Diapositiva 1

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International Conference on the Nondytrophyc
Myotonias Clinical phenotype of NDM
DM2/PROMM
Giovanni Meola, MD Professor and Chair of
Neurology University of Milan IRCCS Policlinico
San Donato Department of Neurology San Donato
Milanese, Milan
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THE MYOTONIC DYSTROPHY
Moxley RT and Meola G. The Myotonic Dystrophies.
Chapter In press 2007
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DM2/PROMM

• How does DM2 differ from NDM?
• How large is the clinical spectrum?
• What is the clinical approach to an adult patient
  with myotonia?
• How different is myotonia of DM2 from NDM?
• Is treatment of myotonia the same in DM2

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DM2 vs NDM
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DM2 vs NDM
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DM2 vs NDM
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DM2 CLINICAL SPECTRUM

• DM1 phenotype
• PROMM phenotype
• PDM phenotype
• pre-symptomatic
• CNS-predominant
• Cardiac predominant
• Unusual phenotype

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DM1 PHENOTYPE

• Large Minnesota family described by Day et al.

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DM1 PHENOTYPE
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DM1 PHENOTYPE
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DM1 PHENOTYPE

• Proximal and distal atrophy
• Grade 4 MRC proximal and distal muscle weakness
• Facial muscle involvement
• Balding

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PROMM PHENOTYPE

• Mild atrophy
• Grade 4 MRC proximal muscle weakness

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PROMM PHENOTYPE

• Mild atrophy
• Grade 4 MRC proximal muscle weakness
• Slow progression

1997
2000
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PROMM PHENOTYPE
1998
2005

• Mild atrophy
• Grade 4 MRC proximal muscle weakness
• Slow progression

2005
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FINNISH PDM FAMILY
Udd B et al. Neuromuscl Disord 19977217-228
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FINNISH PDM FAMILY
Udd B et al. Neuromuscl Disord 19977217-228
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CT AND MUSCLE BIOPSY FINDINGS IN THE PDM FAMILY
Udd B et al. Neuromuscl Disord 19977217-228
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PDM PHENOTYPE

• Severe atrophy
• No cataracts
• No clinical myotonia
• Rotondo et al. Eur J Neurol 2005

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PDM PHENOTYPE

• Severe atrophy
• Proximal weakness, upper and lower extremities
  (MRC 4/3.5)
• No myotonia clinically and at EMG
• Milone M. ENS 2006

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PRESYMPTOMATIC

• High CK
• Merlini L et al. Muscle Nerve 2005
• Muscle pain
• 4/86 patients Italian experience
• observational period
• mean follow-up 8 2.4 years

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PAIN IN DM2 (C. Schneider Gold)

• Pain in thighs, back and proximal muscles
• Tenderness in the muscles
• Symptoms enhanced by cold, static posture and
  heavier exercise
• In 30 of DM2 patients, muscle pain is the most
  disabling symptom and increases with disease
  duration

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CNS PREDOMINANT

• Dementia-like
• IQ lt 70 in 2/86 with MMRC 140/150
• (AAN2005)
• Extrapyramidal traits suggesting PD
• 3 case-reports
• - Serratrice J et al. Press Med 2000)
• - Sansone et al. J Neurol Neurosurg Psychiatry
  2006)

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CNS PREDOMINANT
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CARDIAC PREDOMINANT

• Sudden cardiac death in DM2
• 4/297 patients (1.3)
• 3 asymptomatic, 1 previous heart failure
• (Schoser BG et al. Neurology 2004)

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RARE AFGHAN FAMILY WITH THREE HOMOZYGOUS PATIENTS
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Schoser B et al. Brain 20041271868-1877
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Schoser B et al. Brain 20041271868-1877
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Schoser B et al. Brain 20041271868-1877
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Schoser B et al. Brain 20041271868-1877
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Schoser B et al. Brain 20041271868-1877
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Schoser B et al. Brain 20041271868-1877
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AFGHAN FAMILY

• Their phenotype is not different from the wide
  spectrum of heterozygote phenotype
• Temporal atrophy prominent
• 4/11 heterozygote children ? CK
• 2/11 heterozygote children ? gamma GT

Schoser B et al. Brain 20041271868-1877
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UNUSUAL PHENOTYPE

• Myalgia, athleticism (Marathon runs) ? CK (G.
  Bassez, France)
• Polish family athleticism (son speed skater
  mother championship gymnast) No weakness in
  son, mild weakness in mother later (4 MRC) EMG
  myotonic discharges in son no myotonic
  discharges in mother subsarcolemmal vacuoles at
  muscle biopsy (Toth et al. Muscle Nerve 2007)
• Hearing loss in Finnish PDM family (Udd et al.
  NMD 1997) and in 5/29 DM2 compared to 10/25 in
  DM1 French family

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DM2 CLINICAL SPECTRUM

• Chloride channel mutations may be incidental
• (Lamont PJ, Jacob RL, Mastaglia FL, Laing NG. J
  Neurol Neurosurg Psychiatry 2004)

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DM2 CLINICAL SPECTRUM
Normal appearance
Spinal muscular atrophy - mimicking
camptocormia
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CLINICAL APPROACH ALGORITHM TO THE ADULT
PATIENT WITH MYOTONIA
Moxley RT and Meola G. The Myotonic Dystrophies.
Chapter In press 2007
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MYOTONIA DM2 vs NDM

• May be absent clinically
• Often only in the hands
• Never as severe as patients with MC or PC
• Same warm-up as in MC but less apparent
• May present as stiffness and locking of legs
  only subjective
• Often similar triggers as in NDM
• cold/hot weather temperature-sensitive
• menses
• anxiety

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MYOTONIA DM2 vs NDM
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Phenotype/genotype unsolved issues

• Why does the pattern and severity of muscle
  wasting and weakness vary between kindreds with
  DM2/PROMM and PDM that link to the chromosome
  3q21 locus? Why does the phenotype vary within
  the same kindred?
• Why is clinical myotonia lacking in PDM and why
  does it seem to fluctuate more in DM2/PROMM
  than, for example, in DM1?
• Is the development of cataracts in DM2/PROMM and
  PDM similar for each disorder? Is the
  pathomechanism similar to that in DM1?
• More information is necessary to define the
  natural history and to determine the prevalence
  of PDM

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CONCLUSIONS

• Clinical spectrum of DM2 varies widely
• High CK SMA Extrapiramidal disorders
• Asymptomatic DM2 may share features in common
  with NDM
• Myotonia is different
• Multisystem involvement directs towards diagnosis

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CONCLUSIONS

• PROMM phenotype may be mistaken for MC
• Leg hypertrophy normal strength no cataracts
• Muscle biopsy
• PDM phenotype may be mistaken for SMA
• Neurogenic signs on EMG and muscle biopsy may be
  confounding
• Cataracts may be absent
• Unresponsive camptocormia consider DM2
• High CK screening include DM2
• Athleticism, myalgia, ? CK include DM2

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