Hereditary Metabolic Disorders Research Articles

First Macedonian child with tyrosinemia type 1 successfully treated with nitisinone and report of a novel mutation in the FAH gene

Introduction. Hereditary tyrosinemia type 1 (HT1) is a severe hereditary metabolic disorder of tyrosine metabolism due to fumarylacetoacetate hydrolase (FAH) deficiency and accumulation of toxic products in tissues. More than 80 mutations in the FAH gene are presently reported on the Human Genome Mutation Database. To date, no molecular genetic defects of HT1 in Macedonia have been described. Case outline. A female infant two and a half months old presented with failure to thrive, anemia, edemas, and severe coagulation disturbances. The diagnosis of HT1 was based on high levels of serum ?-fetoprotein, increased serum tyrosine, and positive succinylacetone in urine. Nitisinone treatment with tyrosine-restriction diet was immediately introduced. The patient, currently aged five years, has normal growth, psychomotor development, and no focal lesions on abdominal MRI. A screening of the FAH gene revealed two heterozygous mutations ? c.[1A>G];[784T>A]. The mutation c.784T>A is a novel one (p.Trp262Arg), and was predicted to be the cause of the disease by an in silico analysis. Conclusion. To date, this case is the first and only child with HT1 successfully treated with nitisinone in our country. Also, this is the first report of an HT1 patient caused by the c.784T>A mutation.

Continuous glucose monitoring in children with glycogenosis

Rationale: Glycogen storage diseases (GSD, glycogenosis) are a group of hereditary disorders of carbohydrate metabolism that is characterized by excess glycogen accumulation in various organs and tissues due to deficiency or absence of glycogen-splitting enzymes. GSD diagnostics requires an assessment of the patient's health status, severity and frequency of hypoglycemias, as well as the choice of a strategy for nutritional support to prevent hypoglycemia. Aim: To assess efficacy of continuous glucose monitoring (CGM) as a new method to diagnose hypoglycemia in children with hepatic types of GSD and the role of this assessment method in personalization of nutritional regimen in these disorders. Materials and methods: The study included 51 child with confirmed diagnosis of GSD at the age of 6.9 ± 0.7 years, of them 36 boys and 15 girls. Thirty three percent of patients had GSD type I, 22% – type III, 45% – types VI and IX. All patients had their glycemic levels measured as glycemic profiles and oral glucose tolerance test (OGTT), as well as by means of real-time CGM. The results were analyzed both in the whole group of patients and in the groups with various GSD types. Results: Measurement of glycemic profiles in children with GSD at daytime did not detect any significant abnormalities. During OGTT, more rapid decline of glucose levels was seen in younger kids and in patients with GSD type I; however, the differences were not statistically significant (11 patients (65% of cases) had the lowest glucose levels at 180 minutes of the test: 3.1 ± 0.3 mmol/L, p > 0.05). Fasting hypoglycemia in the OGTT was found in 4 (24%) children with GSD type I and in 3 (13%) children with GSD types VI and IX. Hypoglycemia at the end of the test was seen in 13 (76%) patients with GSD type I, in 3 (27%) with type III, and in 12 (55%) with types VI and IX. CGM showed hyperglycemia (10.2 ± 0.3 mmol/L) for 1 to 1.5 hours after a meal. Hypoglycemic episodes were registered at night time in 48 (94.1%) of children indicating the need for additional night feeding. Maximal total duration of low glucose levels was found in type I of the disease (10.2 ± 2.4 hours). Analysis of CGM results depending on GSD type showed that despite comparable glucose levels, more significant abnormalities are found in GSD type I (the proportion of hyperglycemic periods was 10.2 ± 2.3%, their duration 6.9 ± 1.8 hours; the proportion of hypoglycemic periods was 13.5 ± 2.6%, their duration 10.2 ± 2.4 hours, p < 0.05). Conclusion: The results obtained indicate the necessity to use CGM in all GSD patients to diagnose and prevent hypoglycemia that would be the basis to elaborate individual nutritional recommendations.

