Congenital Muscular Dystrophies

60.1 Clinical Features

and Laboratory Investigations Congenital muscular dystrophies (CMD) are a het- erogeneous group of congenital myopathies that are hereditary and often progressive. They are often asso- ciated with abnormalities of the brain and eyes. Only those types that are associated with significant white matter abnormalities are discussed in the present chapter.

1. Fukuyama congenital muscular dystrophy (FCMD) 2. Muscle–eye–brain disease (MEB)

3. Walker–Warburg syndrome (WWS)

4. Merosin-deficient congenital muscular dystrophy (MDC1A)

5. MDC1C 6. MDC1D

WWS has many alternative names, including Walker’s lissencephaly, Warburg syndrome, cerebro-oculo- muscular syndrome, cerebro-ocular dysplasia–mus- cular dystrophy syndrome, and HARD±E syndrome (hydrocephalus, agyria, and retinal dysplasia with or without encephalocele). The disease has an autoso- mal recessive mode of inheritance. Severe neurologi- cal dysfunction is evident from birth onwards. Hypo- tonia is profound and neonatal reflexes are often poor or absent. In about 40% of the patients congenital contractures are present. The affected neonates are immobile and unreactive. In many patients progres- sive hydrocephalus is evident from birth onwards with macrocephaly and bulging fontanel. Shunting may be required. In other patients hydrocephalus is not evident at birth but develops soon afterwards. A few patients have microcephaly. About 30% of the patients have an occipital meningocele or encephalo- cele. Epileptic seizures occur frequently. Ophthalmo- logical abnormalities are multiple and diverse and in- clude defects of the anterior and posterior chambers:

corneal opacities, microcornea, megalocornea, iris atrophy, iris coloboma, iridolental synechiae, narrow iridocorneal angle with or without glaucoma and buphthalmos, cataract, persistent hyperplastic pri- mary vitreous, chorioretinal coloboma, retinal dys- plasia, retinal detachment, optic disc hypoplasia, op- tic disc coloboma, and unilateral or bilateral mi- crophthalmia. Some patients have cleft palate and cleft lip. Genital abnormalities including small penis and undescended testes are common in males. In the

months following birth, the infants show profound mental and motor retardation with rarely any devel- opment beyond the newborn level. However, the clin- ical picture varies considerably, even within the same sibship. Survival varies from the neonatal period to over 5 years, but most children die within the first year of life.

In Japan, FCMD is the second most frequent of the muscular dystrophies, Duchenne muscular dystrophy being the most frequent. The disease is almost exclu- sively reported in Japan. Inheritance is autosomal re- cessive. Onset of clinical symptoms is in the neonatal or early infantile period with marked hypotonia and hypokinesia. Motor development is delayed to a vari- able degree. In most patients motor functions are ac- quired gradually and the maximum motor develop- ment has been reached by the age of 2–8 years. The majority of patients never manage to stand or walk;

the highest developmental level is usually crawling on hands and knees. The distribution of affected muscles is generalized, but proximal muscles are slightly more severely affected than distal muscles. The facial mus- cles are also affected, resulting in a hypotonic facial expression. Muscular atrophy is prominent. Pseudo- hypertrophy of the calves is found in some patients.

After the age of about 8 years, motor functions grad- ually deteriorate. Joint contractures are not usually found in the neonatal period, but flexion contractures of hips, knees, and elbow joints, limited anteflexion of the cervical spine, and contractures of the joints of the hands develop consecutively during the first few years of life. There is invariable involvement of the CNS, often with microcephaly, and always with severe mental retardation, which is not progressive. Seizures occur in more than half the patients, usually in the form of generalized tonic–clonic convulsions. In a minority, infantile spasms are found. Ophthalmologi- cal abnormalities are present in about half of the pa- tients and include strabismus, nystagmus, optic nerve pallor, mild to severe myopia, cataract, and, less often, chorioretinal degeneration and retinal vascular ab- normalities. The average life span in Fukuyama type CMD is estimated to be about 12 years; patients rarely live beyond the age of 20. However, with respiratory support patients may live beyond this age. In a few cases FCMD is more severe and resembles WWS in phenotype. In these cases patients have more severe muscular weakness, never achieving head control or the ability to sit without support, they may have pro-

Congenital Muscular Dystrophies

Chapter 60

gressive hydrocephalus requiring shunt implantation, and they have more severe ophthalmological abnor- malities.

Most reports concerning MEB come from Finland.

The disease has an autosomal recessive mode of in- heritance. Clinical symptoms are similar to those of WWS, but tend to be milder. Muscle hypotonia and poor visual contact are noted in the neonatal or early infantile period. The typical facial appearance is char- acterized by a relatively large head with a high and prominent forehead, wide fontanel, flat midfacies, short nose, and short philtrum. In about half of the patients there are some signs of hydrocephalus dur- ing the first year of life, with a mildly increased head growth rate, but shunt implantation is required in only some of the patients. Motor development is vari- ably but generally severely retarded. Some of the pa- tients show hardly any developmental progress, whereas others achieve sitting without support at the age of 10 years and walking with support after more than 10 years of life. Muscle weakness is generalized, but in the extremities weakness is slightly more prominent in the proximal muscles. Facial muscles are usually not involved. Contractures develop gradu- ally and not in every patient. There is always involve- ment of the CNS with marked mental retardation.

