinical picture that looks like CMD. Making an appointment with a CMD expert neurologist is the first step in trying to narrow down a genetic diagnosis of CMD whether this is the first round of testing at presentation or revisiting the diagnosis as an older child or adult. As new genes are discovered and added to CMD genetic testing panels, a genetic diagnosis may be possible.
Common words used to describe children with CMD to doctor’s early on prior to a diagnosis, include:
- Slow to feed
- Head always on one side
- Wobbly head
- Unable to lift head off mum’s shoulder when being winded
- Head always stuck on one side
- Not lifting head off floor when on tummy
- Big / heavy head
- Not pushing up on arms
- Weak and floppy arms
- No shoulder stability
- Feels like falling through your arms when lifting
- Joints very flexible
- Not rolling
- Skin very soft
- Feet ‘fold up’ when pushed on
- Not sitting unsupported
- Not bearing weight on arms when on all fours
- Not crawling
- Collapses when placed on floor on all fours
- Not rolling over
- Not putting weight through legs when placed in standing position
- “Crumples” when placed in standing position
- Not pulling up on furniture
- Not cruising
- No feeling of solidity – muscles feel soft
- Not babbling
- Gut feeling that something is wrong
1 -2 years
- Not walking
- Not cruising
- Not standing without support
- Not making words though seems to understand
- Speech seems delayed
- Still not walking
- Walking awkwardly
- Very bendy
- Falling a lot
- When falls seems to be unable to save self (not putting arms out to save self)
Our understanding of the CMD’s continues to grow.
To find out more about the larger muscular dystrophy community or if you have come to this website looking for the following types of muscular dystrophy:
* Duchenne or Becker muscular dystrophy: www.parentprojectmd.org
* LGMD2B (dysferlinopathy), Myoshi myopathy, calpainopathy or calveolinopathy:
* myotonic dystrophy: www.myotonic.org