Perioperative management of living-donor liver transplantation for methylmalonic acidemia.

Methymalonic acidemia (MMA) is a hereditary metabolic disorder characterized by a defect of the methylmalonyl-CoA mutase that breaks down propionate. The efficacy of liver transplantation for MMA was recently reported. However, the anesthetic management of liver transplant for MMA is not clear. The aim of this article is to describe an anesthetic management algorithm of liver transplant for MMA by reviewing our cases of liver transplant for MMA. Fourteen patients received a liver transplant; three cases showed metabolic decompensation during the transplant and two of the patients died. In the two patients who expired, propofol was used for maintenance anesthesia and preoperative continuous hemodiafiltration was used to reduce plasma methylmalonic acid level in one case, and to control severe metabolic decompensation before transplant for the other case. Their renal function was also worse than others and they were already experiencing metabolic decompensation before induction of anesthesia. Based on our experience of these 14 cases, we have established an anesthetic algorithm for patients with MMA undergoing liver transplant or other procedures. There are three important points in our experience: propofol should be avoided, dextrose infusion therapy should be continued to prevent metabolic decompensation, and liver transplant or other procedures should be avoided during metabolic decompensation.

Congenital Bilateral Thenar Amyotrophy due to Carpal Tunnel Narrowing

Bilateral thenar musculature atrophy due to carpal tunnel syndrome is rarely documented in children. It is usually the result either of carpal bone malformation or of hereditary metabolic disorders. We report a case of a 5-year-old female patient presenting with thenar atrophy due to severe median neuropathy at the carpal tunnel of both hands. Using high-resolution ultrasonography, we detected a significant carpal tunnel deformation due to a narrowing at its inlet. Additional tests did not reveal structural alterations of carpal bones nor metabolic disorders. Surgery, which had been initially ruled out, was performed when the patient was 15 years old in view of progressive worsening (complex regional autonomic syndrome). Surgery improved symptoms and confirmed the above morphological findings. We present a case of both acute bilateral median neuropathy at carpus and bilateral symmetric deformation of carpal tunnel due to a narrowing of the entrance in a healthy young girl without other causative pathology. To our knowledge, such a case has not been described before.

Diagnosis of the porphyrias : From A (as in aminolevulinic acid) to Z (as in zinc protoporphyrin)

The porphyrias comprise a clinically, biochemically, and genetically heterogeneous group of predominantly hereditary metabolic disorders resulting from a dysfunction along the heme biosynthetic pathway. Whereas most variants can manifest with different cutaneous symptoms, some types only reveal life-threatening acute neurovisceral attacks. Therefore, interdisciplinary care of these patients is advisable. In this article, we provide an overview of characteristic clinical and laboratory findings in the various forms of porphyria and a diagnostic algorithm.

Hypophosphatemic Rickets in Siblings: A Rare Case Report.

Hypophosphatemic rickets (HR) is a type of hereditary rickets characterized by persistent hypophosphatemia and hyperphosphaturia. The most predominant type is inherited in an X-linked fashion and caused by mutation in the gene encoding the phosphate-regulating endopeptidase homolog, X-linked (PHEX), identified in 1995. The X-linked hypophosphatemic (XLH) rickets is a rare hereditary metabolic disorder with a prevalence of 1 in 20,000 and causes deficient calcification of mineralized structures such as bones and teeth resulting in dental problems in terms of delayed eruption, spontaneous periapical infections, and exfoliation. We report one such unique case of hypophosphatemic vitamin D-resistant rickets in siblings exhibiting classical features of rickets with emphasis on its treatment and dental considerations.

In Vivo NMR Studies of the Brain with Hereditary or Acquired Metabolic Disorders.