However, some patients do acquire the ability to speak. Most patients develop seizures, and occasion- ally infantile spasms. Ophthalmological examination typically reveals severe visual failure with severe my- opia. Additional ocular signs include glaucoma, reti- nal degeneration, choroidal hypoplasia, optic nerve pallor, and cataract. Between the ages of 5 and 25 years progress of psychomotor development ceases in many patients and deterioration sets in with loss of mental and motor abilities and development of signs of spasticity, particularly in the legs. The age at death is highly variable: some patients die at the age of 6 years, whereas others survive until their fifties.

In Europe, merosin-deficient CMD (MDC1A) is the commonest form of CMD. Inheritance is autosomal recessive. Generalized hypotonia is noted in infancy with a delay in motor development. Most children do not acquire independent ambulation. Muscle weak- ness and atrophy are severe and generalized and in- clude facial weakness. Contractures are usually pre- sent, either at birth or later in life. Most children have a normal intelligence, some have a mild intellectual impairment, but severe mental deficiency is rare.

Some of the patients have macrocephaly. Some chil- dren develop seizures. Eyes and visual function are normal. Additionally, there may be cardiac involve- ment that is usually subclinical, rarely clinically evi- dent. There is neurophysiological evidence of periph- eral nerve involvement with reduced motor and sen- sory nerve conduction velocities, but clinically the neuropathy is overshadowed by the myopathy. Pro-

gression of weakness may be noted at the end of the first decade, with death between 10 and 20 years.

However, survival beyond 20 years has been de- scribed. Some patients have a milder presentation, related to partial merosin deficiency. Patients have later-onset slowly progressive muscle weakness, mainly limb-girdle type, and achieve ambulation.

Rarely, they may display signs of CNS dysfunction.

Some patients are adults and (still) asymptomatic.

A new CMD syndrome has been defined, designat- ed MDC1C. The patients present soon after birth with hypotonia and severe weakness. They have weakness and wasting of the shoulder girdle muscles, and weakness and hypertrophy of the leg muscles. In some patients, cognitive development is normal, as is MRI of the brain, whereas other patients display men- tal retardation and, on MRI, cerebral white matter ab- normalities and subcortical cerebellar cysts. MDC1C is allelic with limb-girdle muscular dystrophy 21 (LGMD21), a much milder muscular disease. MDC1C and LGMD21 may occur in the same family.

Another new CMD syndrome has been designated MDC1D. Apart from a congenital muscular dystro- phy, mental retardation is present. The phenotypic variability still has to be defined.

In addition to the above, more or less well-delin- eated syndromes, there are many patients remaining who have an unclassified CMD. Some of these pa- tients have merosin deficiency; most of them do not.

Many of these patients do not have accompanying brain abnormalities, but some do. Some of the pa- tients in this group of unclassified CMD cases have white matter abnormalities. Some patients have white matter abnormalities similar to MDC1A, whereas muscle merosin staining is normal. Other patients have more limited white matter abnormalities. Still others have cerebellar abnormalities, brain stem ab- normalities, or gyral abnormalities. The classification and basic defects in these patients remain to be eluci- dated.

In laboratory examinations, a moderately in-

creased CK level is consistently found in almost all

patients. However, exceptional patients may have a

normal CK level, and, therefore, a normal CK value

does not rule out the presence of a CMD. Patients with

a partial merosin deficiency have lower CK than clas-

sical MDC1A patients, who have markedly increased

CK. Electromyography reveals signs of myopathy. In

MDC1A, peripheral nerve conduction velocities are

decreased. Muscle biopsy contributes to the diagnosis

of CMD, revealing dystrophic changes. These include

marked variation in fiber size with presence of at-

rophic and hypertrophic fibers, fiber necrosis with

presence of phagocytes, increased number of fibers

with internal nuclei, increased interstitial fibrosis,

and replacement by adipose tissue. No inflammatory

infiltration is found, with the exception of some pa-

tients with MDC1A, in whom the findings may be suggestive of myositis. There are no significant histo- logical differences between the different CMD vari- ants. However, the use of different antibodies con- tributes to establishing the correct diagnosis. In MDC1A there is isolated negative (usually complete- ly negative) immunostaining for laminin-a2 in mus- cle. In some patients with a milder phenotype a par- tial deficiency is found. Skin biopsy is also useful to assess the laminin-a2 status of a patient. In FCMD, MEB, MDC1C, and MDC1D muscle, severely de- creased immunostaining for a-dystroglycan and a variable but less severe reduction for laminin-a2 are observed. In WWS immunostaining for a-dystrogly- can is decreased, but immunostaining for laminin-a2 tends to be normal, although decreased immunos- taining has also been reported. It is important to real- ize that there are several antibodies against different epitopes of laminin-a2. The results of immunostain- ing may be different with different antibodies. DNA- based prenatal diagnosis is possible in families with a known mutation in one of the genes related to the CMDs.

