- Email: [email protected]
X-linked myotubular myopathy — A long-term follow-up study
European
Journal
ORIGINAL
of Paediatric
Neurology
1998;
1: 49-56
ARTICLE
X-Linked follow-up
myotubular study
PETER C BARTH’, ‘Departments
VICTOR
of Paediatrics
‘Department
of Paediatrics
and and
myopathy
- A long-term
DUBOWITZ2 Neurology, Neonatal
Emma Medicine,
Children’s
HospitaVAMC,
Hammersmith
University
Hospital,
London,
of Amsterdam,
The
Netherlands;
UK
X-Linked myotubular myopathy is a well delineated congenital myopathy, with a high neonatal and early childhood mortality. Only a single gene, mapping to Xq28 has been implicated and has recently been characterized. Phenotypic variability, both interand intrafamilial, has been recorded. Its severest expression is a uniform disease with polyhydramnios due to prenatal (neuromuscular) swallowing disorder, and partial inability to expand the lungs postnatally leading to early postnatal death in all. The mildest expression appears to be represented by the first family reported in the literature in which intrafamilial phenotypic variability was marked. There was neonatal asphyxia, but recovery took place in most affected patients and very mild expression permitting normal life into adulthood has been found in two patients. A long-term follow-up is given on both these families. Results emphasize the importance of the family history when trying to prognosticate in an individual case. Keywords
X-Linked
myotubular
myopathy.
Congenital
myopathy.
Introduction Myotubular myopathy is a congenital myopathy in which the muscle fibres postnatally resemble the fetal myotube stage. Autosomal recessive, autosomal dominant and X-linked inheritance have been described. The different phenotypes have been reviewed recently. The best studied and probably most common representative is X-linked myotubular myopathy (McKusick *310400) which X-linked links to Xq28. The newborn with myotubular myopathy usually presents with severe muscle hypotonia, weakness, and difficulty in starting breathing. Mechanical ventilation for a shorter or longer period may be necessary. Mechanical ventilation may overcome alveolar collapse and viscosity, while allowing the patient to take over the job of tidal expansion. In some families, however, even prolonged artificial
Received
5.12.97.
Correspondence:
Accepted 13.1.98. Dr PC Barth, Department
of Paediatrics,
Emma Children’s
ventilation does not help the patient to take over breathing, and after shorter or longer tune the fruitless effort has to be terminated. In some families antenatal impairment of swallowing causes polyhydramnios. Contractures may be present. Whilst muscle function often improves postnatally, mortality in infancy and childhood remains high, mainly as a result of bulbar muscle insufficiency or nocturnal hypoventilation. Some patients survive into adulthood with variable degrees of handicap. Because of the divergence in functional prognosis and life expectancy, outcome is often difficult to predict in the individual case. There appears to be both inter-’ and intrafamilial variability. Two early Dutch studies,rJ representing the first and third reports in the literature on the disease, provided evidence of such variability, with rare neonatal mortality in the first family and 100% neonatal mortality in the latter. Long-term clinical follow-up data on both these families are
HospitaVAMC,
University
of Amsterdam,
PO Box 22700,
1100
DE Amsterdam,
The Netherlands 1090-3798/98/010049+8
$18.00
0 1998
European
Paediatric
Neurology
Society
Original
50 presented with the object of presenting the phenotypical extremes of the disease spectrum.
article: PG Barth,
V Dubowitz
I
II
Materials
and methods
Patient data from the X-linked myotubular myopathy-families described by van Wijngaarden et al. (1969)’ and by Barth et al. (1975)* were reviewed for comparison. Patient data were updated by interviews and personal examination.
Results _. __~. Family 7 The pedigree is given in Fig. 1. Patients have been described in a previous report1 History and essential clinical findings are summarized in Table 1. Follow-up on three patients after the previous report is presented here.
Subject
l-l/,
1
This male was born at term after an uneventful pregnancy. He was blue and weak immediately after delivery, but recovered without mechanical ventilation. He was initially very weak, but could sit and stand without support at 2 years. When reviewed at 33 years of age he was an administrator who could adequately manage his everyday life. Examination revealed subtotal external ophthalmoplegia without ptosis, mild facial weakness, retained strength in his masticator-y muscles and moderate paresis of his neck flexors. He had moderate involvement of the musculature of shoulders and pelvic girdle. He rose from his chair with a Gowers’ mameuvre, but could walk some distance without help. His first biopsy (quadriceps muscle) was taken as part of an investigation of his whole family at 33 years. It revealed two muscle fibre populations - one small and one large calibre: the smallest were type I with the characteristics of ‘myotubes’, the larger population had many internal nuclei in cross-section. Subsequently the subject developed cataracts for which he was successfully operated at the age of 39. Progressive involvement of his neuromuscular illness led to contract-m-es of his masticatory muscles with insufficient opening of his mouth. Strength in shoulder and pelvic musculature was severely reduced. Progressive loss of ventilatory capacity led to tracheostomy at the age of 47
III
Fig.
q
Suspected
3 by history
w
Histological
confirmation
1.
