Novel NFU1 Variants Induced MMDS Behaved as Special Leukodystrophy in Chinese Sufferers

Abstract

Multiple mitochondrial dysfunctions syndrome (MMDS) is an autosomal recessive disorder of systemic energy metabolism. This study is to present the diagnosis of two MMDS Chinese sufferers. Physical and auxiliary examination was performed. Next generation sequencing (NGS) was conducted to identify candidate causal genes and Sanger sequencing was adopted to validate the variants detected. Fluorescence quantitative polymerase chain reaction (FQ-PCR) amplification was carried out to testify allelic loss existence. Structural investigation was performed to study the possibility of the candidate variants for disease onset. Physical examination showed that the children were with neurological impairment. Auxiliary examination demonstrated energy metabolism disturbance and abnormal brain signals. NGS found that the probands had homozygous mutation of c.545 + 5G > A and compound heterozygous variants of exon 4 deletion and c.721G > T in NFU1, respectively. NFU1 was considered as candidate molecular etiology and indicating that the kids were with MMDS. Sanger sequencing confirmed the variants. FQ-PCR amplification characterized that patient 1 had a de novo allele mutation while patient 2 inherited from his parents. Structural investigation demonstrated that the variants were possible for MMDS occurrence. This is the first report of patients diagnosed as MMDS with novel mutation types from the Asia-Pacific region.

Clinical and genetic aspects of defects in the mitochondrial iron–sulfur cluster synthesis pathway

“…Cerebral MRI showed bilateral extensive white matter alterations. Recently, another paper confirmed the severe clinical picture in two children aged three and 4 months [71]. In a second group the affected individuals presented with pulmonary hypertension and regression of acquired skills after an intercurrent infection.…”

“…The common feature for all reported subjects was an increased serum glycine and defective lipoylation resulting in decreased activity of complex II and PDHC (pyruvate dehydrogenase complex). Biochemical testing was not performed in the two most recently published cases [ 71 ].…”

Multiple mitochondrial dysfunctions syndrome 1: An unusual cause of developmental pulmonary hypertension

“…Since the initial case descriptions in 2001, fewer than 30 patients with MMDS1 have been reported in the literature (Ahting et al, ; Cameron et al, ; Ferrer‐Cortes et al, ; Invernizzi et al, ; Jin et al, ; Navarro‐Sastre et al, ; Nizon et al, ; Seyda et al, ; Tonduti et al, ). Affected infants usually presented within the first few months of life with various combinations of failure to thrive, neurologic regression or encephalopathy and pulmonary hypertension.…”

“…The complex assembly machinery involves approximately 17 proteins in several steps, and NFU1 is believed to act as a chaperone protein in the final few steps of this process, allowing for proper assembly of the 4Fe-4S complex and its transfer to its target proteins (Maio & Rouault, 2015). Abnormal Since the initial case descriptions in 2001, fewer than 30 patients with MMDS1 have been reported in the literature (Ahting et al, 2015;Cameron et al, 2011;Ferrer-Cortes et al, 2016;Invernizzi et al, 2014;Jin et al, 2017;Navarro-Sastre et al, 2011;Nizon et al, 2014;Seyda et al, 2001;Tonduti et al, 2015). Affected infants usually presented within the first few months of life with various combinations of failure to thrive, neurologic regression or encephalopathy and pulmonary hypertension.…”

Biallelic mutations in carbamoyl phosphate synthetase 1 induced hyperammonemia in a neonate: A case report

“…Patient examination. Upon admission, routine examinations, including physical examination, urinalysis, blood gas analysis, and blood examination, were performed as described previously (11,12). In addition, laboratory tests for C-reactive protein, pro-calcitonin, toxoplasma, rubella, cytomegalovirus and herpes simplex viruses, respiratory viruses (influenza virus, respiratory syncytial virus and adenovirus), biochemistry, routine cerebrospinal fluid analysis, blood ammonia, blood glucose, lactic acid, liver function and renal function were performed (12,13).…”