An Interesting Case of Becker Muscular Dystrophy

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An Interesting Case of Becker Muscular Dystrophy

• Therese Bradley

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Duchenne Muscular Dystrophy

• Duchenne muscular dystrophy (DMD) is a severe
  X-linked recessive, progressive muscle-wasting
  disease affecting 1 in 3,500 boys .
• Patients are usually confined to a wheelchair
  before the age of 12
• Patients die in their late teens or early
  twenties usually of respiratory failure.
• Cognitive problems are also common in boys with
  DMD
• average IQ is one SD below the unaffected
  population.

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Becker Muscular Dystrophy

• Becker muscular dystrophy (BMD) is described as a
  milder form of the disease
• Later onset
• More variable phenotype
• Much longer survival.
• Less has been described on cognitive side
• There are reports of behavioural, psychiatric
  problems and autism in affected males.
• Not believed to be as common

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The Dystrophin gene

• Both result from mutations in the Dystrophin gene
  on Xp21
• It the biggest gene in the genome, spanning 2.5Mb
  comprising of 79 coding exons
• It is an important functional protein in skeletal
  muscle, cardiac muscle and brain.
• To add further complexity, the gene encodes 7
  different protein isoforms shown

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Isoforms of the Dystrophin Protein
Image taken from Blake DJ et al., Physiol Rev,
Apr 2002
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Testing

• Most disease causing mutations are deletions or
  duplications of one or more exons.
• If a deletion destroys the reading frame of the
  gene DMD
• no functional protein produced
• If the reading frame is maintained - BMD
• altered or reduced dystrophin protein produced.
• Routine testing is carried out by MLPA

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Patient KD- medical history

• KD referred aged 4yrs 10 months
• Uneventful birth at 38 weeks gestation
• Walked at 13 months
• Only started babbling at 2½ years
• Referral to community paediatrics due to
• Speech and Language impairment
• Communication Disorder
• Developmental Delay
• Behavioural Problems

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Developmental Delay Investigation Guidelines
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Testing results

• Normal karyotype
• No evidence of Fragile X
• No deletions/ duplications detected by Telomere/
  Mental Retardation MLPA kits
• Biochemical testing elevated Creatine Kinase
• 2544 U/L
• normal levels 25-180 U/L

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DMD MLPA Results
P035 Kit Covers exons 11-20, 31-40, 51-60 and
71-79
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Reporting results

• Exon 56-57 deletion
• Predicted to be in-frame deletion
• Predicted to cause the milder Becker Muscular
  Dystrophy.
• Deletion had not been reported before.
• Carrier testing was offered to KDs mother
• KD was referred to Clinical Genetics and
  Paediatric Neurology Department in Yorkhill.

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Neurological Examination

• Observed to have mild calf hypertrophy
• Lack of bounce when running
• Severe autistic features
• Repetitive play
• Doesnt respond to his name
• Doesnt make eye contact

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KD's Family History
Died from heart problems
10 years Reported to be well
9 weeks pregnant
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Carrier Testing

• KDs mother was shown to be a carrier.
• Prenatal testing was offered.

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Becker and Autism

• Is the autism in KD related to his Becker
  diagnosis or a coincidence?
• A study in the US and Australia looked at a
  cohort of BMD patients.
• Carried out a range of assessments relating to
  intelligence, behaviour, attention and learning
  abilities.
• Intelligence did not differ significantly from
  the general population mean
• However, there was a high frequency of learning
  difficulties despite normal intelligence
• Autism and behavioural and attention problems
  were also more common than in the general
  population (8.3 vs. 0.04)

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Becker and Autism

• The cause is unclear no link to disease
  severity.
• Cognitive decline in DMD is predicted to be due
  to lack of Dystrophin in the brain
• But in BMD, there is still brain dystrophin
  present.
• Some Hypotheses put forward
• there is a genetic susceptibility to autism in
  the dystrophin gene
• they share a similar cerebral pathology
• previous studies have shown a statistical
  relationship between the loss of the Dp140
  isoform and presence of mental retardation in BMD

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Genetic Counselling

• The family were counselled that it was highly
  likely that the two conditions were linked.
• However this was a family who had only recently
  been introduced to Becker muscular dystrophy
• Did not have any first hand experience of the
  muscle side of the disorder.
• They found it to be a difficult decision
• after some deliberation they decided to go ahead
  with prenatal testing.

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Prenatal testing

• A CVS was arranged 13 weeks gestation
• The fetus was determined to be male
• Using both MLPA and a PCR diplex
• the fetus was confirmed to also have the
  deletion.
• The parents had originally decided to terminate
  on receipt of a positive result
• But have since changed their mind.

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Follow Up on the Family
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Summary

• Cognitive dysfunction was the first presenting
  feature of Becker Muscular Dystrophy.
• The phenotype of Becker and its cognitive profile
  is extremely variable and it is therefore
  difficult to predict KDs progression.
• The devdel screen has the potential to diagnose
  Becker as well as Duchenne in young children
• may mean that clinical monitoring and early
  intervention may help with the clinical outcome
• may have more families faced with decisions
  involving a possible teen/adult onset disorder
  with which they have no first hand experience.

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A few last points to consider

• Previous studies have shown a statistical
  relationship between the loss of the Dp140 brain
  isoform (intron 44) and brain function of BMD
  patients
• Patient KD has a deletion of exon 56-57
• Deletions beginning at exon 56 have only been
  reported in DMD patients
• The promoter for the Dp116 isoform (Schwann
  cells) is located in intron 55
• Does his deletion encompass this promoter?
• Is this isoform disrupted/lost?
• Has this any involvement in his phenotype?

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Acknowledgements

• Dr. John Tolmie, Clinical Genetics
• Rachael, Sandy and Jennifer in the lab
• References
• Blake DJ et al.,Function and Genetics of
  Dystrophin and Dystrophin-Related Proteins in
  Muscle. Physiol Rev, Apr 2002 82 291 329
• Young HK et al., Cognitive and psychological
  profile of males with Becker muscular dystrophy.
  J Child Neurol. 2008 Feb23(2)155-62.
• Mehler MF. Brain dystrophin, neurogenetics and
  mental retardation. Brain Res Brain Res Rev. 2000
  Apr32(1)277-307.
• Bardoni M et al., Absence of brain Dp140 isoform
  and cognitive impairment in Becker muscular
  dystrophy. Lancet 353 1999, 897898