Dra. Beatriz San Millán - 'Neuropatías, periféricas hereditarias'
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Los días 11 y 12 de diciembre de 2014, la Fundación Ramón Areces celebró el Simposio Internacional 'Neuropatías periféricas hereditarias. Desde la biología a la terapéutica' en colaboración con CIBERER-ISCIII y el Centro de Investigación Príncipe Felipe. El tipo más común de estas patologías es la enfermedad de Charcot-Marie-Tooth, un trastorno neuromuscular hereditario con una prevalencia estimada de 17-40 afectados por 100.000 habitantes. Durante estos dos días, investigadores mostraron sus avances en la mejora del diagnóstico y el tratamiento y, por ende, de la aproximación clínica y la calidad de vida de las personas afectadas por estas patologías.
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Dra. Beatriz San Millán - 'Neuropatías, periféricas hereditarias'
- 1. Myelinopathies Beatriz San Millán Carmen Navarro Servicio de Anatomía Patológica. Neuropatología Complejo Hospitalario Universitario de Vigo SYMPOSIUM ON NERVE BIOLOGY AND INHERITED PERIPHERAL NEUROPATHY Madrid - 11st 12nd December 2014
- 2. Spinal cord: •Fewer and smaller anterior horn cells •Demyelination of the posterior columns •Atrophy of Lissauer´s zone Nerve trunks •Increased interstitial connective tissue •Hypertrophy of the lamellar sheaths “Are we dealing with a myelopathy? Is it multiple peripheral neuritis? Although to a certain extent there is the hypothesis for a myelopathy however preferable, it seems difficult for us to say absolutely” Jean Martin Charcot Pierre Marie Howard Tooth “Post-mortem examinations point strongly to the conclusion that the disease is a neuropathy, and that it probably belongs to that class known by the vague generic term, neuritis” 1886: First neuropathologic observations in CMT “A particular form of progressive muscular atrophy”
- 3. Dejerine & Sottas • “Hypertrophic interstitial neuritis” • Enlarged nerves • Onion bulbs
- 4. HEREDITARY Autosomal Dominant: •CMT1A •CMT1B, 1C, 1D,1E, 1F, 1G •HMSN3A,B,C X-linked CMT-X HNPP/ Tomaculous neuropathy Autosomal Recessive : •CMT4 (A, B1,B2,C, D (Lom), F, H,J) Metabolic: – Metachromatic leukodystrophy (MLD) – Krabbe’s disease – Adrenoleukodystrophy – Refsum’s disease – Others: Niemann- Pick (A,C), Farber, Tangier • Inflammatory – GBS and CIDP – Paraproteinaemic neuropathy – Leprosy • Neoplastic – Waldestrom’s macroglobulinaemia – Non-Hodgkin’s lymphoma – Hodgkin’s disease • Toxic – Diphteric neuropathy – Amiodarone – Others: Perhexiline maleate, buckthorn DEMYELINATING NEUROPATHIES ACQUIRED
- 5. •CMT 1&4: primary defect in myelination •Failure of mutant Schwann cells to maintain axons •Final common pathway •Therapeutic target to slow disease progression?
- 6. •Pathological process involving the Schwann cell or the myelin sheath: •Preferential damage to internodes (relative sparing of axons): Segmental demyelination •Initial myelinopathy: Vesicular degeneration (may also be an artifact of delayed fixation) Splitting of myelin lamellae Widening of the nodal gap Unusual folding of the myelin sheath •More severe disorder produces demyelination of entire internodes Segmental demyelination
- 7. • Myelinopathic process sustained or severe: • Degeneration of myelin sheath • Myelin degradation begins within the Schwann cell cytoplasm • Haematogenous and intrinsic macrophages engulf the debris • Macrophages containing debris evidences ongoing demyelination • Primary effector cells of active demyelination: GBS, CIDP • Secondarily engulf myelin damaged by other processes Ongoing demyelination
- 8. • Schwann cell proliferation (from demyelinated segments and adjacent unmyelinated axons) • Each lost myelin internode is replaced by several shorter internodes • Subsequent remyelination: – Internodal distance becomes irregular – Decreased thickness of myelin coats Remyelination
- 9. g ratio (axon diameter/ fiber diameter) Remyelinated fibres •Myelin thinnes •G ratio increases, internodal length shortens •Myelin thickens during development, until puberty (15 yr of age) •Consider the normal range before diagnosing hypomyelination
- 10. Onion bulbs • Appear after repeated episodes of demyelination and remyelination. • Concentric layers of Schwann cell processes around a central fibre. • Typical of CMT1, CMT4, CIDP, Refsum, lead, recurrent compression… • Advanced cases: Nerve hypertrophy : Superficial nerves visible and palpable
- 11. CMT1 Pathology overlap between the various forms of CMT1 •Segmental demyelination & remyelination: Many thinly myelinated fibres • Loss of large and small myelinated fibers • CMT1A: • Onion bulbs + increased matrix and collagen: Hypertrophic neuropathy • Some fibres: Myelin thickening before demyelination : overexpression of PMP22?