Pedigree
of family
4
1
with
5
6
X-linked
7
6
myotubular
myopathy.
followed by nocturnal ventilator assistance. He died at the age of 50. A repeat biopsy taken from his left brachial muscle revealed that most of the biopsy consisted of fat. Muscle fibres were almost uniformly type I with extreme variation in diameter. Besides some small sized fibres with the characteristics of myotubes, all larger fibres contained internal nuclei, often arranged in chains on longitudinal section. Some fibres had the additional aspect of ragged red fibres. In comparison with the first biopsy at the age of 33, fatty replacement was more prominent. Other characteristics were similar with the exception of additional ragged red fibres.
Subject
l-l/l,
4
This male was born at full term. He was cyanotic at birth and had some difficulty in establishing independent breathing, but did well subsequently. He could walk independently at 16 months. When seen at 5 years he displayed extraocular paresis, ptosis, moderate facial palsy, neck flexor weakness, and mild weakness of his upper extremities but otherwise had normal power at 5 years. A quadriceps muscle biopsy at the time revealed scattered small ‘myotubes’, mostly type I, intermingled with normal sized muscle fibres which often had internal nuclei. He was seen again by one of us (VD) at the age of 33 years. At the time his only complaint related to his muscles was stiffness of his back musculature, which dated back to his mid-20s. He was not allowed to play rugby in childhood because of the poor control of his neck muscles, but excelled at other sports such as tennis and golf and was also a keen swimmer. He had led an active adult life and had been able to participate in competitive tennis at county level, and also played competitive golf. On examination, the only significant weakness was of the neck flexors and extensors. He had mild limitation of eye closure, limited upward gaze and limited
Original
article:
X-Linked
Table 1
Family 1: Follow-up
myotubular
myopathy
51
Pedigree no.
Neonatal period and early childhood
l-II, 1
Neonatal asphyxia; 33 years: Extraocular paresis, unsupported walking at difficulty in rising from sitting 2 years position; waddling gait Neonatal asphyxia; never able Only anamnesticdata from family to sit unsupported
l-11,2
l-11,6
Neonatal asphyxia; unsupported walking at 4 years
l-II, 9
Neonatal asphyxia; died a few hours old Neonatal asphyxia
l-III, 3
l-111,4
Neonatal asphyxia; unsupported walking at 16 months Neonatal asphyxia; died from sequelaeof meconium aspiration at 18 days Neonatal asphyxia; rising to stand at 11 months, walked in 2nd year
I-III, 5
I-III, 6
Age at first investigation
26 years: Extraocular paresis,able to rise from sitting position with Gowers’ manmuvre
22 months: Extraocular paresis, ptosis, severe genera1paresis, able to rise to sit 5 years: Extraocular and neckflexor paresis,ptosis, facial palsy, mild paresis,otherwise normal power
I-III,
Died at 50 years from progressive respiratory insufficiency Died at 5 years; unable to move eyes, genera1weakness,died from pneumonia At 54 years; anamnesticdata: resident in institute for mentally handicapped; motor condition unchanged
30 years; anamnesticdata: able to rise with Gowers’ manceuvre, still able to walk unsupported 33 years: seetext
7 years: Extraocular and neckflexor 30 years: mild myopathic paresis,hypotrophic musculature, changesnot interfering with otherwise normal normal daily life; seetext.
horizontal movements on both sides. He had some degree of spinal rigidity, with limited flexion, possibly related to shortening of the paravertebral muscles.
Subject
Follow-up
ptosis, mild facial paresis, mild (grade 4) paresis of his neck flexors, and underdevelopment of his shoulder muscles, especially the pectoral muscles, with a flattened thorax. Otherwise his muscles were well developed and strong (Fig. 3a-c).
6
This male was born at full term, had difficulty in establishing unsupported breathing but did well subsequently. He could rise to stand at 11 months and achieved independent walking in his second year. When seen at 7 years he displayed extraocular and neck flexor paresis, had generally hypotrophic musculature, but had normal power in all muscle groups and could keep up physically with children of his age. A quadriceps biopsy at 19 months showed scattered small type I ‘myotubes’ between normal and larger sized normally structured fibres of either type (Fig. 2a,b). He was seen again by one of us (PGB) at the age of 30 years. He had a normal life as a factory owner. He had only very mild complaints, such as difficulty to keep an arm outstretched for some time. On examination he had total ophthalmoparesis without
Family 2 The pedigree is given in Fig. 4. Patients were described in 1975.’ All pregnancies were characterized by polyhydramnios due to impairment of fetal swallowing and all the infants were severely asphyxiated at birth, and were unable to expand their lungs without help. This report essentially describes the situation before prolonged mechanical ventilation became routine in neonatal intensive care. Of these patients one reached the age of 2 weeks, one reached the age of 2 days and the others died within the first 24 hours. One patient (2-V, 38) born after the report was published is reported here in more detail.
