Severe Respiratory and Swallowing Disorders in Infantile-Onset Multisystem Neurologic, Endocrine, and Pancreatic Disease Type 1: Two Cases.

Objectives: The objective of this study was to expand the phenotypic spectrum of infantile-onset multisystem neurologic, endocrine, and pancreatic disease type 1 (IMNEPD1) and highlight the importance of analyzing the PTRH2 gene in patients with neuropathy presenting with pancreatic lipomatosis. Methods: Two sisters, aged 73 and 71 years, respectively, presented a severe, length-dependent sensorimotor axonal neuropathy, associated with deafness and intellectual deficiency. Results: They both needed a wheelchair from the fourth decade. They developed a severe respiratory dysfunction, requiring nocturnal noninvasive ventilation from around 50 years of age. The younger sister developed severe dysphagia complicated by aspiration pneumonia. A muscle biopsy of the younger sister was suggestive of mitochondrial myopathy. The youngest presented a complete pancreatic lipomatosis. A biallelic novel likely pathogenic variant within PTRH2, c.254A>G (p.Gln85Arg), was evidenced in both patients. Discussion: IMNEPD1 is a rare autosomal recessive disorder caused by sequence variant in the PTRH2 gene and characterized by a peripheral neuropathy, cerebellar atrophy, intellectual disability, hearing loss, pancreatic insufficiency, hypothyroidism, and dysmorphic features. In addition to these classic manifestations of the disorder, severe dysphagia and respiratory insufficiency may develop over the course of the disease and should be systematically screened. PTRH2 gene should be considered in patients with pancreatic lipomatosis and neuropathy.

New insights about myofibrillar myopathies: the role of metalloproteinases 2 and 9 in the pathogenesis

Backgroung: There are few reports suggesting that gene expression and activation of various matrix metalloproteinases (MMPs) are deregulated. MMP-2 and MMP-9 represent the two MMPs, which degrade type IV collagen, the component of basement membrane. Methods: We analysed the involvement of gelatinases, MMP-2 and MMP-9, in the pathogenesis of myofibrillar myopathy (MFM). Muscle specimens from 23 patients well diagnosed with MFM, were immunostained by MMP-2 and MMP-9. We analysed qualitatively the immunoexpression in three compartments: subsarcolemmal (SSC), intracytoplasmic (ICC) and perinuclear (PNC).Results: 95,7% and 100% samples showed MMP-2 and MMP-9 upregulation ICC, respectively. PNC showed MMP-2 (82,6%) and MMP-9 (8,7%) regulation (p<0.001). SSC and ICC did not present statistical significance. There was no correlation between mutated gene and immunohistochemical pattern distribution.Conclusion: Our results suggest that MMP-2 and/or MMP-9 could participate in the pathomechanism of MFM, causing damage of sarcomere and deposition of protein aggregates.

Introdução: Existem poucos relatos sugerindo que a expressão gênica e a ativação de várias metaloproteinases de matriz (MMPs) estão desreguladas. MMP-2 e MMP-9 representam as duas MMPs, que degradam o colágeno tipo IV, o componente da membrana basal.Método: Analisamos o envolvimento das gelatinases, MMP-2 e MMP-9, na patogênese da miopatia miofibrilar (MFM). Amostras de músculos de 23 pacientes bem diagnosticados com MFM foram imunocoradas por MMP-2 e MMP-9. Analisamos qualitativamente a imunoexpressão em três compartimentos: subsarcolemal (SSC), intracitoplasmático (ICC) e perinuclear (PNC).Resultados: 95,7% e 100% das amostras apresentaram ICC de regulação positiva de MMP-2 e MMP-9, respectivamente. PNC mostrou regulação MMP-2 (82,6%) e MMP-9 (8,7%) (p <0,001). SSC e ICC não apresentaram significância estatística. Não houve correlação entre o gene mutado e a distribuição do padrão imunohistoquímico.Conclusão: Nossos resultados sugerem que MMP-2 e / ou MMP-9 podem participar do patomecanismo da MFM, causando dano ao sarcômero e deposição de agregados proteicos.