Spinal Muscular Atrophy Type 1 Case File

Spinal Muscular Atrophy Type 1 Case File

Eugene C. Toy, MD, Ericka Simpson, MD, Pedro Mancias, MD, Erin E. Furr-Stimming, MD

CASE 54

A 2-day-old full-term infant is seen in the intermediate care nursery for evaluation of generalized hypotonia. He was born to a 25-year-old G2 P2 mother, who received adequate prenatal care during an uncomplicated pregnancy. However, the mother notes that, in retrospect, she felt much less in utero movement with this baby than with her prior pregnancy. His clinical course thus far has been significant for poor feeding with inadequate sucking upon attempts to breastor bottle-feed. On examination, the patient appears bright, alert, and attentive to visual and auditory stimuli. His respiratory effort seems adequate, but his cry is somewhat muted and weak. He is lying supine with his arms extended, hips abducted, and knees somewhat flexed. There is paucity of spontaneous movement and, upon stimulation, he does not seem to have antigravity strength. He has significant axial and appendicular hypotonia as well as diffuse hyporeflexia. Cranial nerve examination is significant for normal horizontal extraocular movements with fibrillations of the tongue. His hips readily dislocate bilaterally.

▶ What is the most likely diagnosis?

▶ What is the next diagnostic step?

▶ What is the next step in therapy?

ANSWERS TO CASE 54:

Spinal Muscular Atrophy Type 1                                                  

Summary: A 2-day-old full-term infant, product of an uncomplicated pregnancy, has profound hypotonia and weakness. His mother noted decreased in utero movements compared to her prior pregnancies. In addition to hypotonia and weakness, the patient’s examination is significant for an alert and attentive sensorium, a weak cry, congenital hip dislocations bilaterally, diffuse hyporeflexia, normal extraocular muscles, and tongue fibrillations.

• Most likely diagnosis: Spinal muscular atrophy (SMA) type 1
• Next diagnostic step: Molecular testing for survival motor neuron 1 (SMN1) gene
• Next step in therapy: Supportive therapy including respiratory support, physical and occupational therapy, a discussion of prognosis, and consideration of genetic counseling for the parents

ANALYSIS

Objectives

1. Describe the typical clinical presentation of SMA type 1.
2. State the underlying pathogenesis of SMA type 1.
3. Describe a diagnostic approach to hypotonic infants.
4. Discuss newly approved treatment for SMA I.

Considerations

This newborn is profoundly hypotonic and weak yet appears alert and attentive. His examination reveals multiple lower motor neuron findings: hypotonia, weakness, hyporeflexia, and tongue fibrillations. Taken together, this constellation suggests a peripheral etiology rather than a central or combined etiology, as discussed in the following text. Congenital hip dislocations suggest in utero hypotonia, as development of the acetabulum depends on firm application of the femoral head. Similarly, paucity of in utero movement suggests fetal weakness. Poor feeding, tongue fibrillations, and a weak cry suggest involvement of bulbar and respiratory musculature. Given these findings, the most likely diagnosis is SMA type 1. This disorder will be briefly presented, followed by a discussion of the general approach to hypotonic infants—the so-called “floppy baby.”

Spinal Muscular Atrophy Type 1

During in utero development of the spinal cord there is a relative overproduction of motor neurons, which are subsequently winnowed down through a process of programmed cell death. In SMA type 1, this process goes awry and too many cells are pruned, resulting in an insufficient number of these motor neuron cells. SMA is therefore a pure motor neuron disorder characterized by lower motor neuron signs such as hypotonia, weakness, hyporeflexia, and fibrillations. Since this process does not affect the cerebral cortex or subcortical structures, patients appear alert and attentive. Interestingly, although bulbar and respiratory muscles are affected, extraocular muscles are largely spared. While the infantile form of SMA (type 1) is most common and severe, there are also less severe forms that present later in infancy or early childhood (types 2 and 3), as well as an adult-onset form (SMA 4).

