Congenital muscular dystrophies: Clinical review and proposed classification

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Review Article

Congenital Muscular Dystrophies: Clinical Review and Proposed Classification Enrico Parano, MD*'*, Lorenzo Pavone, MD*, Agata Fiumara, MD*, Raffaele Falsaperla, MD*, Rosario R. Trifiletti, MD, PhD*, and William B. Dobyns, MD ~ The clinical spectrum of the congenital muscular dystrophies is reviewed using as a sample population 10 Sicilian patients with various clinical subtypes. A comprehensive classification scheme for the muscular dystrophies is presented based on recent advances in our understanding of this heterogeneous group of syndromes. Parano E, Pavone L, Fiumara A, Falsaperla R, Trifiletti RR, Dobyns WB. Congenital muscular dystrophies: Clinical review and proposed classification. Pediatr Neurol 1995;13:97-103.

dominant inheritance [5]. Recent progress in our understanding of CMD has involved the development of consensus diagnostic criteria for most subtypes of CMD, discovery of merosin deficiency in some CMD patients with normal intelligence, and discovery of a merosin-deficient animal model, the dy mouse [3,4,6,7]. We report 10 Sicilian patients with CMD who represent most major types of CMD, and present a revised classification for CMD based on data from several recent workshops. Some of these patients have been previously reported [8,9] but are briefly presented to better illustrate the clinical spectrum of the CMD syndromes.

Case Reports Introduction Congenital muscular dystrophy (CMD) is an uncommon type of muscular dystrophy which is characterized by generalized and often severe weakness, hypotonia, and joint contractures with onset from birth or early infancy. Considering all patients together, the clinical course varies greatly. It sometimes appears to be progressive, but more often is not. Serum creatine kinase (CK) may be elevated, but often is normal or only slightly elevated. Electromyography (EMG) typically discloses a myogenic-type pattern, with normal nerve conduction velocities (NCV). Muscle biopsy reveals dystrophic changes with large variation in muscle fiber size, a few necrotic and regenerating fibers, marked increase in perimysial and endomysial connective tissue, areas of fat replacement, normal dystrophin distribution, and no specific ultrastructural changes [ 1-4]. Different CMD syndromes have been described including a classical form associated with normal intelligence and several types associated with mental retardation and often brain malformations. All have autosomal recessive inheritance, except for a few reports of possible autosomal

From the *Divisionof Pediatric Neurology; Pediatric Clinic, Universityof Catania; *CNR Catania, Catania, Italy; *Departmentsof Neurology, Neuroscience, and Pediatrics; Cornell UniversityMedical College; New York, New York; ~Departmentsof Neurology and Pediatrics; MinnesotaMedical School; Minneapolis,Minnesota.

© 1995 by Elsevier Science Inc. • 0887-8994/95/$9.50 SSDI 0887-8994(95)00148-9

Ten patients were identifiedbetween 1980 and 1994 in the Pediatric Clinicat the Universityof Catania, Sicily, Italy. The clinical, radiologic, and pathologic manifestationsof these patientsare summarizedin Table 1. Nerveconductionstudy results were normalcomparedto age-adjusted control values [10]. Patient 1. This 8-year-old boy was born to nonconsanguineousparents. Hypotonia and weakness were present since birth, in association with flexioncontracturesof the elbow and wrist. Physicalexaminationat the age of 5 years disclosedhypotoniaand generalizedmuscleweakness, with facial muscle involvement.Tendonreflexes were barelyobtainable. The child walked unaided, but he was unable to climb stairs or get up from the ground. Markedright convexkyphoscoliosis,pectus carinatum, and bilateral flexioncontractures of the elbows, knees, and wrists were present. Intellectualdevelopmentwas normal. RoutinelaboratoryexaminationsincludingCK and pyruvicand lactic acid were normal. Skeletal radiography disclosed severe scoliotic arch deformationwith metameric torsion along the axis and anteriordeformationof the dorsal fifth, sixth, and seventh vertebral bodies. EMG was mainly myogenic in the arms and neurogenicin the legs. NCV was normal. Muscle biopsy disclosed a primitive,dystrophic type musclepathology. Dystrophinantibodydistributionof the protein was normal. Magneticresonanceimaging(MRI) of the spine revealed cystic intramedullarycavity in the dorsal and lumbar regions, with the radiographic appearance of syringomyelia.Cranial MRI was normal as well as ophthalmologicand EKG examinations.At follow-up 3 years later, there w~isno clinicalprogression and CK values

Communicationsshould be addressed to: Dr. Trifiletti;Departmentof Neurology; Cornell UniversityMedical College; Room A-569; 525 East 68th Street; New York, NY 10021. Received January 13, 1995; accepted July 7, 1995.

