Early Predictors of Poor Outcome in Congenital Fiber-Type Disproportion Myopathy Carlos F. Torres, MD, Richard T. \s=b\ We report the cases of eight children with histologic findings in the muscle of congenital fiber-type disproportion myopathy. Five had severe muscle weakness at birth; three
of them died at 6 months, 18 months, and 6.5 years of age, respectively, and the other two are ventilator dependent and need total care at 2.5 and 4 years of age. The five children with severe weakness at birth had profound respiratory muscle weakness and needed assisted ventilation since early infancy. They also had severe facial and bulbar muscle weakness that required tube feeding, and four had gastrostomy. Ptosis and marked external ophthalmoparesis were also noted. Our study shows that the presence of the above constellation of signs at birth or in early infancy is a predictor of a high rate of mortality in infancy and poor developmental outcome in the survivors. (Arch Neurol. 1992;49:855-856)
Although ital
a
in the clinical course and reported in children with congen¬
great variability
outcome has been
fiber-type disproportion myopathy (CFTDM),1"3 some
infants present severe weakness at birth or in early infancy. In this latter group of infants, a high mortality has been re¬ ported among those who exhibit hypoventilation and se¬ vere bulbar muscle weakness.4 The clinical characteristics, associated with poor outcome in infancy and early child¬ hood, although previously noted, have not been well rec¬ ognized. In our study, five of eight children with CFTDM had clinical signs that were predictors of poor develop¬ mental outcome and high mortality rate in infancy. REPORT OF CASES children (six girls and two boys) were followed up since birth (Table). Five patients (cases 1 through 5) had severe signs of muscle weakness since birth. They needed assisted ventilation in the first 3 to 4 weeks of life and tracheostomy later on. They all had external ophthalmoparesis and four had ptosis. The facial and bulbar muscles were markedly affected, they were unable to close the lips, and the mouth was open all the time. Gavage feeding and frequent suctioning of oral se¬ cretions were necessary, and four of them required gastrostomy. Three children (cases 6 through 8) had moderate signs of muscle weakness at birth, they all had moderate
Eight
Accepted for publication April 8, 1992. From the Departments of Neurology and Pediatrics, University of
Rochester (NY) Medical School. Reprints not available.
Moxley,
MD
respiratory distress, while
with mild intercostal retractions,
feeding, and excessive drooling.
fatigue
Clinical Course and Outcome CASE 1.—This child showed no signs of motor development after birth. He remained profoundly weak, with minimal sponta¬ neous motor activity and died of respiratory infection at 6 months of age. Case 2.—The course of this patient was similar to that of the patient in case 1. She was able to move the distal parts of her limbs but had no visible motor function of the hips, shoulders, trunk, or neck. She died of respiratory infection at 18 months of age. Case 3.—This child remained hospitalized during her first year of life because of severe respiratory weakness. Later, she required assisted ventilation only while sleeping. She was able to swallow soft food, to sit with support, and to move around in her electrical wheelchair. She died of respiratorory infection at 6.5 years of age. CASE 4.—This patient is 2.5 years of age. In a supine position, he slowly reaches out and holds a rattle for brief moments. He can fully flex and extend the ankles, knees, wrists, and elbows against gravity but there is only a trace of movement at the hips, shoul¬ ders, trunk, and neck. Ophthalmoparesis, ptosis, and facial and bulbar muscle weakness are moderate to severe. All reflexes are decreased. CASE 5.—At 4 years of age, this child is wheelchair bound. She has moderate head control, rolls over, sits with help, reaches out, and holds objects. She has mild facial weakness, minimal drool¬ ing, and says a few words. CASES 6 Through 8 (Moderate Cases).—The patients in these cases have had similar courses. They had no ptosis or ophthal¬ moparesis and did not need tracheostomy or gastrostomy. One patient had to be fed via gavage for about 1 year. Their speech is dysarthric and their motor development has been very slow. They need some assistance in daily living activities, they walk slowly and waddlingly, and they use the handrail to walk upstairs. They cannot
jump or run.
Laboratory Reports All eight children had normal creatine kinase values, computed tomographic head scans, and/or magnetic resonance imaging head scans. Nerve conduction velocities were normal. Electromyogram showed small motor unit action potentials of short du¬ ration and absence of fibrillations and positive waves. Muscle bi¬ opsy from the quadriceps femori was performed in all infants in the first 4 months of life. Muscle fibers revealed no structural ab¬ normalities or fiber-type predominance. Five percent to 15 % of fibers (types I and II) had the nucleus in the center. Type I fiber size in the children with severe conditions (cases 1 through 5) was less than 5 to 8 µ (normal=8 to 15 µ ), and they were 40% to 60% smaller than type II fibers. In the children with moderate
Downloaded From: http://archneur.jamanetwork.com/ by a University of Auckland User on 05/17/2015
Major Clinical
Features in
Eight
Patients With
Congenital Fiber-Type Disproportion Myopathy* Patient No.
