Fosdenopterin: First Approval.

Fosdenopterin (NulibryTM) is a synthetic cyclic pyranopterin monophosphate that is being developed by Origin Biosciences (a subsidiary of BridgeBio Pharma) for the treatment of molybdenum cofactor deficiency (MoCD) type A. Fosdenopterin was recently approved by the US FDA for use in reducing the risk of mortality in paediatric and adult patients with MoCD type A. This article summarizes the milestones in the development of fosdenopterin leading to this first approval.

Comparative study on clinical, laboratory and electrodiagnostic findings of peripheral neuropathy in patients with hypocupremia and hypercupremia, and literature review.

Copper deficiency (hypocupremia) or toxicosis (hypercupremia) may cause disorders of central and peripheral nervous systems. Hypocupremia causes myeloneuropathy resembling vitamin B12 deficiency. However, the clinical manifestations, particularly peripheral neuropathy (PN), of hypercupremia have not been adequately evaluated. To compare clinical, laboratory and electrodiagnositc features of PN between patients with hypocupremia and hypercupremia, we retrospectively reviewed the charts of patients with abnormal copper levels. Subjects with zinc abnormalities were excluded. Five hypocupremia (Male/Female = 4/1; age: 54.6 ±â€¯17.1 years; copper = 55.0 ±â€¯8.5 µg/dL [normal = 72-175]; zinc = 74.4 ±â€¯15.5 µg/dL [normal = 60-130]) and 3 hypercupremia (M/F = 1/2; age: 57.0 ±â€¯8.2 years; copper = 215.0 ±â€¯10.8 µg/dL; zinc = 72.3 ±â€¯14.6 µg/dL) were studied. The notable clinical findings included ambulatory difficulty in hypocupremia (2/5); paresthesia in both hypocupremia (3/5) and hypercupremia (2/3) but pain was only seen in (3/3) hypercupremia patients. Tendon reflexes were decreased in hypocupremia (3/5) and hypercupremia (1/3) but hyperreflexias in hypocupremia (2/5) only. Preexisting comorbidity such as diarrhea were observed in (2/3) hypercupremia but not in hypocupremia patients. Laboratory findings showed vitamin D deficiency (16.4 ±â€¯5.6 ng/mL) in (2/2) hypercupremia but normal (40.4 ±â€¯4.7 ng/mL) in (2/2) hypocupremia. Neurophysiologic studies showed evidence of neuropathy in (3/5) hypocupremia only. Different patterns of clinical, neurological examination and electrophysiologic findings between hypocupremia and hypercupremia suggest different underlying pathophysiologies.

Mild phenotype in Molybdenum cofactor deficiency: A new patient and review of the literature.

BACKGROUND: Molybdenum cofactor deficiency (MoCD) is a rare autosomal-recessive disorder that results in the combined deficiency of molybdenum-dependent enzymes. Four different genes are involved in Molybdenum cofactor biosynthesis: MOCS1, MOCS2, MOCS3, and GEPH. The classical form manifests in the neonatal period with severe encephalopathy, including intractable seizures, MRI changes that resemble hypoxic-ischemic injury, microcephaly, and early death. To date, an atypical phenotype with late-onset has been reported in the literature in 13 patients. METHODS: We describe a late-onset and a relatively mild phenotype in a patient with MOCS2 homozygous mutation. RESULTS: Pyramidal and extrapyramidal signs are recognized in those patients, often exacerbated by intercurrent illness. Expressive language is usually compromised. Neurological deterioration is possible even in adulthood, probably due to accumulation of sulfite with time. CONCLUSION: Sulfite inhibition of mitochondrial metabolism could be responsible for the ischemic lesions described in patients with MoCD or alternatively could predispose the brain to suffer an ischemic damage through the action of other insults, for instance intercurrent illness. It is possible that sulfite accumulation together with other external triggers, can lead to neurological deterioration even in adulthood. The role of other factors involved in clinical expression should be investigated to establish the reason for phenotypic variability in patients with the same mutation.

Molybdenum cofactor deficiency: Identification of a patient with homozygote mutation in the MOCS3 gene.

