- Email: [email protected]
Congenital muscular dystrophy with central and peripheral nervous system involvement in a Belgian patient
Neuromuscular Disorders 9 (1999) 251–256
Case report
Congenital muscular dystrophy with central and peripheral nervous system involvement in a Belgian patient M.-Cl. Belpaire-Dethiou a ,*, K. Saito b, Y. Fukuyama b, E. Kondo-Iida b , c, T. Toda c, Th. Duprez d, C. Verellen-Dumoulin e, P.Y.K. Van den Bergh f a
Service de Neurologie pe´diatrique, Cliniques Universitaires Saint-Luc, University of Louvain, Brussels, Belgium b Department of Pediatrics, Tokyo Women’s Medical College, Tokyo, Japan c Laboratory of Genome Medicine, Institute of Medical Science, University of Tokyo, Tokyo, Japan d Service de Radiologie, Cliniques Universitaires Saint-Luc, University of Louvain, Brussels, Belgium e Centre de Ge´ne´tique me´dicale, Cliniques Universitaires Saint-Luc, University of Louvain, Brussels, Belgium f Service de Neurologie et Laboratoire de Neuropathologie, Cliniques Universitaires Saint-Luc, University of Louvain, Brussels, Belgium Received 24 September 1998; received in revised form 21 December 1998; accepted 22 January 1999
Abstract We report a patient with congenital muscular dystrophy (CMD), developmental brain defects, and peripheral neuropathy. Marked hypotonia and plagiocephaly were noted at birth. Failure to thrive, generalized muscle weakness and wasting, absent deep tendon reflexes, partial seizures, and secondary microcephaly developed. Brain MRI showed a large area of cortical dysplasia, a thin but complete corpus callosum, and diffuse ventriculomegaly. Nerve conduction velocities were slow and creatine kinase levels only mildly elevated. Muscle biopsy showed dystrophic features with normal merosin, sarcoglycan, and dystrophin immunostaining. The Japanese Fukuyama CMD founder mutation was not detected. This is the first report of a patient with merosin-positive CMD, cobblestone lissencephaly, and demyelinating peripheral neuropathy. 1999 Elsevier Science B.V. All rights reserved. Keywords: Congenital muscular dystrophy; Developmental brain defects; Peripheral neuropathy
1. Introduction The congenital muscular dystrophies (CMD) are a heterogeneous group of autosomal recessively inherited degenerative muscle disorders. The clinical manifestations consist of neonatal hypotonia and muscle weakness, delayed motor milestones, severe and early contractures and joint deformities; developmental brain and eye defects may be associated. Five major types of CMD have been identified [1]. Classical CMD is considered a ’pure’ muscle disorder, although a significant number of patients exhibit cerebral white matter lesions on CT scan or MRI. In these patients, mutations in the gene of the M (a2) chain of merosin lead to merosin deficiency in muscle [2]. In general, merosin-defi* Corresponding author.
0960-8966/99/$ - see front matter PII: S09 60-8966(99)000 09-7
cient patients are more severely affected than patients with normal merosin expression, and they may present with seizures and neurological soft signs [3]. Fukuyama CMD almost exclusively occurs in Japan and is associated with severe developmental central nervous system defects and profound mental retardation [4]. The two other CMD types are known as muscle-eye-brain disease and Walker– Warburg syndrome. In Walker–Warburg syndrome, severe developmental defects of brain and eye, associated with profound weakness and arthrogryposis, are obvious at birth and usually lethal within the first year of life [5]. Similar but less marked abnormalities with survival to 10–30 years of age are found in muscle-eye-brain disease [6]. We here report a Belgian CMD patient with developmental brain defects and demyelinating peripheral neuropathy.
1999 Elsevier Science B.V. All rights reserved.
252
M.-Cl. Belpaire-Dethiou et al. / Neuromuscular Disorders 9 (1999) 251–256
Fig. 1. Transverse T2-weighted fast spin-echo MR images at the age of 11 months. (a) Focal thickening of the frontal parietal cortex is evident (thick white arrows), as is slight enlargement of adjacent subarachnoid spaces and bilateral ventriculomegaly. The germinal layer underlying the abnormal cortex is thickened (black arrows). There is marked hyperintensity of the subcortical white matter, situated between the abnormal cortex and the thickened germinal layer (thin white arrow). In other areas, myelination retardation is less prominent. A thick cortex with a smooth surface and a smooth gray-white matter interface is characteristic of pachygyria. (b) Right frontal parietal gyration and sulcation abnormalities are similar to those shown in the previous figure, but the occurrence of shallow sulci (black arrows) and a bumpy gray-white matter interface are characteristic of polymicrogyria. (c) Mid-sagittal T1-weighted MR image showing hypoplastic but complete corpus callosum and normal posterior fossa.
