Freddie is a 4-year-old boy who presents to his GP after teachers have commented that he seems to fall a lot in the playground and does not run as fast as his friends. His mother is not overly concerned, although she has noticed that Freddie’s stamina is not great. He often asks to be carried when they are out shopping. However, she just thought he might be a bit lazy. Freddie never complains of any pain in his legs. He has not lost any weight recently and generally is very well.
Freddie was born full term and his birth weight was 3.4 kg. He is the first child in the family. Both his mom and dad are well and they are not aware of any significant illnesses running in the family.
Freddie was well at birth and his mother described him as a thriving and chubby baby who breastfed well. He rolled at 6 months and pulled to stand at 14 months. He cruised at 16 months and walked at 20 months. He started talking in short sentences at the age of 3 and is currently awaiting a speech and language assessment.
The GP observes Freddie walking into the consultation room and notices a broad-based gait. Freddie is walking well, but seems unsteady on his legs when picking up a toy from the floor. He seems to push up on his legs to get himself up. His height and weight are both on the 50th centile.
On inspection, Freddie has strong legs with large calf muscles. There is no muscle wasting. His skin looks unremarkable with no bruising and no rash.
Examination of his musculoskeletal system is otherwise normal (pGALS). His respiratory, cardiovascular, and abdominal examinations are unremarkable. The GP attempts a neurological examination, but Freddie is uncooperative. The GP does not detect any obvious abnormalities in reflexes, tone, or power.
What are the key points of concern in this history?
- Slightly delayed motor development (see section on motor milestones)
- Frequent falls
- Seems to struggle to get up from the floor, using hands to “walk up legs” (Gower sign)
- Mild speech delay
- Large calf muscles
What are the key points of concern on examination?
- Broad based gait in a child > age of 2 years. This is abnormal and may indicate muscle weakness.
- Enlarged calves (calf hypertrophy); this is typically seen in Duchenne muscular dystrophy (DMD) and called pseudohypertrophy because it is due to fat and connective tissue replacing damaged muscle cells.
- There may be hypotonia but this can be difficult to detect in young children.
What is the likely diagnosis?
The combination of waddling gait, frequent falls, mildly delayed motor development and mild speech delay point to a muscle disorder (myopathy). There are many different types but the most common is DMD.
Which blood tests should be requested?
Creatine kinase; this test is a highly useful test for muscular dystrophies (often elevated 10-100x), and it is elevated from birth. If CK is normal then muscular dystrophy can be excluded as a diagnosis. In addition the following tests are indicated to exclude differential diagnoses (including malignancy, infection and metabolic disease) - full [complete] blood count (FBC) and blood film, inflammatory markers, electrolytes, liver profile (liver function tests [LFTs] and enzymes) and bone profile (including calcium, phosphorus, ALP, GGT and parathyroid hormones).
These are the results:
Raised CK 17000; the CK is often extremely elevated in muscular dystrophies. Liver enzymes (e.g., ALT can also be raised - this is not a sign of liver failure but this further indicates muscle breakdown). The GP tells the mother that there seems to be a problem with Freddie’s muscles and she refers Freddie urgently to the paediatric team with expertise in neuromuscular diseases.
What other test is needed?
Blood test for DNA analysis (looking for a mutation in the dystrophin gene). The most likely diagnosis is DMD. The combination of the red flags in the clinical history and the elevated CK is highly suggestive. DNA testing for mutation in the dystrophin gene will give the definitive diagnosis in most cases. Genetic testing for siblings or parents (especially mothers) should be considered (see below).
What is the inheritance patterns of this condition?
X-linked recessive. The DMD gene is located on the X chromosome. Boys have one X chromosome and one Y chromosome, girls have two X chromosomes. Women carry the DMD gene but this does not usually cause muscle problems. This is because women have two X chromosomes and the unaffected X chromosome can compensate for the faulty one. In contrast boys only have one X chromosome, therefore cannot compensate for the faulty gene and will present with clinical features. In about 70% of the cases the condition is passed on from mother to child (in 30% of the cases, there is a new mutation). For a mother carrying the DMD gene, there is a 50% chance she passes on her faulty X chromosome on to her child. That means that if the child is a boy, he has a 50% chance of being affected by DMD. With a girl, she has a 50% chance of being a carrier of DMD. This is called X-linked inheritance and typically affects single genes.
What is the trajectory for this condition ?
Typically boys with DMD lose the ability to walk between the ages of ten and fourteen. In their late teens they progressively lose the strength in their upper body, leading to difficulties raising their arms for example for brush their teeth or for feeding. The disease also affects the heart and respiratory muscles and eventually boys with DMD will need help with breathing. Life span is reduced in DMD due to cardiac or respiratory failure but in recent years treatments have significantly slowed down the disease progression and delayed the onset of respiratory complications. Whilst there is not yet a cure for DMD, several potential new therapies are currently being tested in clinical trials. Early diagnosis is important to optimise outcomes and provide families with support.
Further Information is available: Duchenne muscular dystrophy BMJ 2020 https://doi.org/10.1136/bmj.l7012
Are there other types of inherited muscle disease ?
Becker muscular dystrophy (BMD) is a milder form of muscular dystrophy. It is related to DMD as both result from a mutation in the dystrophin gene. However in contrast to DMD, children with Becker muscular dystrophy still have some dystrophin being produced and expressed in the muscles (in Duchenne there is no dystrophin); this results in milder symptoms and signs. The disease onset is later and there is a much slower rate of progression. Loss of ambulation (walking) may not occur until the patient is in his fifties. Patients with Becker muscular dystrophy however are still at risk to develop cardiomyopathy even without a significant skeletal muscle weakness.
In addition to DMD and BMD, there are many other inherited / congenital myopathies, dystrophies and myotonias that result in the floppy weak infant or muscle weakness in older children that need to be differentiated from other neuromuscular causes. An approach to these scenarios is outlined in http://www.cmej.org.za/index.php/cmej/article/view/1008/792.