Early diagnosis and treatment by newborn screening (NBS) or family history is associated with improved visual outcomes for long-chain 3-hydroxyacylCoA dehydrogenase deficiency (LCHADD) chorioretinopathy.

Long chain 3-hydroxyacyl-CoA dehydrogenase (LCHADD) is the only fatty acid oxidation disorder to develop a progressive chorioretinopathy resulting in vision loss; newborn screening (NBS) for this disorder began in the United States around 2004. We compared visual outcomes among 40 participants with LCHADD or trifunctional protein deficiency diagnosed symptomatically to those who were diagnosed via NBS or a family history. Participants completed ophthalmologic testing including measures of visual acuity, electroretinograms (ERG), fundal imaging, contrast sensitivity, and visual fields. Records were reviewed to document medical and treatment history. Twelve participants presented symptomatically with hypoglycemia, failure to thrive, liver dysfunction, cardiac arrest, or rhabdomyolysis. Twenty eight were diagnosed by NBS or due to a family history of LCHADD. Participants diagnosed symptomatically were older but had similar percent males and genotypes as those diagnosed by NBS. Treatment consisted of fasting avoidance, dietary long-chain fat restriction, MCT, C7, and/or carnitine supplementation. Visual acuity, rod- and cone-driven amplitudes on ERG, contrast sensitivity scores, and visual fields were all significantly worse among participants diagnosed symptomatically compared to NBS. In mixed-effects models, both age and presentation (symptomatic vs. NBS) were significant independent factors associated with visual outcomes. This suggests that visual outcomes were improved by NBS, but there was still lower visual function with advancing age in both groups. Early diagnosis and treatment by NBS is associated with improved visual outcomes and retinal function compared to participants who presented symptomatically. Despite the impact of early intervention, chorioretinopathy was greater with advancing age, highlighting the need for novel treatments.

Improved attention linked to sustained phenylalanine reduction in adults with early-treated phenylketonuria.

Pegvaliase is approved to reduce phenylalanine (Phe) levels for people with phenylketonuria (PKU). PRISM-1 (NCT01819727) and PRISM-2 (NCT01889862) data were analyzed to evaluate the relationship between Phe and inattention in adult participants with PKU. In the modified-intent-to-treat population (N = 156), baseline mean (SE) plasma Phe was 1263 (29) µmol/L and the Attention Deficit Hyperactivity Disorder Rating Scale-IV Inattentive (IA) symptoms score was 9.8 (0.5). Mean (SE) IA scores fell 9.0 (1.1) in Quartile 1 (Phe reduction between 1166 and 2229 µmol/L) versus 4.3 (0.7) in Quartile 4 (Phe reduction of 139 µmol/L to increase of 934 µmol/L), p = 0.004. Least squares mean (SE) change from baseline IA score was -7.9 (0.7) for participants with final Phe ≤ 360 µmol/L and -4.5 (0.7) for final Phe > 360 µmol/L, p < 0.001. In the inattention subgroup, IA scores fell 13.3 (1.5) in Quartile 1 (Phe reduction between 1288 and 2229 µmol/L) versus 6.2 (1.3) in Quartile 4 (Phe reduction of 247 to increase of 934 µmol/L), p = 0.009. Inattention symptoms improved among those whose Phe levels decreased, particularly those with high baseline IA scores. IA improvements were larger among participants with the greatest plasma Phe reductions, supporting this value as a therapeutic goal.

Successful orthotopic heart transplantation in CPTII deficiency.

Carnitine palmitoyl transferase II (CPT II) catalyzes the release of activated long-chain fatty acids from acylcarnitines into mitochondria for subsequent fatty acid oxidation. Depending on residual enzyme activity, deficiency of this enzyme leads to a spectrum of symptoms from early onset hypoglycemia, hyperammonemia, cardiomyopathy and death to onset of recurrent rhabdomyolysis in adolescents and young adults. We present a case of successful orthotopic heart transplantation in a patient with severe infantile onset cardiomyopathy due to CPT II deficiency identified through newborn screening. Excellent cardiac function is preserved 12 years post-transplantation; however, the patient has developed intermittent episodes of hyperammonemia and rhabdomyolysis later in childhood and early adolescence readily resolved with intravenous glucose. Successful heart transplant in this patient demonstrates the feasibility of this management option in patients with even severe forms of long chain fatty acid oxidation disorders.

Four children with postnatally diagnosed mosaic trisomy 12: Clinical features, literature review, and current diagnostic capabilities of genetic testing.

