Treatable Inborn Errors Of Metabolism Research Articles

Neurological Involvement in Inherited Metabolic Diseases: An Overview

Neurological involvement is a typical feature of several inherited metabolic diseases. The onset of signs and/or symptoms may appear as early as the first days of life or after an interval of normal or near-normal growth and development. Metabolic decomposition usually presents with a severe clinical phenotype, which include poor feeding, vomiting, lethargy, seizures, and loss of consciousness. This spectrum of manifestations is often fatal; however, severe neurological sequelae and/or regression of neurodevelopmental milestones can be the prominent signs in those who survive. Overall, treatable inborn errors of metabolism can be divided in three groups, namely: (Group 1) inborn errors of intermediary metabolism giving rise to acute or chronic intoxication; (Group 2) inborn errors of intermediary metabolism affect in genergetic processes; and (Group 3) inborn errors involving cellular organelles, including lysosomal, peroxisomal, glycosylation, and cholesterol synthesis defects. The spectrum of neurological manifestations includes developmental delay, seizures and epilepsy, pyramidal and extrapyramidal signs, movement disorders, vision and hearing impairment, peripheral neuropathy, and psychiatric abnormalities. The main anatomical/imaging patterns reflects selective vulnerability of nervous system substance and include atrophy, (predominantly) symmetrical abnormalities, and dysmyelination, As several patients with neurometabolic diseases responds favorably to therapeutic trials, early detection and early intervention is of utmost importance to prevent catabolic-related damage and to revert to normal or near-normal parameters neurodevelopmental milestones.

DNA methylation in the pathophysiology of hyperphenylalaninemia in the PAH(enu2) mouse model of phenylketonuria.

Phenylalanine hydroxylase deficient phenylketonuria (PKU) is the paradigm for a treatable inborn error of metabolism where maintaining plasma phenylalanine (Phe) in the therapeutic range relates to improved clinical outcomes. While Phe is the presumed intoxicating analyte causal in neurologic damage, the mechanism(s) of Phe toxicity has remained elusive. Altered DNA methylation is a recognized response associated with exposure to numerous small molecule toxic agents. Paralleling this effect, we hypothesized that chronic Phe over-exposure in the brain would lead to aberrant DNA methylation with secondary influence upon gene regulation that would ultimately contribute to PKU neuropathology. The PAH(enu2) mouse models human PKU with intrinsic hyperphenylalaninemia, abnormal response to Phe challenge, and neurologic deficit. To examine this hypothesis, we assessed DNA methylation patterns in brain tissues using methylated DNA immunoprecipitation and paired end sequencing in adult PAH(enu2) animals maintained under either continuous dietary Phe restriction or chronic hyperphenylalaninemia. Heterozygous PAH(enu2/WT) litter mates served as controls for normal Phe exposure. Extensive repatterning of DNA methylation was observed in brain tissue of hyperphenylalaninemic animals while Phe restricted animals displayed an attenuated pattern of aberrant DNA methylation. Affected gene coding regions displayed aberrant hypermethylation and hypomethylation. Gene body methylation of noncoding RNA genes was observed and among these microRNA genes were prominent. Of particular note, observed only in hyperphenylalaninemic animals, was hypomethylation of miRNA genes within the imprinted Dlk1-Dio3 locus on chromosome 12. Aberrant methylation of microRNA genes influenced their expression which has secondary effects upon the expression of targeted protein coding genes. Differential hypermethylation of gene promoters was exclusive to hyperphenylalaninemic PAH(enu2) animals. Genes with synaptic involvement were targets of promoter hypermethylation that resulted in down-regulation of their expression. Gene dysregulation secondary to abnormal DNA methylation may be contributing to PKU neuropathology. These results suggest drugs that prevent or correct aberrant DNA methylation may offer a novel therapeutic option to management of neurological symptoms in PKU patients.