Parano et al: CongenitalMuscularDystrophies 97

Table 1.

Characteristics of 10 C M D patients Patient No. 6

Characteristic

1

2

3

4

A g e (yrs; italics = deceased) Sex Consanguinity Onset o f s y m p t o m s (mos) Hypotonia Weakness Contractures Decreased reflexes Calf h y p e r t r o p h y Scoliosis A g e at first w a l k i n g (yrs) Progressive weakness Increased creatine kinase EMG myopathic Biopsy dystrophic Dystrophin normal Mental retardation Microcephaly Macrocephaly Seizures onset (yrs) Cobblestone lissencepbaly Cobblestone cortex White matter abnormalities Hydrocephalus Brainstem h y p o p l a s i a Cerebellar h y p o p l a s i a Dandy-Walker malformation Corpus callosal h y p o p l a s i a Retinal abnormalities Anterior c h a m b e r a b n o r m a l i t y Cataract

8 M -

2 M -

6 F +

3 M +

13 F

0 0 0 + . + 3 ++ + -

4 4 7 +

0 0 0 +

0 0 0 +

0 0 24

2 + + + -

+ 2

.

-

. + + ND -

7

8

9

10

11 F +

3 F -

/.2 F

1.2 M ±

1.3 M t

1 1 1

0 0 4

o 0 0

0 0 0

(J () ()

+

+

÷

+

+

+

+

÷

+

4

÷

H-

+

+

÷

.

-

-

-

+ + + -+

-

3.5

+

ND

,

+

8

2

-

+

+

+

~

+

t

÷

r

+

+

+

t

+

i-

+

+

÷

+

+

-r

+

+

Patients 1~- and 7 were reported previously [8,9]. Abbreviations: C M D = Congenital m u s c u l a r d y s t r o p h y EMG = Electromyography ND = Not determined

were within normal range. At 8 years o f age the child is alert and has normal cognitive function. Patient 2. This 2 4 - m o n t h - o l d b o y was born to n o n c o n s a n g u i n e o u s parents. Hip radiology at birth revealed bilateral subluxation. Motor milestones were delayed and lead to neurologic evaluation. Physical examination at age 14 months disclosed mild generalized hypotonia with facial muscle involvement a n d m a r k e d wasting o f the u p p e r limbs and trunk muscles. Bilateral flexion contractures at the c o x o f e m o r a l joints, knees, and ankles were present. T e n d o n reflexes were diminished. C o g nitive function a p p e a r e d normal for age. C K was normal (80 U/L, normal: < 1 0 0 ) . E K G , o p h t h a l m o l o g i c examinations, skeletal r a d i o g r a p h y , and cranial M R I were normal. E M G revealed m y o g e n i c features and N C V was normal. Muscle biopsy disclosed a total r e p l a c e m e n t of muscle b y fibroadipose tissue. I m m u n o s t a i n i n g for dystrophin could not be performed due to paucity o f muscle fibers. Analysis of l y m p h o c y t i c D N A for c o m m o n dystrophin gene mutations w a s normal. Follow-up at the age 24 months disclosed no progression of the n e u r o m u s c u l a r abnormalities. Patient 3. This 6 - y e a r - o l d girl was born to c o n s a n g u i n e o u s parents (second cousins). She presented at age 1 year with generalized hypotonia and muscle weakness with absence o f tendon reflexes. Physical examination disclosed bilateral c a m p t o d a c t y l y , generalized hypotonia, weakness, a n d areflexia. Facial musculature was involved. Cognitive impairment was not evident. C K w a s normal. E M G was m y o g e n i c with muscle biopsy revealing a dystrophic pattern with normal dystrophin distribu-