60.2 Pathology

In WWS the leptomeninges are thick and tend to obliterate the subarachnoid space with fibrous and heterotopic neuroglial tissue. The brain surface may be smooth on external examination, with only an in- terhemispheric fissure present and a markedly fore- shortened sylvian fissure due to incomplete develop- ment of the opercula. The brain surface may also have areas of pachygyria and polymicrogyria with an ir- regular verrucous appearance. Bands of gliotic tissue cross the interhemispheric fissure, especially frontal- ly, fusing the hemispheres. On sectioning, the lateral ventricles are markedly to severely enlarged; only in exceptional cases are the ventricles normal. The cere- bral mantle is usually seriously reduced in width. The deep nuclei are present in their normal position but are usually small. The corpus callosum and septum pellucidum are often absent or hypoplastic. The aque- duct is small and stenotic. The quadrigeminal surface elevations are fused and the mammillary bodies do not protrude from the ventral surface. The brain stem is small and the pons markedly hypoplastic. Olfacto- ry and optic nerves are attenuated or absent. The cerebellar vermis, especially the posterior vermis, and the cerebellar hemispheres are hypoplastic, often associated with an enlarged fourth ventricle and a retrocerebellar cyst, constituting a Dandy–Walker malformation. In about 25% of the patients a posteri- or encephalocele or meningocele is present, contain- ing either an extension of a retrocerebellar cyst, cere- bellar tissue, or, rarely, tissue of supratentorial origin.

Factors contributing to ventricular enlargement are aqueduct stenosis, disturbed fluid dynamics associat- ed with the Dandy–Walker malformation, and block- age of the arachnoid granulations by fibroglial tissue.

The cerebral cortex is abnormally thick with absent white matter interdigitations or with irregular, shal- low indentations in the otherwise smooth cortical ribbon. On microscopic examination the cortex is se- verely disorganized, with no recognizable lamination and widespread disruption by gliofibrillary bundles accompanying vessels from the pial surface.Agyria or pachygyria with severe disorganization of the cortex and absence of lamination is called lissencephaly type II. Neuronal heterotopias are present scattered in the white matter and in the subependymal region. The white matter is reduced in volume, poorly myelinated, gliotic, spongy, and often strikingly edematous with occasionally cavitations. Myelination is virtually ab- sent in some cases. In the brain stem corticospinal tracts are grossly absent. The pontine nuclei and mid- dle cerebellar peduncles are usually absent. Within the smooth, afoliar cerebellar cortex microscopic changes are found similar to those in the cerebral cor- tex, but the abnormalities are less severe, as some organization into layers is usually present. Cerebellar white matter is better myelinated.

In FCMD superficial gliomesenchymal prolifera- tion is present on the surface of the brain and spinal cord, leading to thickened leptomeninges adherent to the surface of the CNS. Microscopically, glioneural heterotopias are found in the leptomeninges. Exten- sive cortical dysplasia of cerebrum and cerebellum is present. The pattern of the cortical dysplasia is always symmetrical, but varies in severity from site to site and from case to case. As a rule, the cortical dysplasia is most prominent in the frontal and temporal lobes, whereas the occipital lobe is relatively spared. Occa- sionally the frontal cortex shows focal interhemi- spheric fusions. The primary sulci (central, calcarine, parieto-occipital, and cingulate) are present, sec- ondary sulci are shallow, and the gyral surfaces have an irregular appearance. The cortical dysplasia may take the form of unlayered polymicrogyria (lissen- cephaly type II), or smooth, four-layered pachygyria, or verrucose dysplasia with superficial cellular nod- ules within a normally stratified six-layer cortex. The polymicrogyria is also called pachygyric polymicro- gyria (or polymicrogyric pachygyria), because the microgyri are fused and the external appearance of the brain is pachygyric; polymicrogyria is only a mi- croscopic finding. In most patients the three men- tioned types of cortical dysplasia are present to a vari- able extent. Many breaches are present in the glia lim- itans–basal lamina complex overlying the cerebral cortex. In the CNS a basement membrane is observed in the boundary between nervous tissue and lep- tomeninges forming part of the pial–glial barrier. At

60.2 Pathology 453

the site of the breaches, neural tissue protrudes. The exposed surfaces of the extruded neuroglial elements lack basal lamina, come into contact with adjoining elements, and fuse with each other, leading to devel- opment of polymicrogyria. During this process, ves- sels in the subarachnoid space, which were originally located over the cortical surface, become entrapped.

The border between cerebral cortex and white matter is irregular. Ectopic nerve cells are found in the sub- cortical white matter, near the ventricles and dissem- inated within the white matter. The ventricles are of- ten mildly dilated. Overt hydrocephalus is not pre- sent. The pyramidal tracts in the brain stem are hy- poplastic and dysplastic and have an abnormal course. Within the cerebellar cortex, areas of polymi- crogyria are present. In the cerebellum mesenchymal tissue proliferation appears to have occurred inside the cerebellar parenchyma to form numerous small cavities bordered by neuroglial elements. The cere- bral white matter changes vary in severity. Myelin paucity and gliosis are seen, but without signs of breakdown, particularly in the younger children, whereas normal myelination may be seen in older children. In a patient in whom brain tissue was inves- tigated at two different points of time, myelination was very poor and astrogliosis marked in brain biop- sy material, whereas at autopsy 4 years later, myelina- tion proved to be only slightly less than normal and astrocytosis was mild.

In MEB, the cerebral gyral pattern is coarse on in- spection, with an abnormal nodular surface, sugges- tive of pachygyric polymicrogyria. Agyric areas have been found in the lateral convexity of the occipital lobes. On sectioning, the cortex is abnormally thick.

Microscopic examination reveals that almost the entire cortex is severely disorganized apart from the basomedial occipital lobe and hippocampus. The ab- normally thick cortex lacks horizontal laminae and vertical columns. The neurons are haphazardly ori- ented and form irregular clusters or islands separated by gliovascular strands extending from the pia. In places, irregular bundles of myelinated axons pene- trate the cortex from the white matter. The pia–arach- noid is focally thickened and adherent to the cortex.

