Brain & Development 22 (2000) 132±134
Case report
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Congenital myotonic dystrophy: report of paternal transmission Yoko Tanaka a, Yasuyuki Suzuki a,*, Nobuyuki Shimozawa a, Eiji Nanba b, Naomi Kondo a a
Department of Pediatrics, Gifu University School of Medicine, Gifu 500-8705, Japan b Gene Research Center, Tottori University, Yonago 683-8503, Japan
Received 11 August 1999; received in revised form 10 November 1999; accepted 22 November 1999
Abstract A female neonate born to a healthy mother was hospitalized because of enlargement of the lateral ventricles, muscle weakness, irregular respiration, and poor sucking. Characteristic facial appearance such as high forehead and carp mouth were noted. The father had mild manifestations of adult type myotonic dystrophy, including muscle weakness of the extremities, percussion myotonia and atrophy of the facial muscles. PCR analysis and southern blot analysis revealed that CTG repeats in the myotonic dystrophy gene of the infant and the father were about 1000 and 400, respectively. This is a rare case showing paternally transmitted congenital myotonic dystrophy and seems to be the ®rst report describing a neonate. q 2000 Elsevier Science B.V. All rights reserved. Keywords: Congenital myotonic dystrophy; Paternal inheritance; CTG repeat; PCR analysis; Neonatal period
1. Introduction Myotonic dystrophy (DM, McKusick 160900) is an autosomal dominant disease characterized by ®ndings including muscle atrophy of the distal extremities and face, percussion myotonia, cataract, endocrine disorder, diabetes mellitus, decreased immunoglobulin levels, mental deterioration, and cardiac conduction disorder [1]. The DM gene is located on the long arm of chromosome 19 and encodes the mytonin protein kinase. Expansion of the trinucleotide CTG repeat in the 3 0 untranslated region of the DM gene is a common mutation in DM [2]. There is a correlation between expansion of the repeat and the severity of the disease, and anticipation is observed. Congenital myotonic dystrophy (CDM) is recognized by ¯oppiness of an infant during the neonatal period. CDM is almost exclusively transmitted from an asymptomatic mother with percussion myotonia. However, exceptional cases of paternally transmitted CDM have been reported [3±6]. The CTG repeat usually expands when a mutated DM gene is inherited from the mother. Decreased fertility of males with adult onset DM and contraction of the repeat upon male transmission [7] may contribute to the almost absent occurrence of paternal transmission of CDM. Here we report a neonatal patient with CDM whose mutated DM gene was transmitted from the father. * Corresponding author. Tel.: 181-58-265-1241 (ext. 2288); fax: 18158-265-9011. E-mail address:
[email protected] (Y. Suzuki)
Previously reported cases of paternally transmitted CDM are also discussed.
2. Case report This female infant was delivered by cesarian section at the 38th gestational week because of enlargement of the lateral ventricles on echography. Birth weight was 2500 gram and the Apgar score was 9/9 at 1/5 min. Parents were non-consanguineous. The mother was healthy and did not manifest percussion myotonia. Mild dilatation of the lateral ventricles was also identi®ed on brain MRI after birth (Fig. 1). Physical examination revealed general muscle hypotonia, shallow respiration, weak cry, decreased sucking re¯ex and characteristic facial appearance including carp mouth and high forehead. Routine laboratory examination did not detected any abnormality. Family history revealed that the father, 27 years of age and showing normal intelligence, had mild symptoms of adult type DM including muscle weakness of the extremities, percussion myotonia, and atrophy of the facial muscles, detected 1 year earlier. The infant required tube feeding for the ®rst several days and 30% oxygen for one month. However, the patient gradually acquired developmental milestones, and could smile at 5 months of age, control her head at 6 months, roll over at 9 months, sit and speak a few words at 1 year of age. Overall developmental quotient at 1 year of age was 80.
0387-7604/00/$ - see front matter q 2000 Elsevier Science B.V. All rights reserved. PII: S03 87-7604(99)0012 8-X
Y. Tanaka et al. / Brain & Development 22 (2000) 132±134
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Fig. 2. Southern blot analysis of CTG repeat of the DM gene. Lane 1, normal control subject. Lane 2, father. Lane 3, present patient. Father showed a band about 1.1 kb larger and the present patient showed a band about 3.1 kb larger, corresponding to about 400 and 1000 CTG repeats.
Fig. 1. T1-weighted cranial MRI image at 1 month of age. Dilatation of lateral ventricles was observed.
3. Molecular analysis DNA was extracted from peripheral white blood cells obtained from the patient and from the parents. Expansion of the CTG repeat in the DM gene was examined by the PCR method [8] and southern blot analysis of the DM gene. Both the patient and the father had mutated DM genes, but the mother was normal (Fig. 2). The CTG repeat of the patient was about 1000 and longer than that of the father (about 400).
