M. F. Mulder

Phenylalanine tolerance can already reliably be assessed at the age of 2 years in patients with PKU.

SummaryBackground:The clinical severity of phenylalanine hydroxylase deficiency is usually defined by either pre-treatment phenylalanine (Phe) concentration or Phe tolerance at 5xa0years of age. So far, little is known about the course of Phe tolerance or the ability of both pre-treatment Phe and Phe tolerance at early age to predict Phe tolerance at later age.Aim:This study was conducted to investigate the course of the individual Phe tolerance and to assess the predictive value of both the pre-treatment Phe concentration and Phe tolerance at 1 and 6xa0months and 1, 2, 3 and 5xa0years for Phe tolerance at 10xa0years of age.Method:Data on blood Phe concentration, prescribed Phe intake and weight of 213 early and continuously treated Dutch PKU patients up to 10xa0years of age were collected. Data acquired under good metabolic control were used in the study. Tolerance was expressed in mg/day and mg/kg per day.Results:Data at 1 and 6xa0months and at 1, 2, 3 and 5xa0years of 61, 58, 59, 57, 56 and 59 patients were included for comparison with the Phe tolerance at 10xa0years. Phe tolerances (mg/kg per day) at 2, 3 and 5xa0years showed a clear correlation with the tolerance at 10xa0years of age (ru2009=u20090.608, ru2009=u20090.725 and ru2009=u20090.661). Results for tolerance expressed as mg/day were comparable. Pre-treatment Phe concentrations did not correlate significantly with the tolerance.Conclusion:Pre-treatment Phe is unreliable but Phe tolerance is a reliable predictor of the tolerance at 10xa0years of age, starting at 2xa0years of age.

Growth in patients with mucopolysaccharidosis type III (Sanfilippo disease)

BackgroundMucopolysaccharidosis III (MPS III), known as Sanfilippo disease, is a lysosomal storage disorder mainly characterized by progressive neurodegeneration with cognitive decline and relatively attenuated somatic signs and symptoms. Although short stature is invariably present in patients with the other mucopolysaccharidoses, it has not been sufficiently addressed in MPS III. The aim of this study was to investigate growth data of a large Dutch MPS III cohort in order to construct growth charts for MPS III patients.MethodsHeight, weight, head circumference (HC), and body mass index (BMI) data from 118 MPS III patients were used to construct reference curves, using the lambda, mu, sigma (LMS) method. Genotype-group comparisons for height standard deviation scores (SDS) were performed by Kruskal–Wallis analysis for different age groups.ResultsBirth weight and length were within normal ranges for gestational age and showed a significantly stunted growth from age 6xa0years onward. Mean final heights were 169.7xa0cm (−2.0 SDS) and 165.4xa0cm (−0.84 SDS) for adult male and female, patients, respectively. Phenotypic severity, as assessed by genotyping, correlated with growth pattern and final height. In addition, mean BMI and HC SDS were significantly higher when compared with Dutch standards for both boys and girls.ConclusionsGrowth in MPS III is stunted mainly in patients with the severe phenotype. We provide disease-specific growth references that can be used for clinical management of MPS III patients and may be of value for future treatment studies.

Chronological changes of the amplitude-integrated EEG in a neonate with molybdenum cofactor deficiency

Molybdenum cofactor (Moco) deficiency is a rare neurometabolic disorder, characterized by neurological impairment and refractive seizures, due to toxic accumulation of sulfite in the brain. Earlier it was suggested that in Moco-deficient humans maternal clearance of neurotoxic metabolites prevents prenatal brain damage. However, limited data are available about the time profile in which neurophysiologic deterioration occurs after birth. The amplitude-integrated electroencephalography (aEEG) is a bedside method in neonates to monitor cerebral recovery after hypoxic-ischemic insults, detect epileptic activity, and evaluate antiepileptic drug treatment. We describe a chronological series of changes in aEEG tracings in a neonate with Moco deficiency. He presented with myoclonic spasms and hypertonicity a few hours after birth, however, the aEEG pattern was still normal. Within 2xa0days, the aEEG rapidly changed into a burst suppression pattern with repetitive seizures. After antiepileptic treatment, the aEEG remained abnormal. In this patient, the normal aEEG pattern at birth may have been due to maternal clearance of sulfite in utero. After birth, accumulation of sulfite causes progressive brain damage, reflected by the progressive depression of the aEEG tracings. This is in agreement with the results from a Moco-deficient mouse model, suggesting that maternal sulfite clearance suppresses prenatal brain damage. To our knowledge, this is the first case report describing the chronological changes in the aEEG pattern in a Moco-deficient patient. Insight into the time profile in which neurologic deterioration in Moco-deficient humans occurs is essential, especially when potential treatment strategies are being evaluated.