- 14. Onion bulbs
- 16. Congenital hypomyelinating neuropathy: “Basal lamina onion bulbs”
- 17. • Uncompacted myelin • (P0 as a homophilic adhesion molecule) • Focally folded myelin • Compact myelin CMT1B: P0 protein (MPZ) Pathology: Demyelinating; 2 types depending on site of mutation:
- 18. CMTDIE
- 19. Hereditary neuropathy with liability to pressure palsies (HNPP) “Tomaculous neuropathy” • Del17p(PMP22) • Hallmark: Tomaculi (teased fibres) • CIDP, CMT
- 20. • Segmental demyelination, Remyelination • Rare onion bulbs • Myelin thickening: “Jelly rolls” • EM: redundant myelin loops HNPP “Tomaculous neuropathy”
- 24. Neurological disorders in Gypsies caused by founder mutations Disease OMIM Loci Gene/Mutation CMT4D- Lom neuropathy 601455 AR 8q24 NDRG1/R148X Russe neuropathy 605285 AR 10q23 Congenital cataracts, facial dysmorphism, neuropathy syndrome 604168 AR 18qter LGMD2C 253700 AR 13q12 SGCG/C283Y Congenital myasthenia 254210 AR 17p13 ChRNE/1267delG SMA 253300 AR 5q13 SMN
- 25. 1 2 3 4 5 6 1 2 3 5 5 6 8 9 10 12 12 13 14 15 16 18 19 20 21 22 23 24 25 1 3 4 4 6 7 8 9 11 11 10 14 15 16 17 19 20 21 22 23 24 25 26 27 28 30 31 32 33 34 35 36 37 38 39 41 42 43 44 45 46 47 48 49 50 51 52 53 54 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 3 18 13 29 26 27 * * ** *** ** * ** ** ** ** * * 55***** * LGMD2C- C283Y / LOM NEUROPATHY 7 * 38* * * 17 * * 2 * * * PRINCIPE FELIPE FIGUEIRIDO O VAO 40 ALBERTO GABRIEL J.MATOS. ELISA PILAR FÁTIMA MACARENA JIMÉNEZJIMÉNEZ JIMÉNEZJIMÉNEZ J.J. CONCEPCIÓN MªLUISA ALBERTO G.D. EMERITA ENRIQUE GABRIEL LEONOR NOEMI SHEILA ALBERTO LUPE CELSO AZUCENA ROSA BALDUINO ANA BEATRIZ RAQUEL CRISTINA DEBI AMAYA BEATRIZ J.J. GABARRIJIMÉNEZ LUISJ.M. MªdelaO CARMEN SALAZAR MONTOYA ALFONSO GABARRI CONSUELO ARACELI ALFREDO JOSÉ CÉSAR PABLOJ. AMAYA DAVID BEATRIZ LUCIA MANUEL J.MONTOYA 39 5 6 74 56 1 2 8 9 10 * * * ESTUDIO GENÉTICO R148XC283Y*
- 26. • Gait disturbances 6 years • Distal weakness and atrophy • Stepagge • Pes cavus deformity • Sensory loss • Romberg + • Thenar and hypothenar atrophy •Clawhands Lom neuropathy
- 27. Lom neuropathy
- 28. Lom neuropathy
- 29. Lom neuropathy
- 30. • Deficiency of arylsulfatase A • Myelin degeneration in CNS & PNS • Accumulation of galactosyl sulfatide and other sulfatide lipids • Late infantile, juvenile and adult-onset forms • CNS involvement predominates in all forms Metachromatic Leucodystrophy (MLD)
- 31. Metachromatic Leucodystrophy (MLD) • Most patients show clinical / electrophysiological demyelinating polyneuropathy • Sulphatide deposits: Methacromasia with Toluidine blue / Cresyl violet Pink Metachromasia (Toluidine blue) Brown methacromasia (Acidic cresyl violet) CNS: white matter PNS: sural nerve
- 32. MLD
- 33. MLD
- 36. Krabbe disease (globoid cell leucodystrophy, GLD) deficient activity of galactosilceraminidase
- 37. Krabbe
- 38. Krabbe
- 39. Histopathologic Testing in Inherited Neuropathies • Genetic tests (nerve biopsy is seldom indicated) • Common morphologic findings in different demyelinating neuropathies. • Nerve biopsy is performed in selective cases: • Suspect of systemic disorders: vasculitis, neoplastic infiltration, amyloidosis…. • In hereditary neuropathies, it should be limited to cases of unclear hereditary etiology or when acquired etiologies are suspected to be superimposed.
