Pathogenesis

Early onset of NMD can lead to chest wall deformity and lung disease due to developmental factors. In infancy the chest wall is very compliant with relatively stiff lungs and small airways. With progressive weakness of the intercostal muscles, the chest wall becomes even more compliant. Small airways have a tendency to become obstructed, leading to micro-atelectasis and decreased functional residual capacity. The compliant chest wall with initial sparing of diaphragm function leads to development of a small bell-shaped chest with depressed sternum, protruding abdomen, and paradoxical breathing, typically seen in SMA type 1. As the disease progresses, chest wall muscles shorten and lose elasticity, costosternal and costovertebral joints contract, and lung volumes decrease as a result of severe hypotonia. Inspiratory and expiratory pressures decrease, expiratory pressures more so than inspiratory, causing ineffective cough and poor airway clearance. As the child with NMD ages, kyphoscoliosis commonly develops, increasing the severity of restrictive lung disease. Although central control of breathing remains normal, response to central chemoreceptors may decrease because of chronic hypercapnia.

Treatment

Even though gene-targeted therapies are being developed for some NMDs, current interventions are primarily supportive rather than curative. Close surveillance through periodic review of the history and physical examination is critical. The development of personality changes, such as irritability, decreased attention span, fatigue, and somnolence, may point to the presence of sleep-associated gas exchange abnormalities and sleep fragmentation. Changes in speech and voice characteristics, nasal flaring, and the use of other accessory muscles during quiet breathing at rest may provide sensitive indicators of progressive muscle dysfunction and respiratory compromise. Although the frequency of periodic re-evaluation needs to be tailored to the individual patient, tentative guidelines were developed for patients with DMD; an abbreviated summary of such recommendations, applicable to all children with NMDs, is provided in Table 412-1.

Table 412-1 PROPOSED GUIDELINES FOR INITIAL EVALUATION AND FOLLOW-UP OF PATIENTS WITH NEUROMUSCULAR DISEASE

CXR, chest x-ray; MEP, maximal expiratory pressure; MIP, maximal inspiratory pressure; PFT, pulmonary function test.

* Please note that if polysomnography is not readily available, multichannel recordings including oronasal airflow, nocturnal oximetry, and end-tidal carbon dioxide levels may provide an adequate alternative.

Guidelines for evaluation and management of patients with SMA were developed on the basis of expert consensus. Four classifications of SMA, based on age of onset and level of function, are recognized (Table 412-2). Treatment of SMA is focused on level of function (non-sitter, sitter, or walker) rather than SMA type. Unlike patients with DMD, patients with SMA do not demonstrate correlation between pulmonary function and need for mechanical ventilatory support. Rather, longitudinal monitoring for signs and symptoms of sleep-disordered breathing and ineffective airway clearance should be utilized to direct patient care.

Genetics

In 2003, the paired-like homeobox 2B (PHOX2B) gene was identified as the disease-defining gene for CCHS. This gene, which is essential to the embryologic development of the ANS from the neural crest, is expressed in key regions that explain much of the CCHS phenotype. Individuals with CCHS are heterozygous for either a polyalanine repeat expansion mutation (PARM) in exon 3 of the PHOX2B gene (normal number of alanines is 20 with normal genotype 20/20), such that individuals with CCHS have 24-33 alanines on the affected allele (genotype range is 20/24-20/33), or a non–polyalanine repeat expansion mutation (NPARM) resulting from a missense, nonsense, or frameshift mutation. Roughly 90% of the cases of CCHS have PARMs and the remaining ≈10% of cases have NPARMs. The specific type of PHOX2B mutation is clinically significant as it can help with anticipatory guidance in patient management.

The majority of CCHS cases occur because of a de novo PHOX2B mutation, but 5-10% of children with CCHS inherit the mutation from an asymptomatic parent who is mosaic for the PHOX2B mutation. CCHS is inherited in an autosomal dominant manner. Therefore, an individual with CCHS has a 50% chance of transmitting the mutation, and resulting disease phenotype, to each child. Mosaic parents have up to a 50% chance of transmitting the PHOX2B mutation to each offspring. Genetic counseling is essential for family planning and for preparedness in the delivery room for an anticipated CCHS birth. PHOX2B testing is advised for both parents of a child with CCHS to anticipate risk of recurrence in subsequent pregnancies. Further, prenatal testing for PHOX2B mutation is clinically available (www.genetests.org) for families with a known PHOX2B mutation.

Clinical Manifestations

Patients with CCHS usually present in the first few hours after birth. Most children are the products of uneventful pregnancies and are term infants with appropriate weight for gestational age; Apgar scores have been variable. They do not show signs of respiratory distress, but their shallow respirations and respiratory pauses (apnea) evolve to respiratory failure with apparent cyanosis in the first day of life. In neonates with CCHS, the PaCO₂ accumulates during sleep to very high levels, sometimes >90 mm Hg, and may decline to normal levels after the infants awaken. This problem becomes most apparent with failure of multiple attempts at extubation in an intubated neonate (who appears well with ventilatory support but in whom respiratory failure develops after removal of the support). However, the more severely affected infants hypoventilate awake and asleep; thus the previously described difference in PaCO₂ between states is not apparent. Often, the respiratory rate is higher in rapid eye movement (REM) sleep than in non-REM sleep in individuals with CCHS.