Metabolic disorders, whether hereditary or acquired, affect the brain, and abnormalities of the brain are related to cellular integrity; particularly in regard to neurons and astrocytes as well as interactions between them. Metabolic disturbances lead to alterations in cellular function as well as microscopic and macroscopic structural changes in the brain with diabetes, the most typical example of metabolic disorders, and a number of hereditary metabolic disorders. Alternatively, cellular dysfunction and degeneration of the brain lead to metabolic disturbances in hereditary neurological disorders with neurodegeneration. Nuclear magnetic resonance (NMR) techniques allow us to assess a range of pathophysiological changes of the brain in vivo. For example, magnetic resonance spectroscopy detects alterations in brain metabolism and energetics. Physiological magnetic resonance imaging (MRI) detects accompanying changes in cerebral blood flow related to neurovascular coupling. Diffusion and T1/T2-weighted MRI detect microscopic and macroscopic changes of the brain structure. This review summarizes current NMR findings of functional, physiological and biochemical alterations within a number of hereditary and acquired metabolic disorders in both animal models and humans. The global view of the impact of these metabolic disorders on the brain may be useful in identifying the unique and/or general patterns of abnormalities in the living brain related to the pathophysiology of the diseases, and identifying future fields of inquiry.

Cognitive functioning in mild hyperphenylalaninemia

BackgroundHyperphenylalaninemia is a hereditary metabolic disorder that causes elevated blood phenylalanine (Phe). Hyperphenylalaninemias are classified as Phenylketonuria PKU (Phe>6mg/dL) or mild hyperphenylalaninemia (mHPA) (Phe 2–6mg/dL). This study examines the cognitive functioning of early diagnosed children with mHPA compared with early diagnosed and treated children with PKU. Sample and methodsPsychomotor development (BSID-II) at 12 and 36months of age, and cognitive performance at 4 and 7years of age (WPPSI and WISC-R), were assessed in 118 PKU and 97 mHPA patients. Cognitive profile analysis of WISC-R subscales in school age children was performed and results were compared between the two groups. ResultsBoth groups preformed within the average range. Scores were significantly higher in the mHPA group. The mean Mental Development Index (MDI) at 12months of age was 98.1 in the mHPA group and 92.3 in the PKU group (p<0.0002). At 36months the MDI was 94.6 in the mHPA group and 84.7 in the PKU group (p=0.0001. At age four years the mean Full Scale IQ was 106.5 (mHPA group) and 95.9 (PKU group) (p<0.0001). At age seven years the mean Full Scale IQ was 100.9 (mHPA group) and 89.9 (PKU group) (p<0.005). The pattern of deficits was similar in both groups, with relative weaknesses in working memory and attention. ConclusionsChildren with mHPA achieved cognitive performance well within the average range and attained significantly higher scores than children with PKU. However, they appeared to have relative weaknesses in working memory and attention, similar to children with PKU.

Differentiating Gilbert Syndrome from Crigler Najjar Syndrome Type 2 by Phenobarbitone Test

Gilbert syndrome characterized by jaundice with intermittent elevations of indirect bilirubin, in the absence of haemolysis or underlying liver disease, has both autosomal dominant and recessive inheritance. Crigler-Najjar syndrome type II (CNS2) is a hereditary disorder of bilirubin metabolism characterized by unconjugated hyperbilirubinemia due to reduced and inducible activity of hepatic bilirubin glucuronosyltransferase (GT). We report 20 children between age 5 to 15 years with unconjugated hyperbilirubenemia who were given seven days of oral phenobarbitone (5mg/kg/day) and decrease in level of bilirubin was noted. There was only 30-40% reduction of bilirubin in Crigler Najjar Syndrome Type 2 compared to Gilberts Syndrome in which bilirubin level normalised. This case series highlights the importance of simple test to differentiate these two conditions. This test is also very helpful in a place where enzyme level and mutational study cannot be done.J Nepal Paediatr Soc 2015;35(1):82-84

Characterization of Human Dermal Fibroblasts in Fabry Disease.

