Myofibrillar myopathies : A clinicopathological study of 13 cases

Abstract

Myofibrillar myopathies (MFM) are a group of neuromuscular disorders sharing common histological features. We reported thirteen patients from nine families with MFM. Eleven patients have adult onset of weakness between forty to fifty-nine years of age and most of them had lower limb weakness as initial presentation. Two paediatric patients had disease onset at six and eleven years old respectively. One third of the patients have cardiac complications. Four patients needed respiratory support eventually. All have progressive muscle weakness. In general, typical pathology of myofibrillar myopathy (MFM) is noted in all patients. The muscle fibers showed variation in size and shape, with eosinophilic inclusions noted. The numbers of fiber with inclusion varied from abundant to very scanty, requiring diligent search in some cases. Ultrastructural examination was done in all 13 cases. Disorganization of myofilament was noted in general. The granulofilamentous and filamentous inclusions can be focally present and scanty. In one case with FLNC mutation, inclusions were not found in the specimen. Abnormal mitochondria with paracrystalline inclusions were seen in 3 cases, 2 with FLNC mutation. In five patients out of four families c.8129G>A (p.Trp2710*) was detected in FLNC, while in one patient c.626C>T (p.Pro209Leu) and c.772C>T (p.Arg258Trp) were detected in BAG3. In essence, MFM is a slowly progressive disease with onset mostly after forty. Howevert paediatric age of onset is also possible. There is a spectrum of pathology in MFM, from subtle to full-blown histomorphological alterations. High index of suspicion is required for the pathological diagnosis. Mitochondrial abnormalities should alert the pathologist to consider the diagnosis of MFM. The missense variant c.8129G>A (p.Trp2710*) in FLNC appeared to be a recurrent mutation in Hong Kong Chinese.

