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Congenital familial myopathy with type 2 fiber hypoplasia and type 1 fiber predominance
ELSEVIER
Brain & Development 19 (1997) 362-365
Case report
Congenital familial myopathy with type 2 fiber hypoplasia and type 1 fiber predominance H i d e k i M u r a n a k a a'*, S h i n - i c h i O s a r i a'b, H i r o s h i F u j i t a a, Y o s h i h a r u K i m u r a a, A k i r a G o t o a, C h i k a k o I m o t o b, I k u y a N o n a k a b aDepartment of Pediatrics, Hirosaki University School of Medicine, 5 Zaifu-cho, Hirosaki 036, Japan bDepartment of Laboratory Medicine, National Center Hospital for Nervous, Mental and Muscular Disorders, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187, Japan Received 28 June 1996; revised version received 28 April 1997; accepted 7 May 1997
Abstract
A 12-month-old girl with delayed developmental milestones, due to muscle hypotonia and weakness from early infancy, exhibited type 2 fiber hypoplasia. A muscle biopsy specimen disclosed type 1 fiber predominance and type 2B fiber deficiency compatible with congenital myopathy. During the following 4 years, she continued to have mild muscle weakness, but no mental retardation. Her mother had similar symptoms from early infancy with minimal progression. Although type 2 fiber hypoplasia is a non-specific finding in various diseases, it may be a specific finding in a limited number of patients with hereditary congenital non-progressive myopathy. © 1997 Elsevier Science B.V. Keywords: Congenital myopathy; Type 2 fiber hypoplasia; Type 1 predominance; Familial
of CNM, the daughter exhibiting type 2 fiber hypoplasia and type 1 predominance in a muscle biopsy specimen.
1. Introduction
In most patients with congenital non-progressive myopathies (CNM), including nemaline myopathy, central core disease and myotubular myopathy, the most common histochemical changes are hypoplastic type 1 fibers and type 1 fiber predominance [1,2]. Type 2 fiber hypoplasia itself is not a disease-specific finding, but is commonly seen in patients with central nervous system involvement, disuse atrophy and myasthenia gravis, and aged persons [3]. Some patients with type 2 fiber hypoplasia and the clinical characteristics of CNM have been reported [4,5]. However, it remains uncertain whether type 2 fiber hypoplasia plays a primary role for muscle symptom as a distinct clinical entity, because of the limited number of patients described and the lack of evidence of inheritance. We herein report a mother and her daughter who had the clinical characteristics
* Corresponding author. Tel.: +8l 172 395070; fax: +81 172 395071; e-mail: muranaka@ cc.hirosaki.ac.jp
0387-7604/97/$17.00
© 1997 Elsevier Science B.V. All rights reserved
Pll S 0 3 8 7 - 7 6 0 4 ( 9 7 ) 0 0 0 3 6 - 3
2. Patients
2.1. Patient 1
A 12-month-old girl infant was admitted to the pediatric ward of Hirosaki University Hospital for persistent muscle hypotonia. Her mother (patient 2) had generalized muscle weakness with facial muscle involvement from early infancy. Her father was healthy. This infant was the first child of unrelated Japanese parents, born by means of vaginal delivery after 41 weeks gestation with a birth weight of 3.07 kg. Fetal movements were considered normal. At birth she appeared healthy, with Apgar scores of 9 and 10 at 1 and 5 min, respectively. At 1 month, the infant was found to have generalized hypotonia. The baby girl obtained head control at 5 months and rolled over at 6 months of age.
H. Muranaka et al. / Brain & Developlment 19 (1997) 362-365
363
Fig. 1. Muscle CT of patient 1 (a) and her mother (b). Moderate-severe muscle atrophy and fat infiltration (a, b) in the thigh muscles compared with agematched normal controls (c, d) can be seen. a-d, right leg. On admission at 1 year of age, she had a slender stature and a funnel chest. She could not stand up by herself or walk without assistance. Her facial expression was 'myopathic' with a gaping mouth and an inverted V-shaped upper lip. The palate was high-arched. She was hypotonic with a positive scarf sign and the heel-to-ear phenomenon. Deep tendon reflexes were absent. Physical examination revealed no heart, lung or abdominal abnormalities. She was able to walk without assistance at 20 months of age. She had mild generalized muscle weakness with Gowers' maneuver while standing up when last examined at 4 years of age.
