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Continuum mechanical modelling of the dissipative processes in the sediment-water layer below glaciers

Francesco Dell'Isola, Kolumban Hutter


Modal coupling in one-dimensional electromechanical structured continua

A passive continuously distributed control of mechanical vibrations is proposed. The piezoelectric actuators are interconnected by a linear electric transmission line. We introduce coupling and internal resonance criteria to determine the optimal choices for electric parameters. These criteria can be found decomposing the differential operator appearing in the linear evolution equations according to a partition of the state vector into mechanical and electrical parts. The results we find allow for the design of an experimental set up.

Introduction

Today many research efforts are devoted to the structural control by electric devices; they are mainly based on the piezoelectric effect (see [START_REF] Eringen | Electrodynamics of continua I-II[END_REF]- [START_REF]Proceedings of SPIE: Smart materials and structures[END_REF]).

Several technological and theoretical problems arise:

i) to control vibrations by means of concentrated devices requires high actuator performances (often not yet available) and high control power with risk of electric discharges; ii) the electric wave-speed is too high compared to the mechanical wave-speed; this means that a real dynamical coupling between electric and mechanical waves (e.g., in a piezoelectric material) is not possible.

Our paper is intended to overcome these two problems: i) by developing the ideas already discussed in [START_REF] Dell'isola | Continuum modelling of piezoelectro-mechanical truss beams: an application to vibration damping[END_REF] and [START_REF] Dell'isola | Damping of bending-waves in truss beams by electrical transmission line with PZT actuators[END_REF], we introduce a transmission line connecting a series of piezoelectric actuators distributed along the structure. The obtained synergy of actuators seems to improve considerably their control performances: to do the job ten men are better than one alone even if this last is ten times stronger," moreover ten men communicating and helping one another are better than ten men acting alone,"

ii) the speed of electric waves can be easily controlled in electric transmission lines by a proper choice of the line inductances and capacitances: the high capacitance of modern PZT actuators allows to push the electric wave-speed into the mechanical range by means of technically feasible line inductances.

The device we propose has a double practical advantage: it requires lower performances to the PZT actuators and it produces an electro-mechanical interaction based on internal resonance phenomena between the modes of the whole electro-mechanical system: this allows for a strong control action and short times to transfer the energy between electrical and mechanical forms.

In Sect. 2 the balance equations for a one-dimensional continua endowed with an affine electro-mechanical structure are derived following the ideas developed in [START_REF] Di Carlo | A non-standard format for continuum mechanics[END_REF]: the mechanical configuration of the beam and the charge distribution in the electric transmission lines are chosen as state variables of the system; the mechanical contact actions, the inertial actions and the electric potential drops are introduced as dual quantities of the generalized velocity and deformation fields; balance equations and boundary conditions are finally obtained by means of the principle of virtual power (see [START_REF] Maugin | The method of virtual power in continuum mechanics: application to coupled fields[END_REF]).

Section 3 mainly concerns the analytical study of the general linear differential operator of the problem within the partition of the state vector into its mechanical and electrical parts. Criteria for the existence of electro-mechanical coupling are stated, and a representation of the solution by Volterra integral equations allows to understand the coupling mechanism and leads to the proper choice of the electrical parameters such as the line inductance and the line resistance producing internal resonance between electrical and mechanical vibrations. In particular it is proven that mutual excitation between mechanical modes can occur also in the linear case through the electric charge vibrations.

Finally, in Sect. 4 we illustrate the previous results by means of numerical simulations; a purely flexible beam clamped-clamped and electrically insulated is chosen as ad hoc example in a time-evolution problem. In this example the spectral properties of the involved differential operator produce an interesting coupling pattern between electrical and mechanical modes. The results of Sect, 4 allow us to design an experimental set up aiming to prove the technological feasibility of the conceived passive piezoelectric damping.

Balance equations and boundary conditions

The mechanical behavior of beams is sometimes very complex. It has been proposed to model such a behavior introducing one-dimensional microstructured continua in which a set of directors describes the deformations of the beam sections (see [START_REF] Capriz | Continua with mierostructure[END_REF]). The most relevant kinematical descriptor of the state of these sections is represented by the attitude which was introduced by Euler and Bernoulli [START_REF] Euler | Methodus inveniendi lineas curvas maximi minimive proprietati gaudentes[END_REF]. However, no further conceptual effort is required when modelling sections constrained to undergo affine deformations [START_REF] Di Carlo | A non-standard format for continuum mechanics[END_REF]. In the present paper we introduce a further set of descriptors in order to model electrical transmission lines coupled to the beam by means of a set of distributed piezoelectric actuators. We will adapt to the electromechanical case the ideas developed in [ 1 1]. Let 13 be the one-dimensional base manifold, Or the two-dimensional point-shape manifold, Q an N-dimensional charges manifold, 7 9 the three-dimensional positions manifold and VP its translation space. All the manifolds are supposed to be endowed with the euclidean metric.

The configuration is a function:

13 • ~ ---+ 79 • Q (g,y) ~ (x(g,y), q(g)), (2.1)
where q(~) represents the electrical charges stored in the [0, ~] segment of the transmission lines, and x(r y) = p(~) + e(r (y -o) (2.2)

is the position of a beam point defined by p(~) = x(r o) which physically represents the position of an arbitrary point o on 5 c chosen as origin, and by P(r which is a linear embedding 1 of VS in V79 representing the attitude and the affine stretching of the beam fibers. More precisely, Vr E 13, x(r .) is an affine application of 5 c in 79, invertible on its image 5~ := x(r 5 c) so that P(r E IsoLin(V5 c, VS~) 2.

A motion is a one-parameter family of configurations:

(~-, y, 7) ~-+ [x(q, y, v), q(~, 7)] ----[p(~, 7) + P(~, T) (y --O), q(~, T)].

(2.3)

For any pair of time instants (t, -r) it is useflfl to consider the following equations:

x(~-) -p(7) = P(T)P(t) -1 [x(t) -p(t)], (2.4) describing the evolution of the fiber vectors. The time derivative of Eq. (2.4) gives us the velocity of the point:

• = 15 + 15P-1 (x -p) = w + W(x -p), (2.5)
so we are led to define the generalized velocity field as (w, W, co):= (lb, ISP -1, dl).

(2.6)

We note that ~o = dl is a set of electric current fields. Also we remark that the tensor W := IbP -1 c IsoLiN (VS~,t, VS~,~) maps the plane copy of the beam fiber at time t in the copy at time r; we can extend its action to the whole translation by means of the condition:

W n(q, ~-) := -W T n(~, T), (2.7)
being n(~, 7) the unit normal to VSC~,~. We choose as descriptor of the time-rate of the generalized deformation the following field:

(d, D, A, 3) := (w'-(SKW W)p', W', sYMW, to'), (2.8)
which vanishes for every velocity field mechanically rigid and with spatially constant current fields. Here the prime means the derivative with respect to q. We call internal actions its dual quantity (s, S, 2], ~) in the expression of the internal power P~: Pi = f(s.d + S.D +2~.A+a.3) d~, (2.9) /3

where "." denotes the inner product in the set of vectors or tensors (see, e.g., [START_REF] Gurtin | An introduction to continuum mechanics[END_REF]). While s and S represent the standard contact force and couple, the dual quantities 1~ and a represent the contact double force exerted on the beam fiber and the set of local electric potential drops, respectively.

The balance equations can be evaluated assuming that for any generalized velocity field the power Pe expended by the external actions, (b, B,fl), equals the internal power: (2.12) Equations (2.11.1 3) and (2.12) evaluated for ~o = 0 are the standard balance equations of a one-dimensional continuum endowed with affine structure. Equations (2.11.4) and (2.12) evaluated for (w, W) = (0, 0) give a formulation of Tellegen theorem (see [START_REF] Chua | Linear and nonlinear circuits[END_REF]). The problem will be complete when the constitutive relations for (s, S, E, a) and (b, B, fl) are assigned.

Pi = f(s. d+ S-D +l~.A+a.h)& = f(b.w+B-W+fl.eo)& = Pe. ( 2

Electro-mechanical coupling criteria

In the following we will limit our attention to the linearized model and rearrange in vectors (labeled by a tilde) the strict components of the infinitesimal displacement fi, of the deformation field ~], and of the internal and external actions (g and 1~). The compatibility Eqs. (2.8) can be linearized getting

a = G(u), (3.1)
where G is the linear differential operator which determines the time-rate generalized deformation field. The linear constitutive equations can be written in the form:

g : KG(fi), 1~ : -Mu, (3.2)
where K and M are the symmetric positive definite stiffness and inertia matrices; moreover we will assume that M is diagonal. Recalling Eq. (2.10) we get

f [KG(fi) 9 G(•)] d{ : f [GAKG(a) . .3 d< = -f [iV[i]. ~1 d{, V~, (3.3)
B B B
so that the linearized balance equations in terms of infinitesimal displacement fields become

L(fi) + i] = 0, (3.4)
where L := M-1GAKG.

Modal analysis of partitioned operator L

We study Eq. (3.4) partitioning fx in its mechanical and electrical components and we label respectively by m and e indices quantities of mechanical and electrical nature. For sake of simplicity we consider fi as a two-dimensional vector. Let ~4 be the Hilbert space:

A := • Ae, (3.5)
where .A~ and Ae are subspaces of L2(/3), the space of R-valued square-integrable functions defined on B verifying suitable homogeneous boundary conditions, endowed with the usual inner product (D, ~>} := f([]~>)&; let u, ii c .A and let L be a self-adjoint positive definite B differential operator on A. We consider the following evolutionary problem:

L(u) +ii = 0, u(0) = u0, u(0) = u0. (3.6)
The partition (3.5) induces the following decompositions of the state vector u and of Eq. (3.6.1): u = {v, "/}, yEArn, 7 E ,.,4+, (

+ + : 0, + L++r + = 0, 3.7)
where the operators L,~,~ and L~ are self-adjoint and L,~+ is the adjoint of L~,~ because of the selfadjointness of L. Equations (3.8) lead us to regard v as the m-response to m inertial actions but also to the e-action of L~+('7) and viceversa for % Let us determine in a more expressive form this dependence; as a consequence of the spectral representations theorem of self-adjoint oparators (see [START_REF] Reed | Methods of modern mathematical physics[END_REF]), for every a E Am, b E .An and r ~ R we have r;+~(a) = f .Xv@, mA} m~ dl~x,

Coupling representation by integral Volterra kernels

In order to test the coupling properties of Eq. (3.6), we search the solution corresponding to purely mechanical initial data: v~ = v2,0, for every A ~ S.~. Applying Fubini's theorem to the second member integral and changing the integration order where it is possible, we get in which fa(t) represents the standard cosinusoidal evolutions of the mechanical modes, and the integral is the representation of the effects of the back and forth exchange of energy with the electrical system 4. [START_REF]Proceedings of SPIE: Smart materials and structures[END_REF] The solution of the system of equations (3.25) can be easily derived by the following constructive iterat tive scheme (see [START_REF] Krasnov | Equazioni integrali[END_REF]

t~ = t),o VA E S,

): v~(~ = fx(t), vx(~)(t) = f~(t) + fkx,• r)v•

if f(t) is continuous in 0 [0, T] aad the kernel k(t, r) is continuous for t r [0, T] and r E [0, t] (which is verified trivially for Eq. (3.24)).