1
Sex
i Fetal
movementt
M
F
F
M
F
+
+
+
+
+
Intubation
Birth
3 wk
Birth
4 wk
1 d
Tracheostomy, mo Gavage feeding
2
4
3
5
1
+
6 mo4
Gastrostomy
2
Ophthalmoparesis
+++
+++
+++
Ptosis
+
+
+
+ mo
2 wk
+
4
1
+ mo
5
yt
mo
-
+++
+
+++ +++ +++ Facial weakness 6 mo 18 mo 6.5 y Dead 1.5 Age at last visit, y Ventilator dependent + *Plus sign indicates present; two plus signs, moderate; three plus signs, severe; and minus sign, not present. Patients in brother and sister. Patients in cases 6 and 7 are sisters. Their father had bilateral esotropia. tDownward pointing arrow indicates fetal movements were decreased. 4Age at which gavage feeding was discontinued.
9.5
...
...
conditions (cases 6 through 8), the type I fibers were 5 to 10 µ and 30% to 40% smaller than type II. The size for type II fibers was 8 to 18 µ in all eight infants. The child in case 6 underwent re¬ peated quadriceps muscle biopsy at 6 years of age. Twenty per¬ cent of type I fibers were still very small (10 to 15 µ ) and angulated. Thirty percent to 40% of type II fibers were large (>90 µ ). Muscle histologie features in the mothers of cases 4 and 8 were normal.
COMMENT Early reports suggested that CFTDM was a benign my¬ opathy and that affected infants would improve their muscle strength with time.1"3 The clinical findings reported on those children were more consistent with mild to mod¬ erately severe cases. They had no cranial nerve abnormal¬ ities, ptosis, or ophthalmoparesis. In attempting to corre¬ late the muscle histologie findings with the severity of weakness and outcome, it was thought that the absence of central nucleus in the muscle fibers carried a more benign, nonprogressive course.3 However, in a recent report5 of four infants (two with 50% or more fibers with central nu¬ cleus and two with only 10% of fibers with central nucleus), two died in early infancy (one of each category). All had marked bulbar muscle weakness, ophthalmoparesis, and ptosis. The authors of that report5 found that the severity of muscle weakness and hypoventilation at birth predicted the outcome more accurately than the histologie findings in the muscle. Another study of three infants with CFTDM who died before 1 year of age also confirmed the observa¬ tions that when the bulbar and facial weakness and oph¬
thalmoparesis are severe, they carry a poor prognosis for survival beyond infancy.4 Our eight children had a normal percent of muscle fibers with central nucleus and they all fall in the description of fiber-type disproportion with type I hypotrophy (smallness) without centronuclei. The five
cases
1
through
3
were
children (Table) with severe weakness had, in general, smaller type I fibers than the three children with moderate weakness. They also showed more severe facial-bulbar muscle weakness, ophthalmoparesis, and ptosis. None of the children with moderate conditions had ptosis or oph¬ thalmoparesis and they did not require tracheostomy or gastrostomy. Type I muscle fiber predominance, com¬ monly seen in CFTDM,6 was not present in any of our pa¬ tients' muscle abnormalities. The absence of this histologie finding is of unclear significance to us. We would agree with Lo et al5 that our five infants with severe CFTDM could not be clinically distinguished from infants with severe congenital centronuclear myopathy and that it is likely these two clinical entities represent a different state or degree of the same abnormality in the developing muscle fibers. Our study indicates that it is possible to predict the outcome in early infancy in severely affected children with CFTDM. Further analysis of the muscle fiber size in a larger number of patients is necessary to ascertain that there is a correlation between degree of smallness of type I fibers and severity of muscle weakness. References 1. Dubowitz V. Congenital fiber type disproportion. In: Dubowitz V, ed. Muscle Disorders in Childhood: Major Problems in Clinical Pediatrics. 1 st ed. Philadelphia, Pa: WB Saunders Co; 1978;16:93-95. 2. Clancy RR, Kelts KA, Oehlert JW. Clinical variability in congenital fiber type disproportion. J Neurol Sci. 1980;46:257-266. 3. Curless RG, Nelson MB. Congenital fiber type disproportion in identical twins. Ann Neurol. 1977;2:455-459. 4. Reyes MG, Goldbarg H. Fiber type size disproportion in floppy infants. Ann Neurol. 1979;6:175. Abstract. 5. Lo WD, Barohn RJ, Bobulski RJ, Kean J, Mendell JR. Centronuclear myopathy and type I hypotrophy without central nuclei: distinct nosologic en-
tities? Arch Neurol. 1990;47:273-276. 6. Engel A, Banker B. Congenital fiber type disproportion. In: Engel A, Banker B, eds. Myology: Basic and Clinical. New York, NY: McGraw Hill International Book Co; 1986;2:1550-1553.
