Multisystem proteinopathy

DR
HARISUTHAN.T

Overview
Multisystem proteinopathy (MSP) is an inherited pleiotropic degenerative
disorder that can affect muscle, bone, and the nervous system and was first
reported as familial motor neuron disease in association with Paget disease of
bone (PDB).
The MSP phenotype also involves inclusion body myopathy (IBM) or
frontotemporal dementia (FTD).

Trans Assoc Am Physicians 1982;95:12

The acronym IBMPFD describes some families with this syndrome,

but it has outlived its usefulness since other phenotypic features
sometimes dominate the clinical picture: parkinsonism and peripheral
neuropathy occur, and motor neuron dysfunction is frequent

Since the original description, various reports of families with IBMPFD have
made some reference to ALS, either explicitly (e.g., by the mention of family
member with ALS) or implicitly (e.g., through clinical and electrophysiologic
findings that indicate motor neuron involvement, such as fasciculations,
spasticity, hyperreflexia, extensor plantar responses, chronic reinnervation
changes on EMG, and prolonged central motor conduction time).
Invariably, these reports overlooked the possible direct connection between
VCP mutations and ALS.

IBMPFD is an autosomal dominant disorder characterized by incomplete penetrance

of 3 main features: disabling muscle weakness (in 90%), osteolytic bone lesions
consistent with Paget disease (in 51%), and frontotemporal dementia (in 32%).
Recognised features include proximal and distal weakness, early-onset PDB, earlyonset FTD and cardiomyopathy.
Muscle weakness is an isolated symptom in about 30% of patients and the
presenting symptom in greater than half of patients, suggesting that IBMPFD may
commonly be seen in a neuromuscular clinic without its other syndromic features.

Mutations in the valosin-containing protein (VCP) gene were the

first identified cause of IBMPFD but reports of families without
linkage to chromosome 9 established the genetic heterogeneity
of the disorder.
It has recently emerged that mutations in the HNRNPA2B1
(chromosome 7) and HNRNPA1 (chromosome 12) genes account
for some families with IBMPFD.

Initial possibility of a connection between IBMPFD and amyotrophic lateral

sclerosis (ALS) after mutations in the VCP gene were identified in patients
with familial ALS.
Interestingly, the original report of IBMPFD almost 30 years ago described it
as a familial disorder of combined lower motor neuron degeneration and
skeletal disorganization; the presence of fasciculations, EMG evidence of
chronic reinnervation, and muscle biopsy showing grouped atrophy all
pointing toward a primarily neurogenic process.
This family was subsequently found to have an R155Q mutation in the VCP
gene.

VCP (Valosin - containing protein)

VCP is a ubiquitin-dependent segregase that extracts proteins
from multimeric complexes and is required for ubiquitindependent autophagy, including autophagic degradation of RNA
granules; the result of disease mutations in VCP is accumulation
of persistent RNA granules identical to those caused by
mutations in RNA-binding proteins.

Thus, failure to degrade RNA granules via autophagy is likely a key

contributor to pathogenesis. Consistent with this idea, SQSTM1 is a
ubiquitin-dependent autophagic adaptor protein that targets aggregated
proteins to the autophagosome.
Similarly, 2 other adaptors required for ubiquitin-dependent autophagy,
OPTN and UBQLN, are frequently found in the pathology of MSP and
related diseases, and mutations in these 2 genes are causative of ALS
and, in the case of OPTN, FTD.

Clinical Features
Tucker et al. (1982) studied a large kindred with a syndrome of
lower motor neuron degeneration and polyostotic skeletal
disorganization resembling Paget disease of bone.
The disorder begins insidiously at about age 35 with weakness
and atrophy of the leg and proximal arm muscles.
Nerve conductions are normal; EMG shows muscle denervation,
as does muscle biopsy.

Trans. Assoc. Am. Phys. 95: 126-134, 1982.

The disorder progresses to wheelchair confinement and later to

bed confinement, quadriparesis, dementia, respiratory failure,
and death before age 60 years.
Even early in the neurologic illness, patients have coarse
trabeculation, cortical thickening, and spotty sclerosis on bone
x-rays; diffusely increased uptake of radionuclide and elevated
heat-labile serum alkaline phosphatase.

Trans. Assoc. Am. Phys. 95: 126-134, 1982.

