Barakat-Perenthaler syndrome

Barakat-Perenthaler syndrome OMIM 618744 has so far been identified in 22 individuals from 15 families.,[1] According to OMIM's review of all published cases[1] and the initial study from Perenthaler et al,[2] all children presented in early life with severe and intractable epileptic seizures. Severe developmental delay was found in all individuals, with basically absence of all developmental milestones.[1][2] Children were unable to roll over or sit, did not develop speech, had absent visual tracking and most cases required gastro-intestinal tube feeding due to severe orofacial hypotonia.[1][2] Other neurological features included infantile epileptic spasms, axial hypotonia, peripheral spasticity and/or hyperreflexia, and a few cases showed dystonia.[1][2] Head circumference decreased progressively over time.[1][2] MRI brain imaging did not detect major structural brain abnormalities, but showed progressive brain atrophy over time.[1][2] Mild dysmorphic features were noted amongst several individuals, including a sloping forehead, suture ridging, bitemporal narrowing, high hairline, arched eyebrows, pronounced philtrum, and a relatively small mouth and large ears.[2] Most children died early in life[1][2]

Barakat-Perenthaler syndrome[1] is an autosomal recessive disorder and is caused by a recurrent homozygous mutation[4] of the UDP-glucose pyrophosphorylase (UGP2) gene.[5][6] UGP2 encodes an essential protein in nucleotide sugar metabolism, which catabolizes the conversion of glucose-1-phosphate to UDP-glucose.[7][8] In humans, two functionally equivalent protein isoforms are encoded by the UGP2 gene, a longer one (isoform 1)[9] and a slightly shorter one (isoform 2),[10] that only differ by 11 amino acids at the N-terminal.[11] The recurrent mutation (chr2:64083454A>G)[12] identified in all patients with the syndrome affects the start codon of the shorter protein isoform.[1][2] Hence, the shorter isoform can no longer be produced in affected individuals.[2] It was shown by Barakat and colleagues that the shorter UGP2 isoform is predominantly expressed in human brain.[2] Therefore, the recurrent mutation leads to a brain-specific depletion of the essential UGP2 protein, resulting in altered glycogen metabolism, upregulated unfolded protein response and premature neuronal differentiation which likely cause the disease symptoms.[2]

A complete loss of UGP2 isoform 1 and isoform 2 in human embryonic stem cells prevented the formation of functional heart and blood cells in in vitro differentiation experiments. Hence it is likely that bi-allelic loss-of-function of all UGP2 isoforms is incompatible with life in humans; in agreement with this, no bi-allelic loss-of-function variants affecting both protein isoforms are reported in the gnomAD database.[13] The syndrome is therefore an example of a disease caused by the loss of expression of a tissue relevant isoform of an essential gene.[2] Recently, bi-allelic loss of UDP-Glucose 6-Dehydrogenase (UGDH), another gene implicated in nucleotide sugar metabolism,[14] was also shown to cause a similar severe epileptic encephalopathy syndrome, referred to by OMIM as Jamuar syndrome (OMIM #618792),[15][16] showing that nucleotide sugar metabolism can be more broadly implicated in epilepsy.

Barakat and colleagues showed that all identified affected individuals harboring the recurrent mutation shared the same haplotype, suggesting a founder effect and a common ancestor.[2] The mutation was estimated to have originated 26 generations (approximately 600 years) ago.[2] Most cases of Barakat-Perenthaler syndrome could be linked to the Balochistan region (consisting of parts of Iran, Pakistan, India). Since Dutch traders were active in that region in the 17th century,[17] this could be an explanation for the introduction of the founder mutation into the Dutch population, from which the first case was described[2]

So far, no treatment is available for Barakat-Perenthaler syndrome.[18]