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Sengers syndrome (OMIM# 212350) is a rare autosomal recessive mitochondrial disease caused by biallelic pathogenic variants in the AGK gene, which encodes the acylglycerol kinase enzyme. The syndrome was originally defined as a "triad" of hypertrophic cardiomyopathy, cataracts, and lactic acidosis, with or without skeletal myopathy. The clinical manifestation of Sengers Syndrome exhibits substantial heterogeneity, with mild and severe/infantile forms reported. Further, biallelic AGK pathogenic variants have also been identified in a familial case of non-syndromic isolated cataract (OMIM# 614691), expanding our understanding of the gene's influence beyond the originally defined syndrome. In this study, we provide a systematic review of molecularly confirmed cases with biallelic AGK pathogenic variants (Supplementary Table 1). Our analysis demonstrates the variable expressivity and penetrance of the central features of Sengers syndrome, as follows: cataracts (98%), cardiomyopathy (88%), lactic acidosis (adjusted 88%), and skeletal myopathy (adjusted 74%) (Table 1). Furthermore, we investigate the associations between genotype, biochemical profiles, and clinical outcomes, with a particular focus on infantile mortality. Our findings reveal that patients carrying homozygous nonsense variants have a higher incidence of infant mortality and a lower median age of death (p = 0.005 and p = 0.02, Table 2a). However, the location of pathogenic variants within the AGK domains was not significantly associated with infantile death (p = 0.62, Table 2b). Additionally, we observe a borderline association between the absence of lactic acidosis and longer survival (p = 0.053, Table 2c). Overall, our systematic review sheds light on the diverse clinical manifestations of AGK -related disorders and highlights potential factors that influence its prognosis. These provide important implications for the diagnosis, treatment, and counseling of affected individuals and families. [ABSTRACT FROM AUTHOR]

Fabry disease is an X-linked lysosomal storage disorder caused by a deficiency of alpha-gal A, leading to the progressive accumulation of sphingolipids. Enzyme replacement therapy (ERT) is the most common therapy at present which has been approved in Japan since 2004. Different degrees of clinical improvements by ERT were reported in numerous articles based on patients' compliance, improved GFR, improved cardiac activity and etc. Few direct evidences of tissue biopsy during ERT were reported so far except for kidney biopsy. Here, we present plasma lyso-Gb3 data and electron microscopy (EM) of skin biopsy from 30 cases including male and female who are receiving ERT for almost 13 years. All the cases were diagnosed based on their family history, clinical, biochemical and molecular findings. Lyso-Gb3 was measured in plasma, skin biopsy was taken for electron microscopy (EM). The IgG antibody titer of the patients were measured against alpha-gal A enzyme. The male patients having severe type of mutations with high antibody titers showed high plasma lyso-Gb3 and still massive accumulation of sphingolipids in the fibroblasts, exocrine glands and Schwan cells. The severely affected female cases also showed high lyso-Gb3 and sphingolipids accumulation. Morphological pictures in treated female cases showed rather different patterns from those of male. The patients who were receiving ERT before the phenotype appeared, had low plasma lyso-Gb3 and minimal sphingolipids accumulations in skin by EM. Several reports suggested that high plasma antibody titer minimizes the effect of the enzyme and also the uptake of enzyme were varied by tissues or cell types. Our studies clearly indicate that EM studies in skin plus plasma lysoGb3 measurement could be valuable for the evaluation of the efficacy of ERT to follow up Fabry patients. [ABSTRACT FROM AUTHOR]

We first characterized PPT1 and TPP1 enzymes in dried blood spots (DBS), plasma/serum, and leukocytes/lymphocytes using neuronal ceroid lipofuscinosis (NCL) 1 and 2 patients and control subjects. PPT1 enzyme had only one acid form in control DBS, plasma/serum, and leukocytes/lymphocytes and showed deficient activities in these samples from NCL 1 patients. Conversely, TPP1 enzymes in control DBS and leukocytes/lymphocytes consisted of two forms, an acidic form and a neutral form, whereas serum TPP1 enzyme had only a neutral form. In control subjects, the optimal pH of PPT1 enzyme in DBS, plasma/serum, and leukocytes/lymphocytes was 4.5 to 5.0 in the acidic form, whereas TPP1 enzyme in control DBS and leukocytes/lymphocytes was pH 4.5 and 6.5, respectively. In NCL 1 and 2, both PPT1 and TPP1 enzyme activities in DBS, plasma, and leukocytes/lymphocytes were markedly reduced in acidic pH, whereas heterozygotes of NCL 1 and 2 in the acidic form showed intermediate activities between patients and control subjects. In neutral conditions, pH 6.0, the PPT1 enzyme activities in NCL 1 patients showed rather higher residual activities and intermediate activities in heterozygotes in NCL 1, which was probably caused by mutated proteins in three cases with NCL 1 patients. TPP1 enzyme activities at neutral pH 6.5 to 7.0 in DBS and leukocytes/lymphocytes showed higher enzyme activities in NCL 2 patients and heterozygotes. The reason for the increases of neutral TPP1 enzyme activities at pH 6.5 to 7.0 in NCL 2 DBS and leukocytes/lymphocytes, is obscure, but possibly caused by secondary activation of neutral TPP1 enzyme due to the absence of the acidic form. Interestingly, TPP1 activity in serum only consisted of a neutral form, no acidic form, and was not deficient in any NCL 2 patient. Therefore, we can diagnose NCL 1 patients by plasma/serum enzyme assay of PPT1, but not diagnose NCL 2 by serum TPP1 enzyme assay. A pilot study of newborn screening of NCL 1 and 2 has been established by more than 1000 newborn DBS assays. Using this assay system, we will be able to perform newborn screening of NCL 1 and 2 by DBS. [ABSTRACT FROM AUTHOR]

