Sepiapterin Reductase Deficiency Research Articles

Formulation and clinical evaluation of carbidopa/levodopa oral solution for the treatment of sepiapterin reductase deficiency

Backgroundsepiapterine reductase deficiency (SRD) is a rare levodopa (L-dopa)-responsive disorder treated with a combination therapy of controlled-release L-dopa and carbidopa. The currently available formulation of controlled-release carbidopa/L-dopa does not entirely meet the requirements for the long-term therapy in pediatric patients. In fact, administration of a manufactured tablet at a dose intended for adults necessitates its adjustment to the child’s needs, as the splitting of the tablet into smaller portions or its dilution in water. It’s essential to emphasize that tablets must not be crushed, as this can compromise the controlled-release mechanism and affect the efficacy of the medication. At the moment, commercial liquid formulations are not available. Given these limitations, in house drug preparation in hospitals and community pharmacies is a valid option to ensure the proper therapeutic management of these patients. Materials and methodswe described sample preparation, physical and microbiological analyses, taste testing, and tolerability of a 1:10 ratio carbidopa/L-dopa flavored (mint, raspberry, cacao, berries) and unflavored oral formulation (no sweetening agents were added). We also reported long-term follow-up of two pediatric patients with SRD. Resultswe documented the stability for 28 days at 25 °C of the liquid solution. All formulations were well-tolerated, and no adverse events were observed during or after assessing taste and tolerability. The long-term follow up of two patients was characterized by effective symptom control and optimal treatment adherence and compliance. Conclusionsin-house liquid drug formulations can be a valid option for pediatric patients with SRD. Given the significant impact of taste on medication adherence, the use of flavoring agents in the development of liquid formulations of L-dopa/carbidopa results a very useful strategy to obtain optimal adherence in the pediatric population.

Maternal Uniparental Isodisomy of Chromosome 2 Leading to Homozygous Variants in SPR and ZNF142 : A Case Report and Review of the UPD2 Literature.

We report a 4-year-old girl with neurodevelopmental abnormalities who has maternal uniparental isodisomy of chromosome 2 leading to homozygosity for a likely pathogenic variant in SPR , and a variant of uncertain significance in ZNF142 . Biallelic pathogenic variants in SPR lead to sepiapterin reductase deficiency (SRD), a dopa-responsive dystonia. Pathogenic variants in ZNF142 are associated with an autosomal recessive neurodevelopmental disorder characterized by impaired speech and hyperkinetic movements, which has significant clinical overlap with SRD. Our patient showed dramatic improvement in motor skills after treatment with levodopa. We also reviewed 67 published reports of uniparental disomy of chromosome 2 (UPD2) associated with various clinical outcomes. These include autosomal recessive disorders associated with loci on chromosome 2, infants with UPD2 whose gestations were associated with confined placental mosaicism for trisomy 2 leading to intrauterine growth restriction with good postnatal catchup growth, and normal phenotypes in children and adults with an incidental finding of either maternal or paternal UPD2. These latter reports provide support for the conclusion that genes located on chromosome 2 are not subject to imprinting. We also explore the mechanisms giving rise to UPD2.

Approaches for diagnosis and treatment in neurotransmitter disorders of childhood.

Neurotransmitter disorders are a group of neurometabolic syndromes caused by disturbances of neurotransmitter metabolism. The primary aim of this retrospective study is to present patients with disturbances of monoamine neurotransmitter metabolism. Cerebrospinal fluid (CSF) neurotransmitter measurements and genetic analysis were performed on five patients. Five patients who had various movement disorders and motor and cognitive disabilities were included. Four patients were diagnosed with sepiapterin reductase (SR) deficiency, and one was diagnosed with aromatic L-amino acid decarboxylase (AADC) deficiency. Different treatment responses appeared in patients with SR and AADC deficiency. The responses to drug treatment ranged from good to weak in our patients. The diagnosis process is challenging in patients with SR and AADC deficiency, which present similar clinical features to other neurological and metabolic diseases. Investigations of neurotransmitters in CSF and analysis of related genes are essential to differentiate disturbances of monoamine neurotransmitter metabolism from other neurometabolic diseases. For patients with monoamine neurotransmitter disorders, drugs that target these disturbances should be combined as necessary to produce the appropriate response.