Laboratory findings, including the levels of serum creatinine kinase and aldolase, were within normal limits. The results of the motor nerve conduction study, neuroimaging and electrocardiography were normal for her age. An electromyogram (EMG) of the quadriceps revealed no abnormal findings at rest. The T S U M O R I - I N A G E developmental test result at 1 year of age was within normal range. Muscle CT at 4 years of age showed moderate atrophy and fat infiltration (Fig. 1a) compared with an age-matched control (Fig. 1c). Atrophy was more pronounced in the proximal muscles.
14. Muranaka et al. / Brain & Development 19 (1997) 362-365
364
ating fibers. Fibers with centrally placed nuclei comprised less than l% (Fig. 2a). Peripheral nerves, muscle spindles and blood vessels appeared normal. Fibrous tissue was slightly increased in the interstitium. Nemaline bodies or core structure were not seen. Peripheral nerve bundles were well myelinated. As seen on ATPase staining, type 1, 2A, 2B and 2C fibers comprised 80%, 18%, 1% and 1%, respectively, showing the type l fiber predominance. Type 2 fibers were selectively hypoplastic (Fig. 2b and c), which was statistically significant, as judged on morphometric analysis using a VIDAS VIDEOe L A N (Fig. 3). 2.2. Patient 2 (mother o f patient 1)
gVl~4 Q
C
Patient 2 also had the clinical characteristics of CNM. Her developmental milestones were delayed: she obtained head control at 8 months and walked without assistance at 19 months of age. At the age of 6 years, she noticed mild difficulty in walking up and down stairs, though there was no particular aggravation of muscle strength. At the age of 30 years, she exhibited mild generalized muscle weakness including the facial muscle. An EMG study showed a myopathic pattern with polyphasic short duration motor units. No myotonic discharges were recorded. Motor nerve conduction velocity was normal. Muscle CT revealed profound atrophy (Fig. lb), which was more predominant in the proximal muscles, compared to a normal age-matched control (Fig. ld). Muscle biopsy was not performed. She had led a normal daily life and considered herself healthy.
3. Discussion Although the clinical features were mild, this infant and mother had the typical characteristics of CNM, including: (i) delayed motor developmental milestones; (ii) muscle weakness and hypotonia from early infancy; (iii) areflexia; 70 60
Fig. 2. Muscle histochemistry in patient 1. There is mild fiber size variation with neither nemaline bodies nor necrotic fibers (a). On ATPase staining, all type 2A fibers (arrows) were found to be hypoplastic, and type 2B fibers were deficient (b and c). a, modified Gomori trichrome; b, Routine ATPase; c, ATPase with acid preincubation at pH 4.6. a-c, × 80. 2.1.1. Muscle biopsy at the age o f 1 year A biopsy specimen was taken from the left biceps brachii. Serial frozen sections were stained with hematoxylin and eosin (HE), modified Gomori-trichrome (mGT), N A D H tetrazolium reductase, phosphorylase, and ATPase with alkaline and acid preincubation. On HE, mild variation in fiber size, from 5 to 30/zm in diameter, was observed. There were no necrotic or regener-
Type 1fibers(n=200) (19.0--+4.6~m) Type 2fibers(n=200) (i0.6_+2,4~m)
50 40
//r--~\
30 20 I0 0
/ i ul.~ ///]i~ \\•k\\%k\%\ k 10 20 30 Fiberdiameter Fig. 3. Histogram of fiber diameters.