We remark that Eq. (3.25) shows that the evolution of the mechanical mode A (eigenfunction of the operator Lm~) can be influenced by the evolution of all mechanical modes. Because of this property mechanical modal excitation can occur via electro-mechanical energy exchange.

The structure of the kernel ka,~ defined in Eq. (3.24) plays a crucial role to determine the kind of coupling involved: two mechanical modes X and • can influence one another if and only if the number A~A,~ is non-vanishing (i.e., they have a non-vanishing coupling with almost one electrical mode u).

Moreover, Eq. (3.24) shows that for w, ~ wa the Volterra kernel ka,~ becomes resonant; this fact is easily checked by recalling that This fact leads us to expect a strong coupling in the time-evolutions of A (mechanical) and u (electrical) modes when the corresponding pulsations u: are close. Finally, in order to have a dimensionless number measuring the coupling, as consequence of the positive definiteness of L, we introduce the coupling coefficients as the numbers:

2AA~ < 1. (3.27)
Equation (3.27) follows from/Lu, u) > 0 for u = {m~, e~} and for u = {m~, -e~}. The subsequent numerical simulations prove that the closer the number c~ is to 1, the bigger is the coupling between A and u modes.

Applications

The model described in the previous sections can be used to study the behavior of several electro-mechanical systems. In the papers [START_REF] Dell'isola | Continuum modelling of piezoelectro-mechanical truss beams: an application to vibration damping[END_REF] and [START_REF] Dell'isola | Damping of bending-waves in truss beams by electrical transmission line with PZT actuators[END_REF] truss modular beams controlled by distributed PZT actuators were considered. In the present paper we address to the dynamical control of a continuous beam.

System description

In order to prove the feasibility and the efficiency of the distributed PZT control, we consider an experimental set up s made of an aluminum beam coupled with a set of piezoelectric patch actuators spatially distributed on its upper surface (see Fig. 1).

The Aluminum beam, we consider in the numerical simulations, is 60 cm long, 2.3 cm large and 3 mm thick. We will regard it as a Bernoulli-Navier purely flexible beam.

The actuators are connected in series as shown by Fig. 2 by means of impedances, in such a way that a transmission line is formed. The line capacitance is constituted by the actuators only. The beam is clamped-clamped, while the transmission line connecting the actuators is electrically insulated. 5 which is being realized in a laboratory of the "Universitfi dell' Aquila". In our simulations we consider the physical properties of commercial actuators (namely ACX QuickPack actuators) in bonded configuration: this means that the actuators are supposed to supply non-vanishing forces and vanishing couples when subjected to voltages. We will assume that

Identification of continuum constitutive parameters

Km~ = EI § km~92, If,~e = kmefl = kemfl = K~, K~ = kee, (4.5)
being E the Young modulus of the aluminum beam, I the moment of inertia of its section and ~3 = 1.65 mm the distance of the patch actuators from the center axis of the beam. The quantities k~, k.~ = k~.~ and kh~ are respectively the axial stiffness, the electro-mechanical coupling constants and the admittance for unit length of the actuators as read from the ACX catalogue (i.e,, k~ = 2.105 N, kme = kern = 0.4105 V, ke~ = 2.2105 m/Farad). Moreover, recalling that the electrical "inertial" actions physically represent the lines potential drop, we can write Eq. (3.2.2) as

(~ 0) (4.6) 1~ = -{~o9, hY}~M = h '
where Q is the linear mass density of the beam and h is the line inductance. With the stated constitutive relations, Eq, (

becomes

K~,~V Iv + K~F" + ~9 = O, -KemV" -KeeF" + h/~ = 0. (4.7)
In order to apply the results of Sect. 3 we compute a dimensionless form of Eqs. (4 9 introducing V F

where lb is the total length of the beam considered and q := ~lb2/h is the reference charge leaving unchanged the symmetry of the spatial differential operator involved. Finally for the time derivatives the pulsation ~5 = (4.73)2 ~/K~I ~, (

of the first mode of the clamped-clamped uncoupled beam is used.

In dimensionless coordinates the operator L introduced by (3.4) becomes

~2 lb~ ~)21b2 h []

9 (4.10) L = K~ D Ill KeeO [~ n ~2162 h ~2 h 2

Numerical simulations

We consider in this section the spectra S~ and S~ of the operators L,~ and Lee associated with Eq. (4.10) and the boundary conditions specified in Sect. 4.1. These spectra are discrete sets {..A..}, {..u.. } of real positive numbers which we can order using natural numbers 9 Once remarked that the electric spectrum is a function of the line inductance, we estimate the critical line inductances h~, maximizing the electro-mechanical mode couplings, assuming vanishing K~ and solving the equation w~(h) = ~a as is suggested by Eq. (3.26). In this way we can construct a matrix of critical values for line inductance such that the electrical pulsation is closest to the mechanical one; for the examined system we get h* = H/m, (4.11) whose entry hij means the inductance maximizing coupling of/-mechanical with j-electrical modes, and some dots are used when the necessary coupling condition (3.18) is not verified.

In Fig. 3 we plot the spectrum of L as a function of the line inductance h. The obtained set of curves shows a veering phenomenon in the neighborhood of every critical line inductance.

The veering regions are characterized by circles. The intersections of spectral curves occur only when cA~ = 0, i.e., when the necessary coupling condition is not verified. In Fig. 4 the matrix of coupling coefficients ca, is shown; black means 1, white 0, and the intensity of gray is proportional to the estimated value.

Several numerical simulations are performed to obtain time evolutions of the first four mechanical and four electrical modes corresponding to the initial data:

vl = 1, vi = O, 7j = O, i = 2,...4, j = 1,...4
of the modal coefficients.

In Fig. 5 h = h~2, and the line is assumed to be non-dissipative. We observe that: i) only odd mechanical and even electrical modes are excited, as suggested by the coupling matrix shown in Fig. 4; ii) the amplitudes of vibrations decrease with increasing modes; iii) the mechanical vibration of the third mode is excited via the excitations of the (even) electrical ones. In Fig. 8, h = h~4, and the line is assumed dissipative (40X2/m is now the value of optimal line resistance). Comparison with Fig. 6 shows that the damping ratio is now smaller; this fact could be expected observing the shape of the veering region associated in Fig. 3 and the value of the coupling coefficient associated (lm-4e) in Fig. 4.

Concluding remarks

A one-dimensional microstructured continuum has been introduced to model beams coupled to electrical transmission lines by PZT actuators; we have found the evolutions equations for the electro-mechanical system considered in the case of linear constitutive relations; the spatial differential operator governing the problem has been partitioned according to the partition of the state vector into a mechanical and electrical part. This analysis led to the formulation of a necessary coupling condition between mechanical and electrical modes and to the statement of an internal resonance condition. These results were used in Sect. 4 in order to prove that bending waves can be damped and controlled also by means of standard second-order electric transmission lines of distributed piezoelectric actuators.

Moreover it has been proven that electro-mechanical coupling can lead to self-excitation of mechanical modes also in linear systems.

8 )

 8 in Eq. (2.10), integrating by parts and recalling that 3 a. Ab = A 9 a A b for every A 6 SKw, we get: f[(s'+ b).w + (S' +~ + p'A s + B). W+ (a' +fl)-to ld~ = Is. w+ S. W+ a-tO]o~, g that must vanish for every regular velocity field (w, W, m). As a consequence for every ~ E B: s ~+b=0, (sKwS) ~+p~As+sKwB=0, (2.11) (sYMS) ~+I!~+sY~B=0, a ~+fl=0, 3 aAb=a|174 and for ~ E 013: [s.w + S. W + a. ~]~ = 0.

  b = L~+(b) = f(b, ev) ev d#., (3.10) s~ where (s~, dp~) and (Se, d#v) are the spectral measure spaces respectively for Lm~ and L~, while m~ and e,. are the corresponding sets of spectral vectors. Let us define the functions vA --(v, ma), (3.11)% _ (% %), (3.12) dependent on the time variable only, and the scalar numbers A~, = (mA, L,~+(ev)), (3.13) AvA = (e., Lern(mA)), (3.14) A with Aa, = A,A due to L~ = L~. Equations (3.8) can be written as S.+ S+ S+ S~,+ whichas mx and e. are bases of.A.~ and Me respectivelyare equivalent to s+ (3.16) ~'7~ + ;~ + f A~vA d#~ = O, V~ r S~. s,. Equation (3.16) clearly shows that the influence on the mode mA exerted by the mode ev is measured by AAv = fmaL~++(e,) dq, (3.17) B that we can regard as a modal e -~ m coupling matrix. In an absolutely similar way A,a represents the modal m ~ e coupling matrix; it is now easy to formulate the following: Criterion of electro-mechanical coupling A necessary condition for the presence of electro-mechanical energy exchange between e~ and ma modes is fL.~+(e.) mad; = fL+.~(m~) ev & r 0. (3.18) B 13

  /At:A~---~/sin zva(t-{ ) sin w,({-7)d{dlx~]Vk(r)d#kdT. The term in the square brackets can be evaluated to get f A~vAv~ ~ sin ~v(t -~-) -~ sin w~(t -T) d#~, led to recognize (3.22) as a system of Volterra integral equations of the second kind: t ~(t) = A(t) + f f k~,~.(t, ~-) ~(~) d~ d~-, (3.2S)

  lira ~A sin ~(t -7") -~ sin ~),(t -7) _ 1 [sin ~,x(t

Fig. 2 .