- 44. Burnt out Onion Bulbs
Notes de l'éditeur
- Good afternoon, I’m going to comment on the main np aspects of hereditary demyelinating neuropathies. The first np observations about CMT were made In 1886 by Charcot and Marie in their description of a ‘‘particular form of progressive muscular atrophy. The autopsy findings in five cases, consisted of loss of anterior horn cells of the spinal cord, demyelination of the posterior columns and atrophy of Lissauer’s zone (band of unmyelinated gray fibres which reaches the meningeal surface at the dorsolateral sulcus. They observed that the Nerve trunks had increased amounts of interstitial connective tissue and hypertrophy of the lamellar sheaths alongside the atrophic nerve fibers. Therefore, Charcot and Marie hypothesized (haipozesaizsd) that the lesion was mainly located in the spinal cord. Howard Tooth was the first to localize CMT to the peripheral nerves and he concluded that the disorder belonged to the generic term “neuritis” (niuraichiz)
- In the decades after Charcot, Marie, and Tooth’s initial description, the observations of Dejerine and Sottas on the pathology of hypertrophic interstitial neuritis in two siblingslead to the creation of a category of cases with enlarged nerves or onion bulbs as a separate entity.They believed that OB were of connective tissue origin. As will become evident later, OB originate from Schwann cells lamellae and are not a distinctive feature of a single disease Dejerine-Sottas disease: severe demyelination Classification of the hereditary neuropathies, and specifically that of Charcot-Marie-Tooth (CMT) disorders, has never been easy because of phenotypic overlap among different syndromes [15].
- Compared with the large and growing number of mutations in genes known to cause a Charcot-Marie-Tooth type of neuropathy, there are only a limited (límirid) number of structural changes in peripheral nerves. We`ll also comment on briefly systemic disorders that affect peripheral nerve alltogether with CNS involvement and in some cases, demyelinating neuropathy could be the predominant symptom, as the adult form of MLD. involving the Schwann cell and the myelin sheaths , considering CMT I’ll comment on the main neuropathological findings of the demyelinating forms of CMT Compared with the large and growing number of mutations in genes and chromosomal loci known to cause a Charcot-Marie-Tooth (CMT) type of neuropathy, there is only a limited number of structural changes in peripheral nerves (including small nerve fascicles in muscle and skin biopsies). The overwhelming proportion of changes are nonspecific, But in certain diseases,a single nerve biopsy allows a specific diagnosis. Nevertheless, many changes are group-specific and offer ways to estimate the severity and time-course of the disease. There is overlap between the various forms of CMT1; thus their pathology will be discussed together. CMT remains an evolving disease with more gene mutations being discovered. Myelinopathies can be defined as a group of diseases that affects preferably Schwann cell or myelin sheaths, whatever is its origin. We can follow this classification considering hereditary and acquired forms (both of except for toxics, that preferentially affects the schwann cell and the axon. Some of them are not exclusive of peripheral nerve and can accompany central nervous system (CNS) demyelination. We could consider another group in which myelin is severely involved secondary to axonal damage, (such as toxic neuropathies) but this is a matter of another speaker. Myelonipathies can be defined as a group of diseases that affects preferably myelin sheaths, whatever is its origin. In that sense we will revise peripheral neuropathies that course with demyelination, although some of them are not exclusive of peripheral nerve and can accompany central nervous system (CNS) demyelination. Myelin abnormalities can not be strictly separated from Schwann cell pathology; however, there are some disturbances that affect the myelin sheath itself but not the Schwann cell as a whole unit, i.e. congenital hypomyelination. Nerve biopsy has been a method of choice, years ago, to diagnose certain diseases of peripheral nerve. Nowadays, with the advent of genetics and the rapidly increasing knowledge of the large group of hereditary neuropathies, nerve biopsy is not a method of choice for diagnosis, and is almost exclusively performed in systemic diseases that can affect peripheral nerve, such as vasculitis, malignancies or metabolic diseases. Therefore, to prepare this talk we had to go backwards and rescue old cases from the times where nerve biopsy was more frequent. We will follow this classification: CMT Ib: mas severo, mas dismin veloc cond, mas bulbos cebolla, Htrofia nervio. Myelinopathies are the result of process directed against the Schwann cell or the myelin sheath. Hereditary: most of these affect both schwann cell and myelin
- The demyelinating neuropathies are genetically heterogeneous but their common feature is that the primary defect perturbs myelination. More clinically relevant, however, is the failure of mutant Schwann cells to maintain axonal integrity, and therefore the demyelinating neuropathies share their final common pathway with the primary axonal forms, consisting of Axonal loss. This might constitute a promising therapeutic target that would enable disease progression to be slowed. All mutations that cause CMT1 have almost complete penetrance, and the mutated genes are expressed in myelinating Schwann cells The products of CMT-associated genes include not only structural components of myelin, but also proteins that have signallingand regulatory functions in Schwann cells CMT1 and CMT4 are clinically differentiated from primary axonal forms (CMT2) according to electrophysiological criteria. These demyelinating forms of CMT disease are caused by primary genetic defects of Schwann cells that result in failure to make or maintain intact myelin sheaths. More clinically relevant is the failure of mutant Schwann cells to maintain long-term axonal integrity. Note that the demyelinating neuropathies share the final common pathway of disease expression with the primary axonal forms.