M.-Cl. Belpaire-Dethiou et al. / Neuromuscular Disorders 9 (1999) 251–256
2. Case report The patient is a white female, born at term by Caesarean section from non-consanguineous healthy parents. Birth weight was 2.9 kg (P50); head circumference was 35.5 cm (P75, +1 SD). At birth, plagiocephaly, severe hypotonia, stiffness of the lower limbs, bilateral hip dysplasia, and poor feeding were evident. At 6 weeks of age, marked tetraparesis and axial hypotonia with absence of spontaneous movements, and poor suck were noted. At 4 months of age, spells of clonic eye movements and of tonic head and eye deviation to the left were observed. EEG showed delta wave activity and intermittent spike and slow wave activity, predominating right occipitally. The spells were abolished by phenobarbital. Weight was 4.9 kg (,P3), height 51.5 cm (,P3), and head circumference 38.5 cm (P3, −2 SD). The face was expressionless and the mouth tent-shaped. Ocular pursuit was absent, but the infant responded to light. There was horizontal nystagmus in lateral gaze directions. Optic disks were pale. The retina was normal on funduscopic examination and on electroretinography. Flash visual evoked potentials were normal. In dorsal decubitus position, the head was deviated to the left with an asymmetric tonic neck reflex. Spontaneous movements were very poor and there was marked axial hypotonia. Contractures of hip girdle, adductor, and hamstring muscles were present, particularly on the right. High-arched feet and hammer toes were noted. Deep tendon reflexes were absent. There are no siblings and the family history is non-contributory. At the age of 3 years, weight was 8.2 kg (,P3), height 78 cm (,P3), and head circumference 43.5 cm (,P3, −4 SD). Mental retardation was profound. There was ocular pursuit with horizontal nystagmus in lateral gaze directions. Voluntary movements were still very poor and there was marked axial hypotonia. An asymmetric tonic neck reflex persisted. Hypertonic extension of the upper limbs with wrist pronation occurred spontaneously and following external stimuli. Shoulder and elbow mobility was normal. Hand muscles were atrophic. The lower limbs were fixed in extension with the hips in abduction and external rotation. Knee extension was only slightly limited. Pes cavus with toe flexion contractures were present. Deep tendon reflexes were not elicitable.
253
culomegaly, slight diffuse myelination retardation, and local gyration abnormalities. The main feature was a large cortical dysplastic area in the right frontal, temporal, and parietal lobes. The cortex appeared thick with a smooth surface and a smooth interface between gray and white matter as hallmarks for pachygyria (Fig. 1a). In other areas, cortical thickening was less prominent; shallow sulci and a bumpy gray-white matter interface were characteristic of polymicrogyria (Fig. 1b). The white matter exhibited diffuse and moderately retarded myelination, as shown by prolonged T1 and T2 relaxation times, which was most conspicuous in the subcortical white matter, immediately underlying the abnormal cortex. Ventricular enlargement was moderate and diffuse. The corpus callosum was thin but complete and exhibited normal myelination. The cerebellum and the brainstem had a normal appearance (Fig. 1c). A second brain MRI at the age of 3 years showed similar abnormalities, but white matter changes were less prominent. Three-dimensional surface rendering techniques allowed recognition of a cobblestone pattern of the surface of the pachygyric cortex (Fig. 2). 2.3. Neuropathological studies A triceps surae muscle biopsy was performed at the age of
2.1. Blood and spinal fluid examination Serum creatine kinase levels never exceeded 486 IU/l (N , 170). Toxoplasma, enterovirus, herpes, rubella, and CMV serology was negative. Serum amino acid and lactate levels were normal and there was no organic aciduria. Spinal fluid lactate and protein were normal. 2.2. Neuroradiological examination Brain MRI at the age of 11 months showed mild ventri-
Fig. 2. Three-dimensional T1-weighted gradient-echo MR images at the age of 3 years. Asymmetry of the cortical surface of both cerebral hemispheres with cobblestone lissencephaly pattern on the right (arrowheads).
254
M.-Cl. Belpaire-Dethiou et al. / Neuromuscular Disorders 9 (1999) 251–256
Fig. 3. Triceps surae muscle biopsy, showing depletion and atrophy of muscle fibres and marked fibrosis (a; hematoxylin–eosin). Merosin (b), dystrophin (c), and a-sarcoglycan (d) immunoreactivity is normal. Bar = 50 mm.