Assessment of intellectual impairment, health-related quality of life, and behavioral phenotype in patients with neurotransmitter related disorders: Data from the iNTD registry.

Inherited disorders of neurotransmitter metabolism are a group of rare diseases, which are caused by impaired synthesis, transport, or degradation of neurotransmitters or cofactors and result in various degrees of delayed or impaired psychomotor development. To assess the effect of neurotransmitter deficiencies on intelligence, quality of life, and behavior, the data of 148 patients in the registry of the International Working Group on Neurotransmitter Related Disorders (iNTD) was evaluated using results from standardized age-adjusted tests and questionnaires. Patients with a primary disorder of monoamine metabolism had lower IQ scores (mean IQ 58, range 40-100) within the range of cognitive impairment (<70) compared to patients with a BH4 deficiency (mean IQ 84, range 40-129). Short attention span and distractibility were most frequently mentioned by parents, while patients reported most frequently anxiety and distractibility when asked for behavioral traits. In individuals with succinic semialdehyde dehydrogenase deficiency, self-stimulatory behaviors were commonly reported by parents, whereas in patients with dopamine transporter deficiency, DNAJC12 deficiency, and monoamine oxidase A deficiency, self-injurious or mutilating behaviors have commonly been observed. Phobic fears were increased in patients with 6-pyruvoyltetrahydropterin synthase deficiency, while individuals with sepiapterin reductase deficiency frequently experienced communication and sleep difficulties. Patients with BH4 deficiencies achieved significantly higher quality of life as compared to other groups. This analysis of the iNTD registry data highlights: (a) difference in IQ and subdomains of quality of life between BH4 deficiencies and primary neurotransmitter-related disorders and (b) previously underreported behavioral traits.

HYPERPHENYLALANINEMIA: CASE REPORT

Background: Hyperphenylalaninemia (HPA) is a group of autosomal recessive diseases caused by impaired metabolism of the essential amino acid phenylalanine (Phe), which enters the human body with protein food [1]. HFA combines several genetically heterogeneous forms of phenylalanine metabolism disorders similar in clinical features: classical phenylketonuria (PKU), caused by phenylalanine-4-hydroxylase (PAH) deficiency and hyperphenylalaninemia (HPA), associated with tetrahydrobiopterin (BH4) metabolic disorders [2]. The pterin-dependent form of hyperphenylalaninemia accounts for about 2% of all cases of HPA. These conditions are caused by a deficiency of enzymes involved in the synthesis or reduction of tetrahydrobiopterin (BH4), which is a PAH cofactor, as well as tyrosine hydroxylase and tryptophan hydroxylase [3, 4]. Currently, several genetically heterogeneous forms of BH4-deficient HPA are known: type A, 6-pyruvoyltetrahydropterine synthase (PTPS) deficiency, type B, guanosine triphosphate cyclohydrolase 1 (GTPCH) deficiency, type C, dihydropterine reductase (DHPR) deficiency, type D, pterin-4a-α-carbinolamine dehydratase (PCBD) deficiency, DOPA-dependent dystonia caused by sepiapterin reductase (SPR) deficiency and HPA without tetrahydrobiopterin deficiency, caused by mutations in the DNAJC12 gene encoding the JDP1 protein [5, 6]. Pterin-dependent forms of HPA have clinical manifestations similar to classical PKU. In these forms, the main role in the pathogenesis is played by a severe deficiency in the neurotransmitters of the catecholamine and serotonin series, which makes isolated diet therapy meaningless and requires different approaches to treatment. The complex of treatment for such patients includes BH4 or its synthetic analogs [3-5].

Tetrahydrobiopterin deficiencies: Lesson from clinical experience.

