Eur J Pediatr (1990) 150:132-135

European Journal of

Pediatrics

9 Springer-Verlag1990

Severe neonatal asphyxia due to X-linked centronuclear myopathy S. E. Braga 1, A . Gerber a, C. Meier 3, A . Weiersm/iller 4, A . Z i m m e r m a n n 5, U . Herrmann 4, S. Liechti 1, and H . M o s e r 1 Departments of 1Paediatrics, Medical Genetics Unit, 2paediatrics, Intensive Care Unit, 3Neurology, 4Obstetrics & Gynaecology, 5Institute of Pathology, University of Bern, CH-3010 Inselspital-Bern, Switzerland Received December 13, 1989 / Accepted May 4, 1990

Abstract. Severe neonatal centronuclear myopathy is inherited as an X-linked condition characterized by primary asphyxia, extreme muscular hypotonia and absent spontaneous movements. We report seven cases from three families to point out the importance of diagnosis with regard to prognosis, outcome and genetic counselring. In hypotonic diseases, analysis of cerebrospinal fluid, electromyography, nerve conduction velocity creatine kinase and a skin biopsy for fibroblast cultures for metabolic investigations are usually carried out. Needle muscle biopsy is an additional valuable investigation to establish diagnosis. In all our patients we found an increased number of centrally located nuclei with perinuclear halos confirming the diagnosis of centronuclear myopathy. The diagnosis of this disorder will become of greater importance as soon as carrier detection and prenatal diagnosis by D N A - t e c h n o l o g y are routinely available.

neonatal asphyxia and generalized muscular weakness (floppy baby). Differential diagnosis has been discussed by Dubowitz [5]. The outcome of X-linked centronuclear myopathy is always fatal in contrast to other conditions where the babies are extremely hypotonic as in congenital myotonic dystrophy. In order to obtain relevant information for prognosis and later genetic counselling, early and precise diagnosis of X-linked centronuclear myopathy is of crucial importance. In this communication we draw attention to the prenatal onset and the rapid progression of the disorder. We demonstrate that needle biopsy of muscle provides a powerful tool for early diagnosis.

Case reports The striking similarities of pregnancy histories and postnatal clinical findings of our seven patients with X-linked centronuclear myopathy are summarized in Table 1.

Key words: Centronuclear myopathy - X-linked - Muscle needle biopsy Table 1. Clinical findings in patients with x-linked centronuclear myopathy

Introduction Centronuclear myopathies are a heterogeneous group of muscle diseases with a large variation of clinical manifestations concerning age of onset, clinical course and prognosis. They are histologically defined by hypothrophy of muscle fibres with large centrally located nuclei. Sporadic and familial cases with all three Mendelian modes of inheritance have been documented. According to Barth et al. [2] the X-linked inherited congenital form is a distinct entity with prenatal onset and extremely poor prognosis. With the exception of two instances reported by Wijngarden et al. [10] and Hanefeld [6] all patients died within the first months of life. In a review, Bucher et al. [4] pointed out the importance of precise diagnosis in newborn boys with severe Offprint requests to." S. E. Braga

Patient

1

2

3

4

Polyhydramnios Reduced fetal movements Prematurity Neonatal asphyxia Muscularhypotonia Birth weight --<10percentile Birth length ~>90 percentile Head circumference -->90 percentile Spontaneous movement absent reflexes weak cry high-arched palate contractures cryptorchidism male sex Survival (days)

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Fig, 1. Pedigree of first family with patients 1-4 (V47, V48, V49 and V53) (V/21 and 22 were stillborn twins; 26th week of pregnancy)

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$ Fig. 2. Pedigree of second family with patients 5 and 6, children of III4

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Family I

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The three mothers of patients 1-4 are sisters, patient 1 & 2 (V47 & V48) are brothers.

Family 2

(Fig. 2)

Patients 5 and 6 are brothers. In previous generations nine males died perinatally from asphyxia. The pedigree is consistent with a X-linked pattern of inheritance. Patient 7 was the first child of a healthy unrelated couple with a negative family history regarding perinatal death.

Laboratory investigations

Laboratory investigations on blood parameters and biochemistry including creatine kinase were normal in all cases. Bacteriology, virology, amino acids as well as screening for lysosomal defects

were normal. No abnormalities were found in E E G and skull CT. X-ray films showed very thin ribs. The karyotype was 46,XY in all babies.

Muscle histology

Tissue of several muscles has been investigated. In patients 5, 6 and 7 a muscle biopsy with a Bergstr6m needle was taken fi'om the quadriceps femoris muscle and in all other patients with exception of patient 1 muscle samples were taken during autopsy and investigated histochemically and by light and electron microscopy. Samples were taken from different sites: m. sternocleidomastoideus, m. subscapularis, mm. intercostales, m. psoas, m. quadriceps femoris, m. triceps surae, m. rectus abdominis as well as muscle fibres from palate, tongue, diaphragm and diaphragma pelvis. In all muscle samples the number of centrally located nuclei was increased to various degrees (20%-60%) according to site as is known from the literature [1, 9] (Fig. 3). In electromicroscopic preparations destruction of myofibrils were noted (Fig. 4).

134

Fig. 3. (Patient 5) Muscle biopsy: light microscopy with centrally located nuclei, s e e a r r o w s . HE • 160, eryostat section Fig. 4. Electron microscopy: centrally located nucleus with destroyed myofibrils, s e e a s t e r i s k . (bar = 10 g), cryostat section Fig. 5. Cross-section of biopsy from a carrier mother of patients 1 and 2: Showing fibre size variation and centrally located nuclei. HE • 63, cryostat section

135

Muscle histology in carriers Muscle biopsy from the m. quadriceps femoris taken with a Bergstr6m needle of the obligate carrier IV14 from family 1 showed abnormal muscle fibres with 2-3 fold increased diameters and centrally nuclei in about 10% of the fibres (Fig. 5). The biopsy sample of her unmarried sister IV17 was histologically and histochemically normal.