Children or adults with mosaic trisomy 12 diagnosed postnatally are extremely rare. Only a small number of patients with this mosaicism have been reported in the literature. The clinical manifestation of mosaic trisomy 12 is variable, ranging from mild developmental delay to severe congenital anomaly and neonatal death. The trisomy 12 cells are not usually able to be detected by phytohemagglutinin stimulated peripheral blood chromosome analysis. The variability of phenotypes and the limited number of patients with this anomaly pose a challenge to predict the clinical outcomes. In this study, we present the phenotypes and laboratory findings in four patients and review the 11 previously reported patients with mosaic trisomy 12 diagnosed postnatally, as well as 11 patients with mosaic trisomy 12 diagnosed prenatally. The findings of this study provide useful information for laboratory diagnosis and clinical management of these patients.

PLPHP deficiency: clinical, genetic, biochemical, and mechanistic insights.

Biallelic pathogenic variants in PLPBP (formerly called PROSC) have recently been shown to cause a novel form of vitamin B6-dependent epilepsy, the pathophysiological basis of which is poorly understood. When left untreated, the disease can progress to status epilepticus and death in infancy. Here we present 12 previously undescribed patients and six novel pathogenic variants in PLPBP. Suspected clinical diagnoses prior to identification of PLPBP variants included mitochondrial encephalopathy (two patients), folinic acid-responsive epilepsy (one patient) and a movement disorder compatible with AADC deficiency (one patient). The encoded protein, PLPHP is believed to be crucial for B6 homeostasis. We modelled the pathogenicity of the variants and developed a clinical severity scoring system. The most severe phenotypes were associated with variants leading to loss of function of PLPBP or significantly affecting protein stability/PLP-binding. To explore the pathophysiology of this disease further, we developed the first zebrafish model of PLPHP deficiency using CRISPR/Cas9. Our model recapitulates the disease, with plpbp-/- larvae showing behavioural, biochemical, and electrophysiological signs of seizure activity by 10 days post-fertilization and early death by 16 days post-fertilization. Treatment with pyridoxine significantly improved the epileptic phenotype and extended lifespan in plpbp-/- animals. Larvae had disruptions in amino acid metabolism as well as GABA and catecholamine biosynthesis, indicating impairment of PLP-dependent enzymatic activities. Using mass spectrometry, we observed significant B6 vitamer level changes in plpbp-/- zebrafish, patient fibroblasts and PLPHP-deficient HEK293 cells. Additional studies in human cells and yeast provide the first empirical evidence that PLPHP is localized in mitochondria and may play a role in mitochondrial metabolism. These models provide new insights into disease mechanisms and can serve as a platform for drug discovery.

Complex patterns of inheritance, including synergistic heterozygosity, in inborn errors of metabolism: Implications for precision medicine driven diagnosis and treatment.

Inborn errors of metabolism have traditionally been viewed as the quintessential single gene disorders; defects in one gene leads to loss of activity of one enzyme causing a metabolic imbalance and clinical disease. However, reality has never been quite that simple, and the classic "one gene-one enzyme" paradigm has been upended in many ways. Multiple gene defects can lead to the same biochemical phenotype, often with different clinical symptoms. Additionally, different mutations in the same gene can cause variable phenotypes, often most dramatic when a disease can be identified by pre-symptomatic screening. Moreover, response to therapy is not homogeneous across diseases and specific mutations. Perhaps the biggest deviation from traditional monogenic inheritance is in the setting of synergistic heterozygosity, a multigenic inheritance pattern in which mutations in multiple genes in a metabolic pathway lead to sufficient disruption of flux through the pathway, mimicking a monogenic disorder caused by homozygous defects in one gene in that pathway. In addition, widespread adoption of whole exome and whole genome sequencing in medical genetics has led to the realization that individual patients with apparently hybrid phenotypes can have mutations in more than one gene, leading to a mixed genetic disorder. Each of these situations point to a need for as much precision as possible in diagnosing metabolic disease, and it is likely to become increasingly critical to drive therapy. This article examines examples in traditional monogenic disorders that illustrates these points and define inborn errors of metabolism as complex genetic traits on the leading edge of precision medicine.

Clinical outcomes of children with abnormal newborn screening results for Krabbe disease in New York State.