ObjectivesThe present study describes clinical, biochemical, molecular genetic data, current treatment strategies and follow‐up in nine patients with tetrahydrobiopterin (BH4) deficiency due to various inherited genetic defects.MethodsWe analyzed clinical, biochemical, and molecular data of nine patients with suspected BH4 deficiency. All patients were diagnosed at Ege University Faculty of Medicine in Izmir, Turkey and comprised data collected from 2006 to 2019. The diagnostic laboratory examinations included blood phenylalanine and urinary or plasma pterins, dihydropteridine reductase (DHPR) enzyme activity measurement in dried blood spots, folic acid and monoamine neurotransmitter metabolites in cerebrospinal fluid, as well as DNA sequencing.ResultsAmong the nine patients, we identified one with autosomal recessive GTP cyclohydrolase I (ar GTPCH) deficiency, two with 6‐pyruvoyl‐tetrahydropterin synthase (PTPS) deficiency, three with sepiapterin reductase (SR) deficiency, and three with DHPR deficiency. Similar to previous observations, the most common clinical symptoms are developmental delay, intellectual disability, and movement disorders. All patients received treatment with l‐dopa and 5‐hydroxytryptophan, while only the ar GTPCH, the PTPS, and one DHPR deficient patients were supplemented in addition with BH4. The recommended dose range varies among patients and depends on the type of disease. The consequences of BH4 deficiencies are quite variable; however, early diagnosis and treatment will improve outcomes.ConclusionsAs BH4 deficiencies are rare group of treatable neurometabolic disorders, it is essential to diagnose the underlying (genetic) defect in newborns with hyperphenylalaninemia. Irreversible brain damage and progressive neurological deterioration may occur in untreated or late diagnosed patients. Prognosis could be satisfying in the cases with early diagnose and treatment.

Dopa-responsive dystonia, DRD-plus and DRD look-alike: a pragmatic review.

Dopa-responsive dystonia (DRD) and DRD plus are diseases of the dopamine pathway with sizeable genetic diversity and myriad presentations. DRD has onset in childhood or adolescence with focal dystonia, commonly affecting lower limb, diurnal fluctuations with evening worsening of symptoms and a demonstrable sleep benefit. DRD "plus" has "atypical features" which include infantile onset, psychomotor delay, cognitive abnormalities, oculogyric crisis, seizures, irritability, spasticity, hypotonia, ptosis, hyperthermia and cerebellar dysfunction. Neurodegeneration, however, is not a feature of either DRD or DRD-plus disorders. Tetrahydrobiopterin (BH4), a key cofactor, deficiency leads to inadequate dopamine and serotonin synthesis. Norepinephrine deficiency may coexist, depending on the enzyme defect. Hyperphenylalaninemia (HPA) is a clue for BH4 paucity. However, HPA is conspicuously absent in autosomal-dominant guanosine triphosphate cyclohydrolase 1 deficiency and sepiapterin reductase deficiency. DRD look-alike is a group of neurodegenerative disorders involving the nigrostriatal dopaminergic system, which could present with dystonia responsive to dopaminergic drugs or neurodegenerative or non-neurodegenerative disorders without involving the nigrostriatal dopaminergic system yet responsive to levodopa. Although levodopa is the mainstay of therapy, response to this drug can be unsatisfactory in DRD plus and DRD look-alike and other drugs are tried. Simultaneous management of HPA leads to remarkable improvement in both motor and cognitive functions. The aim of this review is to help neurology practitioners in treating patients with DRD, DRD-plus and DRD look-alike as many of them have excellent outcome with appropriate therapy.

PRO10 Identifying Appropriate PROXY Diseases for Estimating LONG-TERM Survival and IMPACT on Health-Related Quality of Life of Patients with Aromatic L-Amino Acid Decarboxylase Deficiency (AADC-D)

We aimed to identify diseases similar in characteristics to AADC deficiency (AADC-d) that can provide proxy estimates for health-related quality of life (HRQoL) and long-term survival of AADC-d patients. These estimates will be used to support the economic model development for eladocagene exuparvovec. A literature search and clinician survey were conducted to identify proxy diseases for AADC-d. The literature was searched for observational studies, single arm clinical trials, randomized clinical trials, systematic reviews, case studies and case reports between January 2015 and January 2020 from clinicaltrials.gov and PubMed.gov. Studies among paediatric patients with motor associated neurological, genetic, or inherited conditions were included. Additionally, a survey was administered electronically to 25 clinicians globally to assess appropriateness of anoxic encephalopathy, paraplegia, tyrosine hydroxylase (TH) deficiency, guanosine triphosphate cyclohydrolase deficiency, sepiapterin reductase deficiency (SR), dopamine transporter deficiency syndrome as proxies. Appropriateness of disease proxy was determined based on similarity in disease characteristics, disease onset, natural history of disease progression, and data availability. Spinal muscular atrophy (SMA), Duchenne muscular dystrophy, metachromatic leukodystrophy, and cerebral palsy (CP) were identified in the literature search as suitable proxies. Survival and HRQoL data were available for SMA type I and CP since motor specific developmental milestones were measured as an endpoint in the related clinical trials. Survey results indicate TH deficiency and SR deficiency could be suitable proxies, but a lack of published data on survival and HRQoL limit their use for economic modeling in AADC-d. CP was preferred by clinicians as an appropriate proxy in AADC-d, in the absence of required data for other proxies. This study provides evidence to fill a gap in the literature for AADC-d patients’ outcomes. The available mortality and HRQoL data for the proxy diseases may be used to estimate the long-term outcomes for patients with AADC-d.