EPILEPSY IN INBORN ERRORS OF METABOLISM

Epilepsy is a frequent and sometimes leading symptom in inborn errors of metabolism, especially in neonatal or infantile ones. Early myoclonic encephalopathy and myoclonus as a seizure type are the prototypes of epilepsy in inherited metabolic diseases. But clinical presentation also includes refractory neonatal seizures, Ohtahara syndrome, infantile spasms and progressive myoclonic epilepsy. Clinical manifestations seems to be similar in different etiology and in majority of cases look like unspecific epileptic encephalopathy. Selected treatable inborn errors of metabolism are discussed alongside with diagnostic approach to inherited metabolic epilepsies. Probably it’s better to avoid the treatment with valproic acid in clinical situations when etiology is unclear. Alternative use of levetiracetam is recommended. Besides the antiepileptic drugs we can also make pyridoxine, pyridoxal-5-phosphate and folinic acid consequent trials for 3-5 days before our diagnostic quest succeed.

Gestational dating by metabolic profile at birth: a California cohort study

BackgroundAccurate gestational dating is a critical component of obstetric and newborn care. In the absence of early ultrasound, many clinicians rely on less accurate measures, such as last menstrual period or symphysis-fundal height during pregnancy, or Dubowitz scoring or the Ballard (or New Ballard) method at birth. These measures often underestimate or overestimate gestational age and can lead to misclassification of babies as born preterm, which has both short- and long-term clinical care and public health implications.ObjectiveWe sought to evaluate whether metabolic markers in newborns measured as part of routine screening for treatable inborn errors of metabolism can be used to develop a population-level metabolic gestational dating algorithm that is robust despite intrauterine growth restriction and can be used when fetal ultrasound dating is not available. We focused specifically on the ability of these markers to differentiate preterm births (PTBs) (<37 weeks) from term births and to assign a specific gestational age in the PTB group.Study DesignWe evaluated a cohort of 729,503 singleton newborns with a California birth in 2005 through 2011 who had routine newborn metabolic screening and fetal ultrasound dating at 11–20 weeks’ gestation. Using training and testing subsets (divided in a ratio of 3:1) we evaluated the association among PTB, target newborn characteristics, acylcarnitines, amino acids, thyroid-stimulating hormone, 17-hydroxyprogesterone, and galactose-1-phosphate-uridyl-transferase. We used multivariate backward stepwise regression to test for associations and linear discriminate analyses to create a linear function for PTB and to assign a specific week of gestation. We used sensitivity, specificity, and positive predictive value to evaluate the performance of linear functions.ResultsAlong with birthweight and infant age at test, we included 35 of the 51 metabolic markers measured in the final multivariate model comparing PTBs and term births. Using a linear discriminate analyses-derived linear function, we were able to sort PTBs and term births accurately with sensitivities and specificities of ≥95% in both the training and testing subsets. Assignment of a specific week of gestation in those identified as PTBs resulted in the correct assignment of week ±2 weeks in 89.8% of all newborns in the training and 91.7% of those in the testing subset. When PTB rates were modeled using the metabolic dating algorithm compared to fetal ultrasound, PTB rates were 7.15% vs 6.11% in the training subset and 7.31% vs 6.25% in the testing subset.ConclusionWhen considered in combination with birthweight and hours of age at test, metabolic profile evaluated within 8 days of birth appears to be a useful measure of PTB and, among those born preterm, of specific week of gestation ±2 weeks. Dating by metabolic profile may be useful in instances where there is no fetal ultrasound due to lack of availability or late entry into care.

The investigation of inborn errors of metabolism as an underlying cause of idiopathic intellectual disability in adults in Norway.

