Genetic Considerations in the Newborn with Hypotonia
By Beth A. Pletcher, MD, March 1998

Evaluation of the floppy infant can prove to be quite a challenge in the newborn period. The vast majority of infants with low normal muscle tone will do well and are likely to have benign hypotonia. However, for a small subset of infants there are other considerations in the work-up for neonatal or infantile hypotonia. Here are a few points to consider:

• The prenatal or perinatal history may provide clues to hypotonia and such history should be sought in the course of the evaluation. Maternal infections, teratogen exposures and decreased fetal movement in utero are a few "red flags" requiring further investigation.

• Intrauterine growth retardation, dysmorphic facial features or any birth defect would raise concerns about a possible cytogenetic disorder or Mendelian syndrome.

• A high arched palate or joint limitation/contractures are signs of prenatal onset of moderate to severe hypotonia. Newborns with early onset spinal muscular atrophy (SMA) may have congenital hip dislocations, flexion deformities of the hands, or chest asymmetries at birth, in addition to hypotonia. The face may have a myopathic expression and tongue fasciculations may or may not be present. Infants with congenital myotonic dystrophy, in addition to severe hypotonia and myopathic facies often hold their feet in a plantar-flexed position. Parents may not be aware of their own diagnosis and therefore the family history is not always helpful in diagnosing myotonic dystrophy. DNA-based testing is available for both conditions, but is best done in consultation with a pediatric neurologist.

• Transitory neonatal myasthenia is seen in 12% of children born to myasthenic mothers. In this case, most affected mothers would be symptomatic and, therefore, neonatal problems might be anticipated and treated promptly. Symptoms may include: feeding difficulties, generalized weakness and hypotonia, myopathic facies, ptosis and occasionally ophthalmoplegia.

• Congenital myopathies account for 20% of severe hypotonia at birth and clinical work-up may require muscle enzyme studies and/or muscle biopsy. Both Mendelian and mitochondrial myopathies can present at birth and muscle tissue may need to be sent for EM studies and mitochondrial DNA analysis in addition to routine histology if one is considering a mitochondrial disorder.

• Prader-Willi syndrome often presents with neonatal hypotonia and poor feeding. Clinical features to look for include: almond-shaped eyes, strabismus, bitemporal narrowing, small hands and feet as well as hypogonadism (small penis, cryptorchidism, hypoplastic scrotum) in males. Testing includes chromosomal analysis for a 15q- (FISH deletion) and molecular testing for uniparental disomy (UPD). One green top and one purple top tube are needed to perform these studies.

• Lastly, inborn errors of metabolism can present with poor feeding and hypotonia. Therefore, metabolic screening should include assessment for acidosis, respiratory alkylosis, hypoglycemia and hyperammonemia. If there is still concern about a metabolic disorder after preliminary testing is done, more definitive testing could include such specialized tests as: urine organic acids, urine and plasma amino acids, serum and urinary carnitines and urine screening for mucopolysaccharides.