The pial–cortical border is irregular. The white mat- ter is reduced in volume and shows a moderate and variable degree of myelin pallor and gliosis. The ven- tricles are dilated to a variable extent. The septum pel- lucidum may be absent. The cerebellar cortex is also severely disorganized and lacks normal foliae, espe- cially on the upper surface. The vermis is severely hypoplastic. The interface between pia–arachnoid and cerebellar cortex is distorted. Gliovascular strands penetrate the cerebellar cortex. The brain- stem is thin and the pons is flat.

In MDC1A only two histopathological reports have been published. Echenne et al. (1984) report on an 18-

year-old patient. The external appearance of the brain was normal. Furthermore, no abnormalities of cere- bral and cerebellar cortex were found on microscopic examination and there were no neuronal heterotopias within the white matter. Extensive myelin pallor was found bilaterally with sparing of the arcuate fibers.

Abnormalities were most severe in the frontoparietal white matter, whereas the occipital white matter was less severely affected. On microscopic examination there was a spongy appearance of myelin. Moderate astrocytic proliferation and vascular hyperplasia were found. No changes were found in basal ganglia, brain stem, or cerebellum, including cerebellar white matter. Taratuto et al. (1999) report on a 4-month-old patient. The patient had bilateral occipital cortical dysplasia with irregular lamination and fusion of adjacent gyri at microscopy. Multifocal glioneural leptomeningeal heterotopias were present. The white matter had a normal stage of myelination for a 4-month-old infant. The cerebellar vermis was hy- poplastic. Sural nerve biopsy in MDC1A patients shows a reduction of large myelinated fibers, short internodes, enlarged nodes, excessive variability of myelin thickness, tomacula, and uncompacted myelin, but no evidence of demyelination.

60.3 Pathogenetic Considerations

The dystrophin-associated glycoprotein (DAG) com- plex is present in several tissues including muscle, heart, nerve, and brain. This complex has a crucial role in linking the cytoskeletal proteins with the ex- tracellular basal lamina. In muscle this complex func- tions by linking the actin-associated cytoskeleton of the muscle fibers to the extracellular matrix via dys- trophin and the laminin-a2 chain of merosin. The dystrophin-associated glycoprotein complex is cru- cial for normal contraction of muscle. a-Dystrogly- can is a peripheral membrane component of the dys- trophin-associated glycoprotein complex. Structural defects in the dystrophin-associated glycoprotein complex, leading to defects in the linkage between merosin in the extracellular matrix and actin in the subsarcolemmal cytoskeleton, cause various muscu- lar dystrophies. Duchenne and Becker muscular dys- trophies are related to mutations in dystrophin. Muta- tions in various sarcoglycans result in limb-girdle muscular dystrophies. Mutations in the gene LAMA, which is located on chromosome 6q and encodes the laminin-a2 chain of merosin, result in MDC1A.

WWS, FCMD, MEB, MDC1C, and MDC1D are charac- terized by hypoglycosylation of a-dystroglycan. Gly- cosylation is the most common form of post-transla- tional protein modification, necessary for proteins to achieve their proper structure, function, and stability.

It is a complex process where sugars are added to pro-

teins as they pass through the endoplasmic reticulum and the Golgi apparatus. Attached glycans can be di- vided into two groups according to their linkage to the protein. N-Glycans are linked to asparagine;

O-glycans are attached to serine or threonine. a-Dys- troglycan is normally a heavily glycosylated protein, and hypoglycosylation abolishes the binding activity of the protein for laminin, neurexin, and agrin, all of which are components of the basement membrane. In 20% of WWS patients the disease is caused by muta- tions in the gene POMT1, which is located on chromo- some 9q34.1 and encodes O-mannosyltransferase 1.

FCMD is related to mutations in the gene FCMD, which is located on chromosome 9q31 and encodes the protein fukutin. The function of fukutin is un- known, but based on amino acid homology with sev- eral phosphoryl-ligand transferases, it is hypothe- sized to be a glycosyltransferase. MEB is caused by mutations in the gene POMGNT1, located on chromo- some 1p33–34, which encodes the protein O-manno- syl-b1,2-N-acetylglucosaminyltransferase-1

(POMGnT1). This enzyme uses an O-linked mannose as a substrate. Fukutin-related protein, encoded by the gene FKRP, located on chromosome 19q13.3, is highly homologous to fukutin and also a putative gly- cosyltransferase. Mutations in the gene LARGE, locat- ed on chromosome 22q12.3-q13.1, lead to MDC1D.

Large is a putative glycosyltransferase.

In WWS, about 20% of the patients have a defect in O-mannosyltransferase 1, the enzyme that putatively catalyzes the first step in O-mannosyl glycan synthe- sis. The O-mannosyl glycans of a-dystroglycan are critical for binding laminin-a2. WWS is genetically heterogeneous and several WWS families do not link to the POMT1 locus. It is very likely that defects in the other proteins involved in O-mannosylglycosyla- tion underlie the remaining, unexplained WWS pa- tients.