Mutation or deletion of the SMN1 gene causes the vast majority of cases of SMA. The most common mutations are readily detected with commercially available molecular genetic testing with targeted mutation analysis. However, point mutations require gene sequencing; a reasonable second step in diagnosis should target mutation analysis and does not reveal the underlying genetic cause in an otherwise typical case. Ancillary testing such as electromyography (EMG) and, particularly, muscle biopsy are much less commonly used given the availability of genetic testing. The prognosis for SMA type 1 has been generally quite poor, with most patients dying in the first year of life, though there are reports of longer-term survivors. The presence of a virtually identical gene—SMN2—contributes to the clinical variability in patients with SMA. Management focuses principally on respiratory and nutritional support as well as avoidance of contractures. However, with the landmark approval of the targeted gene therapy, nusinersen, the natural history of the most severe infantile form is now characterized by increased survival and children achieving motor milestones, which would have never been possible.

APPROACH TO:

Infantile Hypotonia                                                  

When supine, hypotonic neonates generally lack the normal flexed posture of the arms and legs and instead will have their arms extended at their sides with their legs abducted at the hip (Figure 54–1). There is often a history during pregnancy of decreased fetal movements and polyhydramnios due to decreased fetal swallowing of amniotic fluid. Delivery may be prolonged and difficult due to abnormal fetal positioning as well as decreased fetal movement. Because of perinatal difficulties, many patients may manifest initial neonatal depression, regardless of the cause of their hypotonia. As discussed in the following text, the patient’s level of alertness is an important clue to localization, but it must be interpreted in light of this caveat. Severe hypotonia may be associated with congenital contractures (arthrogryposis) or excessive joint flexibility. If weakness is prominent, poor feeding and respiratory difficulties may also be seen. Involvement or sparing of bulbar musculature is an important clue to the underlying localization. For example, normal facial strength with profound appendicular weakness suggests a possible spinal cord process. However, as in the case of SMA, bulbar involvement may be incomplete. Dysmorphic features and involvement of other organ systems suggest a chromosomal abnormality and are therefore important to look for on examination. Developmental reflexes are important to assess as they may help distinguish between cerebral and peripheral causes. The Moro reflex is elicited by rapid extension of the neck relative to the trunk and is characterized by initial abduction and extension of the arms with subsequent adduction and flexion. The asymmetric tonic neck reflex is elicited by turning the head to the side, which results in extension of the arm and leg on the side to which the head is turned with flexion of the arm and leg on the opposite side.

Figure 54–1. An infant demonstrating hypotonia with draping over the examiner’s hand when held in ventral suspension. Normally the head will be kept in the same plane as the trunk and the limbs will be flexed. Head control may be poor or absent, with the head falling backward or to the side with elevation of infant’s body.

Initial categorization into a cerebral, spinal, peripheral, or combined localization helps to narrow down the protean causes of infantile hypotonia, thereby focusing the differential diagnosis and evaluation. Cerebral hypotonia is generally seen in association with other cortical and subcortical findings such as alteration of awareness and attentiveness and epileptic seizures or subcortical myoclonus. On examination, the patient’s tone is likely to be disproportionately reduced as compared to the patient’s strength. The Moro and tonic neck reflexes will likely be present and—in the latter case—may be obligate (ie, the patient’s extended arm remains extended in an obligate fashion until the head is returned to the neutral position). Cerebral causes of infantile hypotonia include chromosomal disorders such as Prader-Willi syndrome, inborn errors of metabolism such as Zellweger syndrome, cerebral dysgenesis such as the various forms of lissencephaly, and cerebral injury as in hypoxic-ischemic encephalopathy.

Common peripheral causes of hypotonia include motor neuron disorders (such as SMA), congenital neuropathies or myopathies, muscular dystrophies, neuromuscular junction disorders, and neurometabolic conditions such as mitochondrial disease. In contrast to cerebral causes, peripheral etiologies tend to produce proportionate weakness and hypotonia as well as lower motor neuron findings as described above.

Also, as in this case, the patient’s sensorium tends to be unaffected unless there is a superimposed secondary encephalopathy caused by, for example, initial respiratory depression and hypoxia. Given the significant weakness, postural reflexes such as the Moro and tonic neck reflex are difficult to elicit (proportionate to the degree of weakness) and, if present, are not obligate in nature. Involvement of other organ systems may be seen (such as cardiac muscle in some congenital myopathies). Ancillary testing may be helpful to further localize a peripheral process to the motor neuron, nerve, neuromuscular junction, or muscle. As with SMA1, a typical clinical presentation may lead to confirmatory genetic testing.