Nephrological abnormalities in patients with transaldolase deficiency

BACKGROUNDnTransaldolase deficiency (OMIM 606003) is a multisystem disorder first described in 2001. Transaldolase is an enzyme of the reversible part of the pentose phosphate pathway. Affected patients have abnormal polyol concentrations in body fluids, mostly in urine. The clinical presentation is variable. The leading symptoms are coagulopathy, thrombocytopenia, hepatosplenomegaly, hepatic fibrosis and dysmorphic features. The objective of our study was to attempt to characterize the renal phenotype of patients with transaldolase deficiency.nnnMETHODSnClinical and laboratory data of all nine patients with transaldolase deficiency presently known were gathered by retrospective chart analysis.nnnRESULTSnNephrological abnormalities were present in seven of the nine patients. The most common findings were low molecular weight (LMW) proteinuria and hypercalciuria. The two oldest patients had moderate chronic kidney failure. In two patients, generalized aminoaciduria was found, two patients had renal phosphate wasting and three patients had hyperchloremic metabolic acidosis. Three patients had anatomical abnormalities.nnnCONCLUSIONSnRenal tubular dysfunction is present in the majority of patients with transaldolase deficiency and may lead to chronic renal failure. The combination of unexplained liver dysfunction with LMW proteinuria should prompt metabolic screening for transaldolase deficiency by measuring urinary polyols. In patients with transaldolase deficiency, monitoring of kidney function is mandatory.

Hydrops fetalis and early neonatal multiple organ failure in familial hemophagocytic lymphohistiocytosis

Familial hemophagocytic lymphohistiocytosis (FHLH) is a genetic heterogeneous autosomal recessive disorder. We report two siblings with FHLH caused by a PRF1 mutation. The first child died in utero with hydrops fetalis and the second presented soon after birth with fatal multiple organ failure. Post-mortem DNA analysis showed a homozygous c.666C>A (p.His222Gln) mutation in the PRF1 gene in both cases, with their non-consanguineous parents being heterozygous for the same mutation. Review of the literature shows that perinatal presentation of FHLH is rare. Diagnosis is difficult because in most cases histologic examination reveals no hemophagocytosis and the disease is rapidly fatal. The association between hydrops fetalis and FHLH has been reported in four previous reports. We present the first case of hydrops fetalis caused by FHLH, confirmed by DNA analysis. FHLH should be included in the differential diagnosis of non-immune hydrops fetalis and neonatal multiple organ failure.

A case of tubulointerstitial nephritis in a patient with an influenza H1N1 infection

BackgroundPatients suffering from an H1N1 infection mainly suffer from respiratory symptoms but may also develop symptoms in other organ systems, such as the kidneys.Case-diagnosis/treatmentA 4 ½u2009year-old boy was admitted with relatively mild respiratory symptoms of H1N1 infection, but developed severe generalized proximal tubular dysfunction with sterile leucocyturia and a reversible rise in serum creatinine. He made a full recovery with supportive therapy.ConclusionInfluenza H1N1 may be associated with acute tubulointerstitial nephritis.

High prevalence of abnormalities on CT and MR imaging in children with unilateral sensorineural hearing loss irrespective of age or degree of hearing loss

OBJECTIVEnEvaluation of causal abnormalities identified on CT and MR imaging in children with unilateral sensorineural hearing loss (USNHL), and the association with age and severity of hearing loss.nnnSTUDY DESIGNnRetrospective cohort study.nnnSETTINGnTertiary referral otology/audiology center.nnnPATIENTS AND DIAGNOSTIC INTERVENTIONSn102 children diagnosed with USNHL between 2006 and 2016 were included. They underwent CT and/or MR imaging for the evaluation of the etiology of their hearing loss.nnnMAIN OUTCOME MEASURESnRadiologic abnormalities of the inner ear and brain associated with USNHL.nnnRESULTSnUsing CT and/or MR imaging, causal abnormalities were identified in 49%, which is higher than previously reported (25-40%). The most frequently affected site was the labyrinth (29%), followed by the cochlear nerve (9%) and brain (7%). No significant difference in the number or type of abnormalities was found for the degree of hearing loss or age categories.nnnCONCLUSIONSnImaging is essential in the etiologic analysis of USNHL because of the high prevalence of causative abnormalities that can be identified with radiology, irrespective of the patients age or degree of hearing loss. CT and MR imaging are complementary imaging options. The ideal imaging algorithm is controversial. Based on our findings, we conclude that there is limited additional diagnostic value of simultaneous dual modality imaging over sequential diagnostics. We therefore perform a stepwise radiological workup in order to maximize the diagnostic yield while minimizing impact and costs. If the primary imaging modality does not identify a cause for USNHL, performing the alternative imaging modality should be considered.nnnLEVEL OF EVIDENCEnRetrospective cohort study 2b.