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tion. O p h t h a l m o l o g i c examination and cranial MRI were normal. She currently has moderate generalized hypotonia and muscle weakness with involvement of the facial muscles. She b e g a n to walk with the assistance of long leg braces at 24 months. Cognitive function remains normal t\)r age. Patient 4. This 3-year-old boy, the y o u n g e r brother of Patient 3, was born with bilateral club foot deformities and isolated m o t o r delay. Hypotonia and muscle weakness were slight and less m a r k e d than in his elder sister. C K was normal. E M G revealed m y o g e n i c pattern with normal NCV. Muscle biopsy disclosed dystrophic findings with normal dystrophin distribution, qualitatively similar to but quantitatively less marked than that of his sister. O p h t h a l m o l o g i c e x a m i n a t i o n was normal. Cranial MRI disclosed m i n o r alterations o f periventricular white matter in the parietal area. Follow-up examination revealed no progression o f weakness: cognitive function remained normal. He b e g a n to walk without braces at 24 months. Patient 5. This 13-year-old girl was born to n o n c o n s a n g u i n e o u s parents. Her mother observed muscle weakness in the child, especially in the upper limbs, beginning shortly after birth. A diagnosis o f 13-thalassemia major was made within the first y e a r of age. N e u r o l o g i c consultation was requested at 13 months because o f weakness unexplained by anemia. Neurologic examination disclosed generalized h y p o t o n i a and muscle weakness involving facial musculature. Deep tendon reflexes were symmetrically depressed. At age 13 months, she c o u l d neither stand

nor sit upright; cognitive function, however, appeared normal. Routine laboratory examination disclosed a mildly elevated CK level (250 U/L, normal level: < 100). EMG was myogenic and NCV was normal. Muscle biopsy revealed dystrophic type alterations; dystrophin immunostaining was not performed. At 2 years of age the patient began to develop bilateral flexion contractures of the wrist, knee, and elbow, as well as scoliosis and rib cage deformities. She was never able to walk. At present she manifests generalized hypotonia and muscle weakness involving facial musculature. Tendon reflexes are absent. She has scoliosis, evident rib cage deformities, and bilateral flexion contractures of the elbows, wrists, and knees. Intellectual development remains normal. Ophthalmologic examination and cranial MRI are normal. She periodically undergoes blood transfusions due to her hematologic condition. Recent analysis of lymphocytic DNA for common dystrophin gene mutations was normal. Patient 6. This 11-year-old girl was born to consanguineous parents (first cousins). Generalized hypotonia, weakness, and ankle contractures were observed at the age of 1 month. She began to walk with difficulty at the age of 31/2 years. She could not climb stairs unaided and frequently fell. At the age of 8 years, she developed generalized tonic-clonic seizures. She now has marked, generalized hypotonia and muscle weakness involving facial musculature. Tendon reflexes are absent. She has bilateral flexion contractures of the ankles and knees and short Achilles tendon and is moderately mentally retarded. Cranial MRI, computed tomography (CT) scan, and ophthalmologic examination were normal. Routine laboratory examinations revealed increased muscle enzymes: CK 434 U/L (normal: < 100) and lactic dehydrogenase (LDH) 1,764 U/L (normal: <100). EMG revealed myogenic features; NCV was normal. Muscle biopsy disclosed severe dystrophic findings with normal dystrophin immunostaining. Generalized hypotonia and muscle weakness are slightly progressive. At the age of 11 years, head circumference was 45 cm (<3rd percentile); review of her head growth suggests acquired microcephaly. Patient 7. This 3-year-old girl was born to nonconsanguineous parents. Generalized hypotonia was observed at birth. Physical examination soon after birth disclosed hyporeflexia in both upper and lower limbs. Macrocephaly (head circumference: 42 cm > 97%) and convergent strabismus were present. The infant appeared to have poor awareness of her environment. CK was increased (500 U/L, normal: < 100). Ophthalmologic examination revealed nystagmus, convergent strabismus, limited bilateral abduction, and chorioretinal dystrophy. Cranial ultrasonography detected the presence of a noncommunicating hydrocephalus. Within the first year of age, flexion contractures of the fingers, elbows, knees, and ankles became evident. EMG was performed when the child was 15 months old and revealed myogenic findings; NCV was normal. Biopsy disclosed marked dystrophic findings with normal dystrophin immunostaining. Cranial MRI at 13 months of age disclosed dilatation of the lateral ventricles, white matter anomalies, partial agenesis of the corpus callosum, and radiographic signs of lissencephaly. Seizures became evident at age 2 years, and anticonvulsant therapy was initiated. Currently, she is moderately retarded and bedridden. Patient 8. This 14-month-old girl was born to nonconsanguineous parents. Head circumference increased rapidly and steadily following birth, reaching 42 cm by age 1 month, prompting neurologic evaluation. Neurologic examination revealed severe generalized muscle weakness and hypotonia with facial and palatal involvement. Flexion contractures at the fingers were present bilaterally. Tendon reflexes were absent and no visual response could be elicited. Ophthalmologic examination revealed numerous findings including a short anterior chamber, marked corticonuclear lenticular opacities, and retinal abnormalities. In addition, pupils were fixed by posterior adhesions. Routine laboratory examinations were normal. Muscle enzymes were markedly increased: CK was 1,000 U/L, LDH was 400 U/L (normal: <100), serum glutamic oxaloacetic transaminase (SGOT) was 90 (normal: <30), and serum glutamic pyruvic transaminase (SGPT) was 100 (normal: <30). CT scan disclosed a poorly visible fourth ventricle, enlarged lateral ventricles, and radiographic signs of marked cerebral atrophy. EMG was myopathic and NCV