Original
52
(a)
article: PG Barth, V Dubowitz
briefly breathed spontaneously with the tracheal tube in situ, but he could not maintain adequate gaseous exchange. He died on the 19th day of life from progressive respiratory and circulatory failure. A muscle biopsy from the quadriceps femoris muscle was taken on the 7th day of life. It showed that 90% of the muscle fibres consisted of ‘myotubes’ with both fibre types affected, confirming the diagnosis of myotubular myopathy. After this experience a policy was adopted for handling further cases in this family. Male infants who were born with the typical symptoms would be intubated and kept on the ventilator pending confirmation of the diagnosis by muscle biopsy. Upon confirmation of the diagnosis the parents would be informed about the poor prognosis and with their consent artificial respiration would be ended allowing the infant to die. Sedatives would be given to treat a possible subjective sense of dyspnoea. This course was taken in a subsequent case (2-VI, 2) who survived 2 days.
Discussion
(b) Fig. 2. Muscle biopsy (quadriceps muscle) from patient l-111, 6, taken at the age of, 19 months. (a) Transverse section stained for myosin adenosine triphosphate 9.4pH, shows small sized fibres belonging to type I with a central area devoid of myofibrils (empty looking). Other fibres belong two either type I or type II, with type I fibres smaller in sized than type II (x 220). (b) Transverse section stained for nicotinamide adenine dinucleotide oxidoreductase. Small type I fibres show highly concentrated mitochondrial activity in the central parts of the fibres, roughly corresponding to the empty areas in Fig. 2a (x352).
Subject
P-V, 38
This male patient was born at 37 weeks gestational age. The mother had polyhydramnios (5 l&es). Birthweight was 1970 g, length 48cm, frontooccipital circumference 34.8 cm. He was very weak and hypotonic, with only small distal movements, breathed poorly and had to be intubated and mechanically ventilated to provide adequate gas exchange. A thoracic radiogram showed hypoplastic ribs. After 1 week of ventilation he was able to maintain adequate respiration with the tracheal tube in situ. However, on changing the tube his condition immediately deteriorated, because of inability to swallow his secretions. At 15 days he
The X-linked type of myotubular myopathy is the best known, probably the most prevalent of the three.3 It is also the only form of which the underlying gene defect has been identified.4 Myotubes represent a stage In myogenesis which lasts from 8 to 15 weeks in the human fetus. Essentially, they are syncitial structures derived from the fusion of still earlier progenitor cells, the mononuclear myoblasts. Their microscopic appearance is a chain of muscle nuclei surrounded by sarcoplasm and organelles. Wedged in between the central sarcoplasm and the sarcolemma is a rim of developing myofibrils. The name ‘myotubes’ derives from an empty tube-like appearance in longitudinal paraffin sections. Abundant myotube-like fibres in the muscle biopsy of a newborn past 20 weeks of gestational age are the hallmark of myotubular myopathies, but are also common in newborns with congenital myotonic dystrophy,46 from which the condition has to be differentiated. The usual clinical presentation of X-linked myotubular myopathy in a newborn is with severe neonatal respiratory impairment due to muscular weakness, often necessitating mechanical ventilation for some time. Survival past the neonatal period occurs, often with improvement of muscle function. Generalized muscle weakness usually includes insufficiency of bulbar and extraocular muscles.‘*s Childhood morbidity and mortality are high. In
Original
article:
X-Linked
myotubular
(a)
myopathy
(b)
Fig .3. F‘atient 1-111, 6 at the age of 30 years. (a) Minimal facial paresis with diminished upturning of the corners of Ithe mo uth wt lile smiling. Slightly divergent eyes due to extraocular pareses. (b) Underdevelopment of the pectoralis muscles. (cl COImplete normal function of the pelvic and leg muscles is demonstrated while attempting to keep balance in a squatti ing pos Ation.
Original
54
El Suspected n Histological
Fig. 4.
Pedigree
of family
2 with
one study compiled clinical findings and survival rates from 81 previously reported case histories, including the families reported here were brought together.g All patients presented with severe neonatal symptoms, including 30% who had prenatal symptoms, i.e. polyhydramnios due to impaired fetal swallowing. Of 81 on whom data were available, 73 had died. Ages reached were O-l months in 82%, 1-12 months in lo%, l-9 years in 7% and lo-29 years in 1%. Clinical experience and muscle pathology in family 2 was uniform. All pregnancies of affected males resulted in polyhydramnios during the latter half of pregnancy. They were born at or near term. None survived the immediate neonatal period without respiratory support. Prompt mechanical ventilation was instituted and prolonged for 19 days in one patient (2-V, 38) without development of adequate independent ventilation. Another affected boy born subsequently in the same family (2-VI, 2) was kept alive on the respirator pending diagnosis by muscle biopsy. After confirmation of the diagnosis, consensus was reached with the parents to withhold further mechanical ventilation while giving sedation to
X-linked
myotubulsr
article:
PG Barth,
V Dubowitz
by history confirmation
myopathy.
