[source]
pmid = PMID:22560515
title = Congenital myopathy caused by a novel missense mutation in the CFL2 gene
[diagnosis]
disease_id = OMIM:610687
disease_label = Nemaline myopathy 7, autosomal recessive
[text]
Patient 1
The proband is the first child of Iraqi Kurdish consanguineous parents (Fig. 1A–C) and was born at term by cesarean section
due to a breech presentation. Her initial development was reportedly normal. She started to sit at the age of 6 months
and to crawl when she was 11 months old. However, she did not walk until the age of 2 years and 6 months.
Her maximum walking distance was a few hundred meters. Fine motor skills were intact. In Iraq, the diagnosis ‘progressive myopathy’ was made.
By age 13, she had developed a severe kyphoscoliosis (Cobb angle of 60°, a kyphosis of 69°, and a torsion of 25° of pelvis and lumbar spine).
Because of unforeseen problems, surgical correction had to be postponed and the kyphosis increased to 118° with a thoracolumbar scoliotic bend
to the left of 57° and a compensatory angle of 44°. At the age of 15 years, the family had fled to the Netherlands and the patient was seen
in our Neurology department. She complained about difficulties keeping her head straight and the need to support it with her hands.
She reported reasonable arm strength but said her legs felt weak. The maximum walking distance was 50–100 m.
Neurological examination showed a girl with normal intelligence and social skills. Vision and hearing were normal. She had a high-arched palate,
a very low-pitched voice and needed to support her head with her hands. Facial muscles showed a slight weakness, MRC grade 4, without involvement of the
eye muscles. She had a fixated back and a cervical lordosis (Fig. 1A–C). The neck muscles were hypotonic with a paresis grade 2 of the flexor muscles
and a paresis grade 4 of the extensor muscles. The shoulder girdle muscles had a paresis grade 2, whereas the rest of the arms showed a grade 4 weakness.
For getting up, she used the Gowers’ manoeuvre. The strength of the iliopsoas muscles was an MRC grade 1, the other legs muscles had a paresis grade 3–4.
The sensory exam was normal and reflexes were absent. The knees had a contracture of 10°. Routine hematological and chemical analysis was normal,
the CK level at the age of 11 years was 134 U/l (normal). CT scanning of the limbs at the age of 12 years revealed fatty changes in a number of leg,
trunk and arm muscles, most conspicuously in the soleus and quadriceps, but sparing the rectus femoris, and also of the semitendinosus, adductor magnus,
serratus anterior and latissimus dorsi. Slight abnormalities were seen in the gluteals and peroneal muscles, largely sparing the tibialis anterior.
Unfortunately the scan quality was insufficient to examine the upper extremity muscles, due to movement artefacts.
Nerve latencies and conduction velocities were normal on EMG examination. Needle examination revealed fibrillations and
positive spikes with small low amplitude polyphasic motor units with an increased recruitment pattern. The ear, nose and throat specialist concluded
that the low-pitched voice was due to her posture. No cardiac abnormalities were found with echocardiography.
In the following years, a gradual decline of strength was noted. Her ability to walk had decreased to a few meters indoors and the head drop increased.
As she complained of shortness of breath on occasions, pulmonary function tests were done. This revealed a chronic respiratory insufficiency due to
 muscle weakness. Non-invasive nocturnal positive pressure ventilation was initiated, resulting in an improvement of her general physical condition.
 At the age of 21 years she is completely wheelchair dependent, but studies architecture and enjoys an active social life.
 The muscle biopsy of patient 1 showed a dystrophic pattern with increased endomysial connective tissue and increased fat cells (Fig. 4).
 There was an increased variability of muscle fiber caliber with a 98% predominance of type 1 fibers. Seventy-two percent of the fibers
 had internal nuclei, several whorled fibers with splitting were seen and there were numerous cytoplasmic bodies. Enzyme histochemistry
 showed uneven distribution of ATP-ase causing a rubbed-out aspect, and core-like areas of diminished to absent staining with SDH and COX.
 In these areas immunohistochemical staining with desmin was enhanced. With immunohistochemistry for dystrophin, sarcoglycans, spectrin,
 dysferlin, and caveolin-3 normal staining of the muscle membranes was seen. With merosin there was a normal staining of the basement
 membrane. With caveolin- 3, vimentin and dysferlin roughly and diffusely stained aggregates were seen in the rubbed out areas of the
 cytoplasm of the fibers. More fine and partly punctiform to linear staining was seen with antibodies against dystrophin and all sarcoglycans.
 Electron microscopy could not be performed because insufficient material was available.
[text]
Patient 2
The proband’s sister was also born at term by cesarean section because of a breech presentation. Because of her affected sibling,
neurological examination was performed in the neonatal period, but no abnormalities were seen until the age of 2 years and 7 months.
From that moment, she started to lag in motor development. Neurological examination at that time showed hypotonia, hyperextension of
the knees and elbows, and a waddling gait. Gowers’ sign was positive. Although due to lack of cooperation formal muscle strength testing
was not possible, no obvious facial and shoulder weakness was seen. She had a lumbar lordosis and pes planes (Fig. 1D–F).
Cardiac examination was normal and routine hematological and chemical analysis showed no abnormalities.
EMG revealed normal motor and sensory conduction velocities, and amplitudes. Due to lack of cooperation, needle examination was limited
to the rectus femoris muscle which showed no abnormalities. Quantitative muscle ultrasound [9] showed abnormal echo intensities
in all extremities (Fig. 2). At the most recent follow-up at the age of 5 years, the parents reported that she had more difficulties with
keeping her head straight with an occasional head drop backwards. Running skills have improved slightly but she stumbled regularly.
Examination showed a girl with normal intelligence. Muscle strength testing showed weakness MRC grade 2 of the neck flexors, axial muscles,
hip abductor, and periscapular muscles, and a weakness grade 4 of the hip flexors, biceps and distal muscles.
The muscle biopsy of patient 2 at the age of 3 years and 3 months showed an increased percentage of fibers (19%) with internal nuclei (Fig. 5).
The fibers were unevenly stained on HE and Gomori trichrome, with the presence of cytoplasmic bodies and large clusters of nemaline rods.
There was a predominance of type 1 fibers. Enzyme histochemistry with ATP-ase revealed rubbed out areas; with NADH, SDH and COX uneven areas
with diminished to absent staining became apparent. Immunohistochemistry with antibodies against alpha-actinin-2 revealed accumulations of rods,
in other areas aggregations of desminpositive material were present. Immunohistochemistry for dystrophin, sarcoglycans, alpha-dystroglycan,
dysferlin, and caveolin-3 showed normal staining of the muscle membranes. With immunocytochemistry for merosin, the muscle basal membrane
stained normally. Nuclei were normally stained with emerin and lamin A/C. With caveolin-3, vimentin, dysferlin and beta-dystroglycan
roughly and diffusely stained aggregates were seen in the rubbed out areas of the cytoplasm of the fibers. More discrete, partly
linear staining was seen with antibodies against dystrophins and all sarcoglycans. Electron microscopy analysis showed areas with
Z-band streaming and rods, often in large aggregates. These aggregates were accompanied by osmiophilic granular material,
degenerating membranous organelles and cytoplasmic bodies. Intranuclear rods were not present. Biochemical analysis for mitochondrial
defects revealed no abnormalities.