~m
H. Muranaka et al. /Brain & Developlment 19 (1997) 362-365
(iv) a 'myopathic' face and a high-arched palate; and (v) a non-progressive clinical course. The normal serum muscle enzyme levels and predominant proximal muscle atrophy observed on CT were also suggestive of CNM. Contrary to our expectations, this infant exhibited neither diagnostic intracytoplasmic abnormalities, including nemaline bodies, central cores or centrally placed nuclei, nor type 1 fiber hypoptasia in a muscle biopsy specimen. The most outstanding finding was the hypoplastic type 2 fiber. In contrast to the two previously described patients with congenital myopathy and type 2 fiber hypoplasia [4,5], our patient exhibited an abnormal fiber type distribution, including type 1 fiber predominance and type 2B fiber deficiency, which were supportive of a diagnosis of CNM. Accordingly, the condition in this infant may share a similar pathogenetic mechanism with a congenital neuromuscular disease with uniform type 1 fiber [6], because of its non-progressive nature and type 1 fiber predominance. It remains to be clarified whether the abnormal fiber type dis-
365
tribution in CNM results from a purely myogenic factor or a defective neural influence on the developing muscles.
References [1] Engel WK, Gold GN, Karpati G. Type 1 fiber hypotrophy and central nuclei. Arch. Neurol. 1968; 18: 435-444, [2] Samat HB. Muscle Pathology and Histochemistry, 1st edn, Chapter 4. Chicago: Am. Soc. Clin. Pathol. Press (ASCP), 1983. [3] Brooke MH, Engel WK. The histographic analysis of human muscle biopsies with regard to fiber type. 4. Children's biopsies. Neurology 1969; 19: 591-605. [4] Matsuoka Y, Gubbay SS, Kakulas BA. A new myopathy with type II muscle fiber fiypoplasia. Proc. Aust. Assoc. Neurol. 1974; 11: 155159. [5] Yoshioka M, Kuroki S, Ohkura K, Itagaki Y, Saida K. Congenital myopathy with type II muscle fiber hypoplasia. Neurology 1987: 37: 860-863. [6] Joong S, Danon MJ. Non-progressive congenital neuromuscular disease with uniform type 1 fiber. Arch. Neurol. 1983, 40: 147-150.
Brain & Development 19 (1997) 362-365
Case report
Congenital familial myopathy with type 2 fiber hypoplasia and type 1 fiber predominance H i d e k i M u r a n a k a a'*, S h i n - i c h i O s a r i a'b, H i r o s h i F u j i t a a, Y o s h i h a r u K i m u r a a, A k i r a G o t o a, C h i k a k o I m o t o b, I k u y a N o n a k a b aDepartment of Pediatrics, Hirosaki University School of Medicine, 5 Zaifu-cho, Hirosaki 036, Japan bDepartment of Laboratory Medicine, National Center Hospital for Nervous, Mental and Muscular Disorders, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187, Japan Received 28 June 1996; revised version received 28 April 1997; accepted 7 May 1997
Abstract
A 12-month-old girl with delayed developmental milestones, due to muscle hypotonia and weakness from early infancy, exhibited type 2 fiber hypoplasia. A muscle biopsy specimen disclosed type 1 fiber predominance and type 2B fiber deficiency compatible with congenital myopathy. During the following 4 years, she continued to have mild muscle weakness, but no mental retardation. Her mother had similar symptoms from early infancy with minimal progression. Although type 2 fiber hypoplasia is a non-specific finding in various diseases, it may be a specific finding in a limited number of patients with hereditary congenital non-progressive myopathy. © 1997 Elsevier Science B.V. Keywords: Congenital myopathy; Type 2 fiber hypoplasia; Type 1 predominance; Familial
of CNM, the daughter exhibiting type 2 fiber hypoplasia and type 1 predominance in a muscle biopsy specimen.