Inborn errors of metabolism (IEMs) may be an unrecognized cause of intellectual disability (ID) in adults. Knowledge and techniques for investigating IEMs have evolved rapidly; therefore adult patients with idiopathic ID may benefit from an up-to-date aetiological work-up. This review aims at establishing recommendations for investigating IEMs as a cause of ID in adults. PubMed was searched for articles published between 2000 and 2015 regarding clinical work-up, IEMs, ID and adults. Information compiled from 61 articles is used to give practical suggestions from a clinical point of view. Many IEMs that cause ID are characterized by increased risk of specific somatic, neurological and psychiatric signs. Neurometabolic investigations of ID should start with a thorough medical history, clinical examination and general screening in blood. Brain imaging with magnetic resonance imaging and if possible magnetic resonance spectroscopy should also be part of the initial work-up. The aim is to detect abnormalities that give clues to a specific IEM. After the initial screening, a first tier of neurometabolic screening tests in blood and urine should be performed. If this fails to give diagnostic clues, a second tier of neurometabolic tests should be considered in order to secure that the treatable IEMs are detected. Whole exome sequencing techniques, when they become available in clinical settings, will offer new opportunities for detection of IEMs. Based on a broad review of the current literature a systematic diagnostic work-up to detect IEMs as a cause of ID in adults is suggested.

Apparent underdiagnosis of Cerebrotendinous Xanthomatosis revealed by analysis of ~60,000 human exomes.

Cerebrotendinous Xanthomatosis (CTX) is a treatable inborn error of metabolism caused by recessive variants in CYP27A1. Clinical presentation varies, but typically includes infant-onset chronic diarrhea, juvenile-onset bilateral cataracts, and later-onset tendinous xanthomas and progressive neurological dysfunction. CYP27A1 plays an essential role in side-chain oxidation of cholesterol necessary for the synthesis of the bile acid, chenodeoxycholic acid, and perturbations in this gene that reduce enzyme activity result in elevations of cholestanol. It is commonly held that CTX is exceedingly rare, but epidemiological studies are lacking. In order to provide an accurate incidence estimate of CTX, we studied the ExAC cohort of ~60,000 unrelated adults from global populations to determine the allele frequency of the 57 variants in CYP27A1 reported pathogenic for CTX. In addition, we conducted bioinformatics analyses on these CTX-causing variants and determined a bioinformatics profile to predict variants that may be pathogenic but have not yet been reported in the CTX patient literature. An additional 29 variants were identified that met bioinformatics criteria for being potentially pathogenic. Incidence was estimated based allele frequencies of pathogenic CTX variants plus those determined to be potentially pathogenic. One variant, p.P384L, previously reported in three unrelated CTX families had an allele frequency ≥ 1% in European, Latino and Asian populations. Three additional mutations had a frequency of ≥ 0.1% in Asian populations. CTX disease incidence was calculated excluding the high frequency p.P384L and separately using a genetic paradigm where this high frequency variant only causes classic CTX when paired in trans with a null variant. These calculations place CTX incidence ranging from 1:134,970 to 1:461,358 in Europeans, 1:263,222 to 1:468,624 in Africans, 1:71,677 to 1:148,914 in Americans, 1:64,267 to 1:64,712 in East Asians and 1:36,072 to 1:75,601 in South Asians. This work indicates CTX is under-diagnosed and improved patient screening is needed as early intervention prevents disease progression.

Angelman syndrome and isovaleric acidemia: What is the link?

We report a toddler affected with Angelman syndrome and isovaleric acidemia (IVA). Such association was due to paternal uniparental isodisomy (UPD) of chromosome 15 in which the proband inherited two paternal copies of an IVA gene point mutation. As both diseases may have severe impact on neurodevelopment, adequate treatment of IVA should be discussed. In our patient however, the variant identified likely causes asymptomatic organic aciduria. Such findings emphasize that paternal UPD 15 can rarely lead to co-occurrence of Angelman syndrome and potentially treatable inborn errors of metabolism.

Retrospective analysis supports algorithm as efficient diagnostic approach to treatable intellectual developmental disabilities.

