Congenital myopathies: Natural history of a large pediatric cohort

Abstract

Objective: To assess the natural history of congenital myopathies (CMs) due to different genotypes.

Methods: Retrospective cross-sectional study based on case-note review of 125 patients affected by CM, followed at a single pediatric neuromuscular center, between 1984 and 2012.

Results: Genetic characterization was achieved in 99 of 125 cases (79.2%), with RYR1 most frequently implicated (44/125). Neonatal/infantile onset was observed in 76%. At birth, 30.4% required respiratory support, and 25.2% nasogastric feeding. Twelve percent died, mainly within the first year, associated with mutations in ACTA1, MTM1, or KLHL40. All RYR1-mutated cases survived and did not require long-term ventilator support including those with severe neonatal onset; however, recessive cases were more likely to require gastrostomy insertion (p = 0.0028) compared with dominant cases. Independent ambulation was achieved in 74.1% of all patients; 62.9% were late walkers. Among ambulant patients, 9% eventually became wheelchair-dependent. Scoliosis of variable severity was reported in 40%, with 1/3 of (both ambulant and nonambulant) patients requiring surgery. Bulbar involvement was present in 46.4% and required gastrostomy placement in 28.8% (at a mean age of 2.7 years). Respiratory impairment of variable severity was a feature in 64.1%; approximately half of these patients required nocturnal noninvasive ventilation due to respiratory failure (at a mean age of 8.5 years).

Conclusions: We describe the long-term outcome of a large cohort of patients with CMs. While overall course is stable, we demonstrate a wide clinical spectrum with motor deterioration in a subset of cases. Severity in the neonatal/infantile period is critical for survival, with clear genotype-phenotype correlations that may inform future counseling.

Figure 1. Perinatal features

(A) Antenatal history: the highest percentage of decreased FM and polyhydramnios was found in MTM1-related myopathy. (B) Age at birth: the overall prematurity rate in our cohort of CMs (21.1%) was higher than in the general population of England and Wales (7.4% in 2008). (C) In the neonatal period, approximately one-third of patients required NGT feeding and respiratory support, with variability according to the genetic background. AD = autosomal dominant; AR = autosomal recessive; CM = congenital myopathy; FM = fetal movements; NGT = nasogastric tube.

Figure 2. Age at onset and survival

(A) Age at onset according to the genetic background: most cases, presented within the first year of life, with neonatal presentations more common than infantile presentations. (B) Kaplan-Meier survival curve: approximately 2 of 3 deaths occurred within the first year of life. (C) Survival according to genotype: no death was registered in patients with RYR1, SEPN1, and NEB mutations. Of note, 8 of 15 of those who died were affected by NM, 7 of 15 by CNM, with MTM1, ACTA1, and KLHL40 the most common identifiable causes. AD = autosomal dominant; AR = autosomal recessive; CM = congenital myopathy; CNM = centronuclear myopathy; NM = nemaline myopathy.

Figure 3. Motor abilities

(A) Maximal motor ability: all patients with SEPN1 and NEB mutations walked independently, whereas motor ability was more variable with other genetic backgrounds. (B) Walking age: the majority of ambulant patients walked late (39.3%) or at the upper limit of normal at 18 months (23.6%). At last follow-up, 3.2% were younger than 18 months. (C) Kaplan-Meier curve showing wheelchair use in patients who achieved independent ambulation: 20 of 89 (22.5%) started manual wheelchair for long distances, whereas a further deterioration of motor performances was observed in 8 of 20, who became wheelchair-bound.

Figure 4. Respiratory, feeding, and orthopedic procedures

(A) Prevalence of NNIV, G/J, and SS according to genetic background: overall about one-third of cases required NNIV and G/J insertion. Only a minority of cases required scoliosis surgery. (B) Kaplan-Meier curves showing ventilation, G/J, and SS-free patients: NNIV was started at a mean age of 8.53 years, whereas G/J was placed earlier, at a mean age of 2.74 years, usually within the first year. SS was performed at a mean age of 12.0 years. AD = autosomal dominant; AR = autosomal recessive; CM = congenital myopathy; G/J = gastrostomy/jejunostomy; NNIV = nocturnal noninvasive ventilation; SS = scoliosis surgery.