Differential Diagnosis in Neurology

3.2. Spinal Muscular Atrophies Linked to Chromosome 5q11.12–13.3

• General considerations:
  • Most cases of SMA are autosomal recessive and are linked to chromosome 5
    • Survival motor neuron gene (SMN):
      • SMN telomeric or SMNI
      • SMN centromeric or SMNII
    • Loose pair exchanges of exons 7 and 8 distinguish the two genes
    • SMNt is deleted in 95% of SMA I, II, III
    • Neuronal apoptosis inhibitory protein gene:
      • Deleted in 70% of SMA I
      • 2% of SMA II and III
    • Less well characterized are BFT 2p44 gene deletions in 15% of SMA patients
    • Genotype-phenotype correlation possibilities:
      • SMAt to SMAc milder phenotype
      • Deletion of NAIP gene occurs with increased severity
    • Function of SMN protein may be ribonucleoprotein synthesis
    • Autopsy of SMA patients reveals loss of anterior horn cells and those from bulbar cranial nerves nuclei
• Clinical features:
  • SMA I (Werdnig Hoffman Disease)
    • Age of onset is birth to six months
    • Floppy infant; poor swallowing and sucking reflexes
    • Normal heart
    • Extraocular muscles are spared
    • Finger tremor
    • Death in less than two years
  • SMA II
    • Can sit independently; onset after six months
    • Normal cognition
    • Deep tendon reflexes retained in up to 25% of patients
    • May live to second or third decade
    • Scoliosis supervenes
  • SMA III (Kugelberg Welander)
    • Diagnosed by age 18 months due to pelvic girdle weakness
    • Some may walk independently; may resemble DMD (Duchenne Muscular Dystrophy)
    • Normal life span
    • Fasciculations > 50% of patients (often proximal muscles)
  • SMA IV
    • Onset after age 20; mean onset mid 30's
    • Slowly progressive
    • Proximal limb weakness with fasciculations
    • Some patients have more aggressive course and are unable to walk by age 20
    • Scoliosis
• Laboratory evaluation:
  • CK may be up to 10× normal
  • EMG:
    • Positive sharp waves
    • Reduced interference pattern
    • No persistent MUAP
    • Motor NCV are normal

Differential Diagnosis of SMA

The differential diagnosis of SMAIII (Kugelberg Welander disease) includes DMD or BMD. In this instance there are no fasciculations and the CK is usually much higher. Congenital myopathies frequently have ptosis, generalized thinness of muscle, cardiac defects, extraocular muscle palsies and dysmorphisms that readily differentiate them from SMAs. Limb girdle muscular dystrophies have pelvic and shoulder girdle weakness, but stronger muscles with less diminution of reflexes. They also may have specific cardiac, laryngeal, and muscle pattern weakness as well as genetic patterns that make them discernible on clinical grounds. Distal SMA, shares pes cavus with CMT, but lack the distal 1/3 of quadriceps wasting ("champagne bottle legs") and sensory loss. They also have normal SNAPs.

SMA II and III patients frequently live to adulthood and therefore must be considered in the differential diagnosis of adult motor neuron disease. The CK level may be markedly elevated in Kugelberg Welander disease (SMA III) up to 10 times normal and are minimally elevated in SMA II and III.

EMG reveals persistent motor unit activity most often in SMA I, rarely in SMA II and not in SMA III. Fasciculations are common in SMA II and III. Denervation is seen in all forms of SMA. SMA III and IV show signs of reinnervation. All have normal SNAPs and motor nerve conduction velocities are normal. Those patients with high CK require that inflammatory muscle disease be ruled out. Extraocular muscle and facial involvement exclude SMAs. The differential diagnosis of the "floppy infant" includes a host of central nervous system and congenital myopathies and applies primarily to SMA I (Werdnig–Hofmann's) disease who do not reach adulthood.