 2 Fig. 1. Beam and actuators setting

3 )

 3 Let us choose as vector of kinematical descriptors fi = {V, r}, (4.1)being V the transverse displacement of the beam section and /7 the charge stored in the segment [0, r of the actuators transmission line. Limiting our analysis to the case of a purely flexible beam the strict components of the deformation time-rate are given by a = {&3, ~} = (v", v'} ~ r = (4.2) 0 E3' ' where 6 Dla = "d" is the field of beam curvature time-rate and ~ =/~' is the field of currents in the PZT actuators. Their dual actions will be physically representing the bending moment field Sla and the potential drop field cr at the extreme points of the PZT actuators.Due to their positioning over the beam, these actuators supply a bending moment when subjected to voltage fields and vice versa: this coupling effect can be mathematically represent-6 Here the tensor D is represented in the basis shown in Fig. i. ed in a coupled constitutive relation between the internal actions ~ and the deformation fields = KG(fi),

Fig. 3 .Fig. 5 .Fig. 6 .Fig, 7 ,Fig. 8 .Figure 7

 356787 Fig. 3. Veering of eigenfrequencies (normalized with respect to co) at the critical line inductances

We mean a linear application VY -+ VP which is invertible on its image.

We use the notation introduced in[START_REF] Gurtin | An introduction to continuum mechanics[END_REF]: LIN is the set of linear applications, IsoLIN the set of linear invertible applications, gYM and SKw respectively the set of symmetric and skewsymmetric linear applications. We will label by SYM A and SKW A the symmetric and skewsymmetric parts of A.

Authors' address: S. Vidoli and F. dell'Isola, Dipartimento di Ingegneria Strutturale e Geotecnica, Universitfi di Roma "La Sapienza", Via Eudossiana 18, 1-00184 Roma, Italia


M.D Bjarne Udd
email: bjarne.udd@netikka.fi

Molecular biology of distal muscular dystrophiessarcomeric proteins on top

Keywords: muscular dystrophy, distal dystrophy, distal myopathy, molecular genetics, molecular pathogenesis, molecular biology

During the last 10 years several muscular dystrophies within the group of distal myopathies have been clarified as to the molecular genetic cause of the disease. Currently, the next steps are carried out to identify the molecular pathogenesis downstream of the gene defects. Some early ideas on what is going on in the muscle cells based on the defect proteins are emerging.

However, in no single distal muscular dystrophy these efforts have yet reached the point where direct trials for therapy would have been launched, and in many distal dystrophies the causative gene is still lacking. When comparing the gene defects in the distal dystrophies with the more common proximal muscular dystrophies such as dystrophinopathies or limbgirdle muscular dystrophies, there is a striking difference: the genes for distal dystrophies encode sarcomere proteins whereas the genes for proximal dystrophies more often encode sarcolemmal proteins.

Introduction

Distal dystrophies -distal myopathies are defined as inherited primary muscle disorders characterized by progressive muscular weakness and atrophy beginning in the hands, forearm, lower legs or feet [START_REF] Udd | Distal myopathies[END_REF]. Distal myopathy has prevailed as the main term for historical reasons even if the disorders in a clinical sense are muscular dystrophies.

The different entities of this category have all first been determined as new disorders based on their clinical findings (Table 1). During the last 10 years, the molecular genetic background of the different entities has been resolved in most of the major forms. This significant progress has shown that many gene defects underlying distal dystrophies may cause not only a distal presentation but a variety of clinical phenotypes [START_REF] Udd | Distal myopathies[END_REF]. Eventually, when most myopathies/dystrophies have been defined by their gene defect, distal myopathy as a category of classification may become less important. In the future, the currently emerging molecular genetic definition may in turn be replaced by categories defining distinct molecular biological functions and pathways disrupted by the gene defects.

The first well documented large family published as a distal myopathy was reported in 1943 [START_REF] Milhorat | Studies in diseases of muscle: XIII. Progressive muscular dystrophy of atrophic distal type: Report on a family: Report of autopsy[END_REF]. Six patients in a dominant family with 12 affected males had distal leg weakness with onset in early adulthood. Later studies in this family showed desmin accumulations in muscle biopsy and a mutation in the desmin gene [START_REF] Sjöberg | A missense mutation in the desmin rod domain is associated with autosomal dominant distal myopathy, and exerts a dominant negative effect on filament formation[END_REF]. The change of classification in this family, from distal myopathy to desminopathy, illustrates current developments following progress in molecular genetics.

In this review the traditional grouping of the different entities based on clinicogenetical presentation has given way to a new molecular biology type of basic approach in order to facilitate the association of the basic clinical problem with the biological and functional units of the muscle cell. However, our current understanding of the molecular

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pathophysiology of these disorders is still highly incomplete and only emerging. Many defects involve large sarcomere proteins and hypotheses on how these defects could be overcome by therapeutic interventions are, at present, very vague. In disorders with dominant gain of function and abnormal accumulations of protein, silencing the mutant gene with small interfering RNA would theoretically look like an option.

Distal muscle weakness and atrophy is sometimes the presenting symptom and sign in myopathies that are mainly characterized by other major findings. These conditions are noted only briefly. The basic molecular biology of dysferlinopathy is covered in the

LGMD-review and GNE-associated hereditary inclusion body myopathy (hIBM) is presented in the corresponding review.

Distal dystrophies caused by defects in structural components of the sarcomere

Defects in the excitation-contraction coupling machinery of the A-band part of the sarcomere generally cause cardiomyopathy (personal comment). Genes and proteins involved include myosin heavy and light chains (MHC and MLC proteins), myosin binding protein C (MYBP-C) and titin. However, if the defects lie outside the A-band region of these proteins, other phenotypes will develop (Fig 1A).. Also mutations in proteins or particular parts of proteins in the Z-disk and I-band of the sarcomere may cause cardiomyopathy.

Some distal dystrophies are very early onset, such as myosinopathy, whereas others are late onset or even very late onset, such as titinopathy or myotilinopathy. In the early onset forms the defect in target muscles is possibly congenital although clinical signs, such as drop foot, are usually observed when patients start to walk. This type of very early onset of muscle weakness is suggestive of developmental/constructional abnormalities in contrast to the late

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onset disorders, which develop after long time usage as a deficiency of maintenance and an imbalance between damage and repair.

Thick filament disorders -myosinopathies

Mutations located in the tail region of the slow myosin heavy chain gene MYH7 are the cause of early onset dominant distal myopathy (Laing myopathy) [START_REF] Laing | Autosomal dominant distal myopathy: linkage to chromosome 14[END_REF][START_REF] Meredith | Mutations in the slow skeletal muscle fiber myosin heavy chain gene (MYH7) cause Laing early-onset distal myopathy (MPD1)[END_REF] (Fig 1A). A number of mutations have been reported in this region between residues 1500 to 1729, with preference for deletions or insertions of lysine residues or single residue changes introducing a proline in the alpha-helix. For example, the K1617del mutation has occurred independently in different populations and also 'de novo' in one of the studied families, forming a hot spot mutation [START_REF] Lamont | Laing early-onset distal myopathy -slow myosin defect with variable abnormalities on muscle biopsy[END_REF]. Moreover, this location in the tail of slow MHC includes the domain defined to interact with myomesin and it is just N-terminal of the defined domain (between residues 1815-1831) for interaction with c-terminal titin [START_REF] Meredith | Distal myopathy[END_REF]. The tails of individual MHC molecules are physically located in the M-line of the sarcomere (see below distal titinopathy), which is of interest regarding the phenotype, but the exact functional molecular consequences of the mutations in this part of the myosin filament are not known. Muscle fibers in affected muscles undergo atrophy more than fiber necrosis and type 1 fibers, besides atrophy, show reprogramming towards hybrid expression of different myosins [START_REF] Lamont | Laing early-onset distal myopathy -slow myosin defect with variable abnormalities on muscle biopsy[END_REF]. Mutations in the ultimate c-terminus of slow MHC cause another phenotype: hyaline body myopathy, with variable clinical presentation and with unstructured myosin deposits in the hyaline bodies in the myofibers [START_REF] Oldfors | Mutation of the slow myosin heavy chain rod domain underlies hyaline body myopathy[END_REF]. Mutations in the proximal neck -head part and different mutations in the rod domains of slow MHC may cause cardiomyopathy [START_REF] Blair | Mutations of the light meromyosin domain of the beta-myosin heavy chain rod in hypertrophic cardiomyopathy[END_REF]10].

Clinical phenotype

Clinically distal myosinopathy is to some extent similar to the first ever reported distal myopathy; Gowers' description of a patient in 1902 [START_REF] Gowers | A lecture on myopathy and a distal form[END_REF][START_REF] Mastaglia | Early onset chromosome 14-linked distal myopathy (Laing)[END_REF]. Weakness begins in the

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lower leg anterior compartment between 1 and 25 years of age with a characteristic hanging big toe-sign and severe atrophy and weakness of neck flexors, the sternocleidomastoid muscles (Fig. 2A). The disease progression is slow, eventually resulting in weakness of finger flexors, shoulder, trunk, facial and tongue muscles. Scoliosis and tendon contractures, mainly in the ankles, are common. Cardiomyopathy has rarely been described [START_REF] Hedera | The second kindred with autosomal dominant distal myopathy linked to chromosome 14q: genetic and clinical analysis[END_REF], and severe respiratory problems have not been encountered.

Laboratory findings and muscle pathology

Serum CK is slightly elevated or normal, and EMG shows early-recruiting short duration, low amplitude and polyphasic motor unit action potentials. Spontaneous activity was found in the more severely affected muscles, without signs of neuropathy [START_REF] Mastaglia | Early onset chromosome 14-linked distal myopathy (Laing)[END_REF]. Muscle imaging is highly suggestive of the diagnosis showing, besides overall small muscle mass, severe changes of degeneration in the anterior tibial muscles (Fig 2B) and, at advanced age, also lesions in posterior calf and the proximal thigh muscles. The early atrophy of sternocleidomastoid muscles can also be captured [START_REF] Lamont | Laing early-onset distal myopathy -slow myosin defect with variable abnormalities on muscle biopsy[END_REF].

On muscle biopsy rimmed or other vacuoles were found in a minority of the reported biopsies [START_REF] Lamont | Laing early-onset distal myopathy -slow myosin defect with variable abnormalities on muscle biopsy[END_REF][START_REF] Mastaglia | Distal myopathies: clinical and molecular diagnosis and classification[END_REF]. Findings in more affected anterior tibial (TA) muscle show very distinct pathology with bimodal fiber size distribution: large number of highly atrophic tiny fibers scattered and in groups in portions with end stage pathology, simulating large group atrophy.

