Brain & Development 21 (1999) 274–278
Case report
Merosin-positive congenital muscular dystrophy in two siblings with cataract and slight mental retardation Umbertina C. Reed a ,*, Ana Maria C. Tsanaclis b, Mariz Vainzof a, Suely K. Marie a, Mary S. Carvalho a, Jaime Roizenblatt c, Christiane C. Pedreira a, Aron Diament a, Jose´ Antonio Levy a a
Department of Neurology, Clı´nicas Hospital, School of Medicine, The University of Sa˜o Paulo, Sa˜o Paulo, Brazil b Department of Pathology, School of Medicine, The University of Sa˜o Paulo, Sa˜o Paulo, Brazil c Department of Ophthalmology, Clı´nicas Hospital, School of Medicine, The University of Sa˜o Paulo, Sa˜o Paulo, Brazil Received 20 August 1998; received in revised form 19 November 1998; accepted 27 November 1998
Abstract We report on two siblings that have been followed for 14 years, with merosin-positive congenital muscular dystrophy (CMD), cataract, retinitis pigmentosa, dysversion of the optic disc, but no cerebral anomalies, except for microcephaly and slight mental retardation (MR). The younger child had three generalized seizures easily controlled by anticonvulsant therapy. Both children presented hypotonia from birth, delayed psychomotor development, generalized muscular weakness, and atrophy and joint contractures of knees and ankles. The course of the disease, apparently static during the first 10 years of life, became progressive during the second decade with loss of deambulation by the age of 13. Creatine kinase was increased in both children. Bilateral cataract was diagnosed at 6-months of age. In spite of the occurrence of microcephaly, MR was slight and the siblings acquired reading and writing skills after the aged 10. Head magnetic resonance imaging showed normal results in both siblings. The classification of these cases within the broad spectrum of CMD is difficult since most of the known muscle-eye-brain syndromes generally show severe MR and brain anomalies. We consider these cases as corresponding to the rarer syndromes of merosin-positive CMD with associated features such as cataract and MR that were particularly emphasized during the 50th ENMC International Workshop on CMD [Dubowitz V. Workshop report: 50th ENMC International workshop on congenital muscular dystrophy. Neuromusc Disord 1997;7:539–547]. Further genetic, pathological, neuroradiological, and immunocytochemical studies will be necessary for better elucidation of the classification and pathogenesis of CMD. 1999 Elsevier Science B.V. All rights reserved. Keywords: Merosin-positive congenital muscular dystrophy; Muscle-eye-brain syndromes; Cataract
The diagnosis of congenital muscular dystrophy (CMD) is applicable to a heterogeneous group of patients which, from birth present hypotonia, weakness and, occasionally, arthrogryposis, that at variable times develop joint contractures and may or may not manifest associated abnormalities of the eyes and of the central nervous system (CNS). Muscle biopsy is consistent with muscular dystrophy showing variability in the size of fibers and marked fibrosis. The type of inheritance is autosomal recessive [1], and very seldom autosomal dominant. We report on two siblings * Corresponding author. Fax: +55-11-3061-4036 or +55-11-842-2340; e-mail:
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with CMD, with ocular and CNS involvement whose manifestations differ from most known muscle-eye-brain syndromes, with typical severe ocular and cerebral anomalies, by presenting cataract, retinitis pigmentosa, dysversion of the optic disc, and no cerebral anomalies, except for microcephaly and a slight mental retardation (MR). During the 50th ENMC International Workshop on CMD [4] in 1997, it was suggested that it would be helpful to try and define individual clinical syndromes, particularly some of the rarer syndromes with associated features such as cataract and MR. The aim of this report is to present one rare CMD syndrome, that after a follow-up of 14 years, produced evidence of a progressive course and poor evolution.