Kimonis et al. (2000) described a family in which autosomal dominant limbgirdle muscular dystrophy (LGMD) was associated with early-onset Paget
disease of bone PDB and cardiomyopathy.
Eight of 11 affected individuals had both disorders.
Onset of PDB occurred at a mean age of 35 years, with classic distribution
involving the spine, pelvis, and skull.
Muscle weakness and atrophy was progressive with mildly elevated to normal
CPK levels.

Genet. Med. 2: 232-241, 2000

Muscle biopsy in the oldest male revealed vacuolated fibers, but in

others revealed nonspecific myopathy.
Affected individuals die from progressive muscle weakness and
respiratory and cardiac failure in their forties to sixties.

Kovach et al. (2001) described the clinical, biochemical, radiologic,

and pathologic characteristics of 49 affected individuals from the
family described by Kimonis et al. (2000) and 3 other unrelated
families with autosomal dominant inclusion body myopathy (IBM),
PDB, and frontotemporal dementia.
Ninety percent of the patients had myopathy, 43% had PDB, and 37%
had premature frontotemporal dementia.

Molec. Genet. Metab. 74: 458-475, 2001.

Kim et al. (2011) reported 3 Korean sibs with IBMPFD confirmed by genetic
analysis. The proband developed progressive dementia presenting as fluent
aphasia and language difficulties with onset at age 47.
She never developed myopathy, but did develop asymptomatic Paget disease
with increased serum alkaline phosphatase and lytic bone lesions on imaging.
Her brother developed slowly progressive proximal muscle weakness at age 50,
followed by frontotemporal dementia characterized initially by comprehension
defects at age 54. He never had Paget disease, although serum alkaline
phosphatase was increased.

Arch. Neurol. 68: 787-796, 2011

A second brother developed muscle weakness at age 47, followed by Paget

disease at age 53, and dementia at age 61.
Brain MRI in all patients showed asymmetric atrophy in the anterior inferior
and lateral temporal lobes and inferior parietal lobule with ventricular
dilatation on the affected side (2 on the left, 1 on the right).
Two had glucose hypometabolism in the lateral temporal and inferior parietal
areas, with less involvement of the anterior temporal and frontal lobes
compared to those with typical semantic dementia.
Arch. Neurol. 68: 787-796, 2011

Watts et al. (2004) reported 13 families with IBMPFD, 12 from the U.S.
and 1 from Canada. Among those individuals, 82% of affected
individuals had myopathy, 49% had PDB, and 30% had early-onset
frontotemporal dementia.
The mean age at presentation was 42 years for both IBM and PDB,
whereas frontotemporal dementia typically presented at age 53 years.
In IBMPFD myopathic muscle and PDB osteoclasts, inclusions appear
similar, suggestive of disruptions in the same pathologic pathway.
Nature Genet. 36: 377-381, 2004.

Viassolo et al. (2008) reported an Italian family in which 2 sibs and their
mother had IBMPFD. All 3 had progressive inclusion body myopathy and
rapidly progressive severe dementia, but only 1 developed Paget disease.
Genetic analysis identified a heterozygous mutation in the VCP gene. Several
other family members were reportedly affected.
Viassolo et al.(2008) discussed the implications of the incomplete penetrance
of some of the features for genetic counseling.

Clin. Genet. 74: 54-60, 2008.

Neuropathologic Findings
Schroder et al. (2005) reported a patient with frontotemporal dementia (FTD) and
inclusion body myopathy caused by mutation in the VCP gene. There was no
evidence of Paget disease. Neuropathologic examination showed cortical atrophy
and widespread neuronal loss; subcortical neuronal loss was less severe.
The cerebral and cerebellar white matter had severe astrogliosis. Surviving
cortical pyramidal neurons contained VCP- and ubiquitin - positive intranuclear
inclusions and displayed cytoplasmic autofluorescence consistent with lipofuscin.

Ann. Neurol. 57: 457-461, 2005.

Nuclear inclusions were not seen in astrocytes, oligodendrocytes, or microglial cells.