- Severe segmental demyelination is a basic (beisic) reaction of nerve fibers in all conditions primárily or secondárily affecting the myelin sheath. When the myelin sheath or the normal function of Schwann cells are disturbed, demyelination results, involving one or several internodes (inernouds), with relative preservation of axonal (eixonal) integrity Initial myelinopathy may be subtle, with vesicular degeneration, splitting of myelin lamellae, widening of the nodal gap due to retraction of myelin at the nodes, or unusual folding of the myelin sheath. A more severe disorder produces demyelination of entire internodal segments It usually starts with paranodal demyelination and spreads to the complete (complít) internode. The onset of demyelination at the paranode is particularly impressive in CMTX in which microvesiculation of terminal myelin loops represents one of the major changes before other pleomorphic changes at this site lead to segmental demyelination
- If sustained (sutínd) or of apprópiate severity, the myelinopathic process results in the degeneration of myelin sheaths If the original Schwann cell survives the insult, myelin degradation typically begins within the Schwann cell cytoplasm. Haematogenous (himátuginous) and intrinsic macrophages engulf the debris provided by the Schwann cell which are usually cleared rapidly. The presence of macrophages containing debris after several weeks is evidenced? for ongoing demyelination. They can be the primary effector cells of active demyelination, as in GBS syndrome and CIDP, where they strip otherwise normal-appearing myelin or secondarily engulf myelin damaged by other processes
- Remyelination (remielineixon) requires (recuaies) Schwann cell proliferation from demyelinated segments as well as adjacent (adyeisent) unmyelinated axons. Which results in the eventual (dievenrual) remyelination of internodes, replacing each lost one by several shorter (xora) internodes. With subsequent (sabsícuent)remyelination, the distance between nodes of Ranvier becomes irregular and the thickness of myelin coats are noticeably (nourisibly) decreased.
- When seen in transvérse sections, the remyelinating sheath may be identified by its relative thinness, that is particularly obvious on large calibre fibres. Thus on cross-sections the ratio (reixo) between axon caliber and myelin thickness appears to be increased, and in longitudinal sections or teased fiber, the internodal length is shortened. For estimating myelin thickness it must be considered that myelin becomes thicker during development, reaching the adult value around puberty (piubery). And thus the normal range must be kept in mind before diagnosing hypomyelination In CMT1 i due to duplication of peripheralmyelin protein 22 PMP22 there is an early excess of myelin production and some fibers have relatively thickened myelin sheaths initially, resulting in lowered mean g ratios (axon diameter/fiber diameter). It is important to know that some paranodal myelin loops are not attached to the axon causing an erroneous impression of pathological “axoglial dysjunction”. The number of these “detached” loops increase in proportion to the growing thickness of the myelin sheaths forming the so-called bracelets of Nageotte. This needs to be considered when discussing changes of the paranode in any type of neuropathy. Although axonal sprouts may also have inappropriately thin myelin, they are usually smaller fibres and often occur in regenerative clusters Single thinly remyelinated fibres may only be distinguishable from single regenerating axons by the examination of teased fibre preparations, which allow examination of several internodes along the same fibre. Regeneration is easily identifiable as the internodes are all equally short with myelin of the same thickness Normal ultrastructural appearance of the peripheral nerve. Note abundant collagen fibrils within the endoneural matrix running in parallel with the axons
- In nearly all demyelinative neuropathies, demyelination and remyelination occur concurrently and repeated episodes lead (lid) to the formation of onion bulbs, a term that refers to multiple layers of supernumerary Schwann cells processes and intervening collagen arranged in rings around longitudinally oriented nerve fibres. OB are characteristically seen in CMT1 and 4, CIDP, Refsum disease, lead neuropathy and recurrent compression. Their presence suggest a cyclical(saiclical) demyelinative/ remyelinativeprócess active for several months or more. In advanced (ádvansd) cases, the added accumulation of extracellular matrix (meitrix) and collagen in the endoneurium results in expansion of the intrafascicular area, which is easily recognizable by light microscopy. This may hypertrophy the nerve fascicles to such an extent that the trunk of a superficial (siuperfixial) nerve may become visible and palpable. The thickness of the collagen filaments and the amount of collagen tends to be directly related to the duration of the disease and the number of fibroblasts involved. Hypertrophic onion bulb changes with concentric Schwann cell proliferation are frequent as a result of successive waves of demyelination and remyelination.
