Stable clinical course in three siblings with late-onset isolated sulfite oxidase deficiency: a case series and literature review

Abstract

Background: Isolated sulfite oxidase deficiency (ISOD) is an autosomal recessive disorder caused by a deficiency of sulfite oxidase, which is encoded by the sulfite oxidase gene (SUOX). Clinically, the disorder is classified as one of two forms: the late-onset mild form or the classic early-onset form. The latter is life-threatening and always leads to death during early childhood. Mild ISOD cases are rare and may benefit from dietary therapy. To date, no cases of ISOD have been reported to recover spontaneously. Here, we present three mild ISOD cases in one family, each with a stable clinical course and spontaneous recovery.

Case presentation: All three siblings had two novel compound heterozygous mutations in the SUOX gene (NM_000456; c.1096C > T [p.R366C] and c.1376G > A [p.R459Q]). The siblings included two males and one female with late ages of onset (12-16 months) and presented with specific neuroimaging abnormalities limited to the bilateral globus pallidus and substantia nigra. The three patients had decreased plasma homocysteine levels. They exhibited a monophasic clinical course continuing up to 8.5 years even without dietary therapy.

Conclusion: This is the first report of mild ISOD cases with a stable clinical course and spontaneous recovery without dietary therapy. Our study provides an expansion for the clinical spectrum of ISOD. Furthermore, we highlight the importance of including ISOD in the differential diagnosis for patients presenting with late-onset symptoms, bilaterally symmetric regions of abnormal intensities in the basal ganglia, and decreased plasma homocysteine levels.

Fig. 1

Genetic analysis of SUOX in our family. a, Family pedigree with mutations in SUOX gene. Filled: affected with ISOD (compound heterozygous mutation); not filled, mutation carrier (heterozygous mutation). b, Sequencing electropherograms of all three affected siblings showing c.1096C > T (mutation 1, maternal) and c.1376G > A (mutation 2, paternal) transition. c, Phylogenetic conservation of the R366 and R459 (highlighted in red). These residues were conserved between species during evolution

Fig. 2

Axial T2-weighted imaging (T2WI) and fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI) scans from Case 1. a, b, T2 W1 and c, d, FLAIR performed 3 days after disease onset at age 1, showing high signal in the bilateral globus pallidus and substantia nigra (arrows). e-h, Follow-up images 1 year after onset revealed that hyper-signal lesions significantly shrank (arrows). i-l, Lesions on the basal ganglia had almost disappeared and the lesion on the substantia nigra disappeared 5.5 years after the onset

Fig. 3

Axial T2WI and FLAIR MRI scans from Case 2. a-d, MRI abnormalities observed 2 days after disease onset at 14 months. T2WI (a, b) and FLAIR (c, d) showed high signal in the bilateral globus pallidus and substantia nigra (arrows). e-h, Follow-up images 1.5 years after onset revealed that the original lesions on the basal ganglia and substantia nigra had almost disappeared

Fig. 4

Axial MRI scans from Case 3. T2WI (a, b), FLAIR (c), and diffusion-weighted imaging (DWI) (d) performed at 3 days after disease onset at age 16 months showing high signal in the bilateral globus pallidus and substantia nigra (arrows). e-h, Follow-up images 20 days after clinical onset revealed more conspicuous lesions than the original scan, with a necrotic lesion on the left globus pallidus on T2-weighted (e, f) and diffusion-weighted imaging (g, h)(arrows). i-l, Follow-up images at 2.5 years after onset revealed that lesions on the substantia nigra disappeared (j) and lesions on the globus pallidus were smaller, with well-delineated cysts (i, k) (arrows) and without new lesions and brain atrophy