PRUNE1‐related disorder: Expanding the clinical spectrum

Abstract

Neurodevelopmental disorder with microcephaly, hypotonia, and variable brain anomalies (NMIHBA) (OMIM #617481) is an autosomal recessive disease characterized by progressive microcephaly, plagiocephaly, hypotonia, spastic quadriparesis, global developmental delay, intellectual disability, optic features and abnormal brain magnetic resonance imaging (MRI). NMIHBA was recently reported to be caused by PRUNE1 mutations. Eight mutations have been reported in 13 unrelated families. Here, we report 3 PRUNE1 mutations in 1 Caucasian and 3 Japanese families. One recurrent missense mutation (p.Asp106Asn) was previously reported in Turkish and Italian families, while the other 2 mutations (p.Leu18Serfs*8 and p.Cys180*) are novel. We also show that mutant PRUNE1 mRNA can be subject to nonsense-mediated mRNA decay. The patients presented in this study showed atypical NMIHBA phenotypes with no progressive microcephaly. Furthermore, one Caucasian case had significant macrocephaly; therefore, patients with PRUNE1 mutations can exhibit a broad and heterogeneous spectrum of phenotypes.

Reconsidering NMIHBA Core Features: Macrocephaly Is Not a So Unusual Sign in PRUNE1-Related Encephalopathy

“…2,4,7,9,11,12 A peripheral motor neuron involvement seems to be a common feature related to this homozygous mutation shared by some Italian patients 2,9 including ours, assuming that involvement of both the central and peripheral nervous system is a hallmark of this severe disorder. Moreover, since the p.Asp106Asn seems to be recurrent in European and Asian populations, 2,4,7,9,11 it is hypothesized as founder effect or a mutational hotspot for this variant. 11 This missense variant provokes a complete loss of function of the protein, which may lead to a more severe clinical presentation and a primarily degenerative phenotype, altering cell migration and differentiation 2 but also impacting on tubulin homeostasis, 8 with a mixed neurodevelopmental and neurodegenerative disease.…”

“…13 Our serial MRI scans showed a severe progression of the disease with increasing age. Many features such as white matter disease, thin corpus callosum and cerebral, cerebellar and brainstem atrophy have already been reported [1][2][3][4][5][6][7][8][9][10][11] to be characteristic, while signal alterations in inferior olives, which appeared at the last examination during the followup, is noteworthy, and adds additional imaging clues to detect the PRUNE1-related phenotypic spectrum, although it should be confirmed by additional descriptions.…”

“…8 Similarly, the OFC of another female patient 7 was above 2.2 SD at birth and above 2 SD at 4 years, thus the head growth curve had mildly reduced. Conversely, a progressive macrocephaly was described in two males and four female patients, 8,11 unfortunately, dead within the age of 35 months, Reconsidering NMIHBA Core Features Milone et al…”

“…9 Abnormalities of the nerve motor conduction velocity (►Table 1) and signs of neurogenic abnormalities at muscle biopsy confirmed this impression and the impression was consistent with a denervation process following degeneration of the motor axons and neurons. 8 To date, 12 different pathogenetic variants in PRUNE1 have been described 1,2,[4][5][6][7][8][9][10][11][12] ; among these, p.Asp106Asn is the most frequently recurrent change in 15 patients from 11 unrelated families. 2,4,7,9,11,12 A peripheral motor neuron involvement seems to be a common feature related to this homozygous mutation shared by some Italian patients 2,9 including ours, assuming that involvement of both the central and peripheral nervous system is a hallmark of this severe disorder.…”

“…8 To date, 12 different pathogenetic variants in PRUNE1 have been described 1,2,[4][5][6][7][8][9][10][11][12] ; among these, p.Asp106Asn is the most frequently recurrent change in 15 patients from 11 unrelated families. 2,4,7,9,11,12 A peripheral motor neuron involvement seems to be a common feature related to this homozygous mutation shared by some Italian patients 2,9 including ours, assuming that involvement of both the central and peripheral nervous system is a hallmark of this severe disorder. Moreover, since the p.Asp106Asn seems to be recurrent in European and Asian populations, 2,4,7,9,11 it is hypothesized as founder effect or a mutational hotspot for this variant.…”