We describe the clinical presentation and 17 years follow up of a boy, born to consanguineous parents and presenting with intellectual disability (ID), autism, "marfanoid" dysmorphic features, and moderate abnormalities of sulfite metabolism compatible with molybdenum cofactor deficiency, but normal sulfite oxidase activity in cultured skin fibroblasts. Genomic exome analysis revealed a homozygous MOCS3 missense mutation, leading to a p.Ala257Thr substitution in the highly conserved ubiquitin-like-domain of the protein. MOCS3 is the third protein, besides MOCS1 and MOCS2, involved in the biosynthesis of the molybdenum cofactor and has a dual ubiquitin-like function in tRNA thiolation. It is plausible that the phenotype results from deficiency of this dual function, not only from defective synthesis of molybdenum cofactor, which would explain similarities and differences from the MOCS1 and MOCS2-related disorders. This observation should encourage testing of additional ID patients with mild abnormalities of sulfite metabolism for MOCS3 mutations.

Molybdenum cofactor and isolated sulphite oxidase deficiencies: Clinical and molecular spectrum among Egyptian patients.

AIM: Molybdenum cofactor deficiency (MoCD) and Sulfite oxidase deficiency (SOD) are rare autosomal recessive conditions of sulfur-containing amino acid metabolism with overlapping clinical features and emerging therapies. The clinical phenotype is indistinguishable and they can only be differentiated biochemically. MOCS1, MOCS2, MOCS3, and GPRN genes contribute to the synthesis of molybdenum cofactor, and SUOX gene encodes sulfite oxidase. The aim of this study was to elucidate the clinical, radiological, biochemical and molecular findings in patients with SOD and MoCD. METHODS: Detailed clinical and radiological assessment of 9 cases referred for neonatal encephalopathy with hypotonia, microcephaly, and epilepsy led to a consideration of disorders of sulfur-containing amino acid metabolism. The diagnosis of six with MoCD and three with SOD was confirmed by biochemical tests, targeted sequencing, and whole exome sequencing where suspicion of disease was lower. RESULTS: Novel SUOX mutations were detected in 3 SOD cases and a novel MOCS2 mutation in 1 MoCD case. Most patients presented in the first 3 months of life with intractable tonic-clonic seizures, axial hypotonia, limb hypertonia, exaggerated startle response, feeding difficulties, and progressive cystic encephalomalacia on brain imaging. A single patient with MoCD had hypertrophic cardiomyopathy, hitherto unreported with these diseases. INTERPRETATION: Our results emphasize that intractable neonatal seizures, spasticity, and feeding difficulties can be important early signs for these disorders. Progressive microcephaly, intellectual disability and specific brain imaging findings in the first year were additional diagnostic aids. These clinical cues can be used to minimize delays in diagnosis, especially since promising treatments are emerging for MoCD type A.

Mouse model for molybdenum cofactor deficiency type B recapitulates the phenotype observed in molybdenum cofactor deficient patients.

Molybdenum cofactor (MoCo) deficiency is a rare, autosomal-recessive disorder, mainly caused by mutations in MOCS1 (MoCo deficiency type A) or MOCS2 (MoCo deficiency type B) genes; the absence of active MoCo results in a deficiency in all MoCo-dependent enzymes. Patients with MoCo deficiency present with neonatal seizures, feeding difficulties, severe developmental delay, brain atrophy and early childhood death. Although substitution therapy with cyclic pyranopterin monophosphate (cPMP) has been successfully used in both Mocs1 knockout mice and in patients with MoCo deficiency type A, there is currently no Mocs2 knockout mouse and no curative therapy for patients with MoCo deficiency type B. Therefore, we generated and characterized a Mocs2-null mouse model of MoCo deficiency type B. Expression analyses of Mocs2 revealed a ubiquitous expression pattern; however, at the cellular level, specific cells show prominent Mocs2 expression, e.g., neuronal cells in cortex, hippocampus and brainstem. Phenotypic analyses demonstrated that Mocs2 knockout mice failed to thrive and died within 11 days after birth. None of the tested MoCo-dependent enzymes were active in Mocs2-deficient mice, leading to elevated concentrations of purines, such as hypoxanthine and xanthine, and non-detectable levels of uric acid in the serum and urine. Moreover, elevated concentrations of S-sulfocysteine were measured in the serum and urine. Increased levels of xanthine resulted in bladder and kidney stone formation, whereas increased concentrations of toxic sulfite triggered neuronal apoptosis. In conclusion, Mocs2-deficient mice recapitulate the severe phenotype observed in humans and can now serve as a model for preclinical therapeutic approaches for MoCo deficiency type B.

Manganese transport disorder: novel SLC30A10 mutations and early phenotypes.