alleviate possible sense of dyspnoea and discomfort, which was followed by death within hours. Because of the 100% mortality present policy in this family is aimed at determination of carrier status of the mother, possibly before pregnancy, gender determination of the fetus, and in the case of male pregnancy mutation analysis, making use of recent developments4 With respect to family 1 the situation is more complex. Early death (l-11, 9 and l-III, 5), death from pulmonary complications in childhood (l-11, 2), recovery with limited ambulation (l-11, 1, l-11, 6, l-III, 3), partial recovery followed by progressive paresis (l-II, 1) and nearby complete recovery with persistent extraocular and neck-muscle weakness (l-III, 4, l-III, 6) have all been documented. The biological basis for the phenotypic diversity within this family is still not clearly understood. With respect to muscle biopsies, neonatal biopsies in the two families are strikingly similar, with a majority of the fibres in transverse section carrying an area devoid of myofibrils. Fibre diameter variation is slightly in excess with normal structured fibres on the average slightly larger than the ‘myotubes’. Older patients with X-linked
Original
article:
X-Linked
myotubular
myopathy
myotubular myopathy including adults were biopsied in family 1. If the biopsies from affected males within that family are sorted according to age a peculiar picture arises. Childhood biopsies show fibre size disparity with persistent mainly type I and normally ‘myotubes’ structured fibres being mainly type II. Patient lIII, 6 whose biopsy was taken at 19 months is given as example (Fig. 2a, b). In adult biopsies a strikingly different pattern occurred, with a tendency to form parallel nuclear chains within muscle fibres. Figure 5 representing a biopsy taken at 26 years from patient l-11, 6 shows multiple internal nuclei in transversely sectioned muscle cells, and no small fibres with a central ‘empty region’. It is unclear how such larger multinucleated muscle cells arise later in life. One possibility is that such large fibres arise by fusion of muscle cells, in which case peripherally located nuclei become internalized. The presence of such nuclei alongside a ‘cleft’ within the muscle fibre, shown in Fig. 5 supports such an assumption. Nuclei in fetal myotubes migrate outward to take their subsarcolemmal position. Semithin sections of muscle from patients with X-linked myotubular myopathy show fibres that are apparently in a transitional stage as shown in Fig. 6 taken from a neonate with the severe type of X-linked myotubular myopathy. The index case, 2V,15, from that family, suggest that this also takes place in ‘myotubes’ from X-linked myotubular myopathy, where one can see nuclei apparently in the progress of migrating externally (arrows). It cannot be excluded that the reduction of numbers of ‘myotubes’ seen in older patients is related to such delayed ‘maturation’.
1
Fig. 5. Muscle biopsy (quadriceps muscle) from patient 1II, 6 taken at 26 years. Haematoxylin and eosin stain. No ‘myotubes’, but large, multinucleated muscle fibres. In the centre a muscle fibre with ‘splitting’ with nuclei aligning along the cleft (x220).
Fig. 6. Muscle from the quadriceps muscle, .obtained at autopsy from patient 2-V,15 who died as a neonate. Semithin section stained with toluidine blue shows that the majority of the fibres has a central empty space (‘myotubes’). This is the typical picture of a neonate with myotubular myopathy. Arrows point to some fibres where nuclei appear in an intermediate position between central and peripheral location (x352).
Summarizing, we have illustrated that X-linked myotubular myopathy shows inter- and intrafamilial variability in phenotypical expression. Furthermore, counselling in X-linked myotubular myopathy should be cautous, especially in small families were the potential for and degree of recovery is not known. Survival to some extent is matched by ongoing muscle fibre maturation which in itself is abnormal. Mutations in the MTMl gene on Xq28, have been found in a number of families with X-linked myotubular myopathy. A search, conducted with the support of the European Neuromuscular Centre (ENMC) International Consortium on Myotubular Myopathy, reported the mutations found in the two families described above.iO Patient l-II, 1, referred to as NL20, was found to carry a C262T nucleotide change in exon 4, resulting in a missense mutation. Patient 2-VI, 2, referred to as Nl-44, was found to carry a G103T nucleotide change in exon 2, resulting in a nonsense mutation. While we expect these results to bear on .the phenotypes described above, discussion of these findings is outside the scope of the present study.
Acknowledgement ._I__lli____
Professor Dr FGI Jennekens kindly allowed us to report his findings (second biopsy and clinical findings) in patient l-l&l.
Original article: I% Barth, V Dubowitz
56
References Van Wijngaarden GK, Fleury P, Bethlem J, Meijer H. Familial ‘myotubular myopathy’. Neurology 1969; 19: 901-8. Barth PG, van Wijngaarden GK, Bethlem J. X-linked myotubular myopathy with fatal neonatal asphyxia.
Neurology1975;25; 531536. Wallgren-Pettersson C, Clarke A, Samson F et al. The myotubular myopathies: differential diagnosis of the X-linked recessive, autosomal dominant, and autosomal recessive forms and present state of DNA studies. ] Med Genef1995; 32: 673-679. Hu LJ, Kretz C, Mandel JL, Kioschis P et nl. A gene mutated in X-linked myotubular myopathy defines a new putative tyrosine phosphatase family conserved in yeast. Nat Gerzet 1996; 13: 175-182.
