**Differential Diagnosis **

The differential diagnosis of SMA varies according to the age of onset.

Onset from prenatal to six months of age: The differential diagnosis for prenatal and neonatal SMA (types 0 and 1) includes other causes of floppy (hypotonic) infants. Many neuromuscular conditions can present in newborns.

X-linked infantile spinal muscular atrophy: X-linked infantile spinal muscular atrophy (XL-SMA or SMAX2) is a rare disorder characterized by congenital hypotonia, areflexia, congenital contractures and/or fractures, and loss of anterior horn cells. The disease course in XL-SMA is similar to the severe forms of classic neonatal SMA (SMA types 0 and 1). The disorder is associated with mutations in the gene for ubiquitin activating enzyme 1 (called UBA1 or UBE1).

Spinal muscular atrophy with respiratory distress type 1: Spinal muscular atrophy with respiratory distress type 1 (SMARD1), also known as autosomal recessive distal spinal muscular atrophy 1 (DSMA1), is characterized by diaphragmatic paralysis and respiratory failure that presents early in life, generally from one to six months of age. There is a high frequency of intrauterine growth retardation and premature birth. Eventration of the diaphragm may be seen on chest radiographs. Clinical deterioration continues for the first two years of life, followed by stabilization or less often by some clinical improvement. While all affected children remain dependent on mechanical ventilation and require full time care, some can participate in daily life activities and schooling. The disorder is caused by biallelic mutations in the immunoglobulin mu binding protein 2 gene (IGHMBP2).

Other neuromuscular disorder: Congenital myasthenic syndromes, congenital myopathies, and myelopathies can present with muscle weakness and hypotonia in infancy.

●Congenital myasthenic syndromes: Newborns with congenital myasthenia frequently have ptosis, in contrast to patients with the transient disorder. In addition, they typically demonstrate ophthalmoplegia and bulbar and respiratory muscle weakness. Affected infants may have fluctuating generalized hypotonia, weakness, and life-threatening episodes of apnea. Arthrogryposis can be present at birth.

●Congenital myopathies: Congenital myopathies (eg, nemaline myopathy, central core disease, myotubular myopathy, and congenital fiber type disproportion) present with hypotonia and weakness that is greater proximally than distally. Tendon reflexes are decreased in proportion to the weakness.

●Congenital myotonic dystrophy: The congenital form of myotonic dystrophy (DM1) is characterized by profound hypotonia, facial diplegia, poor feeding, arthrogryposis (especially of the legs), and respiratory failure. Affected infants have a characteristic "V" shape of the upper lip that results from facial diplegia. In some cases, DM1 may present before birth as polyhydramnios, talipes equinovarus (clubfoot), and reduced fetal movement. Myotonia is not usually present in the first year of life. Respiratory involvement is common and is the leading cause of death in the neonatal period.

●Hypoxic-ischemic myelopathy: Severe hypoxic-ischemic injury can sometimes result in hypotonia or flaccid paralysis with diminished or absent reflexes caused by the death of spinal motor neurons. In these cases, infants typically have encephalopathy and may have seizures or signs of other end-organ damage.

●Traumatic myelopathy: Myelopathy caused by trauma to the high cervical spinal cord is a rare cause of hypotonia in infants. This condition results in flaccid paralysis, which may be asymmetric, and absent reflexes. Physical examination may reveal evidence of trauma, such as bruising or fractures. If no accompanying brain injury is present, the infant will be alert with no cranial nerve abnormalities. A pinprick on the face will elicit a facial grimace but no response below the neck. A useful sign is withdrawal to a noxious stimulus of a limb with no spontaneous activity. Bladder distension, priapism, and absence of sweating below the level of the spinal lesion typically will appear as the myelopathy evolves over several days.

Multisystem disorders: Several multisystem disorders may be associated with muscle weakness and hypotonia in infancy.

●Glycogen storage disease II: The classic infantile form of glycogen storage disease II (Pompe disease) is characterized by hypertrophic cardiomyopathy and severe generalized muscular hypotonia that presents during the first few months of life. The tongue may be enlarged. Hepatomegaly also may be present and is usually due to heart failure.

●Prader-Willi syndrome: Neonatal hypotonia is one of the hallmark features of Prader-Willi syndrome. The profound hypotonia can lead to asphyxia. Affected infants often have feeding difficulties, including a poor suck, which may lead to failure to thrive. Other common features include a weak cry and genital hypoplasia. The hypotonia associated with Prader-Willi syndrome improves gradually during infancy, unlike SMA type 1 in which progressive deterioration occurs.

●Zellweger syndrome: Newborns with Zellweger syndrome present with a characteristic craniofacial dysmorphism. Neurologic abnormalities include hypotonia and weakness with absent reflexes, severe impairment of hearing and vision, neonatal seizures, and developmental delay. Hepatomegaly is common.