Intellectual developmental disorders (IDD(1)), characterized by a significant impairment in cognitive function and behavior, affect 2.5% of the population and are associated with considerable morbidity and healthcare costs. Inborn errors of metabolism (IEM) currently constitute the largest group of genetic defects presenting with IDD, which are amenable to causal therapy. Recently, we created an evidence-based 2-tiered diagnostic protocol (TIDE protocol); the first tier is a 'screening step' applied in all patients, comprising routinely performed, wide available metabolic tests in blood and urine, while second-tier tests are more specific and based on the patient's phenotype. The protocol is supported by an app (www.treatable-ID.org). To retrospectively examine the cost- and time-effectiveness of the TIDE protocol in patients identified with a treatable IEM at the British Columbia Children's Hospital. We searched the database for all IDD patients diagnosed with a treatable IEM, during the period 2000-2009 in our academic institution. Data regarding the patient's clinical phenotype, IEM, diagnostic tests and interval were collected. Total costs and time intervals associated with all testing and physician consultations actually performed were calculated and compared to the model of the TIDE protocol. Thirty-one patients (16 males) were diagnosed with treatable IDD during the period 2000-2009. For those identifiable via the 1st tier (n=20), the average cost savings would have been $311.17 CAD, and for those diagnosed via a second-tier test (n=11) $340.14 CAD. Significant diagnostic delay (mean 9 months; range 1-29 months) could have been avoided in 9 patients with first-tier diagnoses, had the TIDE protocol been used. For those with second-tier treatable IDD, diagnoses could have been more rapidly achieved with the use of the Treatable IDD app allowing for specific searches based on signs and symptoms. The TIDE protocol for treatable forms of IDD appears effective reducing diagnostic delay and unnecessary costs. Larger prospective studies, currently underway, are needed to prove that standard screening for treatable conditions in patients with IDD is time- and cost-effective, and most importantly will preserve brain function by timely diagnosis enabling initiation of causal therapy.

Treatable inborn errors of metabolism presenting as cerebral palsy mimics: systematic literature review.

BackgroundInborn errors of metabolism (IEMs) have been anecdotally reported in the literature as presenting with features of cerebral palsy (CP) or misdiagnosed as ‘atypical CP’. A significant proportion is amenable to treatment either directly targeting the underlying pathophysiology (often with improvement of symptoms) or with the potential to halt disease progression and prevent/minimize further damage.MethodsWe performed a systematic literature review to identify all reports of IEMs presenting with CP-like symptoms before 5 years of age, and selected those for which evidence for effective treatment exists.ResultsWe identified 54 treatable IEMs reported to mimic CP, belonging to 13 different biochemical categories. A further 13 treatable IEMs were included, which can present with CP-like symptoms according to expert opinion, but for which no reports in the literature were identified. For 26 of these IEMs, a treatment is available that targets the primary underlying pathophysiology (e.g. neurotransmitter supplements), and for the remainder (n = 41) treatment exerts stabilizing/preventative effects (e.g. emergency regimen). The total number of treatments is 50, and evidence varies for the various treatments from Level 1b, c (n = 2); Level 2a, b, c (n = 16); Level 4 (n = 35); to Level 4–5 (n = 6); Level 5 (n = 8). Thirty-eight (57%) of the treatable IEMs mimicking CP can be identified by ready available metabolic screening tests in blood or urine, while the remaining IEMs require more specific and sometimes invasive tests.ConclusionsLimited by the rare nature of IEMs and incomplete information in the literature, we conclude that (1) A surprisingly large number of IEMs can present with CP symptoms, as ‘CP mimics’, (2) although individually rare, a large proportion of these diseases are treatable such that neurological damage can either be reversed or prevented, (3) clinician awareness of treatable CP mimics is important for appropriate screening, diagnosis, and early intervention, and (4) systematic studies are required to elucidate the collective frequency of treatable IEMs in CP.Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-014-0197-2) contains supplementary material, which is available to authorized users.

Early identification of treatable inborn errors of metabolism in children with intellectual disability: The Treatable Intellectual Disability Endeavor protocol in British Columbia.

Intellectual disability (ID) is a lifelong, debilitating condition affecting 2% to 3% Canadians (1). It is defined by deficits in cognitive functioning (IQ 2 developmental domains, eg, fine/gross motor skills, speech and interaction) (2,3). In Canada, approximately 7600 to 11,500 children are born with GDD annually (1). In the present commentary, the term ID will be used to refer to ID/GDD.

