informer

Rasmussen encephalitis (RE) is a rare progressive presumed autoimmune disorder characterized by pharmacoresistant epilepsy and progressive motor and cognitive deterioration. Despite immunomodulation, more than half of the patients with RE ultimately require functional hemispherotomy. In this study, the potential beneficial effects of early initiation of immunomodulation in slowing disease progression and preventing the need for surgical interventions is evaluated.

A retrospective chart review over a 10-year period is conducted at the American University of Beirut Medical Center to identify patients with RE.  Five patients with only monthly to weekly seizures at the time of IVIG initiation have favorable outcomes without resorting to surgery, along with a relative preservation of the gray matter volumes in the affected cerebral hemispheres. Motor strength is preserved in those patients, and three are seizure free at their last follow-up visit.

The data in this report suggest that the early initiation of IVIG as soon as a diagnosis of RE is suspected, and particularly before the appearance of motor deficits and intractable seizures, can maximize the beneficial effects of immunomodulation in terms of controlling seizures and reducing the rate of cerebral atrophy. Read the full article here.

Diamond-Blackfan anemia (DBA) is a rare bone marrow failure syndrome, usually caused by loss-of function variants in genes encoding ribosomal proteins. The hallmarks of DBA are anemia, congenital anomalies and cancer predisposition. Although DBA usually presents in childhood, the prevalence in later life is increasing due to an expanding repertoire of implicated genes, improvements in genetic diagnosis and increasing life expectancy. To standardize and optimize care for this rare disease, in this report an updated guidance on the diagnosis and management of DBA, with a specific focus on older adolescents and adults is provided. Recommendations are based upon published literature and pooled clinical experience from three centres in the United Kingdom. Read the full article here.

Clinical trial development in rare diseases poses significant study design and methodology challenges, such as disease heterogeneity and appropriate patient selection, identification and selection of key endpoints, decisions on study duration, choice of control groups, selection of appropriate statistical analyses, and patient recruitment. Therapeutic development in organic acidemias (OAs) shares many challenges with other inborn errors of metabolism, such as incomplete understanding of natural history, heterogenous disease presentations, requirement for sensitive outcome measures and difficulties recruiting a small sample of participants. In this report strategies for the successful development of a clinical trial to evaluate treatment response in propionic and methylmalonic acidemias are reviewed. The significant challenges associated with designing a clinical trial in rare disease can sometimes be successfully met through strategic engagement with experts in the rare disease, seeking regulatory and biostatistical guidance, and early involvement of patients and families. Read the full article here.

Congenital thrombotic thrombocytopenic purpura (cTTP) is an extremely rare disease characterized by the severe deficiency of a disintegrin and metalloproteinase with thrombospondin type 1 motifs 13 (ADAMTS13), caused by ADAMTS13 mutations. While ADAMTS13 supplementation by fresh frozen plasma (FFP) infusion immediately corrects platelet consumption and resolves thrombotic symptoms in acute episodes, FFP treatment can lead to intolerant allergic reactions and frequent hospital visits. Up to 70% of patients depend on regular FFP infusions to normalize their platelet counts and avoid systemic symptoms, including headache, fatigue, and weakness. The remaining patients do not receive regular FFP infusions, mainly because their platelet counts are maintained within the normal range or because they are symptom-free without FFP infusions. However, the target peak and trough levels of ADAMTS13 to prevent long-term comorbidity with prophylactic FFP and the necessity of treating FFP-independent patients in terms of long-term clinical outcomes are yet to be determined. This study suggests that the current volumes of FFP infusions are insufficient to prevent frequent thrombotic events and long-term ischemic organ damage. This report focuses on the current management of cTTP and its associated issues, followed by the importance of upcoming recombinant ADAMTS13 therapy. Read the full article here.

Thauvin-Robinet-Faivre syndrome (TROFAS; OMIM #617107) is a rare autosomal recessive overgrowth syndrome characterized by generalized overgrowth, dysmorphic facial features, and delayed psychomotor development caused by biallelic pathogenic variants in the FGF-1 intracellular binding protein (FIBP) gene. To date, only four patients from two families have been reported. In this report, a 4-year-old male patient with generalized overgrowth and delayed developmental milestones consistent with this syndrome is presented. He has unique features that were not reported in previous patients, including drooling, recurrent pulmonary infections, chronic pulmonary disease, hyperextensible elbow joints, hypoplastic nipples, unilateral cryptorchidism, and frequent spontaneous erections. In this report a homozygous, likely pathogenic variant, c.415_ (p.Asp139AlafsTer3), which causes a frameshift in the FIBP is identified.  In this article, the new observations are set out and also discuss the frequency of the characteristic findings of the syndrome in the patients so far reported. Read the full article here.

Recessive dystrophic epidermolysis bullosa (EB) is a rare disease characterized by painful blistering and erosion of the skin, sometimes referred to as “butterfly skin disease” because patients’ skin becomes as fragile as butterfly wings. In addition to severe dermatologic manifestations, EB patients also experience complications affecting epithelial surfaces including the gastrointestinal tract. While gastrointestinal complications such as oral mucosal ulceration, esophageal strictures, constipation, and gastroesophageal reflux are common in EB patients, reports of colitis are rare. In this report a patient with recessive dystrophic EB who developed EB-associated colitis is described. This case highlights the diagnostic challenges as well as the gaps in our current understanding of the prevalence, pathogenesis, and treatment of EB-associated colitis. Read the full article here.

Chronic granulomatous disease (CGD) is a rare primary immunodeficiency disorder that is characterized by deficiencies in the phagocytes capacity to eliminate ingested microorganisms, which frequently causes bacterial and fungal infections. The extensive involvement of the lungs, ribs, and vertebrae that is complicated by multiple abscesses from aspergillosis is rare. In this casa a 13-year-old boy with CGD who experience concurrent pneumonia, rib osteomyelitis, spondylodiscitis, paravertebral, and epidural abscesses as a result of Aspergillus flavus infection with associated computed tomography scan and magnetic resonance imaging findings is reported. Patients with CGD are susceptible to Aspergillus infection. Correct diagnosis based on clinical and paraclinical findings as well as choosing the best treatment regimen is essential for achieving a favorable outcome. Read the full article here.

Autoimmune lymphoproliferative syndrome (ALPS) is a rare disease characterized by defective FAS signaling, which results in chronic, nonmalignant lymphoproliferation and autoimmunity accompanied by increased risk of developing malignancies later in life.

In this, report a case of a newborn boy with a novel germline homozygous variant identified in the FAS gene, exon 9, c.775del is described, which is considered pathogenic. The consequence of this sequence change is the creation of a premature translational stop signal p.(lle259*), associated with a severe clinical phenotype of ALPS-FAS. The elder brother of the proband is also affected by ALPS and is been found to have the same FAS homozygous variant associated with a severe clinical phenotype of ALPS-FAS, whereas the unaffected parents are heterozygous carriers of this variant. This new variant has not previously been described in population databases (gnomAD and ExAC) or in patients with FAS-related conditions. Treatment with sirolimus effectively improves the patient clinical manifestations with obvious reduction in the percentage of DNTs.

In this report a new ALPS-FAS clinical phenotype-associated germline FAS homozygous pathogenic variant, exon 9, c.775del, that produces a premature translational stop signal p.(lle259*) is described. Sirolimus significantly reduces DNTs and substantially relieves the patient’s clinical symptoms. Read the full article here.