If the history and examination do not suggest a particular diagnosis, EMG and nerve conduction velocity (NCV) testing may be useful. Serum creatine kinase may be significantly elevated in some congenital myopathies or muscular dystrophies. The use of muscle biopsy and nerve biopsy has become much less common given the availability of genetic tests for many conditions. However, these tests are still useful when the diagnosis remains unclear.

Isolated myelopathies are relatively uncommon causes of infantile hypotonia—although the spinal cord may often be affected in conjunction with cortical and subcortical structures. As mentioned previously, significant preservation of bulbar function in a patient with hypotonia of the arms and/or legs and trunk strongly suggests a spinal cord localization. The most common cause of a spinal cord lesion resulting in hypotonia would be an injury to the cord during the process of delivery. Finally, some processes may involve both central and peripheral structures, resulting in a combined phenotype. This may be seen in both genetic syndromes such as mitochondrial disorders, as well as in acquired conditions such as profound hypoxic-ischemic encephalopathy.

COMPREHENSION QUESTIONS

54.1 Which of the following clinical findings would be typically seen in SMA type 1?

A. Encephalopathy

B. Obligate tonic neck reflex

C. Ophthalmoplegia

D. Preserved deep tendon reflexes

E. Tongue fibrillations

54.2 Which of the following pathogenic processes is responsible for SMA type 1?

A. Abnormality of nicotinic acetylcholine receptor function at the neuromuscular junction

B. Absence of a protein connecting the muscle cell membrane with the sliding filaments

C. Accumulation of abnormal protein products in skeletal muscle cells

D. Excessive programmed cell death of spinal motor neurons

E. Failure of spinal motor neuron axons to extend out of the spinal cord

54.3 Which of the following findings would most specifically suggest a cerebral cause of a patient’s hypotonia?

A. Areflexia

B. Epileptic seizures

C. Preservation of bulbar function

D. Visual attentiveness

E. Weakness

ANSWERS

54.1 E. Tongue fibrillations are commonly seen in SMA type 1. These patients also have preserved eye movements, normal sensorium, hyporeflexia, and absence of postural reflexes—all consistent with a peripheral cause of hypotonia.

54.2 D. SMA is caused by excessive programmed cell death of spinal motor neurons, resulting in a pure lower motor neuron disorder.

54.3 B. Epileptic seizures, being a cortical finding, strongly suggest a cerebral cause of hypotonia. Areflexia suggests a peripheral cause. Weakness may be seen in association with any cause of hypotonia but is generally more profound with peripheral causes. Visual attentiveness would suggest that the cortex is intact, while preservation of bulbar function would suggest a spinal cord process.

    CLINICAL PEARLS    

▶ An awake, attentive infant with significant weakness and hypotonia likely has a peripheral process. ▶ Seizures, myoclonus, and altered sensorium strongly suggest cerebral involvement. ▶ Always evaluate respiratory function, ability to protect the airway, and feeding in hypotonic infants.

REFERENCES

Bodensteiner JB. The evaluation of the hypotonic infant. Semin Pediatr Neurol. 2008;15(1):10-20. 

Fenichel G. The hypotonic infant. In: Clinical Pediatric Neurology: A Signs and Symptoms Approach. Philadelphia, PA: Saunders Elsevier; 2009:153-176. 

Prasad AN, Prasad C. Genetic evaluation of the floppy infant. Semin Fetal Neonatal Med. 2011;16(2): 99-108. 

Talbot K, Tizzano EF. The clinical landscape for SMA in a new therapeutic era. Gene Ther. 2017. 

Tulinius M, Oldfors A. Neonatal muscular manifestations in mitochondrial disorders. Semin Fetal Neonatal Med. 2011;16(4):229-235. 

Wee CD, Kong L, Sumner CJ. The genetics of spinal muscular atrophies. Curr Opin Neurol. 2010;23(5):450-458.

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