BACKGROUND: SLC30A10 mutations cause an autosomal recessive disorder, characterized by hypermanganesaemia, polycythemia, early-onset dystonia, paraparesis, or late-onset parkinsonism, and chronic liver disease. This is the first identified inborn error of Mn metabolism in humans, reported in 10 families thus far. METHODS: Methods for this study consisted of clinical examination, neuroimaging studies (MRI), serum dosages, and SLC30A10 genetic analysis. RESULTS: We describe early disease manifestations (including videos) in 5 previously unreported Indian children, carrying novel homozygous SLC30A10 mutations. Gait and speech disturbances, falls, dystonias, and central hypotonia were the presenting neurological features, starting within the first 5 years of life. All children also had severe hypermanganesemia, polycythemia, variable degree of liver disease, and marked brain MRI T1 hyperintensities. CONCLUSIONS: Our findings expand the mutational and clinical spectra of this recently recognized disorder. An early diagnosis is warranted, because treatment with manganese-chelating agents, iron supplementation, or their combination might improve symptoms and prevent progression of this otherwise potentially fatal disease. © 2015 International Parkinson and Movement Disorder Society.

Ultra-orphan diseases: a quantitative analysis of the natural history of molybdenum cofactor deficiency.

PURPOSE: Experimental treatment with substrate replacement was successfully performed in single cases with molybdenum cofactor deficiency type A. The objective of this study was to quantitate the yet undefined natural history in untreated patients to ultimately benefit knowledge in experimental treatments in the future. METHODS: Systematic analysis of published cases with molybdenum cofactor deficiency. The main outcome measures were survival, initial cardinal disease features at onset, and diagnostic delay. RESULTS: The median survival for the overall population was 36 months. Initial cardinal disease features at onset were seizures (72%) as well as feeding difficulties (26%) and hypotonia (11%). In addition, developmental delay (9%), hemiplegia (2%), lens dislocation (2%), and hyperreflexia (1%) were reported. The median age at onset of the disease was the first day of life; the median age at diagnosis was 4.5 months. The median time to diagnosis (diagnostic delay) was 89 days. CONCLUSION: Molybdenum cofactor deficiency has its onset during the neonatal period and infancy. There is considerable diagnostic delay. Although seizures were the most frequent initial cardinal sign, molybdenum cofactor deficiency should be considered as a differential diagnosis in patients presenting with hypotonia, developmental delay, or feeding difficulties. The survival data will inform further natural-history and therapeutic studies.

MEDNIK syndrome: a novel defect of copper metabolism treatable by zinc acetate therapy.

MEDNIK syndrome-acronym for mental retardation, enteropathy, deafness, neuropathy, ichthyosis, keratodermia-is caused by AP1S1 gene mutations, encoding σ1A, the small subunit of the adaptor protein 1 complex, which plays a crucial role in clathrin coat assembly and mediates trafficking between trans-Golgi network, endosomes and the plasma membrane. MEDNIK syndrome was first reported in a few French-Canadian families sharing common ancestors, presenting a complex neurocutaneous phenotype, but its pathogenesis is not completely understood. A Sephardic-Jewish patient, carrying a new AP1S1 homozygous mutation, showed severe perturbations of copper metabolism with hypocupremia, hypoceruloplasminemia and liver copper accumulation, along with intrahepatic cholestasis. Zinc acetate treatment strikingly improved clinical conditions, as well as liver copper and bile-acid overload. We evaluated copper-related metabolites and liver function retrospectively in the original French-Canadian patient series. Intracellular copper metabolism and subcellular localization and function of copper pump ATP7A were investigated in patient fibroblasts. Copper metabolism perturbation and hepatopathy were confirmed in all patients. Studies in mutant fibroblasts showed abnormal copper incorporation and retention, reduced expression of copper-dependent enzymes cytochrome-c-oxidase and Cu/Zn superoxide dismutase, and aberrant intracellular trafficking of Menkes protein ATP7A, which normalized after rescue experiments expressing wild-type AP1S1 gene. We solved the pathogenetic mechanism of MEDNIK syndrome, demonstrating that AP1S1 regulates intracellular copper machinery mediated by copper-pump proteins. This multisystem disease is characterized by a unique picture, combining clinical and biochemical signs of both Menkes and Wilson's diseases, in which liver copper overload is treatable by zinc acetate therapy, and can now be listed as a copper metabolism defect in humans. Our results may also contribute to understand the mechanism(s) of intracellular trafficking of copper pumps.

Molybdenum cofactor deficiency: review of 12 cases (MoCD and review).

