Transcript A 32 year old male with predominantly distal weakness, atrophy and

A 34 year old male with
predominantly distal weakness,
atrophy and myotonia
Cecile L. Phan, M.D., F.R.C.P.C.
Eddie L. Patton, M.D.
Yadollah Harati, M.D., F.A.C.P.
Clinical History
• 34 yo RHD male presented with complaint of
muscle atrophy and weakness affecting the hands
and feet.
• Onset unclear. Probably had symptoms for years
but never interfered with daily activities.
Progression very slow and insidious.
• January 2009:
– Difficulty putting on sandals because he could not lift
the toes.
– Bilateral foot drop
– Hand grip weaker, hand muscles are atrophied
Clinical History
• Recently had difficulty fully lifting the legs up
to put on socks.
• No ocular, facial, bulbar, or respiratory
symptoms.
• No muscle twitches, cramps, difficulty
releasing hand grips, or sensory abnormalities.
• No cognitive complaints
Clinical history
• Evaluated by local neurologist who performed
EMG/NCS which showed a moderate-severe
myopathy with fibrillations and positive sharp
waves.
• He was referred to us for consultation and a
muscle biopsy to rule out an inflammatory
myopathy or a glycogen storage myopathy
Clinical History
• PMHx and SHx:
– Normal development in childhood and adolescence,
although never been involved much in sports.
– Exercise induced asthma
– Vitamin B12 deficiency – has been on B12 injections
without any improvement in symptoms.
– Right wrist surgery
• Medications:
– None
• Allergies:
– None
Clinical History
• Social Hx:
– Computer specialist.
– Married, has twin daughters
– Drinks and smokes socially
• Family history:
–
–
–
–
Parents still alive
3 sisters, 1 brother. One sister has B12 deficiency.
Twin daughters healthy.
French Cajun origin. No other extended family members
with similar symptoms.
• ROS:
– Negative
Physical examination
• General examination unremarkable
• Neurologic exam:
– Normal cognitive function
– Cranial nerves were normal
– Symmetrical wasting of the proximal arm muscles,
paraspinal muscles, intrinsic muscles of the hands
and feet, and anterior compartment of the legs.
Neurologic examination
Right
Left
Right
Left
Neck flexors
5
Iliopsoas
4
4
Neck extensors
5
Hip adductors
4+
4+
Deltoids
5
5
Hip abductors
4+
4+
External rotators
4
4
Quadriceps
5
5
Biceps
4
4
Hamstring
5
5
Brachioradialis
4
4
Tibialis anterior
1
1
Triceps
5
5
Extensor Hallucis L.
0
0
Wrist extensors
4
4+
Peronei
4+
4+
Wrist flexors
4+
5
Tibialis posterior
5
5
Finger extensors
5
5
Gastrocnemius
5
5
Finger flexors
4+
5-
Interossei
4
4
Thenar
4
4
Neurologic exam
Right
Left
Biceps
0
0
Brachioradialis
0
0
Triceps
0
0
Patella
+2
+2
Achilles
+2
+2
Plantar resp
Down Down
• Sensory exam – normal
• Gait and balance – bilateral foot drop
• Remaining neurologic exam normal
Investigations:
• EMG/NCS of the right UE and LE:
– NCS shows low CMAP amplitude secondary to
atrophy with normal dML and CV.
– EMG shows diffuse short duration, polyphasic
units with evidence of myotonia in several
muscles, distal > proximal. Myopathic
abnormalities were also noted in the paraspinous
and sternocleidomastoid muscles.
Investigations
• CPK 411 U/L
• Genetic testing for myotonic dystrophy type I
negative
• Right biceps muscle biopsy was performed.
H&E: Marked increased variability in fiber size and shape. Most fibers
appear rounded. Clusters of rounded, small fibers as well as hypertrophic
fibers (up to 152 microns) are seen. Increased endomysial connective
tissue is also observed.
H&E: several fibers contain one or several rimmed vacuoles
H&E: rimmed vacuole with granular material lining
the vacuole
ATPase 9.4: atrophic and hypertrophic fibers of both fiber types. The
vacuoles are often seen in clusters of atrophic fibers.
NADH (left) and non-specific esterase (right): atrophic, angular fibers with excessive
NADH and non-specific esterase activity indicative of neurogenic atrophy
SMI 31: SMI 31 positive aggregates seen in the cytoplasm of a non-vacuolated fiber
(arrow, left figure) and diffuse increase in the cytoplasm of some atrophic fibers (right
figure
Summary
• A 34 year old male with a few years history of insidious
onset and slowly progressive muscle atrophy and
weakness affecting initially the distal followed by
proximal muscles in the arms and legs.
• EMG/NCS showed a generalized myopathy with
myotonia
• Biopsy showed a moderately severe, chronic, noninflammatory myopathy with abundant rimmed
vacuoles, SMI 31 positive aggregates, rare congophilic
deposits, and mild neurogenic atrophy.