Nephrocalcinosis in genetically proved dopa-responsive dystonia due to sepiapterin reductase deficiency in a Libyan Girl

Dopa-responsive dystonia (DRD) encompasses clinically and genetically heterogeneous disorders that typically manifest as limb-onset, diurnally fluctuating dystonia and exhibit a robust and sustained response levodopa treatment. GCH1 gene mutations are the most frequent cause of DRD. Mutations in the TH or SPR gene less often cause this condition. The index case is a 12-year-old young girl presented to the pediatric neurology clinic at the age of 8 years with tiptoes walking and deterioration of her gait. She is the product of first-degree consanguineous marriage with insignificant history. The index case has two sisters, one of whom suffers from learning difficulties, epilepsy, and bilateral nephrocalcinosis. Her two uncles had severe axonal polyneuropathy and died in their forties of unknown cause. Her magnetic resonance imaging of the brain demonstrated agenesis of the corpus callosum. Renal ultrasound studies showed bilateral nephrocalcinosis. Genetic DNA evaluation (whole-exome sequencing) identified the heterozygous variant c.207C&gt;G,p. (Asp69Glu) in the SPR gene (OMIM: 182125), which leads to an amino acid exchange. Nine out of ten bioinformatic in silica programs predict a pathogenic effect for this variant. Treatment with levodopa\ benserazide 4:1 (Madopar) has not made any changes to the girl's condition.

Selection, characterization, and electrochemical biosensing application of DNA aptamers for sepiapterin

Sepiapterin reductase deficiency (SR) is a rare inborn disorder of neurotransmitter metabolism. The early diagnosis of SR disease should be achieved through the determination of the sepiapterin level in body fluids of suspected patients. Here, we report the selection, identification, and characterization of DNA aptamers against sepiapterin. The aptamer selection was achieved via the systematic evolution of ligand by the exponential enrichment technique. After ten rounds of selection, high-affinity aptamers were identified. The binding affinities of the selected aptamers were evaluated using fluorescence binding assays showing dissociation constants ranging from 37.3 to 79.0 nM. The highest affinity aptamer was then integrated into a competitive electrochemical biosensor. The biosensor achieved outstanding sensitivity with a detection limit of 0.8 pg/ml which was much lower than the reported chromatographic method for sepiapterin quantification. The aptasensor has also shown a high degree of selectivity against the closely-related compound. The aptasensor was then challenged by detecting the sepiapterin in spiked serum samples where a good recovery percentage was achieved.

Evaluation of the silkworm lemon mutant as an invertebrate animal model for human sepiapterin reductase deficiency.

Human sepiapterin reductase (SR) deficiency is an inherited disease caused by SPR gene mutations and is a monoamine neurotransmitter disorder. Here, we investigated whether the silkworm lemon mutant could serve as a model of SR deficiency. A point mutation in the BmSPR gene led to a five amino acid deletion at the carboxyl terminus in the lemon mutant. In addition, classical phenotypes seen in SR deficient patients were observed in the lemon mutant, including a normal phenylalanine level, a decreased dopamine and serotonin content, and an increased neopterin level. A recovery test showed that the replenishment of l-dopa significantly increased the dopamine level in the lemon mutant. The silkworm lemon mutant also showed negative behavioural abilities. These results suggest that the silkworm lemon mutant has an appropriate genetic basis and meets the biochemical requirements to be a model of SR deficiency. Thus, the silkworm lemon mutant can serve as a candidate animal model of SR deficiency, which may be helpful in facilitating accurate diagnosis and effective treatment options of SR deficiency.