Heterozygous Fabry females usually have an attenuated form of Fabry disease, causing them to be symptomatic; however, in rare cases, they can present with a severe phenotype. In this study, we report on a 37-year-old woman with acroparesthesia, a dysmorphic face, left ventricular hypertrophy, and intellectual disability. Her father had Fabry disease and died due to chronic renal and congestive cardiac failure. Her paternal uncle had chronic renal failure and intellectual disability, and her paternal aunt was affected with congestive cardiac failure. The patient has two sisters with no significant medical illness. However, her nephew has acroparesthesia, anhidrosis, and school phobia, and her niece shows mild phenotypes. The patient's enzyme analysis showed very low α-galactosidase A (α-gal A) activity in dried blood spot (DBS), lymphocytes, and skin fibroblasts with massive excretion of Gb3 and Gb2 in urine and lyso-Gb3 in DBS and plasma. Electron microscopic examination showed a large accumulation of sphingolipids in vascular endothelial cells and keratinocytes. Chromosomal analysis and comparative genomic hybridization microarray showed 10q26 terminal deletion. Molecular data showed a novel heterozygous stop codon mutation in exon 1 of the GLA gene in her sisters and niece, and a hemizygous state in her nephew. When we checked the methylation status, we found her non-mutated allele in the GLA gene was methylated. However, the non-mutated alleles of her sisters were non-methylated, and those of her niece were partially methylated. The chromosomal and methylation study may speculate the severity of her clinical phenotypes. [ABSTRACT FROM AUTHOR]

Fabry disease is a lysosomal metabolic disorder with X-linked inheritance caused by a deficiency of alpha-galactosidase which leads to accumulation of globotriaosylceramide (Gb3) in various organs. Clinical features of Fabry disease are renal, cardiac and CNS involvement. However, precise cellular pathogenesis in Fabry disease is still unknown. The iPS technology may be useful for the understanding of pathogenetic mechanism of lysosomal storage disease including Fabry disease. The generation of iPS cells generally have been carried out by the use of Sendai virus vector or episomal vector, but these technologies need the environmental attention and equipment for handling viruses. Therefore, we focused on RNA-reprogramming procedure. Skin fibroblasts from control and Fabry disease were transfected with reprogramming factors (Oct4, Sox2, Klf4, cMyc, Nanog, Lin28), interferon factors (B18, E3, K3), RNA and microRNA and formed iPS colonies were obtained after several cell passages and surveyed for morphological and biochemical studies. Using this method, no virus is used and feeder cells are not required, and also iPS cells can be efficiently obtained in a short period of time. Using this method, the iPS cells were successfully established from healthy human skin fibroblasts and skin fibroblasts derived from three Fabry male sibling patients in same family. Expression of surface markers and undifferentiated markers in these iPS cells showed positive, demonstrated by immunostaining and RT-PCR. Generated iPS cells from these Fabry patients were confirmed as iPS cells by various pluripotency markers. Our RNA reprograming procedure to generate iPS cells could be more widely used for understanding of pathogenetic mechanism of various lysosomal diseases including Fabry disease. [ABSTRACT FROM AUTHOR]

Neuronal ceroid lipofuscinosis (NCL) is lysosomal storage disease caused by accumulation of ceroid/lipofuscin in various tissues, which leads to devastating brain disorders. The NCL consisted of 14 different genetic types and among these, we focused on NCL 1 and 2. NCL 1 is caused by the deficiency of palmitoyl protein thioesterase (PPT1), whereas NCL 2 is caused by the deficiency of tripeptidylepeptidase (TPP1). Currently, intrathecal enzyme treatments/AAV gene therapy for NCL 1 & 2 are now developing. Therefore, early diagnosis and treatment will be essentially necessary for better clinical outcome. We studied the enzyme characteristics of PPT1 and TPP1. We characterized PPT1 and TPP1 enzymes in DBS, plasma/serum, leukocytes/lymphocytes, and fibroblasts from NCL 1 and 2 patients and control subjects, using fluorescent substrates according to Lukacs et al. The PPT1 enzyme activities in control subjects had one acidic form, optimal pH 5.0. The PPT1 enzyme activities in NCL 1 patients showed deficient activities in acidic condition, pH 5.0. Conversely, the TPP1 enzyme activities in control cells consisted of two forms, an acidic form and a neutral form, and the optimal pH was 4.5 and 6.5, respectively. In NCL 2 patients, TPP1 enzyme activities were markedly reduced in acidic conditions, pH 4.5, whereas it showed higher enzyme activities at pH 6.5-7.0. We also carried out high risk screening in epileptic patients with progressive intellectual problem (about 30 patients) and newborn screening (about 2,000 DBSs from newborn infants) were carried out using this new enzyme assay system. We are now continuing both high risk and newborn screening, and we could not yet currently find out a PPT1 or TPP1 deficient patient. [ABSTRACT FROM AUTHOR]