14 months. Routine histological and histochemical stains on 10 mm transverse frozen sections included hematoxylin– eosin, modified Gomori trichrome, PAS, oil red O, NADH-TR, SDH, ATPase after preincubation at pH 9.4,
4.2, and 4.6, and cytochrome c oxydase staining. Immunohistochemical staining with spectrin, dystrophin, a-sarcoglycan (Novocastra), and 300 kDa fragment of merosin (Novocastra) antibodies was performed. Muscle tissue was
255
M.-Cl. Belpaire-Dethiou et al. / Neuromuscular Disorders 9 (1999) 251–256 Table 1 Results of nerve conduction studies at 10 months of age Sensory nerve
Stimulation site
L Median R Median L Ulnar
Wrist Wrist Wrist Elbow
2.7 (,3.3) 6.0
Motor nerve
Stimulation site
CMAP latency (ms)
CMAP amplitude (mV)
L Median
5.3 (,2.8) 9.3 8.4 (,2.8) 12.9
L Peroneus
Wrist Elbow Wrist Elbow Ankle Fibular head Internal malleolus
5.3
L Tibialis post.
180 (.2300) 120 210 (.2300) 170 Absent (extensor digitorum brevis) 600 (tibialis anterior) Absent
R Median
SNAP latency (ms)
SNAP amplitude (mV)
Sensory CV (m/s)
Absent Absent 5.0 (.10) 21 (.42) Motor CV (m/s) 17 (.37) 14 (.37)
SNAP, sensory nerve action potential; CMAP, compound muscle action potential; CV, conduction velocity; L, left; R, right.
largely replaced by fibrous and connective tissue (Fig. 3a). Remaining muscle fibres were often atrophic. Central nuclei were frequent. Muscle fibre necrosis was not observed. Oxydative enzyme staining patterns were normal. There was type II fibre predominance. Cytoskeletal sarcolemmal protein immunoreactivity was normal (Fig. 3b–d). An attempt to obtain sural nerve tissue was unsuccessful. 2.4. Neurophysiological examination Electrodiagnostic studies were performed at the age of 10 months (Table 1). The sensory nerve action potentials of the median and sural nerves were unobtainable. The amplitude of the ulnar sensory nerve action potential was reduced and the sensory nerve conduction velocity markedly slowed. The amplitude of the compound muscle action potentials was markedly diminished; no response was elicited from the peroneal and posterior tibial nerves on recording from foot muscles. Motor conduction velocities were very slow
also. Electromyography of proximal and distal upper and lower limb muscles did not show spontaneous activity. Motor unit action potentials were normal, but recruitment was reduced. 2.5. DNA analysis Haplotype analysis was conducted using microsatellite markers in the Fukuyama CMD candidate region. Initially, the patient and her mother were found to have the same haplotype as the Japanese Fukuyama CMD ancestral founder haplotype, i.e. markers 138–183–301 for D9S2105– D9S2107–D9S172, which is observed in 85% of the Japanese Fukuyama CMD patients. However, when studying the haplotype with the recently developed E6-J7 markers (190– 147), it was found to differ from the Fukuyama CMD founder haplotype. The 3 kb insertion, which is the founder mutation in 95% of the Japanese Fukuyama CMD patients, was not detected [7].