FCMD occurs almost exclusively in Japan. About 95% of FCMD patients share a specific haplotype on one or both alleles in the critical region of chromo- some 9, supporting the hypothesis of a founder of the disease in the Japanese population. In all patients sharing this haplotype, a 3-kb retrotransposal inser- tion into the 3’-untranslated region of the gene is found. Various other mutations have been found. The frequency of a severe phenotype with WWS-like manifestations such as hydrocephalus and microph- thalmia is higher among patients who are compound heterozygous for the Japanese founder mutation than among the patients who are homozygous for the founder mutation. The observed lack of Japanese pa- tients with two nonfounder mutations suggests that such cases might be fatal in utero. This may also ex- plain why few FCMD patients have been reported in non-Japanese populations in which the Japanese founder mutation does not occur. The rare non-

60.3 Pathogenetic Considerations 455 Japanese patients with mutations in FCMD tend to have a very severe, WWS-like clinical phenotype.

MEB is caused by a defect in the O-mannosyl gly- can synthesis. POMGnT1 normally adds an N-acetyl- glucosamine residue to an O-linked mannose. This is the second step in O-mannose glycosylation. It has been demonstrated that sialyl O-mannosyl glycan is the laminin-binding ligand of a-dystroglycan. The hypothesis that defects in O-mannosylation weaken the laminin-binding and consequently may be re- sponsible for muscular dystrophy led to the detection of a defect in POMGnT1 as the cause of MEB. Some patients with severe POMGNT1 mutations have a WWS-like phenotype. Patients with mutations near the 5’-terminus tend to have a more severe clinical phenotype than patients with mutations near the 3’-terminus.

Laminin is a heterotrimer composed of three different polypeptides, called a-, b-, and g-chain, of which different subtypes are known. These chains assemble into a number of different laminin variants, but every laminin has one a-, one b-, and one g-chain.

Laminin-2, or merosin, is composed of a2-b1-g1. It is the a2-chain that is mutated in MDC1A. Classical MDC1A is associated with mutations that drastically affect the expression or structure of laminin-a2. A wide range of milder phenotypes is caused by partial laminin-a2 deficiency, produced by mutations in LAMA2 that permit production of a partially func- tional protein or a reduced amount of normal pro- tein. Merosin is not only present in muscle tissue, but also in the brain. In the brain merosin is localized on the brain surface at the glia limitans and on the base- ment membrane of blood vessels. Furthermore, merosin is present in the endoneurial basement membrane that surrounds the myelin sheath of pe- ripheral nerve fibers and individual Schwann cells. In laminin-a2 deficiency, the basement membrane in skeletal muscle and peripheral nerves is disrupted or completely absent, indicating that laminin-a2 is es- sential for formation of basement membrane in these tissues. There is evidence that the formation of a basement membrane is a prerequisite of myelination in peripheral nerves. Under conditions that prevent basement membrane formation, Schwann cells fail to ensheath and myelinate nerve fibers.

Defects in the gene FKRP lead to a severe form of CMD, designated MDC1C, and a milder limb-girdle muscular dystrophy, designated LGMD21. Most pa- tients with MDC1C do not have structural brain ab- normalities. However, it has been shown that severe mutations in FKRP may lead to an MEB or even WWS phenotype.

Large is a putative bifunctional glycosyltrans-

ferase. One putative catalytic region has a high ho-

mology to members of the bacterial WaaIJ family of

putative a-glycosyltransferases involved in the syn-

thesis of lipopolysaccharides or lipo-oligosaccha- rides. The second catalytic domain is closely related to I-b-1,3-N-acetylglucosaminyl transferase, an en- zyme required for the synthesis of the poly-N-acetyl- lactosamine backbone, which is attached to N-gly- cans, O-glycans, and glycolipids.

Whether the brain and eye symptoms in the WWS, FCMD, MEB, MDC1C, and MDC1D are related to the defect in glycosylation of a-dystroglycan or other proteins is less clear. Brain-specific disruption of a- dystroglycan during embryonic development causes neuronal overmigration and fusion of cerebral hemi- spheres in mice. This suggests that disrupted glycosy- lation of a-dystroglycan is also at least in part respon- sible for the brain abnormalities. The white matter abnormalities reported in the CMDs are variable and

their pathogenesis is unclear. Retarded but ongoing myelination may contribute in some cases, especially in FCMD and MEB. However, in FCMD and MEB, too, the cerebral white matter abnormalities have a higher signal on T

-weighted images and a lower signal on T

-weighted images than is compatible with straight- forward hypomyelination, but reduction in the white matter abnormalities has been observed on follow- up. In WWS and MDC1A the white matter abnormal- ities are more impressive and mildly swollen, suggest- ing sponginess, which has been confirmed at autopsy.

The role of the white matter abnormalities in deter- mining the clinical picture seems to be minor in all CMD variants. The disease is mostly explained by the severity of the cortical dysplasia and the muscular dystrophy.

Fig. 60.1. A 4-month-old boy with WWS. The third and lateral ventricles are highly enlarged due to aqueduct stenosis. The corpus callosum is thin and high-arched. Note the presence of a cingulate gyrus, indicating that there is no agenesis of the corpus callosum. The septum pellucidum is absent. The colli- culi are fused.The pons is extremely hypoplastic and there is a pontomesencephalic kink. The cerebellum is extremely hy- poplastic with characteristics of a Dandy–Walker malforma-

tion. The cerebral cortex is agyric on the outside, whereas the

irregular inner border indicates a disorganized, polymicrogyric

cortex, compatible with lissencephaly type II. The cerebellar

cortex is also disorganized. The cerebral hemispheric white

matter has an abnormal signal throughout. Only the brain

stem appears to contain some normal myelin. From Van de

Knaap et al. (1997), with permission

60.4 Therapy

No definitive treatment is possible, only supportive care. Physiotherapy is of major importance. In some patients a slight improvement in strength and a fall in CK activity have been noted on administration of corticosteroids. However, in other patients no im- provement was found. Considering the major adverse effects of chronic use of corticosteroids, this mode of therapy remains controversial. Respiratory support may prolong life.