1999 Elsevier Science B.V. All rights reserved.
U.C. Reed et al. / Brain & Development 21 (1999) 274–278
1. Case report We report on two siblings, an 18-year-old girl (patient 1) and a 16-year-old boy (patient 2) with non-consanguineous, healthy parents and a healthy younger brother. One maternal uncle had epilepsy and MR and a second cousin died at 6 months of age with cataract plus cardiac dysfunction of an unrevealed cause. Both the siblings were born at term after an uneventful pregnancy and had bilateral cataract observed at 6 months of age, and surgically removed at the age of 2 years. The older child also had an inferior tilted disk in the left eye; an ERG showed abnormal low amplitude recordings on both eyes. The younger child had hyperpigmented diffuse but irregular changes of the fundus and low or unrecordable amplitude ERG recordings. Hypotonia was already evident in the first month of life and their psychomotor development was delayed: Patient 1 walked without support at 24 months of age and patient 2 at 19 months of age. Patient 1 was 3-years old and patient 2 was 1-year old at the time of the first examination. Both the children were microcephalic and had high arched palates. The girl had delayed speech development and slight MR on psychosocial tests. Both patients had generalized muscular weakness and atrophy, the former more prominent in the proximal muscles. Deep tendon reflexes were absent and there was a beginning of contractures at the distal levels of the lower extremities. No cardiac abnormalities were found. Blood and urine chemistry was normal, except for moderately elevated levels of creatine kinase (CK): 356 U/L (4-fold increase) for patient 1 and 274 U/L (3-fold increase) for patient 2. Electroencephalography (EEG) showed unremarkable results and cranial computed tomography (CT scan) performed only in patient 1 was normal. Only patient 1 was submitted to electromyography (EMG) which demonstrated myopathic changes, and to muscle biopsy which was consistent with muscular dystrophy, showing variability of fiber size and marked fibrosis. The disease persisted with little disability and patient 2 manifested speech delay and slight MR, like his older sister. By the age of 9 years, both siblings had gradually developed marked contractures at many joints, but more severely so in the lower limbs (Fig. 1) and patient 2 had had three episodes of generalized seizures, easily controlled by the use of sodium valproate. A new EEG and a CT scan were performed in both the children and results were normal. EMG and muscle biopsy were repeated in patient 1. EMG confirmed the myopathic changes observed 6 years previously; no myotonic discharges were recorded; muscle biopsy showed diffuse pathological muscle, with conspicuous variation in fiber size, internal nuclei, some necrotic and hyaline fibers. Endomysial and perimysial connective tissue was abundant. With histochemical reactions there was preservation of fiber type distribution with no fiber type grouping, predominance of type 1 and scattered dark blue delicate accumulations in the periphery of the cell with a crescent shape on NADH TR.
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Both patients were unable to walk unsupported (Fig. 2) as from the age of 13 (patient 1) and from 14 years (patient 2) and developed cervico-thoracic kyphosis. At the present time they have visual acquity of 20/60 with lens correction. Head magnetic resonance imaging (MRI) was performed in both patients and confirmed the normal results already shown by CT scan. Lactate level was normal in blood and in CSF. From the age of 16 years, patient 1 complained of sudden episodes of tachycardia of variable duration and was referred to a new cardiac evaluation with EcoCG and Holter ECG that revealed only sinusal tachycardia; the girl is taking propranolol 40 mg daily. From the age of 13 years pes cavus in both children seemed to progress quickly with marked deformity; therefore, a new EMG was carried out
Fig. 1. Patients 1 and 2 at, respectively, 12 and 10 years of age. Note muscle atrophy and joint contractures.
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Fig. 2. Patients 1 and 2 at 18 and 16 years of age, already unable to walk unsupported.
in 1997, with nerve conduction velocity evaluation: again the EMG pattern was exclusively myogenic, without any record of electrical myotonia. CK levels were evaluated every 2 years and remained increased at least 3-fold above the upper normal limit. A muscle biopsy was obtained from patient 2 that revealed the same dystrophic aspect already verified in his sisters’ biopsy, without any type of structural abnormalities such as central cores and nemaline rods, fiber type disproportion, nor ragged-red fibers or rimmed vacuoles (Fig. 3); immunohistochemical analysis for dystrophin, a-sarcoglycan and merosin revealed a positive sarcolemmal labeling pattern. The teenagers were enrolled in a school for children with slight MR and after acquiring reading and writing skills, stopped school activities due to of social problems.