- There is overlap between the various forms of CMT1; thus their pathology will be discussed together. There is a reduced number of myelinated nerve fibers, with a deficiency of both large and small diameter elements, alltogether with signs of segmental demyelination and remyelination. The most frequent, CMT1A is characterized by onion bulb formations with expanded fascicular areas due to increased matrix and collagen. It constitutes the benchmark example of hypertrophic neuropathy. Some fibers may have relatively thickened myelin sheaths, before demyelination occurs., probably as a result of overexpression of PMP22. Exceptionally, chronic inflammation can be found. A mayor aumento : fibrosis intersticial, disminucion de axones mielinizados sobre todo de fibras de mayor calibre y bulbos que son…..prolif de cel S en intento de formar mielina. Explicar un bulbo de la imagen CMT desmiel afecta inicialmente a las fibras de mayor calibre. In cases of Dejerine Sottas disease, demyelination is severe. Focal, sausage-like thickenings of the myelin sheath (tomacula) may be present in various types of CMT1, though their numbers have been said to be higher in patients with CMT1B. However, neither disorder has tomaculi present to the extent seen in HNPP. Segmental demyelination, remyelination, and axonal loss are characteristic features. Axonal loss varies with individual patients. There is a loss of both small and large diameter myelinated fibers in nerve biopsies of CMT1 patients. Many thinly myelinated fibres are seen and there is an increase of the myelin spiral length in relation to axonal diameter. This had been interpreted as evidence of axonal atrophy but possibly reflects overexpression of PMP22, leading to myelin thickening before demyelination occurs.
- Semithin section show clearly the 3 characteristics of CMT1; loss of myelinated fibres and axons, increased endoneurial collagen and onion bulb formation.
- At higher magnification some details of the onion bulbs. Most of them are centered by a myelinated axon, although in some others the axon has disappeared, generally related to the long term disease.
- Here we can see an onion bulb in a case of CMT1, composed by multiple concentric layers of Schwann cell processes and intervening collagen arranged in rings around a central myelinated fibres. This is the nucleus of a Schann cell and these are the supernumerary Schwann cells processes and intervening collagen
- There could be several possibility when we look at the EM, for example, on the upper left corner, there is an onion bulb containing a thin myelin as related to the total axonal diameter, significant of demyelination-remyelination. On the other micrograph, myelin is somewhat disestructured. On the bottom, one onion bulb containing 2 different axons and on the right an onion bulb where the myelinated axon has disappeared.
- “Congenital hypomyelinating neuropathy” (CMT4) is characterized by onion bulb of a special type, called , “basal lamina onion bulbs” . In these, the Schwann cells processes have degenerated, whereas their basal laminae are persisting and they can be seen as multiple layers of redundant basal lamina Note that There is no myelin around the central axon Marked reduction or even absence of myelin
- IN CMT1B, the nerve biopsy demonstrates a demyelinating process with onion bulb formation in all cases. These authors differentiate two pathologic phenotypes , in the nerve biopsy of CMT1B, depending on the mutation in P0 protein: some (4) patients, had uncompacted myelin which is in agreement with the role of P0 as an adhesion molecule. The rest of the patients (3) showed normal compact myelin, but morphology was dominated by abundant focally folded myelin. The two divergent pathologic phenotypes exemplify that some mutations act differently on P0 protein formation or function than others, which is probably determined by site and nature of the mutation in the P0 gene.
- In a recent article by the group of Vallat about INF2 related CMT, the authors have observed abnormal accumulation of beta actin in the cytoplasm of Schwann cells, besides unusual proliferation of flattened Schwann cells cytoplasm. This suggest that this could be the first peripheral neuropathy associated with Schwann cells actinopathy. CMT1g (DIE),
- Regarding tomacolous np, this descriptive term was employed in cases showing this sausage-like configuration of the myelin sheath as viewed on teased nerve preparations. Myelin tomaculae may appear in other conditions, such as CIDP, and in the spectrum of CMT. In individualized teased fibers we can see the notorious focal enlargement of the myelin that can be close to Ranvier node. Note that segmental demyelination is clearly seen in this fiber. Immuno-EM studies of sural nerve biopsies have demonstrated the predicted under-expression of PMP22 [1] Hnpp is inherited as an autosomal dominant trait has allelic relationship with CMT1 is ALSO known as tomaculous neuropathy. Focal, sausage-like thickenings of the myelin sheath (tomacula) may be present in various types of CMT1, though their numbers have been said to be higher in patients with CMT1B. However, neither disorder has tomaculi present to the extent seen in HNPP. Immuno-EM studies on two CMT1B patients demonstrate normal levels of PMP22 and MBP but reduced levels of P0 [1] The clinical, physiologic and pathologic findings suggest that it is likely that different mutations of the same gene will lead to different clinical phenotypes, and that alterations in expression patterns of other myelin genes may depend on the particular mutation in question. remyelination, and some loss of large diameter axons have all been described in nerve biopsies from HNPP patients. Tomaculi are hallmarks of HNPP, and have been identified in at least one patient prior to the development of clinical symptoms [21].