Arthrogryposis multiplex congenital: Arthrogryposis multiplex congenita is a syndrome characterized by contractures of multiple joints. It is associated with a heterogeneous group of disorders. Most cases are neurogenic; the remaining cases have connective tissue or mixed mechanisms. Neurogenic arthrogryposis can result from neuromuscular disorders, central nervous system disorders, genetic syndromes, and chromosomal aberrations. The severity is variable. Bulbar and respiratory muscle functions are severely affected in some cases, which have a poor prognosis. In others, muscle strength does not deteriorate and may improve. The disorders that result in neurogenic arthrogryposis are genetically heterogeneous. Some patients (6 of 12 in one series) have deletions of SMN1, the gene that is associated with SMA.

Onset six months to childhood: The differential diagnosis for intermediate forms of SMA (ie, SMA type 2 and SMA type 3) involves a number of neuromuscular conditions including myopathies, neuromuscular junction disorders, inflammatory neuropathies, and other motor neuron disorders. Examples include the following:

●Duchenne and Becker muscular dystrophy: The clinical onset of weakness with Duchenne muscular dystrophy usually occurs between two and three years of age. Affected children usually present with delayed walking (beyond age 18 months) and frequently have varying degrees of mild cognitive impairment. Muscle weakness affects the proximal before the distal limb muscles. Additional features include cardiomyopathy and conduction abnormalities, bone fractures, and scoliosis. Physical examination reveals pseudohypertrophy of the calf and (occasionally) quadriceps muscles, lumbar lordosis, a waddling gait, shortening of the Achilles tendons, and hyporeflexia or areflexia. The serum creatine kinase level is typically very high (eg, several thousand). Becker muscular dystrophy has a similar presentation to Duchenne, but typically has a later onset and a milder clinical course.

●Limb-girdle muscular dystrophy: Limb-girdle muscular dystrophy (LGMD) includes a number of disorders with heterogeneous etiologies. It is used as a generic term to describe those patients with muscular dystrophy of girdle distribution, having a predominantly proximal distribution of weakness that, early in the course of the disease, spares distal muscles as well as facial and extraocular muscles. Weakness in LGMD may affect the shoulder girdle, the pelvic girdle, or both. Facial weakness is usually mild and, in some cases, totally absent. Intellect is usually normal.

●Myasthenia gravis: In generalized myasthenia gravis, the weakness may also commonly affect ocular muscles, but it also involves a variable combination of bulbar, limb, and respiratory muscles. More than 50 percent of patients present with ocular symptoms of ptosis and/or diplopia. Approximately 15 percent of patients present with bulbar symptoms. Less than 5 percent present with proximal limb weakness alone. Age of onset is characterized by an early peak in the second and third decades (female predominance) and a late peak in the sixth to eighth decade (male predominance).

●Guillain-Barré syndrome: Guillain-Barré syndrome (GBS) is often triggered by an antecedent infection that evokes an immune response directed towards the myelin or the axon of peripheral nerve. The end result is an acute polyneuropathy. GBS is the most common cause of acute flaccid paralysis in healthy infants and children. GBS has several variant forms. The classic presentation of GBS is one of ascending paralysis with progressive, mostly symmetric muscle weakness and absent or depressed deep tendon reflexes. Atypical variants present with local or regional involvement of particular muscle groups or nerves.

●Non-5q forms of spinal muscular atrophy: There are a number of rare non-5q spinal muscular atrophies. The non-5q SMAs are genetically and clinically heterogeneous.

●Late-onset hexosaminidase A deficiency: Hexosaminidase A deficiency causes a number of related neurodegenerative disorders characterized by intralysosomal storage of GM2 ganglioside. The acute infantile variant is known as Tay-Sachs disease. Juvenile (subacute), chronic, and adult-onset variants are notable for slower disease progression and variable neurologic phenotypes, which include dystonia, cerebellar degeneration, motor neuron disease, and/or psychosis.

Adult onset: For patients with adult-onset disease, the differential is similar to that of intermediate forms of SMA with onset in childhood. Additional considerations for adults include later-onset neuromuscular disorders, particularly amyotrophic lateral sclerosis and spinobulbar muscular atrophy.

●Amyotrophic lateral sclerosis: The clinical hallmark of amyotrophic lateral sclerosis (ALS) is the combination of upper motor neuron and lower motor neuron signs and symptoms. Upper motor neuron findings of weakness, hyperreflexia, and spasticity result from degeneration of frontal motor neurons. The lower motor neuron findings of weakness, atrophy or amyotrophy, and fasciculations are a direct consequence of degeneration of lower motor neurons in the brainstem and spinal cord. Asymmetric limb weakness is the most common presentation of ALS (80 percent). Bulbar onset, usually manifested as dysarthria or dysphagia, is the next most common pattern (20 percent). However, differences in site and segment (cranial, cervical, thoracic, or lumbosacral) of onset, pattern and speed of spread, and the degree of upper and lower motor neuron dysfunction produce a disorder that is remarkably variable between individuals. Some affected individuals develop cognitive impairment, typically related to frontotemporal executive dysfunction.

●Spinobulbar muscular atrophy: Spinobulbar muscular atrophy (Kennedy disease) is an X-linked disorder characterized with onset from ages 20 to 60 years of slowly progressive weakness and atrophy affecting facial, bulbar and limb muscles that may be predominantly asymmetric, symmetric, proximal, or distal. Associated endocrine disturbances include late-onset gynecomastia, defective spermatogenesis, and a hormonal profile consistent with androgen resistance.