Leaky splicing variant in sepiapterin reductase deficiency: Are milder cases escaping diagnosis?

Sepiapterin reductase deficiency (SRD), an extremely rare but treatable neurotransmitter disease, is an enzyme defect in the final step of tetrahydrobiopterin (BH4) synthesis.1 Unlike other forms of BH4-deficient dopa-responsive dystonia, SRD uniquely does not manifest hyperphenylalaninemia and thus slips through detection by newborn screening. Owing to its variable presenting features and need for a sensitive method of CSF analysis, diagnosis of SRD may be compromised in mild phenotypes.2

Genetic study in a family with dopa-responsive dystonia revealed a novel mutation in sepiapterin reductase gene.

Dopa-responsive dystonia due to sepiapterin reductase deficiency (OMIM#612716) is caused by recessive mutations in the gene encoding sepiapterin reductase (SPR), which plays an important role in the biosynthesis of tetrahydrobiopterin (BH4). One Jordanian patient to first cousin parents is reported in this study. The parents of the proband have recognized the symptoms of their daughter at six months old with motor developmental delay. The symptoms were progressed after-then to include speech delay, seizure, ataxia, oculomotor apraxia, dysarthia and choreoathetosis. Despite of these symptoms, the clinicians in Jordan were unable to diagnose the case. In August 2018, the proband (8 years old) was presented to the department of biotechnology and genetic engineering at Philadelphia University in Jordan for the purposes of performing whole exome sequencing (WES). Analysis of WES data has revealed novel homozygous frameshift variant in the gene SPR (NM_003124.4:c.40delG,p.Ala15Profs*100). The variant is heterozygous in the parents and in the healthy male siblings. Therefore, the studied case was diagnosed with sepiapterin reductase deficiency. Because this disease is likely to be treated recommendations were given to the family immediately to start treatments trials. The case in this study illustrates the difficulties of diagnosing sepiapterin reductase deficiency based on clinical symptoms only and thus renders the possibilities of early management. Also, this study reinforces the importance of running WES to undiagnosed neurodevelopmental cases.

Urinary sulphatoxymelatonin as a biomarker of serotonin status in biogenic amine-deficient patients

Melatonin is synthesized from serotonin and it is excreted as sulphatoxymelatonin in urine. We aim to evaluate urinary sulphatoxymelatonin as a biomarker of brain serotonin status in a cohort of patients with mutations in genes related to serotonin biosynthesis. We analized urinary sulphatoxymelatonin from 65 healthy subjects and from 28 patients with genetic defects. A total of 18 patients were studied: 14 with autosomal dominant and recessive guanosine triphosphate cyclohydrolase-I deficiency; 3 with sepiapterin reductase deficiency; and 1 with aromatic L-amino acid decarboxylase deficiency. Further 11 patients were studied after receiving serotoninergic treatment (serotonin precursors, monoamine oxidase inhibitors, selective serotonin re-uptake inhibitors): 5 with aromatic L-amino acid decarboxylase deficiency; 1 with sepiapterin reductase deficiency; 3 with dihydropteridine reductase deficiency; and 2 with 6-pyruvoyltetrahydropterin synthase deficiency. Among the patients without therapy, 6 presented low urinary sulphatoxymelatonin values, while most of the patients with guanosine triphosphate cyclohydrolase-I deficiency showed normal values. 5 of 11 patients under treatment presented low urine sulphatoxymelatonin values. Thus, decreased excretion of sulphatoxymelatonin is frequently observed in cases with severe genetic disorders affecting serotonin biosynthesis. In conclusion, sulphatoxymelatonin can be a good biomarker to estimate serotonin status in the brain, especially for treatment monitoring purposes.

