Disorder Of Bile Acid Synthesis Research Articles

Large-scale genomic investigation of pediatric cholestasis reveals a novel hepatorenal ciliopathy caused by PSKH1 mutations

PurposePediatric cholestasis is the phenotypic expression of clinically and genetically heterogeneous disorders of bile acid synthesis and flow. Although a growing number of monogenic causes of pediatric cholestasis have been identified, the majority of cases remain undiagnosed molecularly. MethodsIn a cohort of 299 pediatric participants (279 families) with intrahepatic cholestasis, we performed exome sequencing as a first-tier diagnostic test. ResultsA likely causal variant was identified in 135 families (48.56%). These comprise 135 families that harbor variants spanning 37 genes with established or tentative links to cholestasis. In addition, we propose a novel candidate gene (PSKH1) (HGNC:9529) in 4 families. PSKH1 was particularly compelling because of strong linkage in 3 consanguineous families who shared a novel hepatorenal ciliopathy phenotype. Two of the 4 families shared a founder homozygous variant, whereas the third and fourth had different homozygous variants in PSKH1. PSKH1 encodes a putative protein serine kinase of unknown function. Patient fibroblasts displayed abnormal cilia that are long and show abnormal transport. A homozygous Pskh1 mutant mouse faithfully recapitulated the human phenotype and displayed abnormally long cilia. The phenotype could be rationalized by the loss of catalytic activity observed for each recombinant PSKH1 variant using in vitro kinase assays. ConclusionOur results support the use of genomics in the workup of pediatric cholestasis and reveal PSKH1-related hepatorenal ciliopathy as a novel candidate monogenic form.

A104 ATYPICAL PRESENTATION OF HSD3B7 DEFICIENCY

Abstract Background Bile acid synthesis disorders are the result of deficient activity of one of 17 enzymes required for conversion of cholesterol into bile acids. One such bile acid synthesis disorder is 3β-hydroxy-Δ5-C27-steroid oxidoreductase (HSD3B7) deficiency, an autosomal recessive inherited disorder caused by a defect in 3β-hydroxy-Δ5-C27-steroid dehydrogenase (C27 3β-HSD) enzyme. Ultimately, this bile acid synthesis disorder is due to a HSD3B7 gene mutation. With only 53 cases reported between 1993 and 2015, HSD3B7 deficiency is rare. Additionally, the existing literature is primarily in the form of case reports, with the majority of patients with HSD3B7 deficiency presenting in the neonatal period, often with cholestatic jaundice. Aims To showcase an atypical presentation of HSD3B7 deficiency, in an 11 year old male with recurrent epistaxis and a coagulopathy of vitamin K deficiency. Additionally, to complete a review of the literature available on HSD3B7 deficiency. Methods Case report, chart review, and literature review. Results 11 year old male who initially presented to Pediatric Hematology with prolonged PTT and INR in the context of recurrent epistaxis and easy bruising. Upon further work up, the patient was found to have low levels of vitamin K dependent factors, as well as low vitamin levels of A, D, and E. Additionally, the patient had elevation of AST, ALT, GGT, ALP, and total bilirubin. Normalization of the INR and PTT were achieved with vitamin K supplementation. Genetic testing was sent to work up the abnormal liver enzymes and revealed HSD3B7 deficiency. Fast atom bombardment ionization was subsequently completed and confirmed the diagnosis. Conclusions There is limited clinical data available regarding HSD3B7 deficiency. The classic presentation of this bile acid synthesis disorder is in a neonate with cholestatic jaundice, hepatomegaly, fat-soluble vitamin deficiencies, and lipid malabsorption. Therefore, the initial presentation of an 11 year old with recurrent epistaxis and prolonged INR and PTT is thus an atypical presentation of HSD3B7 deficiency. This case report demonstrates that there is diversity in the age of presentation and accompanying signs and symptoms in HSD3B7 deficiency. Funding Agencies None

Sarcopenia is associated with osteopenia and impaired quality of life in children with genetic intrahepatic cholestatic liver disease.

