Novel Pathogenic Variant in a Mild Case of Type B Molybdenum Cofactor Deficiency: Case Report and Literature Review

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Case Report

Novel Pathogenic Variant in a Mild Case of Type B Molybdenum Cofactor Deficiency: Case Report and Literature Review

https://doi.org/10.21203/rs.3.rs-4272138/v1

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Background:

Molybdenum cofactor deficiency (MoCD) is a rare metabolic disorder caused by pathogenic variants in the highly conserved biosynthetic pathway of molybdenum cofactor (MoCo), resulting in sulfite intoxication. MoCD may present in a clinically severe, rapidly fatal form marked by intractable seizures after birth, hyperekplexia, microcephaly and cerebral atrophy, or a later onset form with a more varied clinic course. Three types of MoCD have been described based on the effected gene along the MoCo synthesis pathway: type A (MOCS1); type B (MOCS2 or MOCS3) and type C (GPHN). The MOCS2 gene is bicistronic, encoding the small (MOCS2A) and large (MOCS2B) subunits with an overlapping coding region. This case report describes a patient with the first known variant causative of mild disease in the overlapping bicistronic region (c.263 G>C) and the first ever described in the highly conserved C-terminal glycine-glycine motif of MOCS2A.

Case Presentation:

The patient developed normally until age 12 months when she presented in the setting of acute illness withdevelopmental regression, low serum uric acid, and MRI with bilateral globus pallidus (GP) injury. Whole exome sequencing (WES) identified a homozygous variant of unknown significance in the MOCS2 gene and the diagnosis of MoCD type B was confirmed by the patient’s elevated urine sulfocysteine and low uric acid. Nearly two years after her initial presentation she has demonstrated progress in language and motor domains, consistent with a mild phenotype of MoCD.

Conclusions:

The case emphasizes challenges in identifying atypical forms of rare diseases, the importance of whole exome sequencing (WES) to identify mild cases of MoCD, and the ongoing challenges with understanding the MOCS2 gene. While one FDA approved treatment exists for MoCD type A, further research into the mechanisms of phenotype-genotype differences among this patient population may aid in additional therapeutic options for MoCD.

Molybdenum cofactor deficiency (MoCD)

MoCD type B

MOCS2

molybdenum cofactor (MoCo)

molybdopterin (MPT) synthase

globus pallidus (GP) injury

whole exome sequencing (WES)

single nucleotide variant (SNV)

case report

Molybdenum cofactor deficiency (MoCD) is a rare, autosomal recessive metabolic disorder first described in 1978¹. MoCD is caused by pathogenic variants in genes of the highly conserved biosynthetic pathway of molybdenum cofactor (MoCo) from GTP². In humans, MoCo is essential for its redox function in four key enzymes: sulfite oxidase, aldehyde oxidase, xanthine oxidoreductase, and mitochondrial amidoxime-reducing component (mARC). MoCo deficiency, therefore, leads to a toxic accumulation of the metabolites upstream of these enzymes including sulfite, taurine, S-sulfocysteine and thiosulfate. Of these, sulfite accumulation is the most clinically deleterious, leading to progressive neurological damage through pathogenic, possibly through disrupted DNA alkylation but the mechanisms are not yet fully understood^3,4. Similarly, the clinical presentations of MoCD range from mild to severe and the determinants of disease severity are not yet known⁵.

Disease categorizations for MoCD are variable in the literature, but loosely fall into two categories⁵. Patients with severe MoCD typically present with intractable seizures shortly after birth, feeding difficulties, hyperekplexia, microcephaly and cerebral atrophy, severe developmental delay, and distinctive facial features⁶. Mild cases have similarity to Leigh Syndrome, often presenting with an intercurrent illness within the first 2 years of life after a period of relatively normal development, and follow a more varied clinical course^7,8,9. The incidence of MoCD is likely underestimated due to misdiagnosis of hypoxic ischemic encephalopathy (HIE) or cerebral palsy and the high early fatality rate among the severe phenotype^10,11,36. MoCD diagnostic criteria include elevated urine sulfite, S-sulfocysteine, taurine, thiosulfate, xanthine and hypoxanthine, and decreased urine and serum levels of uric acid due to loss of xanthine dehydrogenase function⁷. Brain MRI differ significantly between patients but usually reveal symmetric lesions, diffusely affecting a variety of brain structures, with abnormalities ranging from poor myelination and gliotic changes to atrophy and cystic necrosis¹².

There are three distinct forms of MoCD based on the function of the deficient enzyme in the MoCo biosynthetic pathway: type A (MOCS1); type B (MOCS2 or MOCS3) and type C (GPHN) (See Figure 1). The MOCS2 gene consists of 7 exons on chromosome 5q and is bicistronic, with two overlapping open reading frames (ORFs) encoding the small (MOCS2A) and large (MOCS2B) subunits of molybdopterin (MPT) synthase¹³. MPT synthase is a heterotetrametric enzyme which converts cPMP to MPT by transferring two sulfide groups, a crucial step in MoCo synthesis and the basis of MoCD type B¹⁴. While type A is potentially responsive to supplementation with cPMP, which is downstream of MOCS1, treatment must be initiated very soon after symptom onset. Likelihood of response is to cPMP is low for type B due to the inability to convert cPMP to MPT, and prognosis for severe type B cases is poor^15,16.