60.5 Magnetic Resonance Imaging 457

60.5 Magnetic Resonance Imaging

In WWS, MRI almost invariably shows severe hydro- cephalus (Figs. 60.1–60.3). A normal ventricular size is highly unusual. Because of the severe hydro- cephalus and very thin cerebral mantle, the quality of the white and gray matter may be difficult to assess. In patients in whom a cerebral mantle of some thickness is present, the abnormalities are easier to recognize.

The cortex is either totally agyric (Fig. 60.1) or folded in broad, somewhat better formed gyri (Figs. 60.2 and 60.3). The cortex is smooth on the external side but the border with the white matter is irregular, reflect- ing the underlying polymicrogyria and disorganiza- tion of the cortex with frequent disruption by glio- fibrillary bundles (Figs. 60.1–60.3). In some cases ex-

Fig. 60.2. A 10-month-old girl with WWS.The lateral and third ventricles are markedly dilated despite the shunting. Note the thin and high-arched corpus callosum, which is just visible.The septum pellucidum is absent. The colliculi are fused. The pons and cerebellar vermis are hypoplastic. The cerebral cortex is pachygyric. In the anterior region the cortex is abnormally thick, whereas it is thinner in the parietal areas.The irregular in- ner border indicates a disorganized, polymicrogyric cortex, compatible with lissencephaly type II.There is a rim of periven-

tricular heterotopias. The cerebellar cortex is also disorga-

nized, with the presence of many small subcortical cysts. The

cerebral hemispheric white matter has an abnormal signal

throughout. Only the brain stem and cerebellar white matter

appear to contain myelin. Courtesy of Dr. C.E. Catsman-

Berrevoets, Department of Child Neurology, Sophia Children’s

Hospital and Erasmus University Medical Center, Rotterdam,

The Netherlands

Fig. 60.3. A 6-year-old boy with WWS. The lateral and third ventricles are mildly dilated. The corpus callosum is high- arched.The septum pellucidum is partially absent.The colliculi are fused. The pons and cerebellar vermis are hypoplastic. The cerebral cortex is pachygyric and irregular, compatible with lissencephaly type II.There are many small periventricular het- erotopias. The cerebellar cortex is disorganized, with the pres-

ence of many small subcortical cysts. The cerebral hemispher- ic white matter has an abnormal signal throughout and is swollen.There are multiple large subcortical cysts.The cerebel- lar white matter also has an abnormal signal intensity. Only the corpus callosum and the brain stem have a normal low signal.

From Van der Knaap et al. (1997), with permission

60.5 Magnetic Resonance Imaging 459

Fig. 60.4.

tensive subcortical and subependymal heterotopic neuronal nodules are seen (Figs. 60.2 and 60.3). The cerebral white matter has a high signal intensity on T

-weighted images throughout and a low signal in- tensity on the T

-weighted images (Figs. 60.1–60.3).

The white matter may have a mildly swollen appear- ance and multiple cysts may be present within this highly abnormal looking white matter (Fig. 60.3).

The corpus callosum is often very thin and high- arched, and may not be visible. However, the presence of a gyrus cinguli strongly suggests that it is not an agenesis of the corpus callosum, but rather an extreme thinning due to severe hydrocephalus (Figs. 60.1–60.3). The septum may be absent, proba- bly also related to the long-standing hydrocephalus of antenatal origin (Figs. 60.1–60.3). The third ventricle

is also enlarged and the aqueduct is narrow. Fusion of the superior and inferior colliculi is typically seen (Figs. 60.1–60.3). There is often a pontomesence- phalic kink and the pons is extremely hypoplastic (Figs. 60.1–60.3). The cerebellum is highly hypoplas- tic in all its elements, in particular in the vermis. The cerebellar surface is smooth, without foliae or with ir- regular, small foliae. Multiple small subcortical cere- bellar cysts are seen (Figs. 60.2 and 60.3). In some pa- tients the posterior fossa is extremely small, but in other patients the fourth ventricle is enlarged and in open communication with an enlarged retrocerebel- lar space, forming either the full-blown Dandy–Walk- er malformation or the less severe Dandy–Walker variant (Fig. 60.1). A posterior meningocele or ence- phalocele is often present.

Fig. 60.4. (continued). A male patient with FCMD.The first and second rows show the MRI at 5 months, the third and fourth rows contain the MRI obtained at 21 months, the fifth and sixth rows show the MRI obtained at 7 years. The frontoparietal cor- tex displays the characteristics of a polymicrogyric pachygyria, whereas the occipital cortex is smooth and very thick. The cerebellar cortex is also dysplastic with distortion of the nor- mal horizontal foliae and presence of subcortical cerebellar cysts. The pons is flat. The lateral ventricles are somewhat

dilated. The cerebral white matter is diffusely abnormal in sig-

nal at 5 months, but improvement is seen over time. At 7 years

the posterior cerebral white matter is normally myelinated,

whereas the frontal periventricular and deep white matter has

an abnormal signal intensity.The corpus callosum and internal

capsule have a normal signal intensity. Courtesy of Dr. N. Aida,

Department of Radiology, Kanagawa Children’s Medical Cen-

ter, Yokohama, Japan

In FCMD, MRI reveals cerebral cortical dysplasia, showing gyri that are too few and too broad, and in- complete opercularization (Fig. 60.4). In most areas the slightly thickened cortex has an irregular aspect with little dots and an irregular inner border, reflect- ing polymicrogyria and verrucose cortical dysplasia.