Fabry disease (FD) is a hereditary X-linked metabolic lysosomal storage disorder due to insufficient amounts or a complete lack of the lysosomal enzyme α-galactosidase A (α-GalA). The loss of α-GalA activity leads to an abnormal accumulation of globotriaosylcerami (Gb3) in lysosomes and other cellular components of different tissues and cell types, affecting the cell function. However, whether these biochemical alterations also modify functional processes associated to the cell mitotic ability is still unknown. The goal of the present study was to characterize lineages of human dermal fibroblasts (HDFs) of FD patients and healthy controls focusing on Gb3 accumulation, expression of chloride channels that regulate proliferation, and proliferative activity. The biochemical and functional analyses indicate the existence of quantitative differences in some but not all the parameters of cytoskeletal organization, proliferation, and differentiation processes.

MMACHC gene mutation in familial hypogonadism with neurological symptoms

Recent studies have convincingly documented that hypogonadism is a component of various hereditary disorders and is often recognized as an important clinical feature in combination with various neurological symptoms, yet, the causative genes in a few related families are still unknown. High-throughput sequencing has become an efficient method to identify causative genes in related complex hereditary disorders. In this study, we performed exome sequencing in a family presenting hypergonadotropic hypogonadism with neurological presentations of mental retardation, epilepsy, ataxia, and leukodystrophy. After bioinformatic analysis and Sanger sequencing validation, we identified compound heterozygous mutations: c.482G>A (p.R161Q) and c.609G>A (p.W203X) in MMACHC gene in this pedigree. MMACHC was previously confirmed to be responsible for methylmalonic aciduria (MMA) combined with homocystinuria, cblC type (cblC disease), a hereditary vitamin B12 metabolic disorder. Biochemical and gas chromatography-mass spectrometry (GC-MS) examinations in this pedigree further supported the cblC disease diagnosis. These results indicated that hypergonadotropic hypogonadism may be a novel clinical manifestation of cblC disease, but more reports on additional patients are needed to support this hypothesis.

Defective roles of ATP7B missense mutations in cellular copper tolerance and copper excretion.

Wilson's disease (WD) is a hereditary disorder of copper metabolism resulting from mutations within ATP7B. Clinical investigations showed that ATP7B missense mutations cause a wide variety of symptoms in WD patients, which implies that those mutations might affect ATP7B function in a number of ways and each would have deleterious consequences on normal copper distribution and lead to WD. Nonetheless, it is still unknown about the influences of those mutations on ATP7B function of increasing copper excretion and enhancing cellular copper tolerance. Here we established the stable expression cell lines of wild-type (WT) ATP7B and its four missense mutants (R778L, R919G, T935M and P992L), tested cellular copper tolerance and copper excretion using those cell lines, and also observed cellular distribution of WT ATP7B proteins and those mutants in transiently transfected cells. We found that extrinsic expressing WT ATP7B reduced CuCl2-induced copper accumulation and enhanced cellular copper tolerance by accelerating copper excretion, which was selectively compromised by R778L and P992L mutations. Further investigation showed that R778L mutation disrupted the subcellular localization and trafficking of ATP7B proteins, whereas P992L mutation only affected the trafficking of ATP7B. This indicates that ATP7B missense mutants have distinct effects on cellular copper tolerance.

Peroxisomal D-bifunctional protein deficiency: First case reports from Slovakia

D-bifunctional protein deficiency (#OMIM 261515) is a rare autosomal recessive hereditary metabolic disorder causing severe clinical and biochemical abnormalities that are usually fatal in the course of the first years of life. This disease is classified as single enzyme peroxisomal disorder affecting the β-oxidation pathway in this compartment. In this paper we present a full overview of the clinical presentation, magnetic resonance imaging, biochemical and molecular data of two Slovak D-bifunctional protein deficient patients. In the clinical presentation of both patients severe generalized hypotonia, depression of neonatal reflexes, craniofacial dysmorphism and seizures dominated starting from the second day of life. In both patients, who died up to two years of life, we found elevated plasma levels of very long chain fatty acids and we identified the presence of causative mutations in the HSD17B4 gene. In the first case, we found the homozygous mutation c.46G>A, which is responsible for a defect in the dehydrogenase domain. In the second patient, the heterozygous mutations c.1369A>G and c.1516C>T were present and functionally they are related to the hydratase domain of the protein. This combination of mutations in the second patient is very rare and has not been reported until now. The presence of mutations was examined in all family members, and the resulting data were successfully utilized for prenatal diagnosis.

