Predominant neurological phenotype in a Hungarian family with two novel mutations in the XPA gene—case series

Objective The prevalence of xeroderma pigmentosum (XP) is quite low in Europe, which may result in a delay in determining the appropriate diagnosis. Furthermore, some subtypes of XP, including XPA, may manifest themselves with quite severe neurological symptoms in addition to the characteristic dermatological lesions. Accordingly, the aim of the current study is to highlight the predominant neurological aspects of XPA, as well as mild-to-moderate dermatological signs in a Hungarian family with 5 affected siblings. Case reports The symptoms of the Caucasian male proband started to develop at 13–14 years of age with predominantly cerebellar, hippocampal, and brainstem alterations. His elder sister and three younger brothers all presented similar, but less expressed neurological signs. The diagnostic work-up, including clinical exome sequencing, revealed 2 novel compound heterozygous mutations (p.Gln146_Tyr148delinsHis, p.Arg258TyrfsTer5) in the XPA gene. Surprisingly, only mild-to-moderate dermatological alterations were observed, and less severe characteristic ophthalmological and auditory signs were detected. Conclusions In summary, we present the first family with genetically confirmed XPA in the Central-Eastern region of Europe, clearly supporting the notion that disturbed function of the C-terminal region of the XPA protein contributes to the development of age-dependent neurologically predominant signs. This case series may help clinicians recognize this rare disorder. Electronic supplementary material The online version of this article (10.1007/s10072-019-04044-6) contains supplementary material, which is available to authorized users.

The demonstrated cognitive dysfunction is caused by the impairment of two functional neuroanatomical networks, the hippocampus-dependent and that related to the prefronto-cerebellar system, with similar degrees of impairment. The mother has an overall slight (ACE: 84 points) cognitive disability which is seemingly attributed to her poor performance in anterograde verbal memory test. This alteration may be the consequence of regular benzodiazepine use. Despite the lack of severe depression or anxiety, the patient takes this medication to keep with the stressful events related to the care of her disabled children.
Regarding the father, the impairment in overall cognitive functions is not clinically significant (ACE: 89 points, MMSE: 30 points), but the executive functions and processing speed are seemingly decreased. Brain magnetic resonance imaging of the proband with XPA. T2-weighted axial images (1.5 Tesla) (a) and T1-weighted coronal images (1.5 Tesla) (b) demonstrate generalized brain atrophy with slight predominance at the parieto-occipital region (indicated with white arrows) and in the cerebellum (indicated with gray arrows) in patient II-2.

Supplementary Material 1.4
Macroscopic neuropathological alterations of the proband with XPA. The total brain weight was 815 grams, the cerebellum-brainstem The presence of astrogliosis/microgliosis/neuronal loss, and degree of various protein depositions were semi-quantitatively (none, mild, moderate, severe) evaluated in the following anatomical regions: frontal, temporal, occipital and premotor cortex, basal ganglia and thalamus, amygdala, hippocampus and brainstem levels (mesencephalon, pons, medulla oblongata). Histological examination revealed mild loss of neurons with edema-related spongy loosening of the neuropil in the superficial layers of cortical areas. There was a lack of ballooned neurons or eosinophilic inclusion bodies. The basal ganglia, thalamus and amygdala were also relatively well preserved.
In the hippocampus we observed prominent loss of neurons and reactive astrogliosis in the CA1 (a; H&E staining) and CA4 subregions. This was asymmetrical and involved mostly the left side.
Further mild to moderate neuronal loss was seen in the substantia nigra (b; H&E staining) and severe loss was observed in the cerebellum (c; H&E staining, arrow indicates a torpedo), where the Purkinje cell layer showed significant depletion with Bergmann-gliosis and formation of axonal torpedos. Other brainstem nuclei did not show relevant neuronal loss, except for moderate gliosis in the inferior olives. The anterior horn motor neurons were moderately depleted (d; H&E staining). There was a lack of vascular lesions in the examined areas. Microglial activation was seen in areas with neuronal loss and additionally scattered CD8 positive cytotoxic T cells, but no CD20 positive B cells, were also observed in the hippocampus (e), substantia nigra (f), cerebellar white matter and dentate nucleus. In further anatomical regions mild CD8 positive cell infiltrations were seen around vessels in the white matter. Immunostaining for α-synuclein, amyloid-beta, TDP-43, phospho-TDP-43, ubiquitin and p62 did not reveal pathological protein deposits in any of these regions. In the immunostaining for phospho-tau only a single neuron was seen in the entorhinal cortex on the side where sclerosis was observed.
The bar in (a) represents 50 micrometer for all images.
Method for immunohistochemistry: In addition to Hematoxylin and Eosin and Luxol Fast Red, the following monoclonal antibodies were used for immunohistochemistry: anti-tau AT8 only lentigos were noted on the sun-exposed skin. Written informed consent was obtained from the participants of the study for the publication of photo materials with identifying information.
Method for immunohistochemistry: Following punch biopsy of the sun-exposed skin, p53 immunohistochemistry (clone PA0057 ready to use dilution with heat induced epitope retrieval at pH = 9 for 30 minutes; Leica Biosystems, UK) was performed.

Supplementary Material 1.11
Sanger

Supplementary Material 1.12
The figure demonstrates that the in-frame mutation is located in a conserved region of the XPA protein.

Supplementary Material 1.13
The demographic and clinical characteristics of patients with mutations in the XPA gene.