Western blot analysis showed a single 97-kD band corresponding to normal-sized
VCP that was similar to control brains.
Schroder et al. (2005) concluded that mutant VCP causes a novel form of
frontotemporal dementia, distinct from tau -associated FTD, characterized by
neuronal nuclear inclusions containing ubiquitin and VCP.
The authors suggested that mutant VCP interferes with ubiquitin-dependent
pathways, leading to abnormal intracellular and intranuclear protein aggregation.

An operational definition of MSP is a combination of 2 or more of IBM,

PDB, and amyotrophic lateral sclerosis (ALS)/FTD (where ALS and FTD are
considered as one spectrum).

Histopathologically,

MSP-affected tissues have ubiquitin-positive

inclusions that contain RNA-binding proteins, such as TDP-43, hnRNPA1,

and hnRNPA2B1, but may also include positive staining for proteins that
mediate ubiquitin-dependent autophagy, including p62/SQSTM1, VCP,
optineurin, and ubiquilin-2.

Disease-causing mutations in VCP provided the first insight into the molecular etiology of
MSP, accounting for up to 50% of families with this genetically heterogeneous syndrome.
Mutations in HNRNPA2B1 and HNRNPA1 were subsequently identified in families with MSP
that was clinically and histopathologically indistinguishable from VCP mutation cases.
These discoveries prompted recognition that rare pathogenic genetic mutations are
lurking in larger populations of patients with more common MSP-related diseases, such as
ALS and FTD.
For example, mutations in VCP, HNRNPA1, and HNRNPA2B1 have been identified in
sporadic and familial forms of ALS.

Bucelli et al. report the identification of disease-causing mutations in SQSTM1 in a family with an
autosomal dominant IBM that clinically and histopathologically closely resembles that seen in
association with VCP, HNRNPA2B1, and HNRNPA1 mutations.
The pattern of muscle weakness was that of a distal or facioscapulo distal myopathy, and the
muscle pathology demonstrated rimmed vacuoles as well as inclusions of both TDP-43 and SQSTM1.
Pathogenic mutations in SQSTM1 are a frequent cause of PDB and are responsible for rare cases of
sporadic and familial ALS and FTD.
Mutations in SQSTM1 are now associated with pleiotropic clinical features that include myopathy,
dementia, motor neuron disease, and PDB and should, be included among the MSPs.

The genes associated with MSP or related

diseases fall into 2 conspicuous categories:
RNA-binding proteins and proteins that mediate ubiquitin-dependent autophagy.
hnRNPA2B1, hnRNPA1, hnRNPDL, and TIA-1 are all paralogous RNA-binding proteins of
the hnRNP family, as are the ALS-/FTD-related proteins TDP-43 and FUS.
Disease-causing mutations in these RNA-binding proteins typically reside in a conserved domain

found in each protein that mediates the assembly of RNA granules, specialized cytoplasmic RNA
protein assemblies that control posttranscriptional messenger RNA metabolism. The
consequence of disease mutations is excess assembly and persistence of RNA granules,
probably accounting for accumulation of granule components in pathologic inclusions.

This disturbance of RNA granule dynamics likely alters RNA metabolism and probably
contributes to disease pathogenesis.

Conclusion
IBMPFD presents as a multisystem disorder affecting brain, skeletal and
cardiac muscle, spinal cord and bone.
Clinical reports of this disease are scarce.
Family members usually presented with proximal weakness, progressing to
wheelchair disability and premature death.
The R155H mutation, an arginine-to-histidine substitution in the N-terminal
CDC48 domain of the VCP protein, results in loss of VCP function and is found
exclusively in individuals affected with IBMPFD.

The phenomenon of MSP raises 2 major

questions.
First, why do patients with identical mutations in the same gene
sometimes develop quite distinct clinical phenotypes affecting
different tissues?
The existence of modifier genes is an obvious possibility, but the
high prevalence of pleiotropy even among closely related family
members argues that other stochastic factors, perhaps at the
cellular level, may be at work.

Second, what can we learn from MSP about the etiologic relationship
between seemingly distinct age-related degenerative diseases of muscle,
bone, and brain?
The current evidence suggests that subsets of patients with ALS, FTD, IBM,
and PDB share a common molecular pathogenesis related to the
metabolism of RNA granules and their destruction by autophagy.
Thus, therapeutic development for restoring RNA granule homeostasis, socalled ribostasis, may apply to a broad spectrum of age-related
degenerative diseases.

Thank you