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of them died at 6 months, 18 months, and 6.5 years of age, respectively, and the other two are ventilator dependent and need total care at 2.5 and 4 years of age. The five children with severe weakness at birth had profound respiratory muscle weakness and needed assisted ventilation since early infancy. They also had severe facial and bulbar muscle weakness that required tube feeding, and four had gastrostomy. Ptosis and marked external ophthalmoparesis were also noted. Our study shows that the presence of the above constellation of signs at birth or in early infancy is a predictor of a high rate of mortality in infancy and poor developmental outcome in the survivors. (Arch Neurol. 1992;49:855-856)
Although ital
a
in the clinical course and reported in children with congen¬
great variability
outcome has been
fiber-type disproportion myopathy (CFTDM),1"3 some
infants present severe weakness at birth or in early infancy. In this latter group of infants, a high mortality has been re¬ ported among those who exhibit hypoventilation and se¬ vere bulbar muscle weakness.4 The clinical characteristics, associated with poor outcome in infancy and early child¬ hood, although previously noted, have not been well rec¬ ognized. In our study, five of eight children with CFTDM had clinical signs that were predictors of poor develop¬ mental outcome and high mortality rate in infancy. REPORT OF CASES children (six girls and two boys) were followed up since birth (Table). Five patients (cases 1 through 5) had severe signs of muscle weakness since birth. They needed assisted ventilation in the first 3 to 4 weeks of life and tracheostomy later on. They all had external ophthalmoparesis and four had ptosis. The facial and bulbar muscles were markedly affected, they were unable to close the lips, and the mouth was open all the time. Gavage feeding and frequent suctioning of oral se¬ cretions were necessary, and four of them required gastrostomy. Three children (cases 6 through 8) had moderate signs of muscle weakness at birth, they all had moderate
Eight
Accepted for publication April 8, 1992. From the Departments of Neurology and Pediatrics, University of
Rochester (NY) Medical School. Reprints not available.
Moxley,
MD
respiratory distress, while
with mild intercostal retractions,
feeding, and excessive drooling.
fatigue
Clinical Course and Outcome CASE 1.—This child showed no signs of motor development after birth. He remained profoundly weak, with minimal sponta¬ neous motor activity and died of respiratory infection at 6 months of age. Case 2.—The course of this patient was similar to that of the patient in case 1. She was able to move the distal parts of her limbs but had no visible motor function of the hips, shoulders, trunk, or neck. She died of respiratory infection at 18 months of age. Case 3.—This child remained hospitalized during her first year of life because of severe respiratory weakness. Later, she required assisted ventilation only while sleeping. She was able to swallow soft food, to sit with support, and to move around in her electrical wheelchair. She died of respiratorory infection at 6.5 years of age. CASE 4.—This patient is 2.5 years of age. In a supine position, he slowly reaches out and holds a rattle for brief moments. He can fully flex and extend the ankles, knees, wrists, and elbows against gravity but there is only a trace of movement at the hips, shoul¬ ders, trunk, and neck. Ophthalmoparesis, ptosis, and facial and bulbar muscle weakness are moderate to severe. All reflexes are decreased. CASE 5.—At 4 years of age, this child is wheelchair bound. She has moderate head control, rolls over, sits with help, reaches out, and holds objects. She has mild facial weakness, minimal drool¬ ing, and says a few words. CASES 6 Through 8 (Moderate Cases).—The patients in these cases have had similar courses. They had no ptosis or ophthal¬ moparesis and did not need tracheostomy or gastrostomy. One patient had to be fed via gavage for about 1 year. Their speech is dysarthric and their motor development has been very slow. They need some assistance in daily living activities, they walk slowly and waddlingly, and they use the handrail to walk upstairs. They cannot
jump or run.
Laboratory Reports All eight children had normal creatine kinase values, computed tomographic head scans, and/or magnetic resonance imaging head scans. Nerve conduction velocities were normal. Electromyogram showed small motor unit action potentials of short du¬ ration and absence of fibrillations and positive waves. Muscle bi¬ opsy from the quadriceps femori was performed in all infants in the first 4 months of life. Muscle fibers revealed no structural ab¬ normalities or fiber-type predominance. Five percent to 15 % of fibers (types I and II) had the nucleus in the center. Type I fiber size in the children with severe conditions (cases 1 through 5) was less than 5 to 8 µ (normal=8 to 15 µ ), and they were 40% to 60% smaller than type II fibers. In the children with moderate
Downloaded From: http://archneur.jamanetwork.com/ by a University of Auckland User on 05/17/2015
Major Clinical
Features in
Eight
Patients With
Congenital Fiber-Type Disproportion Myopathy* Patient No.