2. Discussion The diagnosis of CMD has been used for a heterogeneous group of infants who present congenital muscle disorder with variable degrees of severity, muscle biopsy with dys-
trophic changes, and an inconsistent association with ocular and/or CNS anomalies. The mode of inheritance is autosomal recessive, but the autosomal dominant type was verified in a few families [1]. Classification of CMD was greatly simplified by the discovery of gene location for the Fukuyama type of CMD [2] and of merosin (a-2 laminin) deficiency for one subtype of the classic or pure form of CMD [3]. Four types of CMD were recognised [1]: type I, without severe impairment of intellectual development, that includes subtypes IA and IB, the first with normal merosin expression and normal brain white matter and the second with deficient merosin status and brain white matter expression; type II, FCMD, with structural brain abnormalities and MR; type III, the Finnish type of ‘muscle-eye-brain’ syndrome, with MR, and eye and structural brain abnormalities; type IV, the Walker–Warburg syndrome, with MR, retinal abnormalities and severe cobblestone lissencephaly. Particularly within the merosinpositive subgroup there are some apparently specific clinical phenotypes that might be better defined in order to identify possible new genetically and biochemically distinct subtypes [4]. Recently Moghadaszadeh et al. [5] described a
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Fig. 3. Muscle biopsy of patient 2. (A) H and E, ×200 showing marked variation in fiber size and fibrosis (B) Laminin a2 immunohistochemistry using the monoclonal Mer3/22B2 antibody against the N-terminal region (kindly provided by Dr. LVB Anderson); (C and D) Double reaction for dystrophin (Nterminal antibody 303-8, kindly provided by Dr. Jeff Chamberain) and C-terminal region of laminin a2 (Gibco), respectively.
new locus, on chromosome 1p35-36, for a subgroup of merosin-positive CMD patients with early rigidity of the spine. Despite the cerebral and ocular involvement, our patients do not fit into the Fukuyama type of CMD (FCMD) [6], nor into the muscle-eye-brain syndromes [7,8], since in all these disorders the patients have severe MR; also neuroimaging methods show many different aspects of developmental malformative cerebral defects, and ophthalmological findings comprise various types of congenital eye abnormalities commonly associated in the same patient. Apart from the muscle–eye–brain syndromes, the presence of cataract in other types of CMD as in our patients is exceptional. Recently, during the 50th ENMC International Workshop on CMD [4], Professor Michel Fardeau and Professor Carlo P. Trevisan considered that a minor or benign form of Walker–Warburg syndrome could occur in merosin-positive patients, one showing marked mental and sensory disturbances (microphthalmia, myopia, and deafness), the other three presenting with altered visual evoked potential and ERG, normal ophthalmological examination and cerebellar hypoplasia. The youngest of our siblings also had retinal abnormalities but no cerebellar change. During the same workshop [4], Professor Haluk Topaloglu mentioned two families of CMD merosin-positive patients with MR plus cataracts but normal cranial MRI, corresponding exactly to our patients; however, we could not find the correspondent register in the literature. The same author had previously reported a clinically similar case but with MRI changes represented by prominent cerebellar and vermian hypoplasia [9]. We regarded the report on our cases opportune, not only because there is a long, detailed follow-up,
but also because, the conclusions/future strategy of the 50th ENMC International Workshop on CMD [4], among other items, emphasized that it would be helpful to recognize individual homogeneous clinical syndromes, particularly with associated features such as cataract and MR. There were both of these associated features in our cases and, in spite of the absence of neuroimaging changes, the evolution could be considered poor, showing a progressive course. Cataract in combination with congenital muscular diseases may also be observed in some mitochondrial myopathies with cardiac involvement [10,11], with adrenal insufficiency [12] and in MELAS [13]. As a first cousin of our patients had died at 6 months of age with cataract and cardiac trouble of unknown origin, the siblings were cardiologically evaluated, and blood and CSF lactate levels were normal. The sinusal tachycardia developed by patient 1 when she was 16 years old was not dependent on myocardiac involvement, because a complete cardiac evaluation proved normal. In some cases of the rare Marinesco– Sjo¨gren syndrome, the muscle pathology consists of dystrophic aspects [14]; however, despite the presence of cataract and MR, this diagnosis was not considered in our patients due to the absolute lack of any cerebellar symptom or sign and correspondent neuroimaging changes. We did not consider the possibility of congenital myotonic dystrophy [15] because, in this condition, cataracts are observed only at the end of the first decade of life and electrical myotonia, seldom found during the first year of life, is always recorded on EMG over the age of 5; in throughout the last 15 years the siblings’ mother did not manifest any complaint of muscular weakness or visual abnormality.
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In conclusion, our two siblings well demonstrate the clinical heterogeneity of merosin-positive CMD and the difficulty in establishing adequate clinical classification. Further pathological, genetic, biochemical, and neuroradiological studies are indispensable to define the correlation between muscle, eye, and brain involvement and, while we are waiting for conclusive findings in the genetic molecular area, all patients with any form of CMD must submit to better-documented follow-up by means of MRI, to detect white matter alterations and cortical dysgenesis and an adequate immunocytochemical study with antibodies against laminin subunits. A complete ophthalmological and psychological evaluation is also necessary for all children with any form of CMD.
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