Sarcopenia occurs in pediatric chronic liver disease, although the prevalence and contributing factors in genetic intrahepatic cholestasis are not well-described. The objective of this study was to measure muscle mass in school-aged children with genetic intrahepatic cholestasis and assess relationships between sarcopenia, clinical variables, and outcomes. Estimated skeletal muscle mass (eSMM) was calculated on dual-energy x-ray absorptiometry obtained in a Childhood Liver Disease Research Network study of children with bile acid synthesis disorders(BASD) alpha-1 antitrypsin deficiency (a1ATd), chronic intrahepatic cholestasis (CIC), and Alagille syndrome (ALGS). Relationships between eSMM, liver disease, and transplant-free survival were assessed. eSMM was calculated in 127 participants (5-18y): 12 BASD, 41 a1ATd, 33 CIC, and 41 ALGS. eSMM z-score was lower in CIC (-1.6 ± 1.3) and ALGS (-2.1 ± 1.0) than BASD (-0.1 ± 1.1) and a1ATd (-0.5 ± 0.8, p < 0.001). Sarcopenia (defined as eSMM z-score ≤- 2) was present in 33.3% of CIC and 41.5% of ALGS participants. eSMM correlated with bone mineral density in the 4 disease groups (r=0.52-0.55, p < 0.001-0.07), but not serum bile acids, bilirubin, aspartate aminotransferase/platelet ratio index, or clinically evident portal hypertension. Of the 2 patients who died (1 with sarcopenia) and 18 who underwent liver transplant (LT, 4 with sarcopenia), eSMM z-score did not predict transplant-free survival. eSMM z-score correlated with the Physical Pediatric Quality of Life Inventory score (r=0.38-0.53, p = 0.007-0.04) in CIC and a1ATd. Severe sarcopenia occurs in some children with ALGS and CIC. The lack of correlation between eSMM and biochemical cholestasis suggests mechanisms beyond cholestasis contribute to sarcopenia. While sarcopenia did not predict transplant-free survival, LT and death were infrequent events. Future studies may define mechanisms of sarcopenia in genetic intrahepatic cholestasis.

Dried blood spot-based newborn screening for bile acid synthesis disorders, Zellweger spectrum disorder, and Niemann-Pick type C1 by detection of bile acid metabolites

ObjectiveTo examine whether it is possible to screen for bile acid synthesis disorders (BASDs) including peroxisome biogenesis disorder 1a (PBD1A) and Niemann-Pick type C1 (NPC1) at the time of newborn mass screening by measuring the intermediary metabolites of bile acid (BA) synthesis. MethodsPatients with 3β-hydroxy-ΔSuchy et al. (2021)5-C27-steroid dehydrogenase/isomerase (HSD3B7) deficiency (n = 2), 3-oxo-ΔPandak and Kakiyama (n.d.)4-steroid 5β-reductase (SRD5B1) deficiency (n = 1), oxysterol 7α-hydroxylase (CYP7B1) deficiency (n = 1), PBD1A (n = 1), and NPC1 (n = 2) with available dried blood spot (DBS) samples collected in the neonatal period were included. DBSs from healthy neonates at 4 days of age (n = 1055) were also collected for the control. Disease specific BAs were measured by newly optimized liquid chromatography-tandem mass spectrometry with short run cycle (5-min/run). The results were validated by comparing with those obtained by the conventional condition with longer run cycle (76-min/run). ResultsIn healthy specimens, taurocholic acid and cholic acid were the two major BAs which constituted approximately 80% in the measured BAs. The disease marker BAs presented <10%. In BASDs, the following BAs were determined for the disease specific markers: Glyco/tauro 3β,7α,12α-trihydroxy-5-cholenoic acid 3-sulfate for HSD3B7 deficiency (>70%); glyco/tauro 7α,12α-dihydroxy-3-oxo-4-cholenoic acid for SRD5B1 deficiency (54%); tauro 3β-hydroxy-5-cholenoic acid 3-sulfate for CYP7B1 deficiency (94%); 3α,7α,12α-trihydroxy-5β-cholestanoic acid for PBD1A (78%); and tauro 3β,7β-dihydroxy-5-cholenoic acid 3-sulfate for NPC1 (26%). *The % in the parenthesis indicates the portion found in the patient's specimen. ConclusionsEarly postnatal screening for BASDs, PBD1A and NPC1 is feasible with the described DBS-based method by measuring disease specific BAs. The present method is a quick and affordable test for screening for these inherited diseases.