P94 – 2991: GLUT1-DS presenting as movement disorder in a male adolescent: Possible effect of late treatment with MAD

Glucose transporter-1 deficiency syndrome (GLUT1-DS, OMIM 606777) is a treatable hereditary disorder of brain energy metabolism caused by heterozygous mutation in SLC2A1 gene on chromosome 1p34. Resulting deficient GLUT1 protein is responsible for impaired GLUT-1 mediated glucose transport into the brain clinically leading to a wide range of neurological symptoms. We report on a 15 years old male with genetically confirmed glucose transporter type 1 deficiency syndrome (GLUT1-DS; DYT9/DYT18). Developmental delay was already present before two years of age. Sudden episodes of exercise induced weakness without loss of consciousness were assumed to be myoclonic astatic epilepsy or atypical absences and therefore treated with valproinic acid and later with ethosuximide, both ineffectively. Hypoglycorrhachia and decreased CSF to blood glucose ratio found at the age of 14 years finally led to subsequent direct sequencing of SLC2A1 gene. Standard treatment in GLUT1-DS is ketogenic diet. Modified Atkins Diet (MAD) is an alternative ketogenic diet with the advantages preserving acceptable nutrition and obtaining compliance in adolescent patients. MAD has been described to improve movement disorder, seizures, alertness, cognitive abilities, and electroencephalography findings in GLUT1-DS in children. In our adolescent patient MAD was initiated in January 2015 to ameliorate symptoms such as movement disorder, paroxysmal exercise-induced dyskinesia, hypokinesia, tremor, rigor, spasticity and intellectual disability. In spite of abnormal EEG findings, symptomatic epilepsy has never been the leading symptom in this patient. We assume that even late treatment initiation of MAD in this adolescent patient could ameliorate movement disorder, cognitive function and EEG findings. Presenting this case report we will discuss actual literature concerning ketogenic diet in GLUT1-DS.

708. Treatment of Inherited Eye Defects By Systemic Hematopoietic Stem Cell Transplantation

Corneal disease is a significant cause of blindness worldwide, largely due to the low availability of donor corneas and the risks associated with transplantation, such as immune rejection, cataract, and glaucoma. Stem cell transplantation represents an attractive alternative for corneal repair because of their capacity to differentiate into corneal cells. Limbal epithelial stem (LEST) cells, which reside within the corneo-limbus, have been used for more than a decade to repair corneal epithelium, and mesenchymal stem cells (MSCs) have been shown to migrate and promote corneal healing and even differentiate into epithelial/keratocyte-like cells. However, risks of immune rejection with LEST cells, and heterogeneity in repair mechanisms with MSCs have led to discrepancies in treatment outcomes. Alternatively, very little is known about the potential for hematopoietic stem cells (HSCs) in eye repair. HSCs have attractive features; they are multipotent cells capable of self-renewal and easily mobilized from bone marrow into the circulatory system. Here we report that engraftment of HSPCs can treat corneal defects in a mouse model of a degenerative hereditary metabolic disorder, cystinosis. Cystinosis is caused by a deficiency in the lysosomal cystine transporter, cystinosin, resulting in cystine crystal accumulation in tissues. In eyes, a primary affected organ, crystals accumulate within the cornea causing photophobia and eventually blindness, if untreated. Using the mouse model of cystinosis, Ctns-/- mice, which develops similar eye anomalies than patients, we showed that systemic HSC transplantation led to the long-term preservation of the eyes. Effective therapy, however, was dependent on achieving relatively high level of donor-derived blood cell engraftment (more than 50%). Abundant GFP-expressing bone marrow-derived cells were detected within the cornea but also in the sclera, ciliary body, retina, choroid, and lens. In addition, HSCs engraftment led to substantial decrease in corneal cystine crystals, restoration of normal corneal thickness and intraocular pressure, and improved vision after one-year post-transplantation. Finally, we showed that HSCs mainly differentiated into MHC class II+ macrophages, which transferred cystinosin-bearing lysosomes via tunneling nanotubes to disease cells. This work is the first demonstration that HSCs can rescue corneal defects, which brings forth a new potential therapeutic strategy for treating ocular pathologies.

