Artificial intelligence (AI)-based protein structure databases are expected to have an impact on drug discovery. Here, we show how AlphaFold could support rare diseases research programs. We focus on Alsin, a protein responsible for rare motor neuron diseases, such as infantile-onset ascending hereditary spastic paralysis (IAHSP) and juvenile primary lateral sclerosis (JPLS), and involved in some cases of amyotrophic lateral sclerosis (ALS). First, we compared the AlphaFoldDB human Alsin model with homology models of Alsin domains. We then evaluated the flexibility profile of Alsin and of experimentally characterized mutants present in patients with IAHSP. Next, we compared preliminary models of dimeric/tetrameric Alsin responsible for its physiological action with hypothetical models reported in the literature. Finally, we suggest the best animal model for drug candidates testing. Overall, we computationally show that drug discovery efforts toward Alsin-involving diseases should be pursued.

Kikuchi-Fujimoto Disease (KFD) is a rare disease marked by necrotizing lymphadenitis, often presenting as unilateral cervical lymphadenopathy, along with various extranodal manifestations such as fever, skin rash, hepatosplenomegaly, and arthritis, etc. KFD is thought to be secondary to either a viral infection or an autoimmune process, however, evidence in favor of both models is scarce and non-definitive. We report a case of a young female who presented with persistent high-grade fever, bilateral cervical and axillary lymphadenopathy, and leukopenia. Excisional biopsy of affected lymph nodes revealed well-circumscribed foci of necrosis with karyorrhectic debris and scattered fibrin deposits characteristic of KFD. The patient was promptly initiated on non-steroidal anti-inflammatory drugs (NSAIDs), however, despite an early improvement in symptoms, the patient soon developed aseptic meningitis, a rare neurological complication of KFD. Intravenous followed by oral corticosteroid therapy reported a good prognosis, with no observable residual neurological deficits. Knowledge of the disease and its complications significantly helped in the avoidance of unnecessary investigations and a delay in treatment.

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Sofia
Journal Co-ordinator
Journal of Rare Disorders: Diagnosis & Therapy