Treatment of cerebrotendinous xanthomatosis in pregnancy: Patient and physician perspectives

Cerebrotendinous xanthomatosis (CTX) is a rare, autosomal recessive disorder of bile acid synthesis that presents with varied and progressive symptomology. Early treatment with chenodeoxycholic acid (CDCA) improves symptoms and slows degeneration. Patients with CTX are commonly recommended to discontinue CDCA treatment during pregnancy because of theoretical risks to the fetus, but patient and clinician concerns about the risks of stopping treatment cause uncertainty. Herein, we report the experiences and perspectives of two women with CTX from the time of diagnosis through pregnancy, as well as decisions regarding CDCA treatment during pregnancy. Before becoming pregnant, both women were concerned about potential risks to their newborns if they continued or stopped CDCA treatment during pregnancy. Reassurance from their CTX specialist was the primary factor in their decision to continue treatment during pregnancy. After pregnancies complicated by preeclampsia, one gave birth to a healthy infant and the other gave birth to an infant later diagnosed with periventricular leukomalacia. Neither experienced CDCA-related complications.

Bile Acid Synthesis Disorder, the First Reported Case from Iran, (Proven by Genetic Study), How the Unavailability of Drug Affected the Course of Treatment

Introduction: Bile acid synthesis disorder is a very rare autosomal recessive disorder, which is mainly diagnosed by detecting mutations in the genes encoding enzymes that are involved in bile metabolism, including Δ4-3-oxosteroid-5β-reductase and 3β-Δ5-hydroxy-C27-steroid oxidoreductase. The enzymatic impairments can result in the accumulation of atypical and hepatotoxic bile acid intermediates, which clinically lead to cholestasis and progress to cirrhosis and hepatic failure. Herein, we describe a case of bile acid synthesis disorder diagnosed using molecular genetic assessment. Case Presentation: A 7-year-old girl is presented with failure to thrive since early in life. She had a history of urinary tract infection at four years of age. The sonography was performed at that time and revealed renal microcalculi. She also had a history of abdominal pain, nausea, and vomiting. She underwent upper endoscopies three times to rule out celiac disease; nevertheless, duodenal biopsies were all reported as normal. Muscle weakness was detected at five years of age and electromyography and muscle biopsy findings were non-specific. She underwent a whole-genome study and was diagnosed with bile acid synthesis disorder (BASD). After six months, she was treated with ursodeoxycholic acid, 250 mg, which led to growth compensation and liver enzyme reduction. No adverse effect was reported during the treatment. Conclusions: Bile acid synthesis disorder is a rare disorder with non-specific features and several organ involvements. It may take several years to achieve the correct diagnosis. To our knowledge, this is the first genetically confirmed case of bile acid synthesis disorder reported in Iran.

Newborn screening for Cerebrotendinous Xanthomatosis: A retrospective biomarker study using both flow-injection and UPLC-MS/MS analysis in 20,000 newborns

Background and aimsCerebrotendinous Xanthomatosis (CTX) is a treatable disorder of bile acid synthesis caused by deficiency of 27-sterol hydroxylase -encoded by CYP27A1- leading to gastrointestinal and progressive neuropsychiatric symptoms. Biochemically, CTX is characterized by accumulation of the bile alcohol cholestanetetrol glucuronide (GlcA-tetrol) and the deficiency of tauro-chenodeoxycholic acid (t-CDCA) and tauro-trihydroxycholestanoic acid (t-THCA). Materials and MethodsTo ascertain the feasibility of CTX newborn screening (NBS) we performed a study with deidentified Dutch dried blood spots using reagents and equipment that is frequently used in NBS laboratories. 20,076 deidentified newborn blood spots were subjected to flow-injection (FIA)-MS/MS and UPLC-MS/MS analysis to determine the concentration of GlcA-tetrol and calculate the GlcA-tetrol/t-CDCA and t-THCA/GlcA-tetrol ratios. ResultsUsing UPLC-MS/MS analysis both GlcA-tetrol concentration and/or metabolite ratios GlcA-tetrol/t-CDCA proved to be informative biomarkers; newborn DBS results did not overlap with those of the CTX patients. For FIA-MS/MS, GlcA-tetrol also was an excellent marker but when using the combination of the GlcA-tetrol/t-CDCA and t-THCA/GlcA-tetrol ratios also did not yield any screen positives. ConclusionNewborn screening for CTX using only metabolite ratios following the measurement of three CTX biomarkers is possible using either FIA-MS/MS or UPLC-MS/MS, which paves the way for introduction of CTX NBS.

