Classification of Myelin Disorders

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The history of classifications of myelin disorders shows how each classification reflects the state of scientific development of its time. A revised classification based on the most recent scientific insights is proposed at the end of this chapter.

Interest in CNS myelin dates back to the nineteenth century. In 1854, Virchow was the first to suggest the name ‘myelin’ when he described the sheaths around axons in the CNS. It is not certain when Schwann (1810–1882) first described the cells since named af- ter him, which supply the myelin sheaths around the peripheral nerve fibers. In 1878, Ranvier described the nodes that have since been given his name in his

“Leçons sur l’histologie du système nerveux.” He be- lieved that the nodes prevented the essentially liquid myelin from flowing to the bottom of the nerve fiber (axon). But despite this conviction, he showed consid- erable insight into the functional role of the myelin sheath, both as an insulator and as a facilitatory agent in CNS functions. It was not until 1960–1961 that the role of the oligodendrocyte in the formation of myelin in the CNS became clear, and this was due to the work of Bunge.

During the nineteenth century and early twentieth century, important progress was made in the clinical and histological description of several demyelinating disorders. Multiple sclerosis was recognized as a clinical disease entity, and the characteristic histological abnormalities, in the form of multiple demyelinated, sclerotic plaques within otherwise normal white matter, were described. Prominent names in this development are Carswell (1838), Cruveilhier (1835–1842) and Charcot (1868).

In 1897, Heubner described a rare neurological disease in children, using the name diffuse sclerosis as opposed to multiple sclerosis. The disease was histologically characterized by diffuse demyelination of the cerebral white matter and eventual striking hardening of the white matter. Since that time, the term

‘diffuse sclerosis’ has commonly been used to de- scribe cerebral diseases with diffuse demyelination and sclerotic hardening of the cerebral white matter.

Pelizaeus in 1899 and Merzbacher in 1910 reported on a chronic progressive familial type of diffuse sclerosis.

In 1912, Schilder described a nonfamilial case of more acute diffuse cerebral demyelination in a child, and he suggested the name encephalitis periaxialis diffusa rather than diffuse sclerosis. In this case, more prominent signs of inflammation and a less symmet-

rical distribution were observed than in the familial cases described up to that time. Schilder considered that this disease was a nosological and histological entity related to multiple sclerosis and thought there were acute and chronic variants of diffuse sclerosis just as there were acute and chronic types of multiple sclerosis.

Since Schilder’s time a number of familial neurological disorders have been recognized, which were histologically characterized by diffuse demyelination and again presented under the heading of diffuse sclerosis. In 1916, Krabbe described a familial infantile form of diffuse sclerosis. Another familial variant, with a later onset and a less rapid progression, was reported in 1925 by Scholz and in 1928 by Bielschowsky and Henneberg. Scholz noted that in this case the myelin breakdown products did not show the usual (orthochromatic) staining properties, but stained metachromatically.

In 1921, Neubürger drew attention to the fact that the term diffuse sclerosis was being applied to several very different disease entities, and he proposed a distinction between inflammatory and degenerative forms. In 1928, Bielschowsky and Henneberg suggested the name ‘hereditary progressive leukodystro- phies’ for the degenerative forms of diffuse sclerosis and devised the following classification, based on the time of onset of the disease and its clinical course:

1. Infantile type of Krabbe

2. Subacute juvenile type of Scholz 3. Chronic type of Pelizaeus-Merzbacher

Hallervorden (1940) recognized that there were endogenous and exogenous factors causing diffuse demyelination and that a distinction was possible between disorders in which demyelination is invariably present and forms a specific part of the disease and disorders in which demyelination occurs occasional- ly and is nonspecific. He proposed a more extended classification based on these subdivisions:

I. Endogenous central demyelination A. Specific demyelinating diseases a. Diffuse sclerosis of Krabbe and Scholz b. Pelizaeus-Merzbacher disease

B. Nonspecific occasional demyelination e.g. Tay-Sachs disease

II. Exogenous central demyelination A. Specific demyelinating diseases

Classification of Myelin Disorders

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a. Inflammatory types:

– Disseminated sclerosis (= multiple sclerosis) – Diffuse sclerosis (Schilder) – Concentric sclerosis (Balò) – Neuromyelitis optica (Devic) – Encephalomyelitis disseminata – Infectious encephalitis

b. Toxic-metabolic types:

– Funicular myelosis (= vitamin B12deficiency) – Marchiafava-Bignami disease B. Nonspecific occasional demyelination

a. Disturbances of blood flow, e.g. subcortical atherosclerosis (= Binswanger disease) b. Edema

c. Toxic processes (carbon monoxide) d. Tumors

Until that time, distinctions between different diseases had been based on neuropathological and clinical aspects of different demyelinating disorders.