SMA Variants Linked to Chromosome 5q

Arthrogryposis multiplex congenita

• General considerations:
  • Forms linked to muscle abnormalities, joint, and anterior horn cell disease
  • Anterior horn cell form associated with deletion of the telomeric motor neuron survival gene (SMNt)
• Clinical features:
  • Severe joint deformities
  • Poor muscle tone
  • Poor movement in utero
  • Bilateral congenital hip dislocations

Congenital Axonal Neuropathy

• General considerations:
  • Homogeneous deletion of SMA gene in the paternal haplotype
  • Mutations in the MP2 gene
• Clinical features:
  • Early onset CMT 1B
  • HSP associated with ataxia, thin corpus callosum, cataracts and axonal neuropathy

Spinal Muscular Atrophies Not Linked to Chromosome 5q

Late Onset Tay Sach Disease

• General considerations:
  • Autosomal recessive
  • Loss of hexosaminidase A; a lysosomal enzyme whose deficiency causes accumulation of GM2 ganglioside in neurons
  • Gene coding for the α or β chain is located on chromosome 15 or 5 respectively; dysfunction of either causes decreased hexosaminidase A
  • Partial deficiency of hexosaminidase causes late onset anterior horn cell disease
  • Various forms of mutations:
    • Homozygosity for a single mutation
    • Compound heterozygotes with two abnormal alleles on the same chromosome
• Clinical features:
  • Age of onset is the second decade; between 11 to 67 years
  • Dysarthria and truncal ataxia precede appendicular ataxia often the earliest sign
  • Lower motor neuron involvement is prominent
  • Lower extremities > upper extremities
  • Proximal > distal muscle involvement that simulates Kugelberg–Welander disease
  • Recurrent psychosis which may precede or follow the neurologic manifestations
  • Psychosis may be the sole manifestation
  • Rare neurologic features:
    • Extrapyramidal tract disease
    • Dementia
    • Dystonia
• EMG evaluation:
  • Neurogenic; normal motor NCV; normal sensory nerve conduction velocities

Monomelic Muscular Atrophy

• General considerations:
  • Primarily cervical muscles affected
• Clinical features:
  • Non progressive
  • Asymmetric
  • Usually one upper extremity affected more than the other
  • Rarely the tongue may be affected

Fazio-Londe Disease (see ALS)

• General considerations:
  • AR
• Clinical features:
  • Limited to the lower cranial nerves
  • Death in 1–5 years

Distal SMA

• General considerations:
  • Phenotypic CMT
  • Juvenile or early adult onset with variable rates of progression
  • AD and AR recessive variants
• Clinical features:
  • Distal muscular wasting with pes cavus
  • Proximal musculature is involved with time to a lesser degree
  • No sensory loss

Adult Onset SMA

• General considerations:
  • AD inheritance
• Clinical features:
  • Proximal limb girdle weakness
• EMG:
  • Normal sensory nerve action potentials

Scapuloperoneal Syndrome

• General considerations:
  • Both myopathic and neurogenic forms
  • AD inheritance
• Clinical features:
  • Scapuloperoneal distribution of muscle wasting and weakness
  • Variable onset and progression

Fascioscapulohumeral Form of SMA

• General considerations:
  • Adolescent onset
  • AD inheritance

Non-Immune Lower Motor Syndrome

• Spinal muscular atrophies
• X-Linked Recessive Bulbar Neuronopathy (Kennedy's disease)

Kennedy's Disease

• General considerations:
  • X-linked recessive inheritance; CAG repeat in the first exon of the androgen receptor gene
  • Phenotypic expression varies within families and does correlate with CAG length; the more repeats the earlier the age of onset
  • Intranuclear androgen receptor protein found in the brainstem and anterior horn cells
• Clinical features:
  • Presents in men in the 3rd to 5th decade
  • Proximal > distal weakness and wasting
  • Distal weakness upper > than lower extremities
    • Wasting of intrinsic hand muscles
  • Exercised induced muscle cramps (neurogenic cramps)
  • Hand tremor may occur prior to weakness (phenotypical of ET)
  • Facial fasciculations (most prominent around the mouth and chin); noted at rest and with contraction
  • Weakness and atrophy of facial muscles and those of mastication; tongue wasting and fasciculation may precede that of other muscles
  • Rare complaints of dysarthria and dysphoria early; they are prominent after 10 years of disease
  • Sensory examination is usually normal
  • Gynecomastia and impotence are present
  • Absent or hypoactive deep tendon reflexes
  • Congenital fractures
  • Some patients with joint contractures
• Laboratory evaluation:
  • Elevated CK (900 to 8000 units/dl) higher than any other AHC disease
  • Muscle biopsy characteristic of denervation
• EMG evaluation:
  • Normal NCSs; CMAP is low from weak and wasted muscle; low amplitude or absent SNAPs
  • Needle EMG demonstrates denervation of extremity muscles; facial and mentalis muscles demonstrate grouped repetitive discharges with activation