Practically all fibers express fast myosin, whereas normally only a small minority of fibers is type 2 fibers and 80-90% may be slow type 1 fibers in TA (Fig 2C -D). In distal myosinopathy almost all type1 fibers expressing slow myosin are highly atrophic group and they also express fast myosin, suggesting a complete reprogramming of fiber type specifications due to the slow myosin MYH7-gene defect. [START_REF] Lamont | Laing early-onset distal myopathy -slow myosin defect with variable abnormalities on muscle biopsy[END_REF].

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Thin filament disorders -nebulinopathies

The hallmark of defects in thin filament proteins actin, troponin, tropomyosins and nebulin is congenital myopathy, and even more specifically: nemaline myopathy [START_REF] Wallgren-Pettersson | 138th ENMC Workshop: Nemaline myopathy[END_REF]. Nemaline rods occurring in myofibers on light and electron microscopy is a diagnostic corner stone in the differential diagnostics of congenital myopathies, and if present, they direct molecular genetic search in the five genes encoding thin filament proteins known to cause nemaline myopathy. So far, there is no good pathophysiological explanation why thin filament proteins and not other sarcomere proteins cause this specific type of protein aggregates. Possibly some intrinsic property of the thin filament structure, lacking in the other filament systems, may account for nemaline type of aggregation if one of the basic components is defect and harms the correct turnover.

However, not all genetic defects in the thin filament proteins cause nemaline myopathy. We have recently identified recessive missense mutations in nebulin (NEB) gene which do not cause nemaline rods to occur in affected muscle cells, but they cause a recessive distal myopathy [manuscript in preparation]. Interestingly, exactly the same missense mutations induce nemaline rod pathology when they combine with truncating or splicing mutations in compound heterozygous patients, in the same way as with other than missense mutations on both chromosomes.

Clinical phenotype and laboratory findings

Mutations in nebulin are a well known cause of autosomal recessive congenital nemaline myopathy [START_REF] Pelin | Mutations in the nebulin gene associated with autosomal recessive nemaline myopathy[END_REF]. Besides generalized weakness and muscle atrophy of variable severity, the distal muscles are usually more involved than the proximal ones. In our distal nebulin myopathy patients with missense mutations on both chromosomes, the clinical and the myopathology phenotype is clearly different. Extensor muscles of hands and feet are severely affected, but the progression is very mild, walking is preserved and patients do not have

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Third filament system -titinopathies

The first identified genetic defect underlying autosomal dominant distal dystrophy was mutations in c-terminal titin that cause tibial muscular dystrophy (TMD, OMIM #600334, Udd myopathy) [START_REF] Hackman | Tibial muscular dystrophy is a titinopathy caused by mutations in TTN, the gene encoding the giant skeletal-muscle protein titin[END_REF][START_REF] Haravuori | Assignment of the tibial muscular dystrophy (TMD) locus on chromosome 2q31[END_REF]. Titin is the largest single polypeptide protein in nature and each molecule spans over one half of the sarcomere from Z-disk to M-line, interacting both with thin filaments and thick filaments (Fig 1A -1B). During myofibrillogenesis titin is expressed before the other filament systems of the sarcomere and is thought to form a scaffolding ruler for the highly organized structure of the sarcomere [START_REF] Hackman | The role of titin in muscular disorders[END_REF]20]. Titin interacts repeatedly with myosin filaments in the A-band region and through the interface of MYBP-C, causing strong positional fixation of the contractile system and keeping the myosin thick filaments always centered in the sarcomere [START_REF] Freiburg | A molecular map of the interactions between titin and myosinbinding protein C. Implications for sarcomeric assembly in familial hypertrophic cardiomyopathy[END_REF]. In the middle of the sarcomere, in the M-line portion, titin has less modular and more complex sequence properties, including a kinase domain, interaction domains for myomesin and unique sequences with unknown functions [START_REF] Kolmerer | Genomic Organization of M Line Titin and its Tissue-specific Expression in Two Distinct Isoforms[END_REF]. In the M-line, c-

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termini of titin molecules from both flanking Z-disks meet and probably overlap. Since nterminal titins also overlap each other from neighboring sarcomeres in the Z-disk, titins in consecutive sarcomeres may form a continuous filament structure extending from one sarcomere to the other (Fig 1A -1B). Recently, we have identified M-line titin, i.e. the kinase domain (Fig 1B ), as a sensor of mechanical contraction activity in the myofiber with a physically interacting signaling complex of proteins [START_REF] Lange | The kinase domain of titin controls muscle gene expression and protein turnover[END_REF]. This signaling complex includes MURF2, which in the normal state of muscle activity stays in the complex in the M-line, but dissociates and shuttles to the nucleus where it inactivates the activity of the transcription factor SRF, if muscle activity is blocked chemically or by denervation [START_REF] Lange | The kinase domain of titin controls muscle gene expression and protein turnover[END_REF]. M-line titin thus seems to have important signaling functions for regulation of transcription and turnover in relation to variable contractional demands. One point mutation in the regulatory tail of the kinase domain is able to totally disrupt the function of the signaling complex and causes a severe dominant muscle disease HMERF with respiratory failure [START_REF] Lange | The kinase domain of titin controls muscle gene expression and protein turnover[END_REF].

Molecular genetics

In close proximity to the kinase domain in the periphery of the M-line is the ultimate cterminus of the titin molecule. In its last domain, the Ig-like M10, encoded by the last exon of the gene, Mex6, we found the first mutations in TMD distal dystrophy (Fig 1B) [START_REF] Hackman | Tibial muscular dystrophy is a titinopathy caused by mutations in TTN, the gene encoding the giant skeletal-muscle protein titin[END_REF]. The mutation in Finnish patients, FINmaj, is a complex in frame ins/del of 11 consecutive base pairs exchanging four amino acids in M10 [START_REF] Hackman | Tibial muscular dystrophy is a titinopathy caused by mutations in TTN, the gene encoding the giant skeletal-muscle protein titin[END_REF]. The protein, however, is damaged beyond M10 since epitopes in the third last domain M9 are not recognized by specific antibodies [START_REF] Hackman | Tibial muscular dystrophy is a titinopathy caused by mutations in TTN, the gene encoding the giant skeletal-muscle protein titin[END_REF]. The mutant titin is incorporated in the sarcomeres shown by immunohistochemistry with antibodies to different other parts of the protein in homozygous mutant muscle, and mutant titin seems to be intact up to the fourth last domain M8 (Fig 1B).

In two unrelated French families a point mutation changing a lysine to proline was found in the same last Mex6 exon [START_REF] Hackman | The role of titin in muscular disorders[END_REF]. Later a third mutation in the same last exon was found in a

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Belgian TMD family [START_REF] Van Den Bergh | Tibial muscular dystrophy in a Belgian family[END_REF], and more unpublished mutations, also in the last Mex6 exon, have been identified in Spanish and other French families (Udd, personal communication). These mutations are available for diagnostic testing. In new unrelated TMD patients searching for mutations by sequencing the last Mex 6 exon may be productive.

Molecular pathomechanism of c-terminal titinopathy -TMD

Even in homozygous mutant muscle the overall sarcomere structure is intact on electron microscopy, suggesting no major mechanical disruption caused by the mutations [START_REF] Udd | Tibial muscular dystrophy -Late adult onset distal myopathy in 66 Finnish patients[END_REF]. The downstream chain of molecular events is, however, not yet defined. It will be complex, because in the few rare patients with homozygous FINmaj mutation the phenotype is completely different: early childhood onset proximal limb-girdle muscular dystrophy with loss of ambulation around age 25 (LGMD2J) [START_REF] Udd | Muscular dystrophy with separate phenotypes in a large family[END_REF][START_REF] Udd | Titinopathies and extension of the M-line mutation phenotype beyond distal myopathy and LGMD2[END_REF]. Whereas in TMD, the muscle involvement is focal and selective targeting first the tibial anterior muscles, in LGMD2J the dystrophy is generalized with replacement in all large muscles at the age when clinical symptoms from weakness of ankle dorsiflexion start to emerge in the heterozygous TMD [START_REF] Udd | Titinopathies and extension of the M-line mutation phenotype beyond distal myopathy and LGMD2[END_REF]. This complete difference may suggest that downstream molecular pathways are partly different in TMD vs. LGMD2J.

The only established ligand of c-terminal titin is muscle specific calpain-3, that is responsible for LGMD2A when mutated [28,[START_REF] Richard | Mutations in the Proteolytic Enzyme Calpain Cause Limb-girdle Muscular Dystrophy Type 2A[END_REF]. In homozygous LGMD2J calpain-3 is severely reduced [START_REF] Haravuori | Secondary calpain3 deficiency in 2q linked muscular dystrophytitin is the candidate gene[END_REF], but not in heterozygote TMD muscle, indicating that some other disrupted protein interaction may mediate pathology later in life in the heterozygotes. Myosin heavy chain (MYH7) tail region has been shown to interact with titin (see above), but the interacting region on titin is not defined yet.

Clinical phenotype

The clinical findings present after age 35, selectively involving the tibialis anterior

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and, in advanced stages, the long toe extensor muscles [START_REF] Udd | Tibial muscular dystrophy -Late adult onset distal myopathy in 66 Finnish patients[END_REF] (Fig. 3 A). Weakness at onset may be asymmetric and progression is slow. Mild to moderate proximal leg muscle weakness occurs after age 70 in a minority of the patients, but patients rarely become wheel-chair bound even at advanced age. Clinically, the sparing of short toe extensors (extensor digitorum brevis) is an important finding to make distinction from neurogenic foot drop.

Unlike in Welander distal myopathy (WDM), hand muscles are rarely affected in TMD [START_REF] Udd | Tibial muscular dystrophy -Late adult onset distal myopathy in 66 Finnish patients[END_REF].

Despite this characteristic presentation, a recent study of 207 mutation confirmed patients showed unexpected variants of the phenotype in 9% of the patients [START_REF] Udd | Tibial muscular dystrophy -Late adult onset distal myopathy in 66 Finnish patients[END_REF].