Cerebral creatine deficiencies: a group of treatable intellectual developmental disorders.

Currently there are 91 treatable inborn errors of metabolism that cause intellectual developmental disorders. Cerebral creatine deficiencies (CDD) comprise three of these: arginine: glycine amidinotransferase [AGAT], guanidinoacetate methyltransferase [GAMT], and X-linked creatine transporter deficiency [SLC6A8]. Intellectual developmental disorder and cerebral creatine deficiency are the hallmarks of CDD. Additional clinical features include prominent speech delay, autism, epilepsy, extrapyramidal movement disorders, and signal changes in the globus pallidus. Patients with GAMT deficiency exhibit the most severe clinical spectrum. Myopathy is a distinct feature in AGAT deficiency. Guanidinoacetate (GAA) is the immediate product in the creatine biosynthetic pathway. Low GAA concentrations in urine, plasma, and cerebrospinal fluid are characteristic diagnostic markers for AGAT deficiency, while high GAA concentrations are characteristic markers for GAMT deficiency. An elevated ratio of urinary creatine /creatinine excretion serves as a diagnostic marker in males with SLC6A8 deficiency. Treatment strategies include oral supplementation of high-dose creatine-monohydrate for all three CDD. Guanidinoacetate-reducing strategies (high-dose ornithine, arginine-restricted diet) are additionally employed in GAMT deficiency. Supplementation of substrates for intracerebral creatine synthesis (arginine, glycine) has been used additionally to treat SLC6A8 deficiency. Early recognition and treatment improves outcomes. Normal outcomes in neonatally ascertained siblings from index families with AGAT and GAMT deficiency suggest a potential benefit of newborn screening for these disorders.

Psychiatric signs and symptoms in treatable inborn errors of metabolism

Possible underlying organic causes of psychiatric symptoms can be overlooked in the clinical setting. It is important to increase awareness amongst psychiatric and neurological professionals with regard to certain inborn errors of metabolism as, in some cases, disease-specific therapies are available that can, for instance, treat underlying metabolic causes. The following article describes the basic pathophysiology, clinical and neurological features, and available diagnostic procedures of six treatable metabolic diseases that are associated with neuropsychiatric symptoms: Wilson’s disease, cerebrotendinous xanthomatosis, porphyrias, homocysteinemia, urea cycle disorders, and Niemann-Pick disease type C (NP-C). NP-C is taken as a particularly relevant example because, while it is traditionally considered to be a condition that presents with severe neurological and systemic manifestations in children, an increasing number of patients are being detected who have the adolescent- or adult-onset form, which is frequently associated with neuropsychiatric signs. A notable proportion of adult-onset cases have been reported where NP-C has mistakenly been diagnosed and treated as a psychiatric condition, usually based on patients’ initial presentation with psychotic or schizophrenia-like symptoms. Underlying organic causes of psychiatric disorders such as psychosis should be considered among patients with atypical symptoms and/or resistance to standard therapy. Alongside improved frameworks for additional multidisciplinary diagnostic work in patients with suspected organic disease, the development of convenient and affordable biochemical screening and/or diagnostic methods has enabled new ways to narrow down differential diagnoses.

Niemann-Pick disease type C: introduction and main clinical features.

Niemann-Pick disease type C: introduction and main clinical features.

High-throughput tandem mass spectrometry multiplex analysis for newborn urinary screening of creatine synthesis and transport disorders, Triple H syndrome and OTC deficiency

BackgroundCreatine synthesis and transport disorders, Triple H syndrome and ornithine transcarbamylase deficiency are treatable inborn errors of metabolism. Early screening of patients was found to be beneficial. Mass spectrometry analysis of specific urinary biomarkers might lead to early detection and treatment in the neonatal period. We developed a high-throughput mass spectrometry methodology applicable to newborn screening using dried urine on filter paper for these aforementioned diseases. MethodsA high-throughput methodology was devised for the simultaneous analysis of creatine, guanidineacetic acid, orotic acid, uracil, creatinine and respective internal standards, using both positive and negative electrospray ionization modes, depending on the compound. ResultsThe precision and accuracy varied by <15%. Stability during storage at different temperatures was confirmed for three weeks. The limits of detection and quantification for each biomarker varied from 0.3 to 6.3μmol/l and from 1.0 to 20.9μmol/l, respectively. Analyses of urine specimens from affected patients revealed abnormal results. Targeted biomarkers in urine were detected in the first weeks of life. ConclusionsThis rapid, simple and robust liquid chromatography/tandem mass spectrometry methodology is an efficient tool applicable to urine screening for inherited disorders by biochemical laboratories.

