Management of early treated adolescents and young adults with phenylketonuria: Development of international consensus recommendations using a modified Delphi approach.

BACKGROUND: Early treated patients with phenylketonuria (PKU) often become lost to follow-up from adolescence onwards due to the historical focus of PKU care on the pediatric population and lack of programs facilitating the transition to adulthood. As a result, evidence on the management of adolescents and young adults with PKU is limited. METHODS: Two meetings were held with a multidisciplinary international panel of 25 experts in PKU and comorbidities frequently experienced by patients with PKU. Based on the outcomes of the first meeting, a set of statements were developed. During the second meeting, these statements were voted on for consensus generation (≥70% agreement), using a modified Delphi approach. RESULTS: A total of 37 consensus recommendations were developed across five areas that were deemed important in the management of adolescents and young adults with PKU: (1) general physical health, (2) mental health and neurocognitive functioning, (3) blood Phe target range, (4) PKU-specific challenges, and (5) transition to adult care. The consensus recommendations reflect the personal opinions and experiences from the participating experts supported with evidence when available. Overall, clinicians managing adolescents and young adults with PKU should be aware of the wide variety of PKU-associated comorbidities, initiating screening at an early age. In addition, management of adolescents/young adults should be a joint effort between the patient, clinical center, and parents/caregivers supporting adolescents with gradually gaining independent control of their disease during the transition to adulthood. CONCLUSIONS: A multidisciplinary international group of experts used a modified Delphi approach to develop a set of consensus recommendations with the aim of providing guidance and offering tools to clinics to aid with supporting adolescents and young adults with PKU.

Liver-Directed Adeno-Associated Virus-Mediated Gene Therapy for Mucopolysaccharidosis Type VI.

BACKGROUND: Mucopolysaccharidosis type VI (MPS VI) is an inherited multisystem lysosomal disorder due to arylsulfatase B (ARSB) deficiency that leads to widespread accumulation of glycosaminoglycans (GAG), which are excreted in increased amounts in urine. MPS VI is characterized by progressive dysostosis multiplex, connective tissue and cardiac involvement, and hepatosplenomegaly. Enzyme replacement therapy (ERT) is available but requires life-long and costly intravenous infusions; moreover, it has limited efficacy on diseased skeleton and cardiac valves, compromised pulmonary function, and corneal opacities. METHODS: We enrolled nine patients with MPS VI 4 years of age or older in a phase 1/2 open-label gene therapy study. After ERT was interrupted, patients each received a single intravenous infusion of an adeno-associated viral vector serotype 8 expressing ARSB. Participants were sequentially enrolled in one of three dose cohorts: low (three patients), intermediate (two patients), or high (four patients). The primary outcome was safety; biochemical and clinical end points were secondary outcomes. RESULTS: The infusions occurred without severe adverse events attributable to the vector, meeting the prespecified end point. Participants in the low and intermediate dose cohorts displayed stable serum ARSB of approximately 20% of the mean healthy value but returned to ERT by 14 months after gene therapy because of increased urinary GAG. Participants in the high-dose cohort had sustained serum ARSB of 30% to 100% of the mean healthy value and a modest urinary GAG increase that did not reach a concentration at which ERT reintroduction was needed. In the high-dose group, there was no clinical deterioration for up to 2 years after gene therapy. CONCLUSIONS: Liver-directed gene therapy for participants with MPS VI did not have a dose-limiting side-effect and adverse event profile; high-dose treatment resulted in ARSB expression over at least 24 months with preliminary evidence of disease stabilization. (Funded by the Telethon Foundation ETS, the European Commission Seventh Framework Programme, and the Isaac Foundation; ClinicalTrials.gov number, NCT03173521; EudraCT number, 2016-002328-10.)

Complicated peripartum course in a patient with very long-chain acyl-coenzyme A dehydrogenase (VLCAD) deficiency.

Very long-chain acyl-coenzyme A (CoA) dehydrogenase (VLCAD) deficiency is an autosomal recessive fatty acid oxidation disorder characterized by rhabdomyolysis, hypoglycemia and cardiomyopathy. The general treatment approach in adult patients is based on the prevention of catabolism. High carbohydrate, low fat diet and supplementation of medium-chain triglycerides are essential in the treatment. There is little experience with pregnancy follow-up in this patient group. We present a complicated peripartum course and successful management in a patient with VLCAD deficiency. Although high-dose glucose infusion was initiated, creatine kinase levels significantly increased in the immediate postpartum period, but the patient remained asymptomatic and rhabdomyolysis resolved rapidly after increasing the glucose infusion rate.

Imaging liver nodules in tyrosinemia type-1: A retrospective review of 16 cases in a tertiary pediatric hospital.