- Nerve biopsy shows, some segmental demyelination, occasional regenerating clusters, rare onion bulbs and , most characteristically, segmental thickening of myelin with a jelly roll appearance on cross sections that on EM corresponds to the wrapping of redundant loops of myelin around itself and the axon.
- This is a semithin section where we can observe the striking difference between normal or even thin myelin sheaths around the axons and enlarged ones Typical tomaculous fibers are the result of a pathomechanism of intussusception or invagination of a hypertrophic myelin sheath by a double, complete ring of additional myelin around itself thus causing three complete layers of myelin sheaths on cross-sections. This results in focal tomaculous (sausage-like) thickening of the myelin sheath at the paranode or at other, circumscribed portions of the internode, best visualized on longitudinal sections or in teased fiber preparations. Tomaculous fibers are not absolutely specific; they may also occur in PMP22 duplication (CMT1A) or other conditions, although a single typical tomaculous fiber can already lead to the correct diagnosis of a PMP22 deletion Tomacula must be distinguished from the most frequent traumatic (artificial) damage of myelin sheaths consisting in severe distortion of the myelin sheath, usually in a larger number of adjacent fibers; the focal accumulation of clumsy myelin sheaths usually allows distinction between artefacts and real tomaculous fibers. This traumatic lesion leads to the most frequent misinterpretation of a nerve biopsy.
- On EM, these differences are more clearly seen; thin myelin sheaths regarding the axonal diameter and hypermyelinated fibres with redundant myelin loops that may wrap around the axon to varying degress, reaching up to three or four tightly packed turns. . On the right, we can appreciate the redundancy of one myelin sheath. The configuration of hypermyelinated segments of the nerve fibre are better defined by ultrastructural examination as a double folded Additional myelin abnormalities include the presence of uncompacted myelin in the inner layers of the myelin sheath The term tomaculous neuropathy should be used only in a descriptive sense HNPP (tomacular) es la misma alteracion q la q CMT1a (dupl cr 17). Decir frecuencia. No se suele biopsiar porque la Hª es típica y la genetica tb. Es AD.
- Sometimes the redundant myelin goes into the axon itself and part of the myelin seems to be separated and included into the axon as a pseudo inclusion.
- Within the group of CMT4 we have had the opportunity to see several patients from 2 different gipsy families (one in Galicia and one in Pamplona), with Lom np. Lom neuropathy was described in gipsy patients, and is one of the relatively common Autosomal Recessive neuromuscular disorders in this etnia, altogether with gamma Sglicanopathy , SMA and others. All of them have their founder mutations.
- This is the large family tree of a gallician gipsy family where the dark figures dorrespond to LGMD2C and the grey ones to Lom np. Note that the healthy grandfather of this pt was carrier of the 2 mutations.
- In these pictures we can see several characteristics such as the foot deformity with distal amyotrophy both in lower legs and hands with involvement of thenar and hypothenar muscles and clawhands. Forma desmielinizante de CMT Alteraciones de la marcha entre los 5 y 10 años Dificultad en el uso de las manos 2-3 años más tarde Debilidad y amiotrofia distal Deformidades esqueléticas Alteraciones sensitivas (todas las modalidades) Velocidades de conducción muy disminuidas Sordera neural en la 2ª-3ª década
- In this semithin section, the disproportion between axon and myelin sheaths is notorious as well as a mild axonal loss, and endoneurial fibrosis. A new entity was identi®ed by Luba Kalaydjieva et al. [1] in a Gypsy population that settled near the Bulgarian town of Lom, and has been termed hereditary motor and sensory neuropathy type Lom (HMSNL). It is cof autosomal recessive inheritance and is characterized by distal lower and upper limb wasting and weakness that begins in the ®rst decade of life leading to severe disability. Sensorineural deafness is an invariable part of the phenotype and usually develops in the third decade of life. I t has subsequently been identi®ed in Gypsy families from several European countries. early onset demyelinating sensorimotor neuropathy with abnormal BAEP recordings and an evident hearing loss in the oldest patient The severe loss of myelinated axons was the most significant feature in the nerve biopsy studies. Very few myelinated axons survived and the remaining myelin sheaths were of reduced thickness. Evidence of active demyelination was not seen. Schwann cell proliferation producing onion bulbs was not prominent, but attenuated processes surrounding myelinated or unmyelinated axons were evident. These changes are compatible with a severe demyelinating neuropathy with marked axonal loss. The hypertrophy changes that were present probably represent regressing onion bulbs and are a characteristic feature in HMSNL OSMIO severe depletion of myelinated fibers with very thin myelin sheaths in the surviving fibers. Hypertrophic onion bulb changes are present in younger cases that regress in older patients severe loss of myelinated axons. Those that remained were of relatively small size with thin myelin sheaths. No active ®ber degeneration or demyelination was seen but there were a few regenerative clusters. In all fascicles there were fairly numerous collection of Schwann cells with attenuated processes arranged in an approximately circular pattern, sometimes surrounding small myelinated or unmyelinated axons although many had no obvious associated nerve ®bers
- On Em level, we can see the ob formation and the axonal loss This confirmed a severely depleted nerve with very few surviving myelinated fibers. Those that were present mostly possessed thin myelin sheaths. Many of Schwann cell processes were arranged in circular configurations. Only rarely was a myelinated fiber present in the center of one of these structures. There was a high density of unmyelinated axons. Most of the Schwann cell processes associated with unmyelinated axons contained more than the normal complement of one or two per Schwann cell unit. Occasional crystalline Schwann cell inclusions were seen but no specific inclusions were detected.