1
Sex
i Fetal
movementt
M
F
F
M
F
+
+
+
+
+
Intubation
Birth
3 wk
Birth
4 wk
1 d
Tracheostomy, mo Gavage feeding
2
4
3
5
1
+
6 mo4
Gastrostomy
2
Ophthalmoparesis
+++
+++
+++
Ptosis
+
+
+
+ mo
2 wk
+
4
1
+ mo
5
yt
mo
-
+++
+
+++ +++ +++ Facial weakness 6 mo 18 mo 6.5 y Dead 1.5 Age at last visit, y Ventilator dependent + *Plus sign indicates present; two plus signs, moderate; three plus signs, severe; and minus sign, not present. Patients in brother and sister. Patients in cases 6 and 7 are sisters. Their father had bilateral esotropia. tDownward pointing arrow indicates fetal movements were decreased. 4Age at which gavage feeding was discontinued.
9.5
...
...
conditions (cases 6 through 8), the type I fibers were 5 to 10 µ and 30% to 40% smaller than type II. The size for type II fibers was 8 to 18 µ in all eight infants. The child in case 6 underwent re¬ peated quadriceps muscle biopsy at 6 years of age. Twenty per¬ cent of type I fibers were still very small (10 to 15 µ ) and angulated. Thirty percent to 40% of type II fibers were large (>90 µ ). Muscle histologie features in the mothers of cases 4 and 8 were normal.
COMMENT Early reports suggested that CFTDM was a benign my¬ opathy and that affected infants would improve their muscle strength with time.1"3 The clinical findings reported on those children were more consistent with mild to mod¬ erately severe cases. They had no cranial nerve abnormal¬ ities, ptosis, or ophthalmoparesis. In attempting to corre¬ late the muscle histologie findings with the severity of weakness and outcome, it was thought that the absence of central nucleus in the muscle fibers carried a more benign, nonprogressive course.3 However, in a recent report5 of four infants (two with 50% or more fibers with central nu¬ cleus and two with only 10% of fibers with central nucleus), two died in early infancy (one of each category). All had marked bulbar muscle weakness, ophthalmoparesis, and ptosis. The authors of that report5 found that the severity of muscle weakness and hypoventilation at birth predicted the outcome more accurately than the histologie findings in the muscle. Another study of three infants with CFTDM who died before 1 year of age also confirmed the observa¬ tions that when the bulbar and facial weakness and oph¬
thalmoparesis are severe, they carry a poor prognosis for survival beyond infancy.4 Our eight children had a normal percent of muscle fibers with central nucleus and they all fall in the description of fiber-type disproportion with type I hypotrophy (smallness) without centronuclei. The five
cases
1
through
3
were
children (Table) with severe weakness had, in general, smaller type I fibers than the three children with moderate weakness. They also showed more severe facial-bulbar muscle weakness, ophthalmoparesis, and ptosis. None of the children with moderate conditions had ptosis or oph¬ thalmoparesis and they did not require tracheostomy or gastrostomy. Type I muscle fiber predominance, com¬ monly seen in CFTDM,6 was not present in any of our pa¬ tients' muscle abnormalities. The absence of this histologie finding is of unclear significance to us. We would agree with Lo et al5 that our five infants with severe CFTDM could not be clinically distinguished from infants with severe congenital centronuclear myopathy and that it is likely these two clinical entities represent a different state or degree of the same abnormality in the developing muscle fibers. Our study indicates that it is possible to predict the outcome in early infancy in severely affected children with CFTDM. Further analysis of the muscle fiber size in a larger number of patients is necessary to ascertain that there is a correlation between degree of smallness of type I fibers and severity of muscle weakness. References 1. Dubowitz V. Congenital fiber type disproportion. In: Dubowitz V, ed. Muscle Disorders in Childhood: Major Problems in Clinical Pediatrics. 1 st ed. Philadelphia, Pa: WB Saunders Co; 1978;16:93-95. 2. Clancy RR, Kelts KA, Oehlert JW. Clinical variability in congenital fiber type disproportion. J Neurol Sci. 1980;46:257-266. 3. Curless RG, Nelson MB. Congenital fiber type disproportion in identical twins. Ann Neurol. 1977;2:455-459. 4. Reyes MG, Goldbarg H. Fiber type size disproportion in floppy infants. Ann Neurol. 1979;6:175. Abstract. 5. Lo WD, Barohn RJ, Bobulski RJ, Kean J, Mendell JR. Centronuclear myopathy and type I hypotrophy without central nuclei: distinct nosologic en-
tities? Arch Neurol. 1990;47:273-276. 6. Engel A, Banker B. Congenital fiber type disproportion. In: Engel A, Banker B, eds. Myology: Basic and Clinical. New York, NY: McGraw Hill International Book Co; 1986;2:1550-1553.
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