Isolated sulfite oxidase deficiency (ISOD; OMIM #272300) is a devastating rare neurometabolic disorder due to biallelic pathogenic variants in the SUOX gene, that typically results in neonatal refractory epilepsy and progressive severe encephalopathy. Knowledge on the quantitative natural history of ISOD is limited and clinical outcome parameters for future clinical trials remain to be defined. We performed a comprehensive analysis of published cases (N=74) with ISOD applying quantitative retrospective natural history modeling (QUARNAM). Main outcome parameters were age of disease onset, diagnostic delay and survival. Clinical characteristics and potential associations between biochemical parameters and clinical outcome (i.e. age of disease onset, survival) were explored. The median survival period of the study cohort was 60 months. ISOD typically presented shortly after birth with a median age of onset of 3 days. Median age at diagnosis was 10 months, leading to a substantial median diagnostic delay of 5.7 months. Homocysteine concentrations in plasma correlated with age of disease onset. An association of biochemical parameters of cysteine metabolism and survival could not be identified. The present analysis describes long-term outcome measures adding to the quantitative understanding of the natural history of ISOD, which might be helpful in the planning of prospective clinical trials and potentially stimulate development of targeted therapies in the future.

Molybdenum cofactor deficiencies (MoCD) are a group of inborn errors of metabolism that result in impaired synthesis of molybdenum cofactor, crucial for the function of three oxidases (sulfite oxidase, xanthine oxidase and aldehyde oxidase). Most patients present with severe neonatal-onset epileptic encephalopathy, hypotonia, poor feeding and apnoea, with death typically occurring within the first three years of life. Whilst there is now an emerging therapy for MoCD Type A (cPMP/fosdenopterin), this treatment is not effective for MoCD Type B and there is no treatment for isolated sulfite oxidase deficiency (ISOD). Liver directed gene delivery is a potential alternative therapy for sulfite intoxication disorders. We report an attempt to use hepatocyte transplantation as a treatment option for MoCD Type B, in an infant with a strong family history of neonatal-onset disease and early mortality. Six transfusions of hepatocytes were given between Day 1 and Day 18 of life, totalling around 1 × 109 cells with immunosuppressive cover. Concomitantly dietary protein restriction was maintained at 2 g/kg, including 0.7 g/kg of methionine- and cyst(e)ine-free amino acid mixture. The aim was to utilize hepatocyte transplantation as a bridge to liver transplantation. Whilst there was evidence of biochemical stabilization with reduction in concentrations of sulfite and S-sulfocysteine and a moderate increase in urate levels compared to the sibling, the treatment was not able to prevent acute brain injury from sulfite toxicity which was evident in neuroimaging at 35 h of age. This correlated clinically with ongoing seizures as well as minimal developmental progress.

Sulfite oxidase deficiencies, either caused by deficiency of the apoenzyme or the molybdenum cofactor, and ethylmalonic encephalopathy are inherited disorders that impact sulfur metabolism. These patients present with severe neurodeterioration accompanied by cerebral cortex and cerebellum abnormalities, and high thiosulfate levels in plasma and tissues, including the brain. We aimed to clarify the mechanisms of such abnormalities, so we assessed the ex vivo effects of thiosulfate administration on energetic status and oxidative stress markers in cortical and cerebellar tissues of newborn rats. Thiosulfate (0.5 µmol/g) or PBS (vehicle) was injected into the fourth ventricle of rat pups. Thirty minutes after the injection, animals were euthanized and the brain structures were utilized for the experiments. Our data showed that thiosulfate decreased the reduced glutathione (GSH) concentrations, and superoxide dismutase (SOD), catalase (CAT) and glutathione S-transferase (GST) activities in the cortical structure. Thiosulfate also increased DCFH oxidation, hydrogen peroxide generation and glutathione reductase activity. In the cerebellum, thiosulfate reduced SOD and glutathione peroxidase activities but increased GST and CAT activities as well as DCFH oxidation. Regarding energy metabolism, thiosulfate specifically decreased complex IV activity in the cortex, whereas it increased cerebellar complex I and creatine kinase activities, indicating bioenergetic disturbances. The results suggest that the accumulation of thiosulfate causing redox disruption and bioenergetic alterations has a prominent role in the pathogenesis of sulfur metabolism deficiencies.

Molybdenum cofactor deficiency (MoCD) classically presents shortly after birth, with neurological symptoms ascribed to postnatal toxicity of accumulating sulphite. Case reports suggest that cerebral damage associated with MoCD may have a prenatal onset. A meta-analysis of case reports was performed on individuals with genetically proven MoCD retrieved through a systematic review and in-house search. Cases were categorized as classical or late-onset, based on the time of onset of symptoms. Available cerebral images were scored for the presence of restricted diffusion, pathological signal, subcortical cysts, and atrophy. Estimated onset of each event and the minimal number of events needed to explain the observed imaging abnormalities were deduced by combining age at imaging, type of imaging abnormality, and known natural evolution of the imaging abnormalities. Of a total of 30 retrieved cases, 21 were classical. Prenatal origin of damage was possible in all classical cases and certain in 11 of 21 (52%). Multiple events were deduced in 5/21 classical cases based on imaging data alone and in 11 of 21 cases when presuming that a postnatal onset of symptoms signifies a recent event. Multiple, but postnatal, events were also described in 3 of 9 late-onset cases. Prenatal onset of cerebral damage in patients with classical MoCD is more frequently encountered than anticipated. It may have been overlooked by the overwhelming postnatal symptoms erroneously pointing to a single culprit. This insight is important when counseling for prognosis, particularly in the context of considering the timing and anticipated prospects of therapeutic intervention.

Sulfite intoxication is the hallmark of four ultrarare disorders that are caused by impaired sulfite oxidase activity due to genetic defects in the synthesis of the molybdenum cofactor or of the apoenzyme sulfite oxidase. Delays on the diagnosis of these disorders are common and have been caused by their unspecific presentation of acute neonatal encephalopathy with high early mortality, followed by the evolution of dystonic cerebral palsy and also by the lack of easily available and reliable diagnostic tests. There is significant variation in survival and in the quality of symptomatic management of affected children. One of the four disorders, molybdenum cofactor deficiency type A (MoCD-A) has recently become amenable to causal treatment with synthetic cPMP (fosdenopterin). The evidence base for the rational use of cPMP is very limited. This prompted the formulation of these clinical guidelines to facilitate diagnosis and support the management of patients. The guidelines were developed by experts in diagnosis and treatment of sulfite intoxication disorders. It reflects expert consensus opinion and evidence from a systematic literature search.