5 Samat HB, Silbert SW. Maturational 6 7 8 9
10
arrest of fetal muscle in neonatal myotonic dystrophy: a pathologic study of four cases. Arch Neural1976; 33: 466474. Dubowitz V. A Colour Atlas of Muscle Disordersin Childhood.London: Mosby-Wolfe, 1989. Dubowitz V. Lesson for the month. Genetic counselling. NeuromuscDisord1992; 1: 85-88. Heckmatt JZ, Sewry CA, Hodes D, Dubowitz V. Congenital centronuclear (myotubular) myopathy. Brain 1985; 108: 941-964. De Angelis MS, Pahnucci L, Leone M, Doriguzzi C. Centronuclear myopathy: clinical, morphological and genetic characters. Review article. J Neurol Sci 1991; 103: 2-9. Laporte J, Guiraud-Chaumeil Ch, Vincent MC et nl. Mutations in the MTMl gene implicated in X-linked myotubular myopathy. Hu?f~n~z Molec Genet1997; 6: 1505-1511.
Journal
ORIGINAL
of Paediatric
Neurology
1998;
1: 49-56
ARTICLE
X-Linked follow-up
myotubular study
PETER C BARTH’, ‘Departments
VICTOR
of Paediatrics
‘Department
of Paediatrics
and and
myopathy
- A long-term
DUBOWITZ2 Neurology, Neonatal
Emma Medicine,
Children’s
HospitaVAMC,
Hammersmith
University
Hospital,
London,
of Amsterdam,
The
Netherlands;
UK
X-Linked myotubular myopathy is a well delineated congenital myopathy, with a high neonatal and early childhood mortality. Only a single gene, mapping to Xq28 has been implicated and has recently been characterized. Phenotypic variability, both interand intrafamilial, has been recorded. Its severest expression is a uniform disease with polyhydramnios due to prenatal (neuromuscular) swallowing disorder, and partial inability to expand the lungs postnatally leading to early postnatal death in all. The mildest expression appears to be represented by the first family reported in the literature in which intrafamilial phenotypic variability was marked. There was neonatal asphyxia, but recovery took place in most affected patients and very mild expression permitting normal life into adulthood has been found in two patients. A long-term follow-up is given on both these families. Results emphasize the importance of the family history when trying to prognosticate in an individual case. Keywords
X-Linked
myotubular
myopathy.
Congenital
myopathy.
Introduction Myotubular myopathy is a congenital myopathy in which the muscle fibres postnatally resemble the fetal myotube stage. Autosomal recessive, autosomal dominant and X-linked inheritance have been described. The different phenotypes have been reviewed recently. The best studied and probably most common representative is X-linked myotubular myopathy (McKusick *310400) which X-linked links to Xq28. The newborn with myotubular myopathy usually presents with severe muscle hypotonia, weakness, and difficulty in starting breathing. Mechanical ventilation for a shorter or longer period may be necessary. Mechanical ventilation may overcome alveolar collapse and viscosity, while allowing the patient to take over the job of tidal expansion. In some families, however, even prolonged artificial
Received
5.12.97.
Correspondence:
Accepted 13.1.98. Dr PC Barth, Department
of Paediatrics,
Emma Children’s
ventilation does not help the patient to take over breathing, and after shorter or longer tune the fruitless effort has to be terminated. In some families antenatal impairment of swallowing causes polyhydramnios. Contractures may be present. Whilst muscle function often improves postnatally, mortality in infancy and childhood remains high, mainly as a result of bulbar muscle insufficiency or nocturnal hypoventilation. Some patients survive into adulthood with variable degrees of handicap. Because of the divergence in functional prognosis and life expectancy, outcome is often difficult to predict in the individual case. There appears to be both inter-’ and intrafamilial variability. Two early Dutch studies,rJ representing the first and third reports in the literature on the disease, provided evidence of such variability, with rare neonatal mortality in the first family and 100% neonatal mortality in the latter. Long-term clinical follow-up data on both these families are
HospitaVAMC,
University
of Amsterdam,
PO Box 22700,
1100
DE Amsterdam,
The Netherlands 1090-3798/98/010049+8
$18.00
0 1998
European
Paediatric
Neurology
Society
Original
50 presented with the object of presenting the phenotypical extremes of the disease spectrum.
article: PG Barth,
V Dubowitz
I
II
Materials
and methods
Patient data from the X-linked myotubular myopathy-families described by van Wijngaarden et al. (1969)’ and by Barth et al. (1975)* were reviewed for comparison. Patient data were updated by interviews and personal examination.
Results _. __~. Family 7 The pedigree is given in Fig. 1. Patients have been described in a previous report1 History and essential clinical findings are summarized in Table 1. Follow-up on three patients after the previous report is presented here.