Successful treatment of an infant with congenital bile acid synthesis disorder type 3 by ursodeoxycholic acid: a case report

BackgroundCongenital bile acid synthesis disorder type 3 caused by oxysterol 7α-hydroxylase deficiency is an extremely rare genetic liver disease. As it may cause rapid progression to end-stage liver disease, a high cautiousness in diagnosis and early treatment are required. Here we describe the first case of congenital bile acid synthesis disorder type 3 in China that was confirmed by genetic analysis.Case presentationA 5-month-old Chinese male infant suffered skin yellowing since birth. The patient showed significantly increased alanine transaminase, aspartate transaminase, and total and direct bilirubin levels, and enlarged liver at admission. Whole-exome sequencing confirmed homozygous mutation in the CYB7B1 gene that encodes oxysterol 7α-hydroxylase. Ursodeoxycholic acid treatment significantly mitigated the condition of the patient and lowered biochemical indicators. Unfortunately, the patient developed septicemia and gave up treatment.ConclusionsThe patient was successfully treated with ursodeoxycholic acid, which has not been reported previously. Ursodeoxycholic acid replacement therapy is an effective and affordable treatment for congenital bile acid synthesis disorder type 3 caused by oxysterol 7α-hydroxylase deficiency.

Clinical features and genetic analysis of congenital bile acid synthesis disorder type 2 in four children

Clinical features and genetic analysis of congenital bile acid synthesis disorder type 2 in four children

Bile Acid Synthesis Disorders in Japan: Long-Term Outcome and Chenodeoxycholic Acid Treatment.

We encountered 7 Japanese patients with bile acid synthesis disorders (BASD) including 3β-hydroxy-Δ5-C27-steroid dehydrogenase/isomerase (3β-HSD) deficiency (n = 3), Δ4-3-oxosteroid 5β-reductase (5β-reductase) deficiency (n = 3), and oxysterol 7α-hydroxylase deficiency (n = 1) over 21years between 1996 and 2017. We aimed to clarify long-term outcome in the 7 patients with BASD as well as long-term efficacy of chenodeoxycholic acid (CDCA) treatment in the 5 patients with 3β-HSD deficiency or 5β-reductase deficiency. Diagnoses were made from bile acid and genetic analyses. Bile acid analysis in serum and urine was performed using gas chromatography-mass spectrometry. Clinical and laboratory findings and bile acid profiles at diagnosis and most recent visit were retrospectively obtained from medical records. Long-term outcome included follow-up duration, treatments, growth, education/employment, complications of treatment, and other problems. Medians with ranges of current patient ages and duration of CDCA treatment are 10 years (8 to 43) and 10years (8 to 21), respectively. All 7 patients, who had homozygous or compound heterozygous mutations in the HSD3B7, SRD5B1, or CYP7B1 gene, are currently in good health without liver dysfunction. In the 5 patients with CDCA treatment, hepatic function gradually improved following initiation. No adverse effects were noted. We concluded that CDCA treatment is effective in 3β-HSD deficiency and 5β-reductase deficiency, as cholic acid has been in other countries. BASD carry a good prognosis following early diagnosis and initiation of long-term CDCA treatment.

C.1263+1G>A Is a Latent Hotspot for CYP27A1 Mutations in Chinese Patients With Cerebrotendinous Xanthomatosis.

BackgroundCerebrotendinous xanthomatosis (CTX) is an autosomal recessive disorder of bile acid synthesis caused by mutations in the CYP27A1 gene. CTX is an underdiagnosed and potentially treatable disease, thus a detailed appreciation of the phenotypic spectrum and genetic characteristics are crucial for early diagnosis and treatment.Objectives and MethodsFour CTX families with mutations in the CYP27A1 gene were enrolled in our study. We investigated the clinical characteristics and molecular genetic features of the probands with CTX. Genetic analysis was performed for detecting gene variants. Sanger sequencing and segregation analysis were conducted for haplotype analysis.ResultsAll the four probands were compound heterozygote for two CYP27A1 variants, including one mutation in c.1263+1G>A (intron 7) splice site, two novel likely pathogenic mutations (c.255+1G>T and c.1561dupA) and three pathogenic mutations including c.379C>T, c.1263+1G>A and c.1537C>T previously reported. All of the subjects presented with spastic paraparesis. The other common clinical features included ataxia, childhood-onset diarrhea, cataracts, intellectual disability, tendinous xanthomas and dentate nuclei signal alterations at MRI.ConclusionTwo novel likely pathogenic mutations (c.255+1G>T and c.1561dupA) were reported in our study. The 1263+1G>A mutation was commonly seen in Chinese reported case series (7/25, 28%) and could be a latent hotspot for Chinese CTX mutations. Our study expanded the mutation spectrum of CYP27A1 gene and provide an insightful view of the phenotypic spectrum and genetic characteristics to help early diagnosis and treatment with to improve neurologic dysfunction.

