Case Report: Two Families With HPDL Related Neurodegeneration

Abstract

There are recent reports of associations of variants in the HPDL gene with a hereditary neurological disease that presents with a wide spectrum of clinical severity, ranging from severe neonatal encephalopathy with no psychomotor development to adolescent-onset uncomplicated spastic paraplegia. Here, we report two probands from unrelated families presenting with severe and intermediate variations of the clinical course. A homozygous variant in the HPDL gene was detected in each proband; however, there was no known parental consanguinity. We also highlight reductions in citrate synthase and mitochondrial complex I activity detected in both probands in different tissues, reflecting the previously proposed mitochondrial nature of disease pathogenesis associated with HPDL mutations. Further, we speculate on the functional consequences of the detected variants, although the function and substrate of the HPDL enzyme are currently unknown.

Keywords: ataxia; brain diseases; citrate-synthase; mitochondrial diseases; spastic paraplegia.

FIGURE 1

Head MRI.(A–D) Proband 1, 6 years of age. (A), (B)—axial T2, frontal subcortical hyperintensity. (C)—axial T1, white matter reduction in frontal lobes. (D)—sagittal T1, smaller anterior parts of corpus callosum. (E–G) Proband 2, 5 weeks of age, showing significant diffuse white matter abnormalities sparing basal ganglia. (E)—axial T2, (F)—axial T1, (G)—coronal T2. (H–J) Proband 2, 2 years of age, showing a diffuse severe cotico-subcortical atrophy with white matter abnormalities but with progression of myelination. (H)—axial T2 flair, (I)—axial T2, (J)—sagittal T1.

FIGURE 2

The probands’ pedigrees and HPDL variants. Pedigree of proband 1 (A) and proband 2 (B) with the harboured genotypes. Schematic of the HPDL protein and different disease-associated variants published so far (C) (Ghosh et al., 2020; Husain et al., 2020; Morgan et al., 2021; Numata-Uematsu et al., 2021; Sun et al., 2021; Wiessner et al., 2021; Yu et al., 2021). MTS, mitochondrial targeting sequence; Fe BS, iron binding site; variants reported in this manuscript are indicated in bold.

FIGURE 3

The Leu338Pro mutation disrupts HPDL structure and function. (A): Model of one subunit of HPDL, based on the HPPD structure. Identical residues between HPPD and HPDL are colored red, similar residues are colored yellow. The N-terminal dimerization domain is colored in gray. Note that the four iron-binding residues are conserved between the two proteins, as are most residues surrounding the putative iron binding site. (B top): HPDL Leu338Pro model showing how the beta strands that neighbor Pro388 dissociate. (B bottom): This separation is due to a lack of inter-strand hydrogen bonds involving Pro338, along with missing hydrogen bonds between residues 327-337 (A) and 327-257 (B).