Differential Diagnosis of Kennedy's Disease

The primary differentials are progressive muscular atrophy variants of ALS; facial fasciculations, essential tremor, bulbar involvement make an easy distinction from inflammatory myopathy or any congenital neuropathy. The extremely high CK differentiates it from anterior horn cell disease. Myokymia and neuromyotonia occur spontaneously while mild voluntary contractions produce fasciculations in Kennedy's disease.

Monomelic Amyotrophy (Hirayama's Disease)

• General considerations:
  • Worldwide distribution; most patients are from Japan and India
  • Putative mechanisms:
    • Spinal cord ischemia
    • Abnormal neck movement with secondary ischemia
    • Traction of the cord due to increased neck flexion
    • Abnormal cervical ligaments
• Clinical features:
  • Overwhelmingly a sporadic disease
  • Unilateral weakness and atrophy of intrinsic hand muscles
  • Progresses for 1–3 years then stops in 75% of patients
  • Fine tremor of extended fingers in 10% of patients
  • Normal deep tendon reflexes; no upper motor signs
  • Sensation is normal; rarely a rare mild sensory loss over the dorsum of the hand
• Laboratory evaluation:
  • Slightly elevated CK
  • Normal blood chemistries and CSF
• EMG evaluation:
  • Motor NCVs are normal; may have asymmetrical low median and ulnar CMAP amplitudes
  • Preserved SNAPs
  • Signs of denervation in most patients, 20% demonstrate reinnervated units
  • EMG abnormalities may be seen contralaterally ("mirror pattern")
• MRI evaluation:
  • Cervical and upper thoracic cord atrophy

Differential Diagnosis of Monomelic Amyotrophy

Few diseases resemble one extremity with atrophy that is out of a nerve or root distribution without sensory loss. Syringomyelia invariably has sensory loss (dissociated), inherited or sporadic distal myopathies are not this asymmetric and progress; adult onset SMA is not asymmetrical and is adult onset while this is a disease of young people; spinal cord infarction is not asymmetrical and has specific sulcal artery patterns (most often follows X-RT), asymmetry and lack of sensory loss is not compatible with either posterior medullary (dorsal column) or anterior spinal artery infarction. Tumors progress, are more symmetrical and swell the cord. ALS demonstrates hyperactive reflexes in a wasted extremity. MMN neuropathy is remarkable for little or no atrophy.

Brachial Amyotrophic Diplegia

• General considerations:
  • Adult onset
• Clinical features:
  • Bilateral proximal arm and shoulder girdle weakness and atrophy
  • Pure LMN weakness; legs are not affected
  • Slower progression than typical ALS
  • Some patients have distal arm involvement
  • Respiratory and bulbar muscles are spared
• EMG evaluation:
  • Denervation of the upper extremities
• Pathology:
  • One autopsied case
    • Degeneration of pyramidal tracts and anterior horn cells

Differential Diagnosis of Brachial Amyotrophic Diplegia

Hirayama's disease or monomelic atrophy is unilateral with strictly arm involvement. Rare adult onset SMAs have lower extremity involvement and are AD. Watershed infarcts ("man in the barrel") between ACA/MCA territories affect shoulder muscles more than those of the hand and other central features are present such as ideomotor apraxia with hyperactive reflexes. There is no hand wasting. Cervical spondylosis is primarily a C5–C6 disease which is asymmetric and usually is associated with lumbosacral disease and increased knee jerks. Spinal artery infarctions have sensory loss and a different pattern of motor involvement.

Post radiation amyotrophy has (obvious history) fasciculations (if the plexus is involved). EMG reveals no evidence of conduction block that are seen with MMN.

Progressive Muscular Atrophy

• General considerations:
  • Considered an ALS variant
• Clinical features:
  • Middle aged patients
  • Slowly progressive asymmetric weakness of upper and lower extremities
  • Fasciculations with wasting
  • Progresses for years
  • No upper motor neuron signs
  • Phenotypically mimics FSHD
• EMG evaluation:
  • Denervation and reinnervation