Sepiapterin reductase deficiency: Report of 5 new cases

Sepiapterin reductase deficiency is a rare, under-recognized, autosomal recessively inherited disorder of neurotransmitter metabolism. Five new patients from 3 unrelated Saudi consanguineous families are reported. Symptoms began at 6 months, with delay to diagnosis averaging 8 years. All 5 patients presented with severe symptoms including axial hypotonia, dystonia, and cognitive impairment, associated with hyper-reflexia (4 patients), spasticity (4 patients), bulbar dysfunction (4 patients), and oculogyric crisis (2 patients) with diurnal fluctuation and sleep benefit. Cerebrospinal fluid neurotransmitters analysis showed a typical pattern with increased sepiapterin and increased 7,8-dihydrobiopterin. Analysis of the SPR gene identified 3 novel mutations: c.1A>G, c.370T>C, and c.527C>T. Patient one, with early diagnosis, is currently developing within the normal range. The 4 other patients showed significant improvement in their motor function, but only mild improvement in their cognitive dysfunction. Our cases illustrate the difficulties in the diagnosis of sepiapterin reductase deficiency in infancy, and the importance of early recognition and management.

Neurological Involvement in Tetrahydrobiopterin Deficiency

Tetrahydrobiopterin (BH4) is a natural and essential cofactor for the enzymatic hydroxylation of phenylalanine (Phe) and tyrosine (Tyr), and for two tryptophan hydroxylases, three nitric oxide synthases, and glyceryl-ether monooxygenase. Five separate genetic conditions affecting BH4 synthesis or recycling have been identified so far, including deficiency in (1) 6-pyruvoyltetrahydropterin synthase; (2) dihydropteridine reductase; (3) GTP cyclohydrolase I; (4) sepiapterin reductase; and (5) pterin-4α-carbinolamine dehydratase. These disorders cause hyperphenylalaninemia and impaired synthesis of serotonin and dopamine since tyrosine hydroxylase and neuronal tryptophan hydroxylase require BH4 and serotonin/dopamine products (5-hydroxytryptophan and L-dopa). All these five genetic conditions can be identified by newborn screening procedures due to elevated blood levels of Phe (with the sole exception of sepiapterin reductase deficiency). BH4 loading tests and measurement of neurotransmitter metabolites, pterins, and folates in cerebrospinal fluid can add further important information on disease severity. Untreated patients develop a complex neurological phenotype, which includes Parkinson-like features, brain degeneration, and early death. The gold standard treatment of severe disorders of BH4 metabolism is based on replacement therapy with BH4, 5-hydroxytryptophan, L-dopa, and carbidopa, with the addition, in certain cases, of folinic acid supplements and pramipexole. Dopamine agonists can improve L-dopa therapy, making treatment easier, relieving symptoms, stabilizing clinical course, and possibly ameliorating long-term outcomes. The outcome of patients with disorders of biopterin synthesis can be favorable, with either normal or near-normal cognition, and with some residual neurological symptoms usually manifesting diurnal variation, that is, worst when patients become tired or when the dosage or interval for medications is inadequate.

The Spectrum of Early Movement Disorders in Congenital Defects of Biogenic Amine Metabolism

This article analyzes the pattern of movement disorders in children with primary defects of biogenic amine metabolism emerging during the first 3 year of life. A PubMed search was performed using the keywords “monoamine neurotransmitter disorders,” “congenital defects of biogenic amine metabolism,” “early onset movement disorders,” “autosomal dominant guanosine-triphosphate-cyclohydrolase deficiency,” “autosomal recessive guanosine-tryphosphate-cyclohydrolase deficiency,” “6-pyruvoyl-tethrahydropterin synthase deficiency,” “sepiapterin reductase deficiency,” “dihydropteridine reductase deficiency,” “tyrosine hydroxilase deficiency,” “aromatic l-amino acid decarboxylase deficiency,” “dopamine transporter deficiency,” and “vesicular monoamine transporter 2.” A personal series of 27 patients affected by these disorders was presented and discussed. Primary defects of biogenic amine metabolism result in a spectrum of movement disorders associated with derangement of postural reaction and global development delay. Movement disorders virtually represent the presentation symptoms in most of these diseases. The prominent early clinical patterns of movement disorders are akinesia (with rigidity or hypotonia) and hyperkinesia (dystonia, myoclonic jerks, and tremor). While some diseases present with a rather stereotyped clinical pattern (i.e., Aromatic l -amino acid decarboxylase, sepiapterin reductase, and Dopamine transporter deficiencies), others (i.e., Guanosine-triphosphate-cyclohydrolase, 6-pyruvoyl tetrahydropterin synthase, dihydropteridine reductase, and tyrosine hydroxylase deficiencies) may present with more pleomorphic features. As a general rule, earlier the onset of the disease is, more severe and generalized is the derangement of motor functions. Inherited disorders of monoamine neurotransmitter metabolism include the few idiopathic movement disorders with the possibility of etiological treatments. For these reasons, they should always be considered in the diagnostic work-up of children with early onset movement disorders.