From about this time onwards, histochemical meth- ods and chemical analyses became increasingly important. The classification proposed by Blackwood in 1957 is a reflection of this development. It is based not only on morphological but also on histochemical differences between various subgroups of diffuse sclerosis:

I Disseminated sclerosis (= multiple sclerosis) II Diffuse demyelinating cerebral sclerosis

1. With replacement of myelin by sudanophilic lipid

a. With large bilateral cerebral plaques b. With concentric demyelination (Balò type) 2. a. With replacement of myelin by metachro-

matic PAS-positive lipid (Norman type or Scholz type)

b. With associated degeneration of interfasci- cular oligodendroglia (Greenfield type) 3. With replacement of myelin by nonmetachro-

matic PAS-positive lipid (globoid cell or Krabbe type)

Meanwhile, insight into normal biochemistry and in- to mechanisms of biochemical derangement was growing. The concept of hereditary inborn errors of metabolism caused by an enzyme defect leading to dysfunction and breakdown of myelin started to emerge. Fölling (1934) reported 10 patients in the same family with mental retardation and phenyl- pyruvic acid in their urine. Jervis discovered in 1947 that the underlying metabolic defect in phenylketonuria is a deficiency of phenylalanine hydroxylase.

In 1955, Diezel found that the lipids stored in the globoid cells in Krabbe disease have very similar properties to those of cerebroside. In 1970, Suzuki

and Suzuki were the first to propose a deficiency of galactocerebrosidase as the underlying biochemical cause of this disease. Advances in histochemistry also made it possible to discover the basis of metachromatic leukodystrophy. Metachromasia had already been found by Alzheimer in 1910, by Scholz in 1925, and later by Von Hirsch and Peiffer (1955 and 1957).

Edgar (1955) pointed out that this condition was characterized by a remarkable elevation of white matter hexosamine. In 1964, Austin et al. demonstrated a decrease in arylsulfatase A activity in metachromatic leukodystrophy.

The enzyme defects of an increasing number of hereditary diseases were detected, whereas in other cases the precise enzyme defect could not yet be discovered but typical biochemical abnormalities characteristic for the diseases could be demonstrated. The increased insight into hereditary metabolic disorders and the ongoing ability to distinguish different hereditary and acquired demyelinating disorders on the basis of a combination of clinical, histological and biochemical data, were reflected in the classification proposed by Raine (1984). Raine distinguished five main categories:

I Acquired inflammatory and infectious diseases of myelin

1. Multiple sclerosis

2. Multiple sclerosis variants (Schilder, Balò, Devic)

3. Acute disseminated encephalomyelitis 4. Acute hemorrhagic leukoencephalopathy 5. Progressive multifocal leukoencephalopathy II Hereditary metabolic disorders of myelin

1. Metachromatic leukodystrophy 2. Globoid cell leukodystrophy (Krabbe) 3. Adrenoleukodystrophy

4. Refsum disease

5. Pelizaeus-Merzbacher disease 6. Dysmyelinogenetic leukodystrophy

(Alexander)

7. Spongy degeneration (Canavan) 8. Phenylketonuria

III Acquired toxic-metabolic diseases of myelin 1. Hexachlorophene neuropathy

2. Hypoxic encephalopathy IV Nutritional diseases of myelin

1. Vitamin B12deficiency 2. Central pontine myelinolysis 3. Marchiafava-Bignami disease V Traumatic diseases of myelin

1. Edema 2. Compression 3. Barbotage 4. Pressure release

In this classification, four of the five categories in- volve acquired demyelinating disorders, and only one

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involves hereditary demyelinating disorders. The logical continuation of this development is a refinement of the classification of hereditary demyelinating disorders. For instance, in some diseases the inborn er- ror affects the metabolism of amino acids, and in other diseases it affects the lipid metabolism. A further subdivision can be made among the disorders of lipid metabolism according to the type of lipids involved.