Table 2 Features of our patient as compared to those of the recognized CMD types
Onset before 12 months CMD Head circumference Mental retardation Seizures Eye abnormalities Ventricular dilatation Cobblestone cortex White matter lucency Cerebellar malformation Corpus callosum Brainstem hypoplasia Neuropathy
Patient
Merosin + CMD (pure CMD)
Merosin − CMD
Fukuyama CMD
Muscle-eye-brain disease
Walker–Warburg syndrome
+ + , −2 SD + + − Mild + + − Hypoplasia − +
+ + Variable − or mild − or mild − − − − − − − −
+ + Variable − or mild − or mild − − − + − − − +
+ + 0–2 SD + .50% − or mild Mild + +, regressive + Hypoplasia − (or +) −
+ + Variable + + + + + Mild ++ Hypoplasia + −
+ + .2 SD + + + + + Severe, persistent ++ Agenesis + −
256
M.-Cl. Belpaire-Dethiou et al. / Neuromuscular Disorders 9 (1999) 251–256
3. Discussion Our patient presents with CMD with progressive microcephaly, mental retardation, epilepsy, and sensorimotor demyelinating peripheral neuropathy. Brain MRI shows developmental abnormalities with pachygyria, micropolygyria, ventriculomegaly, mild retardation of myelination, and hypoplasia of the corpus callosum. Muscle biopsy shows replacement of muscle fibres by fibrous and adipose tissue, muscle fibre atrophy without necrosis, and normal merosin, dystrophin, and a-sarcoglycan immunohistochemistry. The clinical and laboratory findings do not correspond to those observed in ’pure’ CMD, merosin-deficient CMD, muscle-eye-brain disease, or Walker–Warburg syndrome (Table 2). Microcephaly, mental retardation, epilepsy, and the muscle biopsy and brain MRI findings are reminiscent of Fukuyama CMD [7,8]. Unlike patients with Fukuyama CMD, however, our patient does not present major contractures, exhibits upper motor neurone signs, has only mildly elevated serum creatine kinase levels, and shows evidence of a demyelinating peripheral neuropathy. Moreover, the mutation in the Fukuyama CMD gene commonly present in Japanese patients was not found in our patient [9]. Evidence of peripheral nerve demyelination is observed in merosin-negative occidental CMD [10]. Although cerebral white matter changes are characteristic of the latter disorder [1], there are no structural central nervous system defects and mild mental retardation and epilepsy are relatively rare findings [3]. Several merosin-positive CMD patients with severe brain involvement and cortical dysplasia without overt ocular abnormalities not conforming to the recognized CMD types have been reported [3,11]. Peripheral nerve involvement has been described by Leyten et al. [12] in two female siblings with merosin-positive CMD, spastic tetraplegia, contractures, lack of cognitive development, and microcephaly. Motor nerve conduction velocities were slow and sural nerve biopsy revealed absence of large myelinated nerve fibers. Neuropathological examination of the brain of one sibling, who died at the age of 30 months, showed subtotal depletion of neurones in the cerebral and cerebellar
cortex and in the ventral pons as well as secondary loss of myelin. These findings are different from CMD-associated cobblestone lissencephaly. In conclusion, this is the first report of a patient, presenting with merosin-positive CMD, cobblestone lissencephalylike MRI findings, and electrodiagnostic evidence of a demyelinating peripheral neuropathy. The molecular defect remains to be identified.
References [1] Dubowitz V, Fardeau M. Workshop report: proceedings of the 27th ENMC sponsored workshop on congenital muscular dystrophy. Neuromusc Disord 1995;5:253–258. [2] Hillaire D, Leclerc A, Faure S, et al. Localization of merosin-negative congenital muscular dystrophy to chromosome 6q2 by homozygosity mapping. Hum Mol Genet 1994;3:1657–1661. [3] Leyten QH, Gabree¨ls FJM, Renier WO, ter Laak HJ. Congenital muscular dystrophy: a review of the literature. Clin Neurol Neurosurg 1996;98:267–280. [4] Fukuyama Y, Osawa M, Suzuki H. Congenital progressive muscular dystrophy of the Fukuyama type: clinical, genetic and pathologic considerations. Brain Dev 1981;13:1–29. [5] Williams RS, Swisher CN, Jennings M, Ambler M, Caviness VS Jr. Cerebro-ocular dysgenesis (Walker–Warburg syndrome): neuropathologic and aetiologic analysis. Neurology 1984;34:1531–1541. [6] Santavuori P, Somer H, Sainio K, et al. Muscle-eye-brain disease (MEB). Brain Dev 1989;11:147–153. [7] Van der Knaap MS, Smit LME, Barth PG, et al. MRI in classification of congenital muscular dystrophies with brain abnormalities. Ann Neurol 1997;42:50–59. [8] Aida N. Fukuyama congenital muscular dystrophy: a neuroradiologic review. J Magn Reson Imag 1998;8:317–326. [9] Kobayashi K, Nakahori Y, Miyake M, et al. An ancient retrotransposal insertion causes Fukuyama-type congenital muscular dystrophy. Nature 1998;394:388–392. [10] Shorer Z, Philpot J, Muntoni F, Sewry C, Dubowitz V. Demyelinating peripheral neuropathy in merosin-deficient congenital muscular dystrophy. J Child Neurol 1995;10:472–475. [11] Dubowitz V. Workshop report: proceedings of the 50th ENMC sponsored workshop on congenital muscular dystrophy. Neuromusc Disord 1997;7:539–547. [12] Leyten QH, Barth PG, Gabree¨ls FJM, et al. Congenital muscular dystrophy and severe central nervous system atrophy in two siblings. Acta Neuropathol 1995;90:650–656.