- And better in this picture note that the ob are mainly composed by flattend sc processes
- Among the neuropathies that accompany CNS demyeliantion MLD is charaterized by a defect of arilsulfatase a, with accumulation of sulfatides (sulfataids). This is an example of an adult form of Metacromatic leucodystrophy. with extensive loss of myelin in the white matter in a Coronal section of an occipital lobe . Note the preservation of “U fibres” with myelin staining. MLD comprises a group of genetically determined disorders characterized by myelin degeneration in both the central and peripheral nervous systems, associated with the accumulation of galactosyl sulfatide and other sulfatide lipids. They are related to a deficiency of arylsulfatase A Late infantile, juvenile and adult-onset forms are recognized; most cases are due to a deficiency of arylsulphatase A Regardless of the age of onset of MLD, CNS involvement predominates but most patients show clinical or electrophysiolical evidence of a demyelinating polyneuropathy.
- Sulfatide deposits give a pink metachromasia when stained with toluidine blue and a brown methacromasia when treated with cresyl violet in a peripheral nerve Although CNS involvement predominates in MLD, most patients show clinical or electrophysiolical evidence of a demyelinating polyneuropathy We can see the storage material in the macrophages and glial cells in the demyelinating white matter, showing pink metachromasia on frozen section Metacromatic deposits. Typicall ultrastructural sulfatid inclusions giving a honeycomb appearence in a dermal nerve (are demonstrated in Schwann cells and macrophages) stained with Cresyl Violet.
- The peripheral nerves, show a reduction in myelinated fibres and demyelination. Large diameter fibres tend to be affected more severely than small diameter ones. In semithin sections we can suspect the presence of some pathological accumulation that we see here as clear vacuoles in the Schwann cell cytoplasm Loss of axons is mild in the late infantile and juvenile type but is more pronounced in the adult type, which is often associated with endoneurial fibrosis Fibre loss is usually less obvious in juvenile and adult onset cases, but demyelination and remyelination ultimately become greater.
- Under EM, Schwann cells and endoneurial macrophages contain heterogeneous inclusions showing alternating fine electron-dense and lucent structures We can also apreciate the thinning of the myelin sheaths and the onion bulbs in the 2 pictures of the bottom
- At larger magnification, the most characteristic lysosomal lamellated inclusions in MLD are tuffstone bodies, with its typical fine prismatic lamellar structure in both longitudinal and transversal sections
- Another aspect of the inclusions in MLD are striated bodies with some resemblance to zebra bodies The pathogenesis of demyelination is uncertain and it is known that Schwann cells associated with myelinated axons tolerate significant amounts of stored material without evidence of myelin damage. This inclusions are not derived from myelin breakdown, as they are present in Schwann cells associated with myelinated and unmyelinated axons and in fetal nerves before demyelination is evident.
- In GLD the deficiency in the activity of galactosilceraminidase result in marked demyelination throughout the brain, with the characteristic infiltration of numerous globoid macrophages containing PAS positive storage materials . This globoid cells are abundant in areas of active demyelination and are often clustered around blood vessels. Most cases have onset in infancy, but late infantile, juvenile and even adult -onset cases are encountered occasionally.
