Table 30-6 gives an overview of the most common causes of congenital hypotonia.
Prader-Willi syndrome is characterized by a deletion of the proximal arm of chromosome 15. Most cases are due to maternal dysomia, a defective inheritance of both chromosomes 15 from the mother. This is the basis of genetic imprinting, a phenomenon also seen in patients with Angelman syndrome. Clinically, the patient presents with hypotonia, hypogonadism, obesity, short stature, and psychomotor slowing. Not uncommonly, patients affected are born with congenial hip dysplasia or club foot. On physical examination, deep tendon reflexes are absent and hypotonia is profound. Usually, the neonate is fed by prolonged period of time through a nasogastric tube because of swallowing difficulties. By the first anniversary, these feeding difficulties are replaced by a voracious appetite. Mental deficiencies of different ranges are a constant throughout the lifespan. Several dysmorphic features are more evident after the second year of life and include almond-shaped eyes and small, puffy hands and feet. Short stature is treated with growth hormone2 and the patients are usually enrolled in a judicious dietary therapy.
Congenital Muscular Dystrophy
Congenital muscular dystrophy (CMD) is a group of disorders characterized by the presence of hypotonia, joint contractures, diffuse muscle weakness, and atrophy. There are two recognized forms: merosin positive and negative. This protein is located in the extracellular matrix and is the bridging protein for the dextroglycan complex. The deficiency is considered primary or secondary. Patients with primary merosin deficiency have symptoms localizing only to muscle. In secondary merosin deficiency, muscle and brain are affected.
There is a subset of patients with congenital muscular dystrophy with clinical symptoms affecting only the muscle but with a muscle biopsy positive for the presence of merosin, which demonstrates the genetic heterogeneity of this disorder. Examples of this subtype are rigid spine syndrome and Ullrich disease. Serum creatine kinase (CK) levels are elevated and muscle biopsy demonstrates fiber necrosis and regeneration. Typically, the brain MRI is normal. Other than prevention of contractions with physical therapy, no other specific therapies are available for the treatment of this disorder.
A different subset of patients with primary merosin deficiency and a CMD phenotype has been described. The abnormal gene is located on chromosome 6. In addition to hypotonia and arthrogryposis, severe respiratory insufficiency and contractures are present at birth. Clubfoot and bilateral congenital hip dislocation are associated features. The cause of death is related to pulmonary hypoventilation. CK is high and electromyogram (EMG) demonstrates a myopathic pattern. Muscle biopsy typically demonstrates variation in fiber size and replacement of normal muscle tissue by extensive fibrosis and adipose tissue. A mononuclear infiltrate surrounding the scarce muscle fibers is typically present. Brain MRI would demonstrate abnormal myelination patterns, particularly of the occipital lobes. Genetic testing is available. Therapy is limited to aggressive physical therapy to prevent contractions.
Patients with CMD affecting both brain and muscle may have one of the following three disorders: Fukuyama disease, muscle–eye–brain disease, or Walker-Warburg syndrome. The distinguishing feature of these three disorders is an abnormality in neuronal migration, which may result in liscencephaly, polymicrogyria, and heterotopic tissue. Fukuyama disease occurs almost universally in Japanese descendents and there is a reduction on merosin activity. Most mothers with an affected child have a history of spontaneous abortions. Diffuse hypotonia, facial weakness, weak cry, and poor sucking are accompanying features. Deep tendon reflex are absent. Seizures occurring early in life are a common manifestation of cerebral involvement. The degree of developmental delay is severe and global. Severe handicaps and caquexia are progressive, and patients usually do not survive the first decade of life.
Muscle–eye–brain disease occurs mainly in Finland and patients usually have a normal merosin activity. Congenital hypotonia and several types of congenital eye malformations are present, including glaucoma, myopia, retinal atrophy, and cataracts. Mental retardation is also present.
Although Walker-Warburg syndrome is characterized by a reduction of merosin activity, this syndrome shares similar phenotypic brain and muscle abnormalities of patients with muscle–eye–brain disease. Ocular abnormalities present in this disorder are cataracts, retinal dysplasia, detachment, and optic nerve hypoplasia. The diagnosis of these three entities is suspected by an elevated CK level, myopathic EMG features, and muscle biopsy showing proliferation of adipose and collagen tissue that replaces muscle tissue. The MRI shows exvacuo hydrocephalus and lucency of white matter. Despite the advances in the understanding of this disorder, treatment is supportive.
