16 research outputs found
Extension of the Pompe mutation database by linking disease-associated variants to clinical severity
Pompe disease is an autosomal recessive lysosomal storage disorder caused by
disease‐associated variants in the acid alpha‐glucosidase (GAA) gene. The current
Pompe mutation database provides a severity rating of GAA variants based on in silico
predictions and expression studies. Here, we extended the database with clinical
information of reported phenotypes. We added additional in silico predictions for
effects on splicing and protein function and for cross reactive immunologic material
(CRIM) status, minor allele frequencies, and molecular analyses. We analyzed 867
patients and 562 GAA variants. Based on their combination with a GAA null allele (i.e.,
complete deficiency of GAA enzyme activity), 49% of the 422 disease‐associated
variants could be linked to classic infantile, childhood, or adult phenotypes.
Predictions and immunoblot analyses identified 131 CRIM negative and 216 CRIM
positive variants. While disease‐associated missense variants were found throughout
the GAA protein, they were enriched up to seven‐fold in the catalytic site. Fifteen
percent of disease‐associated missense variants were predicted to affect splicing. This
should be confirmed using splicing assays. Inclusion of clinical severity rating in the
Pompe mutation database provides an invaluable tool for diagnosis, prognosis of
disease progression, treatment regimens, and the future development of personalized
medicine for Pompe disease
Modelling the neuropathology of lysosomal storage disorders through disease-specific human induced pluripotent stem cells
Mucopolysaccharidosis II (MPS II) is a lysosomal storage disorder (LSD), caused by iduronate 2-sulphatase (IDS)
enzyme dysfunction. The neuropathology of the disease is not well understood, although the neural symptoms
are currently incurable. MPS II-patient derived iPSC lines were established and differentiated to neuronal
lineage. The disease phenotype was confirmed by IDS enzyme and glycosaminoglycan assay. MPS II neuronal
precursor cells (NPCs) showed significantly decreased self-renewal capacity, while their cortical neuronal differentiation potential was not affected. Major structural alterations in the ER and Golgi complex, accumulation
of storage vacuoles, and increased apoptosis were observed both at protein expression and ultrastructural level
in the MPS II neuronal cells, which was more pronounced in GFAP + astrocytes, with increased LAMP2 expression but unchanged in their RAB7 compartment. Based on these finding we hypothesize that lysosomal
membrane protein (LMP) carrier vesicles have an initiating role in the formation of storage vacuoles leading to impaired lysosomal function. In conclusion, a novel human MPS II disease model was established for the first
time which recapitulates the in vitro neuropathology of the disorder, providing novel information on the disease
mechanism which allows better understanding of further lysosomal storage disorders and facilitates drug testing
and gene therapy approaches
Segmental and total uniparental isodisomy (UPiD) as a disease mechanism in autosomal recessive lysosomal
Analyses in our diagnostic DNA laboratory include genes involved in autosomal recessive (AR) lysosomal storage disorders
such as glycogenosis type II (Pompe disease) and mucopolysaccharidosis type I (MPSI, Hurler disease). We encountered 4
cases with apparent homozygosity for a disease-causing sequence variant that could be traced to one parent only. In addition,
in a young child with cardiomyopathy, in the absence of other symptoms, a diagnosis of Pompe disease was considered.
Remarkably, he presented with different enzymatic and genotypic features between leukocytes and skin fibroblasts. All cases
were examined with microsatellite markers and SNP genotyping arrays. We identified one case of total uniparental disomy
(UPD) of chromosome 17 leading to Pompe disease and three cases of segmental uniparental isodisomy (UPiD) causing
Hurler-(4p) or Pompe disease (17q). One Pompe patient with unusual combinations of features was shown to have a mosaic
segmental UPiD of chromosome 17q. The chromosome 17 UPD cases amount to 11% of our diagnostic cohort of
homozygous Pompe patients (plus one case of pseudoheterozygosity) where segregation analysis was possible. We conclude
that inclusion of parental DNA is mandatory for reliable DNA diagnostics. Mild or unusual phenotypes of AR diseases
should alert physicians to the possibility of mosaic segmental UPiD. SNP genotyping arrays are used in diagnostic workup
of patients with developmental delay. Our results show that even small Regions of Homozygosity that include telomeric
areas are worth reporting, regardless of the imprinting status of the chromosome, as they might indicate segmental UPiD
Definitive radiotherapy with image-guided adaptive brachytherapy for primary vaginal cancer
Primary vaginal cancer is a rare cancer and clinical evidence to support recommendations on its optimal management is insufficient. Because primary vaginal cancer resembles cervical cancer in many aspects, treatment strategies are mainly adopted from evidence in locally advanced cervical cancer. To date, the organ-sparing treatment of choice is definitive radiotherapy, consisting of external beam radiotherapy and brachytherapy, combined with concurrent chemotherapy. Brachytherapy is an important component of the treatment and its steep dose gradient enables the delivery of high doses of radiation to the primary tumour, while simultaneously sparing the surrounding organs at risk. The introduction of volumetric CT or MRI image-guided adaptive brachytherapy in cervical cancer has led to better pelvic control and survival, with decreased morbidity, than brachytherapy based on x-ray radiographs. MRI-based image-guided adaptive brachytherapy with superior soft-tissue contrast has also been adopted sporadically for primary vaginal cancer. This therapy has had promising results and is considered to be the state-of-the-art treatment for primary vaginal cancer in standard practice
Right hemisphere mediation of verbal learning and memory in acquired right hemisphere speech dominant patients
Inferring Function from Structure: Relationship of Magnetic Resonance Imaging-Detected Hippocampal Abnormality and Memory Function in Epilepsy
Although temporal lobectomy is an effective alternative treatment for many patients with medication-resistant epilepsy, the risk of cognitive morbidity is not inconsequential. The ability to predict cognitive outcome is increasingly dependent on convergent information from multiple sources, including direct (e.g., Wada test) and indirect (e.g., psychometric testing) functional assessments along with magnetic resonance imaging studies that detect structural abnormalities. This brief review summarizes the relationship between imaging and function at baseline and predicting cognitive outcome following temporal lobectomy