Homozygous NEK8 Mutations in Siblings With Neonatal Cholestasis Progressing to End‐stage Liver, Renal, and Cardiac Disease

Homozygous <i>NEK8</i> Mutations in Siblings With Neonatal Cholestasis Progressing to End‐stage Liver, Renal, and Cardiac Disease

Pathways and Inborn Errors of Bile Acid Synthesis

Bile acids are synthesized from cholesterol through 17 different enzymes located in different intracellular compartments of hepatocytes. Defects have been identified in the genes encoding the enzymes involved in the bile acid synthesis pathways and nine different diseases have been identified so far. In this review, four different biosynthetic pathway of bile acids together with disorders of bile acid synthesis is described. In inborn errors of bile acid synthesis clinical findings can range from liver failure to cirrhosis in infancy or progressive neuropathy in adolescence / adulthood. Laboratory analysis of urine profiling of bile acids is important in early diagnosis and early treatment.

Intractable Vitamin D Deficiency Rickets in twin siblings

Background: Bile acid synthesis disorders (BASD) are a group of uncommon metabolic disorders caused by inborn genetic defects in the synthesis of bile acids. Bile acids are a chemical compound that are produced in the liver to promote the flow and excretion of bile in the liver, a key element in absorption of fats and fat-soluble vitamins, and also work in the elimination of cholesterol from the body. Defects in the bile acid synthesis process lead to a failure in creating normal bile acids, resulting in malabsorption of vital nutrients, …

The effectiveness of correcting abnormal metabolic profiles.

Inborn errors of metabolism cause disease because of accumulation of a metabolite before the blocked step or deficiency of an essential metabolite downstream of the block. Treatments can be directed at reducing the levels of a toxic metabolite or correcting a metabolite deficiency. Many disorders have been treated successfully first in a single patient because we can measure the metabolites and adjust treatment to get them as close as possible to the normal range. Examples are drawn from Komrower's description of treatment of homocystinuria and the author's trials of treatment in bile acid synthesis disorders (3β‐hydroxy‐Δ5‐C27‐steroid dehydrogenase deficiency and Δ4‐3‐oxosteroid 5β‐reductase deficiency), neurotransmitter amine disorders (aromatic L‐amino acid decarboxylase [AADC] and tyrosine hydroxylase deficiencies), and vitamin B6 disorders (pyridox(am)ine phosphate oxidase deficiency and pyridoxine‐dependent epilepsy [ALDH7A1 deficiency]). Sometimes follow‐up shows there are milder and more severe forms of the disease and even variable clinical manifestations but by measuring the metabolites we can adjust the treatment to get the metabolites into the normal range. Biochemical measurements are not subject to placebo effects and will also show if the disorder is improving spontaneously. The hypothesis that can then be tested for clinical outcome is whether getting metabolite(s) into a target range leads to an improvement in an outcome parameter such as abnormal liver function tests, hypokinesia, epilepsy control etc. The metabolite‐guided approach to treatment is an example of personalized medicine and is a better way of determining efficacy for disorders of variable severity than a randomized controlled clinical trial.

Δ4-3-oxosteroid-5β-reductase deficiency: Responses to oral bile acid therapy and long-term outcomes.

