Molybdenum Cofactor Deficiency: Results of Rapid S-Sulfocysteine Analysis and Genome Sequencing Still Not Rapid Enough
Biochemical/Metabolic and Therapeutics
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Introduction
Molybdenum cofactor deficiency (MoCD) is an autosomal recessive inborn error of metabolism (IEM) characterized by neonatal/infantile refractory seizures, encephalopathy, hypotonia, feeding difficulties, and acquired microcephaly. FDA-approved, disease-modifying treatment is available for patients with MOCS1 deficiency, responsible for MoCD Type A (MoCDA). Biochemical results consistent with MoCD will include elevated urine S-sulfocysteine with low plasma uric acid. These findings are sufficient for treatment initiation and are recommended to be instituted as early as possible due to the rapidly progressive nature of this fatal disease.
Case Presentation
We present a term male of Nepalese descent, without a family history of consanguinity, presenting on day of life (DOL) 3 with irritability. On DOL 5, he had explosive-onset, drug-resistant seizures requiring three antiepileptics for control. Results of newborn screening (NBS) were normal and laboratory investigations showed normal plasma ammonia and lactate with no anion gap. Brain MRI showed dysmorphic ventricles bilaterally, hypoplastic cerebellum, thin corpus callosum, and bilateral signal abnormality within the basal ganglia. Physical examination revealed a prominent philtrum, small appearing mouth, and deep plantar creases.
Diagnostic Workup
Genetics consultation on DOL 9 recommended trio rapid genome sequencing and in-house biochemical testing of plasma acylcarnitines, plasma amino acids, urine organic acids, urine S-sulfocysteine, and urine creatine/guanidinoacetate. On DOL 10, ~6 hours after urine was received in the Duke Biochemical Genetics Laboratory (BGL) for testing, a marked elevation of S-sulfocysteine (1592 µmol/g Cr (normal<80)) was reported. Uric acid was undetectable, making MoCD highest on the differential. Overnight into DOL 11, prior to discussion of the abnormal biochemical findings with the family, the patient acutely decompensated, becoming acidotic with loss of pulses, quickly followed by demise.
Outcome and Follow-Up
Genome sequencing results were obtained 8 days after demise revealing homozygosity for 2 likely pathogenic missense variants in MOCS1 (c.484C>T (p.R162W) and c.970G>T (p.G324W)). He had a secondary finding of 1 heterozygous, paternally inherited, pathogenic variant in KCNQ1 associated with long QT arrhythmogenic spectrum disorder. The family was counseled appropriately, including the implications for paternal arrhythmia monitoring and management.
Discussion
Despite having a biochemical diagnosis of MoCD within 24 hours of the urine S-sulfocysteine being ordered and molecular findings consistent with the treatable form of MoCD, these results did not come soon enough for the patient. The literature recommends treatment initiation when MoCD is suspected, even if the molecular results are pending. Despite its FDA-approval in 2021, the treatment is not immediately available at our center. It is unclear if initiation of treatment would have changed the outcome for this infant and whether the KCNQ1 variant contributed to his rapid demise. His case underlines areas of opportunity for future patients’ care.
Conclusion
This case highlights many salient issues facing the biochemical genetics field. First, as more disease-altering treatments become available for IEMs, early detection and immediate treatment are imperative. Biochemical and molecular testing must be utilized simultaneously. A lab-specific protocol at Duke BGL is to provide a preliminary S-sulfocysteine result within 24 hours of sample receipt for newborns <6 months of age; the biochemical testing rapidly narrowed the differential diagnosis and molecular testing confirmed that it was the treatable form of MoCD. Second, this case is an example of the need for protocols within neonatal intensive care units to determine appropriate cases for rapid exome/genome sequencing. Third, as more disease-altering treatments become available, there will be more disorders considered candidates for NBS. MoCDA is no exception, lending itself to larger conversations around workforce and scalability of NBS efforts.
Molybdenum cofactor deficiency (MoCD) is an autosomal recessive inborn error of metabolism (IEM) characterized by neonatal/infantile refractory seizures, encephalopathy, hypotonia, feeding difficulties, and acquired microcephaly. FDA-approved, disease-modifying treatment is available for patients with MOCS1 deficiency, responsible for MoCD Type A (MoCDA). Biochemical results consistent with MoCD will include elevated urine S-sulfocysteine with low plasma uric acid. These findings are sufficient for treatment initiation and are recommended to be instituted as early as possible due to the rapidly progressive nature of this fatal disease.
Case Presentation
We present a term male of Nepalese descent, without a family history of consanguinity, presenting on day of life (DOL) 3 with irritability. On DOL 5, he had explosive-onset, drug-resistant seizures requiring three antiepileptics for control. Results of newborn screening (NBS) were normal and laboratory investigations showed normal plasma ammonia and lactate with no anion gap. Brain MRI showed dysmorphic ventricles bilaterally, hypoplastic cerebellum, thin corpus callosum, and bilateral signal abnormality within the basal ganglia. Physical examination revealed a prominent philtrum, small appearing mouth, and deep plantar creases.
Diagnostic Workup
Genetics consultation on DOL 9 recommended trio rapid genome sequencing and in-house biochemical testing of plasma acylcarnitines, plasma amino acids, urine organic acids, urine S-sulfocysteine, and urine creatine/guanidinoacetate. On DOL 10, ~6 hours after urine was received in the Duke Biochemical Genetics Laboratory (BGL) for testing, a marked elevation of S-sulfocysteine (1592 µmol/g Cr (normal<80)) was reported. Uric acid was undetectable, making MoCD highest on the differential. Overnight into DOL 11, prior to discussion of the abnormal biochemical findings with the family, the patient acutely decompensated, becoming acidotic with loss of pulses, quickly followed by demise.
Outcome and Follow-Up
Genome sequencing results were obtained 8 days after demise revealing homozygosity for 2 likely pathogenic missense variants in MOCS1 (c.484C>T (p.R162W) and c.970G>T (p.G324W)). He had a secondary finding of 1 heterozygous, paternally inherited, pathogenic variant in KCNQ1 associated with long QT arrhythmogenic spectrum disorder. The family was counseled appropriately, including the implications for paternal arrhythmia monitoring and management.
Discussion
Despite having a biochemical diagnosis of MoCD within 24 hours of the urine S-sulfocysteine being ordered and molecular findings consistent with the treatable form of MoCD, these results did not come soon enough for the patient. The literature recommends treatment initiation when MoCD is suspected, even if the molecular results are pending. Despite its FDA-approval in 2021, the treatment is not immediately available at our center. It is unclear if initiation of treatment would have changed the outcome for this infant and whether the KCNQ1 variant contributed to his rapid demise. His case underlines areas of opportunity for future patients’ care.
Conclusion
This case highlights many salient issues facing the biochemical genetics field. First, as more disease-altering treatments become available for IEMs, early detection and immediate treatment are imperative. Biochemical and molecular testing must be utilized simultaneously. A lab-specific protocol at Duke BGL is to provide a preliminary S-sulfocysteine result within 24 hours of sample receipt for newborns <6 months of age; the biochemical testing rapidly narrowed the differential diagnosis and molecular testing confirmed that it was the treatable form of MoCD. Second, this case is an example of the need for protocols within neonatal intensive care units to determine appropriate cases for rapid exome/genome sequencing. Third, as more disease-altering treatments become available, there will be more disorders considered candidates for NBS. MoCDA is no exception, lending itself to larger conversations around workforce and scalability of NBS efforts.