Case report
Congenital muscular dystrophy with central and peripheral nervous system involvement in a Belgian patient M.-Cl. Belpaire-Dethiou a ,*, K. Saito b, Y. Fukuyama b, E. Kondo-Iida b , c, T. Toda c, Th. Duprez d, C. Verellen-Dumoulin e, P.Y.K. Van den Bergh f a
Service de Neurologie pe´diatrique, Cliniques Universitaires Saint-Luc, University of Louvain, Brussels, Belgium b Department of Pediatrics, Tokyo Women’s Medical College, Tokyo, Japan c Laboratory of Genome Medicine, Institute of Medical Science, University of Tokyo, Tokyo, Japan d Service de Radiologie, Cliniques Universitaires Saint-Luc, University of Louvain, Brussels, Belgium e Centre de Ge´ne´tique me´dicale, Cliniques Universitaires Saint-Luc, University of Louvain, Brussels, Belgium f Service de Neurologie et Laboratoire de Neuropathologie, Cliniques Universitaires Saint-Luc, University of Louvain, Brussels, Belgium Received 24 September 1998; received in revised form 21 December 1998; accepted 22 January 1999
Abstract We report a patient with congenital muscular dystrophy (CMD), developmental brain defects, and peripheral neuropathy. Marked hypotonia and plagiocephaly were noted at birth. Failure to thrive, generalized muscle weakness and wasting, absent deep tendon reflexes, partial seizures, and secondary microcephaly developed. Brain MRI showed a large area of cortical dysplasia, a thin but complete corpus callosum, and diffuse ventriculomegaly. Nerve conduction velocities were slow and creatine kinase levels only mildly elevated. Muscle biopsy showed dystrophic features with normal merosin, sarcoglycan, and dystrophin immunostaining. The Japanese Fukuyama CMD founder mutation was not detected. This is the first report of a patient with merosin-positive CMD, cobblestone lissencephaly, and demyelinating peripheral neuropathy. 1999 Elsevier Science B.V. All rights reserved. Keywords: Congenital muscular dystrophy; Developmental brain defects; Peripheral neuropathy
1. Introduction The congenital muscular dystrophies (CMD) are a heterogeneous group of autosomal recessively inherited degenerative muscle disorders. The clinical manifestations consist of neonatal hypotonia and muscle weakness, delayed motor milestones, severe and early contractures and joint deformities; developmental brain and eye defects may be associated. Five major types of CMD have been identified [1]. Classical CMD is considered a ’pure’ muscle disorder, although a significant number of patients exhibit cerebral white matter lesions on CT scan or MRI. In these patients, mutations in the gene of the M (a2) chain of merosin lead to merosin deficiency in muscle [2]. In general, merosin-defi* Corresponding author.
0960-8966/99/$ - see front matter PII: S09 60-8966(99)000 09-7
cient patients are more severely affected than patients with normal merosin expression, and they may present with seizures and neurological soft signs [3]. Fukuyama CMD almost exclusively occurs in Japan and is associated with severe developmental central nervous system defects and profound mental retardation [4]. The two other CMD types are known as muscle-eye-brain disease and Walker– Warburg syndrome. In Walker–Warburg syndrome, severe developmental defects of brain and eye, associated with profound weakness and arthrogryposis, are obvious at birth and usually lethal within the first year of life [5]. Similar but less marked abnormalities with survival to 10–30 years of age are found in muscle-eye-brain disease [6]. We here report a Belgian CMD patient with developmental brain defects and demyelinating peripheral neuropathy.
1999 Elsevier Science B.V. All rights reserved.
252
M.-Cl. Belpaire-Dethiou et al. / Neuromuscular Disorders 9 (1999) 251–256
Fig. 1. Transverse T2-weighted fast spin-echo MR images at the age of 11 months. (a) Focal thickening of the frontal parietal cortex is evident (thick white arrows), as is slight enlargement of adjacent subarachnoid spaces and bilateral ventriculomegaly. The germinal layer underlying the abnormal cortex is thickened (black arrows). There is marked hyperintensity of the subcortical white matter, situated between the abnormal cortex and the thickened germinal layer (thin white arrow). In other areas, myelination retardation is less prominent. A thick cortex with a smooth surface and a smooth gray-white matter interface is characteristic of pachygyria. (b) Right frontal parietal gyration and sulcation abnormalities are similar to those shown in the previous figure, but the occurrence of shallow sulci (black arrows) and a bumpy gray-white matter interface are characteristic of polymicrogyria. (c) Mid-sagittal T1-weighted MR image showing hypoplastic but complete corpus callosum and normal posterior fossa.