BACKGROUND: Early infantile Krabbe disease is rapidly fatal, but hematopoietic stem cell transplantation (HSCT) may improve outcomes if performed soon after birth. New York State began screening all newborns for Krabbe disease in 2006. METHODS: Infants with abnormal newborn screen results for Krabbe disease were referred to specialty-care centers. Newborns found to be at high risk for Krabbe disease underwent a neurodiagnostic battery to determine the need for emergent HSCT. RESULTS: Almost 2 million infants were screened. Five infants were diagnosed with early infantile Krabbe disease. Three died, two from HSCT-related complications and one from untreated disease. Two children who received HSCT have moderate to severe developmental delays. Forty-six currently asymptomatic children are considered to be at moderate or high risk for development of later-onset Krabbe disease. CONCLUSIONS: These results show significant HSCT-associated morbidity and mortality in early infantile Krabbe disease and raise questions about its efficacy when performed in newborns diagnosed through newborn screening. The unanticipated identification of "at risk" children introduces unique ethical and medicolegal issues. New York's experience raises questions about the risks, benefits, and practicality of screening newborns for Krabbe disease. It is imperative that objective assessments be made on an ongoing basis as additional states begin screening for this disorder.Genet Med 18 12, 1235-1243.

Newborn screening for Krabbe disease in New York State: the first eight years' experience.

PURPOSE: Krabbe disease (KD) results from galactocerebrosidase (GALC) deficiency. Infantile KD symptoms include irritability, progressive stiffness, developmental delay, and death. The only potential treatment is hematopoietic stem cell transplantation. New York State (NYS) implemented newborn screening for KD in 2006. METHODS: Dried blood spots from newborns were assayed for GALC enzyme activity using mass spectrometry, followed by molecular analysis for those with low activity (≤12% of the daily mean). Infants with low enzyme activity and one or more mutations were referred for follow-up diagnostic testing and neurological examination. RESULTS: Of >1.9 million screened, 620 infants were subjected to molecular analysis and 348 were referred for diagnostic testing. Five had enzyme activities and mutations consistent with infantile KD and manifested clinical/neurodiagnostic abnormalities. Four underwent transplantation, two are surviving with moderate to severe handicaps, and two died from transplant-related complications. The significance of many sequence variants identified is unknown. Forty-six asymptomatic infants were found to be at moderate to high risk for disease. CONCLUSIONS: The positive predictive value of KD screening in NYS is 1.4% (5/346) considering confirmed infantile cases. The incidence of infantile KD in NYS is approximately 1 in 394,000, but it may be higher for later-onset forms.

Outcomes of cases with 3-methylcrotonyl-CoA carboxylase (3-MCC) deficiency - Report from the Inborn Errors of Metabolism Information System.

INTRODUCTION: 3-Methyl crotonyl CoA carboxylase (3MCC) deficiency is an inborn error of leucine metabolism whose detection was increased with the advent of expanded newborn screening. While most NBS-identified infants appear clinically normal, prior studies suggest a possible increased risk for developmental or metabolic abnormalities. As yet, no predictive markers are known that can identify children at risk for biochemical or developmental abnormalities. METHOD: All available 3-MCC cases diagnosed by newborn screening in the Inborn Errors of Metabolism Information System (IBEM-IS) were reviewed for markers that might be predictive of outcome. RESULTS: A limited number of cases were identified with traditional biochemical symptoms including acidosis, hyperammonemia or lactic acidosis, and 15% of those with available developmental information had recorded developmental disabilities not clearly attributable to other causes. There was no correlation between newborn screening (NBS) C5OH level and presence of metabolic, newborn, later-life or developmental abnormalities in these cases. DISCUSSION: This sample, obtained from the IBEM-IS database, attempts to avoid some of the ascertainment bias present in retrospective studies. An increase in developmental abnormalities and in traditionally described metabolic symptoms remains apparent, although no specific biochemical markers appear predictive of outcome. The role that prevention of fasting plays in outcome cannot be ascertained. These data suggest that C5OH level found on newborn screening by itself is not sufficient for diagnostic or predictive purposes.

221 newborn-screened neonates with medium-chain acyl-coenzyme A dehydrogenase deficiency: Findings from the Inborn Errors of Metabolism Collaborative.