In 1987, Poser proposed a classification of hereditary myelin disorders based on the biochemical group of compounds whose metabolism is disturbed. He distinguished six categories:

1. Disorders of glycosphingolipid metabolism a. Ganglioside: GM1and GM2gangliosidoses,

hematoside sphingolipodystrophy b. Sulfatide: metachromatic leukodystrophy c. Galactocerebroside:

globoid cell leukodystrophy

2. Disorders of phosphosphingolipid metabolism a. Sphingomyelin: Niemann-Pick disease 3. Disorders of fatty acid metabolism

a. Adrenoleukodystrophy

4. Disorders of amino acid metabolism a. Phenylalanine: phenylketonuria b. Branched-chain amino acids:

maple syrup urine disease c. Many other amino acidopathies 5. Multiple abnormalities

a. Mucosulfatidosis 6. Unknown abnormalities

a. Idiopathic spongy sclerosis (Canavan) b. Fibrinoid leukodystrophy (Alexander) c. Pelizaeus-Merzbacher disease

d. Idiopathic sudanophilic leukodystrophy An important development during the last few decades concerns the knowledge of subcellular struc- tures, their role in normal metabolism and the conse- quences of their dysfunction. Major subcellular struc- tures are the nucleus, lysosomes, mitochondria, per- oxisomes, cytoplasm matrix, smooth and rough en- doplasmic reticulum, Golgi apparatus, ribosomes, and microtubules.

Demyelinating disorders have been described as resulting from nuclear, lysosomal, mitochondrial, peroxisomal, and cytoplasmic enzyme dysfunctions.

Classification of hereditary demyelinating disorders according to the subcellular localization of the underlying metabolic defect stresses the clinical, biochemical, and neuropathological similarities within one category and the differences between the different categories. For the same reason, it is preferable to classify the acquired demyelinating disorders according to their underlying causes into noninfectious–inflammatory, infectious–inflammatory, toxic–metabolic, hypoxic–ischemic and traumatic. A number of

disorders remain for which the primary defect is largely or completely unknown.

An important point is that with increasing scientific insight the difference between ‘primary demyelinating disorders’ or ‘myelin disorders’ and ‘primary neuronal or axonal degenerative disorders’ is becom- ing less clear. It is evident now that in a classic ‘primary demyelinating disorder’ such as multiple sclerosis, early and important axonal damage and loss occurs.

Some disorders, such as vanishing white matter, are characterized by serious loss of both axons and myelin sheaths, and it may be that neither of them is really ‘primary.’ Several ‘primary neuronal disorders’

with infantile onset are accompanied by prominent white matter abnormalities, which are not seen in the later onset forms of the same disorders. This is the case, for instance, in infantile GM2gangliosidosis, infantile GM1 gangliosidosis, and infantile neuronal ceroid lipofuscinosis. We agree with Hallervorden and Poser that these disorders must have a place in a classification of myelin disorders, just as they also be- long in a classification of neuronal disorders. Because of the difficulties in distinguishing ‘primary neuronal/axonal disorders’ from ‘primary myelin disorders,’ we use the neutral word ‘leukoencephalopathies’ to comprise all disorders that predominantly affect the white matter of the CNS, irrespective of whether or not the white matter abnormalities are the result of a primary abnormality of myelin.

We propose the following classification of leukoencephalopathies:

I Hereditary disorders

1. Lysosomal storage disorders a. Metachromatic leukodystrophy b. Multiple sulfatase deficiency c. Globoid cell leukodystrophy

(Krabbe disease) d. GM1gangliosidosis e. GM2gangliosidosis f. Fabry disease g. Fucosidosis

h. Mucopolysaccharidoses i. Sialic acid storage disorders j. Neuronal ceroid lipofuscinoses k. Polyglucosan body disease 2. Peroxisomal disorders

a. Peroxisome biogenesis defects b. Bifunctional protein deficiency c. Acyl-CoA oxidase deficiency d. X-linked adrenoleukodystrophy

and adrenomyeloneuropathy e. Refsum disease

3. Mitochondrial dysfunction with leukoencephalopathy

a. Mitochondrial myopathy encephalopathy, lactic acidosis, and stroke-like episodes (MELAS)