M.-Cl. Belpaire-Dethiou et al. / Neuromuscular Disorders 9 (1999) 251–256
2. Case report The patient is a white female, born at term by Caesarean section from non-consanguineous healthy parents. Birth weight was 2.9 kg (P50); head circumference was 35.5 cm (P75, +1 SD). At birth, plagiocephaly, severe hypotonia, stiffness of the lower limbs, bilateral hip dysplasia, and poor feeding were evident. At 6 weeks of age, marked tetraparesis and axial hypotonia with absence of spontaneous movements, and poor suck were noted. At 4 months of age, spells of clonic eye movements and of tonic head and eye deviation to the left were observed. EEG showed delta wave activity and intermittent spike and slow wave activity, predominating right occipitally. The spells were abolished by phenobarbital. Weight was 4.9 kg (,P3), height 51.5 cm (,P3), and head circumference 38.5 cm (P3, −2 SD). The face was expressionless and the mouth tent-shaped. Ocular pursuit was absent, but the infant responded to light. There was horizontal nystagmus in lateral gaze directions. Optic disks were pale. The retina was normal on funduscopic examination and on electroretinography. Flash visual evoked potentials were normal. In dorsal decubitus position, the head was deviated to the left with an asymmetric tonic neck reflex. Spontaneous movements were very poor and there was marked axial hypotonia. Contractures of hip girdle, adductor, and hamstring muscles were present, particularly on the right. High-arched feet and hammer toes were noted. Deep tendon reflexes were absent. There are no siblings and the family history is non-contributory. At the age of 3 years, weight was 8.2 kg (,P3), height 78 cm (,P3), and head circumference 43.5 cm (,P3, −4 SD). Mental retardation was profound. There was ocular pursuit with horizontal nystagmus in lateral gaze directions. Voluntary movements were still very poor and there was marked axial hypotonia. An asymmetric tonic neck reflex persisted. Hypertonic extension of the upper limbs with wrist pronation occurred spontaneously and following external stimuli. Shoulder and elbow mobility was normal. Hand muscles were atrophic. The lower limbs were fixed in extension with the hips in abduction and external rotation. Knee extension was only slightly limited. Pes cavus with toe flexion contractures were present. Deep tendon reflexes were not elicitable.
253
culomegaly, slight diffuse myelination retardation, and local gyration abnormalities. The main feature was a large cortical dysplastic area in the right frontal, temporal, and parietal lobes. The cortex appeared thick with a smooth surface and a smooth interface between gray and white matter as hallmarks for pachygyria (Fig. 1a). In other areas, cortical thickening was less prominent; shallow sulci and a bumpy gray-white matter interface were characteristic of polymicrogyria (Fig. 1b). The white matter exhibited diffuse and moderately retarded myelination, as shown by prolonged T1 and T2 relaxation times, which was most conspicuous in the subcortical white matter, immediately underlying the abnormal cortex. Ventricular enlargement was moderate and diffuse. The corpus callosum was thin but complete and exhibited normal myelination. The cerebellum and the brainstem had a normal appearance (Fig. 1c). A second brain MRI at the age of 3 years showed similar abnormalities, but white matter changes were less prominent. Three-dimensional surface rendering techniques allowed recognition of a cobblestone pattern of the surface of the pachygyric cortex (Fig. 2). 2.3. Neuropathological studies A triceps surae muscle biopsy was performed at the age of
2.1. Blood and spinal fluid examination Serum creatine kinase levels never exceeded 486 IU/l (N , 170). Toxoplasma, enterovirus, herpes, rubella, and CMV serology was negative. Serum amino acid and lactate levels were normal and there was no organic aciduria. Spinal fluid lactate and protein were normal. 2.2. Neuroradiological examination Brain MRI at the age of 11 months showed mild ventri-
Fig. 2. Three-dimensional T1-weighted gradient-echo MR images at the age of 3 years. Asymmetry of the cortical surface of both cerebral hemispheres with cobblestone lissencephaly pattern on the right (arrowheads).
254
M.-Cl. Belpaire-Dethiou et al. / Neuromuscular Disorders 9 (1999) 251–256
Fig. 3. Triceps surae muscle biopsy, showing depletion and atrophy of muscle fibres and marked fibrosis (a; hematoxylin–eosin). Merosin (b), dystrophin (c), and a-sarcoglycan (d) immunoreactivity is normal. Bar = 50 mm.
