Additional Investigation After Muscle Biopsy Diagnosis

Next generation sequence panel showed that he had a heterozygous de novo mutation of the Dynamin 2 (DNM2) gene (c.1393C > T, p.Arg465Trp) which is a known pathogenic mutation.

Final Diagnosis

Autosomal dominant centronuclear myopathy from a de novo DNM2 mutation

Patient Follow-up

At the time of last follow-up , 1 year from the initial diagnosis, there was no progression of his muscle weakness. He was getting regular physical therapy and did not require assistive devices for ambulation. He was followed in pulmonary clinic for his asthma and there was no concern for respiratory muscle weakness.

Discussion

The child in this vignette presented with proximal lower limb weakness from early childhood. Pertinent negatives were absence of family history, ocular/bulbar findings, facial or neck muscle weakness, calf hypertrophy, and joint contractures.

Though anterior horn cell disorders (spinal muscular atrophy) and radiculoneuropathies could present with proximal limb weakness, retained tendon reflexes were against those diagnoses. Neuromuscular junction disorders seemed unlikely due to absence of ocular-bulbar involvement and lack of diurnal variation of symptoms. Myopathy was the most likely possibility in this case. Chronic course and early onset of symptoms suggested a genetic myopathy. In a boy with autism spectrum disorder and myopathy, dystrophinopathy (Duchenne and Becker muscular dystrophy) should be considered. Nonprogressive course, absence of calf hypertrophy and normal CK were against dystrophinopathy.

The investigative approach in a child with myopathy includes measurement of serum CK, EMG, muscle ultrasound or muscle MRI, muscle biopsy and finally genetic testing [1, 2]. Normal CK in our patient ruled out most of the muscular dystrophies. Congenital myopathies can have normal CK. EMG can further differentiate myopathy from a neurogenic process. EMG was however, not performed in this patient. A muscle biopsy was considered as the next step in this case which showed features of CNM. Next generation sequencing confirmed the final diagnosis of CNM due to DNM2 mutation.

Centronuclear myopathies are a group of clinical and genetically heterogeneous entity characterized by the presence of centralized nuclei in majority of the muscle fibers [3]. Additional histologic features include hypotrophy of the type I fibers and characteristic patterns of disorganization of oxidative enzymes [4]. Clinically, there is a wide spectrum of severity ranging from severe neonatal presentation to more mild adult disease [5, 6]. Ophthalmoparesis is commonly encountered which may help to differentiate CNM from other congenital myopathies [7]. Mutations in at least eight genes are described as causes of CNM: MTM1, DNM2, BIN1, RYR1, TTN, MTMR14, SPEG, and CCDC78 [8, 9]. Based on the inheritance pattern , CNM can be divided into the following groups: (1) X-lined recessive due to mutation of myotubularin gene-MTM1 (mytotubular myopathy) which has a severe neonatal presentation with profound hypotonia and respiratory failure [10]; (2) autosomal dominant caused by mutation of DNM2 gene causing a milder phenotype [11]; and (3) autosomal recessive form which is of intermediate severity caused by mutations of amphiphysin 2 (BIN1) and ryanodine receptor (RYR1) genes respectively [8, 9]. Heterozygous variants in CCDC78 and MTMR14 genes are associated with autosomal dominant early-onset centronuclear myopathy [12, 13]. Recently mutations in TTN and SPEG are considered as additional cases of autosomal recessive CNM [14, 15].

Mutations in DNM2 gene account for about 50% of cases of CNM [4]. A wide spectrum of clinical severity has been described in DNM2-related CNM varying from severe disease with neonatal onset to a milder disease with adult onset [11, 16, 17] Facial weakness, bilateral ptosis and ophthalmoparesis are common manifestations along with distal muscle atrophy, finger and ankle contractures and pes cavus [18]. However, the child described in this vignette had proximal muscle weakness without other features. There are only a few cases of DNM2-CNM presenting as late-onset dilated cardiomyopathy, ventricular septal defect or valvular irregularities and non-life-threatening arrhythmias [6, 18]. Cognitive impairment has been rarely reported in this condition, only in two families carrying the E368Q and R465W mutations and in one additional patient also showing the R465W mutation [17, 19]. Our patient had R465W mutation and had autism spectrum disorder.

Muscle imaging in DNM2 related myopathy shows a characteristic pattern with early involvement of the following muscles: medial gastrocnemius and soleus in the lower leg, adductor longus and hamstrings in the thighs, and gluteus minimus in the pelvis [18–20].

Histopathological hallmarks on muscle biopsy in DNM2-related CNM are (1) hypotrophy and predominance of type I fibers, (2) radial arrangement of sarcoplasmic strands and (3) centrally located nuclei [4].

To date, 19 different DNM2 mutations have been reported in approximately 100 families [6]. Mutations affecting the middle domain (MD) are generally associated with a milder clinical course [11, 20] whereas those associated with mutations affecting the pleckstrin-homology (PH) and GTPase effector (GED) domains of DNM2 are frequently associated with a severe phenotype [6, 16]. It has been found that DNM2 mutations affecting the PH domain have also been associated with dominant intermediate Charcot Marie Tooth Disease [21], and in an axonal variant of the same group of disorders, CMT2M [22]. The majority of patients with DNM2 mutations are sporadic cases with de novo dominant heterozygous mutations [6]. Mutational hot spots for DNM2 related CNM myopathy involve two adjacent amino acids, Glu368 and Arg369, encoded on exon 8, and a single amino acid Arg465, encoded on exon 11 [6], the latter was found in our case.

There is no specific cure for DNM2 related CNM. There are case reports of some patients with improvement with neuromuscular junction augmentation therapy (pyridostigmine) [23]. Allele-specific siRNA sequences have been recently shown to achieve functional restoration in patient-derived fibroblasts and murine DNM2-mRNA harboring p.R465W mutation (most commonly encountered mutation) which can pave the path for future gene-based therapies [24].

Pearls