Recurrent subacute post-viral onset of ataxia associated with a PRF1 mutation

  title={Recurrent subacute post-viral onset of ataxia associated with a PRF1 mutation},
  author={Cristina Dias and Allison McDonald and Murat Sincan and Rosemarie Rupps and Thomas C. Markello and Ramona Salvarinova and Rui F Santos and Kamal Menghrajani and Chidi Ahaghotu and Darren P. Sutherland and Edgardo S. Fortuno and Tobias R. Kollmann and Michelle K Demos and Jan M. Friedman and David Paul Speert and William A. Gahl and Cornelius F. Boerkoel},
  journal={European Journal of Human Genetics},
Inflammation is an important contributor to pediatric and adult neurodegeneration. Understanding the genetic determinants of neuroinflammation provides valuable insight into disease mechanism. We characterize a disorder of recurrent immune-mediated neurodegeneration. We report two sisters who presented with neurodegeneration triggered by infections. The proband, a previously healthy girl, presented at 22.5 months with ataxia and dysarthria following mild gastroenteritis. MRI at onset showed a… 

Histopathologic Correlates of Familial Hemophagocytic Lymphohistiocytosis Isolated to the Central Nervous System

3 patients with CNS-isolated familial HLH presented with a variety of neurological symptoms and underwent brain biopsies for multifocal enhancing supratentorial and infratentorial lesions, with no evidence of systemic disease except decreased NK-cell function.

Predominant Neurologic Manifestations Seen in a Patient With a Biallelic Perforin1 Mutation (PRF1; p.R225W).

A case with FHL2 in whom hemophagocytic lymphohistiocytosis was a presenting manifestation which responded to specific therapy, however, there was isolated central nervous system relapse while patient was in remission and off therapy.

Neuroinflammatory Disease as an Isolated Manifestation of Hemophagocytic Lymphohistiocytosis

HLH-directed therapy followed by HSCT seems to improve survival and outcome and isolated CNS-HLH is a rare and often overlooked cause of inflammatory brain disease.

RF1 Gene Mutation in Familial Hemophagocytic Lymphohistiocytosis 2: A Family Report and Literature Review

According to the clinical manifestations, laboratory tests, and results of the family molecular genetic testing, the probands could be clinically diagnosed as FHL2, an autosomal recessive family with familial hemophagocytic syndrome.

Neuroinflammation Associated With Inborn Errors of Immunity

This review focuses on the signs and symptoms of neuroinflammation that have been reported in association with established pathogenic variants in immune genes and suggests the following subdivision based on proposed underlying mechanisms: autoinflammatory disorders, tolerance defects, and immunodeficiency disorders.

PGPM_A_326921 1637..1645

Gene mutation analysis was performed on a family with familial hemophagocytic lymphohistiocytosis to provide an accurate etiological diagnosis, leading to genetic counseling for the family members, who could be clinically diagnosed as FHL2.

Genetic studies of susceptibility to inflammation, autoimmunity, and hematological malignancy

These findings suggest the existence of IFN-γ-independent mechanisms for the development of HLH, and display the power of high-throughput sequencing in diagnostics of individuals affected by severe inflammation, autoimmunity, and hematological malignancies.

Allogeneic hematopoietic stem cell transplantation is associated with cure and durable remission of late‐onset primary isolated central nervous system hemophagocytic lymphohistiocytosis

While patients with systemic HLH and active CNS disease have relatively poorer outcomes, a high index of suspicion may aid with early diagnosis of primary isolated CNS HLH; prompt treatment with HSCT may be associated with improved cure and durable remission of this rare disease.

Spectrum of Atypical Clinical Presentations in Patients with Biallelic PRF1 Missense Mutations

Perforin, encoded by PRF1, is a pore‐forming protein crucial for lymphocyte cytotoxicity that invariably result in early‐onset hemophagocytic lymphohistiocytosis (HLH), termed familial HLH type 2 (FHL2).

The NIH Undiagnosed Diseases Program and Network: Applications to modern medicine.



Primary necrotizing lymphocytic central nervous system vasculitis due to perforin deficiency in a four-year-old girl.

The findings described herein indicate that, even in the absence of classic non-neurologic symptoms of hemophagocytic lymphohistiocytosis, measurement of perforin expression should be one of the diagnostic tests used to identify the cause of unexplained CNS vasculitis.

A teenage boy with late onset hemophagocytic lymphohistiocytosis with predominant neurologic disease and perforin deficiency

A case of an 18‐year‐old male with a 2‐year history of symptoms attributed to a demyelinating disorder, who succumbed to rapidly progressive hemophagocyte lymphohistiocytosis and post‐mortem, two distinct perforin mutations were identified.

Familial hemophagocytic lymphohistiocytosis in a pediatric patient diagnosed by brain magnetic resonance imaging.

The reported case demonstrates that MRI pattern recognition can lead to early diagnosis of fHLH, with subsequent adequate treatment, according to the international HLH-2004 protocol.

STXBP2 mutations in children with familial haemophagocytic lymphohistiocytosis type 5

Current knowledge on the genetic heterogeneity of FHL is expanded and it is suggested that patients with FHL5 may have different results in degranulation assays under different conditions.

Six novel mutations in the PRF1 gene in children with haemophagocytic lymphohistiocytosis

Nine different mutations, three nonsense and six missense, in the two coding exons of the perforin 1 gene (PRF1) are identified in a group of eight unrelated patients, providing the first evidence for a disease related to PRF1 .

Novel spectrum of perforin gene mutations in familial hemophagocytic lymphohistiocytosis in ethnic omani patients

The first comprehensive molecular analysis of 16 unrelated cases of FHL in ethnic Omanis is reported, using direct DNA sequencing analysis in 11 families, and seven different mutations were identified in the coding region of the perforin gene, of which five were novel.

CNS involvement at the onset of primary hemophagocytic lymphohistiocytosis

Brain MRI showed that patients with HLH, unlike patients with ADEM, had symmetric periventricular lesions, without thalamic and brainstem involvement and with infrequent hyposignal intensity on T1, and Neurologic symptoms are frequent at the onset of primary HLH and are mostly associated with abnormal CSF findings, but with normal brain MRI.

Hemophagocytic lymphohistiocytosis with neurological presentation: MRI findings and a nearly miss diagnosis

A 13-year-old girl presented with progressive increase in intracranial pressure and ataxia, and two bone marrow biopsies were needed to demonstrate hemophagocytosis, which was confirmed by perforin gene mutations.