INTRODUCTION: There is limited understanding of relationships between genotype, phenotype and other conditions contributing to health in neonates with medium-chain acyl-coenzyme A dehydrogenase deficiency (MCADD) identified through newborn screening. METHODS: Retrospective analysis of comprehensive data from a cohort of 221 newborn-screened subjects identified as affected with MCADD in the Inborn Errors of Metabolism - Information System (IBEM-IS), a long term follow-up database of the Inborn Errors of Metabolism Collaborative, was performed. RESULTS: The average age at notification of first newborn screen results to primary care or metabolic providers was 7.45days. The average octanoylcarnitine (C8) value on first newborn screen was 11.2µmol/L (median 8.6, range 0.36-43.91). A higher C8 level correlated with an earlier first subspecialty visit. Subjects with low birth weight had significantly lower C8 values. Significantly higher C8 values were found in symptomatic newborns, in newborns with abnormal lab testing in addition to newborn screening and/or diagnostic tests, and in subjects homozygous for the c.985A>G ACADM gene mutation or compound heterozygous for the c.985A>G mutation and deletions or other known highly deleterious mutations. Subjects with neonatal symptoms, or neonatal abnormal labs, or neonatal triggers were more likely to have at least one copy of the severe c.985A>G ACADM gene mutation. C8 and genotype category were significant predictors of the likelihood of having neonatal symptoms. Neonates with select triggers were more likely to have symptoms and laboratory abnormalities. CONCLUSIONS: This collaborative study is the first in the United States to describe health associations of a large cohort of newborn-screened neonates identified as affected with MCADD. The IBEM-IS has utility as a platform to better understand the characteristics of individuals with newborn-screened conditions and their follow-up interactions with the health system.

Outcomes and genotype-phenotype correlations in 52 individuals with VLCAD deficiency diagnosed by NBS and enrolled in the IBEM-IS database.

Very long chain acyl-CoA dehydrogenase (VLCAD) deficiency can present at various ages from the neonatal period to adulthood, and poses the greatest risk of complications during intercurrent illness or after prolonged fasting. Early diagnosis, treatment, and surveillance can reduce mortality; hence, the disorder is included in the newborn Recommended Uniform Screening Panel (RUSP) in the United States. The Inborn Errors of Metabolism Information System (IBEM-IS) was established in 2007 to collect longitudinal information on individuals with inborn errors of metabolism included in newborn screening (NBS) programs, including VLCAD deficiency. We retrospectively analyzed early outcomes for individuals who were diagnosed with VLCAD deficiency by NBS and describe initial presentations, diagnosis, clinical outcomes and treatment in a cohort of 52 individuals ages 1-18years. Maternal prenatal symptoms were not reported, and most newborns remained asymptomatic. Cardiomyopathy was uncommon in the cohort, diagnosed in 2/52 cases. Elevations in creatine kinase were a common finding, and usually first occurred during the toddler period (1-3years of age). Diagnostic evaluations required several testing modalities, most commonly plasma acylcarnitine profiles and molecular testing. Functional testing, including fibroblast acylcarnitine profiling and white blood cell or fibroblast enzyme assay, is a useful diagnostic adjunct if uncharacterized mutations are identified.

Long-term safety and efficacy of sapropterin: the PKUDOS registry experience.

The Phenylketonuria (PKU) Demographics, Outcomes and Safety (PKUDOS) registry is designed to provide longitudinal safety and efficacy data on subjects with PKU who are (or have been) treated with sapropterin dihydrochloride. The PKUDOS population consists of 1189 subjects with PKU: N = 504 who were continuously exposed to sapropterin from date of registry enrollment, N = 211 who had intermittent exposure to the drug, and N = 474 with some other duration of exposure. Subjects continuously exposed to sapropterin showed an average 34% decrease in blood phenylalanine (Phe)--from 591 ± 382 µmol/L at baseline to 392 ± 239 µmol/L (p = 0.0009) after 5 years. This drop in blood Phe was associated with an increase in dietary Phe tolerance [from 1000 ± 959 mg/day (pre-sapropterin baseline) to 1539 ± 840 mg/day after 6 years]. Drug-related adverse events (AEs) were reported in 6% of subjects, were mostly considered non-serious, and were identified in the gastrointestinal, respiratory, and nervous systems. Serious drug-related AEs were reported in ≤ 1% of subjects. Similar safety and efficacy data were observed for children<4 years. Long-term data from the PKUDOS registry suggest that sapropterin has a tolerable safety profile and that continuous use is associated with a significant and persistent decrease in blood Phe and improvements in dietary Phe tolerance.

Interstitial 10p11.23-p12.1 microdeletions associated with developmental delay, craniofacial abnormalities, and cryptorchidism.

