Additional Investigation After the Muscle Biopsy Diagnosis

Next generation sequence panel showed compound heterozygous mutations of the ryanodine receptor (RYR1) gene : c.3381 + 1G > A (known pathogenic mutation) and c.3235_3240dup, p.Ser1079_Tyr1080dup (predicted to be pathogenic).

Final Diagnosis

CFTD due to autosomal recessive RYR1 myopathy (compound heterozygous)

Patient Follow-up

At the time of last follow-up , 1.5 years from the initial diagnosis, the child had significant improvements in his gross motor milestones. He could walk unassisted for few steps. He was able to feed orally and his gastrostomy tube was removed. He continued to have muscle hypotonia and diminished reflexes. He was getting regular physical therapy. Family had been counseled regarding malignant hyperthermia risk due to RYR1 mutation.

Discussion

The child in this vignette presented with neonatal hypotonia, poor feeding, and possible respiratory muscle weakness. Pertinent negatives were absence of family history and ocular findings (ptosis and ophthalmoplegia). He most likely had peripheral hypotonia from a neuromuscular disorder rather than central hypotonia as his reflexes were diminished and he had normal sensorium. The differential diagnosis for neonatal hypotonia is broad and involves different parts of the lower motor unit [1]. Anterior horn cell disorders particularly spinal muscular atrophy (SMA) type 1 was a consideration as he had diminished tendon reflexes. Peripheral neuropathies were also possible due to depressed reflexes. He did not have ocular manifestations but had possible bulbar and respiratory muscle involvement which might suggest the possibility of a neuromuscular junction (NMJ) disorder . Lastly genetic myopathies (congenital muscular dystrophy, congenital myopathy, and congenital myotonic dystrophy) are in the differential. His mother did not have clinical features of myotonic dystrophy type 1 making congenital myotonic dystrophy less likely (frequently transmitted from the affected mother). Negative family history either suggested autosomal recessive inheritance or a de novo mutation. The genetic disorders presenting with neonatal hypotonia and feeding difficulties which frequently mimics a neuromuscular disorder is Prader-Willi syndrome [2].

The investigative approach in a child with neonatal hypotonia from a peripheral neuromuscular disorder includes measurement of serum CK and metabolic work-up (lactate, serum carnitine, acylcarnitine, urine organic acids and acylglycine) [1]. A normal CK ruled out most of the congenital muscular dystrophies, though collagen-6-related myopathies can have normal or mildly high CK [3]. Metabolic work-up and genetic testing for PWS was negative. EMG will be the next important investigation. In this case, it helped to rule out anterior horn cell disorder and peripheral neuropathy. Myopathic EMG without signs of membrane irritability suggested the possibility of congenital myopathy. It should be kept in mind that in congenital myotonic dystrophy, typical myotonic discharges may not be present in the neonatal period [4]. Repetitive nerve stimulation can show decremental response in NMJ disorders (not performed in this case).

A muscle biopsy was considered as the next step in this case which showed features of CFTD. Next generation sequencing confirmed the final diagnosis of CFTD due to RYR1 mutation.

Congenital fiber type disproportion (CFTD) is a relatively rare subtype of congenital myopathy. In order to qualify for this diagnosis, 2 important criteria must be met: (1) type I fibers are small while type II fibers are either normal or hypertrophied in absence of other major structural abnormalities (such as cores or rods) and (2) the clinical features are consistent with congenital myopathy [5, 6]. Our patient met both these criteria. The term CFTD has been used when the mean diameter of type I fiber is at least 12% smaller than the mean type II fiber diameter irrespective of clinical features [4]. As this definition is rather nonspecific, some authors prefer to use the term fiber size disproportion (FSD) and reserve CFTD only for patients when the patients have clinical features of a congenital myopathy [7]. Two studies looking at the children’s muscle biopsies found that about 7% had FSD; only 10–20% of them (approximately 1% of all children biopsied) have CFTD [6].

Using the minimum cut off of 12% FSD, 67 children were identified with CFTD which fell to 50 children when the cut off was increased to 50% FSD, the latter group had a severe phenotype [6]. Majority of the patients present with neonatal hypotonia like our patient. Patients have varying degrees of weakness ranging from mild to severe either proximal muscle or generalized weakness [8]. Reflexes are usually reduced or absent. Joint contractures can be present at birth or develop later. Spinal deformities including scoliosis, kyphoscoliosis, and lordosis are seen in 25% of the patients [8]. Facial weakness/myopathic facies (long face, high-arched palate, and tented upper lip) and ophthalmoparesis can be present [6]. Feeding difficulties and respiratory involvement can be seen in about 30% of the patients [8]. Cardiac involvement and cognitive impairment are rarely noted [8, 9]. Serum CK is usually normal or mildly elevated [6, 8]. EMG can be normal, myopathic or mixed myopathic/neuropathic [6, 8]. CFTD can be caused by mutations in several genes. The following 6 genes have been implicated in CFTD: ACTA1 (~6% of individuals with CFTD), MYH7 (unknown), RYR1 (~10–20%), SELENON (SEPN1) (rare), TPM2 (rare) and TPM3 (~20–25% of individuals with CFTD) [9–15]. Patients with RYR1 mutation may have ophthalmoparesis but our patient did not have ophthalmoparesis [8].

At present, there are no specific or effective medical therapies for different genetic types of CFTD [8]. Treatment is mainly supportive with regular physical therapy and follow-up to detect respiratory failure, bulbar symptoms and orthopedic complications.

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