1. Introduction
In most patients with congenital non-progressive myopathies (CNM), including nemaline myopathy, central core disease and myotubular myopathy, the most common histochemical changes are hypoplastic type 1 fibers and type 1 fiber predominance [1,2]. Type 2 fiber hypoplasia itself is not a disease-specific finding, but is commonly seen in patients with central nervous system involvement, disuse atrophy and myasthenia gravis, and aged persons [3]. Some patients with type 2 fiber hypoplasia and the clinical characteristics of CNM have been reported [4,5]. However, it remains uncertain whether type 2 fiber hypoplasia plays a primary role for muscle symptom as a distinct clinical entity, because of the limited number of patients described and the lack of evidence of inheritance. We herein report a mother and her daughter who had the clinical characteristics
* Corresponding author. Tel.: +8l 172 395070; fax: +81 172 395071; e-mail: muranaka@ cc.hirosaki.ac.jp
0387-7604/97/$17.00
© 1997 Elsevier Science B.V. All rights reserved
Pll S 0 3 8 7 - 7 6 0 4 ( 9 7 ) 0 0 0 3 6 - 3
2. Patients
2.1. Patient 1
A 12-month-old girl infant was admitted to the pediatric ward of Hirosaki University Hospital for persistent muscle hypotonia. Her mother (patient 2) had generalized muscle weakness with facial muscle involvement from early infancy. Her father was healthy. This infant was the first child of unrelated Japanese parents, born by means of vaginal delivery after 41 weeks gestation with a birth weight of 3.07 kg. Fetal movements were considered normal. At birth she appeared healthy, with Apgar scores of 9 and 10 at 1 and 5 min, respectively. At 1 month, the infant was found to have generalized hypotonia. The baby girl obtained head control at 5 months and rolled over at 6 months of age.
H. Muranaka et al. / Brain & Developlment 19 (1997) 362-365
363
Fig. 1. Muscle CT of patient 1 (a) and her mother (b). Moderate-severe muscle atrophy and fat infiltration (a, b) in the thigh muscles compared with agematched normal controls (c, d) can be seen. a-d, right leg. On admission at 1 year of age, she had a slender stature and a funnel chest. She could not stand up by herself or walk without assistance. Her facial expression was 'myopathic' with a gaping mouth and an inverted V-shaped upper lip. The palate was high-arched. She was hypotonic with a positive scarf sign and the heel-to-ear phenomenon. Deep tendon reflexes were absent. Physical examination revealed no heart, lung or abdominal abnormalities. She was able to walk without assistance at 20 months of age. She had mild generalized muscle weakness with Gowers' maneuver while standing up when last examined at 4 years of age.
Laboratory findings, including the levels of serum creatinine kinase and aldolase, were within normal limits. The results of the motor nerve conduction study, neuroimaging and electrocardiography were normal for her age. An electromyogram (EMG) of the quadriceps revealed no abnormal findings at rest. The T S U M O R I - I N A G E developmental test result at 1 year of age was within normal range. Muscle CT at 4 years of age showed moderate atrophy and fat infiltration (Fig. 1a) compared with an age-matched control (Fig. 1c). Atrophy was more pronounced in the proximal muscles.
14. Muranaka et al. / Brain & Development 19 (1997) 362-365
364
ating fibers. Fibers with centrally placed nuclei comprised less than l% (Fig. 2a). Peripheral nerves, muscle spindles and blood vessels appeared normal. Fibrous tissue was slightly increased in the interstitium. Nemaline bodies or core structure were not seen. Peripheral nerve bundles were well myelinated. As seen on ATPase staining, type 1, 2A, 2B and 2C fibers comprised 80%, 18%, 1% and 1%, respectively, showing the type l fiber predominance. Type 2 fibers were selectively hypoplastic (Fig. 2b and c), which was statistically significant, as judged on morphometric analysis using a VIDAS VIDEOe L A N (Fig. 3). 2.2. Patient 2 (mother o f patient 1)
gVl~4 Q
C
Patient 2 also had the clinical characteristics of CNM. Her developmental milestones were delayed: she obtained head control at 8 months and walked without assistance at 19 months of age. At the age of 6 years, she noticed mild difficulty in walking up and down stairs, though there was no particular aggravation of muscle strength. At the age of 30 years, she exhibited mild generalized muscle weakness including the facial muscle. An EMG study showed a myopathic pattern with polyphasic short duration motor units. No myotonic discharges were recorded. Motor nerve conduction velocity was normal. Muscle CT revealed profound atrophy (Fig. lb), which was more predominant in the proximal muscles, compared to a normal age-matched control (Fig. ld). Muscle biopsy was not performed. She had led a normal daily life and considered herself healthy.
