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Recent Advances in 25 year-old woman Normal motor and cognitive - - PowerPoint PPT Presentation

Oct 18, 2023 107 likes •213 views

2/14/2014 Patient #1: Young woman with severe polyneuropathy Recent Advances in 25 year-old woman Normal motor and cognitive development Neurology 2014: Short stature At age 18, became amenorrheic Neuromuscular Case At age

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2/14/2014 1

Recent Advances in Neurology 2014: Neuromuscular Case Presentations

Jeffrey W. Ralph, MD Associate Clinical Professor

Patient #1: Young woman with severe polyneuropathy

25 year-old woman

Normal motor and cognitive development Short stature At age 18, became amenorrheic At age 18 or 19, developed steppage gait and

numbness in the lower extremities

EMG/NCS – severe axonal polyneuropathy At age 24, developed memory and word finding

problems, though still able to work

Multiple hospitalizations for worsened weakness

Lactic acidosis Chronic thrombocytopenia Macrocytic anemia Developed diabetes Cirrhosis

Case History #2

Family History

No neurodegenerative disorders Parents are second cousins

Exam

Enlarged liver Cranial Nerves—normal including fundoscopic Normal muscle tone; striking atrophy and weakness of the hand

and leg muscles

Reflexes absent/hypoactive Sensory examination—stocking distribution impairments of

vibration and pain sensation

HKS- Clumsy; Wide-based, unsteady gait

Labs

CK—Normal INR 1.8 Hb 9.5 g.dL and MCV 105 fL (ULN < 100 fL) Normal B12 Plasma lactate--Elevated

MR brain

T2 weighted, axial image. Confluent and symmetrical hyperintensities in deep and subcortical white matter of posterior frontal and parietal lobes, involving the subcortical U-fibers. There was no enhancement of these areas with gadolinium.

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2/14/2014 2

Leukoencephalopathy

Cirrhosis Lactic Acidosis

Poly- neuropathy Mitochondrial syndrome was suspected.

Which is true?

PLEASE SHOW RESPONSES!!

E a c h m i t

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d . . . m t D N A i s d

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b l . . . m t D N A

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h

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19% 60% 4% 17%

1.

Each mitochondrion has multiple copies

  • f mtDNA

2.

mtDNA is double stranded and linear

3.

mtDNA only replicates during cell division

4.

Mitochondrial disorders are only inherited maternally

Mitochondria Nucleus TESTING: Hepatocerebral-DNA depletion syndrome panel: Apparent homozygous mutations of MPV17

Mitochondrial DNA Depletion Syndromes

Mitochondrial DNA Depletion Syndromes

Autosomal recessive Most syndromes present very early in life, but

greater appreciation of adult-onset cases

nDNA genes encode key proteins

Mitochondrial nucleotide synthesis mtDNA replication

nDNA mutations

Cause depletion (reduced copy number) of mtDNA May also cause multiple mtDNA deletions

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Mitochondrial DNA Depletion Syndromes

Mitochondrial Depletion Syndrome Phenotype Gene Typical Age of Onset Common Clinical Features Myopathic TK2 Infancy or early childhood Muscle weakness, hypotonia, bulbar weakness, elevated CK Encephalomyopathic SUCLA2, SUCLG1, RRM2B Neonatal- Infancy Hypotonia and muscle weakness, psychomotor delay, short stature, lactic acidosis, epilepsy Hepatocerebral DGUOK, MPV17, POLG, C10orf2 (Twinkle) Neonatal- childhood Hepatic dysfunction, psychomotor delay, hypotonia, neuropathy, ataxia, lactic acidosis, stroke or stroke-like episodes, myoclonus and choreoathetosis, epilepsy, leukoencephalopathy, hearing loss Neurogastrointestinal TYMP Late childhood- adolescence GI dysmotility, weight loss, neuropathy, ptosis, ophthalmoplegia, elevated thymidine and deoxyuridine in plasma, leukoencephalopathy

MPV17 Mitochondrial DNA Depletion Syndrome

Autosomal recessive Function of MPV17 is not known In addition to mtDNA depletion, patients accrue multiple

mtDNA deletions

Clinical:

Severe axonal, mixed fiber polyneuropathies Liver: Steatohepatitis, cholestasis, cirrhosis and liver failure Lactic acidosis Leukoencephalopathy: Disabling cognitive problems and upper

motor neuron signs not common

Novel in this case: Amenorrhea

Mutations in the nuclear DNA may cause?