BACKGROUNDDisorders of primary bile acid synthesis may be life-threatening if undiagnosed, or not treated with primary bile acid replacement therapy. To date, there are few reports on the management and follow-up of patients with Δ4-3-oxosteroid 5β-reductase (AKR1D1) deficiency. We hypothesized that a retrospective analysis of the responses to oral bile acid replacement therapy with chenodeoxycholic acid (CDCA) in patients with this bile acid synthesis disorder will increase our understanding of the disease progression and permit evaluation of this treatment regimen as an alternative to the Food and Drug Administration (FDA) approved drug cholic acid, which is currently unavailable in China.AIMTo evaluate the therapeutic responses of patients with AKR1D1 deficiency to oral bile acid therapy, specifically CDCA.METHODSTwelve patients with AKR1D1 deficiency, confirmed by fast atom bombardment ionization-mass spectrometry analysis of urine and by gene sequencing for mutations in AKR1D1, were treated with differing doses of CDCA or ursodeoxycholic acid (UDCA). The clinical and biochemical responses to therapy were monitored over a period ranging 0.5-6.4 years. Dose adjustment, to optimize the therapeutic dose, was based on changes in serum biochemistry parameters, notably liver function tests, and suppression of the urinary levels of atypical hepatotoxic 3-oxo-Δ4-bile acids measured by mass spectrometry.RESULTSPhysical examination, serum biochemistry parameters, and sonographic findings improved in all 12 patients during bile acid therapy, except one who underwent liver transplantation. Urine bile acid analysis confirmed a significant reduction in atypical hepatotoxic 3-oxo-Δ4 bile acids concomitant with clinical and biochemical improvements in those patients treated with CDCA. UDCA was ineffective in down-regulating endogenous bile acid synthesis as evidenced from the inability to suppress the urinary excretion of atypical 3-oxo-Δ4-bile acids. The dose of CDCA required for optimal clinical and biochemical responses varied from 5.5-10 mg/kg per day among patients based on maximum suppression of the atypical bile acids and improvement in serum biochemistry parameters, and careful titration of the dose was necessary to avoid side effects from CDCA.CONCLUSIONThe primary bile acid CDCA is effective in treating AKR1D1 deficiency but the therapeutic dose requires individualized optimization. UDCA is not recommended for long-term management.

A case of congenital bile acid synthesis disorder type 2 and literature review

To summarize the clinical features, biochemical change and genetic mutations of a neonate with congenital bile acid synthesis disorder type 2. Clinical features, blood biochemical index, gene analysis and treatment of the patient were reviewed. The patient presented with the symptoms of jaundice 3 days after birth but without skin itching. Pale stool was noted. Subsequently, he presented with hepatomegaly, blood coagulation disorders, left cochlear nerve damage, liver cirrhosis and remarkable growth retardation. Serum biochemistries showed that bilirubin and transaminase were elevated, while γ -GT and total bile acid was normal. Abdominal ultrasonography indicated decline of gallbladder contraction. Cholangiography showed normal extra- and intrahepatic bile ducts and patent biliary tract. Liver biopsy showed intrahepatic cholestasis. Gene testing has identified a homozygous mutation in AKR1D1 gene. Congenital bile acid synthesis disorder should be suspected when a neonate has presented with jaundice, elevated bilirubin and transaminase, normal or reduced TBA and γ -GT. Genetic testing and urine mass spectrometry analysis can diagnose congenital bile acid synthesis disorder. Early therapy is crucial to patients with congenital bile acid synthesis disorder.

PRM194 - INVESTIGATING THE RELATIONSHIP BETWEEN AGE AND EXPANDED DISABILITY STATUS SCALE SCORE IN UNTREATED AND CHENODEOXYCHOLIC ACID-TREATED CEREBROTENDINOUS XANTHOMATOSIS PATIENTS