Cryptorchidism is the most common genital problem encountered in males and is associated with many chromosomal disorders; however, the genetic factors are mostly unknown. To delineate critical genes affecting testicular migration, we performed genotype-phenotype correlation in patients with deletions involving the proximal short arm of chromosome 10 (10p11-p12), a rare abnormality characterized by developmental delay, craniofacial abnormalities, and in some cases, cryptorchidism. Here we report on a male patient with developmental delay, mild craniofacial dysmorphism, bilateral cryptorchidism, and an 850-kb deletion, within the 10p11.2 region, involving three genes-MKX, ARMC4, and MPP7-as determined by array comparative genomic hybridization analysis. Comparison with four previously reported male patients with overlapping deletions revealed a 140-kb common region, containing the MKX gene, in association with cryptorchidism. The MKX gene is a member of the three amino acid loop extension (TALE) superclass of homeobox genes that is expressed in developing male gonads (male gonadal ridge and testis cords) in temporal relationship to SOX9, a critical regulator of sexual differentiation. Our results suggest that haploinsufficiency of the MKX gene may affect the developmental process during testis migration or serve as a genetic susceptibility locus for cryptorchidism. We propose that deletions of the proximal 10p represent a contiguous gene syndrome; therefore, patients may present with a complex phenotype, depending on the extent of the deletion.

A proposal for an updated staging system for LCHADD retinopathy.

OBJECTIVE: To develop an updated staging system for long-chain 3-hydroxyacyl coenzyme A dehydrogenase deficiency (LCHADD) chorioretinopathy based on contemporary multimodal imaging and electrophysiology. METHODS: We evaluated forty cases of patients with genetically confirmed LCHADD or trifunctional protein deficiency (TFPD) enrolled in a prospective natural history study. Wide-field fundus photographs, fundus autofluorescence (FAF), optical coherence tomography (OCT), and full-field electroretinogram (ffERG) were reviewed and graded for severity. RESULTS: Two independent experts first graded fundus photos and electrophysiology to classify the stage of chorioretinopathy based upon an existing published system. With newer imaging modalities and improved electrophysiology, many patients did not fit cleanly into a single traditional staging group. Therefore, we developed a novel staging system that better delineated the progression of LCHADD retinopathy. We maintained the four previous delineated stages but created substages A and B in stages 2 to 3 to achieve better differentiation. DISCUSSION: Previous staging systems of LCHADD chorioretinopathy relied on only on the assessment of standard 30 to 45-degree fundus photographs, visual acuity, fluorescein angiography (FA), and ffERG. Advances in recordings of ffERG and multimodal imaging with wider fields of view, allow better assessment of retinal changes. Following these advanced assessments, seven patients did not fit neatly into the original classification system and were therefore recategorized under the new proposed system. CONCLUSION: The new proposed staging system improves the classification of LCHADD chorioretinopathy, with the potential to lead to a deeper understanding of the disease's progression and serve as a more reliable reference point for future therapeutic research.

Development of clinical guidelines for inborn errors of metabolism: commentary.

This is one of an occasional series of articles commenting on trends, advances, and challenges in understanding and treating inborn errors of metabolism (IEMs). Previously, we have called attention to the critical lack of a clinical trial infrastructure to routinely evaluate new therapies for IEMs and the adverse effect of this deficit (Vockley and Vockley, 2010 [1]). In this article, we highlight the role of therapeutic guidelines in implementing best practice for IEMs and the processes used to generate them. Current conventions for evidence-based guidelines are best applied to studies involving significantly more subjects than is feasible for IEMs, and can lead to relative weak-appearing recommendations when applied to rare disorders. We propose a guideline development process that maintains the use of conventional methodologies but adapts to unique features and inherent difficulties dealing with rare conditions such as IEMs. Such guidelines will consist of a hybrid between evidence and consensus based processes. Implementation of these recommendations and subsequent therapeutic guidelines for IEMs provides an opportunity to define current knowledge as well as starting points for future clinical trials.

Outcome of infants diagnosed with 3-methyl-crotonyl-CoA-carboxylase deficiency by newborn screening.