Subject
l-l/,
1
This male was born at term after an uneventful pregnancy. He was blue and weak immediately after delivery, but recovered without mechanical ventilation. He was initially very weak, but could sit and stand without support at 2 years. When reviewed at 33 years of age he was an administrator who could adequately manage his everyday life. Examination revealed subtotal external ophthalmoplegia without ptosis, mild facial weakness, retained strength in his masticator-y muscles and moderate paresis of his neck flexors. He had moderate involvement of the musculature of shoulders and pelvic girdle. He rose from his chair with a Gowers’ mameuvre, but could walk some distance without help. His first biopsy (quadriceps muscle) was taken as part of an investigation of his whole family at 33 years. It revealed two muscle fibre populations - one small and one large calibre: the smallest were type I with the characteristics of ‘myotubes’, the larger population had many internal nuclei in cross-section. Subsequently the subject developed cataracts for which he was successfully operated at the age of 39. Progressive involvement of his neuromuscular illness led to contract-m-es of his masticatory muscles with insufficient opening of his mouth. Strength in shoulder and pelvic musculature was severely reduced. Progressive loss of ventilatory capacity led to tracheostomy at the age of 47
III
Fig.
q
Suspected
3 by history
w
Histological
confirmation
1.
Pedigree
of family
4
1
with
5
6
X-linked
7
6
myotubular
myopathy.
followed by nocturnal ventilator assistance. He died at the age of 50. A repeat biopsy taken from his left brachial muscle revealed that most of the biopsy consisted of fat. Muscle fibres were almost uniformly type I with extreme variation in diameter. Besides some small sized fibres with the characteristics of myotubes, all larger fibres contained internal nuclei, often arranged in chains on longitudinal section. Some fibres had the additional aspect of ragged red fibres. In comparison with the first biopsy at the age of 33, fatty replacement was more prominent. Other characteristics were similar with the exception of additional ragged red fibres.
Subject
l-l/l,
4
This male was born at full term. He was cyanotic at birth and had some difficulty in establishing independent breathing, but did well subsequently. He could walk independently at 16 months. When seen at 5 years he displayed extraocular paresis, ptosis, moderate facial palsy, neck flexor weakness, and mild weakness of his upper extremities but otherwise had normal power at 5 years. A quadriceps muscle biopsy at the time revealed scattered small ‘myotubes’, mostly type I, intermingled with normal sized muscle fibres which often had internal nuclei. He was seen again by one of us (VD) at the age of 33 years. At the time his only complaint related to his muscles was stiffness of his back musculature, which dated back to his mid-20s. He was not allowed to play rugby in childhood because of the poor control of his neck muscles, but excelled at other sports such as tennis and golf and was also a keen swimmer. He had led an active adult life and had been able to participate in competitive tennis at county level, and also played competitive golf. On examination, the only significant weakness was of the neck flexors and extensors. He had mild limitation of eye closure, limited upward gaze and limited
Original
article:
X-Linked
Table 1
Family 1: Follow-up
myotubular
myopathy
51
Pedigree no.
Neonatal period and early childhood
l-II, 1
Neonatal asphyxia; 33 years: Extraocular paresis, unsupported walking at difficulty in rising from sitting 2 years position; waddling gait Neonatal asphyxia; never able Only anamnesticdata from family to sit unsupported
l-11,2
l-11,6
Neonatal asphyxia; unsupported walking at 4 years
l-II, 9
Neonatal asphyxia; died a few hours old Neonatal asphyxia
l-III, 3
l-111,4
Neonatal asphyxia; unsupported walking at 16 months Neonatal asphyxia; died from sequelaeof meconium aspiration at 18 days Neonatal asphyxia; rising to stand at 11 months, walked in 2nd year
I-III, 5
I-III, 6
Age at first investigation
26 years: Extraocular paresis,able to rise from sitting position with Gowers’ manmuvre
22 months: Extraocular paresis, ptosis, severe genera1paresis, able to rise to sit 5 years: Extraocular and neckflexor paresis,ptosis, facial palsy, mild paresis,otherwise normal power
I-III,
Died at 50 years from progressive respiratory insufficiency Died at 5 years; unable to move eyes, genera1weakness,died from pneumonia At 54 years; anamnesticdata: resident in institute for mentally handicapped; motor condition unchanged
30 years; anamnesticdata: able to rise with Gowers’ manceuvre, still able to walk unsupported 33 years: seetext
7 years: Extraocular and neckflexor 30 years: mild myopathic paresis,hypotrophic musculature, changesnot interfering with otherwise normal normal daily life; seetext.
horizontal movements on both sides. He had some degree of spinal rigidity, with limited flexion, possibly related to shortening of the paravertebral muscles.
Subject
Follow-up
ptosis, mild facial paresis, mild (grade 4) paresis of his neck flexors, and underdevelopment of his shoulder muscles, especially the pectoral muscles, with a flattened thorax. Otherwise his muscles were well developed and strong (Fig. 3a-c).
