Genetic evaluation of the pediatric patient with hypotonia: perspective from a hypotonia specialty clinic and review of the literature

Abstract

CPT Carnitine palmitoyltransferase MDC1ACongenital muscular dystrophy type 1A SLO Smith-Lemli-Opitz syndrome SMA Spinal muscular atrophy AIM Hypotonia is a symptom of diminished tone of skeletal muscle associated with decreased resistance of muscles to passive stretching, which can be caused by abnormalities of the central nervous system, any element of the lower motoneuron, or both. Hypotonia is not a specific diagnosis, but can be part of over 500 different genetic disorders, with many other conditions waiting to be identified. This review proposes a pragmatic approach to evaluating hypotonia in neonatal and pediatric populations by using a diagnostic algorithm.METHOD We use a dedicated literature review combined with clinical experience in a newly established multidisciplinary center for hypotonia to establish a diagnostic algorithm.RESULTS Hypotonia can be a symptom of over 500 different genetic disorders. It can present as peripheral, central, or combined hypotonia, providing necessity for rational and systematic diagnostic testing.INTERPRETATION Our analyses demonstrate that a staged diagnostic approach categorizing patients as having peripheral, central, or combined hypotonia is the most efficient to providing a rational work-up. Establishing a diagnosis is crucial for prognosis, management, and treatment strategies, and for ascertaining an accurate recurrence risk for future offspring in a family.

Congenital Muscular Dystrophies: A Brief Review

“…Overall differential diagnosis of CMD has to take into account congenital myopathies, ie, myopathies with typical structural or ultrastructural features on the muscle biopsy, congenital myotonic dystrophy, congenital myasthenic syndromes, early-onset metabolic myopathies, Marinesco–Sjögren syndrome, and other subtypes of congenital ataxia, congenital disorders of the motor neuron and the peripheral nerve, and other genetic syndromes such as Prader–Willi syndrome, 7 and the more frequently acquired conditions leading to profound hypotonia, such as acute hypoxic ischemic encephalopathy and neonatal sepsis.…”

De novo unbalanced translocation leading to monosomy 9p24.3p24.1 and trisomy 19q13.42q13.43 characterized by microarray‐based comparative genomic hybridization in a child with partial cortical dysplasia and craniofacial dysmorphisms without trigonocephaly

“…However, a CGH was performed because the phenotype was evocative of genomic imbalance [Miller et al, 2010] and chromosome microarray analysis has been proposed as a valuable tool for genetic evaluation of pediatric patients with hypotonia [Lisi and Cohn, 2011].…”

Cellular function of satellite cells does not play a role in muscle weakness of adult Ts1Cje mice

“…Hypotonia is a state of low muscle tone accompanied by a slower response speed together with reduced muscle strength [3][4]. Cowley et al [5] reported that the force generated by the knee extensor muscle of DS individuals is approximately 40%-70% less than that generated by individuals with intellectual disabilities other than DS and those with normal intellectual ability.…”