was normal. Muscle biopsy revealed typical dystrophic findings with normal dystrophin immunostaining. The child died of bronchopneumonia at the age of 14 months. At autopsy the brain manifested marked hydrocephalus and characteristics of lissencephaly with a smooth cortical surface and few enlarged gyri. Strikingly, olfactory bulbs were absent. The corpus callosum was thin, white matter was reduced, and pyramidal tracts were hypoplastic. The fourth ventricle was enlarged and communicated openly with an enlarged prepontine cistern; the foramen of Magendie was atretic. In addition, a Dandy-Walker cyst was present. Histologic examination of skeletal muscle disclosed severe degeneration of the few remaining muscle fibers. Patients 9 and 10. These patients, monozygotic male twins, were born to consanguineous parents (first cousins). Their clinical courses were so similar that they are described together. Generalized hypotonia and hyporeflexia were observed at birth. There was no reaction to visual stimuli. Both twins were macrocephalic. Laboratory examination revealed increased CK values (800 U/L and 1,200 U/L, respectively). In both twins ophthalmologic examination revealed retinal abnormalities, a shortened anterior chamber, and marked lenticular opacities. MRI disclosed wide communicating hydrocephalus, white matter anomalies, lissencephaly, agenesis of corpus callosum, and hypoplasia of pyramidal structures. Muscle biopsy disclosed markedly dystrophic features with normal dystrophin immunostaining. Bilateral flexion contractures of the fingers gradually became apparent within the first year of age. Psychomotor retardation was profound. Both patients died (at age 14 and 15 months, respectively) due to respiratory complications. Autopsy disclosed similar findings in the brain of both infants; hydrocephalus, Dandy-Walker malformation, and cobblestone lissencephaly were evident, along with hypoplasia of the corpus callosum, brainstem, and cerebellum.

Discussion The classification of CMD has long been a source of uncertainty, largely because it is rare and few large series of patients have been studied. The two best known forms are classical CMD and Fukuyama congenital muscular dystrophy (FCMD). Most children with classical CMD have normal intelligence, although some have had unusual white matter changes of unknown significance which consist of increased radiolucency on CT scans or increased T 2 signal on MRI [2,11]. Children with FCMD have severe mental retardation associated with specific brain malformations [ 12,13]. Some CMD subtypes included in previous reviews are based on old reports with no recent confirmation, such as "atonic-sclerotic" CMD [1]. The status of CMD with rigid spine syndrome and the Ullrich syndrome [14] also remains uncertain. Significant progress in the classification and understanding of CMD has been made recently based on results of clinical and laboratory investigations presented at two ENMC-sponsored workshops on CMD [3,4]. Especially significant is the discovery of merosin deficiency in a large subset of classical CMD patients [7] and discovery of merosin deficiency in the dy mouse [6]. Our proposed classification of CMD syndromes is presented in Table 2 and discussed below. Classical CMD With Merosin Deficiency. Discovery of the role of merosin in CMD followed several recent discoveries regarding the function of dystrophin and related proteins which together form a complex structure that links the sarcolemmal membrane of muscle fiber to the

Parano et al: Congenital Muscular Dystrophies 99

Table 2.