6
This male was born at full term, had difficulty in establishing unsupported breathing but did well subsequently. He could rise to stand at 11 months and achieved independent walking in his second year. When seen at 7 years he displayed extraocular and neck flexor paresis, had generally hypotrophic musculature, but had normal power in all muscle groups and could keep up physically with children of his age. A quadriceps biopsy at 19 months showed scattered small type I ‘myotubes’ between normal and larger sized normally structured fibres of either type (Fig. 2a,b). He was seen again by one of us (PGB) at the age of 30 years. He had a normal life as a factory owner. He had only very mild complaints, such as difficulty to keep an arm outstretched for some time. On examination he had total ophthalmoparesis without
Family 2 The pedigree is given in Fig. 4. Patients were described in 1975.’ All pregnancies were characterized by polyhydramnios due to impairment of fetal swallowing and all the infants were severely asphyxiated at birth, and were unable to expand their lungs without help. This report essentially describes the situation before prolonged mechanical ventilation became routine in neonatal intensive care. Of these patients one reached the age of 2 weeks, one reached the age of 2 days and the others died within the first 24 hours. One patient (2-V, 38) born after the report was published is reported here in more detail.
Original
52
(a)
article: PG Barth, V Dubowitz
briefly breathed spontaneously with the tracheal tube in situ, but he could not maintain adequate gaseous exchange. He died on the 19th day of life from progressive respiratory and circulatory failure. A muscle biopsy from the quadriceps femoris muscle was taken on the 7th day of life. It showed that 90% of the muscle fibres consisted of ‘myotubes’ with both fibre types affected, confirming the diagnosis of myotubular myopathy. After this experience a policy was adopted for handling further cases in this family. Male infants who were born with the typical symptoms would be intubated and kept on the ventilator pending confirmation of the diagnosis by muscle biopsy. Upon confirmation of the diagnosis the parents would be informed about the poor prognosis and with their consent artificial respiration would be ended allowing the infant to die. Sedatives would be given to treat a possible subjective sense of dyspnoea. This course was taken in a subsequent case (2-VI, 2) who survived 2 days.
Discussion
(b) Fig. 2. Muscle biopsy (quadriceps muscle) from patient l-111, 6, taken at the age of, 19 months. (a) Transverse section stained for myosin adenosine triphosphate 9.4pH, shows small sized fibres belonging to type I with a central area devoid of myofibrils (empty looking). Other fibres belong two either type I or type II, with type I fibres smaller in sized than type II (x 220). (b) Transverse section stained for nicotinamide adenine dinucleotide oxidoreductase. Small type I fibres show highly concentrated mitochondrial activity in the central parts of the fibres, roughly corresponding to the empty areas in Fig. 2a (x352).
Subject
P-V, 38
This male patient was born at 37 weeks gestational age. The mother had polyhydramnios (5 l&es). Birthweight was 1970 g, length 48cm, frontooccipital circumference 34.8 cm. He was very weak and hypotonic, with only small distal movements, breathed poorly and had to be intubated and mechanically ventilated to provide adequate gas exchange. A thoracic radiogram showed hypoplastic ribs. After 1 week of ventilation he was able to maintain adequate respiration with the tracheal tube in situ. However, on changing the tube his condition immediately deteriorated, because of inability to swallow his secretions. At 15 days he
The X-linked type of myotubular myopathy is the best known, probably the most prevalent of the three.3 It is also the only form of which the underlying gene defect has been identified.4 Myotubes represent a stage In myogenesis which lasts from 8 to 15 weeks in the human fetus. Essentially, they are syncitial structures derived from the fusion of still earlier progenitor cells, the mononuclear myoblasts. Their microscopic appearance is a chain of muscle nuclei surrounded by sarcoplasm and organelles. Wedged in between the central sarcoplasm and the sarcolemma is a rim of developing myofibrils. The name ‘myotubes’ derives from an empty tube-like appearance in longitudinal paraffin sections. Abundant myotube-like fibres in the muscle biopsy of a newborn past 20 weeks of gestational age are the hallmark of myotubular myopathies, but are also common in newborns with congenital myotonic dystrophy,46 from which the condition has to be differentiated. The usual clinical presentation of X-linked myotubular myopathy in a newborn is with severe neonatal respiratory impairment due to muscular weakness, often necessitating mechanical ventilation for some time. Survival past the neonatal period occurs, often with improvement of muscle function. Generalized muscle weakness usually includes insufficiency of bulbar and extraocular muscles.‘*s Childhood morbidity and mortality are high. In
Original
article:
X-Linked
myotubular
(a)
myopathy
(b)
Fig .3. F‘atient 1-111, 6 at the age of 30 years. (a) Minimal facial paresis with diminished upturning of the corners of Ithe mo uth wt lile smiling. Slightly divergent eyes due to extraocular pareses. (b) Underdevelopment of the pectoralis muscles. (cl COImplete normal function of the pelvic and leg muscles is demonstrated while attempting to keep balance in a squatti ing pos Ation.
Original
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El Suspected n Histological
Fig. 4.
