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Centronuclear myopathy (CNM) is a rare hereditary congenital myopathy characterized by muscular hypotonia and abnormal centralization of nuclei in muscle fibers. The autosomal recessive (AR) form presents from birth to childhood, followed by a mild progression of muscle weakness. Despite recently identified genetic loci in the AR form, genotype-phenotype correlations are poorly established. Our index case is a 17 year old boy with recessive CNM causing loss of ambulation at 13 years of age and requiring ventilatory assistance nightly. Recent genetic testing revealed a c.1723A > T mutation in the BIN1 gene. The phenotype of the index case contrasts to previously published cases, where recessive CNM patients have lost ambulation in their 20s and have not required ventilatory assistance. The disease severity of our index case, carrying a c.1723A > T mutation, widens the phenotypic spectrum of AR CNM to include earlier loss of ambulation and respiratory failure.
Centronuclear myopathy (CNM) is a rare congenital myopathy characterized by muscular hypotonia and abnormal centralization of nuclei on muscle biopsy. The condition is hereditary and is divided into three forms according to genetic inheritance: X-linked recessive, autosomal dominant (AD) and autosomal recessive (AR) (1, 2).
The clinical features are variable, but generally, the AR form, which is discussed in this case report, has an onset from birth to childhood followed by a mild progression of muscle weakness (2). The phenotypic features include facial weakness, ptosis and external ophthalmoplegia, as well as secondary joint contractures and foot deformities. No case has been reported of respiratory deterioration requiring ventilatory assistance (2), and there is no abnormality in the mental status of these patients. Serum creatine kinase levels are in the normal range or slightly elevated, ENeG results are normal, and EMG findings are either normal or show small-amplitude motor unit potentials typical of myopathies (3).
The genetic causes underlying the AR form have previously been unknown, but a recent (2007) finding of mutations in the gene coding for amphiphysin 2 (BIN1) has opened up for a better understanding of the pathophysiology behind this form of CNM (1). It is important to note that there remain a significant number of CNM patients that have typical clinical features and histopathological findings, but in which no responsible genetic mutation has been identified.
In this case report, the index case is a 17-year-old boy with recessive CNM, in which genetic testing (2007) revealed a homozygous nonsense mutation in the BIN1 gene (1). Noteworthy is that despite recent findings of new genetic loci in the AR form, the correlations between genotype and phenotype are less established. The aim of this case report is to describe that the phenotype of a patient with a homozygous BIN1 mutation is more severe than previously reported for AR cases of CNM.
Biopsy material from the patient was obtained from the anterior tibial muscle at 6 years of age and from paraspinal back muscle at 15 years of age, using the percutaneous conchotome method (1st biopsy) or open surgery (2nd). The biopsies were frozen in isopentane chilled with liquid nitrogen and stored at -80 degrees C before cryotome sectioning.
Cross sections of muscle biopsies underwent routine histochemical, enzymatic and immunohistochemical stainings.
The index case is a 17 year old boy with generalized muscle weakness requiring use of a wheelchair. His parents have first cousin consanguinity and there is no family history of neuromuscular disorders. Pregnancy and delivery proceeded without remark. At one month of age, his parents noted the first symptoms as weakness in arm extension, ptosis, and later, a general delay in motor skills. He acquired independent ambulation at 16 months of age and speech and intellectual development has been appropriate. His first documented visit to a neurologist was at six years of age, in which examination revealed bilateral ptosis, facial weakness, ophthalmoplegia in the form of horizontal gaze palsy, and a wide-based gait. He also showed weakness in rising from a supine to sitting position, and diffuse hypotonia was noted in combination with general areflexia. His weight and height were determined to be two standard deviations below normal reference values. At the time, his parents described a maximum walking time of ten minutes after which he would get tired and sit down.
At age nine, he underwent an orthopedic operation to correct his bilateral foot deformities, pes equinovarus adductus. Another operation was undertaken, at 15 years of age, to reduce a rapidly progressive scoliosis. Tests of his respiratory function, preoperatively to the scoliosis operation, showed a restrictive pattern with significant carbon dioxide retention (pCO2 7.6kPa) and poor saturation (≈ 90%). This has required the use of nightly ventilatory assistance since then. Cardiac function has been normal, but with a persistent slight tachycardia (100 beats per minute).
In terms of ambulation, his maximum walking distance was 50 metres at 12 years of age but a rapid deterioration over the course of one year caused complete loss of independent ambulation. At the time of writing, he only possesses the physical capacity to slightly move his fingers.
Genetic analysis has detected a c.1723A > T mutation in exon 20 of the BIN1 gene, in homozygous form. Both parents were heterozygous carriers, while his healthy siblings were not genetically tested (Fig. (Fig.1).1). Early on, the clinical picture suggested congenital myopathy. The diagnosis was established when skeletal muscle biopsy had been performed, showing centrally placed nuclei in most muscle fibers (Fig. (Fig.22 A-C), which is consistent with centronuclear myopathy. A subsequent biopsy showed further derangements of the muscle, including massive infiltration of fatty tissue and to a lesser extent of connective tissue, as well as frequent occurrence of vacuoles (Fig. (Fig.22 D-G). In both biopsies ATPase staining demonstrated all fibers to be of type 1 (not shown). Laboratory tests revealed normal creatine kinase levels and EMG and ENeG, at six years of age, in m tibialis anterior dx and n fibularis dx, respectively, showed no abnormal changes.
The BIN1 gene consists of several domains (1, 3) and Nicot et al identified three novel homozygous mutations in this gene in four patients with recessive centronuclear myopathy, one of which was the patient in this case report. This patient carried a c.1723A > T nonsense change producing a premature stop codon (K575X) in the SH3 domain of the BIN1 gene. Amphiphysin 2 has been shown to recruit dynamin through its SH3 domain (4), and Nicot et al accordingly revealed a weakened interaction between amphiphysin 2 and dynamin 2 (DNM2) in transfected cells with the c.1723A > T mutation. Due to the importance of the BIN1-DNM2 interaction in endocytosis, the study suggested that this mutation disrupts normal muscle function and causes abnormal positioning of nuclei.
According to previous clinical findings, one can divide recessive CNM into three subgroups: 1) early onset (that is, infancy or childhood) AR form with ophthalmoparesis; 2) early onset without ophthalmoparesis; and 3) late onset (adulthood) form without ophthalmoparesis (5). The first subgroup showed the greatest disease severity with loss of walking in the majority of subjects in their 20s. It is worth mentioning that the mode of inheritance in this study was not based on any genetic markers, as none were known at the time. In terms of this classification, our index case would seemingly be eligible for inclusion in the first group; that is, early onset recessive CNM with ophthalmoparesis. However, our patient appears to be more severely affected since he lost the ability to walk at 13 years of age, which is considerably earlier than the patients described in that study. This is reflected also by pronounced changes in the muscle morphology. In fact, he has an unusually progressive course in light of his clear need for ventilatory assistance, which has not been documented in any other case up to date (2). It is unclear, however, to what extent the acquired scoliosis has impacted on his respiratory function.
In reference to the attempt to draw genotype-phenotype correlations, our case report could suggest that the c.1723A > T genotype is an indicator of a more severe phenotype. We encourage further studies on this topic, which might lead to an improved assessment of disease progression and hence, a better appraisal of patients’ needs.
This work was supported by Stiftelsen Frimurare Barnhuset.