Discussion The clinical findings and fatal course of the congenital type of centronuclear myopathy are remarkably constant. The X-linked mode of inheritance has been established by several authors [2-4]. Signs that should arise the paediatrician's suspicion of this condition are: severe muscular hypotonia, absent or very scarce spontaneous movements in a primary asphyctic male newborn, especially when polyhydramnios and lack of fetal movements are noted prenatally. Respiratory distress and muscular weakness with hypotonia may be present in a number of congenital neuromuscular disorders. Differential diagnosis includes congenital myotonic dystrophy, infantile spinal muscular atrophy, congenital muscular dystrophy, certain myopathies with structural abnormalities and several metabolic myopathies. To exclude a myotonic dystrophy a careful family history and clinical examination of the mother are necessary. Muscular fasciculations are found in babies with spinal muscular atrophy but not in boys with X-linked centronuclear myopathy. Newborns with congenital muscular dystrophy often show arthrogryposis-like contractures. Morphological changes of muscle tissue found in metabolic disorders and myopathies with structural abnormalities such as nemaline myopathy and central core disease are distinct from the findings in X-linked centromuscular myopathy and the clinical course is much less severe. A family history with one or several boys who died shortly after birth from severe asphyxia may furnish an additional clue. From our own experience and reports from the literature [4] this disease is probably much more frequent than previously thought. Diagnosis may well be missed because of the severe asphyxia with resuscitation having priority over diagnostic procedures. Therefore diagnosis should be stressed in order to obtain early and precise information with regard to prognosis and later genetic counselling of the family, as 50% of the sons of carrier mothers will be affected and 50% of the daughters will be healthy carriers. We show that the needle muscle biopsy is a powerful method to achieve early and precise diagnosis of this disorder. The biopsy by Bergstr/3m needle [7] with a diameter of 4 mm can already be carried out in newborns. The technique is an easy, fast and safe method in skilled hands. Local anaesthesia is usually sufficient although general anaesthesia may be considered in an already intubated baby. A previous test of blood coagulation is indispensable. If laboratory facilities are available the re-

sult of histological and histochemical investigations from fresh frozen samples can be obtained within hours. If biopsy is not feasible before death occurs, a careful investigation of different muscles is required at autopsy. These investigations are not only important in cases where an X-linked inheritance is suspected by family history but also in sporadic cases. Diagnosis has surely been missed in a number of cases and new mutations are probably much more frequent than previously thought [3]. Needle biopsy to establish the carrier state in female relatives is only reliable in cases where the muscle histology is pathological. Several investigators have found normal histology in genetically proven carriers [2, 4, 8], which is expected according to the large variation of X-inactivation in myoblast-precursor cells. Recently the gene for the X-linked congenital centronuclear myopathy has been mapped to Xq28 by Williams et al. [11]. Preliminary results from our own DNAlinkage studies show close linkage to 4 markers in the Xq28 region and are awaiting confirmation.

Acknowledgments. This work has been supported by the Swiss National Science Foundation, grant no. 3.845-0.86 and the Swiss Foundation for Research in Muscle Disease. We thank Mrs. T. Lauterburg and Mrs. U. Walker for excellent technical assistance.

References 1. Ambler MW, Neave C, Singer DB (1964) X-linked recessive myotubular myopathy: II. Muscle morphology and human myogenesis. Hum Pathol 15:1107-1120 2. Barth PG, Vijngaarden GK van, Bethlem J (1975) X-linked myotubular myopathy with fetal neonatal asphyxia. Neurology 25 : 531-536 3. Bruyland M, Liebaers I, Sacre L, Vandeplas Y, De Meirleir L, Martin JJ (1984) Neonatal myotubular myopathy with a probable X-linked inheritance: observations on a new family with a review of the literature. J Neuro1231:220-222 4. Bucher HU, Boltshauser E, Briner J, Gnehm HE, Jancer RC (1986) Severe neonatal centronuclear (myotubular) myopathy: an X-linked recessive disorder. Helv Paediatr Acta 41:291300 5. Dubowitz V (1978) Muscle disorders in childhood. WB Saunders Company Ltd, London, pp 223-231 6. Hanefeld F (1986) Neuromuskul~ireErkrankungen als Ursache neonataler Atemst/3rungen. In: Moderne Intensivmedizin bei Kindern. Zuckschwerdt, Mtinchen 7. Heckmatt JZ, Moosa A, Hutson C, Maunder-Sewry CA, Dubowitz V (1984) Diagnostic needle muscle biopsy. Arch Dis Child 59 : 528-532 8. Keppen LD, Hussian M, Woody B (1986) X-linked myotubular myopathy with intrafamilial variability and normal muscle biopsy in a definite female carrier. Am J Med Genet 25 : 723724 9. Silver MM, Gilbert JJ, Steward S, Brabyn D, Jung J (1986) Morphologic and myometric analysis of muscle in X-linked myotubular myopathy. Hum Pathol 17:1167-1178 10. Wijngarden GK, Fleury P, Bethlem J, Meijer AEFH (1969) Familial "myotubular" myopathy. Neurology 19 : 901-908 11. Williams H, Sarafarazi M, Roberts K, Thomas NST, Cole G, Liechti-Gallati S, Harper PS (1987) X-linked myotubular myopathy (XLMTM): another muscle disease gene localized to Xq28 (Abstract). Am J Hum Genet 41 :All0