Pedigree
of family
2 with
one study compiled clinical findings and survival rates from 81 previously reported case histories, including the families reported here were brought together.g All patients presented with severe neonatal symptoms, including 30% who had prenatal symptoms, i.e. polyhydramnios due to impaired fetal swallowing. Of 81 on whom data were available, 73 had died. Ages reached were O-l months in 82%, 1-12 months in lo%, l-9 years in 7% and lo-29 years in 1%. Clinical experience and muscle pathology in family 2 was uniform. All pregnancies of affected males resulted in polyhydramnios during the latter half of pregnancy. They were born at or near term. None survived the immediate neonatal period without respiratory support. Prompt mechanical ventilation was instituted and prolonged for 19 days in one patient (2-V, 38) without development of adequate independent ventilation. Another affected boy born subsequently in the same family (2-VI, 2) was kept alive on the respirator pending diagnosis by muscle biopsy. After confirmation of the diagnosis, consensus was reached with the parents to withhold further mechanical ventilation while giving sedation to
X-linked
myotubulsr
article:
PG Barth,
V Dubowitz
by history confirmation
myopathy.
alleviate possible sense of dyspnoea and discomfort, which was followed by death within hours. Because of the 100% mortality present policy in this family is aimed at determination of carrier status of the mother, possibly before pregnancy, gender determination of the fetus, and in the case of male pregnancy mutation analysis, making use of recent developments4 With respect to family 1 the situation is more complex. Early death (l-11, 9 and l-III, 5), death from pulmonary complications in childhood (l-11, 2), recovery with limited ambulation (l-11, 1, l-11, 6, l-III, 3), partial recovery followed by progressive paresis (l-II, 1) and nearby complete recovery with persistent extraocular and neck-muscle weakness (l-III, 4, l-III, 6) have all been documented. The biological basis for the phenotypic diversity within this family is still not clearly understood. With respect to muscle biopsies, neonatal biopsies in the two families are strikingly similar, with a majority of the fibres in transverse section carrying an area devoid of myofibrils. Fibre diameter variation is slightly in excess with normal structured fibres on the average slightly larger than the ‘myotubes’. Older patients with X-linked
Original
article:
X-Linked
myotubular
myopathy
myotubular myopathy including adults were biopsied in family 1. If the biopsies from affected males within that family are sorted according to age a peculiar picture arises. Childhood biopsies show fibre size disparity with persistent mainly type I and normally ‘myotubes’ structured fibres being mainly type II. Patient lIII, 6 whose biopsy was taken at 19 months is given as example (Fig. 2a, b). In adult biopsies a strikingly different pattern occurred, with a tendency to form parallel nuclear chains within muscle fibres. Figure 5 representing a biopsy taken at 26 years from patient l-11, 6 shows multiple internal nuclei in transversely sectioned muscle cells, and no small fibres with a central ‘empty region’. It is unclear how such larger multinucleated muscle cells arise later in life. One possibility is that such large fibres arise by fusion of muscle cells, in which case peripherally located nuclei become internalized. The presence of such nuclei alongside a ‘cleft’ within the muscle fibre, shown in Fig. 5 supports such an assumption. Nuclei in fetal myotubes migrate outward to take their subsarcolemmal position. Semithin sections of muscle from patients with X-linked myotubular myopathy show fibres that are apparently in a transitional stage as shown in Fig. 6 taken from a neonate with the severe type of X-linked myotubular myopathy. The index case, 2V,15, from that family, suggest that this also takes place in ‘myotubes’ from X-linked myotubular myopathy, where one can see nuclei apparently in the progress of migrating externally (arrows). It cannot be excluded that the reduction of numbers of ‘myotubes’ seen in older patients is related to such delayed ‘maturation’.
1
Fig. 5. Muscle biopsy (quadriceps muscle) from patient 1II, 6 taken at 26 years. Haematoxylin and eosin stain. No ‘myotubes’, but large, multinucleated muscle fibres. In the centre a muscle fibre with ‘splitting’ with nuclei aligning along the cleft (x220).
Fig. 6. Muscle from the quadriceps muscle, .obtained at autopsy from patient 2-V,15 who died as a neonate. Semithin section stained with toluidine blue shows that the majority of the fibres has a central empty space (‘myotubes’). This is the typical picture of a neonate with myotubular myopathy. Arrows point to some fibres where nuclei appear in an intermediate position between central and peripheral location (x352).
Summarizing, we have illustrated that X-linked myotubular myopathy shows inter- and intrafamilial variability in phenotypical expression. Furthermore, counselling in X-linked myotubular myopathy should be cautous, especially in small families were the potential for and degree of recovery is not known. Survival to some extent is matched by ongoing muscle fibre maturation which in itself is abnormal. Mutations in the MTMl gene on Xq28, have been found in a number of families with X-linked myotubular myopathy. A search, conducted with the support of the European Neuromuscular Centre (ENMC) International Consortium on Myotubular Myopathy, reported the mutations found in the two families described above.iO Patient l-II, 1, referred to as NL20, was found to carry a C262T nucleotide change in exon 4, resulting in a missense mutation. Patient 2-VI, 2, referred to as Nl-44, was found to carry a G103T nucleotide change in exon 2, resulting in a nonsense mutation. While we expect these results to bear on .the phenotypes described above, discussion of these findings is outside the scope of the present study.
Acknowledgement ._I__lli____
Professor Dr FGI Jennekens kindly allowed us to report his findings (second biopsy and clinical findings) in patient l-l&l.
Original article: I% Barth, V Dubowitz
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