EPA-1489 – Which atypical signs of schizophrenia may trigger us to treatable neuro metabolic diseases?

Organic schizophrenia, or schizophrenia-like syndrome is an important concern in psychiatry and various medical conditions and substances may be associated with it. Among them, Inborn Errors of Metabolism (IEM) are rare disease with interesting features : (i) some of them could be (or seems to be) presenting with schizophrenic psychiatric symptoms; (ii) when they are treatable, treatment leads to decrease schizophrenic symptoms; (iii) treatment is more efficient when beginning at early stage (i.e. before neurological or physical signs) and (iv) most psychiatrists have no specific knowledge about IEM. Moreover, IEM is a growing field in medicine because of improvement of biochemical and genetic techniques and new treatments are approved. Incidence is underestimated and psychiatric patients may be an at risk population. We propose a brief and comprehensive review of the literature focuses on treatable IEM with possible presenting psychiatric signs (Cerebrotendinous- Xanthomatosis, Wilson Disease, homocysteimia due to MTHFR deficiency, homocystinuria due to cystathionine beta-synthase deficiency, urea cycle disorders and Niemann Pick type C). We also present a simple diagnosis tool helping psychiatrist and caregivers in this field. The key objective is to devise a simple means of identifying patients with atypical psychiatric symptoms and to: (i) know when schizophrenic symptoms may be atypical and should draw our attention to organic disease, and IEM and (ii) learn which physical and neurological signs may trigger for each of the specific IEM. Looking for atypical signs of psychosis or minor physical signs may be extremely useful in rare cases of treatable disease.

GAMT deficiency: 20 years of a treatable inborn error of metabolism

Article history: Received 4 November 2013 Accepted 5 November 2013 Available online 10 November 2013 SLC6A8 deficiencies), as well as intractable epilepsy (GAMT and SLC6A8 deficiencies), autism, automutilating behavior, extrapyramidal syndrome and hypotonia (GAMT deficiency). Their common phenotype (except for SLC6A8-deficient heterozygous females) is the virtual absence of Cr peak measured by H-MRS in cortex and basal ganglia [9,10]. The reason why CNS is the most affected organ in CDS, and particu-

Treatable inborn errors of metabolism causing neurological symptoms in adults

BackgroundThe identification of inborn errors of metabolism (IEM) in adults presenting with a wide range of neurological symptoms is a relatively new field in medicine. We sought to identify which treatable IEM have been diagnosed for the first time in adults and generate a protocol for metabolic screening targeting those treatable disorders. MethodsMedline/Pubmed searches of English language literature limited to the adult age group were performed. Diseases identified through this search were then compared to previously published lists of treatable IEM in both adults and children. Results85% of the treatable conditions known to cause global developmental delay or intellectual disability in children had reports where the diagnosis of that IEM was made in one or more adult patients with neurological symptoms. Screening tests in blood, urine, CSF and MRI can detect most of these treatable conditions but the diagnostic accuracy of these screening tests in adults is not clear. ConclusionTreatable IEM need to be considered in the differential diagnosis of neurological symptoms in patients of any age.