Epidemiology

Recent studies have shown a high TMD prevalence in Finland of more than 8/100,000 [START_REF] Udd | Titinopathies and extension of the M-line mutation phenotype beyond distal myopathy and LGMD2[END_REF][START_REF] Udd | Tibial muscular dystrophy -from clinical description to linkage on chromosome 2q31[END_REF]. Patients are found all over the country, although the origins of their families can be traced back to the west coast region of middle Finland and to the Savo-Karelia area of eastern Finland [START_REF] Udd | Tibial muscular dystrophy -Late adult onset distal myopathy in 66 Finnish patients[END_REF] . TMD has also been identified in Sweden, Norway, Germany and Canada in descendants of Finnish immigrants. Moreover, TMD families have recently been identified in other populations without connections to the Finnish background and with other mutations in c-terminal titin in France, Belgium and Spain [START_REF] Van Den Bergh | Tibial muscular dystrophy in a Belgian family[END_REF][START_REF] De Seze | The first European tibial muscular dystrophy family outside the Finnish population[END_REF] (Udd personal communication 2006), and there is no reason to believe that titin mutations should be restricted to certain populations.

Laboratory findings and muscle pathology

Patients with TMD have normal or mildly elevated CK [START_REF] Udd | Tibial muscular dystrophy -Late adult onset distal myopathy in 66 Finnish patients[END_REF]. In affected muscles EMG studies showed low-amplitude, short-duration motor unit potentials on moderate activity [START_REF] Udd | Muscular dystrophy with separate phenotypes in a large family[END_REF]. Increased insertional activity, frequent fibrillation potentials, and occasional high-frequency and complex repetitive discharges at rest may be obtained in clinically affected muscles. In clinically unaffected muscles of the upper limbs polyphasic potentials

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may be recorded [START_REF] Udd | Tibial muscular dystrophy -Late adult onset distal myopathy in 66 Finnish patients[END_REF].

CT and MRI provide accurate data on the selective involvement of individual muscles in TMD. Changes of fatty degeneration appear at the time of clinical weakness [START_REF] Udd | Imaging methods reveal unexpected patchy lesions in late onset distal myopathy[END_REF]. The evolution of selective involvement over time is very distinct in TMD. Together with the presenting weakness of ankle dorsiflexion, fatty degenerative changes appear in the anterior tibial muscle. After 10-15 years of symptoms, lesions usually appear in the long toe extensor muscles, and in hamstring, gluteus medius, and tensor fasciae latae muscles [START_REF] Udd | Imaging methods reveal unexpected patchy lesions in late onset distal myopathy[END_REF] (Fig. 3B).

Initially, the involvement may be asymmetric. Later, focal lesions may appear in apparently asymptomatic muscles, such as the soleus, when other unaffected muscles mask the loss of power and prevent the lesion from being observed clinically [START_REF] Udd | Imaging methods reveal unexpected patchy lesions in late onset distal myopathy[END_REF].

Muscle specimens in TMD reveal myopathic alterations, including variation of fiber size, thin atrophic fibers, central nuclei, structural changes within the fibers, endomysial fibrosis, and fatty replacement in the end stage muscle [START_REF] Udd | Nonvacuolar myopathy in a large family with both late adult onset distal myopathy and limb-girdle type muscular dystrophy[END_REF]. Necrotic fibers, some showing phagocytosis, are rare in TMD. Fiber type differentiation was normal, both major fiber types being equally involved in the pathological process(Fig 3C). Many rimmed vacuoles were acid phosphatase positive, while others were ubiquitin positive and, with rare exceptions, they were not lined by sarcolemmal membrane proteins. Congo red stains and immunohistochemistry for beta-amyloid and amyloid precursor protein were negative in TMD specimens containing fibers with rimmed vacuoles, in contrast to sporadic inclusion body myositis.Ultrastructural studies in TMD revealed overall well preserved sarcomere structure, even in the homozygote LGMD2J mutants. Focal cytoplasmic and sarcomeric degradation products and occasional tubulofilamentous inclusions were encountered in the vacuolated fibers [START_REF] Udd | Tibial muscular dystrophy -Late adult onset distal myopathy in 66 Finnish patients[END_REF]. Rimmed vacuoles in TMD are usually not membrane bound and thus do not fulfill the morphological criteria of autophagic vacuoles, even though the vacuolar space contains numerous small vesicles compatible with lysosomal autophagic components.

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Telethoninopathy

The other name of this protein, T-cap, indicates its function as capping titin molecules in the periphery of Z-disks, and telethonin may thus be connected to the third filament functions rather than characterized by its location to the z-disk region (Fig 1).. Telethonin is shown to be a substrate of the serine-threonine kinase in c-terminal titin. In mature muscle these locations are physically distant, suggesting either shuttling of telethonin or phosphorylation regulation only temporarily during myofibrillogenesis when c-terminal titin and the kinase is located also in emerging Z-disk regions. No further molecular pathomechanisms are detailed on the effects of mutations in telethonin, which usually are reported to cause a proximal

LGMD2G phenotype, but, in fact, many of the patients have more distal atrophies and weakness at onset [START_REF] Udd | Distal myopathies[END_REF]. The myopathology is myofibrillar rimmed vacuolar.

Defects in Z-disk proteins and distal muscular dystrophies

Recent progress has delineated several genes that underlie the muscle pathology characteristics of myofibrillar myopathy (MFM): desmin, αB-crystallin, myotilin, ZASP and filaminC (Fig 1A) [START_REF] Selcen | Mutations in myotilin cause myofibrillar myopathy[END_REF][START_REF] Selcen | Mutations in ZASP define a novel form of muscular dystrophy in humans[END_REF][START_REF] Vorgerd | A mutation in the dimerization domain of filamin c causes a novel type of autosomal dominant myofibrillar myopathy[END_REF]. Patients with dominant myofibrillar myopathy frequently present as distal myopathies [38][START_REF] Sugawara | A novel de novo mutation in the desmin gene causes desmin myopathy with toxic aggregates[END_REF][START_REF] Dalakas | Desmin myopathy, a skeletal myopathy with cardiomyopathy caused by mutations in the desmin gene[END_REF][START_REF] Fidzianska | Familial inclusion body myopathy with desmin storage[END_REF]. There is a wide range of onset, patterns of muscle involvement, and progression rates. Patients may have additional features cardiomyopathy, respiratory muscle weakness, neurogenic findings and even EMG myotonia. The pathology includes accumulations of all these proteins irrespective of primary gene defect, suggesting that these share molecular pathways involved in actin dynamics organized by the Z-disk. Besides accumulations of these proteins, congophilic amyloid products of myofibrillar degradation and ectopic aggregation of dystrophin and gelsolin appear in abnormal myofibers [START_REF] Selcen | Mutations in myotilin cause myofibrillar myopathy[END_REF].

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Desminopathy

Desmin is a muscle-specific cytoskeletal protein and belongs to the type III family of intermediate filaments. Desmin mediates attachments between the Z-disks of parallel myofilaments and provides attachments between Z-disk and membrane-associated proteins to form a force-transmitting system (Fig 1A).. One of the earliest reports on distal myopathy described a very large autosomal dominant family with branches both in Europe and in North America [START_REF] Milhorat | Studies in diseases of muscle: XIII. Progressive muscular dystrophy of atrophic distal type: Report on a family: Report of autopsy[END_REF]. This family later proved to have a mutation in the desmin gene [START_REF] Sjöberg | A missense mutation in the desmin rod domain is associated with autosomal dominant distal myopathy, and exerts a dominant negative effect on filament formation[END_REF]. What properties exactly are lost or gained by the mutations that cause desmin together with other Z-disk proteins to agglomerate in desminopathy is not known. Transfection studies of some mutations caused incorrect forming of desmin intermediate filament network, induced the collapse of a pre-existing desmin cytoskeleton, altered the subcellular distribution of mitochondria, and led to abnormal cytoplasmic protein aggregates [START_REF] Schroder | On noxious desmin: functional effects of a novel heterozygous desmin insertion mutation on the extrasarcomeric desmin cytoskeleton and mitochondria[END_REF].

Myotilinopathy

Myotilin (myofibrillar protein with titin-like Ig domains) is a 57 kDa Z-disk component that interacts with alpha-actinin [START_REF] Salmikangas | Myotilin, a novel sarcomeric protein with two Ig-like domains, is encoded by a candidate gene for limb girdle muscular dystrophy[END_REF], filamin-C, FATZ (calsarcin) [START_REF] Gontier | The Z-disc proteins Myotilin and FATZ Interact with each other and are potentially connected to the sarcolemmal Membrane via Muscle-Specific filamins[END_REF], and actin [START_REF] Von Nandelstadh | Actin-organising properties of the muscular dystrophy protein myotilin[END_REF] (Fig 1A).. It also controls sarcomere assembly [START_REF] Salmikangas | Myotilin, the limb-girdle muscular dystrophy 1A (LGMD1A) protein, cross-links actin filaments and controls sarcomere assembly[END_REF]. Myotilin contains a serine-rich amino-terminal region (residues 28 to 124) with a hydrophobic stretch (residues 57 to 79), two Ig-like domains with considerable homology to certain Ig domains of titin (residues 252 to 341 and 351 to 441), and a carboxy terminal tail. The alpha-actinin binding site resides between myotilin residues 79 to 150, and the filamin-C binding site is located in the second Ig-like domain. Myotilin dimerizes via its C-terminal half, which may be necessary for the actin-bundling activity. Myotilin is strongly expressed in skeletal muscle and weakly in cardiac muscle [START_REF] Van Der Ven | Indications for a novel muscular dystrophy pathway: γ-filamin, the muscle specific filamin isoform, interacts with myotilin[END_REF]. Intramuscular nerve fibers are stained with myotilin antibody [START_REF] Selcen | Myofibrillar myopathy: clinical, morphological and genetic studies in 63 patients[END_REF].

Myotilin is important for actin dynamics [START_REF] Salmikangas | Myotilin, the limb-girdle muscular dystrophy 1A (LGMD1A) protein, cross-links actin filaments and controls sarcomere assembly[END_REF].

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Molecular genetic findings

Several TTID missense mutations have been reported. In 2004, three novel mutations (S60C, S60F, and S95I) and the previously identified LGMD1A S55F mutation were reported in 6 unrelated patients with myofibrillar myopathy [START_REF] Selcen | Mutations in myotilin cause myofibrillar myopathy[END_REF]. In a Spanish cohort of 13 patients, three of the known and two new missense mutations were identified [START_REF] Olivé | Myotilinopathy: refining the clinical and myopathological phenotype[END_REF]. All these 6 mutations are located in same region of the gene, the serine-rich exon 2 encoded domain, and many caused predominantly late onset distal dystrophy.