OBJECTIVE: To describe the liver imaging findings of Hereditary tyrosinemia type-1 (HT1) patients. MATERIALS AND METHODS: We report 16 patients (8 Female and 8 Male) with HT-1. Their demographic features, imaging findings and alpha feto protein (AFP) levels were recorded. Imaging features on CT and MR were evaluated for the following characteristics: contour of the liver and liver nodules. Liver nodules were categorized as; regenerative, dysplastic, fatty and malignant nodules (HCC). RESULTS: Thirteen (81%) patients had multiple liver nodules (>20) on imaging studies. Five patients (31%) had regenerative nodules, six (38%) had dysplastic nodules and ten (63%) had fatty nodules. Dysplastic nodules were encountered in two patients with HCC and in four patients without a tumor. Four patients (25%) had HCC nodule on imaging studies. Those four patients had biopsy and all of them had HCC nodule on histopathology. In the follow-up period, in one patient fatty nodules had increased in size, in one patient regenerative nodules had disappeared and in one patient dysplastic nodules had disappeared. CONCLUSIONS: Multiple fatty nodules can be seen in HT1 patients and in some patients, the regenerative and dysplastic nodules can disappear during the follow-up period.

Understanding the Early Presentation of Mucopolysaccharidoses Disorders: Results of a Systematic Literature Review and Physician Survey

Abstract As therapies are developed for rare disorders, challenges of early diagnosis become particularly relevant. This article focuses on clinical recognition of mucopolysaccharidoses (MPS), a group of rare genetic diseases related to abnormalities in lysosomal function. As quality of outcomes with current therapies is impacted by timing of intervention, minimizing time to diagnosis is critical. The objective of this study was to characterize how, when, and to whom patients with MPS first present and develop tools to stimulate earlier recognition of MPS. A tripartite approach was used, including a systematic literature review yielding 194 studies, an online physician survey completed by 209 physicians who described

Mucopolysaccharidosis: Otolaryngologic findings, obstructive sleep apnea and accumulation of glucosaminoglycans in lymphatic tissue of the upper airway.

OBJECTIVE: The aim of this study is to evaluate otolaryngologic problems (upper airway obstruction, obstructive sleep apnea, restriction of mouth opening, middle ear effusion, hearing and breathing problems) and their treatments on mucopolysaccharidoses (MPS) patients and to investigate accumulation of glucosaminoglycans (GAG) in the upper airway biochemically and pathologically. METHODS: 76 MPS patients were evaluated. Forty-two MPS patients underwent polysomnography (PSG) for obstructive sleep apnea (OSA). Pre- and postoperative PSG results of 18 patients were compared. The success and complications of treatments for OSA in MPS were evaluated. Biochemical and histopathological accumulation of GAG in tonsil and adenoid tissue and middle ear effusion were analyzed and compared with the control group. RESULTS: Forty patients out of 42 tested with PSG had OSA (95%). Adenoid grade, Mallampati grade, restricted mouth opening, rate of difficult intubation were significantly different among MPS subtypes. MPS types III and IV had significantly lower Mallampati scores; type VI had significantly worse mouth opening; and type III had significantly better mouth opening and higher rate of easy intubation when compared to other MPS types. There was no significant difference between MPS subtypes according to tonsil grade, adenoid grade, rate of otitis media with effusion and OSA severity. Statistically significant difference was found between GAG accumulation in adenoid tissue and middle ear effusion of MPS and control group (p<0.05). However, GAG accumulation in tonsil was not significantly different between MPS and control group. There was a statistically significant improvement in postop Apnea-Hypopnea Index (AHI) compared to preop AHI (p<0.05). CONCLUSIONS: Most MPS patients have airway obstruction and OSA due to adenotonsillar hypertrophy. Most of these children benefit from adenotonsillectomy, after which OSA significantly improves. They experience high recurrence rate after adenoidectomy; though this is not clinically problematic. They also suffer from conductive hearing loss due to OME, which has to be treated with ventilation tube insertion. However, such operations are usually complicated by difficult endotracheal intubation and restricted mouth opening. Sometimes tracheotomy may be necessary. Tracheotomy is also highly complicated in MPS patients. Significant accumulation of GAG in middle ear fluid and adenoid tissue is present; however, GAG appears not to accumulate in tonsillar tissue.

A Patient With Pyruvate Carboxylase Deficiency and Nemaline Rods on Muscle Biopsy.

Nemaline rods are the pathologic hallmark of nemaline myopathy, but they have also been described as a secondary phenomenon in a variety of other disorders. Nemaline rods have not been reported in pyruvate carboxylase deficiency before. Here we present a patient with pyruvate carboxylase deficiency and nemaline rods detected on muscle biopsy. The nemaline rods may be due to cellular energy shortage and altered energy metabolism in pyruvate carboxylase deficiency, similar to that in the previously reported patients. The mechanism of nemaline rod formation may be associated with the role of pyruvate carboxylase in cellular energy pathways.