Congenital Myotonic Dystrophy
Congenital myotonic dystrophy is a multisystemic autosomal dominant disorder characterized by a triplet repeat of the DMPK gene on chromosome 19. Genetic anticipation has been reported and the number of repeats can be increased in successive generations. Hence, symptoms can be more severe and of earlier onset in younger affected siblings. Mothers are usually affected because the repeat changes from mother to child are greater. Typically, pregnancy is characterized by polyhydramnios and reduced fetal movements. Premature difficult labor follows due to weak uterine contractions. Respiratory muscles such as the diaphragm and the intercostal muscles could be affected, requiring prompt ventilatory assistance. Several typical dysmorphic features are present, which include a prominent mouth in which the upper lip forms an inverted "V," facial hypotonia, arthrogryposis, and bilateral clubfoot. Several gastrointestinal complications such as swallowing difficulties, aspiration, and regurgitation are present. Deep tendon reflexes are usually absent. Percussion maneuvers and EMG are unreliable tests for evaluation of CMD in the newborn. Other complications include congenital cataracts, cardiomyopathy, and diabetes mellitus. Hence, screening for these potentially treatable disorders is recommended. Nonetheless, severe mental retardation is the rule. The diagnosis of CMD is suspected by examining the mother. Genetic testing is available. Prevention of contractures includes physical therapy and casting. Yearly blood glucose monitoring and formal eye examination is recommended.
Acid Maltase Deficiency (Pompe Disease)
A multisystemic autosomal recessive lysosomal disorder, acid maltase deficiency is characterized by the abnormal storage of glycogen in the cell, due to a deficient acid maltase activity. The mutation is linked to chromosome 17. There are three recognized forms according to the age of onset: infantile, childhood, and adult. Symptoms in the infantile form usually appear at 2 months of age. Hypotonia and congestive heart failure are presenting symptoms and the ECG typically shows short PR intervals and high QRS complexes. Signs of nervous system dysfunction are altered mental status and hyporeflexia. The muscle biopsy shows large vacuoles packed with glycogen and diminished acid maltase activity. Enzyme replacement therapy with the recombinant human alpha glycosidase (rhGAA) drug (Myozime) seems to be a long-term effective therapy. Respiratory insufficiency, maintenance of normal cardiac function, improvement of skeletal function, and decrease of initially raised laboratory parameters such as creatine kinase, lactic dehydrogenase, and transaminases are potential benefits.3 However, nearly all infants with Pompe disease develop antibodies, some of which inactivate the enzyme. Alternatives of care under investigation include the use of immunosuppressant agents to curb this antibody response and suppress the production of anti-rhGAA antibodies.
There are three different types of spinal muscular atrophy (SMA), of which type I is described in this chapter. Invariable, symptoms are evident in the first 6 months of life. Normal individuals have two almost identical copies of the survival motor gene (SMN1 and SMN2). Affected individuals have a missing copy and usually the SMN1 on chromosome 5 is the primary SMA disease-causing gene. Reduced fetal movements due to early neuronal degeneration may occur. The affected newborns are diffusely weak, hypotonic, hyporeflexic, and may even have respiratory compromise leading to hypoxic encephalopathy. Intercostal muscle paralysis and thoracic collapse may occur and patients may develop paradoxical breathing. Others may have diaphragmatic paralysis as the initial presenting feature. Most patients adapt well to extra uterine life and the respiratory drive is not compromised. Facial expression and extraocular movements are in general intact. Progressive weakness, tongue atrophy, or tongue fasciculations are evident in older infants. Once gag reflex is lost the risk of aspiration and pneumonia is increased. Death may occur in the first 6 months of life. However, prediction of survival is not possible and the infant may be able to sit but not to walk. CK levels are usually normal but may be mildly elevated in severe cases. EMG shows fibrillations and fasciculations at rest. Nerve conduction velocities are typically normal. Muscle biopsy demonstrates combinations of small and hypertrophied fibers. Genetic testing is available. Hence, muscle biopsy is not any longer needed to confirm the diagnosis. Most individuals are homozygous for the point mutation of the SMN1 gene. Five percent could be compound heterozygotes for the point mutation. Treatment is supportive. Compassionate clinical trials with histone deacetylase inhibitors such as valproic acid or hydroxyurea have shown trend to improvement in some clinical outcome measures.4
Cytochrome-C Oxidase Deficiency
The mitochondrial disorder cytochrome-c oxidase deficiency is a clinically heterogeneous multi-phenotypic disorder, ranging from isolated myopathy to severe systemic disease. In normal subjects, the electron transfer chain and the oxidative phosphorilation are the principal sources of ATP. Deficiencies of this group of mitochondrial enzymes may cause several upper and lower motor neuron symptoms. Isolated cytochrome-c oxidase deficiency is autosomal recessive and most cases are sporadic. However, clinical manifestations depend on the number of deficient enzymes, the percentage of reduction, and the genetic heterogeneity of this group of disorders. Onset of symptoms is usually in the first 6 months of life and those include diffuse weakness, respiratory failure, severe lactic acidosis, glycosuria, proteinuria, phosphaturia, and aminoaciduria. The prognosis is poor and survival usually is not longer than 6 months of age. CK levels are high and EMG is usually normal. Muscle biopsy reveals enlarged vacuoles that stain positive for glycogen and lipids. Ragged red fibers are also present. No effective treatment is available. Clinical trials utilizing dichloroacetate blunted the postprandial increase in circulating lactate. However, it did not improve neurological or other measures of clinical outcome.5