We present a case of a one year old patient with an acute but mild clinical presentation of MoCD type B due to a novel pathogenic variant, c.263 G>C in MOCS2. Imaging demonstrated bilateral acute injury to the globus pallidus. Diagnosis of MoCD was confirmed by low uric acid, elevated urine sulfocysteine, and whole exome sequencing (WES). A literature review of all MoCD type B cases confirmed by genetic testing to date, with all available clinical and genetic data, are summarized in Supplementary Table S1 (online only).

The patient presented as a 12-month old female with apparently normal development who suffered an episode of acute suppurative otitis media leading to altered mental status and meningismus including stiff neck, photophobia and emesis. Upon admission she was afebrile, irritable and drowsy, with low tone and negative Kernig and Brudzinski signs.

The medical history of the patient was significant for birth via cesarean section at 39 and 6/7 weeks due to difficult labor. Mother was 25 years old with gestational diabetes and pre-eclampsia. Birth weight was 7 lbs., 13 oz. Apgar scores were 9 at 1 minute and 5 minutes. At the time of birth, she was noted to have difficulty feeding resulting in a 9.4% decrease in weight by day 3 of life. Acylcarnitines, amino acids and fatty acids were negative on day 2 of life. Muscle tone was within normal limits, and Moro and grasp reflexes were present. No other clinical concerns were noted until a routine office visit at 10 months noted strabismus, for which a referral was placed. She was noted to be walking and otherwise developing normally prior to acute presentation. The patient was the second child of first-degree consanguineous Pakistani parents. The elder sister was unaffected. Family history was significant for one maternal aunt who died in her 40s due to an unknown illness.

Upon her acute presentation at 12 months, a head CT noted areas of hypodensity within the basal ganglia. A follow up MRI demonstrated increased T2 FLAIR signal within the bilateral globus (see Figure 2). Diffusion weighted imaging (DWI) (Figure 2) and apparent diffusion coefficient (ADC) (Figure 2) confirmed a pattern of restricted diffusion consistent with acute injury. CSF meningitis/encephalitis PCR panel, CSF and blood cultures, and Sars-Cov-19 test were all negative. CSF protein was 12, lymphocytes 52, monocytes 48, and glucose was within normal limits. Carboxyhemoglobin (2.7%) and methylhemoglobin (1.3%) were slightly elevated on admission, but normalized on repeat testing. Urine toxicology screen was negative for methanol, ethanol, isopropanol, and acetone. Urine organic acids noted elevated 3-hydroxybutyric and acetoacetic acids, consistent with ketosis, but not diagnostic of a recognized inborn error of organic acid metabolism. Plasma acylcarnitine assay revealed elevated Tetradecanoylcarnitine C14 and Octadecanoylcarnitine C18, which were of unclear significance. Serum amino acid and fatty acid profiles were similarly nondiagnostic. An EEG showed 6 Hz PDR bursts of slowing and no seizures, consistent with mild global neurologic dysfunction consistent with the patient’s clinical examination. The patient was discharged after 4 days showing significant improvement but remained non-ambulatory with persistent fussiness and diffuse hypotonia.

On outpatient follow up, the patient remained unable to walk and had not regained her pre-hospitalization baseline. Outpatient notes from the pediatrician describe orange deposits in the patient’s diapers. Additional metabolic and genetic testing was recommended. Quantitative urine organic acid evaluation showed elevated taurine to 5495.1 picomole/g creatine (normal 168-2446), and a slightly elevated the 2-methylglutaconic acid/3-methylglutaconic acid ratio. The latter was suggestive of ECHS1 deficiency, but additional urine testing for C4-acylcarnitine, C5-DC acylcarnitine and 2,3 dihydroxy-methylbutanoic acid, were normal. Whole exome sequencing (WES) was also performed and identified a homozygous variant of unknown significance in the MOCS2 gene (c.263 G>C, MOCS2A:p.G88A, MOCS2B:p.D26H) which was a candidate gene for the patient’s clinical phenotype. The variant consists of a single nucleotide polymorphism (SNP) G>C at coding strand position 263 which lies in the overlapping region of the two bicistronic subunits MOCS2A and MOCS2B (Figure 3). The SNP is predicted to lead to amino acid change Gly > Ala at protein position 88 in MOCS2A, and Arg > His in MOCS2B. The diagnosis of MoCD type B was confirmed by our patient’s elevated urine sulfocysteine (121.5 mmol/mol creatinine) and low uric acid (<0.2 mg/dL). Of note, taurine may be elevated in MoCD as well¹⁷.