14 months. Routine histological and histochemical stains on 10 mm transverse frozen sections included hematoxylin– eosin, modified Gomori trichrome, PAS, oil red O, NADH-TR, SDH, ATPase after preincubation at pH 9.4,
4.2, and 4.6, and cytochrome c oxydase staining. Immunohistochemical staining with spectrin, dystrophin, a-sarcoglycan (Novocastra), and 300 kDa fragment of merosin (Novocastra) antibodies was performed. Muscle tissue was
255
M.-Cl. Belpaire-Dethiou et al. / Neuromuscular Disorders 9 (1999) 251–256 Table 1 Results of nerve conduction studies at 10 months of age Sensory nerve
Stimulation site
L Median R Median L Ulnar
Wrist Wrist Wrist Elbow
2.7 (,3.3) 6.0
Motor nerve
Stimulation site
CMAP latency (ms)
CMAP amplitude (mV)
L Median
5.3 (,2.8) 9.3 8.4 (,2.8) 12.9
L Peroneus
Wrist Elbow Wrist Elbow Ankle Fibular head Internal malleolus
5.3
L Tibialis post.
180 (.2300) 120 210 (.2300) 170 Absent (extensor digitorum brevis) 600 (tibialis anterior) Absent
R Median
SNAP latency (ms)
SNAP amplitude (mV)
Sensory CV (m/s)
Absent Absent 5.0 (.10) 21 (.42) Motor CV (m/s) 17 (.37) 14 (.37)
SNAP, sensory nerve action potential; CMAP, compound muscle action potential; CV, conduction velocity; L, left; R, right.
largely replaced by fibrous and connective tissue (Fig. 3a). Remaining muscle fibres were often atrophic. Central nuclei were frequent. Muscle fibre necrosis was not observed. Oxydative enzyme staining patterns were normal. There was type II fibre predominance. Cytoskeletal sarcolemmal protein immunoreactivity was normal (Fig. 3b–d). An attempt to obtain sural nerve tissue was unsuccessful. 2.4. Neurophysiological examination Electrodiagnostic studies were performed at the age of 10 months (Table 1). The sensory nerve action potentials of the median and sural nerves were unobtainable. The amplitude of the ulnar sensory nerve action potential was reduced and the sensory nerve conduction velocity markedly slowed. The amplitude of the compound muscle action potentials was markedly diminished; no response was elicited from the peroneal and posterior tibial nerves on recording from foot muscles. Motor conduction velocities were very slow
also. Electromyography of proximal and distal upper and lower limb muscles did not show spontaneous activity. Motor unit action potentials were normal, but recruitment was reduced. 2.5. DNA analysis Haplotype analysis was conducted using microsatellite markers in the Fukuyama CMD candidate region. Initially, the patient and her mother were found to have the same haplotype as the Japanese Fukuyama CMD ancestral founder haplotype, i.e. markers 138–183–301 for D9S2105– D9S2107–D9S172, which is observed in 85% of the Japanese Fukuyama CMD patients. However, when studying the haplotype with the recently developed E6-J7 markers (190– 147), it was found to differ from the Fukuyama CMD founder haplotype. The 3 kb insertion, which is the founder mutation in 95% of the Japanese Fukuyama CMD patients, was not detected [7].