Considering that the pathology in the family reported by Penisson-Besnier et al. [START_REF] Penisson-Besnier | Autosomal dominant late adult onset distal leg myopathy[END_REF] resembled more that of myofibrillar myopathies, the myotilin gene was a good candidate in this family. Sequencing showed that a previously reported mutation S60F [START_REF] Selcen | Mutations in myotilin cause myofibrillar myopathy[END_REF], segregated completely with the affected patients in the family and was not present in healthy individuals [START_REF] Pénisson-Besnier | Myotilinopathy in a late onset myopathy family[END_REF]. Interestingly, this is another muscle specific protein that in some instances may cause a dystrophy with a predominant proximal LGMD-phenotype (LGMD 1A) [START_REF] Hauser | Myotilin is mutated in limb girdle muscular dystrophy 1A[END_REF] and in others a very pronounced distal affection [START_REF] Penisson-Besnier | Autosomal dominant late adult onset distal leg myopathy[END_REF].

Clinical example

Penisson-Besnier et al. described an autosomal dominant French family with a very late onset of distal myopathy around the age of 60 years [START_REF] Penisson-Besnier | Autosomal dominant late adult onset distal leg myopathy[END_REF]. Weakness and atrophy was more severe in the posterior calf muscles than in the anterior lower legs muscles at onset.

Later the patients experienced progression to proximal and upper limb muscles, although with retained walking ability even into later age. Cardiomyopathy was not observed in the patients.

Laboratory findings and muscle pathology

Muscle enzyme CK was either normal or mildly elevated. EMG showed myopathic changes with fibrillations and complex repetitive discharges. Muscle imaging confirmed the primarily responsible for the alpha-actinin binding [START_REF] Klaavuniemi | Zasp/Cypher internal ZM-motif containing fragments are sufficient to co-localize with alpha-actinin-Analysis of patient mutations[END_REF]55]. Mutations in the alternatively expressed cardiac exon 4 are shown to cause cardiomyopathy [START_REF] Vatta | Mutations in Cypher/ZASP in patients with dilated cardiomyopathy and left ventricular non-compaction[END_REF]. Studies on mouse models including knock-outs suggest that ZASP is required for striated muscle function and maintenance during the stress of contraction, but not for initial formation of the Z-disk [START_REF] Zhou | Ablation of Cypher, a PDZ-LIM domain Z-line protein, causes a severe form of congenital myopathy[END_REF].

Clinical example

In 1974, an autosomal dominant family (Markesbery-Griggs) with six patients affected by distal myopathy was reported [START_REF] Markesbery | Late onset hereditary distal -myopathy[END_REF]. Weakness started in the anterior distal leg muscles between 43 and 51 years of age, then spread to the intrinsic hand and wrist extensor muscles, and eventually to the proximal limb and trunk muscles. Facial, bulbar or respiratory muscles were not involved. The disease progressed slowly, did not alter the length of life, but caused

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loss of ambulation in senescence. Cardiomyopathy was present in one of the patients.

Molecular genetics

Early linkage studies in this classical Markesbery-Griggs family indicated the disorder could be linked to the titin locus 2q31 [START_REF] Haravuori | Tibial muscular dystrophy and late onset distal myopathy are linked to the same locus on chromosome 2q[END_REF]. Extensive mutation search in the huge titin gene was not productive and no mutations were detected. With the reports of myotilin and ZASP mutations in subsets of myofibrillar myopathy patients [START_REF] Selcen | Mutations in myotilin cause myofibrillar myopathy[END_REF][START_REF] Selcen | Mutations in ZASP define a novel form of muscular dystrophy in humans[END_REF]

Laboratory findings and muscle pathology

Patients have normal or only slightly elevated CK [START_REF] Markesbery | Late onset hereditary distal -myopathy[END_REF]. EMG studies showed lowamplitude, short-duration motor unit potentials on moderate activity. Most patients have increased insertional activity, frequent fibrillation potentials, and occasional high-frequency and complex repetitive discharges at rest [START_REF] Markesbery | Late onset hereditary distal -myopathy[END_REF].

Muscle biopies reveal myopathic alterations, including variation of fiber size, central nuclei, structural changes within the fibers, endomysial fibrosis, and fatty replacement of muscle [START_REF] Markesbery | Late onset hereditary distal -myopathy[END_REF]. Necrotic fibers, some showing phagocytosis, and fibers with rimmed vacuoles are abundant. In addition, some fibers contain single or multiple non-rimmed vacuoles whose contents fail to stain for lipids or polysaccharides. Focal accumulation of homogeneous, granular material blue-red with Gomori trichrome was prominent in some fibers.

Immunohistochemistry showed excessive ectopic expression of myotilin with less similar changes in desmin, aB-crystallin and ZASP in the abnormal fibers. Early electron microscopy changes included dilation and vacuolization of the sarcoplasmic reticulum and streaming and

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disruption of the Z-disk. Clumps of Z-disk material were found without the periodicity of nemaline rods [START_REF] Markesbery | Distal myopathy: Electron microscopic and histochemical studies[END_REF]. Sarcoplasmic masses composed of glycogen granules, lipofuscin bodies, tiny vacuoles, degenerated myofilaments, Z-disk fragments, and myeloid figures were common. In retrospect these alterations are well compatible with reported changes in myofibrillar myopathy. The vacuoles are membrane-bound and contain osmiophilic vesicles, granular membrane structures, myeloid figures, and other products of cytoplasmic degeneration and fit the morphological criteria of autophagic vacuoles. They are frequently at the fiber periphery and sometimes covered only by the basement membrane indicating that they may undergo exocytosis.

Autopsy studies were conducted in two patients [START_REF] Markesbery | Late onset hereditary distal -myopathy[END_REF]. One patient had clinical evidence of a cardiomyopathy with cardiomegaly, congestive heart failure, and intractable tachyarrhythmias requiring pacemaker implantation. At autopsy there was diffuse interstitial fibrosis and diffuse degenerative change in cardiac muscle fibers consistent with a cardiomyopathy.

Mutation defects in membrane signal transduction and repair proteins

Caveolinopathy

Defect caveolin-3 is the molecular cause of LGMD1C. However, mutated caveolin-3 may also cause 'rippling muscle disease', and other phenotypes associated with caveolin-3 mutations include distal myopathy with pronounced atrophy of intrinsic muscles in hands and feet [START_REF] Tateyama | Mutation in the caveolin-3 gene causes a peculiar form of distal myopathy[END_REF][START_REF] Sotgia | Phenotypic behavior of caveolin-3 R26Q, a mutant associated with hyperCKemia, distal myopathy, and rippling muscle disease[END_REF]. The molecular pathomechanism of caveolinopathy is not clarified. Based on the function of the caveolae on the sarcolemma, disruption of signal transduction through caveolae is thought to be the consequence of mutant caveolin-3 (Fig 1A).. CAV3 mutations are dominant, implicating a negative effect of the mutant on the wild type copies of the

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protein. Dysferlin seems to interact with caveolin-3, and dysferlin immunostaining is markedly attenuated in patients who harbor mutations in caveolin-3 [START_REF] Tateyama | Mutation in the caveolin-3 gene causes a peculiar form of distal myopathy[END_REF][START_REF] Matsuda | The sarcolemmal proteins dysferlin and caveolin-3 interact in skeletal muscle[END_REF].

Distal dysferlinopathy

Dysferlin is a sarcolemmal protein with expression also in the cytoplasm (Fig 1A).

Dysferlin has not been found to have a role in the dystrophin associated protein complex, although all its functions are not yet known [64]. Dysferlin, by analogy to FER-1 gene in C.

elegans and by having calcium-binding C2 domains, may have a role in membrane fusion and maintaining the structural integrity of the sarcolemma [64]. Dysferlin interaction with caveolin-3 suggests, that one function of dysferlin may be to subserve signaling functions of caveolae [START_REF] Matsuda | The sarcolemmal proteins dysferlin and caveolin-3 interact in skeletal muscle[END_REF]. Secondary calpain3 defects have also been shown in patients with dysferlinopathies [START_REF] Anderson | Secondary reduction in calpain 3 expression in patients with limb girdle muscular dystrophy type 2B and Miyoshi myopathy[END_REF], but the interaction of calpain-3 with dysferlin remains to be clarified.

New reports demonstrate a cytoplasmic localization of dysferlin and association with Ttubule system, resulting in co-precipitating of dysferlin with dihydropyridine receptor together with caveolin-3 [START_REF] Ampong | Intracellular location of Dysferlin and its association with the dihydropyridin receptor[END_REF].

Molecular genetic findings

The two phenotypes of dysferlinopathy: distal Miyoshi Myopathy (MM) and

LGMD2B occurred with the same mutation in different individuals even within the same family [START_REF] Bashir | A gene related to Caenorhabditis elegans spermatogenesis factor fer-1 is mutated in limb-girdle muscular dystrophy type 2B[END_REF][START_REF] Liu | Dysferlin, a novel skeletal muscle gene, is mutated in Miyoshi myopathy and limb girdle muscular dystrophy[END_REF][START_REF] Illarioshkin | Clinical and molecular analysis of large family with three distinct phenotypes of progressive muscular dystrophy[END_REF][START_REF] Illarioshkin | Identical dysferlin mutation in limb-girdle muscular dystrophy type 2B and distal myopathy[END_REF][START_REF] Weiler | Limb-girdle muscular dystrophy and Miyoshi myopathy in an aboriginal Canadian kindred map to LGMD2B and segregate with the same haplotype[END_REF]. Why the identical homozygous mutation may cause different phenotypes within the same family is not clarified. Numerous different mutations have been reported and they are widely distributed along the large gene. Newer methodology for mutation screening using cDNA from muscle has been described [START_REF] Thierren | Validation of Time-and Cost-Effective RNA based approach in detecting human dysferlin gene mutations[END_REF].

Not all patients with MM-like phenotype have dysferlinopathy. In four families with adult and later onset of symptoms, linkage to the MM locus 2p was excluded [START_REF] Linssen | Genetic heterogeneity in Miyoshi type distal muscular dystrophy[END_REF]. In two of these families a genome wide screen suggested linkage to a locus on chromosome 10 (LOD

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2.57). One family was unlinked to both loci. Thus, the phenotype is apparently genetically heterogeneous, and MM might be reserved for the dysferlin mutated form, whereas others may be termed MM-like phenotypes until their molecular etiology has been clarified.

