Elsevier

Brain and Development

Volume 25, Issue 7, October 2003, Pages 457-476
Brain and Development

Review article
The floppy infant: contribution of genetic and metabolic disorders

https://doi.org/10.1016/S0387-7604(03)00066-4Get rights and content

Abstract

The floppy infant syndrome is a well-recognized entity for pediatricians and neonatologists. The condition refers to an infant with generalized hypotonia presenting at birth or in early life. The diagnostic work up in many instances is often complex, and requires multidisciplinary assessment. Advances in genetics and neurosciences have lead to recognition of newer diagnostic entities (several congenital myopathies), and rapid molecular diagnosis is now possible for several conditions such as spinal muscular atrophy (SMA), congenital muscular dystrophies (CMD), several forms of congenital myopathies and congenital myotonic dystrophy. The focus of the present review is to describe the advances in our understanding in the genetic, metabolic basis of neurological disorders, as well as the investigative work up of the floppy infant. An algorithm for the systematic evaluation of infants with hypotonia is suggested for the practicing pediatrician/neonatologist.

Introduction

The term ‘floppy baby or infant’ is used to denote an infant with poor muscle tone affecting the limbs, trunk and the cranial–facial musculature. The condition is usually evident at birth or is identified during early life as poor muscle tone results in an inability to maintain normal posture during movement and rest. There are numerous etiologies and establishing a specific diagnosis in the individual case can be labor intensive. The rapid expansion in the knowledge of genetic disorders, underlying gene mutations and availability of DNA based diagnostic tests has made non-invasive and rapid diagnosis possible for several disorders (Prader–Willi syndrome (PWS), congenital myotonic dystrophy, spinal muscular atrophy (SMA)). On the other hand, the list of disorders that can be presently considered in the differential diagnosis of the floppy infant grows longer and more complex. The focus of the present review is the process of clinical evaluation and investigation of generalized hypotonia in the neonatal period and infancy. We examine the advances in our understanding of these disorders and propose a systematic approach to the evaluation of the floppy infant.

The concept of central vs. peripheral disorders causing hypotonia is clinically useful. The myotactic reflex is the basis of normal tone in a muscle. Muscle tone is maintained at the peripheral level by the participation of the fusimotor system: pathways involving the muscle spindles that promote muscle contraction in response to stretch and the inverse myotactic reflex involving the golgi tendon organ that provides a braking mechanism to the contraction of muscle. A lesion interrupting the stretch reflexes at any level in the lower motor neuron (LMN) will result in a loss of muscle tone and stretch reflexes i.e. flaccidity [1]. The output of gamma motor neurons to the muscle spindle is influenced by supraspinal influences. These influences are predominantly inhibitory, thus lesions affecting the upper motor neuron result in the reduction of these inhibitory influences, in turn causing an increase in excitatory output of the gamma motor neurons to the muscle spindle [2]. However, in early infancy, contrary to expected increase in muscle tone, the response to an upper motor neuron lesion in the early stages is flaccidity and loss of muscle tone [3]. This pattern of hypotonia is usually associated with preserved or hyperactive reflexes, and later evolves into spasticity. The clinical distinction between an upper motor neuron and LMN lesion provides a rationale for investigations based on the localization of lesion in the pathway of motor control (central vs. peripheral hypotonia).

Section snippets

Prenatal, neonatal and perinatal assessment

The assessment should include a detailed pedigree and documentation of prenatal risk factors: a history of drug or teratogen exposure, breech presentation, reduced fetal movements and presence of polyhydramnios, maternal diseases (diabetes, epilepsy). The importance of parental age, consanguinity, a family history of neuromuscular disease and the identification of other affected siblings cannot be overemphasized. Details of perinatal birth trauma, birth anoxia, delivery complications, low APGAR

Laboratory investigations

The disorders leading to the floppy infant syndrome will be considered under two categories for the purpose of our discussion: to the first group belong infants with pure hypotonia of central or peripheral origin, while the second group includes infants with hypotonia and multisystem features (hypotonia plus). Appropriate and cost effective use of laboratory investigations to establish a specific etiologic diagnosis is always desirable. The history and physical assessment will provide clear

Chromosomal disorders

These syndromes are often associated with distinctive craniofacial and physical dysmorphisms that suggest a diagnosis to the clinical geneticist (Table 3). Aneuploidy, microdeletions and subtelomeric cryptic deletions can present with hypotonia as a prominent feature in early life. A karyotype study is essential in the work up of a hypotonic infant, as extensive and expensive investigations are rendered unnecessary, if a cytogenetic abnormality is picked up early in the course of

Spinal muscular atrophy (Werdnig–Hoffman disease)

(Table 2) SMA is an autosomal recessive disorder involving the degeneration of the anterior horn cells. Infants with SMA are hypotonic and weak, at birth or soon after. The combination results in poverty of spontaneous movements and an abnormal posture typical for a floppy infant. The presence of tongue fasciculation and absent deep tendon reflexes, mild contractures and decreased fetal movements before birth complete the clinical picture. The weakness usually involves the bulbar and

Conclusions

Our understanding of genetic, neurological and metabolic considerations in the floppy infant is reaching a far greater degree of complexity, in comparison to earlier descriptions of this condition [121]. In a majority of disorders, the hypotonia is due to consequences of genetic and/or metabolic deficits at a molecular level. These genetic alterations affect key structural proteins, ion channels, receptors or metabolic pathways within the nervous system, in the nerve, neuromuscular junction and

Electronic database sources accessed in the preparation of this manuscript

Gene clinics: Clinical Genetic Information Resource [Database online]. Copyright, University of Washington, Seattle, 1995. Available at http://www.geneclinics.org.

Online Mendelian Inheritance in Man, OMIM (™) [62][database online]: McKusick-Nathans Institute for Genetic Medicine, Johns Hopkins University (Baltimore, MD) and National Center for Biotechnology Information, National Library of Medicine (Bethesda, MD), 2000. Available at http://www.ncbi.nlm.nih.gov/omim/ Online mendelian inheritance

Acknowledgements

The authors would like to extend their thanks to Dr N. Shah (Section of Pediatric Neurosciences), Drs B. Chodirker and A. Chudley (Section of Genetics) for their comments and suggestions.

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