Molybdenum cofactor deficiency is a rare inborn error of metabolism. The major clinical symptoms are intractable neonatal seizures, progressive encephalopathy, facial dysmorphic features and feeding difficulties. Most of the patients are misdiagnosed as hypoxic ischemic encephalopathy. The majority of patients have mutations in the MOCS1 and MOCS2 genes. Although the therapeutic treatment strategies have not been improved, genetic analysis is essential to elucidate the disease. Here, we report a review of 12 patients with Molybdenum cofactor deficiency reported from Turkey.

Chronological changes of the amplitude-integrated EEG in a neonate with molybdenum cofactor deficiency.

Molybdenum cofactor (Moco) deficiency is a rare neurometabolic disorder, characterized by neurological impairment and refractive seizures, due to toxic accumulation of sulfite in the brain. Earlier it was suggested that in Moco-deficient humans maternal clearance of neurotoxic metabolites prevents prenatal brain damage. However, limited data are available about the time profile in which neurophysiologic deterioration occurs after birth. The amplitude-integrated electroencephalography (aEEG) is a bedside method in neonates to monitor cerebral recovery after hypoxic-ischemic insults, detect epileptic activity, and evaluate antiepileptic drug treatment. We describe a chronological series of changes in aEEG tracings in a neonate with Moco deficiency. He presented with myoclonic spasms and hypertonicity a few hours after birth, however, the aEEG pattern was still normal. Within 2 days, the aEEG rapidly changed into a burst suppression pattern with repetitive seizures. After antiepileptic treatment, the aEEG remained abnormal. In this patient, the normal aEEG pattern at birth may have been due to maternal clearance of sulfite in utero. After birth, accumulation of sulfite causes progressive brain damage, reflected by the progressive depression of the aEEG tracings. This is in agreement with the results from a Moco-deficient mouse model, suggesting that maternal sulfite clearance suppresses prenatal brain damage. To our knowledge, this is the first case report describing the chronological changes in the aEEG pattern in a Moco-deficient patient. Insight into the time profile in which neurologic deterioration in Moco-deficient humans occurs is essential, especially when potential treatment strategies are being evaluated.

Copper metabolism disorders affect testes structure and gamete quality in male mice.

In the present study, animals with a genetic defect in copper metabolism were used as a model organism to study the role of copper in reproduction and to determine whether the disturbances in copper and zinc metabolism affect the testicular tissue and gamete quality in males. Mice with an X-linked mosaic mutation (Atp7a(mo-ms)) exhibit pathological features characteristic of affected copper metabolism. This mutation usually leads to lethality of the mutant males which generally expire on about day 16. Only 4% of mutant animals survive the critical period, achieve maturity, and become fertile. To improve the mutants' viability they were treated with subcutaneous injections of cupric chloride. We measured copper and zinc concentration in the gonads of young (14-day-old) and adult (5-month-old) mutant and control males. Results indicate that copper content was increased but zinc was decreased in the mutant testes. Analysis of the morphology of the testis of the young animals indicate that apoptosis (characteristic for the gonads of young males) was increased in the gonads of the 14-day-old mutants. This process was less advanced in the group of 14-day-old copper treated control males. Apoptosis was also increased in the testes of the adult mutants. Moreover in adult mutants we observed pathological changes in testes morphology (atrophic and sclerotic tubules). Copper and zinc disorders also negatively influenced semen quality parameters, including sperm motility, head morphology, tail cytoplasmic membrane integrity, and number of viable spermatozoa. Poor semen quality of the mutant males seems to be responsible for affected in vivo fertilization efficiency. Treatment with cupric chloride did not influence semen quality except in maturation rate, which was even slower in both mutant and control males after treatment. Additionally, in mutants, copulatory plugs and fertile copulation outcome were decreased after copper treatment.

Iron, copper, and zinc distribution of the cerebellum.

Synchrotron rapid-scanning X-ray fluorescence (RS-XRF) is employed for the first time to simultaneously map iron, copper, and zinc in the normal cerebellum. The cerebellum is a major repository of metals that are essential to normal function. Therefore, mapping the normal metal distribution is an important first step towards understanding how multiple metals may induce oxidative damage, protein aggregation, and neurotoxicity leading to cerebellar degeneration in a wide range of diseases. We found that cerebellar white and grey matter could be sharply defined based upon the unique metal content of each region. The dentate nucleus was particularly metal-rich with copper localized to the periphery and iron and zinc abundant centrally. We discuss how RS-XRF metal mapping in the normal brain may yield important clues to the mechanisms of degeneration in the dentate nucleus.