4. Discussion Five reported cases of paternally transmitted CDM are
listed in Table 1. Of 11 children in these families, 6 had CDM, 3 had adult type DM, and 2 were asymptomatic. Six CDM cases manifested muscle weakness during the neonatal period, however, the present patient seems to be the ®rst case diagnosed during the neonatal period. Clinical manifestations in the 6 CDM cases were milder than those of maternally transmitted CDM. Only one patient needed arti®cial ventilation, walking started between 14 months of age and 8 years of age, and IQ levels ranged from 75 to under 40. In the present patient, gross motor development was delayed, but she can speak a few words, and the overall developmental quotient was 80 at 1 year of age. Of 5 fathers, 3 were asymptomatic when the ®rst child was born, and one had cataract. In the present family, the father had complained of muscle weakness beginning one year before this patient was born. Adult type DM was suspected by a neurophysician in another hospital, however, this history was not clari®ed until we asked the father. As the gene analysis of DM progresses, milder and atypical CDM cases will be diagnosed, and paternal transmission may be recognized more often than previously. Careful history taking is necessary.
Table 1 Reported cases of paternally transmitted CDM a Author Father Age at ®rst child (years) Symptoms (age, years) Children
CTG repeat
Ohya [3]
Nakagawa [4]
Bergoffen [5]
Die-Smulders [6]
Present case
36 Asympt.
28 Muscle weak (39) 15y F: CDM Walk 8y IQ , 40 10y F: DM IQ 55 Father , 15yF , 10yF
39 Cataract
? Muscle weak (30) 24y M: DM IQ 90 23y M: CDM Walk 18m 20y F: DM 24yM: ca.1000 23yM: ca.2000 20yF: ca.1000
27 Muscle weak (26) 1y F: CDM sit 1y word 1y
9y M: asympt. 6y M: CDM walk 21m 2y F: CDM walk 19m father , 9yM , 2yF , 6yM
24y F: asympt. 14y M: CDM art. vent. walk 14m IQ 50 father: ca.100 14yM: ca.1000
father: ca.400 1yF: ca.1000
a CDM, congenital myotonic dystrophy; DM, adult type myotonic dystrophy; M, male; F, female; y, year; m, month; asympt., asymptomatic; art. vent., arti®cial ventilation.
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Y. Tanaka et al. / Brain & Development 22 (2000) 132±134
The CTG repeat exclusively expands when the mutated allele is inherited from the mother, however, the expansion is milder or even shorter when the paternal repeat size is above several hundred copies [7]. Small pool PCR analyses of somatic and germline tissues from DM males revealed a bias of somatic tissues toward increasing allele length, suggesting that the reduction of CTG repeat size may be artifacts of somatic expansion in the parent [9]. There may be a negative selection operating on the sperm as the repeat size gets longer, and an early postzygotic instability may cause expansion of the repeat in fetal somatic tissues. However, 2 sperm samples showed a bias toward increasing size, concordant with the phenomenon of anticipation [9]. As shown in Table 1, 4 of 5 reported families with paternal CDM showed expansion of the CTG repeats in the progeny. Hypermethylation on the 5 0 side of the expanded CTG repeat in the DM gene was found in the mutated allele of maternally transmitted CDM [10], however, there have not been any such data on paternally transmitted CDM. Further analyses of germline and fetal somatic tissues are essential to clarify the molecular basis of paternally inherited CDM. References [1] McKusick VA. Mendelian Inheritance in Man. A Catalog of Human Genes and Genetic Disorders, 12th edn. Baltimore, MD: The Johns Hopkins University Press, 1998.
[2] Brook JD, McCurrach ME, Harley HG, Buckler AJ, Church D, Aburatani H, et al. Molecular basis of myotonic dystrophy: expansion of a trinucleotide (CTG) repeat at the 3-prime end of a transcript encoding a protein kinase family member. Cell 1992;68:799±808. [3] Ohya K, Tachi N, Chiba S, Sato T, Kon S, Kikuchi K, et al. Congenital myotonic dystrophy transmitted from an asymptomatic father with a DM-speci®c gene. Neurology 1994;44:1958±1960. [4] Nakagawa K, Yamada H, Higuchi I, Kaminishi Y, Miki T, Johnson T, et al. A case of paternally inherited congenital myotonic dystrophy. J Med Genet 1994;31:397±400. [5] Bergoffen J, Kant J, Sladky J, McDonald-McGinn D, Zackai EH, FischBeck KH. Paternal transmission of congenital myotonic dystrophy. J Med Genet 1994;31:518±520. [6] Die-Smulders CEM, Smeets HJM, Loots W, Anten HBM, Mirandolle JF, Geraedts JPM, et al. Paternal transmission of congenital myotonic dystrophy. J Med Genet 1997;34:930±933. [7] Ashizawa T, Dunne PW, Ward PA, Seltzer WK, Richards CS. Effects of the sex of myotonic dystrophy patients on the unstable triplet repeat in their offsprings. Neurology 1994;44:120±122. [8] Nanba E, Ito T, Kadowaki K, Makio A, Nakagawa M, Yamamoto T, et al. Prenatal diagnosis of congenital myotonic dystrophy in two Japanese families: direct mutation analysis by a non-radioisotope PCR method and haplotype analysis with ¯anking DNA markers. Brain Dev. 1996;18:122±126. [9] Monckton DG, Wong LJ, Ashizawa T, Caskey CT. Somatic mosaicism, germline expansions, germline reversions and intergenerational reductions in myotonic dystrophy males: small pool PCR analyses. Hum Mol Genet 1995;4:1±8. [10] Steinbach P, Glaser D, Vogel W, Wolf M, Schwemmle S. The DMPK gene of severely affected myotonic dystrophy patients is hypermethylated proximal to the largely expanded CTG repeat. Am J Hum Genet 1998;62:278±285.