INTRODUCTION: 3-Methyl CoA carboxylase (3-MCC) deficiency is an inborn error of metabolism in the catabolism of the amino acid leucine. Original reports suggested this disorder was associated with significant neurological and biochemical effects. However newborn screening has identified a higher than expected incidence of this disorder with apparent normal outcome in most cases. METHOD: A retrospective analysis of thirty-five cases of 3-MCC deficiency identified by newborn screening and diagnosed by enzyme or molecular analysis. RESULTS: There was a strong inverse correlation between initial C5OH level and residual enzyme activity. A few reports of hypoglycemia, ketosis, poor feeding/failure to thrive or fasting intolerance were reported, but there was no clear relationship between symptoms and residual enzyme activity. Developmental outcome included several children with mental retardation (including one with Down syndrome and one with schizencephaly) and two with Autism Spectrum disorders but there was no apparent relationship to residual enzyme activity. Free carnitine deficiency was relatively common. DISCUSSION: Although residual enzyme activity was clearly related to metabolite elevation, there was no apparent relationship with other measures of outcome. The number of reports of neurologic abnormalities or metabolic symptoms (poor feeding, hypoglycemia, fasting intolerance, etc.) is concerning, but the significance is unclear in this retrospective sample.

Internet use by parents of infants with positive newborn screens.

BACKGROUND: Internet searches on health topics are common, but not enough is known about online use during serious health concerns. The aim of this study was to investigate parents' internet use and responses to online information following the referral of their newborn screen-positive infants. METHODS: Forty-four parents were interviewed about their internet use during their infants' evaluations for a potential metabolic disorder. Responses to open-ended questions were audio taped and transcribed. Content analysis was used in analyzing the interview data. RESULTS: An overwhelming majority of parents (89%) accessed the internet and most went online before meeting with genetic providers at metabolic treatment centers. Primary and genetic providers did not routinely recommend websites to parents. Online descriptions of metabolic disorders increased parents' anxieties. Some parents allayed their distress by enlisting others to search and filter information for them and by seeking optimistic internet content about the disorders. Parents with fewer years of education were often baffled by complex disease information. Parents found limited information about treatments or what to expect during the clinical evaluations of their infants. CONCLUSIONS: The internet is an integral part of health care and an important source of information for newborn screening parents. Parents may benefit from recommendations of credible websites and discussions of internet information with health care providers.

Outcomes and genotype correlations in patients with mitochondrial trifunctional protein or isolated long chain 3-hydroxyacyl-CoA dehydrogenase deficiency enrolled in the IBEM-IS database.

Purpose: Mitochondrial trifunctional protein deficiency (TFPD) and isolated long chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) are two related defects of fatty acid ß -oxidation. While NBS has decreased mortality, morbidity remains significant. Additionally, the relationship of genotype to clinical outcome remains unclear. To better understand these issues, we collected natural history data for these conditions by reviewing seven years of retrospective data from 45 cases of TFPD or LCHADD in the Inborn Errors of Metabolism - Information System. Methods: Available data included age at database entry, last datapoint, and development of various complications. Data were analyzed by clinical assigned diagnosis (LCHADD or TFPD), subdivided by method of ascertainment (newborn screening-NBS, or other than by newborn screening-NNBS), then re-analyzed based on four genotype groups: homozygous c.1528GC (p.E510Q) (common LCHAD variant); heterozygous c.1528GC (p.E510Q), other HADHA variants; and HADHB variants. Results: Forty-five patients from birth to 34 years of age were analyzed by assigned diagnosis (30 LCHADD and 15 TFPD) and method of ascertainment. Thirty had further analysis by genotype (22 biallelic HADHA variants and 8 biallelic HADHB variants). With regards to maternal complications, retinopathy, cardiomyopathy and hypoglycemia, patients with biallelic HADHA variants (with or without the common LCHAD variant) manifest a traditional LCHADD phenotype, while those with HADHB gene variants more commonly reported neuromusculoskeletal type TFPD phenotype. While retinopathy, rhabdomyolysis and peripheral neuropathy tended to present later in childhood, many features including initial report of cardiomyopathy and hypoglycemia presented across a wide age spectrum. Conclusion: This study demonstrates the utility of genotypic confirmation of patients identified with LCHADD/TFPD as variants in the HADHA and HADHB genes lead to different symptom profiles. In our data, biallelic HAHDA variants conferred a LCHADD phenotype, regardless of the presence of the common LCHAD variant.

Thoroughly modern medicine.

Personalized medicine is receiving increasing attention in the medical literature and lay press as one way to optimize therapy and reduce complications of treatment for almost any disorder. However, understanding the systemic complexities necessary to implement the ambitious goals of personalized medicine is unlikely to arise from the study of common disorders. Rather, dissecting out the individual components to therapeutic response is far more feasible with defined disorders of known cause. Inborn errors of metabolism offer an attractive opportunity to better define the hyperbole surrounding development and institution of personalized medicine.