Initially after hospitalization, the patient demonstrated persistent regression of walking skills, with muscle stiffness, fisting, and continued irritability. In the subsequent 2 years she demonstrated a slow but persistent course of recovery. Nearly two years after her initial presentation she is able to speak multiple words together, roll over, and ambulate with minimal assistance. She exhibits intermittent, alternating exotropia and mild hyperopic astigmatism not requiring correction. She received therapies through early intervention with a plan to transition to her school district. The family of the patient described in this case report provided written informed consent for this publication.

33 pathogenic variants have so far been identified across all 7 exons and 3 introns of MOCS2 (Figure 3). Efforts have been made to distinguish which known MoCD variants correlate with the mild phenotype, based on the hypothesis that these variants exhibit residual enzymatic function^5,18. However, to date research has been limited by small sample sizes of patients with this ultra-rare disease and additional enzyme assays are needed to determine disease severity. However, among the five patients with pathogenic variants described in the overlapping region of exon 3, our patient is this first who presented with a mild phenotype. This patient’s variant is the first ever discovered in the highly conserved C-terminal glycine-glycine motif of MOCS2A. PolyPhen-2 predicts that our patient’s variant is “probably damaging” in MOCS2A and “benign” in MOCS2B¹⁹. The MOCS2A C-terminus has been shown to form the active site of MPT synthase which acts as a sulfur donor¹⁴. As these residues have been shown to be essential to MOCS1A function, our findings suggest they may be similarly necessary in MOCS2A²⁰.

To date, of the 49 cases of MoCD type B confirmed by genetic testing, only 8 cases (16%) of mild MOCS2 have been identified including the patient described in this report (see Supplementary Table S1, online only). Among the 49 reported cases of type B MoCD, 31 included data regarding clinical phenotypes. The majority (81%) of cases reported seizure activity, while only 19% noted lens dislocation. 35% described facial dysmorphism. 48% of cases reported feeding difficulty at birth, a finding which has not generally been included in general clinical descriptions of the disease (Figure 4). Four cases including the patient presented here were noted to have yellow or orange xanthine stones in their urine which may represent a novel diagnostic aid^21,22,23.

Among the 52 known cases of type B MoCD, our patient is rare in that she had normal health and development until an intercurrent illness at age 12 months when she presented acutely with isolated GP injury. The MRI findings were non-diagnostic and were initially suggestive of carbon monoxide toxicity given the focality with the GP. Despite extensive metabolic testing, exome sequencing was the first source of a potential diagnosis in this case. Ultimately, the diagnosis of MoCD was confirmed by uric acid testing after whole exome sequencing had provided a variant of concern. We found that patients who presented after 3 months of age were more likely to demonstrate a mild phenotype (50%), as compared with those presenting as newborns (10%) (see Figure 4). Misko et al., provide an alternative way to view MoCD by grouping them with sulfite oxidase deficiency to create a spectrum of neurologic disease secondary to sulfite toxicity⁵. The current patient would fall into their Class II subgroup, who had milder phenotypes. As the authors of that manuscript suggest, the current patient serves to raise awareness and promote diagnosis of these ultra-rare diseases.

Variants implicated in mild cases were evenly distributed among the 7 exons and were all SNPs except for 1 frameshift deletion in a heterozygous patient, indicating that specific genetic loci are not predictors of mild disease. However, among the 5 variants in the overlapping bicistronic region of exon 3 for which clinical data is available, the novel variant reported here is the only mild case and the only case which presented after 3 months of age. Given that the variant is also housed within the highly conserved C-terminal glycine-glycine motif of MOCS2A, it suggests a gap in our current understanding of the factors contributing to pathogenicity of MOCS2 variants.

Limitations to this study included the lack of reported clinical phenotype data for 18 of the 49 cases described in the literature (see Supplementary Table S1). The limited number of cases prevented adequately powered analysis of statistically significant differences between early- and late-presenting groups.

In addition to identifying a novel pathogenic variant in the bicistronic region of MOCS2, the present case supports the presence of an atypical, mild cases MoCD Type B²⁴. Further research is needed to characterize the mild MoCD or Class II phenotypes, investigate the mechanisms that account for the clinical differences among patients, and identify future directions for treatment and prognostication. The present case suggests that milder cases of MoCD could be underdiagnosed due to nonspecific clinical or radiographic findings, and that there may be a benefit to rapid deployment of broad genetic testing for patients with undifferentiated metabolic abnormalities.

Ethics approval and consent to participate:

Not Applicable

Consent for publication:

The family of the patient described in this case report provided written informed consent for this publication.

Availability of data and materials:

All data generated or analyzed during this study are included in this published article and its supplementary information files.

Competing interests:

The authors declare that they have no competing interests.

Funding:

The authors have no funding sources to declare.

Authors' contributions:

MK made substantial contributions to the MoCD type B literature review, analysis of genetic testing results, generation of graphics, and drafting the work. DM made substantial contributions to the conception of the paper, interpretation of genetic testing results and clinical course, and substantively revised the work. All authors read and approved the final manuscript.

Acknowledgements:

Maura Ryan MD, Emily Bryant CGC

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No competing interests reported.

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Novel Pathogenic Variant in a Mild Case of Type B Molybdenum Cofactor Deficiency: Case Report and Literature Review

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