3. Discussion Although the clinical features were mild, this infant and mother had the typical characteristics of CNM, including: (i) delayed motor developmental milestones; (ii) muscle weakness and hypotonia from early infancy; (iii) areflexia; 70 60
Fig. 2. Muscle histochemistry in patient 1. There is mild fiber size variation with neither nemaline bodies nor necrotic fibers (a). On ATPase staining, all type 2A fibers (arrows) were found to be hypoplastic, and type 2B fibers were deficient (b and c). a, modified Gomori trichrome; b, Routine ATPase; c, ATPase with acid preincubation at pH 4.6. a-c, × 80. 2.1.1. Muscle biopsy at the age o f 1 year A biopsy specimen was taken from the left biceps brachii. Serial frozen sections were stained with hematoxylin and eosin (HE), modified Gomori-trichrome (mGT), N A D H tetrazolium reductase, phosphorylase, and ATPase with alkaline and acid preincubation. On HE, mild variation in fiber size, from 5 to 30/zm in diameter, was observed. There were no necrotic or regener-
Type 1fibers(n=200) (19.0--+4.6~m) Type 2fibers(n=200) (i0.6_+2,4~m)
50 40
//r--~\
30 20 I0 0
/ i ul.~ ///]i~ \\•k\\%k\%\ k 10 20 30 Fiberdiameter Fig. 3. Histogram of fiber diameters.
~m
H. Muranaka et al. /Brain & Developlment 19 (1997) 362-365
(iv) a 'myopathic' face and a high-arched palate; and (v) a non-progressive clinical course. The normal serum muscle enzyme levels and predominant proximal muscle atrophy observed on CT were also suggestive of CNM. Contrary to our expectations, this infant exhibited neither diagnostic intracytoplasmic abnormalities, including nemaline bodies, central cores or centrally placed nuclei, nor type 1 fiber hypoptasia in a muscle biopsy specimen. The most outstanding finding was the hypoplastic type 2 fiber. In contrast to the two previously described patients with congenital myopathy and type 2 fiber hypoplasia [4,5], our patient exhibited an abnormal fiber type distribution, including type 1 fiber predominance and type 2B fiber deficiency, which were supportive of a diagnosis of CNM. Accordingly, the condition in this infant may share a similar pathogenetic mechanism with a congenital neuromuscular disease with uniform type 1 fiber [6], because of its non-progressive nature and type 1 fiber predominance. It remains to be clarified whether the abnormal fiber type dis-
365
tribution in CNM results from a purely myogenic factor or a defective neural influence on the developing muscles.
References [1] Engel WK, Gold GN, Karpati G. Type 1 fiber hypotrophy and central nuclei. Arch. Neurol. 1968; 18: 435-444, [2] Samat HB. Muscle Pathology and Histochemistry, 1st edn, Chapter 4. Chicago: Am. Soc. Clin. Pathol. Press (ASCP), 1983. [3] Brooke MH, Engel WK. The histographic analysis of human muscle biopsies with regard to fiber type. 4. Children's biopsies. Neurology 1969; 19: 591-605. [4] Matsuoka Y, Gubbay SS, Kakulas BA. A new myopathy with type II muscle fiber fiypoplasia. Proc. Aust. Assoc. Neurol. 1974; 11: 155159. [5] Yoshioka M, Kuroki S, Ohkura K, Itagaki Y, Saida K. Congenital myopathy with type II muscle fiber hypoplasia. Neurology 1987: 37: 860-863. [6] Joong S, Danon MJ. Non-progressive congenital neuromuscular disease with uniform type 1 fiber. Arch. Neurol. 1983, 40: 147-150.