Proposed classification of congenital muscular dystrophies CMD Syndromes

Inheritance

Classical CMD (without mental retardation) With merosin deficiency With normal merosin CMD with forebrain malformations/mental retardation Cobblestone lissencephaly syndromes Fukuyama congenital muscular dystrophy Muscle-eye-brain disease Walker-Warburg syndrome Cobblestone lissencephaly only CMD with occipital agyria CMD with mental retardation (not otherwise classified) Atypical CMD syndromes Autosomal dominant CMD CMD with CNS malformations and normal intelligence With cerebellar hypoplasia/atrophy With syringomyelia CMD with prominent extra-CNS manifestations With Hirschsprung disease With severe cardiac disease Other atypical syndromes Ullrich syndrome/rigid spine/"atonic sclerotic" CMD

AR AR

AR AR AR AR AR AR? (heterogeneous} AD Few cases Single case Single case AR Unknown

Abbreviations: AD = Autosomaldominant AR = Autosomalrecessive CMD = Congenital muscular dystrophy CNS = Central nervous system extracellular matrix [ 15,16]. This large structure consists of dystrophin which is located just beneath the sarcolemmal membrane, several dystrophin-associated glycoproteins which span the membrane, several additional proteins of uncertain function, and laminin which links the glycoprotein complex to the extracellular matrix. The marked increase in connective tissue observed in muscle biopsies of CMD patients resembled the changes seen in other dystrophies and suggested that another abnormality of this complex multiprotein structure, other than dystrophin, might be involved [7]. Recent immunocytochemical studies disclosed complete or nearly complete deficiency of one isoform of laminin, known as laminin-M or merosin, in a significant proportion of patients with the classical form of CMD [4,7]. Merosin is a tissue-specific form of laminin which is located primarily in striated muscle and Schwann cells. Patients with classical CMD and merosin deficiency represent a clinically homogeneous group [4]. All reported patients have had severe hypotonia at birth or soon after, severe weakness involving most muscle groups including facial, pharyngeal, and respiratory muscles, severe and often progressive contractures, marked delay in motor development with none able to walk without support, and normal mental development. Serum CK levels have been elevated in the early stages of

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the disease (i.e., 1,700-15,000 U/L). CT and MRI scans disclose striking myelin changes in white matter which consist of abnormal radiolucency on CT and increased T 2 signal on MRI. The white matter abnormalities are diffuse in the centrum semiovale, patchy in the external capsule and cerebellum, and essentially absent in the internal capsule, corpus callosum, and brainstem [2,11]. The merosin-deficient form of classical CMD thus corresponds to the so-called "occidental" form of CMD described in earlier reports [2,11,17]. Although merosin staining was not performed in our patients, none had the combination of greatly elevated CK, normal mental development, and white matter abnormalities, the main characteristics of classical CMD associated with merosin deficiency. Thus, this specific form of CMD might be less common in Sicily than in France or England where half of the classical CMD patients may have merosin deficiency [4-7]. Classical CMD With Normal Merosin. Children with classical CMD and normal merosin staining on muscle biopsy comprise a more heterogeneous group and may represent several different genetic diseases. In general, the clinical abnormalities are less severe. Most patients have milder and less frequent neonatal hypotonia, mild weakness which is more often progressive, rare and limited respiratory involvement, and milder contractures. Motor

development is often better and most are eventually able to walk. As in the case of classical CMD with merosin deficiency, intelligence is often normal. Serum CK is usually normal or only mildly elevated [4]. A few patients have severe manifestations similar to the merosindeficient group including high serum CK. In our series, Patients 3 and 4 had relatively mild motor delay and normal serum CK. Both eventually became ambulatory. Clinical and laboratory features of Patient 2 are similar to that of Patients 3 and 4; it is probably too early to determine whether Patient 2 will achieve ambulation, but we believe that he will. Patients 2-4 thus correspond to the most common subgroup of classical CMD with normal merosin. Patient 5 had mildly elevated serum CK and was unable to walk at age 13 years; she also had 13-thalassemia major. CMD With Occipital Pachygyria. This rare disorder had been described briefly in a brother and sister from Sweden [18] and an unrelated boy from Italy [19]. In all three, muscle weakness was severe but intelligence was apparently normal. Neuropathology in two of the children revealed occipital pachygyria but no other change of cobblestone lissencephaly. None of our patients appears to fall within this category.