Kayser-Fleischer Ring evaluation in Wilson's Disease in a tertiary eye care centre of Nepal

Wilson’s disease is a hereditary disorder of copper metabolism which is characterized by neuropsychiatric and hepatic manifestations as well as appearance of Kayser-Fleischer ring. This is a retrospective review of the records of the patients of Wilson’s disease who attended Neuro-ophthalmic clinic for the identification of Kayser-Fleischer (K-F) ring from January2010 to June 2012. Detailed eye examination included visual acuity assessment, slit lamp biomicroscopy and intra-ocular pressure measurement. Data regarding clinical features, laboratory investigations and the status of K-F ring was recorded. Seven cases of Wilson’s disease with age range of 9-15 years were included in the study. Among them four (57.1%) had neuropsychiatric symptoms, two (28.5%) had hepatic disease and one (14.3%) was asymptomatic, diagnosed by positive family history and laboratory tests. Among four subjects having K-F ring, three (75%) subjects had neuropsychiatric symptoms and one subject had hepato-billiary disease. Besides K-F rings, other ophthalmic findings were sunflower cataract (14.3%) and vernal keratoconjuctivitis (14.3%). The identification of K-F ring is a simple and cost effective screening test for the diagnosis of Wilson’s disease. K-F is present in majority of the patients with neurological manifestations. DOI: http://dx.doi.org/10.3126/jcmc.v4i3.11934Journal of Chitwan Medical College 2014; 4(3): 17-20

Cardiac involvement of primary hyperoxaluria accompanied with non compaction cardiomyopathy and patent ductus arteriosus

Primary hyperoxaluria is a rare hereditary metabolic disorder resulting in accumulation of calcium oxalate in visceral organs, including the heart. We report a 19-year-old male with non- compaction cardiomyopathy combined with patent ductus arteriosus awaiting combined liver-kidney transplantation for primary hyperoxaluria. After surgical closure of the patent ductus arteriosus, the patient underwent a successful renal and subsequent liver transplantation. The presence of hypertrophic cardiomyopathy in hyperoxaluria patients has been reported before, but this is the first report of non-compaction myocardium with patent ductus arteriosus in a patient with primary hyperoxaluria. At the third month after combined liver and renal transplantation, improvement in cardiac functions were observed. Primary hyperoxaluria is a clinical entity to be taken into consideration in differential diagnosis of hypertrophied myocardium with high myocardial echocardiographic intensity. In cases of hyperoxaluria, additional congenital abnormalities may complicate the clinical picture.

同型半胱氨酸尿症临床与实验室诊断

同型半胱氨酸尿症，常伴血浆同型半胱氨酸和蛋氨酸水平增高，是一种涉及胱硫醚β-合成酶活性改变的蛋氨酸代谢遗传性疾病。常导致心血管系统、中枢神经系统、肌肉和结缔组织等多系统功能障碍。此种代谢疾病的特点为血清同型半胱氨酸堆积和同型半胱氨酸在尿液中排出的增加。同型半胱氨酸的实验室分析复杂，综合分析对于确诊同型半胱氨酸尿症，及对疾病治疗疗效的监测有所裨益。 Homocystinuria with increased plasma homocysteine and methionine level is an inherited disorder of the metabolism of methionine, often involves the change of cystathionine beta synthase activity. This disorder leads to a multi-systemic disease of the cardiovascular system, CNS, muscles, and connective tissue. Homocystinuria represents a group of hereditary metabolic disorders characterized by the accumulation of homocysteine in serum and elevated excretion of homocysteine in urine. Despite the lab analysis of homocysteine is complicated, it gives a clue to make a definite diagnosis of homocystinuria and esepcially helps to monitor therapy efficacy.