This type of cortical dysplasia is seen in frontopari- etotemporal areas (Fig. 60.4). In some areas the cortex is thicker and has a smooth inner and outer surface.

This type of cortical dysplasia is mainly seen in the temporo-occipital region (Fig. 60.4). The ventricular system is mildly enlarged and often has a colpo- cephalic aspect. In neonates the cerebral white matter looks normal for unmyelinated white matter. In in- fants and young children the cerebral white matter looks diffusely abnormal, with a higher signal on T

-weighted images and lower signal on T

-weighted images than is compatible with straightforward hypomyelination (Fig. 60.4a). On repeated MRI pro- gress of myelination is seen, the rate being variable (Fig. 60.4b,c). In some patients there is still hardly any myelin after several years. In some older children diffuse white matter lesions are seen. Most patients have multifocal lesions in the cerebral white matter (Fig. 60.4b, c). The lesions vary in size and distribu- tion. In a few patients no white matter abnormalities are found. The corpus callosum, internal capsule, and brain stem display a normal myelin signal. MRI also shows cerebellar cortical dysplasia, with irregularly distorted folia. There are subcortical cerebellar cysts (Fig. 60.4b, c). The pons is flat (Fig. 60.4).

In MEB, MRI shows a variable ventricular enlarge- ment, ranging from normal to markedly dilated. The cortical dysplasia is variable, both between different areas of the brain and between patients (Figs. 60.5 and 60.6). The frontal, temporal, and parietal areas are the most abnormal, whereas the configuration of the occipital cortex is close to normal. The cortex is slightly too thick and folded in broad gyri with an irregular inner border, compatible with pachygyric polymicrogyria (Figs. 60.5 and 60.6). Operculariza- tion is incomplete. Neuronal heterotopias may be seen in the white matter. The cerebral white matter is either normal (Fig. 60.6) or contains multifocal white matter abnormalities (Fig. 60.5). The corpus callosum may be dysplastic and thin and the septum pellu- cidum may be incomplete. The superior and inferior colliculi are fused. The pons is hypoplastic. The cere- bellum, in particular the vermis, may be small. The cerebellar cortex is dysplastic and there are multiple small subcortical cerebellar cysts (Figs. 60.5 and 60.6).

In classical MDC1A, MRI shows prominent white matter changes (Figs. 60.7 and 60.8). The white matter appears mildly swollen, leading to broadening of the gyri with stretching of the overlying cortex. On CT it is difficult to distinguish between primary cortical dysplasia and secondary broadening of the gyri as a

60.5 Magnetic Resonance Imaging 461 consequence of white matter swelling. MRI shows that the cortex is not thicker than normal and does not have the irregular inner border of pachygyric polymicrogyria (Figs. 60.7 and 60.8). However, some MDC1A patients have occipital cortical dysplasia with an agyric outer border but irregular inner border and evidence of subcortical ectopic neurons, similar to the lissencephaly type II seen in WWS (Figs. 60.9 and 60.10). In patients with occipital agyria the occipital horn of the lateral ventricles may be focally dilated (Fig. 60.9). The dysplasia is bilateral but may be larger on one side than the other, with al- so a more prominent enlargement of the occipital horn on the most seriously affected side. In MDC1A, the white matter is near-normal in the first few months of life (Fig. 60.9). From the second half of the first year onwards, MRI shows swollen white matter with a high signal on T

-weighted images, low on T

- weighted images. In most patients the white matter abnormalities are extensive and confluent, but in some patients they are a bit less extensive and some- times they are multifocal. The abnormalities have a frontal predominance and the occipital white matter is better preserved. In some cases the subcortical areas are spared throughout. The corpus callosum, internal capsule, optic radiation, brain stem, and cere- bellar white matter are consistently spared. The white matter changes appear to be nonprogressive over the years. In patients with occipital agyria, the occipital white matter may be markedly abnormal (Fig. 60.9). In some patients hypoplasia of the pons is seen (Fig. 60.7). The cerebellum may also be hy- poplastic. In CMD patients with partial merosin defi- ciency, white matter abnormalities are more variable.

Some patients have extensive white matter abnormal- ities similar to those seen in classical MDC1A. In oth- ers the white matter abnormalities are more limited in extent (Fig. 60.10). Occipital agyria may also occur in patients with partial merosin deficiency (Fig.

60.10).

In the two patients with adult-onset signs of mus- cular dystrophy and cerebral dysfunction reported by van Engelen et al. (1992), the white matter abnormal- ities are identical to those of MDC1A patients. A spe- cial finding is that the oldest patient, 29 years of age, has cysts in the subcortical area in the tips of the tem- poral lobes and the parietal area. With these cysts the MR pattern becomes indistinguishable from the pat- tern of megalencephalic leukoencephalopathy with subcortical cysts, described in Chap. 59.

In the MDC1C patients with mutations in the

FKRP gene and cerebral abnormalities, variable cere-

bral white matter abnormalities and the presence of

subcortical cerebellar cysts have been reported

(Figs. 60.11 and 60.12). However, most patients with

FKRP mutations have normal MRI.