Molecular pathogenesis

Recent ultrastructural studies indicate numerous submicron sized defects in the plasma membrane, replacement of the plasma membrane by small vesicles, frequently disintegrating small papillary projections, as well as numerous small subsarcolemmal vacuoles as early events in the pathology [START_REF] Selcen | The earliest pathologic alterations in dysferlinopathy[END_REF]. These findings support concepts on the role of dysferlin in maintaining muscle fiber surface membrane integrity and resealing of continuous minor disruptions of the sarcolemma in muscle activity. Dysferlin apparently serves multiple functions and a tempting explanation for the variable clinical phenotype at onset of the disease would be that individual genetic backgrounds modify which pathway of dysferlin is more or less affected. Later in the disease course both the distal and the LGMD presentations merge and have similar outcomes.

Clinical findings

In 1977, two sporadic cases of distal myopathy with onset at the age of 19 and 20 years were reported from the USA [START_REF] Markesbery | Late onset hereditary distal -myopathy[END_REF], and Miyoshi et al. described a series of similar patients in Japan [75]. All patients had weakness and atrophy starting in the distal lower extremities, particularly in the calf muscles (Fig. 4A). First symptoms were difficulty in climbing stairs, walking briskly, or running, and inability of patients to hop on one leg [START_REF] Barohn | Autosomal recessive distal dystrophy[END_REF][START_REF] Miyoshi | Autosomal recessive distal muscular dystrophy as a new type of progressive muscular dystrophy: Seventeen cases in eight families, including an autopsied case[END_REF]. Proximal muscles were only minimally affected at the onset, as were hand muscles.

Distal dysferlinopathy (MM) shows slow progression towards proximal muscle involvement and after 10 to 20 years of disease duration there are similarities with the evolution of the

LGMD2B phenotype. Dysferlinopathy patients presenting with anterior tibial rather than with

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calf muscle weakness have also been reported [START_REF] Illa | Distal anterior compartment myopathy: a dysferlin mutation causing a new muscular dystrophy phenotype[END_REF], but imaging studies of these patients revealed marked fatty degeneration also of the posterior gastrocnemius and soleus muscles [START_REF] Brown | Distal anterior dystrophy: A distinct Spanish phenotype[END_REF].

Epidemiology

Since molecular diagnosis for dysferlinopathy became available by immunohistochemistry and immunoblotting using anti-dysferlin antibodies, and by direct DNA genetic analysis, patients with MM have been diagnosed in many different populations [START_REF] Linssen | Genetic heterogeneity in Miyoshi type distal muscular dystrophy[END_REF][START_REF] Cupler | Miyoshi myopathy in Saudi Arabia: clinical, electrophysiological, histopathological and radiological features[END_REF][START_REF] Eymard | Miyoshi distal myopathy: specific signs and incidence (in French)[END_REF][START_REF] Argov | Muscular dystrophy due to dysferlin deficiency in Libyan Jews. Clinical and genetic features[END_REF][START_REF] Mcnally | Splicing mutation in dysferlin produces limb-girdle muscular dystrophy with inflammation[END_REF]. The disorder seems to occur worldwide with a frequency of about 1-2/10 6 .

Laboratory findings and muscle pathology

MM patients have very high serum CK values 10-100 fold the upper normal level [START_REF] Barohn | Autosomal recessive distal dystrophy[END_REF][START_REF] Miyoshi | Autosomal recessive distal muscular dystrophy as a new type of progressive muscular dystrophy: Seventeen cases in eight families, including an autopsied case[END_REF][START_REF] Cupler | Miyoshi myopathy in Saudi Arabia: clinical, electrophysiological, histopathological and radiological features[END_REF], and this high leakage of CK is present even at preclinical stages [START_REF] Barohn | Autosomal recessive distal dystrophy[END_REF]. EMG shows increased insertional activity, fibrillation potentials and abundant small motor unit potentials with early recruitment [75-77]. Muscle imaging with CT or MRI give clear insight in the involvement of different muscles during the disease process, and can also be used for assessment of individuals at risk (Fig. 4B).

Muscle biopsy shows nonspecific myopathic/dystrophic features with abundant necrotic fibers, regenerating fibers, abnormal variation in fiber size, and later connective tissue increase [START_REF] Barohn | Autosomal recessive distal dystrophy[END_REF]. In many dysferlinopathy biopsies inflammatory infiltrates have been observed [START_REF] Gallardo | Inflammation in dysferlin myopathy: immunohistochemical characterization of 13 patients[END_REF], and dysferlinopathy has been confused with polymyositis on many occasions.

Immunohistochemistry and immunoblotting with anti-dysferlin antibodies showing absent dysferlin has become the gold standard for pathological assessment and diagnosis. [START_REF] Selcen | The earliest pathologic alterations in dysferlinopathy[END_REF].

Immunoblots of MM muscle extracts accurately reveal dysferlin deficiency, whereas immunostaining of cryostat sections of MM muscle is less reliable. Currently available antidysferlin antibodies may stain the normal muscle surface only weakly, even at high

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concentration. On the other hand dysferlin may be non-specifically over-expressed in regenerative fibers in any myopathic disorder (personal comment).

Distal muscular dystrophy caused by sarcoplasmic enzyme defects

GNE-mutated distal myopathy with rimmed vacuoles (DMRV)

GNE is a dual epimerase/kinase enzyme and the rate-limiting enzyme in the sialic acid biosynthetic pathway [START_REF] Nishino | Molecular pathomechanism of distal myopathy with rimmed vacuoles[END_REF]. (see the corresponding Chapter for GNE-details).

Molecular genetic findings

After the gene was identified in autosomal recessive quadriceps sparing myopathy/hereditary inclusion body myopathy AR-hIBM, DMRV in Japanese patients proved to be caused by mutations in the same GNE-gene, confirming these are allelic disorders [86]. Many different mutations in GNE have been reported in Japanese DMRV patient [START_REF] Kayashima | Nonaka myopathy is caused by mutations in the UDP-Nacetylglucosamine-2-epimerase/N-acetylmannosamine kinase gene (GNE)[END_REF][START_REF] Nishino | Distal myopathy with rimmed vacuoles is allelic to hereditary inclusion body myopathy[END_REF], and one of them, V572L, is more common and accounts for a founder effect [86].

Molecular pathogenesis

Mechanistic explanation of why the double enzyme defects cause rimmed vacuolar myofibrillar degeneration is still lacking. However, defect sialyation is one major hypothesis and experimental cell studies have shown encouraging results in reverting the phenotype by adding sialic acid (Nishino personal communication). Further experiments are ongoing including mouse models. For more details, see further the Chapter on hIBM.

Clinical findings

Distal myopathy patients with onset in early adulthood of weakness in the lower legs, typically in the anterior compartment, causing foot drop were reported by Nonaka et al. [START_REF] Nonaka | Familial distal myopathy with rimmed vacuole and lamellar (myeloid) body formation[END_REF].

Progression to posterior compartment and proximal muscles was always present and major

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disability usually was the outcome after 10-15 years of disease duration. Intrinsic muscles were also involved. DMRV followed an autosomal recessive inheritance pattern.

Laboratory findings and muscle pathology

CK values are normal or slightly elevated in DMRV patients and EMG shows abundant small motor units potentials and spontaneous discharges including positive sharp waves and fibrillations [START_REF] Nonaka | Familial distal myopathy with rimmed vacuole and lamellar (myeloid) body formation[END_REF][START_REF] Nonaka | Autosomal recessive distal muscular dystrophy: A comparative study with distal myopathy with rimmed vacuole formation[END_REF]. By definition DMRV is characterized by rimmed vacuoles in muscle fibres [START_REF] Nonaka | Autosomal recessive distal muscular dystrophy: A comparative study with distal myopathy with rimmed vacuole formation[END_REF][START_REF] Kumamoto | Distal myopathy: Histochemical and ultrastructural studies[END_REF]. Necrotic fibers may or may not be present. Ubiquitin expression was increased suggestive of increased non-lysosomal degradative activity as another part of the degradative pathogenesis [START_REF] Kumamoto | Increased lysosome-related proteins in the skeletal muscles of distal myopathy with rimmed vacuoles[END_REF][START_REF] Mizusawa | Rimmed vacuolar distal myopathy: An ultrastructural study[END_REF]. Finally, tubulofilamentous inclusions like those occurring in sporadic IBM were also observed in DMRV [START_REF] Sunohara | Distal myopathy with rimmed vacuole formation. A follow up study[END_REF] . These morphological studies were mostly done before the gene defect in DMRV was known and, thus, it is not known whether all studied patients were GNE-mutated cases.

Distal dystrophies with unknown molecular defects

Welander distal myopathy

In her thesis in 1951 Welander described 249 patients with this disease [START_REF] Welander | Myopathia distalis tarda hereditaria[END_REF]. The initial symptoms were clumsiness in precise finger movements, beginning as extensor weakness in the thumb or index fingers and spreading to the other fingers. Distal leg involvement occurred later, with stumbling, difficulty in walking, and, eventually, inability to stand on the heels or development of a steppage gait. In a minority symptoms may start in the lower limbs. These early clinical observations have been documented 50 years later by muscle imaging [START_REF] Mahjneh | Muscle magnetic resonance imaging shows distinct diagnostic patterns in Welander and tibial muscular dystrophy[END_REF]. Coldness of the hands and feet occurred in 90 percent of patients and the disease shows autosomal dominant inheritance.

The possibility of a neurogenic component in WDM was first considered by Welander

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ACCEPTED MANUSCRIPT [START_REF] Welander | Myopathia distalis tarda hereditaria[END_REF]. Mild neurogenic features were later detailed by Borg and coworkers who found abnormalities of sensory function and sural nerve histology [97], but no abnormalities of sensory nerve conduction velocities, nor any neurogenic findings in 8 anterior tibial muscle biopsies in young and middle-aged adults with early symptoms [START_REF] Borg | Intranuclear and cytoplasmic filamentous inclusions in distal myopathy (Welander)[END_REF].

Epidemiology

There are no exact studies on epidemiology of WDM, but estimates based on patient numbers at different regional neuromuscular centers indicate a prevalence about 5/10 5 in Sweden (Edström, personal communication). Recent data emerged from Finland where WDM has been identified in several families [START_REF] Von Tell | Welander distal myopathy outside the Swedish population: phenotype and genotype[END_REF].

Molecular genetic findings

Genetic studies in well defined WDM families determined linkage of the disease to a In the affected muscles rimmed vacuoles were found in atrophic fibers of both fiber types. On electron microscopy tibialis anterior specimens revealed autophagic vacuoles harboring dense bodies, myelin figures, and tubulofilamentous inclusions [97,[START_REF] Borg | Intranuclear and cytoplasmic filamentous inclusions in distal myopathy (Welander)[END_REF].