PLEASE SHOW RESPONSES!!

R e d u c e d a m

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n t . . . M u l t i p l e m t D N A . . . A b n

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3% 85% 3% 10%

1.

Reduced amounts of mtDNA in tissues

2.

Multiple mtDNA deletions

3.

Abnormalities on respiratory chain enzyme testing

4.

All of the above

Mitochondrial DNA depletion syndromes:

PLEASE SHOW RESPONSES!!

A r e a u t

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a l . . . U s u a l l y p r e s e n . . . M a y h a v e d i f f e . . . A l l

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2% 91% 5% 2%

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Are autosomal recessive

2.

Usually present in infancy or early childhood

3.

May have different phenotypes at different ages of presentation

4.

All of the above

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SLIDE 4

2/14/2014 4 Patient #2: Myotonia congenita…or something else?

  • 25 year-old man

Lifelong muscle pain Exercise was pain-limited since childhood No bouts of visible myoglobinuria; no muscle

contractures

  • Family history: Mother and Maternal GF --similar

symptoms; MGF US Army dx: congenital myotonia

  • Exam:

Normal tone; normal or inc bulk; no grip myotonia Percusssion of muscles produced:

Rapid contractions Mounding of the muscles Some rippling

Reflex, sensory, and gait examinations normal

Testing: CK 693 U/L

Mutations of which of the following genes is not associated with myotonia?

PLEASE SHOW RESPONSES!!

S C N 4 A – s

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i u m c . . . C A C N A 1 S – c a l c i u . . . C L C N 1 – c h l

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16% 24% 49% 11%

1.

SCN4A–sodium channel

2.

CACNA1S–calcium channel

3.

CLCN1–chloride channel

4.

All of the above

Muscle Channelopathies

Chloride Channelopathies: Myotonia

Myotonia Congenita

Autosomal Dominant – Thomsen disease Autosomal Recessive – Becker disease

Sodium Channelopathies: Myotonia or Paralysis or Both

Potassium-Aggravated Myotonia Paramyotonia Congenita Hyperkalemic Periodic Paralysis

Other Cation Channelopathies: Paralysis without

Myotonia

Calcium Channelopathy

Hypokalemic Periodic Paralysis (*some SCN4A)

Potassium Channelopathy

Andersen-Tawil syndrome Thyrotoxic Periodic Paralysis

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Myotonia: Electrodiagnostic Testing

Fournier et al., Annals, 2006

TESTING: INCREASED INSERTIONAL ACTIVITY BUT NO MYOTONIA; NO DECREMENT OF CMAP ON REPEATED SHORT EXERCISE TESTING

?

Myotonia Congenita

Symptoms: Stiffness; falls;

difficulty letting go; warm-up phenomenon

Onset: Early childhood Despite limitations, usually do well;

can play some sports

Exam: Muscle hypertrophy; clinical and EMG myotonia;

Becker patients may have fixed weakness

Caused by mutations of CLCN1

AD (Thomsen) AR forms (Becker)

AR > AD: Transient weakness shortly after initiating

exercise

Could it be genetic rippling muscle disease?

Not again.

Caveolinopathies

Caveolinopathies

CAV3-Related Distal Myopathy CAV3-Related Hypertrophic Cardiomyopathy CAV3-Related Isolated HyperCKemia CAV3-Related Rippling Muscle Disease Limb-Girdle Muscular Dystrophy Type 1C

Patient TR: Mutation in CAV3

Arginine27Glutamine

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Rippling Muscle Disease

Historical

1975: Torbergsen described a

family with dominant hereditary “myotonia,” muscular hypertrophy, and muscular irritability.

Distinct from myotonia congenita

1980: Alberta probably reported

the first sporadic case.

“Increased mechanical muscle

irritability syndrome.”

Rippling Muscle Disease

Rippling Muscles

The direction of rippling is perpendicular to the

  • rientation of the muscle fibers.

