Project Abstract

Anterior horn cell diseases are a group of pure motor disorders involving both upper and lower motor neurons. They are currently untreatable and carry variable course based on the phenotype. The nervous system is vulnerable for oxidative stress due to its high oxygen consumption, low antioxidants, poor regenerative capacity, and presence of metal ions. A 36‑year‑old female had exertion induced cramps of her right lower limb, coldness in the right lower limb, progressive weakness, wasting, and fasciculation; became bilateral within 4 years. She had cyanosis, hypothermia, and decreased sweating of right leg with psoriasis. Her nerve conduction and electromyography studies were suggestive of anterior horn cell disease, which was supported by histopathology. She had severe reduction in total volume of sweat produced and prolonged sweat latency on the right‑sided limbs as assessed by Quantitative sudomotor axon reflex test. DNA testing showed SOD1 cytogenetic band exon 4 of the SOD1 gene. chr. 2133039650c>C/T; c. 319c>C/T. We report a new phenotype in dominantly inherited amyotrophic lateral sclerosis, with asymmetrical vasomotor and sudomotor changes and psoriasis.

Project Overview

Charles Bell in 1824 was the first to describe amyotrophic lateral sclerosis (ALS). Later in 1860, Jean‑Martin Charcot and Marie described amyotrophy with spasticity, fibrillation, dropped heads, and childish behavior [1]. Motor neuron disorders are neuronopathies, which are slowly progressive pure motor disorders; which can be symmetrical, asymmetrical, proximal, distal, with or without the involvement of cranial neurons. Based on the heritability, it is classified as familial ALS or sporadic ALS. Based on the regions affected, it is classified as lower motor neuron, upper motor neuron, or combined. There is a lack of uniformity in the phenotype. However, it has key features which suggest the common diagnosis. The first categorization of these common features was done by Dr. Edward Lambert in 1957. This was revised by El-Escoril and Awaji [2,3]. Later, all the available criteria were clubbed to form the revised El-Escoril criteria by Brooks et al. in the year 2000. Case Presentation Different patterns and associations of anterior horn cell disease The patterns are categorized into asymmetrical distal weakness without a sensory loss (NP5). This includes progressive muscular atrophy (PMA), primary lateral sclerosis, ALS. Next pattern is a symmetric weakness without a sensory loss (NP7), which includes spinal muscular atrophy (SMA), PMA; and differential diagnosis is Charcot Marie Tooth which is NP2 and hereditary motor neuropathy. The next pattern is focal midline proximal symmetric (NP8) under this subtype patterns MP6 if neck and trunk are affected, MP7 if bulbar. They can present as pure lower motor, mixed upper and lower motor, pure upper motor. The well‑known associations are cognitive deficits, behavioral symptoms, psychiatric symptoms, and Parkinsonian features. Familial amyotrophic lateral sclerosis ALS is found to be familial in about 10% of patients [4]. Familial aggregation is seen, mostly indicating dominant inheritance. SODI gene, ALS1, HNRNPA1, ALS20, MATR3, ALS21, OPTN, ALS12, PFN1, ALS18, SETX, ALS4, SIGMAR!, ALS!^, SPG11, SQSTM1, TARDBP, ALS10, TBK1, TUBA4A, ALS22C/T; c.319c>C/T that results in the amino acid substitution of phenylalanine for leucine at codon 107 (p. Leu107Phe) was detected in our index case. This was further validated by Sanger sequencing (Figure 4). This SOD1 mutation was detected heterozygous in the affected cousins of the patient and unaffected son. However, QSART test was abnormal in the son who was otherwise clinically normal bur carrying the heterozygous mutation. Figure 4: (a) DNA Test result; (b) Gel picture. Discussion Superoxides such as reactive oxygen species, superoxide radicals, hydrogen peroxide, hydroxyl radicles, and single oxygen have a very short half‑life as they are extremely active and postulated to be involved in several neurodegenerative diseases. There are naturally occurring scavengers which when imbalanced results in tissue damage. Superoxide dismutase catalyzes the conversion of reactive oxygen into hydrogen peroxide [8]. There are three types of dismutases: superoxide dismutase SOD1 otherwise called Cu‑Zn Sod present in the cytosol, nuclei and mitochondrial matrix; SOD2 or manganese superoxide dismutase found in the mitochondrial matrix, and SOD 3 or extracellular‑superoxide dismutase, constituted by a complex of Cu and ZN and is seen in extracellular space [9]. Oxidative stress occurs due to an imbalance in oxidant and antioxidant homeostasis. Suboptimal levels of reactive oxygen species serve (ROS) as a cell signaler, but unregulated ROS causes toxicity [10,11]. The nervous system is vulnerable because of high oxygen consumption, low antioxidant levels, low regenerative capacity, and high levels of metal ions to maintain function; which will cause ROS generation. These act on unsaturated lipids, proteins and DNA. Lipid peroxidation causes breakdown products such as 4(oh) 2.3‑nonenal, acrolein, Malondialdehyde, and F2‑isoprostanes which inhibit Glucose transporter type 3, GLT1, Na+ K+ Atpase and activate apoptotic protein kinases. Interaction with DNA causes mutations [12]. ALS results from gain of function due to aggregation of misfolded form of SOD and its conversion to a pro‑oxidant protein [13]. Psoriasis and neurological diseases Apart from the direct complications of psoriasis induced skeletal changes, an association with Parkinson’s disease is reported based on a population‑based study which was not supported by other studies and no other association is reported to our knowledge [14]. Unique features of this amyotrophic lateral sclerosis family Right lower limb was the first affected part in all the all affected members of this family. Vasomotor and sudomotor changes were also seen in the right lower limb. They had associated psoriasis. Death was due to respiratory distress and occurred early. Even the clinically asymptomatic son of the patient showed abnormality in QSART test involving his right‑sided limbs. It is possible that the right side being dominant and involved in more work than the left it became vulnerable. Any other unique nature of the anterior horn cells and intermediolateral grey needs to be understood. Conclusion We report an index case and her family with a unique phenotype of ALS, for which the authors could not find any earlier reference in the literature. Vasomotor and sudomotor changes on the right‑sided limbs were observed in both symptomatic and asymptomatic family members with the heterozygous gene mutation. They also had psoriasis and early death. The current SOD1 heterozygous mutation seen in all affected persons also is not reported to the best of our knowledge. The QSART abnormalities seen in the child with no clinical symptoms indicate this could be an early biomarker for persons with this mutation. This unique combination needs further study to explore new treatment options other than antioxidants, antiexcitotoxins and caloric restriction currently practiced, if its pathomechanisms are identified. Limitations We did not do the SOD1 mutation analysis in family members who had psoriasis but no evidence of MND. We could not exactly establish the pathogenesis of this phenotype with the available tools. Declaration of Patient Consent The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published, and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed. 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