Table 2 Features of our patient as compared to those of the recognized CMD types
Onset before 12 months CMD Head circumference Mental retardation Seizures Eye abnormalities Ventricular dilatation Cobblestone cortex White matter lucency Cerebellar malformation Corpus callosum Brainstem hypoplasia Neuropathy
Patient
Merosin + CMD (pure CMD)
Merosin − CMD
Fukuyama CMD
Muscle-eye-brain disease
Walker–Warburg syndrome
+ + , −2 SD + + − Mild + + − Hypoplasia − +
+ + Variable − or mild − or mild − − − − − − − −
+ + Variable − or mild − or mild − − − + − − − +
+ + 0–2 SD + .50% − or mild Mild + +, regressive + Hypoplasia − (or +) −
+ + Variable + + + + + Mild ++ Hypoplasia + −
+ + .2 SD + + + + + Severe, persistent ++ Agenesis + −
256
M.-Cl. Belpaire-Dethiou et al. / Neuromuscular Disorders 9 (1999) 251–256
3. Discussion Our patient presents with CMD with progressive microcephaly, mental retardation, epilepsy, and sensorimotor demyelinating peripheral neuropathy. Brain MRI shows developmental abnormalities with pachygyria, micropolygyria, ventriculomegaly, mild retardation of myelination, and hypoplasia of the corpus callosum. Muscle biopsy shows replacement of muscle fibres by fibrous and adipose tissue, muscle fibre atrophy without necrosis, and normal merosin, dystrophin, and a-sarcoglycan immunohistochemistry. The clinical and laboratory findings do not correspond to those observed in ’pure’ CMD, merosin-deficient CMD, muscle-eye-brain disease, or Walker–Warburg syndrome (Table 2). Microcephaly, mental retardation, epilepsy, and the muscle biopsy and brain MRI findings are reminiscent of Fukuyama CMD [7,8]. Unlike patients with Fukuyama CMD, however, our patient does not present major contractures, exhibits upper motor neurone signs, has only mildly elevated serum creatine kinase levels, and shows evidence of a demyelinating peripheral neuropathy. Moreover, the mutation in the Fukuyama CMD gene commonly present in Japanese patients was not found in our patient [9]. Evidence of peripheral nerve demyelination is observed in merosin-negative occidental CMD [10]. Although cerebral white matter changes are characteristic of the latter disorder [1], there are no structural central nervous system defects and mild mental retardation and epilepsy are relatively rare findings [3]. Several merosin-positive CMD patients with severe brain involvement and cortical dysplasia without overt ocular abnormalities not conforming to the recognized CMD types have been reported [3,11]. Peripheral nerve involvement has been described by Leyten et al. [12] in two female siblings with merosin-positive CMD, spastic tetraplegia, contractures, lack of cognitive development, and microcephaly. Motor nerve conduction velocities were slow and sural nerve biopsy revealed absence of large myelinated nerve fibers. Neuropathological examination of the brain of one sibling, who died at the age of 30 months, showed subtotal depletion of neurones in the cerebral and cerebellar
cortex and in the ventral pons as well as secondary loss of myelin. These findings are different from CMD-associated cobblestone lissencephaly. In conclusion, this is the first report of a patient, presenting with merosin-positive CMD, cobblestone lissencephalylike MRI findings, and electrodiagnostic evidence of a demyelinating peripheral neuropathy. The molecular defect remains to be identified.
References [1] Dubowitz V, Fardeau M. Workshop report: proceedings of the 27th ENMC sponsored workshop on congenital muscular dystrophy. Neuromusc Disord 1995;5:253–258. [2] Hillaire D, Leclerc A, Faure S, et al. Localization of merosin-negative congenital muscular dystrophy to chromosome 6q2 by homozygosity mapping. Hum Mol Genet 1994;3:1657–1661. [3] Leyten QH, Gabree¨ls FJM, Renier WO, ter Laak HJ. Congenital muscular dystrophy: a review of the literature. Clin Neurol Neurosurg 1996;98:267–280. [4] Fukuyama Y, Osawa M, Suzuki H. Congenital progressive muscular dystrophy of the Fukuyama type: clinical, genetic and pathologic considerations. Brain Dev 1981;13:1–29. [5] Williams RS, Swisher CN, Jennings M, Ambler M, Caviness VS Jr. Cerebro-ocular dysgenesis (Walker–Warburg syndrome): neuropathologic and aetiologic analysis. Neurology 1984;34:1531–1541. [6] Santavuori P, Somer H, Sainio K, et al. Muscle-eye-brain disease (MEB). Brain Dev 1989;11:147–153. [7] Van der Knaap MS, Smit LME, Barth PG, et al. MRI in classification of congenital muscular dystrophies with brain abnormalities. Ann Neurol 1997;42:50–59. [8] Aida N. Fukuyama congenital muscular dystrophy: a neuroradiologic review. J Magn Reson Imag 1998;8:317–326. [9] Kobayashi K, Nakahori Y, Miyake M, et al. An ancient retrotransposal insertion causes Fukuyama-type congenital muscular dystrophy. Nature 1998;394:388–392. [10] Shorer Z, Philpot J, Muntoni F, Sewry C, Dubowitz V. Demyelinating peripheral neuropathy in merosin-deficient congenital muscular dystrophy. J Child Neurol 1995;10:472–475. [11] Dubowitz V. Workshop report: proceedings of the 50th ENMC sponsored workshop on congenital muscular dystrophy. Neuromusc Disord 1997;7:539–547. [12] Leyten QH, Barth PG, Gabree¨ls FJM, et al. Congenital muscular dystrophy and severe central nervous system atrophy in two siblings. Acta Neuropathol 1995;90:650–656.