Diagnosis of Biogenic Amines Synthesis Defects

Defects of biogenic amines synthesis encompass a group of rare genetic disorders that have been described during the last few decades. They include tyrosine hydroxylase deficiency, aromatic L-amino acid decarboxylase deficiency, and pterin defects such as 6-pyruvoyl-tetrahydropterin synthase deficiency, dihydropteridine reductase deficiency, guanosine triphosphate cyclohydrolase-I deficiency, and sepiapterin reductase deficiency. These diseases cause low brain concentrations of catecholamines (dopamine and norepinephrine) and serotonin, which may affect motor, cognitive, and autonomic nervous system. Although most patients have recognizable phenotypes, and share a collection of overlapping symptoms, presentations vary widely and may appear to be nonclassic for the specific disorder. In general, the spectrum of clinical manifestations range from benign forms such as L-3,4-dihydroxyphenylalanine responsive movement disorders to severe encephalopathies that are difficult to treat. These conditions require the specialized analysis of the cerebrospinal fluid because every defect has a very suggestive profile in regard to monoamine and pterin metabolites. However, secondary deficiencies of these metabolites in the cerebrospinal fluid can also be found in a wide variety of neurological disorders. Owing to the still existing challenges of the diagnostic approach, it is important to highlight some of the most relevant clinical and biochemical signatures, as well as to propose practical algorithms that may help clinicians to detect and treat these patients.

Urine sepiapterin excretion as a new diagnostic marker for sepiapterin reductase deficiency

Sepiapterin reductase deficiency (SRD) causes depletion of biogenic amines in the brain, early onset motor disorder, and intellectual disability. The diagnostic marker for this rare disease is increased sepiapterin and biopterin in CSF. Through a new analytic methodology we demonstrated accumulation of sepiapterin in urine of four SRD patients several times greater than that found in healthy controls and carriers, regardless of age or treatment. Our findings suggest a new interpretation of current theories of peripheral pterin metabolism and provide a new noninvasive diagnostic tool for children with early onset cryptogenetic developmental delay and/or movement disorder.

Combined Sepiapterin Reductase and Methylmalonyl-CoA Epimerase Deficiency in a Second Patient: Cerebrospinal Fluid Polyunsaturated Fatty Acid Level and Follow-Up Under L-DOPA, 5-HTP and BH4 Trials.

Objective/context: We describe the second patient presenting the combination of two homoallelic homozygous nonsense mutations in two genes distant from 1.8Mb in the chromosome 2p13-3, the methylmalonyl-CoA epimerase gene (MCEE) and the sepiapterin reductase gene (SPR). The patient was born from consanguineous parents. He has presented a moderate but constant methylmalonic acid (MMA) excretion in urine associated with a mental retardation. The first homozygous mutation was identified in the MCEE gene (c.139C>T; p.Arg47*). Progressive dystonia and cataplexy narcolepsy led to diagnose the second homozygous mutation in the SPR gene: c.751A>T; p.Lys251*. Sepiapterin reductase deficiency (SRD) was characterized by a defect in tetrahydrobiopterin (BH4), the cofactor of several hydroxylases needed for the synthesis of neurotransmitters. A treatment with L-DOPA/carbidopa and 5-HTP dramatically improved the dystonic posture, the mood and the hypersomnia, proving that the pathogenesis was due to SRD. A supplementation with BH4 did not induce additional clinical benefit, although HVA and HIAA increased in CSF. The polyunsaturated fatty acids were measured in CSF as the markers of the neuronal stress. We have shown that DHA and its precursor EPA were high before and during the time course of the different treatments. The patient has inherited two copies of the two mutations from his consanguineous parents in the MCEE and SPR genes in the chromosome 2p13-3. DHA and EPA increased in CSF as a response to the neuronal stress induced by the defect in neurotransmitters or the altered metabolism of the odd-chain fatty acids and cholesterol.