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b. Leber hereditary optic neuropathy c. Kearns-Sayre syndrome

d. Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE)

e. Leigh syndrome and mitochondrial leukoencephalopathies

f. Pyruvate carboxylase deficiency g. Multiple carboxylase deficiency h. Cerebrotendinous xanthomatosis 4. Nuclear DNA repair defects

a. Cockayne syndrome

b. Trichothiodystrophy with photosensitivity 5. Defects in genes encoding myelin proteins

a. Pelizaeus-Merzbacher disease b. 18q^–syndrome

6. Disorders of amino acid and organic acid metabolism

a. Phenylketonuria b. Glutaric aciduria type 1 c. Propionic acidemia

d. Nonketotic hyperglycinemia e. Maple syrup urine disease

f. 3-Hydroxy 3-methylglutaryl-CoA lyase deficiency

g. Canavan disease

h. L-2-Hydroxyglutaric aciduria i. D-2-Hydroxyglutaric aciduria j. Hyperhomocysteinemias k. Urea cycle defects l. Serine synthesis defects 7. Miscellaneous

a. Sulfite oxidase deficiency and molybdenum cofactor deficiency

b. Galactosemia

c. Sjögren-Larsson syndrome d. Lowe syndrome

e. Wilson disease f. Menkes disease g. Premutation fragile X h. Hypomelanosis of Ito i. Incontinentia pigmenti j. Alexander disease k. Giant axonal neuropathy

l. Megalencephalic leukoencephalopathy with subcortical cysts

m. Congenital muscular dystrophies n. Myotonic dystrophy type I o. Proximal myotonic dystrophy

p. X-linked Charcot-Marie-Tooth disease q. Oculodigitodental dysplasia

r. Vanishing white matter

s. Aicardi-Goutières syndrome and variants t. Leukoencephalopathy with calcifications and

cysts

u. Leukoencephalopathy with involvement of brain stem and spinal cord and elevated white matter lactate

v. Hypomyelination with atrophy of the basal ganglia and cerebellum

w. Hereditary diffuse leukoencephalopathy with neuroaxonal spheroids

x. Dentatorubropallidoluysian atrophy y. Amyloid angiopathy

z. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)

aa. Cerebral autosomal recessive arteriopathy with subcortical infarcts

and leukoencephalopathy (CARASIL) bb. Nasu-Hakola disease

cc. Pigmentary orthochromatic leukodystrophy

dd. Adult autosomal dominant leukoencephalopathies II Acquired myelin disorders

1. Noninfectious-inflammatory disorders a. Multiple sclerosis and variants

b. Acute disseminated encephalomyelitis and acute hemorrhagic encephalomyelitis 2. Infectious-inflammatory disorders

a. Subacute HIV encephalitis

b. Progressive multifocal leukoencephalitis c. Brucellosis

d. Subacute sclerosing panencephalitis e. Congenital cytomegalovirus infection f. Whipple disease

g. Other infections 3. Toxic-metabolic disorders

a. Toxic leukoencephalopathies (endogenous and exogenous toxins) b. Central pontine and extrapontine

myelinolysis c. Salt intoxication

d. Marchiafava-Bignami syndrome

e. Vitamin B12 deficiency, folate deficiency f. Malnutrition

g. Paraneoplastic syndromes

h. Posterior reversible encephalopathy syndrome

4. Hypoxic–ischemic disorders

a. Posthypoxic–ischemic leukoencephalopathy of neonates

b. Delayed posthypoxic–ischemic leukoencephalopathy

c. Subcortical arteriosclerotic encephalopathy (Binswanger disease)

d. Vasculitis

e. Vasculopathy of other origin 5. Traumatic disorders

a. Diffuse axonal injury

The category of so-called cytoplasmic enzyme defi- ciencies is not listed in this classification. The ratio- nale is that such a disease category would represent a

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very heterogeneous group of disorders as the cytoplasm contains enzymes of many different biochemical pathways. This is why it is preferable in this case to make a subdivision according to the specific metabolic pathway involved. However, the group of amino acidopathies and organic acidopathies is heterogeneous, as some of the enzymes concerned are in fact mitochondrial or peroxisomal. In view of the relative ho- mogeneity in clinical presentation, diagnostic tests, and treatment strategies, we prefer to place them in one category, which is also in keeping with general practice.

Over the years, this classification has been modi- fied repeatedly. The basic defects of a steadily increasing number of hereditary myelin disorders have been elucidated, and the number of ‘unknown’ disorders is decreasing. Even the present classification of leukoencephalopathies is provisional and will have to be adapted in the future to take account of expanding scientific insights. The structure of the proposed classification allows easy integration of further informa- tion.