Progressive disability due to neurodegeneration is a hallmark feature of cerebrotendinous xanthomatosis (CTX), a rare autosomal recessive disorder of primary bile acid synthesis. With an estimated 200 patients diagnosed in Europe, defining natural history, outcome measures, and treatment benefit in CTX is challenging. Expanded Disability Status Scale (EDSS) scores have been used to monitor progression in CTX patients. To assess the natural history of disability in CTX, we investigated the relationship between age and EDSS in untreated patients, and then assessed whether patients treated with chenodeoxycholic acid (CDCA), the standard of care, had better EDSS scores than expected for their age. The baseline EDSS scores and ages of untreated patients aged 0–64 years [N=82] from two retrospective studies (CDCA-STUK-15-001 [n=30] and CDCA-STRCH-14-001 [n=27]) and a Spanish case series1 (n=25) were pooled. Simple linear regression was used to calculate the correlation between age and EDSS score. Actual EDSS scores of patients treated with commercially available CDCA (CDCA-STUK-15-001) and pharmacy compounded CDCA (CDCA-STRCH-14-001) were compared with the EDSS score expected for untreated patients at the same age, as derived from the linear regression. A moderate correlation was observed between EDSS and age for untreated patients (R2=0.4764; y=0.1265x-0.6251). Following treatment, EDSS scores were lower than expected in 96% (25/26) of patients treated with commercially available CDCA (mean/median treatment duration 10.77/8.5 years) and in 54% (14/26) treated with locally compounded product (mean/median duration 7.19/6.3 years). These results suggest that long-term CDCA treatment may improve disability, as assessed by EDSS scores, when compared with the natural history. Patients treated with the commercial formulation fared better than those treated with the compounded formulation; this may be due to differences in patient cohort demographics, although product differences cannot be ruled out. REFERENCE: 1. Pilo-de-la-Fuente B et al. Eur J Neurol 2011;18:1203–11.

A337 KABUKI SYNDROME: A NEW ADDITION TO THE DIFFERENTIAL DIAGNOSIS OF LOW-GGT NEONATAL CHOLESTASIS

Neonatal low-GGT cholestasis has a unique differential diagnosis centered on congenital disorders of bile acid transport or synthesis. Kabuki syndrome is a genetic condition with distinctive facies, developmental delay, and skeletal, renal and cardiac defects. While Kabuki has been associated with high-GGT cholestatic conditions including biliary atresia, patients with low-GGT cholestasis have not previously been described. To describe 2 patients with Kabuki syndrome and low-GGT neonatal cholestasis Chart review. Case 1: A female infant of non-consanguinous South Asian parents was born at 35 6/7 weeks. Antenatal US was normal. Facial dysmorphisms and hypotonia were noted at birth. Whole exome sequencing analysis confirmed Kabuki syndrome with de novo deletion in the KMT2D gene. Ventilation was needed from birth, with right-sided heart failure from pulmonary hypertension. She required TPN. Cholestasis was identified at 6 weeks: conjugated bilirubin 175umol/L, AST 404U/L, ALT 121U/L, ALP 289U/L, GGT 64U/L (70–130). Abdominal US: hepatosplenomegaly and ascites without biliary abnormalities. CMV infection occurred at 12 weeks. Liver biochemistry improved with ursodeoxycholic acid, cessation of TPN and CMV resolution. She was discharged home at 7 months. Case 2: A male infant of non-consanguinous Filipino parents was born at 25 4/7 weeks. He had a patent ductus arteriosis and solitary renal cyst but no dysmorphisms or other congenital abnormalities. He required TPN. Intractable pulmonary hypertension necessitated prolonged ventilation. Cholestasis was identified at 4 weeks. Stools were initially pale. HIDA scan was non-excretory. Liver biopsy: giant cell transformation, mild portal fibrosis, no bile duct proliferation. Stools later became pigmented. A jaundice gene chip (EGL) found no mutations of familial intrahepatic cholestasis (PFIC). Kabuki syndrome was diagnosed at 4 months on chromosome array. Peak liver biochemistry: conjugated bilirubin 512umol/L, AST 731U/L, ALT 345 U/L, ALP 891U/L, GGT 65U/L. Repeat liver biopsy at 3 months: extensive giant cell transformation. EM: canaliculi with markedly reduced stubby microvilli, with finely granular to filamentous material suggesting BSEP deficiency (PFIC type 2). He died at 5 months from pulmonary hypertension. These are the first reported cases of Kabuki syndrome with low-GGT neonatal cholestasis. KMT2D gene mutations should be considered on the short list of genetic disorders causing low-GGT cholestasis. We hypothesize that in Kabuki syndrome, KMT2D gene mutations modify lysine methytransferase activity and impair FXR expression of target gene products including BSEP, leading to phenotypic PFIC type 2 disorders. Kabuki syndrome gene mutations should be included in next generation jaundice gene chip panels for neonatal cholestasis. None

Oral Cholic Acid Is Efficacious and Well Tolerated in Patients With Bile Acid Synthesis and Zellweger Spectrum Disorders.

Oral Cholic Acid Is Efficacious and Well Tolerated in Patients With Bile Acid Synthesis and Zellweger Spectrum Disorders.