Propogation of contraction is 10x slower than muscle

fiber action potential propagation.

Rippling is (mostly) electrically silent.

Percussion-Induced Rapid Muscle Contractions Percussion-Induced Myoedema Muscular Hypertrophy Mild CK elevations (<10x upper limit of normal)

Rippling Muscle Disease Hereditary Acquired/Autoimmune Main Symptoms Myalgias; Stiffness ± Weakness Stiffness; Weakness if MG also present CK Mildly elevated Mildly elevated EMG Increased Insertional Activity Increased Insertional Activity Treatment Dantrolene or Calcium Channel blockers (single case reports) Immunosuppressive medications; Given benign natural history, may not be necessary Disease Associations None Myasthenia gravis Thymoma Other lab findings… None + Anti-striated muscle antibodies + Ach Receptor antibodies Symptom Onset Childhood 33-60 years old

Show Video of Rippling Muscles

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2/14/2014 7

Ca++

Ca++ Ca++ Ca++ Ca++

mV

Ca++ Ca++ Ca++ Ca++

CONTRACTION

Normal Neuromuscular Junction

Ca++ mV

Rippling Muscle Disease

Abnormal Abnormal

Ca++ Ca++ Ca++ Ca++

Propogation of the Region

  • f Contraction

Pathophysiology of Rippling

Mechanical stretch activates the ryanodine receptor

sarcomere contracts resulting stretch activates adjacent ryanodine receptors etc.

Problems with hypothesis:

Very large, rapid stretches do not induce direct activation of SR

Ca++ release in neonatal rat muscle fibers.

Activating 220,000 sarcomeres per second to cause the

contraction seems implausible.

Why would a stretch affect the T-tubule system anyway?

Possible Explanation: Combined

Mechanical and Electrical Hyperexcitability

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2/14/2014 8

Caveolin-3: Normal Gene Product

Three isoforms (CAV1; CAV2; CAV3)

Cav-3 is a muscle-specific protein (cardiac,

skeletal, and smooth muscle) Roles

Sarcolemmal Stability

Forms multimers that are the scaffolding for caveolae.

Caveolae are 50-100 nm invaginations on the

sarcolemma

Necessary for normal formation of the T-tubule

system.

Binds to dystrophin-glycoprotein complex Interacts with dysferlin

Signalling

Regulates Src kinase and nitric oxide synthase In cardiac muscle, multiple ion channels are

targeted to the caveolae

Important for myoblast cell differentiation and

survival

Caveolin-3: Abnormal Gene Product

Mutations

Dominant-Negative Effect Abnormal gene product sequesters the normal protein in the Golgi

apparatus

Structural Effects Loss of Caveolae T-tubule system derangement Large subsarcolemmal vesicle formation Causes mislocation of dysferlin

Genotype-phenotype correlations do not exist

Caveolinopathies

Caveolinopathies

CAV3-Related Distal Myopathy CAV3-Related Hypertrophic Cardiomyopathy CAV3-Related Isolated HyperCKemia CAV3-Related Rippling Muscle Disease Limb-Girdle Muscular Dystrophy Type 1C

Final Points

In patients with hyperCKemia and myalgias

(geez…lots of patients), consider caveolinopathy.

Muscle rippling can have a genetic or

autoimmune cause

If a patient complains of stiffness or myalgias,

GO AHEAD AND PERCUSS THE MUSCLE!!

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2/14/2014 9

Mutations of CAV3 are NOT associated with:

PLEASE SHOW RESPONSES!!

R i p p l i n g m u s c l . . . C a r d i

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0% 4% 31% 4% 60%

1.

Rippling muscle disease

2.

Cardiomyopathy

3.

Retinopathy

4.

Isolated HyperCKemia

5.

Limb-Girdle muscular dystophy

Which of the following is NOT a feature of rippling muscle disease:

PLEASE SHOW RESPONSES!!

P e r c u s s i

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2% 98% 0% 0%

1.

Percussion-induced rapid muscle contractions

2.

Muscle mounding

3.

Rippling muscles

4.

Electrical myotonia

Thanks for Your Attention & Happy Valentine’s Day.