Fig. 60.5. A 2.5-year-old girl with MEB. The frontal, temporal, and parietal cortex is the most abnormal, whereas the config- uration of the occipital cortex is close to normal.The abnormal cortex is slightly too thick and folded in broad gyri with an irregular inner border, indicative of pachygyric polymicro- gyria. Neuronal heterotopias are seen in the white matter along the lateral ventricles. The frontal, parietal, and temporal

white matter contains extensive signal abnormalities, whereas

the occipital white matter is normal. The corpus callosum,

internal capsule, brain stem, and cerebellar white matter have

a normal signal.The inferior vermis is hypoplastic.The superior

and inferior colliculi are fused. The pons is hypoplastic. There

are multiple small subcortical cerebellar cysts

In the single MDC1D patient reported (Long- man et al. 2003), MRI revealed diffuse cerebral white matter abnormalities with mild swelling of the ab- normal white matter leading to broadening of gyri (Fig. 60.13). The cerebral cortex showed signs of diffuse polymicrogyria. The pons was hypoplas- tic.

60.5 Magnetic Resonance Imaging 463

It is clear that MRI plays an important role in the classification of CMD patients during life. The corti- cal dysplasia, pons hypoplasia, subcortical cerebellar cysts, and different types of white matter involvement are highly suggestive of the diagnosis CMD. MDC1A may be confused with megalencephalic leuko- encephalopathy with subcortical cysts, but the sub- cortical cysts are as a rule lacking.

Fig. 60.6. A 9-year-old boy with MEB.

The frontal cortex is too thick and has an irregular inner border, indicative of underlying polymicrogyria. The inferi- or vermis is hypoplastic. The superior and inferior colliculi are fused. The pons is hypoplastic. There are multiple small subcortical cerebellar cysts.

The lateral ventricles are mildly dilat- ed, more so on the right than the left.

The white matter is normal. Courtesy

of Dr. P.G. Barth, Department of Child

Neurology, Academic Medical Center,

Amsterdam, The Netherlands

Fig. 60.7. A 6-year-old girl with classical MDC1A. The MRI shows prominent white matter changes. The abnormal white matter is mildly swollen with broadening of the gyri. MRI shows that the cortex is of normal thickness and does not have an irregular border.The frontal white matter is most abnormal

whereas the occipital white matter is better preserved. The

corpus callosum, internal capsule, optic radiation, brain stem,

and cerebellar white matter are spared. The pons is mildly

hypoplastic

60.5 Magnetic Resonance Imaging 465

Fig. 60.8. A 9-year-old girl with MDC1A. The abnormalities are very similar to those seen in Fig. 60.7

Fig. 60.9. A 2-month-old girl with MDC1A. Note the occipital agyria.The white matter under the area of agyria has an abnormally

high signal. The remainder of the white matter looks normal for unmyelinated white matter

Fig. 60.10. A 7-year-old boy with CMD and partial merosin deficiency. Note the agyria in the occipital and basotemporal region. There are multifocal white matter abnormalities. Cour-

tesy of Dr. H. Stroink and Dr. C.E. Catsman-Berrevoets, Depart- ment of Child Neurology, Sophia Children’s Hospital and Eras- mus University Medical Center, Rotterdam, The Netherlands

Fig. 60.11. A girl with MDC1C. The first MRI (first row) was ob- tained at the age of 3 years; the follow-up MRI (second row) at the age of 6 years. The initial MRI shows multifocal large white matter lesions, mainly involving the deep white matter. On fol- low-up, most white matter abnormalities have disappeared and only a few foci of abnormal signal remain. The cerebellar

cortex is dysplastic and there are subcortical cerebellar cysts.

The pons is hypoplastic. From Louhichi et al. (2004), with per-

mission, and courtesy of Dr. F. Fakhfakh, Laboratoire de Géné-

tique Moleculaire Humaine, Faculté de Médecine de Sfax, and

Dr. C. Triki, Service de Neurologie, CHU Habib Bourguiba, Sfax,

Tunisia

467

Fig. 60.12. A 7-year-old boy with MDC1C. The MRI shows ex- tensive white matter abnormalities, which partially spare the U fibers. The pons and cerebellar vermis are hypoplastic. The cerebellar cortex is dysplastic and there are subcortical cere-

bellar cysts. From Louhichi et al. (2004), with permission, and

courtesy of Dr. F. Fakhfakh, Laboratoire de Génétique Molecu-

laire Humaine, Faculté de Médecine de Sfax, and Dr. C.Triki, Ser-

vice de Neurologie, CHU Habib Bourguiba, Sfax, Tunisia

Fig. 60.13. A 14-year-old girl with MDC1D.The sagittal images show hypoplasia of the pons and fusion of the superior and in- ferior colliculi. There is no cerebellar hypoplasia and there are no evident subcortical cerebellar cysts. The cerebral white matter is diffusely highly abnormal in signal. In the frontal and particularly the anterior temporal region the abnormal white matter is swollen with broadening of gyri. The corpus callo-

sum, internal capsule, brain stem, and cerebellar white matter

have a normal signal. The U fibers in the occipitotemporal re-

gion are spared. The cerebral cortex diffusely has an irregular

border, suggesting underlying polymicrogyria.From Longman

et al. (2003), with permission, and courtesy of Dr. F. Muntoni,

Dubowitz Neuromuscular Centre, Hammersmith Campus,

London, UK