A prospective population pharmacokinetic analysis of sapropterin dihydrochloride in infants and young children with phenylketonuria.

Background and ObjectivesUntreated phenylketonuria (PKU), a hereditary metabolic disorder caused by a genetic mutation in phenylalanine hydroxylase (PAH), is characterized by elevated blood phenylalanine (Phe) and severe neurologic disease. Sapropterin dihydrochloride, a synthetic preparation of naturally occurring PAH cofactor tetrahydrobiopterin (BH4), activates residual PAH in a subset of patients, resulting in decreased blood Phe and increased Phe tolerance. The objective of this study was to determine the appropriate dose of sapropterin in pediatric patients (0–6 years). The study design used D-optimization and was prospectively powered to achieve precise estimates of clearance and volume of distribution.MethodsOral sapropterin (5 or 20 mg/kg) was administered once daily. Sapropterin plasma concentrations were measured by a validated method. Population pharmacokinetic analysis was performed with NONMEM® version 7.2 on pooled data from 156 pediatric and adult PKU patients in two phase III clinical studies.ResultsThe best pharmacokinetic model was a one-compartment model with an absorption lag, first-order input, and linear elimination, with a factor describing endogenous BH4 levels. Body weight was the only covariate significantly affecting sapropterin pharmacokinetics. Based on recommended dosing, exposure across age groups was comparable. The absorption rate and terminal half-life suggest flip-flop pharmacokinetic behavior where absorption is rate limiting.ConclusionThe effect of weight on sapropterin pharmacokinetics was significant and exposure was comparable across age groups; thus, weight-based dosing is appropriate. The doses selected for pediatric patients provided similar exposure as in adults. Given the slow absorption and elimination half-life, once-daily dosing is justified.Electronic supplementary materialThe online version of this article (doi:10.1007/s40262-014-0196-4) contains supplementary material, which is available to authorized users.

Psychiatric manifestations of treatable hereditary metabolic disorders in adults.

Detecting psychiatric disorders of secondary origin is a crucial concern for the psychiatrist. But how can this reliably be done among a large number of conditions, most of which have a very low prevalence? Metabolic screening undertaken in a population of subjects with psychosis demonstrated the presence of treatable metabolic disorders in a significant number of cases. The nature of the symptoms that should alert the clinician is also a fundamental issue and is not limited to psychosis. Hereditary metabolic disorders (HMD) are a rare but important cause of psychiatric disorders in adolescents and adults, the signs of which may remain isolated for years before other more specific organic signs appear. HMDs that present purely with psychiatric symptoms are very difficult to diagnose due to low awareness of these rare diseases among psychiatrists. However, it is important to identify HMDs in order to refer patients to specialist centres for appropriate management, disease-specific treatment and possible prevention of irreversible physical and neurological complications. Genetic counselling can also be provided. This review focuses on three HMD categories: acute, treatable HMDs (urea cycle abnormalities, remethylation disorders, acute intermittent porphyria); chronic, treatable HMDs (Wilson’s disease, Niemann-Pick disease type C, homocystinuria due to cystathionine beta-synthase deficiency, cerebrotendinous xanthomatosis); and chronic HMDs that are difficult to treat (lysosomal storage diseases, X-linked adrenoleukodystrophy, creatine deficiency syndrome). We also propose an algorithm for the diagnosis of HMDs in patients with psychiatric symptoms.