Differential Diagnoses of Amyotrophic Lateral Sclerosis are More Variegated than Anticipated.

Sir,

With interest we read the review article by Singh et al. about the differential diagnoses of amyotrophic lateral sclerosis (ALS).[1] Differential diagnoses discussed in the article include benign fasciculation syndrome, multifocal motor neuropathy, neuralgic amyotrophy, bulbospinal muscular atrophy (Kennedy's disease) (spinal and bulbar muscular atrophy), chronic inflammatory demyelinating polyneuropathy, inclusion body myositis, polymyositis, ischemic stroke, Guillain–Barre syndrome, Miller Fisher syndrome, oculopharyngeal muscular dystrophy, neck extensor myopathy, radiation-induced radiculopathy, myasthenia gravis, multiple sclerosis, hereditary spastic paraplegias, Vitamin-B12 deficiency, copper deficiency, adrenomyeloneuropathy, adult polyglucosan disease, syringomyelia, cervical myelopathy, four-A syndrome (Allgrove syndrome), thyreotoxicosis, hyperparathyroidism, HIV infection, and Post-polio syndrome.[1] We have the following comments and concerns.

Missing in this list of differentials of ALS are mitochondrial disorders, compression-induced painless cervical radiculopathy,[2] late-onset Hirayama disease,[3] Niemann–Pick disease type C,[4] Herpesvirus myelitis,[5] mitochondrial membrane protein-associated neurodegeneration,[6] spinocerebellar ataxia Type 3,[7] hexosaminidase A deficiency,[7] Parkinson's disease,[7] spinal muscular atrophy,[7] monomelic amyotrophy,[7] Morvan syndrome,[8] capecitabine-induced leukoencephalopathy,[9] tumor necrosis factor-alpha therapy of psoriatic arthritis,[10] GM2 gangliosidoses (Sandhoff disease, AB-variant, and Tay–Sachs disease), frontotemporal dementia, Huntington's disease, Alzheimer's disease, flail arm syndrome, Lyme disease, progressive muscular atrophy, cramp fasciculation syndrome, pure motor neuropathy with or without conduction block, Sjögren syndrome, aluminium intoxication, and lead intoxication.

The most frequent of these additional differential diagnoses include neuroborreliosis, mitochondrial disorders, and Parkinson's disease. Neuroborreliosis is clinically characterized by muscle weakness, sensory disturbances, meningitis, encephalitis, polyradicular pain, and sphincter dysfunction. Neuroborreliosis can be easily delineated from ALS by appropriate studies of the cerebrospinal fluid for antibodies against borrelia burgdorferi or DNA of this spirochaete. Remission of the clinical manifestations under antibiotic treatment is a further means to differentiate neuroborreliosis from ALS. Parkinson's disease can be easily delineated from ALS on the clinical presentation (tremor, rigor, and akinesia) and the results of the single-photon emission computed tomography investigations of presynaptic dopamine receptors in the midbrain. More difficult to delineate from ALS are mitochondrial disorders. Mitochondrial disorders are usually progressive multisystem diseases affecting the brain, eyes, ears, endocrine organs, heart, lungs, gastrointestinal tract, kidneys, hematological cells, immune system, skin, or cartilage. Particularly nonspecific mitochondrial disorders either due to mutations in genes located on the mitochondrial DNA (mtDNA) or the nuclear DNA may mimic ALS. Mitochondrial disorders mimicking ALS have been reported in patients carrying multiple mtDNA deletions, in patients with SIGMAR1 mutations, patients with combined complex-II/complex-III defects, patients carrying AIFM1 mutations, DNAJC11 mutations, and some other conditions associated with mitochondrial disease.

In summary, this review could be more meaningful if not only some of the differential diagnoses of ALS would have been discussed but also if the more widespread spectrum of differentials would have been considered. It would be also helpful for the reader to indicate which differentials are frequent and which are rare differentials that have to be taken into consideration.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.