- About 50% of adult patients have peripheral neuropathy, some as a presenting feature. Peripheral nerves may be grossly enlarged and firm due to marked endoneurial fibrosis and features of segmental demyelination and remyelination with onion bulb formation. Pathognomonic inclusions in Schwann cell cytoplasm and endoneurial macrophages consist of straight or curved prismatic or tubular inclusions that Depending on the plane of section, may appear as empty clefts or needle like structures. There is also loss of myelinated fibres, disproportionately thin myelin sheaths and axonal degeneration ?Semifino / Osmio Peripheral nerve lesions include thinly myelinated nerve fibers, and segmental demyelination-remyelination , with hypertrophic features. This AR disease is caused by a deficiency of beta galactosidase, resulting in the accumulation of galactosylceramide (psychosine) in oligodendrocytes and Schwann cells. Multinucleate 2globoid cells of histiocytic orign in the cerebral white matter constitute the morphological hallmark of diagnosis. Although nerves show histiocytic infiltration, typical globoid cells are rare.
- This kind of inclusions are somewhat similar to those seen in ALD
- In conclusion, Nowadays, with the advent of genetics pn biopsy is seldom indicated in hereditary neuropahties The neuropathological findings in nerve biopsy are very similar in all demyelinating neuropathies And nerve biopsy is mostly performed when suspecting systemic disorders such as vasculitis, neoplastic infiltration , amyloidosis or rare metabolic disorders. Nerve biopsies for inherited neuropathies should be limited to cases in which a hereditary etiology is unclear or acquired etiologies are considered to be superimposed on a primary inherited mechanism. Such situations are frequently seen in varties of demyelinating neuropathies, particularly in children, when the temporal course is unclear and family history of neuropathy is absent. Nerve biopsy may remain useful, especially in those patients with atypical presentations and therefore an unanticipated diagnosis. The presence of interstitial inflammatory collections within the endoneurium, epineurium, and perineurium would be uncharacteristic of hypertrophic inherited demyelinating neuropathy and should raise strong consideration of treatable CIDP. In our experience, nerve biopsy has been most instructive when an inherited mechanism was not suspected. Specifically, the discovery of various types of infiltrative inclusions of inherited neuropathies can lead to the diagnosis of a genetic systemic metabolic disorder. Transthyretin amyloidosis is a disorder in which this scenario occurs commonly (Fig. 4). Patients are often unaware of their family history. Mass spectrometric evaluation to analyze nerve infiltration with amyloid can further assist in rapid diagnosis of the specific amyloid type. Mutant transthyretin amyloid protein, including the predicted amino acid alteration can be determined directly from the tissue without ambiguity. This is especially useful among those amyloid transthyretin patients who have incidental circulating serum monoclonal proteins that can lead to consideration of primary AL amyloidosis, where treatment and prognosis is quite different. Some patients with metabolic storage diseases and neuropathy have intraneuronal and Schwann cell inclusions that may be very characteristic of a specific genetic diagnosis, such as giant axonal neuropathy (Fig. 5) or adult-onset polyglucosan disease (Fig. 6). Other metabolic disorders that have less distinct inclusions in various portions of nerve, including organelles are Krabbe disease (prismatic inclusions in endoneurial macrophages), Fabry disease (dispersed perivascular osmophilic granules), metachromatic leukodystrophy (Schwann cell methachromatic granules), ceroid lipofuscinosis (curvilinear granular inclusions in Schwann cells), and cerebrotendonous xanthomatosis ) (minor Schwann cell lipids). These histopathologic features can suggest a narrowed differential diagnosis that can lead to confirmatory metabolic or genetic testing, and revisiting the clinical picture for additional clues can be helpful.
- Not all onion bulbs are composed of concentric Schwann cell processes. The inner processes may take the form of numerous interdigitating, branching Schwann cell processes rather than the concentric arrangement more usually seen. When axons are not identifiable in such structures, immunostaining for EMA and S100 is necessary, as there are rare diseases where the apparent onion bulbs are composed of perineural cells.
- In some severely hypomyelinated np in children, it may be very difficult to find any myelin in the onion bulbs and the whorls consist of numerous layers of Schwann cell processes separated by extensive collagen deposits. They are hypomyelinated OB If Initially, at least the axon remains normal Explicar tipos de bulbos Si al cel S degenera tanto solo se ve mbna basal
- Some cases of CMT1A have considerable axonal loss and the only indications of an hypertrophic process are the concentric Schwann cell formations. It seems probable that, when the central axon in an onion bulb degenerates, the encircling Schwann cell will also eventually disappear.
- Immuno electron miscroscopic analysis of sural nerve biopsies from CMT1A patients demonstrates increased PMP22 labeling compared to controls. The most common variant of CMT, (CMT1), accounting for 70-80 per cent of all patients is due to a defect in expression of PMP22 protein, that is caused by a tandem duplication of the PMP22 gene on chromosome 17p11.2-p12. It has been demonstrated that Messenger RNA for PMP22 is significantly elevated in nerve biopsies of pts with CMT1A.