Evidence for treatable inborn errors of metabolism in a cohort of 187 Greek patients with autism spectrum disorder (ASD)

We screened for the presence of inborn errors of metabolism (IEM) in 187 children (105 males; 82 females, ages 4–14 years old) who presented with confirmed features of autism spectrum disorder (ASD). Twelve patients (7%) manifested increased 3-hydroxyisovaleric acid (3-OH-IVA) excretion in urine, and minor to significant improvement in autistic features was observed in seven patients following supplementation with biotin. Five diagnoses included: Lesch Nyhan syndrome (2), succinic semialdehyde dehydrogenase (SSADH) deficiency (2), and phenylketonuria (1) (2.7%). Additional metabolic disturbances suggestive of IEMs included two patients whose increased urine 3-OH-IVA was accompanied by elevated methylcitrate and lactate in sera, and 30 patients that showed abnormal glucose-loading tests. In the latter group, 16/30 patients manifested increased sera beta hydroxybutyrate (b-OH-b) production and 18/30 had a paradoxical increase of sera lactate. Six patients with elevated b-OH-b in sera showed improved autistic features following implementation of a ketogenic diet (KD). Five patients showed decreased serum ketone body production with glucose loading. Twelve of 187 patients demonstrated non-specific MRI pathology, while 25/187 had abnormal electroencephalogram (EEG) findings. Finally, family history was positive for 22/187 patients (1st or 2nd degree relative with comparable symptomatology) and consanguinity was documented for 12/187 patients. Our data provide evidence for a new biomarker (3-OH-IVA) and novel treatment approaches in ASD patients. Concise 1 sentence take-home message: Detailed metabolic screening in a Greek cohort of ASD patients revealed biomarkers (urine 3-hydroxyisovaleric acid and serum b-OH-b) in 7% (13/187) of patients for whom biotin supplementation or institution of a KD resulted in mild to significant clinical improvement in autistic features.

Molecular Diagnosis for a Fatal Case of Very Long-chain Acyl-CoA Dehydrogenase Deficiency in Hong Kong Chinese With a Novel Mutation

Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency is one of the most common fatty acid oxidation defects that cause sudden unexpected deaths in infants. The death attributed to VLCAD deficiency can be prevented by early diagnosis with expanded newborn screening using tandem mass spectrometry. A favorable outcome can be achieved with early diagnosis and prompt treatment. However, such newborn screening has not yet been available in Hong Kong. We report a 2-month-old boy who succumbed 5 hours after admission with the diagnosis of VLCAD deficiency confirmed by genetic analysis performed after death. The patient was compound heterozygous for a novel splicing mutation ACADVL NM_000018.2:c.277+2T>G; NC_000017.10:g.7123997T>G and a known disease-causing mutation ACADVL NM_000018.2:c.388_390del; NP_000009.1: p.Glu130del. Family screening was performed for at-risk siblings. The rapid downhill course of the patient clearly illustrates the need of newborn screening for early diagnosis. Our patient was asymptomatic before metabolic decompensation. However, once metabolic decompensation occurred, rapid deterioration and death followed, which obviated the opportunity to diagnose and treat. The only way to save these patients' lives and improve their outcome is early diagnosis and appropriate treatment. Therefore, we strongly urge the implementation of newborn screening using tandem mass spectrometry for VLCAD deficiency and other highly treatable inborn errors of metabolism in Hong Kong.

The first reported HLCS gene mutation causing holocarboxylase synthetase deficiency in a Vietnamese patient

Holocarboxylase synthetase deficiency is an inborn error of biotin metabolism leading to multiple carboxylase deficiency which is often biotin responsive. This disease is believed to be relatively common among the Asian population. A 6-year-old Vietnamese boy presented with recurrent episodes of severe metabolic acidosis precipitated by intercurrent illnesses. An extensive skin rash was present since the onset of his illness. Multiple carboxylase deficiency was considered a likely diagnosis based on the history and the characteristic skin rash. This diagnosis was later confirmed by urine organic acid and molecular genetic studies. Urine organic acid showed characteristic excretion of glycine conjugates. Serum biotinidase activity was normal. Sequencing of the holocarboxylase synthetase gene revealed the patient being homozygous for a common mutation R508W. The patient showed a dramatic response to biotin within days of its administration. This case illustrates a potential highly treatable inborn error of metabolism that can be recognized on clinical grounds and its favorable response to biotin treatment.