Case report: Rapidly progressive neurocognitive disorder with a fatal outcome in a patient with PU.1 mutated agammaglobulinemia

Abstract

Introduction: PU.1-mutated agammaglobulinemia (PU.MA) represents a recently described autosomal-dominant form of agammaglobulinemia caused by mutation of the SPI1 gene. This gene codes for PU.1 pioneer transcription factor important for the maturation of monocytes, B lymphocytes, and conventional dendritic cells. Only six cases with PU.MA, presenting with chronic sinopulmonary and systemic enteroviral infections, have been previously described. Accumulating literature evidence suggests a possible relationship between SPI1 mutation, microglial phagocytic dysfunction, and the development of Alzheimer's disease (AD).

Case description: We present a Caucasian female patient born from a non-consanguineous marriage, who was diagnosed with agammaglobulinemia at the age of 15 years when the immunoglobulin replacement therapy was started. During the following seventeen years, she was treated for recurrent respiratory and intestinal infections. At the age of 33 years, the diagnosis of celiac-like disease was established. Five years later progressive cognitive deterioration, unstable gait, speech disturbances, and behavioral changes developed. Comprehensive microbiological investigations were negative, excluding possible infective etiology. Brain MRI, ¹⁸FDG-PET-CT, and neuropsychological testing were suggestive for a diagnosis of a frontal variant of AD. Clinical exome sequencing revealed the presence of a novel frameshift heterozygous variant c.441dup in exon 4 of the SPI1 gene. Despite intensive therapy, the patient passed away a few months after the onset of the first neurological symptoms.

Conclusion: We describe the first case of PU.MA patient presenting with a rapidly progressive neurocognitive deterioration. The possible role of microglial dysfunction in patients with SPI1 mutation could explain their susceptibility to neurodegenerative diseases thus highlighting the importance of genetic testing in patients with inborn errors of immunity. Since PU.MA represents a newly described form of agammaglobulinemia, our case expands the spectrum of manifestations associated with SPI1 mutation.

Keywords: Alzheimer’s disease; PU.1; SPI1; agammaglobulinemia; exome sequencing; neurocognitive disorders.

Figure 1

CT enterography. In the D2 part of the duodenum, a mosaic distribution of folds is present, some of them are thickened and lowered [(A, B), yellow arrow], while some merge into plates [(C), orange arrow] and form pseudopolypoid lesions [(A, D), red arrow]. After the second knee of the duodenum, the folds are thinned [(A), green arrow]. In the jejunum, the height and number of folds are preserved, but in several foci they are grouped into pseudopolypoid lesions [(E, F), blue arrows]. There are longer spasms of ileal loops, possibly as a result of infiltration [(G), blue arrows], surrounded by fibrolipomatous proliferation of the mesentery [(I), blue arrows]. The patient’s spleen is absent, in its expected position there is presence of peritoneal fat [(H), purple asterisks].

Figure 2

CT of the lung. In the lungs there are multiple foci of “crazy-paving” depicted by ground-glass opacities [Image (A–D), yellow arrows] permeated by thickened septal interstitium [(B, D), orange arrow], with air-bronchogram and traction bronchiectasis [(A, B), red arrow], and thickened subpleural bands [(C), blue arrow]. Described lesions of organizing pneumonia are localized in the upper left lobe in apicoposterior segment [(E), yellow arrow] and lingula [(F-I), orange arrow], upper right lobe anterior segment [(F, G), red arrow], right lower lobe [(H-K), blue arrow] and left lower lobe posterobasal segment [(K), green arrow]. Pulmonary artery is dilatated, with transversal diameter of 35 mm [(L, M), purple arrow].

Figure 3

Integrative Genomics Viewer (IGV) showing insertion of one adenine nucleotide at position c.441 in exon 4 of the SPI gene.

Figure 4

Brain MRI. T2W MRI scans depicts generalized cerebral atrophy with enlarged ventricular system [(A, B), yellow arrow], and subarachnoid spaces [(D), green arrow]. There is bifrontoparietal pachymeningopathy on postcontrast FLAIR [(C), blue arrow]. T2W/SWI MRI scans depicts hypointensity as part of ferro deposition on both side in the dentate nuclei [(E), purple arrow] and the globus pallidus [(F), red arrow].

Figure 5

Timeline of major clinical events of the patient. ARA-autosomal-recessive agammaglobulinemia, IRT-immunoglobulin replacement therapy, HSCT- hematopoietic stem cell transplant, IVIG-intravenous immunoglobulin, HLA-human leukocyte antigen, COVID-19- coronavirus disease 2019, SIBO-small intestine bacterial overgrowth, NGS-Next-generation sequencing, PU.MA-PU.1 mutated agammaglobulinemia.