Inherited forms of renal hypomagnesemia: an update.

The kidney plays an important role in ion homeostasis in the human body. Several hereditary disorders characterized by perturbations in renal magnesium reabsorption leading to hypomagnesemia have been described over the past 50 years, with the most important of these being Gitelman syndrome, familial hypomagnesemia with hypercalciuria and nephrocalcinosis, familial hypomagnesemia with secondary hypocalcemia, autosomal dominant hypomagnesemia with hypocalciuria, and autosomal recessive hypomagnesemia. Only recently, following positional cloning strategies in affected families, have mutations in renal ion channels and transporters been identified in these diseases. In this short review, I give an update on these hypomagnesemic disorders. Elucidation of the genetic etiology and, for most of these disorders, also the underlying pathophysiology of the disease, has greatly increased our understanding of the normal physiology of renal magnesium handling. This is yet another example of the importance of studying rare disorders in order to unravel physiological and pathophysiological processes in the human body.

The neurological presentation of ceruloplasmin gene mutations.

Aceruloplasminemia is an autosomal recessive disorder of iron metabolism resulting from mutations of the ceruloplasmin gene. To better define the neurological phenotype of aceruloplasminemia we reviewed reports of published cases and sought details of unpublished ones. We identified 32 published reports and 1 unpublished case. The age at diagnosis ranged from 16 to 71 years with a mean of 51. For the 28 homozygous cases the most common presentation was with cognitive impairment (12/28, 42%) accompanied by craniofacial dyskinesia (8/28, 28%), cerebellar ataxia (13/28, 46%) and retinal degeneration (21/28, 75%). Four heterozygotes presented with cerebellar signs or tremor, whilst 1 had chorea-athetosis. There were no genotype-phenotype associations, but homozygotes tended to have severer disease.

Aceruloplasminemia, an iron metabolic disorder.

Aceruloplasminemia is an inherited disorder of iron metabolism caused by the complete lack of ceruloplasmin ferroxidase activity caused by mutations in the ceruloplasmin gene. It is characterized by iron accumulation in the brain as well as visceral organs. Clinically, the disease consists of the triad of adult-onset neurologic disease, retinal degeneration and diabetes mellitus. The neurological symptoms, which include involuntary movements, ataxia, and dementia, reflect the sites of iron deposition. Severe iron overload and extensive neuronal loss were observed in the basal ganglia, while iron deposition and neuronal cell loss were trivial in the frontal cortices. The cerebellar cortex showed marked loss of Purkinje cells. Iron deposition was more prominent in the astrocytes than in the neurons. Excess iron functions as a potent catalyst of biologic oxidation. Astrocytic deformity and globular structures are characteristic features in aceruloplasminemia brains. The globular structures in the astrocytes were seen in proportion to the degree of iron deposition and reacted positively to anti-4-hydroxynonenal, one of the indicators of lipid peroxidation, and anti-ubiquitin antibodies, but not to anti-alpha-synuclein antibody. The lack of ceruloplasmin may primarily damage astrocytes in the aceruloplasminemia brains through lipid peroxidation. Ceruloplasmin may play an essential role in neuronal survival in the central nervous system.

Pattern of neuropsychological deficits in patients with treated Wilson's disease.

The study aimed to describe the neuropsychological profiles in patients with treated Wilson's disease (WD). The series included 19 symptomatic and 2 asymptomatic patients with a mean age of 35.3 +/- 9.2 years. They were tested with the Automated Psychological Test system (APT), a comprehensive computerised neuropsychological test battery. APT comprised eleven separate tests and assessed five essential types of neuropsychological functions: motor functions, basic neuropsychological functions, specific cognitive functions, memory, and executive functions. The results were compared to current norms of the test battery. The symptomatic WD patients had significantly lower performance than the norms on all finger tapping tasks, the simple reaction time, the simultaneous capacity background task, the short-term memory test, the index of word decoding speed, the grammatical reasoning test, and the perceptual maze test. They were significantly higher on the index of impulsive errors, and used a significantly more global processing mode in the test of selective attention. The female symptomatic patients displayed more pronounced neuropsychological deficits than the males in the complex tasks. WD patients displayed a specific profile of moderate neuropsychological impairment. The results are theoretically interesting and have practical implications for the management of WD patients, e.g. some patients confronted with the results have had increased compliance.