Full text

Myofibrillar Myopathies: A clinicopathological study of 13 cases
WONG Shun1, LEE Chi Nam2, LEE Hencher1, CHENG Yue3, CHEUNG Yuk Fai4, FU Michael5, SHENG Bun6, HO Ronnie7,
HO Luen Cheung8, CHANG Shek Kwan9, FUNG Sharon10, YAU Eric11, KAN Amanda12, CHAN Angel7, CHAN Sophelia13
1Department of Pathology, Princess Margaret Hospital, HKSAR ; 2Department of Medicine and Geriatrics, Pamela Youde Nethersole Eastern Hospital, HKSAR; 3 Department
of Pathology, Pamela Youde Nethersole Eastern Hospital, HKSAR ; 4 Department of Medicine, Queen Elizabeth Hospital, HKSAR; 5 Department of Medicine and Geriatrics, Tuen Mun
Hospital, HKSAR; 6Department of Medicine and Geriatrics, Princess Margaret Hospital, HKSAR; 7 Department of Pathology and Clinical Biochemistry,Queen Mary Hospital, HKSAR; 8
Department of Pathology, Queen Elizabeth Hospital, HKSAR; 9 Department of Medicine , Queen Mary Hospital, HKSAR; 10Department of Paediatrics, Kwong Wah Hospital, HKSAR;
11Department of Paediatrics and Adolescent Medicine, Princess Margaret Hospital, HKSAR; 12 Department of Pathology, Tuen Mun Hospital, HKSAR; 13 Department of Paediatrics and
Adolescent Medicine, Queen Mary Hospital, The University of Hong Kong, HKSAR
Background: Myofibrillar myopathies (MFM) are a group of
neuromuscular disorders sharing common histological features.
Objective: To describe the clinical , pathologically and some of
the available mutation analysis findings in 13 MFM patients.
Results:
Patients: Thirteen patients from 9 families with pathological
diagnosis of MFM from different hospitals in Hong Kong were
studied.
Clinical Findings: For the 11 adult patients, all have symptom onset
between 40 to 60 years of age, with 10 patients have presenting
symptoms of limb girdle weakness especially difficulty in walking
and only 1 patient presented with acute respiratory failure after
pneumonia that subsequently required ventilation support. Four
patients required long term non-invasive ventilation with the
starting age between 62 to 72 years. Cardiac problems are also
common with 2 patients have hypertrophic cardiomyopathy and 1
patient with sick sinus syndrome requiring pack maker. For the 9
patients that are older than 60, 4 required walking stick and 3
became wheelchair bound. Two patients also have feeding problem
managed by dietary modification. All patients reported progressive
deterioration of motor performance over time.
For the 2 paediatric patients, one child presented with lower limb
weakness and tendoachilles tightness at the age of 6. She
subsequently developed respiratory failure required non-invasive
ventilation and hypertrophic restrictive cardiomyopathy on atenolol.
At 17, she could continue walking with walking sticks. The second
child complaint of difficulty in walking and climbing stairs at the age
of 11. Nerve conduction study confirmed demyelinating sensory and
motor peripheral neuropathy. When last follow-up at the age of 15,
he walked independently and had no cardiac or respiratory problem.
Histopathological findings: There is a spectrum of pathology
in MFM, from subtle to full-blown histomorphological alterations.
In ultrastructural examination, the granulofilamentous and
filamentous inclusions can be focally present and scanty. In one case
with FLNC mutation, inclusions were not found in the specimen.
High index of suspicion is required for the pathological diagnosis.
Histopathological features cannot predict underlying genetic defect.
Abnormal mitochondria with paracrystalline inclusions were seen in
3 cases, 2 with FLNC mutation. Mitochondrial abnormalities should
alert the pathologist to consider the diagnosis of MFM.
Genetic findings: Using sanger sequencing , Six adult patients
out of four families have been diagnosed to have c.8129G>A
(p.Trp2710*) in the FLNC gene. In the first paediatric patient,
c.626C>T (p.Pro209Leu) and c.772C>T (p.Arg258Trp) were detected
in BAG3.
Conclusion:
Myofibrillar myopathy is a slowly progressive disease with mostly
adult onset but possible onset at paediatric age. There is a spectrum
of pathology in MFM, from subtle to full-blown histomorphological
alterations. The missense variant c.8129G>A (p.Trp2710*) in FLNC
appeared to be a recurrent mutation in Hong Kong Chinese.
6 patients with positive genetic findings
Gene
Mutation
Onset symptoms and age
/ Current
age
Mobility/ Respiratory/
Cardiac
FLNC
c.8129G>A (p.Trp2710*)
LL weakness
at 40/ 62
Walk
alone, Sick Sinus Sx
FLNC
*
c.8129G>A (p.Trp2710*)
LL weakness
at59 / 62 (D)
Wheelchair
bound, NIV
FLNC
*
c.8129G>A (p.Trp2710*)
LL weakness at50/ 62
Walk with stick
FLNC
*
c.8129G>A (p.Trp2710*)
LL weakness at 50/ 61
Walk with stick
FLNC
c.8129G>A (p.Trp2710*)
LL weakness at 50 / 52
Walk
alone, Palpitation
FLNC
c.8129G>A (p.Trp2710*)
LL weakness
at 60/ 65
Walk with stick, NIV, LVH
BAG3
c.626C>T (p.Pro209Leu)
c.772C>T (p.Arg258Trp)
LL weakness at 6 / 17
Walk with stick,
HCM,
NIV
Histopathological Features:
From florid to subtle
Florid histopathological changes with many inlcusions
Scanty inlcusions in some cases
Inclusions variably positive for dystrophin, ab-crystalline, and myotilin
Granulofilamentous inclusions; abnormal mitochondria with paracrystalline
inclusions
H&E
H&E
NADH GT
NADH GT
Dystrophin Ab-crystalline Myotilin
* Same family; LL=lower limb; NIV=non invasive ventilation; HCM=hypertrophic
cardiomyopathy; LVH = left ventricular hypertrophy; D = died; Sx = syndrome