Clinical, biochemical, and molecular overview of transaldolase deficiency and evaluation of the endocrine function: update of 34 patients

BackgroundTransaldolase deficiency (TALDO-D) is a rare autosomal recessive inborn error of the pentose phosphate pathway. Since its first description in 2001, several case reports have been published, but there has been no comprehensive overview of phenotype, genotype, and phenotype–genotype correlation.MethodsWe performed a retrospective questionnaire and literature study of clinical, biochemical, and molecular data of 34 patients from 25 families with proven TALDO-D. In some patients, endocrine abnormalities have been found. To further evaluate these abnormalities, we performed biochemical investigations on blood of 14 patients.Results and conclusionsMost patients (nu2009=u200922) had an early-onset presentation (prenatally or before 1xa0month of age); 12 patients had a late-onset presentation (3xa0months to 9xa0years). Main presenting symptoms were intrauterine growth restriction, dysmorphic facial features, congenital heart disease, anemia, thrombocytopenia, and hepato(spleno)megaly. An older sib of two affected patients was asymptomatic until the age of 9xa0years, and only after molecular diagnosis was hepatomegaly noted. In some patients, there was gonadal dysfunction with low levels of testosterone and secondary luteinizing hormone (LH) and follicle-stimulating hormone (FSH) abnormalities later in life. This overview provides information that can be helpful for managing patients and counseling families regarding prognosis. Diagnostic guidelines, possible genotype–phenotype correlations, treatment options, and pathophysiological disease mechanisms are proposed.

Evaluation of the outcome of CT and MR imaging in pediatric patients with bilateral sensorineural hearing loss

OBJECTIVEnTo evaluate the clinically relevant abnormalities as visualized on CT and MR imaging in children with symmetric and asymmetric bilateral sensorineural hearing loss (SNHL), in relation to age and the severity of hearing loss.nnnSTUDY DESIGNnRetrospective cohort study.nnnSETTINGnTertiary referral otology and audiology center.nnnPATIENTS AND DIAGNOSTIC INTERVENTIONSnFrom January 2006 until January 2016, a total of 207 children diagnosed with symmetric and asymmetric bilateral SNHL were included. They underwent CT and/or MR imaging for the evaluation of the etiology of their hearing loss.nnnMAIN OUTCOME MEASURESnRadiologic abnormalities associated with SNHL.nnnRESULTSn302 scans were performed in 207 children (median age of 0.8 years old) with bilateral SNHL. The most frequently identified cause of bilateral SNHL was a malformation of the labyrinth. The combined diagnostic yield of CT and MR imaging was 32%. The diagnostic yield of MR (34%) was considerably higher than that of CT (20%). We found a higher rate of abnormalities in children with profound hearing loss (41%) compared to milder hearing loss (8-29%), and in asymmetric SNHL (52%) compared to symmetric SNHL (30%).nnnCONCLUSIONnImaging is essential in the etiologic evaluation of children with bilateral SNHL. The highest diagnostic yield is found in children with bilateral asymmetric SNHL or profound SNHL. Based on our findings, MR is the primary imaging modality of choice in the etiological evaluation of children with bilateral SNHL because of its high diagnostic yield.

Aminoacyl-tRNA synthetase deficiencies in search of common themes

PurposePathogenic variations in genes encoding aminoacyl-tRNA synthetases (ARSs) are increasingly associated with human disease. Clinical features of autosomal recessive ARS deficiencies appear very diverse and without apparent logic. We searched for common clinical patterns to improve disease recognition, insight into pathophysiology, and clinical care.MethodsSymptoms were analyzed in all patients with recessive ARS deficiencies reported in literature, supplemented with unreported patients evaluated in our hospital.ResultsIn literature, we identified 107 patients with AARS, DARS, GARS, HARS, IARS, KARS, LARS, MARS, RARS, SARS, VARS, YARS, and QARS deficiencies. Common symptoms (defined as present in ≥4/13 ARS deficiencies) included abnormalities of the central nervous system and/or senses (13/13), failure to thrive, gastrointestinal symptoms, dysmaturity, liver disease, and facial dysmorphisms. Deep phenotyping of 5 additional patients with unreported compound heterozygous pathogenic variations in IARS, LARS, KARS, and QARS extended the common phenotype with lung disease, hypoalbuminemia, anemia, and renal tubulopathy.ConclusionWe propose a common clinical phenotype for recessive ARS deficiencies, resulting from insufficient aminoacylation activity to meet translational demand in specific organs or periods of life. Assuming residual ARS activity, adequate protein/amino acid supply seems essential instead of the traditional replacement of protein by glucose in patients with metabolic diseases.