Laboratory findings and muscle pathology

Other distal myopathies -single families

Several single families have been reported with distal myopathy distinct to the known entities as shown by linkage exclusion to established loci or by linkage assignment to specific new loci. These are comprehensively reviewed elsewhere [START_REF] Udd | Distal myopathies[END_REF] Distal phenotypes in other myopathies

The disorders described above were all reported as distal myopathies. However, there are many disorders which can present with a distal phenotype that were classified or reported under different headings. These are important when discussing phenotypes versus molecular pathogenesis, and they illustrate the further development of molecular genetics serving as a new basis for classification of myopathies. Moreover, molecular genetics has disclosed allelic disorders or even identical gene defects that may present with highly variable phenotypes [START_REF] Udd | Titinopathies and extension of the M-line mutation phenotype beyond distal myopathy and LGMD2[END_REF]. Because of noteworthy general aspects on molecular pathomechanisms and selective muscle involvement, two entities are separately notified.

Myotonic dystrophy type 1

Myotonic dystrophy type 1 (Steinert's disease) is worldwide the most common cause of a distal muscular dystrophy phenotype, not classified so because of the overt multi-system character of the disease. The molecular biological reason of why distal muscles are preferentially involved is not known. The repeat expansion underlying the disease alters the

Oculopharyngodistal myopathy

The extraocular muscles are rarely affected in muscular dystrophy.

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A

  C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPTclinical findings of extensive involvement of calf muscles showing dystrophic fatty replacement and very mild proximal leg muscle involvement. Histopathology of proximal upper limb muscles showed a variety of pathological findings including multiple large nonrimmed vacuoles, focal sarcoplasmic desmin reactive masses that stained darker on Gomori trichrome, rimmed vacuoles, and IBM-like cytoplasmic and nuclear filaments on electron microscopy[START_REF] Penisson-Besnier | Autosomal dominant late adult onset distal leg myopathy[END_REF]. Immunohistochemistry revealed abnormal myotilin aggregations and less pronounced ectopic expression of desmin, ZASP and aB-crystallin in the same aggregations.[52] Zaspopathy ZASP (Z-disk alternatively spliced PDZ-domain containing protein) is a component of the Z-disc and has known interactions with alpha-actinin (Fig1A)[START_REF] Selcen | Mutations in ZASP define a novel form of muscular dystrophy in humans[END_REF][START_REF] Klaavuniemi | Zasp/Cypher internal ZM-motif containing fragments are sufficient to co-localize with alpha-actinin-Analysis of patient mutations[END_REF]. Further mechanisms by which mutated ZASP causes such widespread disintegration of the sarcomere structure are so far elusive, but most mutations identified to cause MFM pathology are located in the Zasp-like motif encoded by exon 6, which is expressed in skeletal muscle and

  locus on chromosome 2p13 close to, but outside the dysferlin locus [100,101]. All known genes in the linked locus have been sequenced without identification of the causative gene [102]. All WDM patients in Sweden and Finland carry the same haplotype at the locus indicating one single common founder mutation [99,100]. In one of the families included in the linkage studies, one patient was homozygous for the linked haplotype and he, indeed, displayed a much more severe myopathy compared to typical WDM [100].

Serum

  CK may be normal or up to a threefold elevated in WDM patients[103]. EMG studies in WDM patients show brief, short and polyphasic motor unit potentials, and in severely affected muscles a decreased number of motor unit potentials. Spontaneous electrical activity at rest, fibrillation potentials, and discharges have been reported[103].Computed tomography (CT) and magnetic resonance imaging (MRI) both show fattyA C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPTdegeneration of affected muscles with replacement lesions in the anterior compartment and frequently in the soleus and gastrocnemius muscles in the leg[START_REF] Mahjneh | Muscle magnetic resonance imaging shows distinct diagnostic patterns in Welander and tibial muscular dystrophy[END_REF]104].

A

  C C E P T E D M A N U S C R I P TACCEPTED MANUSCRIPTsplicing machinery of gene transcription. At present a dozen different genes are shown to be affected and the list may grow to hundreds or more, but which of the abnormally spliced genes are responsible the distal muscle involvement is unknown[105].

1 . 2 . 4 .

 124 Schematic drawing of the structural proteins of the sarcomere and proteins involved in distal myopathies indicated (1A). Below in Fig. 1B the same schematic sarcomere structure detailed for titin and known mutations in c-terminal titin causing TMD titinopathy (Udd myopathy) disease (1B). Legs of a 42 year old male patient with mutation in slow myosin heavy chain MYH7 gene causing MPD1 myosinopathy (Laing myopathy), showing the 'hanging big toe' sign but clinically not much visible tibial anterior atrophy despite total loss of function (2A). CT scan of lower leg muscles in a 12 year old male patient with MYH7 mutation showing total replacement by fat and connective tissue in anterior compartment muscles and also severe changes in soleus muscles bilaterally (2B). Serial sections of end stage pathology muscle tissue from tibial anterior muscle (same patient as 2B) showing just one atrophic muscle fiber expressing slow myosin (2C), and all other highly atrophic fibers express fast myosin (2D), where the proportions normally are the opposite in this particular muscle. 3. Lower legs of a 48 years old male patient with FINmaj mutation in c-terminal titin causing TMD titinopathy (Udd myopathy) showing clear atrophies of the anterior compartment muscles with subsequent prominent ventral edge of the tibial bone (3A). CT scans of lower leg muscles in a 62 year old female patient with FINmaj mutation showing selective total replacement of all anterior compartment muscles: tibialis anterior, extensors hallucis longus and digitorum longus, with normal appearance of the other lower leg muscles (3B). Hematoxylin and eosin stained tibial anterior muscle biopsy from early stages of the disease in a 42 year old female patient with FINmaj mutation showing large variation of fiber size, increased connective tissue and one atrophic fiber with rimmed vacuolar change (3C).A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT Legs of a 24 year old male patient with dysferlin mutation showing clinically atrophic calf muscles on the left side (4A). Low field MRI muscle imaging in 32 year old male patient with dysferlin mutations causing total replacement of posterior calf muscle bilaterally (4B).

Figure 1 Figure 1 A

 11 Figure 1 Figure 1

  The exceptions are mitochondrial muscle disorders such as PEO, and oculopharyngeal muscular dystrophy (OPMD) which is caused by a short repeat expansion in the PABP gene. Japanese families with late onset dominant distal myopathy and prominent oculopharyngeal weakness, in one associated with cardiomyopathy, have been reported [106,107]. In other families the trait seemed to be autosomal recessive [108,109].

	Other disorders with occasional distal presentation
	Rare instances of distal weakness have been described in chronic polymyositis [110].
	Inclusion body myositis (s-IBM) often presents with anterior compartment leg or forearm
	weakness [111].
	Patients with either facioscapulohumeral dystrophy (FSHD) or scapuloperoneal
	syndromes, presenting with anterior tibial muscle weakness before facial or shoulder
	weakness is evident, are not very rare and may cause diagnostic confusion. In FSHD isolated
	calf muscle involvement has been reported rarely. Mutation analysis is mandatory to identify
	'sporadic' cases of FSHD [112]. Most recently, the increased expression of FGR1 gene that
	follows the FSHD mutation, was shown to also alter splicing machinery [113]. In other
	disorders rare cases may have a distal presentation such as: centronuclear myopathy [114],
	debrancher enzyme deficiency myopathy (glycogenosis type 3) [115], phosphorylase b kinase

deficiency

[116]

, and lipid storage myopathies

[117]

. A distal phenotype can also occur secondary to nephropathic cystinosis

[118]

.

Table 1 DISTAL MYOPATHIES with genetic definition OMIM

 1

						CK	Muscle pathology
	Type				Onset			Genetics
			#
			Refer.	Age Initial weakness			Fam	Gene&
									Locus
	Laing early onset distal		#160500	1-25	Anterior lower leg	1-8x	Type 1 fiber atrophy in TA	AD	Myosin
	myopathy	MPD1					muscle, (no) vacuoles		MYH7,14q
	Distal nebulin myopathy	Udd pers	2-15	Anterior lower leg	1-3x	No nemaline rods on light	AR	Nebulin
		DNM	communic				microscopy, no vacuoles		NEB, 2q21
	Udd distal myopathy		#600334	>35	Anterior lower leg	1-4x	Dystrophic, rimmed vacuoles AD	Titin
		TMD							TTN, 2q31
	Distal onset in telethoninopathy Vainzof pers	early	Lower leg, anterior	3-10x	Rimmed vacuoles	AR	Telethonin
			comm						17q
	Desminopathy MFM		#601419	15-40 Distal leg and forearm	1-3x	Dystrophic, rimmed vacuoles	AD	Desmin
	(myofibrillar myopathy)				+cardiomyopathy		+ desmin bodies		2q35
			#609200	40-60 Lower legs and hands	1-3x	Rimmed and non-rimmed	AD and	Myotilin
	Distal myotilinopathy MFM	Penisson-				vacuoles, GTC dark and	sporadic	5q31
			Besnier				hyaline structures, desmin+
	(myofibrillar myopathy)
			#609452	40-60 Lower legs and hands	1-3x	Rimmed and non-rimmed	AD and	ZASP
	Zaspopathy MFM		Markesbery				vacuoles, GTC dark and	sporadic	10q
			1974				hyaline structures, desmin+
	(myofibrillar myopathy)
	Distal MFM		#608810	adult Distal leg and hands		+desmin granulofilamentous AD	αB-crystallin
	(myofibrillar myopathy)				+cardiomyopathy				11q
	Distal Caveolinopathy		#601253	early hands	3-10x	Reduced caveolin-3	AD	CAV3
	Miyoshi myopathy		#254130	15-30 Posterior lower leg, calf	10-100x Dystrophic	AR	Dysferlin
		MM							2p13
	Nonaka distal myopathy	#605820	15-30 Anterior lower leg	1-5x	Rimmed vacuoles	AR	GNE
	DMRV/ hIBM							9p1-q1
	Welander distal myopathy	#604454	>40	Hands, finger extensors	1-4x	Dystrophic, rimmed vacuoles AD	2p13
		WDM
	Distal myopathy with vocal cord	#606070	35-60 Asymmetric lower leg and	1-8x	Rimmed vacuoles	AD	5q31
	and pharyngeal signs MPD2			hands + dysphonia
	Distal myopathy with pes cavus	#601846	15-50 Anterior+posterior lower leg,	2-6x	Dystrophic, rimmed vacuoles AD	19p13
	and areflexia				dysphonia+dysphagia