CMD With Mental Retardation (not otherwise classified). In several recent series of classical CMD patients, with or without merosin deficiency, the frequency of mental retardation was low [3,4]. However, many patients with CMD and mental retardation have been reported. Most of these patients have one of the cobblestone lissencephaly syndromes, but some children with CMD and mental retardation have been reported in whom no other cause was identified. In a European collaborative study, 5 of 6 patients with CMD and white matter changes on CT had moderate mental retardation but no other manifestations of any of the cobblestone lissencephaly syndromes [11]. In a study of Saudi children, 2 of 11 patients with CMD and white matter changes had mild mental retardation but again no other change of the cobblestone lissencephaly syndromes [2]. In a series of children from northern Italy, 5 of 12 CMD patients had mental retardation, including some with and others without white matter changes; this series included two siblings discordant for mental retardation [19]. Among our patients, only 1 child (Patient 6) had CMD and mental retardation without other changes of cobblestone lissencephaly. Several hypotheses can be advanced to explain the presence of mental retardation in patients with classical CMD without cobblestone lissencephaly as defined by radiologic or autopsy studies. Some of these children may have a subtle change in one of the cobblestone lissencephaly syndromes, rendering it radiographically undetectable. Alternatively, classical CMD with mental retardation could represent a severe expression of one of the classical CMD syndromes. Classical CMD with merosin deficiency does have associated white matter changes and so could conceivably result in mental retardation in some patients

(although patients with classical CMD with merosin deficiency are typically of normal intelligence). Of course, it is possible that CMD is associated with another unrelated condition causing mental retardation by chance alone. Taken together, it seems unlikely that all of the reported cases of CMD with mental retardation but without cobblestone lissencephaly can be explained by the abovementioned possibilities. Thus, we suggest that the combination of CMD and mental retardation without other changes of cobblestone lissencephaly might represent a separate disorder or group of disorders. Some heterogeneity is apparent as some patients have had white matter changes while others have not. We propose the term "CMD with mental retardation (not otherwise classified)" to categorize these rare patients. Cobblestone Lissencephaly Syndromes. Several syndromes with cobblestone (type II) lissencephaly have been observed. This type of lissencephaly in its complete form consists of an unusual cortical dysplasia known as cobblestone cortex, white matter changes, ventriculomegaly, cerebellar hypoplasia, and brainstem hypoplasia. The socalled cobblestone cortex (after M. Haltia, personal communication, 1993) consists of mixed agyria, pachygyria, and polymicrogyria, partial obstruction of the subarachnoid space by fibroglial tissue, and other changes [20]. There are three well-described cobblestone lissencephaly syndromes: Fukuyama congenital muscular dystrophy (FCMD), muscle-eye-brain disease (MEB), and WalkerWarburg syndrome (WWS). Fukuyama congenital muscular dystrophy and muscleeye-brain disease both manifest striking founder effects. The typical form of FCMD occurs only in Japan while MEB has been reported primarily from Finland. In contrast, WWS has a worldwide distribution. All nonJapanese patients reported to have FCMD probably have MEB or mild WWS. MEB, WWS, and cobblestone lissencephaly with normal eyes and muscle [20] are classified separately, but are likely allelic. The typical form of FCMD differs from MEB and WWS. Muscle-eye-brain disease. MEB consists of cobblestone lissencephaly, retinal hypoplasia with reduced or absent response on electroretinogram (ERG), and congenital muscular dystrophy [4,21]. Most patients have mixed pachygyria and polymicrogyria with the polymicrogyria most common over the occipital region. The frequent white matter changes of cobblestone lissencephaly are patchy or absent. Some have had progressive hydrocephalus. The ERG may be normal in infancy but is always abnormal by age 2 years. Most children develop very high amplitude responses on visual evoked potentials (VEP) by 2 years of age [3,4,21]. Affected children have moderate or severe mental retardation, hypotonia, mild distal spasticity, weakness, and poor vision. Although several have died in childhood, most survive 10-30 years and a few survive longer. Walker-Warburg syndrome. WWS consists of cob-