DDx of muscle disorders with rimmed
vacuoles:
• Inclusion body myositis
• Hereditary inclusion body myopathy:
–
–
–
–
h-IBM1 (desmin myofibrillar myopathy)
h-IBM2 (Nonaka distal myopathy)
h-IBM3 (myosin heavy chain IIa)
h-IBM with Paget disease and frontotemporal dementia (IBMPDFTD)
• Distal myopathies/muscular dystrophies:
– Early adult onset – Gowers-Laing, Miyoshi
– Late adult onset – Welander, Markesbery-Griggs, Udd
• Myofibrillar myopathies
• Others:
–
–
–
–
–
–
OPMD
Oculopharyngodistal myopathy
Pompe, Danon
Emery-Dreifuss X linked
LGMD 1A, 1G, 2G
X-linked myopathy with excessive autophagy
A diagnostic test was performed…
What is the diagnosis?
• Genetic testing for Inclusion Body Myopathy
via GNE gene sequencing:
– Homozygous mutation in exon 10 of the GNE gene
 substitution of isoleucine by threonine at
codon 618 (p.Ile618Thr)
– This mutation has been found in 2 families, one
originating from a French Cajun family in
Louisiana, and another from Italy.
Final diagnosis
Hereditary Inclusion Body Myopathy
type 2
(h-IBM2 OMIM#600737)
h-IBM2
• The term “hereditary inclusion body
myopathy” refers to several syndromes with
AD or AR inheritance.
• Most common form (h-IBM2) was originally
described in Persian Jewish families
• Patients from other ethnicities have been
identified (Caucasian, Indian, Thai, Japanese,
African)
h-IBM2
• Clinical course:
– onset in 2nd-3rd decade of life
– weakness and atrophy of distal lower limbs followed
by proximal progression
– Partial or complete sparing of quadriceps even in
advanced stage
– Upper limbs – shoulder girdle, wrist extensors, hands
affected in more advanced stage
– Progression of muscle weakness continues over the
next 10-20 years after onset
– Usually spares ocular, bulbar, and respiratory muscles.
Cardiac involvement in rare, severe cases.
h-IBM2
• Investigations:
– CPK normal or mildly elevated (2-5X)
– EMG/NCS:
• Myopathic changes
• Spontaneous activity fibs, PSW, CRD
• ? Myotonia (recent case report* of patient with
IBMPFD –hereditary IBM with Paget’s disease and
frontotemporal dementia – also showed myotonic
discharges)
– MRI – fatty replacement of muscles (early –
anterior tibialis, hamstring; later – gastrocnemius)
*Barohn RJ, Watts GD, Amato AA. A case of late onset proximal and distal muscle
weakness. Neurology 2009; 73 (19):1592-1597
h-IBM2
• Pathology:
– Chronic myopathic changes
– Rimmed vacuoles
– Protein aggregates:
• SMI 31 positive hyperphosphorylated tau aggregates
• βAPP, ubiquitin, ApoE
– Intracytoplasmic and intranuclear tubulofilamentous
inclusions on EM
– Variable degree of neurogenic atrophy
– Occasional congophilic deposits
– Usually lack inflammation
h-IBM2
• Molecular Genetics:
– Autosomal Recessive inheritance
– Gene encoding GNE, chromosome 9:
• Over 60 mutations described world wide
• Usually missense mutations
GNE function:
GNE
Sialic acid is present on distal
ends of N- and O-glycans and
involved in many biological
functions
h-IBM2
• Role of GNE in the pathogenesis of hIBM2:
– Hypothesis:
• Impaired GNE function  hyposialylation of important
muscle glycoproteins such as α dystroglycan and
NCAM perturbed folding and trafficking through ER
and Golgi apparatus  accumulation of these
abnormal proteins in cytoplasm  activating ubiquitinproteosome system or the autophagic process 
progressive muscle fiber degeneration.
h-IBM2
• Treatment:
BMC Neurology 2007, 7:3
h-IBM2 treatment
• 4 h-IBM2 patients were treated with IVIg because IVIg
contains 8μmol of sialic acid/g
• Loading dose 1g/kg X 2 consecutive days followed by 400
mg/kg q weekly X 3 weeks
• Results:
– Quadriceps strength improved by 22% after loading dose and
35% at end of study
– Shoulder abduction improved by 44% after loading dose and
46% at end of study
– Composite improvement for 8 other muscle groups were 5%
after loading dose and 19% at end of study.
– Patients experienced subjective improvement in daily activities
– No evidence of increased sialylation on α dystroglycan and
NCAM in muscle samples after IVIg treatment.
h-IBM2 treatment
• Use of sialic acid
precursors such as ManNAc could be a source of
sialic acid.
• Human Man-NAc trial is
currently on hold
because of a lack of
funding to complete
animal toxicity trials
Conclusions
• h-IBM is a very rare disease! However, the
striking histopathologic similarities between hIBM and Inclusion Body Myositis suggest that
they share downstream pathologic mechanisms
that lead to progressive muscle fibers
degeneration.
• The pathogenesis of this disease and the role of
GNE is still unclear. Sialylation abnormalities may
be epiphenomena and GNE mutation could affect
cellular functions unrelated to sialic acid
pathway.