Parano et al: CongenitalMuscularDystrophies 101

blestone lissencephaly, retinal abnormalities, and congenital muscular dystrophy or myopathy [3,4,20]. The previous diagnostic criteria of type II lissencephaly and cerebellar hypoplasia are both included in cobblestone lissencephaly. Most children have agyria with smaller regions of pachygyria and polymicrogyria, while a few have had milder gyral malformations identical to MEB. The white matter changes are usually widespread. Almost all children with WWS have enlarged ventricles and many have progressive hydrocephalus which often requires treatment with a shunt. Almost all have cerebellar (especially vermis) hypoplasia, frequently associated with a retrocerebellar cyst and thus meeting criteria of DandyWalker malformation. Some affected children have posterior encephaloceles which most often communicate with a Dandy-Walker cyst. A wide spectrum of retinal malformation has been observed including retinal detachment or dysplasia, retinal (especially choroidal) hypoplasia, optic nerve hypoplasia, or optic atrophy. Other common eye abnormalities include microphthalmia, congenital glaucoma, cornea-iris-lens adhesions, cataracts, and persistent fetal blood vessels. ERG and VEP have been performed in very few patients. Most children with WWS have profound mental retardation and hypotonia, mild distal spasticity, and poor vision. Children with less severe gyral malformations similar to MEB usually have moderate to severe mental retardation. The median survival is 4 months, although some patients may survive more than 5 years. Other congenital anomalies have been observed in a few patients, such as cleft lip and palate or cleft palate alone, minor renal anomalies, and cryptorchidism. MEB and WWS are usually classified separately because WWS is usually much more severe than MEB, and because progressive changes on ERG and VEP have been reported in MEB but not WWS. However, many non-Finnish patients with mild WWS or possibly MEB have been reported. ERG and VEP have been reported in few WWS patients. While controversial, it is likely that MEB and WWS are allelic disorders. Our Patients 8, 9, and 10 had severe WWS with profound mental retardation, hydrocephalus, severe eye anomalies, and other abnormalities. Patient 7 had mild WWS with moderate to severe mental retardation. She was classified as mild WWS rather than MEB because of the widespread white matter change. Fukuyama congenital muscular dystrophy. Typical FCMD as observed in most affected Japanese children consists of severe CMD with progressive weakness involving the face and body, congenital and progressive joint contractures, elevated serum CK (10-50 times normal), mental retardation with IQ usually below 50, and cobblestone lissencephaly which is less severe than in MEB or WWS [ 12,13]. The cobblestone cortex consists of pachygyria and polymicrogyria with partial obstruction of the subarachnoid space and hemispheric fusion. Other abnormalities include white matter abnormalities which improve with age (in about 80% of cases), mildly enlarged ventricles, mild cerebellar polymicrogyria usually without

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cerebellar hypoplasia, and hypoplasia of pyramidal tracts. About half of the patients with typical FCMD have minor eye anomalies such as strabismus, abnormal eye movement, or mild myopia. A few have severe myopia, cataracts, optic disk pallor, or unusual round lesions of the retinal periphery. Some patients have other minor congenital anomalies such as brachycephaly, high arched palate, hypertrichosis, and protruding heels. Several patients have had more severe brain or eye malformation such as progressive hydrocephalus, cerebellar hypoplasia, retinal detachment, optic atrophy, or other birth defects such as cleft lip and palate, anal atresia, or congenital heart disease. It appears possible that some, if not all, of these patients with severe ocular malformations had MEB or WWS rather than typical FCMD. Most non-Japanese patients diagnosed to have FCMD have had more severe anomalies typical of MEB or WWS, or less severe anomalies consistent with CMD with mental retardation. The gene responsible for FCMD was recently mapped to chromosome 9q31-33 [22[. MEB has been excluded from this region by linkage analysis [41, proving that FCMD and MEB are distinct disorders. Atypical CMD Syndromes. A few other rare CMD syndromes have been reported, but their relationship to the better defined syndromes described above is not clear. There have been a few reports of CMD associated with extra-CNS abnormalities. Goebel et al. [23] reported a series of 5 patients with CMD in northeastern Germany; several of these patients developed right cardiac ventricular hypertrophy (leading to fatal right heart failure in two). Mandel et al. [24] reported a patient with CMD and Hirschsprung disease with small white matter hypodensities on cranial MRI with a normal ophthalmologic examination; this patient had numerous dysmorphic features and a rapidly progressive course with death at age 5 months. Autosomal recessive inheritance has been proposed tor most categories of CMD. Autosomal dominant inheritance of CMD has been reported in some families, but the muscle biopsy disclosed subtle mitochondrial changes unlike typical CMD [51. Finally, there are CMD patients who have CNS malformations but normal or near normal intelligence. Several patients have had CMD plus cerebellar hypoplasia or atrophy with either normal intelligence or only mild mental retardation [25,26]. We recently reported [91 a patient (Patient 1 here) who has CMD with syringomyelia. Thus there may be rare patients with CMD and CNS malformations that spare supratentorial structures; these patients have normal ophthalmologic examinations and normal mental development, and so might be difficult to distinguish from classical CMD on clinical grounds alone.

Rosario R. Trifiletti, MD, PhD was supported by a grant from the John Merck Fund.

References

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